Occupational & Environmental Epidemiology Reference Library

COPD

COPD and Asbestos Exposure

• Dement et al. (2009): The article, “Airways Obstruction Among Older Construction and Trade Workers at Department of Energy Nuclear Sites,” is a study of COPD risk in 7,579 workers at U.S. DOE sites. The study found a high prevalence of moderate to very severe COPD (GOLD Stages II-IV) at 15.0%, which was significantly higher than the general U.S. population. After adjusting for smoking and other confounders, the risk of COPD was elevated across most trades, with odds ratios ranging from 1.57 to 3.09. The researchers identified statistically significant associations between COPD risk and occupational exposure to specific agents, including asbestos, silica, welding fumes, and cement dust. The findings confirm that asbestos exposure is associated with obstructive lung impairment and may interact with smoking to increase COPD risk. This study emphasizes the need for continued prevention efforts to control both smoking and workplace exposures to reduce the burden of COPD among construction workers.¹

  • Notes: Not specific to railroad workers, but many trades (electrician, painter, laborer) seem related to railroad tasks

• Silver et al. (2020): This longitudinal cohort study assessed the risk of incident COPD in 7,907 older U.S. adults from the Health and Retirement Study (HRS) who were initially undiagnosed. Using subhazard ratios (SHRs) to account for the competing risk of death, the study found that those reporting ever being exposed to asbestos had a statistically significant elevated risk of incident COPD (SHR: 1.79; 95% CI: 1.38, 2.31). This risk was one of the highest observed among all individual exposures analyzed. The highest combined risk was found in workers from the blast furnaces, steelworks, rolling and finishing mills industry who also reported exposure to asbestos (SHR: 5.08; 95% CI: 3.16, 8.15). Despite relying on self-reported ‘ever/never’ exposure status, the findings were consistent with the literature supporting asbestos as a risk factor for COPD. The authors recommended that workers with this exposure history be prioritized for medical surveillance.

• Moitra et al. (2020): The article “Non-Malignant Respiratory Illnesses in Association with Occupational Exposure to Asbestos and Other Insulating Materials: Findings from the Alberta Insulator Cohort” is a cross-sectional study of 990 unionized insulators. The study found a high prevalence of chronic obstructive pulmonary disease (COPD) at 16% and that asbestos was the only material significantly associated with the condition. The Prevalence Ratio (PR) for asbestos exposure and COPD was 1.44 (95% CI: 1.01, 2.05) in single-exposure models, increasing to 1.55 (95% CI: 1.08, 2.22) in multi-exposure models. The findings also linked asbestos and several other insulating materials to an increased risk of recurrent chest infections, independent of smoking history. Researchers concluded that chronic occupational exposure to insulation materials is associated with an increased burden of respiratory illnesses, underscoring the need for immediate workplace surveillance and the use of less hazardous materials.²

AMA-Style References

Dement JM, Welch L, Ringen K, Bingham E, Quinn P. Airways obstruction among older construction and trade workers at Department of Energy nuclear sites. Am J Ind Med. 2009;52(12):917-936.

Silver SR, Alarcon WA, Li J. Incident chronic obstructive pulmonary disease associated with occupation, industry, and workplace exposures in the Health and Retirement Study. Am J Ind Med. 2020;63(2):162-174.

Moitra S, Tabrizi AF, Machichi KI, et al. Non-Malignant Respiratory Illnesses in Association with Occupational Exposure to Asbestos and Other Insulating Materials: Findings from the Alberta Insulator Cohort. Int J Environ Res Public Health. 2020;17(19):7085.

COPD and Silica

Gemini Summary: Epidemiological studies have consistently established a strong link between occupational exposure to respirable crystalline silica and an increased risk of chronic obstructive pulmonary disease (COPD). While silica is most famously associated with silicosis, a specific form of lung scarring, evidence shows that it can also cause COPD, even in the absence of a silicosis diagnosis.

• Lenander-Ramirez, Bryngelsson, Vihlborg, Westberg, and Andersson (2022) – This study of Swedish iron foundry workers found a strong, statistically significant association between silica exposure and respiratory diseases, including Chronic Obstructive Pulmonary Disease (COPD). The morbidity for COPD was increased across all cumulative silica exposure groups, with the Standardized Incidence Ratios (SIRs) ranging from 2.35 to 1.64. A severe risk for silicosis was also observed, with an SIR of 45.87 in the high-exposure group. Crucially, these risks for both COPD and silicosis occurred at average silica exposure levels as low as 0.05 mg/m^3. The mortality for respiratory diseases was also significantly increased, marked by an SMR of 1.80 in the high-exposure group. The authors concluded that the magnitude of these risks suggests the current Swedish OEL for silica is insufficiently protective against COPD.

• Möhner and Nowak (2020): This paper established a method to define an exposure threshold for compensating silica-induced Chronic Obstructive Pulmonary Disease (COPD) using longitudinal lung function data from miners. The analysis determined an optimal exposure concentration threshold of 0.089 mg/m^3 for respirable crystalline silica (RCS), finding that a threshold model best fit the data. Exposure primarily impacted lung function (FEV_1/FVC ratio) only when concentrations exceeded this threshold. The study calculated a reference dose of 2.33 mg/m^3-years of cumulative RCS exposure above the threshold to cause lung function decline consistent with COPD. This suggests that 2mg/m^3-years above 0.1 mg/m^3 concentration threshold should be the criterion for recognizing occupational COPD.

• Calvert, Rice, Boiano, Sheehy, and Sanderson (2003): This major US mortality study linked qualitatively assigned silica exposure categories to disease risk using death certificate data. The study established a clear dose-response relationship for Chronic Obstructive Pulmonary Disease (COPD) mortality, with the Mortality Odds Ratio (MOR) increasing across exposure tiers. The risk for COPD in the highest exposure category reached an MOR of 1.47 (95% CI, 1.30 to 1.66) compared to the low/no exposure group. Crucially, those who died with silicosis had a significantly higher risk of COPD mortality, reflected by an MOR of 4.38 (95% CI, 3.39 to 5.67) when compared to non-silicotic controls. The findings also corroborated links to pulmonary tuberculosis (MOR 2.48 in the highest group). The study concluded that occupational crystalline silica exposure is strongly associated with COPD and other respiratory illnesses.

• Grahn, Gustavsson, Andersson, Lindén, Hemmingsson, Selander, and Wiebert (2021): This cohort study investigated the risk of developing Chronic Obstructive Pulmonary Disease (COPD) from occupational particle exposures, successfully adjusting for smoking. Men exposed to respirable crystalline silica (RCS) demonstrated an increased smoking-adjusted risk, with a Hazard Ratio (HR) of 1.46 (95% CI, 1.13 to 1.90) for all exposed men. For the high RCS exposure group, the HR rose to 1.63 (95% CI, 1.17 to 2.27). This high-risk group was exposed at a mean level of 0.052 mg/m^3, a concentration below the European OEL (0.1 mg/m^3). Positive dose-response relationships were also found for diesel exhaust and welding fumes. The authors concluded that particle exposure is a significant risk factor, and the finding regarding the low-level RCS exposure indicates a need for OEL re-evaluation.

• Ulvestad, Bakke, Melbostad, Fuglerud, Kongerud, and Lund (2000): This study compared tunnel workers to outdoor construction workers to assess the risk of respiratory disease from mixed exposure. The tunnel workers were found to have a significantly higher Odds Ratio for COPD of 2.50 (95% CI, 1.31 to 4.96) compared to the control group. This increased risk was supported by a drastically accelerated decline in lung function, with adjusted FEV_1 dropping by 17 mL/year for each year of tunnel work. The ratio of FEV_1/FVC (FEV_1%) was also lower in tunnel workers by an adjusted mean difference of 4.9% (95% CI, 3.2 to 6.5). The mixed exposure included significantly higher levels of alpha-quartz, diesel exhaust, and NO_2. The authors concluded that this enhanced risk for COPD was due to the combined exposure to the various high-level pollutants.

• Reid and Sluis-Cremer (1996): This long-term cohort study of gold miners tracked the contribution of mine dust (silica) exposure to mortality from Chronic Obstructive Pulmonary Disease (COPD). The SMR for COPD was 189% compared to the general male population, reflecting a significant excess mortality. The crucial finding from the case-control analysis was that dust exposure alone was insufficient to cause death from COPD in non-smokers. However, cumulative dust exposure was found to act synergistically with smoking, increasing the risk of COPD further. This relationship was quantified by a Relative Risk (RR) of 1.20 (95% CI, 1.0 to 1.4) for each unit of cumulative dust exposure, adjusted for smoking. The authors concluded that dust contributes to COPD, but only as a co-factor to smoking.

Lenander-Ramirez A, Bryngelsson IL, Vihlborg P, Westberg H, Andersson L. Respiratory diseases among Swedish iron foundry workers. J Occup Environ Med. 2022;64(7):593-598.

Möhner M, Nowak D. Estimation of an exposure threshold value for compensation of silica-induced COPD based on longitudinal changes in pulmonary function. Int J Environ Res Public Health. 2020;17(23):9040.

Calvert GM, Rice FL, Boiano JM, Sheehy JW, Sanderson WT. Occupational silica exposure and risk of various diseases: an analysis using death certificates from 27 states of the United States. Occup Environ Med. 2003;60(2):122-129.

Grahn K, Gustavsson P, Andersson T, Lindén A, Hemmingsson T, Selander J, Wiebert P. Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden. Environ Res. 2021;200:111739.

Ulvestad B, Bakke B, Melbostad E, Fuglerud P, Kongerud J, Lund MB. Increased risk of obstructive pulmonary disease in tunnel workers. Thorax. 2000;55(4):277-282.

Reid PJ, Sluis-Cremer GK. Mortality of white South African gold miners. Occup Environ Med. 1996;53(1):11-16.

COPD and Diesel Exhaust

• Hart et al. (2009) – COPD Mortality in Railroad Workers This retrospective cohort study investigated COPD mortality in U.S. railroad workers exposed to diesel exhaust, meticulously adjusting for imputed smoking history and the healthy worker survivor effect (HWSE). For workers hired after the major conversion to diesel power (1945 or later), analysis showed a significant linear relationship between work duration and risk. The adjusted Hazard Ratio (HR) indicated a 2.5% increase in COPD mortality risk for each additional year of diesel-exposed work (HR=1.025; 95% CI: 1.009, 1.042). Furthermore, those with 20 or more years of diesel-exposed work had an HR of 1.85 (95% CI: 1.15, 3.00) when fully adjusted for age and HWSE. This association was only slightly weakened when further adjusted for smoking (HR: 1.67; 95% CI: 1.03, 2.71) , leading to the conclusion that occupational diesel exhaust exposure is associated with increased COPD mortality.

• Neophytou et al. (2024) – COPD Mortality in Miners (DEMS II) This survival study used the extended follow-up of the Diesel Exhaust in Miners Study (DEMS II) to examine COPD mortality in relation to exposure to respirable elemental carbon (REC) (diesel surrogate) and respirable dust (RD). Traditional survival analysis using cumulative exposure yielded inverse associations, providing strong evidence of healthy worker survivor bias (HWSE). However, Cox models using average exposure intensity (less susceptible to HWSE) showed elevated HRs: 1.46 (95% CI: 1.12, 1.91) for an interquartile range increase in REC, and 1.20 (95% CI: 0.96, 1.49) for RD. Applying the bias-correcting parametric g-formula, researchers estimated that eliminating REC exposure would result in a Risk Ratio (RR) of 0.85 (95% CI: 0.55, 1.06) compared to observed risk. The findings suggest that both REC (diesel exhaust) and RD exposures increase COPD mortality risk.

• Grahn et al. (2021) – COPD Incidence and Particles This population-based cohort study investigated the risk of developing COPD associated with occupational exposure to various airborne particles in Stockholm, Sweden, rigorously adjusting for individual smoking history. For exposed men, various particle types, including respirable crystalline silica (RCS), gypsum/insulation material, and diesel exhaust, showed elevated risks. Exposure to diesel exhaust specifically yielded a Hazard Ratio (HR) of 1.18 (95% CI: 0.99, 1.41) for ever-exposure in men, a risk estimate that was borderline statistically significant. Crucially, the analysis also identified a significant positive exposure-response trend for diesel exhaust exposure, strengthening the evidence for a true association. The authors concluded that occupational particle exposure, including diesel exhaust, increases the smoking-adjusted risk of developing COPD.

• Weinmann et al. (2008) – COPD and Occupational Exposures This U.S. case-control study assessed the association between self-reported lifetime occupational exposures and prevalent COPD using detailed industrial hygienist-reviewed job histories. After adjusting for age, sex, and smoking, the strongest associations were observed for diesel exhaust and mineral dust. Ever-exposure to diesel exhaust resulted in a highly significant Odds Ratio (OR) of 1.9 (95% CI: 1.3, 3.0) for prevalent COPD. Irritant gases and vapors (OR=1.6; 95% CI: 1.2, 2.2) and mineral dust (OR=1.7; 95% CI: 1.1, 2.7) were also significantly associated. The association was markedly higher among the smaller group of never-smokers, with an OR for ever-exposure to diesel exhaust rising to 6.4 (95% CI: 1.3, 31.6). The study concluded that diesel exhaust and several other workplace factors are positively associated with prevalent COPD, including among non-smokers

• Ferguson et al. (2020) – COPD Mortality in Miners (DEMS) The Ferguson et al. (2020) study investigated COPD mortality in the Diesel Exhaust in Miners Study (DEMS) cohort, focusing on exposure to respirable elemental carbon (REC). For surface-only workers, a key finding was a significantly elevated Hazard Ratio (HR) of 2.34 (95% CI: 1.11, 4.61) in the middle REC exposure category (0 lag). This isolated finding suggested a true effect, but was attenuated in the higher-exposed ever-underground workers. For the ever-underground group, the g-formula suggested that eliminating REC exposure would have reduced the lifetime cumulative risk of COPD mortality to a Risk Ratio (RR) of 0.62 (95% CI: 0.30, 1.26). Overall, the study concluded that long-term exposure to diesel exhaust may increase the risk of COPD in miners, though the results lacked precision due to low power

Hart JE, Laden F, Eisen EA, Garshick E. Chronic obstructive pulmonary disease mortality in railroad workers. Occup Environ Med. 2009;66(4):221-226.

Ferguson JM, Costello S, Elser H, Neophytou AM, Picciotto S, Silverman DT, Eisen EA. Chronic obstructive pulmonary disease mortality: The Diesel Exhaust in Miners Study (DEMS). Environ Res. 2020;180:108876.

Grahn K, Gustavsson P, Andersson T, Lindén A, Hemmingsson T, Selander J, Wiebert P. Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden. Environ Res. 2021;200:111739.

Weinmann S, Vollmer WM, Breen V, Heumann M, Hnizdo E, Villnave J, Doney B, Graziani M, McBurnie MA, Buist AS. COPD and occupational exposures: A case-control study. J Occup Environ Med. 2008;50(5):561-569.

Neophytou AM, Ferguson JM, Costello S, Picciotto S, Balmes J, Koutros S, Silverman DT, Eisen EA. Diesel exhaust and respiratory dust exposure in miners and chronic obstructive pulmonary disease (COPD) mortality in DEMS II. Environ Int. 2024;185:108528.

Kachuri L, Villeneuve PJ, Parent ME, Johnson KC, the Canadian Cancer Registries Epidemiology Research Group, Harris SA. Workplace exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer in Canadian men. Environ Health. 2016;15:4.

Talibov M, Sormunen J, Weiderpass E, Kjaerheim K, Martinsen JI, Sparen P, Tryggvadottir L, Hansen J, Pukkala E. Workplace diesel exhausts and gasoline exposure and risk of colorectal cancer in four Nordic countries. Saf Health Work. 2019;10(2):141-150.

Kang SK, Burnett CA, Freund E, Walker J, Lalich N, Sestito J. Gastrointestinal cancer mortality of workers in occupations with high asbestos exposures. Am J Ind Med. 1997;31(6):713-718.

Goldberg M, Parent ME, Siemiatycki J, Désy M, Nadon L, Richardson L, Lakhani R, Latreille B, Valois M-F. A case-control study of the relationship between the risk of colon cancer in men and exposures to occupational agents. Am J Ind Med. 2001;39(6):531-546.

COPD and Benzene

• Liu et al. (2024): Association of volatile organic compound levels with chronic obstructive pulmonary diseases in NHANES 2013-2016 – This study provides strong epidemiological evidence that elevated blood concentrations of several volatile organic compounds (VOCs) are significantly associated with an increased prevalence of Chronic Obstructive Pulmonary Disease (COPD) among U.S. adults. Using a fully adjusted logistic regression model, the odds ratio for COPD was found to be 2.70 for participants in the highest quartile of blood benzene concentration compared to the lowest. The study emphasized that VOC mixtures jointly contribute to the risk, with benzene and o-xylene having the greatest proportional weights in the overall mixture effect. The dual-pollutant model indicated that an increase of 1 ng/mL in blood benzene was associated with an 88% higher incidence of COPD. These findings suggest that environmental VOC exposure, particularly from aromatic hydrocarbons like benzene, may be a novel risk factor in COPD pathogenesis, demonstrating a non-linear relationship.

• Lv et al. (2023): Assessing volatile organic compounds exposure and chronic obstructive pulmonary diseases in US adults- This research identified a medium strength, positive correlation between blood concentrations of benzene and o-xylene and the risk of COPD, even after adjusting for a comprehensive set of confounding factors. The most heavily adjusted model showed that an increase in blood benzene was associated with an odds ratio of 78.31 for COPD, suggesting a long-term exposure link to pulmonary damage. A key finding was the identification of a concentration-risk relationship, with the highest risk of COPD observed when blood benzene reached 0.28 ng/mL and o-xylene reached 0.08 ng/mL. The association was found to be more prominent in specific subgroups, notably women and younger individuals, indicating potential demographic susceptibility factors. The study concluded that long-term exposure to these environmental chemicals, particularly benzene and o-xylene, may be an independent risk factor for respiratory diseases.

COPD and TCE

• Dumas et al. (2018) Summary: This review systematically evaluated the respiratory effects of Trichloroethylene (TCE) exposure, concluding that the most consistent data links TCE to autoimmune and vascular conditions, specifically Pulmonary Veno-Occlusive Disease (PVOD) and systemic sclerosis. The paper is considered the best evidence for these rarer conditions, although it is limited for common ones. For common respiratory disorders like asthma, chronic bronchitis (a COPD symptom), and rhinitis, the evidence for a direct link to TCE was found to be limited and inconclusive. For example, one finding showed an association between higher TCE concentration and breathlessness at night among the elderly (OR 2.81, 95% CI: 1.02-7.76), but the wide confidence interval limited the conclusion. Furthermore, a meta-analysis of occupational cohort studies found TCE was not associated with an increased risk of lung cancer (Relative Risk 0.96, 95% CI: 0.76-1.21), leading the authors to conclude that the evidence for a lung cancer link is very limited. Overall, while TCE is a human carcinogen, the evidence suggests clinicians should prioritize awareness of its link to PVOD over common respiratory illnesses.

• Elonheimo et al. (2022) Summary: This scoping review investigated associations between several European Human Biomonitoring Initiative (HBM4EU) priority substances and Chronic Obstructive Pulmonary Disease (COPD) or decreased lung function. The study identified that while certain substances like pesticides, lead (Pb), and Polycyclic Aromatic Hydrocarbons (PAHs) had a positive association with COPD, TCE and other chlorinated solvents were not among the seven substances/groups prioritized as having a definite or possible association with COPD. The authors categorized cadmium (Cd), chromium (Cr), arsenic (As), and diisocyanates as having a possible association with COPD, with some, like diisocyanates and As, being more strongly associated with decreased lung function and respiratory symptoms than COPD itself. The review highlights that the role of chemical exposure in the development of COPD is likely underestimated due to the disease’s long latency and the complexity of real-life exposure to multiple mixed chemicals and other factors. Consequently, the paper stresses that more epidemiological studies are necessary to better understand and protect public health from the harmful effects of various environmental substances on lung health.

• Montani et al. (2015) Summary (as referenced in Dumas et al. 2018): The Montani et al. paper, heavily referenced in the Dumas review, specifically investigated occupational exposure to organic solvents as a risk factor for Pulmonary Veno-Occlusive Disease (PVOD), a rare and severe form of pulmonary hypertension. The paper, conducted as a case-control study, found that a history of TCE exposure was significantly associated with PVOD. This specific finding represents the “most consistent data” and the “best evidence to date” for TCE’s adverse effects on the respiratory system as described by the Dumas review. This association is supported by plausible mechanistic studies suggesting TCE can damage the vascular system and induce an autoimmune response. The conclusion is a crucial finding for clinicians, who should be encouraged to take a detailed occupational history in patients with PVOD or systemic sclerosis to check for past TCE exposure. The consistency and strength of this PVOD finding distinguish it from the inconclusive evidence for TCE’s link to more common conditions like asthma and chronic bronchitis.

COPD and Welding Fumes

• Galarneau et al. (2025) – Respiratory Ill-Health and Welding Exposures: A Canadian Cohort Study found that welders had a 1.87 times higher risk of physician-diagnosed COPD/bronchitis compared to electrical workers (HR 1.87, 95% CI 1.27-2.77). This risk was specifically related to cumulative exposure to total dust (HR 1.01, 95% CI 1.00-1.03) and to chromium (HR 1.14, 95% CI 1.04-1.26) within the welder cohort. While the risk of physician-diagnosed asthma was weakly related to cumulative nickel exposure (HR 1.08, 95% CI 1.00-1.17), the overall risk for both COPD/bronchitis and asthma significantly reduced with the time-weighted proportion of using Local Exhaust Ventilation (LEV). The study concluded that welders are at an increased risk of COPD/bronchitis, a risk linked to dust and chromium exposure.

• Grahn et al. (2021) – Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden reported that men exposed to high levels of welding fumes had a 1.57 times increased smoking-adjusted risk of developing COPD (HR 1.57, 95% CI 1.12-2.21). They also found significant COPD risks for men exposed to respirable crystalline silica (RCS) (HR 1.46, 95% CI 1.13-1.90) and gypsum and insulation material (HR 1.56, 95% CI 1.18-2.05). A statistically significant positive exposure-response trend was found for RCS, gypsum and insulation material, diesel exhaust, and welding fumes. The study indicated that occupational exposure to particles leads to an increased smoking-adjusted risk of developing COPD.

• Koh et al. (2015) – Welding fume exposure and chronic obstructive pulmonary disease in welders found that male shipyard welders exposed to intermediate cumulative fume levels had a 3.9 times greater risk of COPD (OR 3.9, 95% CI 1.4-13.3) compared to the low exposure group. Welders exposed to high cumulative fume levels had a 3.8 times greater risk of COPD (OR 3.8, 95% CI 1.03-16.2) compared to the low exposure group. These statistically significant results for the overall cohort support an association between welding fume exposure and increased COPD risk. However, the risk became statistically non-significant when the analysis was restricted to workers aged ge40 or never-smokers, possibly due to limited statistical power.

• Tung et al. (2022) – Associations of PM_2.5 with Chronic Obstructive Pulmonary Disease in Shipyard Workers: A Cohort Study found the overall incidence rate of COPD in the shipyard cohort was 2.51 cases per 100 person-years. The incidence rate was higher for welding workers (2.96 cases per 100 person-years) and markedly higher for non-smokers (4.12 cases per 100 person-years). An IQR increase in welding fume PM_2.5 exposure was associated with statistically significant declines in lung function, such as an FEV_1 decrease of 0.091-L and an FVC decrease of 0.115-L. The study emphasized that the most severe pulmonary effects were associated with PM_2.5 deposition in the alveolar region. The paper concluded that this occupational PM_2.5 exposure is an urgent health issue.

Grahn K, Gustavsson P, Andersson T, Lindén A, Hemmingsson T, Selander J, Wiebert P. Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden. Environ Res. 2021;200:111739.

Galarneau J-M, Beach J, Cherry N. Respiratory Ill-Health and Welding Exposures: A Canadian Cohort Study. Am J Ind Med. 2025;68(1):99-111.

Koh D-H, Kim J-I, Kim K-H, Yoo S-W. Welding fume exposure and chronic obstructive pulmonary disease in welders. Occup Med (Lond). 2015;65(1):72-77.

Tung NT, Lai C-H, Pan C-H, et al. Associations of PM_2.5 with Chronic Obstructive Pulmonary Disease in Shipyard Workers: A Cohort Study. Aerosol Air Qual Res. 2022;22(5):210272.

COPD and Creosote/PAHs

• Rahman et al. (2022) on COPD and PAH Exposure: This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey for US adults to find associations between urinary pollutants and self-reported Chronic Obstructive Pulmonary Disease (COPD). The researchers found a strong, positive association between all seven forms of urinary Polycyclic Aromatic Hydrocarbons (PAHs) metabolites studied and an increased odds of having COPD. The strongest correlation was seen with 1-hydroxypyrene, which had an odds ratio of 4.949, suggesting a significantly heightened risk for exposed individuals. Other metabolites, including 2-hydroxyfluorene (OR: 3.628) and 2-hydroxynaphthalene (OR: 3.361), also showed strong positive associations. The study’s cross-sectional nature, however, limits its ability to determine a causal link between PAH exposure and the development of COPD. Ultimately, the paper concluded that urinary PAHs, along with cadmium and tin, are significantly associated with COPD in the adult US population.

• Rahman et al. (2022) on Chronic Bronchitis and PAH Exposure: This is a companion cross-sectional analysis using three different NHANES datasets (2011–2016) to investigate the correlation between urinary pollutants and self-reported chronic bronchitis, which is a form of COPD. The study revealed a strong, positive association between all seven forms of urinary PAH metabolites measured and increased odds of chronic bronchitis. The metabolite 2 & 3-hydroxyphenanthrene showed the highest odds ratio at 3.690, while 2-hydroxyfluorene also had a high odds ratio of 3.461. This corroborates previous findings and suggests that PAH exposure is a major contributing factor to this specific obstructive lung disease. The authors concluded that the seven forms of urinary PAHs, along with urinary cadmium, were significantly associated with an increased odds of chronic bronchitis in US adults.

• Xiao et al. (2023) on Systemic Inflammation, PAHs, and COPD: This cross-sectional study utilized NHANES data from 2005-2016 for middle-aged and older adults to explore the relationship between Polycyclic Aromatic Hydrocarbons (PAHs) and COPD risk, specifically investigating a mediation pathway through systemic inflammation. The analysis found a strong association, showing that all four tested PAH metabolites (NAP, FLU, PA, and PYR) were significantly and positively correlated with increased COPD risk. Crucially, the study was able to demonstrate a statistically significant mediation effect, where 5.34% of the association between 2-hydroxyfluorene (FLU) and COPD risk was attributed to elevated systemic inflammation (measured by the Systemic Immune-Inflammation Index or SII). This suggests a mechanism where PAH exposure increases inflammation, thereby increasing COPD risk. The authors concluded that there is a strong association between PAH exposure and COPD risk, mediated through systemic inflammation.

COPD and Herbicides/Roundup/Glyphosate

• Pourhassan et al. (2019) – Systematic Review and Meta-Analysis: This meta-analysis provided a strong conclusion by combining data from nine occupational studies across multiple countries to assess the link between pesticide exposure and obstructive pulmonary diseases (OPD). The pooled analysis showed a significant direct relationship between occupational pesticide exposure and an increased risk of OPD. Specifically, exposure to all pesticides was associated with a 44% increased risk of COPD (OR 1.44), and exposure to herbicides alone was associated with a 34% increased risk (OR 1.34). The risk increased substantially under conditions of high exposure, where herbicides showed a 72% increased risk of COPD (OR 1.72). The findings support the hypothesis that occupational pesticide exposure, including herbicides, is a major risk factor for chronic lung diseases, independent of other factors like smoking.

• Alif et al. (2017) – Tasmanian Longitudinal Health Study: This population-based cohort study provided medium-strength evidence by using the gold standard post-bronchodilator spirometry to define fixed airflow obstruction (Fixed AO), a definitive sign of COPD, in middle-aged participants. The researchers used lifetime work calendars to assess “ever exposure” and “cumulative exposure” to pesticides and found significant associations for both measures. Ever exposure to herbicides was associated with a striking 109% increased risk of Fixed AO (RR 2.09). Furthermore, cumulative lifetime exposure to all pesticides or herbicides was significantly associated with Fixed AO. The study was the first of its kind to demonstrate a link between pesticide exposure and Fixed AO using this rigorous methodology, highlighting the need to reduce workplace exposure.

• 3. Shi et al. (2025) – NHANES Cross-Sectional Analysis: This cross-sectional study of US adults provided medium-strength evidence by analyzing urinary glyphosate concentrations as a direct biomarker of recent exposure and linking it to the prevalence of COPD. The main finding was a significant positive association between glyphosate levels and COPD; a one-unit increase in the natural logarithm of urinary glyphosate was associated with a 35% increased risk of COPD (OR 1.35). The highest tertile of glyphosate concentration (above 0.475 ng/mL) was associated with more than a doubling of COPD risk (OR 2.16). The association was particularly pronounced in current smokers (OR 1.90), suggesting a potential synergistic effect, and was also significant in females. The robust findings, confirmed by sensitivity analyses, indicate that environmental exposure to glyphosate may contribute to the burden of COPD in the US adult population.

COPD and Secondhand Smoke

• Su et al., 2024: This large, longitudinal study of never-smokers in Taiwan found that secondhand smoke (SHS) exposure significantly increased the risk of developing COPD¹. After adjusting for multiple confounding factors, the relative risk (RR) of incident COPD was 1.49 (95% CI 1.04-2.14) for the exposed group compared to the non-exposed group². The study established a dose-response relationship, demonstrating that for each additional hour of weekly SHS exposure, the likelihood of developing COPD increased 1.03-fold (95% CI 1.00-1.05)³. These findings suggest a potential causal effect and underscore that even relatively low levels of exposure contribute to an elevated risk of developing COPD⁴⁴⁴. The strong evidence from this study provides a reference for formulating anti-smoking policies⁵.

• He et al., 2012: This 17-year prospective cohort study in China examined the relationship between SHS exposure and major tobacco-related deaths, including COPD, in 910 never-smokers⁶. The study found a significantly increased mortality risk from COPD among those exposed to SHS, with an adjusted Relative Risk of 2.30 (95% CI 1.06-5.00) for men and women combined⁷. A significant dose-response relationship was also observed between the cumulative exposure index from home and work and the increased risk of COPD mortality⁸. This prospective evidence strongly suggests a causal link between SHS exposure and death from COPD among never-smokers⁹.

• Chen et al., 2023: This systematic review and meta-analysis synthesized data from 15 studies (cohort, case-control, and cross-sectional) to assess the association between SHS exposure and COPD prevalence¹⁰. The overall pooled estimate indicated that SHS exposure was associated with a statistically significant increased risk of COPD, with an Odds Ratio (OR) of 2.25 (95% CI 1.40-3.62)¹¹. The risk increased with exposure duration: the OR for those exposed for more than 5 years was 4.38 (95% CI 1.28-15.00), versus an OR of 1.78 for exposures le5 years¹². Furthermore, the analysis showed a significant risk in the only-female subgroup, with an OR of 2.02 (95% CI 1.52-2.67), suggesting a strong effect in women¹³.

• Fischer and Kraemer, 2015: This meta-analysis calculated effect sizes for the association between secondhand smoke (SHS) exposure and three major disease outcomes: ischemic heart disease, stroke, and COPD¹⁴. The highest overall risk was found for COPD, with a pooled Relative Risk (RR) of 1.66 (95% CI 1.38-2.00) for both sexes combined¹⁵. When stratified by sex, the estimated risk for women was higher at an RR of 2.17 (95% CI 1.48-3.18), while the association for men alone was not statistically significant¹⁶. The authors emphasized that the magnitude of the effect size for COPD indicates the high relevance of public health measures to protect non-smokers¹⁷.

• Diver et al., 2018: This large prospective cohort study investigated the association between childhood and adult SHS exposure and adult mortality from COPD in over 70,000 never-smokers¹⁸. It uniquely established that childhood SHS exposure (living with a smoker for 16-18 years) was significantly associated with adult COPD mortality, yielding a Hazard Ratio (HR) of 1.31 (95% CI 1.05-1.65)¹⁹. Furthermore, adult SHS exposure of ge 10 hours per week was associated with a higher risk, and exposure both inside and outside the home was associated with a substantially higher HR of 1.76 (95% CI 1.06-2.90) for COPD death²⁰. These findings suggest that both early and later life exposure contribute to increased COPD death risk in adulthood²¹.

• Jindal et al., 2006: This multicentric cross-sectional study in India examined the prevalence of COPD (defined by chronic bronchitis criteria) and its risk factors among adults aged 35 and above²². The odds ratio (OR) for any environmental tobacco smoke (ETS) exposure among nonsmokers was found to be 1.4 (95% CI 1.21-1.61)²³. Focusing on different exposure periods, the strongest risk was seen for ETS exposure in adulthood only, with an OR of 1.569 (95% CI 1.295-1.901)²⁴. The study concluded that ETS exposure is an important, strong risk factor among nonsmokers, particularly for women exposed to smoking from their husbands²⁵.

• Chen et al., 2024: This large, 12-year prospective cohort study in China with nearly half a million participants assessed the role of both active and passive smoking on COPD incidence²⁶. Among never/occasional smokers, weekly SHS exposure was associated with a marginal but statistically significant increased risk of COPD, with a Hazard Ratio (HR) of 1.06 (95% CI 1.01-1.12) compared to non-weekly exposure²⁷. The risk was more pronounced in urban residents, where ge 4 hours per day of SHS exposure was associated with a 45% increased risk compared to non-weekly exposure²⁸. Overall, while the association is slight, the study concludes that the risk associated with SHS exposure deserves attention given its high prevalence²⁹.

• Korsbæk et al., 2021: In this cross-sectional study of over 20,000 adults, the authors examined the risk of COPD based on the timing of secondhand smoke exposure (SHS)³⁰. The greatest risk for COPD was seen in individuals exposed to lifelong SHS (childhood and adulthood exposure), with an Odds Ratio (OR) of 1.24 (95% CI 1.03-1.48)³¹. Exposures limited to childhood only or adulthood only were not statistically significant for COPD risk³². The study also found that lifelong exposure resulted in a measurable reduction of 3-4% in predicted lung function (FEV_1% and FVC%), further supporting the adverse respiratory impact of chronic SHS exposure³³.

Footnotes

1. Su WC, Juan HL, Lee JI, et al. Secondhand smoke increases the risk of developing chronic obstructive pulmonary disease. Sci Rep. 2024;14(1):7481.

2. Fischer F, Kraemer A. Meta-analysis of the association between second-hand smoke exposure and ischaemic heart diseases, COPD and stroke. BMC Public Health. 2015;15(1):1202.

3. Diver WR, Jacobs EJ, Gapstur SM. Secondhand smoke exposure in childhood and adulthood in relation to adult mortality among never smokers. Am J Prev Med. 2018;55(3):345-352.

4. Chen P, Li Y, Wu D, et al. Secondhand smoke exposure and the risk of chronic obstructive pulmonary disease: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2023;18:1067-1076.

5. Jindal SK, Aggarwal AN, Chaudhry K, et al. A multicentric study on epidemiology of chronic obstructive pulmonary disease and its relationship with tobacco smoking and environmental tobacco smoke exposure. Indian J Chest Dis Allied Sci. 2006;48(1):23-29.

6. He Y, Jiang B, Li LS, et al. Secondhand smoke exposure predicted COPD and other tobacco-related mortality in a 17-year cohort study in China. Chest. 2012;142(4):909-918.

7. Chen L, Xiong H, Wen Q, et al. The role of active and passive smoking in chronic obstructive pulmonary disease and systemic inflammation: a 12-year prospective study in China. J Epidemiol Global Health. 2024;14(4):1332-1340.

8. Korsbæk N, Landt EM, Dahl M. Second-hand smoke exposure associated with risk of respiratory symptoms, asthma, and COPD in 20,421 adults from the general population. J Asthma Allergy. 2021;14:1277-1284.

Lung

Lung Cancer and Diesel Exhaust

• Laden 2006: In 2006, Francine Laden and her colleagues published a study on the link between diesel exhaust exposure and lung cancer mortality in a cohort of 52,812 U.S. railroad workers. The study, which followed workers from 1959 to 1996, used historical railroad locomotive information to better estimate exposure to diesel exhaust. The results showed that workers hired after 1945, when diesel locomotives were first introduced, had a relative risk (RR) of lung cancer of 1.77 (95% CI=1.50−2.09) for any exposure, with evidence of an exposure-response relationship as the duration of exposure increased. For these workers, the RR ranged from 1.15 for those with 0-10 years of exposure to 1.89 for those with 15-<20 years of exposure. In contrast, exposed workers hired before 1945 had an RR of 1.30 (95% CI=1.19−1.43) and showed no evidence of a dose-response relationship with duration. The authors concluded that their findings provided further evidence of the carcinogenicity of diesel exhaust.

• Swanson et al 1993: A population-based study in the Detroit metropolitan area that examined the association between occupation and lung cancer among black and white men. The study found that among white men, there was a trend of increasing lung cancer risk with increasing length of employment in the railroad industry. The odds ratio (OR) for white men in the railroad industry was 2.4 (95% CI 1.1-5.1) for those employed for 10 or more years, compared to those with no exposure. The odds ratio (OR) for black men in the railroad industry was 2.7 (95% CI 0.6-12.1) for those employed for 10 or more years.

• Villeneuve et al 2011: A case-control study by Villeneuve et al. investigated the link between occupational exposure to diesel and gasoline emissions and lung cancer in men from eight Canadian provinces. The study found a dose-response relationship between cumulative exposure to diesel engine emissions and lung cancer, particularly for squamous cell and large cell carcinomas. For all lung cancers, the study found an odds ratio of 0.98 (95% CI 0.55-1.73) for railway transport workers, 0.49 ((95% CI 0.15-1.64) for locomotive operators, and 1.88 (95% CI 0.80-4.24) for railway conductors and brake work. For squamous cell lung cancer, the study found an odds ratio of 1.68 (95% CI 0.78-3.62) for railway transport workers, 0.89 (95% CI 0.17-4.60) for locomotive operators, and 2.66 (95% CI 0.83-8.51) for railway conductors and brake work.

• Howe et al 1983: A study was conducted on a cohort of 43,826 male Canadian National Railway Company pensioners to assess cancer mortality between 1965 and 1977. The study found an elevated risk of lung cancer in workers who were exposed to diesel fumes and coal dust. The standardized mortality ratio (SMR) for lung cancer in the entire cohort was 1.06 compared to the Canadian population. The risk of lung cancer increased with the level of exposure to diesel fumes. The relative risk for “possibly exposed” workers was 1.20. The relative risk for “probably exposed” workers was 1.35.

Lung Cancer and Silica

• Lai et al 2018: A retro-prospective study of 7,665 iron mine workers in China investigated the combined effects of silica dust exposure and cigarette smoking on mortality. The research found that exposure to silica dust and smoking independently increased the risk of mortality from all causes, malignant neoplasm, and non-malignant respiratory diseases. The study reported an elevated hazard ratio (HR) for lung cancer among silica-exposed workers compared to the unexposed group, with HRs of 1.671 (95% CI 1.132, 2.466), 1.663 (95% CI 1.193, 2.318), and 1.671 (95% CI 1.216, 2.298) for low, medium, and high levels of exposure, respectively. Furthermore, the combined exposure to silica dust and smoking showed a significant joint effect on lung cancer mortality, with a HR of 6.586 for workers exposed to both compared to non-exposed, non-smoking workers.

• McDonald et al 2005: This report followed up on a previously published cohort study of some 2670 employees of the North American sand industry. In this report, researchers confirmed a causal link between quartz exposure and lung cancer. A nested case-referent analysis showed that the odds ratios (ORs) for lung cancer were consistently higher in silica-exposed groups compared to the unexposed group, with the risk related to cumulative silica exposure and average concentration. The updated odds ratios for those in the highest cumulative exposure category (>4500 μg/m³-years) was 2.64, compared to an OR of 1.00 for the lowest category (≤700 μg/m³-years). The original odds ratios for the same groups were similar, being 1.00 and 2.58. The study also evaluated lung cancer risk by average silica exposure. The highest group (>260 μg/m³-years) had an OR of 2.36 (95% CI 1, 5.59), as compared to the lowest group (=<70), which had an OR of 1.

• McLaughlin et al 1992: A nested case-control study was conducted on 316 male lung cancer cases and 1,352 controls among Chinese pottery workers and miners (tungsten, iron-copper, and tin) to evaluate the link between silica exposure and lung cancer. The study’s findings offered limited support for a causal association between silica exposure and lung cancer. For groups with low cumulative exposures (0.1-8.69 μg/m³-years), ORs ranged from 1.3-1.8. For groups with high cumulative exposure (>= 26.3) ORs ranged from 0.5-3.1.

Lung Cancer and Asbestos

• Villeneuve et al 2012: A study of men in Canada found that those who were ever exposed to asbestos had an unadjusted odds ratio (OR) of 1.31 (95% CI: 1.07-1.59) and an adjusted OR of 1.28 (95% CI: 1.02-1.61) for lung cancer. Those with low occupational exposure had an adjusted OR of 1.17 (95% CI: 0.92-1.50) while those with medium or high exposure had an adjusted OR of 2.16 (95% CI: 1.21-3.88) compared to unexposed individuals. The study also found a multiplicative relationship between asbestos exposure and cigarette smoking on the risk of lung cancer.

• Olssen et al 2017: Researchers pooled data from 14 case-control studies in Europe and Canada to investigate the relationship between occupational asbestos exposure and lung cancer risk. The study, part of the SYNERGY project, included 17,705 lung cancer cases and 21,813 controls, with detailed information on smoking habits and work history. A job-exposure matrix (SYN-JEM) was used to estimate individual asbestos exposure levels in fiber-years (ff/ml-years). For those ever exposed to asbestos, the fully adjusted odds ratio (OR) for lung cancer was 1.24 (95% CI 1.18, 1.31) for men and 1.12 (95% CI 0.95, 1.31) for women. Increasing asbestos exposure was linked to a higher lung cancer risk in men across all smoking categories and for major lung cancer subtypes. The joint effect of smoking and asbestos exposure was more than additive in both men and women.

• Morabia 1992: This large case-control study analyzed data from 1,793 male lung cancer cases across US hospitals to determine the risk attributable to occupational factors, independent of smoking. The overall adjusted odds ratio (OR) for lung cancer due to asbestos exposure was 1.8 (95% CI 1.5–2.2). The highest association was found among never smokers exposed to asbestos (OR ≥3.8 depending on years exposed to asbestos). Overall, the ORs increased with increasing duration of asbestos exposure across most smoking categories.

• Suraya 2020: This hospital-based case-control study investigated the link between occupational asbestos exposure and lung cancer in Indonesian workers. The OR for those ever exposed to asbestos compared to those never exposed was 2.23 (95% CI 1.39-3.60). The OR was adjusted for age, gender, homeownership, and smoking. The overall adjusted risk of lung cancer was more than doubled for those ever exposed to asbestos compared to those never exposed (OR=2.04, 95% CI 1.21–3.42).

Lung Cancer and Benzene

• Villeneuve et al 2013: A case-control study conducted in Toronto, Ontario, between 1997 and 2002 investigated the link between lung cancer and long-term exposure to ambient volatile organic compounds (VOCs) and nitrogen dioxide. The study estimated exposure by linking residential addresses to land-use regression models, considering time-weighted averages across past residences. Analyses using population-based controls found that an interquartile-range increase in the time-weighted average benzene concentration was associated with a lung cancer odds ratio of 1.84 (95% CI: 1.26, 2.68). The authors suggest that long-term exposure to these air pollutants, even at low concentrations, is associated with an increased risk of lung cancer.

• Babigumira et al 2024: In a prospective case-cohort study of Norwegian offshore petroleum workers, the authors found limited evidence for a clear association between low-level benzene exposure and lung cancer overall. For all lung cancer subtypes combined, the hazard ratios (HRs) for the highest quartiles of exposure were 1.15 for cumulative exposure, 1.43 for duration, and 1.22 for average intensity, though none of these results were statistically significant. However, the study did find a suggested association for adenocarcinoma, the largest histological subtype, particularly with the duration of benzene exposure, which showed a significant positive trend. The authors note that the limited evidence may be due to restricted statistical power, as other studies with higher exposure levels and/or more cases have found stronger associations.

• Warden et al 2018: A case-control study conducted in Montréal assessed the association between occupational exposure to benzene, toluene, and xylene (BTX) and the risk of lung cancer in men. The study found that ever exposure to benzene was associated with an odds ratio of 1.35 (95% CI: 0.99 to 1.84). While the results were adjusted for smoking and other risk factors, they were not mutually adjusted for the three BTX agents due to considerable exposure overlap. The study concludes that there is suggestive evidence that occupational exposure to one or more of these agents may be associated with an increased risk of lung cancer.

Lung Cancer and Chlorinated Solvents

• Vizcaya et al 2012: The paper presents results from two case-control studies in Montreal, Canada, investigating the association between occupational exposure to six specific chlorinated solvents and two chemical families (chlorinated alkanes and alkenes) and the risk of lung cancer in men. The pooled analysis of the two studies suggested an increased risk of lung cancer associated with occupational exposure to perchloroethylene. The OR for any exposure to PCE was 2.5 (95% CI 1.2 to 5.6). The OR for substantial exposure to PCE was 2.4 (95% CI 0.8 to 7.7). The OR for any exposure to carbon tetrachloride was 1.2 (95% CI 0.8 to 2.1) and the OR for substantial exposure to carbon tetrachloride was 2.5 (95% CI 1.1 to 5.7). These findings suggest, though with some inconsistencies and limitations, that exposure to perchloroethylene and carbon tetrachloride may increase the risk of lung cancer.

• Mattei et al 2014: This case-control study (ICARE) in France investigated the association between occupational exposure to five chlorinated solvents and lung cancer. Overall, exposure to at least one solvent showed an increased risk for both men (OR=1.42, 95% CI 1.23 to 1.64) and women (OR=1.52, 95% CI 1.03 to 2.23 for PCE). Exposure to a combination of perchloroethylene (PCE), trichloroethylene (TCE), and dichloromethane (DCM) was positively and significantly associated with lung cancer for both men and women, even after adjusting for asbestos and socioeconomic status (SES). The association was stronger in women (OR=5.16, 95% CI 1.30 to 20.54 before SES adjustment; OR=4.57, 95% CI 1.14 to 18.34 after SES adjustment). Individual solvent analyses often showed confounding by asbestos, except for PCE, and the results suggest that PCE exposure, possibly alone or in combination, may be a risk factor for lung cancer, especially among women.

Lung Cancer and Welding Fumes

• Honaryar et al 2019: This meta-analysis examined 37 eligible studies (case-control and cohort) to quantify the association between welding or exposure to welding fumes and lung cancer risk. The overall meta-relative risk (mRR) for lung cancer for ‘ever’ compared with ‘never’ being a welder or exposed to welding fumes was 1.43 (95% CI 1.31 to 1.55). Specifically, cohort studies reported an mRR of 1.29 (95% CI 1.20 to 1.39) and case-control studies reported an mRR of 1.87 (95% CI 1.53 to 2.29). Importantly, the increased risk persisted in the subset of studies that adjusted for both tobacco smoking and asbestos exposure, with an mRR of 1.17 (95% CI 1.04 to 1.38).

• Kendzia et al 2013: This pooled analysis of 16 case-control studies (SYNERGY project) investigated the association between welding and lung cancer risk in 15,483 male cases and 18,388 male controls. The study found an increased risk of lung cancer for men who had ever worked as welders (regular welders) with a fully-adjusted odds ratio (OR) of 1.44 (95% CI: 1.25, 1.67) compared to those never in welding-related occupations. Working in occasional welding occupations was also associated with an elevated risk, having an OR of 1.19 (95% CI: 1.10, 1.28). The risk increased with longer duration of welding and was particularly high in never or light smokers who worked as welders (OR=1.96, 95% CI: 1.37, 2.79).

• Jockel et al 1998: This case-control study in Germany used 839 male lung cancer cases and 839 matched controls to investigate lung cancer risk associated with welding, adjusting for smoking and asbestos. The odds ratio (OR) for having ever worked as a welder or burner (a specific occupational category) was 2.65 crude, reducing to 1.93 (95% CL: 1.03−3.61) after adjustment for smoking and asbestos. For having a history of welding in general for at least a half-year (a much broader exposure category), the adjusted OR was 1.25 (95% CL: 0.94−1.65). The authors concluded that the observed excess risk for welders in the literature may be partly, but not entirely, due to smoking and occupational asbestos exposure. They noted a moderately increased, though statistically insignificant, risk remained for long exposures to oxyacetylene welding after all adjustments.

• Siew et al 2008: This cohort study of economically active Finnish men investigated the association between cumulative occupational exposure to iron fumes/dust and welding fumes and lung cancer incidence. The relative risk (RR) for all lung cancers increased with cumulative exposure, with the highest exposure category (≥50 mg/m³-years) for welding fumes showing an RR of 1.15 (95% CI 0.90−1.46). The strongest association was observed for squamous-cell carcinoma, where the highest welding fume exposure category had an RR of 1.55 (95% CI 1.08−2.24). The study was adjusted for smoking, socioeconomic status, age, periods of follow-up, and exposure to asbestos and silica.

Lung Cancer and PAHs

• Olssen et al 2022: This pooled analysis (SYNERGY) of 14 case-control studies investigated the association between occupational exposure to Polycyclic Aromatic Hydrocarbons (PAH), proxied by benzo[a]pyrene (BaP), and lung cancer risk. The adjusted odds ratio (OR) for ever occupational PAH exposure versus never was 1.08 (95% CI, 1.02-1.15) in men and 1.20 (95% CI, 1.04-1.38) in women.

• Bruske-Hohlfeld 2000: This pooled analysis of two German case-control studies (3,498 male cases and 3,541 controls) investigated the risk of lung cancer associated with several occupational exposures. For exposure to Polycyclic Aromatic Hydrocarbons (PAH), the adjusted odds ratio (OR) for ever exposed versus never exposed was 1.53 (95% CI 1.14,2.04), after adjusting for smoking and asbestos exposure. The risk for PAH exposure was markedly higher in the highly/long time exposed workers (>20 BaP-years) with an adjusted OR of 2.09 (95% CI 1.36,3.22).

Lung Cancer and Herbicides

• Kangkhetkron et al 2020: This case-control study in Nakhon Sawan, Thailand, investigated the association between lifetime pesticide exposure and lung cancer in 233 cases and 447 controls. The risk of lung cancer was positively associated with the use of herbicides and insecticides, showing a dose-response pattern with increasing days of use. The OR for any exposure to herbicides was 1.30 (95% CI 0.94, 1.79). The adjusted OR for any exposure to herbicides was 1.34 (95% CI 0.91, 1.98). The OR was adjusted for gender, age, cigarette smoking, occupation, cooking fumes exposure, and pollution exposure. The OR for any exposure to glyphosate was 1.26 (95% CI 0.91-1.74). The adjusted OR for any exposure to glyphosate was 1.29 (95% CI 0.89-1.88).

• Alavanja et al 2004: This prospective cohort study, the Agricultural Health Study (AHS), examined the link between 50 agricultural pesticides and lung cancer incidence in over 57,000 pesticide applicators. A low lung cancer standardized incidence ratio of 0.44 (95% CI: 0.39,0.49) was observed due to the cohort’s low smoking prevalence. The study identified two herbicides, metolachlor and pendimethalin, that showed significant evidence of an exposure-response relationship with lung cancer risk based on lifetime exposure days. For metolachlor, the adjusted odds ratios (OR) for the exposure categories (from low-exposed to higher-exposed groups) were 1.0,1.6,1.2,5.0 (p trend =0.0002), and for pendimethalin, they were 1.0,1.6,2.1,4.4 (p trend =0.003). These excesses could not be explained by previously identified lung cancer risk factors, but the possibility of chance findings could not be ruled out since 50 pesticides were evaluated with few a priori hypotheses.

• Bonner et al 2016: This study is an updated reevaluation of the Agricultural Health Study (AHS) cohort, analyzing the association between 43 pesticides and 654 lung cancer cases that occurred over a mean follow-up of 14.8 years. The Cox proportional hazards models showed that only three pesticides had elevated hazard ratios (HRs) in the highest exposure category for lifetime days of use: pendimethalin (HR 1.50; 95% CI 0.98,2.31), dieldrin (HR 1.93; 95% CI 0.70,5.30), and the herbicide chlorimuron ethyl (HR 1.74; 95% CI 1.02,2.96).

Lung Cancer and Secondhand Smoke

• Brennan 2004: This pooled analysis of two large case-control studies from the U.S. and Europe provided strong evidence of a causal association between adult secondhand smoke (SHS) exposure and lung cancer risk among never smokers. Analyzing data from 1,263 cases and 2,740 controls, the study found clear, statistically significant dose-response relationships for all three major sources of exposure: spousal, workplace, and social settings. The odds ratio (OR) for long-term spousal exposure was 1.23 (95% CI: 1.01-1.51), for workplace exposure was 1.25 (95% CI: 1.03-1.51), and for all combined sources was 1.32 (95% CI: 1.04-1.66). The findings were not confounded by occupation, education, or diet, and sensitivity analysis suggested the true risks might be even higher due to exposure misclassification.

• Asomaning 2008: This case-control study investigated the impact of the age of first exposure to secondhand smoke (SHS) on lung cancer risk, hypothesizing that exposure during the critical period of lung growth (ages 0-25) would confer a greater risk. Using data from 1,669 lung cancer cases and 1,263 controls, the study found that for subjects exposed to SHS at both work and leisure, the adjusted odds ratio (AOR) for lung cancer was statistically significant at 1.30 (95% CI: 1.08-1.57) when first exposure occurred before age 25. Conversely, exposure starting after age 25 showed no increased risk (AOR 0.66, 95% CI: 0.21-1.57). The results suggest that individuals first exposed to SHS during the period of lung development have a higher lifetime risk of lung cancer.

• Kreuzer 2000: This German case-control study assessed the association between exposure to environmental tobacco smoke (ETS) and lung cancer in 292 lifelong nonsmoking lung cancer cases and 1,338 controls. The findings provided limited evidence for an association with spousal ETS or childhood ETS exposure. However, the study observed statistically significant increased risks for the highest category of ETS exposure in public indoor settings. Specifically, the odds ratio (OR) for the highest weighted exposure category at the workplace was 1.93 (95% CI: 1.04, 3.58), and for vehicles was 2.64 (95% CI: 1.30, 5.36). The study concluded that high exposures in the workplace and other public indoor settings appear to be important risk factors for lung cancer in nonsmokers.

• Boffetta 1998: This multicenter, case-control study coordinated by the International Agency for Research on Cancer (IARC) aimed to provide a precise estimate of lung cancer risk from environmental tobacco smoke (ETS) in western European nonsmokers. Analyzing 650 lung cancer patients and 1,542 controls, the overall estimated odds ratio (OR) for ever exposure to spousal ETS was 1.16 (95% CI: 0.93-1.44) and for workplace ETS was 1.17 (95% CI: 0.94-1.45). The risk for ETS exposure during childhood was not increased (OR 0.78, 95% CI: 0.64-0.96). While overall “ever exposure” risks were statistically weak, the study found evidence of a significant dose-response relationship for the highest categories of cumulative exposure from both spousal and workplace sources combined.

• Brenner 2010: This population-based case-control study conducted in the greater Toronto area aimed to evaluate various non-smoking risk factors for lung cancer, particularly focusing on never smokers. The study included 445 cases (35% never smokers) and 948 controls. Notably, the study found no association between environmental tobacco smoke (ETS) exposure (at home or at the workplace) and lung cancer risk among never smokers. The strongest and most significant risk factors identified among never smokers were exposure to potential occupational carcinogens (OR 2.1, 95% CI: 1.3-3.3) and a family history of cancer with young onset (OR 1.8, 95% CI: 1.0-3.2). The authors acknowledged that the lack of association with ETS may be due to limitations such as low study power.

Asthma

Asthma and Silica

• Rumchev et al. 2022: This cross-sectional analysis examined associations between modeled respirable crystalline silica (RCS) exposure and respiratory symptoms similar to asthma in mine workers. For symptom outcomes the authors report adjusted odds ratios per log RCS: cough OR 1.05 (95% CI 0.99–1.11), phlegm OR 1.06 (1.00–1.13), and wheeze OR 1.05 (1.00–1.11) in their most adjusted model. The paper reports elevated (but modest) point estimates for asthma-related outcomes in silica-exposed workers though CIs for physician-diagnosed asthma cross unity in some models. Exposure–response patterns were observed for respiratory symptoms with higher modeled RCS associated with greater symptom odds. Overall the study provides modest, quantitative evidence that increasing occupational RCS exposure is associated with small but consistent increases in wheeze and other asthma-like symptoms, supporting a link between silica-containing dust exposure and asthma-related outcomes.

• Lenander-Ramírez et al. 2022: This review examined the relationship between respirable silica/dust exposure with respiratory morbidity and mortality amongst a cohort of 1,752 Swedish iron foundry workers. The paper reported a statistically significant under risk for all but one exposure group for silica exposure and the development of asthma. For respirable silica (m³/mg), the study found the following standardized incident ratio (SIR) : <= 0.14 SIR 0.59 (95% CI 0.30-1.06), 0.15 – 0.38 SIR 0.42 (0.18-0.33), >= 0.39 SIR 0.29 (0.09-0.67). These results are consistent with other studies finding no link between asthma development and industries with silica exposure. One explanation for asthma’s seemingly low morbidity rate, regardless of silica exposure, is that silica predominantly affects lung capacity, causing fibrotic changes and the development of emphysema, instead of the larger airways.

• Tomic et al. 2025: This paper examined the relationship between respirable silica exposure and asthma amongst a cohort of 450 stone benchtop industry workers. For those in the highest exposure category, the study found statistically significant odds ratios (OR) for the following asthma-like symptoms when controlling for age, smoking status, and silicosis diagnosis: cough on winter mornings OR 3.13 (95% CI 1.17 – 8.36), cough during the day or night during winter OR 3.04 (1.14 – 8.11), phlegm from chest during winter OR 2.66 (1.06 – 6.69), and period of increased cough for over three weeks in the past three years OR 3.31 (1.13 – 9.75). When only controlling for age and smoking status, they found statistically significant OR for shortness of breath, coughing, wheezing, and chest tightness when walking up stairs, and sleep broken or woken up by wheezing and chest tightness. Additionally, there was a statistically significant difference between self-diagnosed asthma rates between high or very high exposure workers (24.1%) and low or medium exposure workers (12.6%, p = 0.004). This study found a link between occupational exposure to silica from stone benchtop industry and the prevalence of asthma, independent of silicosis, amongst workers.

Eagan et al. 2002: This paper examined the relationship between exposure to various occupational hazards, including quartz dust, composed predominantly of silica, and the development of asthma, amongst an 11-year cohort of 2,819 Norwegians. When controlling for age, educational level, sex, and smoking status and duration, the study found no significant odds ratios between exposure to quartz and the development of asthma (OR 0.8, 95% CI 0.3 – 2.3). This study found no link between exposure to quartz dust and the development of asthma.

• Bakke et al. 1991: This paper examined the relationship between exposure to various occupational hazards, including quartz dust, composed predominantly of silica, and the development of asthma amongst a random sample (n = 4,992) or people aged 15-70 years in Hordaland county. When controlling for sex, age, smoking habits, and residence, the study found a significant odds ratio between exposure to asbestos and the development of asthma: OR 2.4 (95% CI 1.1 – 5.3). This study found a link between exposure to asbestos and the development of asthma.

Asthma and Benzene

• Lawrence et al. 2022: This paper examined the relationship between hydrocarbon exposure (including benzene) and asthma amongst a cohort of 24,963 cleanup workers and 7,167 nonworkers following the 2010 Deepwater Horizon oil spill. There was a statistically significant relationship (p < 0.0001) between increasing benzene exposure and risk of developing asthma. When controlling for age, gender, race, ethnicity, smoking, pack-years, previous oil spill cleanup work, previous oil industry experience, educational attainment, and exposure to burning/flaring crude oil, the odds ratios (OR) are as follows: first quartile of benzene exposure was the reference, second quartile OR 1.60 (95% CI 1.30 – 1.98), third quartile OR 1.91 (1.55 – 2.35), and fourth quartile OR 2.67 (2.17 – 3.28). The study found a link between exposure to benzene and development of asthma amongst oil spill workers.

• Nazari et al. 2024: This paper performed a meta-analysis and systemic review of the relationship between traffic related air pollution (TRAP), predominantly benzene, and asthma. Four studies were used for benzene, each assigned a weight, and a weighted odds ratio (OR) was calculated. For benzene, the OR for developing asthma in the TRAP-exposed group, in comparison with the non-exposed group, was 1.19 (95% CI 1.10 – 1.29), with a p-value < 0.001. This study found a link between exposure to traffic-related benzene and the development of asthma.

• Arif and Shah 2007: This paper examined the relationship between physician-diagonized asthma and exposure to VOCs, including benzene, amongst a cohort of 550 subjects who partook in the National Health and Nutrition Examination Survey (NHANES) from 1999-2000. The study found a statistically significant odds ratio (OR) for exposure to benzene and physician diagnosed asthma: OR 1.13 (95% CI 1.13 – 1.56). Additionally, the study found a statistically significant odd ratio for exposure to benzene and three or more attacks of wheezing, OR 1.85 (95% CI 1.13 – 3.04), but not more one-two attacks of wheezing, OR 0.91 (95% CI 0.66 – 1.26). This study found a link between benzene exposure and the development of asthma and asthma-like symptoms.

• Gordian et al. 2010: This paper examined the relationship between gasoline exposure, which contains 5% benzene, and respiratory illness, including asthma amongst randomly chosen homes in Anchorage Alaska. Amongst those with intermediate exposure, the study found no statistically significant odds ratios (OR) for the following respiratory symptoms: asthma attacks OR 1.06 (95% CI 0.52, 2.17), exercise-induced asthma OR 1.28 (95% CI 0.76, 2.13), diagnosed asthma OR 1.04 (0.67, 1.63), and severe asthma OR 1.34 (0.70, 2.54). Amongst those with high exposure, the study found no statistically significant OR for the following respiratory symptoms–asthma attacks OR 1.80 (0.80 – 4.06), exercise-induced asthma OR 1.48 (0.80, 2.76), and diagnosed asthma OR 1.06 (0.61, 1.85)–but did find a significant OR for severe asthma (OR 2.49, CI 1.22 – 5.07). This study found a link between benzene exposure through gasoline and the development of severe asthma.

Maesano et al. 2019: This paper examined the relationship between exposure to VOCs, including benzene, and respiratory impacts, including asthma, amongst a cohort of 109 French farmers. When controlling for gender, age, smoking, humidity, pets, and mold presence, for occupational exposure to benzene and the development of asthma, the study found no significant odds ratios: OR 4.11 (95% CI 0.91 – 18.5). However, for indoor, home exposure to chlorinated solvents, the study found significant odds ratios for benzene OR 6.64 (1.56 – 28.27). The study found links between home exposure to benzene and the development of asthma.

Asthma and Welding Fumes

• Lillianburg et al. 2008: This paper examined the relationship between welding work and the development of asthma amongst 316 males from 22 European countries. When controlling for geographical region, smoking status, age, and molecular weight, no significant prevalence ratios was found for the duration of welding and development of asthma: <1 hour PR 0.83 (95% CI 0.51-1.35), 1-4 hours PR 0.56 (0.22 – 1.46), >4 hours PR 0.83 (0.32 – 2.12). For steel type and duration of welding, with the same controls as for welding duration, they found the following PR: stainless steel and <1 hour PR 0.87 (0.31 – 2.46), stainless steel and >=1 hour PR 1.38 (0.46 – 4.15), mild steel and <1 hour PR 1.00 (0.46 – 2.16), mild steel and >=1 hour PR 1.06 (0.40 – 2.81), galvanized steel or iron and <1 hour PR 1.15 (0.54 – 2.46), galvanized steel or iron and >= 1 hour PR 1.58 (0.56 – 4.50), aluminum and <1 hour PR 1.55 (0.50 – 4.80), aluminum and >=1 hour PR 0.78 (0.09 – 6.71), painted metal and <1 hour PR 0.32 (0.10 – 0.97), and painted metal and >=1 hour PR 0.26 (0.05 – 1.29). For welding method and duration of welding, with the same controls as before, they found the following PR: MMA welding and <1 hour PR 0.86 (0.43 – 1.73), MMA welding and >=1 hour PR 1.19 (0.53 – 2.66), metal gas welding and <1 hour PR 0.88 (0.38 – 2.05), metal gas welding and >=1 hour PR 0.40 (0.12 – 1.33), tungsten inert gas welding and <1 hour 0.78 (0.18 – 3.34), tungsten inert gas welding and >=1 hour PR 1.25 (0.39 – 4.02), submerged arc welding and >= 1 hour PR 2.38 (0.39 – 14.59), flux core arc welding and <1 hour PR 1.43 (0.46 – 4.44), and flux core arc welding and >=1 hour PR 0.55 (0.07 – 4.36). This study found no significant relationship between metal welding and the development of asthma.

• LeVan et al. 2006: This paper examined the relationship between various occupational exposures, including welding work, and the development of asthma amongst a population-based cohort of adults aged 45-74 who participated in the 1993-1998 Singapore Chinese Health Study. When controlling for age, gender, dialect, and smoking, the study found no significant odds ratios for the development of adult-onset asthma and exposure to welding: OR 1.17 (95% CI 0.92 – 1.48). The study found no links between occupational exposure to welding and the development of adult-onset asthma.

Asthma and Secondhand Smoke

• Korsbaek et al. 2021: This paper examined the relationship between the development of asthma and exposure to secondhand smoke amongst a cohort of 20,421 adults that partook in the Danish Suburban Population Study. When controlling for age, sex, and smoking status, the paper found the following odds ratios (OR) for time of exposure to secondhand smoke and asthma: childhood exposure OR 1.13 (95% CI 0.99 – 1.30), adulthood exposure OR 1.49 (1.09 – 2.05), and lifelong exposure OR 1.36 (1.14 – 1.63). The study found a link between exposure to secondhand smoke during adulthood and throughout the subject’s life and the risk of developing asthma.

• Wang et al. 2015: This paper performed a meta-analysis to examine the relationship asthma morbidity and exposure to secondhand smoke amongst children. 10 studies were used for secondhand smoke exposure. The overall odds ratio for a hospital admission due to an exacerbation of asthma or asthma attack when exposed to secondhand smoke was 1.85 (95% CI 1.20 – 2.86). This study found a link between exposure to secondhand smoke and hospital visits due to asthma.

• He et al. 2020: This paper performed a meta-analysis and systemic review to examine the relationship between asthma exacerbations and exposure to secondhand smoke amongst children. 78 studies were used for secondhand smoke exposure. The odds ratio (OR) for the relationship between secondhand smoke exposure and doctor-diagnosed asthma was 1.24 (95% CI 1.29 – 1.28) and secondhand smoke exposure and asthma-like syndrome was 1.34 (1.34 – 1.64). Additionally, they point that prenatal maternal exposure to secondhand smoke had greater impact than postnatal secondhand smoke exposure for both doctor-diagnosed asthma (OR = 1.25 vs OR = 1.24) and asthma-like syndrome (OR = 1.60 vs OR = 1.30). This study found a link between exposure to secondhand smoke and asthma.

• Flexeder et al. 2019: This paper examined the relationship between secondhand smoke exposure in adulthood and lower respiratory health, including asthma, amongst a cohort of 3011 adults in 12 countries that participated in the European Community Health Surveys I-III and were current non-smokers. The study found that amongst those who have experienced increases in secondhand smoke exposure, the odds ratio (OR) for diagnosed asthma was 2.70 (95% CI 1.2 – 2.9) and count ratio (CR) for asthma symptom score was 1.9 (1.2 – 5.9). This study found a link between exposure to secondhand smoke in adulthood and asthma.

• Fernandes et al. 2018: This paper performed a cross-sectional study to examine the relationship between smoking, household pollution, and both upon asthma severity in adults in Brazil amongst a cohort of 452 individuals with mild to moderate asthma and 544 individuals with severe asthma. When examining the relationship between household pollution and asthma, the study found an odds ratio (OR) of 1.753 (95% CI 1.202 – 2.557) for lack of asthma control and OR of 1.457 (1.038 – 2.046) for asthma severity. Amongst those exposed to smoking and household pollution, the study found an OR of 2.031 (1.260 – 3.273) for lack of asthma control and OR of 1.586 (0.980 – 2.567) for asthma severity. This study found a link between exposure to household smoke in adults and asthma.

• Radon et al. 2002: This paper examined the relationship between passive smoke exposure in adulthood and lower respiratory health, including asthma, amongst a cohort of 1,890 German adults that participated in the European Community Health Surveys I-III. When controlling for city, age, sex, level of education, and smoking status, the study found the odds ratio (OR) for developing asthma when passively exposed to smoke at home was 0.95 (95% CI 0.59 – 1.52) and at the workplace 1.51 (0.99 – 2.32). This study found a potential link between household smoke in adults and asthma.

Asthma and Herbicides

• Patel et al. 2018: This paper examined the relationship between exposure to herbicides and asthma amongst a cohort of 11,210 primary farm operators that responded to the 2011 Farm and Ranch Safety Survey. When controlled for sex and region, overall, the study found a significant prevalence odds ratio (POR) of asthma amongst those that used herbicides: 1.3 (95% 1.0 – 1.8). Additionally, the study broke down the POR for specific herbicides: phenoxy POR 1.4 (0.9 – 2.2), 2,4-o POR 1.3 (0.8 – 2.1), and glyphosate POR 1.3 (0.97 – 1.80). This study found a link between herbicide exposure and asthma.

• Hoppin et al. 2009: This paper examined the relationship between the exposure to herbicides and adult-onset asthma amongst a cohort of 19,704 male farmers who partook in the Agricultural Health Study. When controlled for age, state, smoking, high pesticide exposure events, and BMI, the study found significant odds ratios (OR) for exposure to certain herbicides and development of allergic asthma: 2,4,5-TP OR 1.91 (1.06 – 3.44), EPTC OR 1.61 (1.06 – 2.43), and Paraquat OR 1.67 (1.05 – 2.65). For nonallergic asthma, the study found significant odds ratios for petroleum oil, with OR 1.35 (1.04 – 1.74). They found a link between herbicide exposure and adult-onset asthma.

• Hoppin et al. 2008: This paper examined the relationship between exposure to herbicides and adult-onset asthma amongst a cohort of 25,814 farm women who partook in the Agricultural Health Study. When controlled for age, state, smoking, rural childhood, and BMI, the study found significant odds ratios (OR) for exposure to herbicides and development of allergic asthma: herbicide OR 1.43 (95% CI 1.12 – 1.83). Specifically, they found significant OR for the following herbicides: 2,4-o OR 1.53 (1.12 – 2.10) and glyphosate OR 1.31 (1.02 – 1.67). This study found a link between herbicide exposure and adult-onset allergic asthma.

Asthma and Creosote / PAH

Jin et al. 2025: This paper examined the relationship between exposure to PAH and adult-onset asthma amongst a cohort of 8,729 adult participants that partook in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. When controlled for age, race, and gender, the study found significant odds ratios for all six PAHs: 1-Hydroxynaphthalene, 2-Hydroxynaphthalene, 3-Hydroxyfluorene, 2-Hydroxyfluorene, 1-Hydroxyphenanthrene, 1-Hydroxypyrene. Under the final model, where educational level, marital status, diabetes, hypertension, drinking and smoking status, income-to-poverty ratio, and BMI were adjusted, the study found significant odds ratios for three PAHs: 3-Hydroxyfluorene OR 1.24 (1.06, 1.44), 2-Hydroxyfluorene OR 1.23 (1.04, 1.46), and 1-Hydroxypyrene OR 1.23 (1.01, 1.50). This study found a link between PAH exposure and the development of adult-onset asthma.

Liu et al. 2016: This paper examined the relationship between exposure to PAH and asthma amongst children aged 6-19 years old who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2008 and 2011 to 2012. When controlled for age, race, PIR, BMI, and gender, the study found significant odds ratios for the following PAHs: 2-naphtol for all exposure levels (Q2 OR 1.611, 95% CI 1.118 – 2.321; Q3 OR 1.584, 95% CI 1.095 – 2.290; Q4 OR 1.466, 95% CI 1.011 – 2.126), 1-phenanthrene at the highest exposure level (Q4 OR 1.411, 95% CI 1.022 – 2.031), 2-phenanthrene at the highest exposure level (Q4 OR 1.521, 95% CI 1.063 – 2.175), and 1-pyrene at the highest exposure level (Q4 OR 1.444, 95% CI 1.003 – 2.080). Additionally, they found a positive association between increasing exposure to 1-pyrene and diagnosed asthma. This study found a link between PAH exposure and the development of childhood asthma.

• Huang et al. 2018: This paper utilized a case control study to examine the relationship between exposure to PAH and adult-onset asthma. When controlled for gender, age, educational level, dust exposure, family history, smoking and alcohol, and BMI, the study found significant odds ratios for the following PAHs: 2-OHFLU for all exposure levels (Q2 OR 2.58, 95% CI 1.75 – 3.82; Q3 OR 3.32, 95% CI 2.24 – 4.91; Q4 OR 1.466, 95% CI 1.84 – 4.07), 4-OPHE for all exposure levels (Q2 OR 5.31, 95% CI 3.47 – 8.11; Q3 OR 7.20, 95% CI 4.76 – 10.89; Q4 OR 4.37 95% CI 2.87 – 6.65), 1-OPHE for all exposure levels (Q2 OR 1.69, 95% CI 1.15 – 2.50; Q3 OR 3.74 95% CI 1.85 – 4.04; Q4 OR 3.14 95% CI 2.08 – 4.74), 1-OHPYR for two exposure levels (Q2 OR 15.55, 95% CI 9.49 – 25.49; Q4 OR 7.43, 95% CI 4.53 – 12.18), and the sum of all OH-PAHs for the lowest exposure level (Q2 OR 1.93, 95% CI 1.32 – 2.83). This study found a link between PAH exposure the development of adult-onset asthma.

Asthma and Chlorinated Solvents:

Arif and Shah 2007: This paper examined the relationship between exposure to VOCs, including TCE and PCE, and asthma in adults amongst a cohort of 550 adult participants that partook in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000. The study found the following odds ratio for exposure to chlorinated solvents: PCE OR 1.02 (95% CI 0.90 – 1.15) and TCE OR 0.94 (0.77 – 1.14). This study found no link between exposure to chlorinated solvents and the development of adult-onset asthma.

Burg and Gist 1999: This paper examined the relationship between exposure to chlorinated solvents and various health impacts, including asthma, amongst a cohort of 4,041 living individuals in the Trichloroethylene Subregistry. Cumulative chemical exposure refers to the sum of exposure to dichloroethylene (DCE), dichloroethane (DCA), trichloroethane (TCA), and perchloroethylene (PCE). For cumulative exposure to chlorinated solvents, the study found significant odds ratios for 50 – 500 ppb of exposure when controlling for age and sex: OR 1.835 (95% 1.00 – 3.28). However, the study did not find significant odds ratios for other exposure categories or when controlling for smoking, occupational exposure, and education. This study found limited links between exposure to chlorinated solvents and the development of asthma.

Maesano et al. 2019: This paper examined the relationship between exposure to VOCs, including TCE and PCE, and respiratory impacts, including asthma, amongst a cohort of 109 French farmers. When controlling for gender, age, smoking, humidity, pets, and mold presence, for occupational exposure to chlorinated solvents and the development of asthma, the study found no significant odds ratios: PCE OR 1.40 (95% CI 0.38 – 5.08) and TCE OR 3.20 (59 – 17.21). However, for indoor, home exposure to chlorinated solvents, the study found significant odds ratios for TCE: OR 4.8 (1.0 – 23.3). The study found links between home exposure to TCE and the development of asthma.

Asthma and Asbestos

Eagan et al. 2002: This paper examined the relationship between exposure to various occupational hazards, including asbestos, and the development of asthma, amongst an 11-year cohort of 2,819 Norwegians. When controlling for age, educational level, sex, and smoking status and duration, the study found no significant odds ratios between exposure to asbestos and the development of asthma (OR 2.0, 95% CI 0.95 – 4.1). This study found no link between exposure to asbestos and the development of asthma.

• Toren et al. 1999: This paper examined the relationship between exposure to various occupational hazards, including asbestos, and the development of asthma using a case-control study of 321 subjects with asthma and 1,459 non-asthmatic individuals from the same area. With no controls, the study found a significant odds ratio between exposure to asbestos and the development of asthma: OR 1.9 (95% CI 1.0 – 3.7). When controlling for sex, age, and smoking status, the study found no significant OR 1.2 (0.5 – 2.5). This study found limited links between exposure to asbestos and the development of asthma.

• Bakke et al. 1991: This paper examined the relationship between exposure to various occupational hazards, including asbestos, and the development of asthma amongst a random sample (n = 4,992) or people aged 15-70 years in Hordaland county. When controlling for sex, age, smoking habits, and residence, the study found no significant odds ratio between exposure to asbestos and the development of asthma: OR 1.8 (95% CI 0.9 – 3.6). This study found no link between exposure to asbestos and the development of asthma.

Mesothelioma

Summaries of each exposure contaminant/carcinogen and relation to mesothelioma are provided by Gemini.

Mesothelioma and Asbestos:

• Xu et al. 2018: A systematic review and meta-analysis estimating the association between mesothelioma and non-occupational asbestos exposure. The primary meta-analyses for different exposure types yielded the following summary relative risk estimates (SRREs) for mesothelioma: Neighborhood exposure: 5.33 (95% CI: 2.53,11.23), Domestic exposure: 4.31 (95% CI: 2.58,7.20), and Household exposure: 2.41 (95% CI: 1.30,4.48). All types were significantly associated with an elevated risk.

• Bourgault et al. (2014): A prospective cancer risk assessment for the general population of Thetford Mines, Quebec, environmentally exposed to asbestos. It selected fiber-specific potency factors (from Berman and Crump) and estimated the lifetime mortality risk from current environmental concentrations. The estimated lifetime mortality risk for both cancers combined was between 1.4 and 4.9 per 100,000. This risk slightly exceeded Health Canada’s “negligible” threshold (1 per 100,000).

• LaCourt et al. (2014): A French population-based case-control study estimating attributable risk from occupational and non-occupational exposure. Confirmed a clear dose-response for occupational exposure. Showed that the burden in women is largely driven by non-occupational exposure. Occupational ORs for men ranged from 4.0 (low CEI) to 67.0 (high CEI). The Attributable Risk (ARp) for all asbestos exposure was 87.3% for men and 64.8% for women.

• Jiang et al. (2017): A case-control study in Southeastern China focusing on hand-spinning chrysotile exposure, with the majority of cases being women. Found a significantly elevated risk and a dose-response relationship between chrysotile exposure and mesothelioma risk. It noted that nearly half of the cases were peritoneal mesothelioma.ORs ranged from 10 for possible exposure to 64 for definite exposure. The highest CEI category led to an OR of 79 (14−451).

• Offermans et al. (2014): A prospective Netherlands Cohort Study (n=58,279 men) using Job-Exposure Matrices (JEMs) to study occupational exposure risk at the lower end of the exposure distribution. Found overall positive associations for all levels of asbestos exposure and mesothelioma, lung cancer, and laryngeal cancer. No statistically significant interaction between asbestos and smoking was found for any cancer. HRs for the lowest tertile of cumulative exposure were significantly elevated for pleural mesothelioma (2.69) and lung cancer (1.47) compared to never exposed subjects (FINJEM model).

• Kurumatani et al. (2008): Investigated neighborhood exposure around a former asbestos cement plant in Japan using relative asbestos concentrations derived from diffusion models and meteorological data. Found a linear dose-dependent risk over a wide area, with significantly elevated risk reaching 2,200 m from the plant. The risk was higher for women than for men. SMRs for neighborhood exposure were very high: 41.4 (95% CI: 15.2−90.1) for women and 13.9 (95% CI: 5.6−28.7) for men closest to the plant (0 to <300 m)

• Rödelsperger et al. (2001): A German hospital-based case-control study examining asbestos and Man-Made Vitreous Fibers (MMVFs) as risk factors. It confirmed a clear dose-response relationship for asbestos. The study suggested MMVF exposure is heavily confounded by asbestos, but a causal relationship could neither be detected nor excluded for MMVF. ORs increased sharply, reaching 47.1 for cumulative exposure >1.5−15 fiber years (vs. non-exposed)

• Tuomi et al. (1991): The study was a case-referent (case-control) evaluation involving 51 mesothelioma patients (cases) and 51 sarcoidosis patients (referents) matched for gender and age, along with other reference groups for comparison of lung fiber concentration. The article uses the Odds Ratio (OR) as the main measure of relative risk to quantify the association between asbestos exposure and mesothelioma

• Spirtas et al. (1994) This case-control study, which confirmed 208 malignant mesothelioma cases (pleural and peritoneal) in the United States, aimed to quantify the proportion of cases attributable to asbestos exposure based on next-of-kin interviews. The study concluded that most pleural and peritoneal mesotheliomas in men were attributable to asbestos exposure, with the overall attributable risk (AR) for men with pleural mesothelioma being very high at 88% (95% CI 76–95%). For men with peritoneal tumors, the AR was substantially lower at 58% (95% CI 20–89%), and for women (both sites combined), the AR was only 23% (95% CI 3–72%), suggesting a less definitive link, likely due to lower exposure and greater misclassification among women. The odds ratios (ORs) for asbestos exposure were nearly an order of magnitude higher for men than for women for all exposure measures.

• Vianna and Polan (1978) Focusing specifically on non-occupational asbestos exposure in females, this case-control study investigated 52 confirmed malignant mesothelioma cases in New York State. The main finding was that women are at an increased risk for mesothelioma not only from working in asbestos-related industries, but also from indirect, environmental asbestos exposure. The most important non-occupational risk factor identified was the husband’s occupation in asbestos-related work, which resulted in household exposure (paraoccupational exposure), likely from routinely hand-laundering the contaminated work clothes. The estimated relative risk (equivalent to odds ratio) for this factor was a ten-fold increase.

• Howel et al. (1997) This case-control study in an English region confirmed the contribution of different exposure routes to mesothelioma development, showing that occupational and paraoccupational exposures to asbestos are both significantly associated with developing mesothelioma. The odds of having likely or possible occupational exposure were substantially higher in cases than controls. Crucially, after excluding subjects with likely or possible occupational exposure, a strong association for paraoccupational exposure (household contact with an asbestos worker) was still demonstrated. In contrast, purely residential exposure (living near a potential industrial source) accounted for only 3% of identified cases, and the small number of subjects without other exposures meant no firm conclusion could be drawn regarding residential risk alone.

• Rake et al. (2009) In the largest population-based study of its kind in Britain, this research quantified the risk of mesothelioma associated with detailed occupational and domestic asbestos exposure histories. The study demonstrated extraordinarily high risks for specific occupations in the construction industry, particularly carpenters, and noted a strong relationship between risk and exposure occurring before 30 years of age. The only significant non-occupational risk factor identified was living with an occupationally exposed relative (domestic exposure). Overall, while 85% of male cases were attributed to occupational exposure, 62% of female cases were not, suggesting a higher background or unrecognised environmental risk in women.

• Mensi et al. (2015) This study quantified the impact of a former asbestos cement factory in Broni, Italy, on mesothelioma incidence by classifying cases based on the source of exposure: occupational, familial, or environmental. The factory had a large overall impact, with an excess of approximately 130 cases over a 12-year period. Although the absolute burden from occupational exposure was greatest in men, the overall burden was higher in women, primarily due to diffuse familial and environmental exposure. The case attribution showed that approximately a quarter of cases were due to occupational exposure, a quarter to familial exposure, and almost half to environmental exposure from the industrial source.

• Ferrante et al. (2007) This cohort study of 1,780 wives of asbestos-cement workers in Casale Monferrato, Italy, confirmed that household (domestic) exposure significantly increases the risk of malignant pleural mesothelioma (MM), but not lung cancer, among women not directly employed in the factory. The standardized mortality ratio (SMR) for pleural cancer and the standardized incidence ratio (SIR) for pleural MM were both dramatically increased compared to expected rates, and the risk trend increased with both longer duration of domestic exposure and longer latency period. The estimated risk was notably high, with the SIR exceeding the SMR, possibly due to the misclassification of mesothelioma on death certificates.

• Maule et al. (2007) Investigating the risk around the Casale Monferrato asbestos cement plant in Italy, this case-control study developed a model to estimate mesothelioma risk as a function of residential distance from the factory, adjusting for occupational and domestic exposures. The key finding was that asbestos pollution from the factory greatly increased the risk of mesothelioma, with risk decreasing rapidly with distance but remaining significantly elevated up to 10 km away. Furthermore, the study demonstrated that the relative risk of occupational exposure was seriously underestimated when residential proximity was not factored in, suggesting that workers were subject to both high occupational exposure and high environmental exposure, and failing to account for the latter led to a low occupational risk estimate.

• McDonald and McDonald (1980) This comprehensive survey of fatal malignant mesothelial tumors in North America (Canada: 1960–75; U.S.A.: 1972) provided a foundational epidemiological analysis of the link with asbestos exposure, particularly for males. The study determined that nearly half of male mesothelioma cases, but only about 5% of female cases, could be attributed to occupational asbestos exposure. The analysis ranked occupational groups by relative risk, confirming insulation work as carrying the highest risk, followed by asbestos production/manufacture and heating trades. The findings were deemed consistent with a much greater mesothelioma-producing potential for crocidolite and amosite than for chrysotile.

• Newhouse and Thompson (1965): An early study of mesothelioma cases at a large London hospital, this investigation focused on identifying occupational, domestic, and neighborhood asbestos exposure histories. It determined that 52.6% of the traced mesothelioma patients had a history of asbestos exposure compared to only 11.8% of controls, a statistically highly significant difference. Three main exposure types were recognized: work in asbestos factories, employment as laggers or insulators, and exposure to dust brought home by relatives (domestic exposure). Among cases with no occupational or domestic exposure, there was a statistically significant excess of patients who lived within a half-mile of an asbestos factory (neighborhood exposure) compared to controls in the same area.

• Case et al. (2002) This descriptive study of pleural mesothelioma among women in the Québec chrysotile mining regions found that all ten identified cases resided in the Thetford Mines area (none in Asbestos), which is known to have chrysotile and higher tremolite content. The cases had accumulated very high cumulative asbestos exposures, with 50% having worked in the asbestos industry (relative risk 53.8), and 90% having lived with one or more asbestos workers (domestic exposure). Estimated mean combined cumulative exposure for cases was nearly triple that of the controls.

Mesothelioma and Silica:

Summary: Mesothelioma is overwhelmingly caused by exposure to asbestos. Asbestos is a mineral silicate, and is the primary known cause. However, there is evidence suggesting a potential relationship between silica exposure and mesothelioma risk. In summary, while asbestos is the main established cause of mesothelioma, some research points to a potential role for silica, particularly when a person has been exposed to both asbestos and silica

• Lacourt et al. (2013): In the study of pleural mesothelioma and occupational coexposure by Lacourt et al., the direct association between occupational silica exposure alone and pleural mesothelioma risk was found to be statistically weak or inconclusive. Adjusted Analysis: All Odds Ratios (ORs) for silica exposure were “around the null” (suggesting no association) when models were adjusted for occupational asbestos and mineral wool exposure.Coexposure: The study highlighted that coexposure to both asbestos and silica appeared to increase the risk of pleural mesothelioma compared to exposure to asbestos alone, suggesting a possible synergistic or modifying effect. Biological Plausibility: The authors note that the lack of a direct association for silica is consistent with knowledge about its shorter biopersistence (how long it stays in the lungs) compared to asbestos fibers.

Diesel Exhaust/PAHs and Mesothelioma:

Summary: A direct, causal link between exposure to diesel exhaust or Polycyclic Aromatic Hydrocarbons (PAHs) and mesothelioma has not been firmly established in the way that asbestos exposure has. Both diesel exhaust and PAHs are established human carcinogens linked to several cancers, most notably lung cancer, but their association with mesothelioma is not established or considered causal.

• Forsell et al. 2007 In this study, the authors attribute the two cases of malignant mesothelioma to former asbestos exposure. The men diagnosed with mesothelioma had worked in the engine room and had estimated cumulative asbestos exposures of 2−5 fibreyears/mL. Although the engine room crew had daily exposure to PAHs and nitroarenes from engine exhaust, soot, and oils, the study specifically states that smoking is not a risk factor for mesothelioma. For the lung cancer cases, PAHs and nitroarenes were noted only as possible contributing risk factors. Therefore, based on the findings and conclusions of this article, PAH and diesel exhaust exposure were not considered the causal factors for mesothelioma; the primary cause was determined to be asbestos.

• Koutros et al. 2023: Although the external SMR analysis observed an excess of mesothelioma deaths in the cohort, the internal exposure-response analyses did not support an association between diesel exhaust/REC exposure and an increased risk for mesothelioma mortality. It is important to note that mines in the study were selected to minimize exposure to co-confounders such as asbestos.

Benzene Exposure and Mesothelioma

Summary: While benzene is a serious carcinogen that can also be a component of other exposures like diesel exhaust, and some studies suggest limited evidence of a link to lung cancer (separate from mesothelioma), it is not recognized as a cause of mesothelioma.

• Sorahan et al. (2005): The study by Sorahan et al. examined mortality and cancer incidence in a cohort of 5,514 workers in England and Wales who were occupationally exposed to benzene. The researchers observed a significantly increased incidence (Standardized Registration Ratio or SRR) for cancer of the pleura (mesothelioma), with an SRR of 237 based on 15 cases. However, the authors explicitly concluded that benzene was likely not the cause of this excess, stating, “There is no reason to suspect that benzene is responsible for the increased lung and pleural cancer risks in this study“. Instead, the excess mesothelioma and lung cancer cases were attributed to the fact that “many study subjects would have been exposed to carcinogens other than benzene (for example, asbestos…)” in the factories, which included coking plants, rubber, and iron/steel foundries, all known for other carcinogenic exposures. The carcinogenic effect of benzene in this cohort was found to be limited only to Acute Non-Lymphocytic Leukemia (ANLL)

TCE Exposure and Mesothelioma:
Summary: While Trichloroethylene (TCE) is classified as a likely human carcinogen and is strongly associated with other cancers, particularly kidney cancer, liver cancer, and non-Hodgkin lymphoma, there is no strong, consistent epidemiological evidence directly linking TCE exposure to mesothelioma in the same way that asbestos is linked.

• Bove et al. (2024): This study investigated cancer incidence among personnel and civilian workers exposed to industrial solvents, including Trichloroethylene (TCE), in the contaminated drinking water at US Marine Corps Base Camp Lejeune from 1953 to 1985. The analysis specifically tracked the incidence of 33 different cancer types and subtypes, including an entry for mesothelioma. The results for the Marines/Navy personnel subgroup showed a slight, non-statistically significant elevation in risk for mesothelioma, with an adjusted Hazard Ratio (aHR) of 1.15 (95% CI: 0.54, 2.46). The civilian workers analysis also showed a non-statistically significant aHR of 0.96 (95% CI: 0.26, 3.61) for mesothelioma. Due to the low number of cases (14 in the exposed military cohort and 5 in the exposed civilian cohort), the Confidence Intervals (CI) for mesothelioma were wide (a CIR of 4.6 for military and 13.9 for civilians), suggesting a lack of reasonable precision in these specific risk estimates. The study highlighted a number of other cancers with stronger, statistically significant associations, such as myeloid cancers and non-small cell lung cancer for the military personnel, but not mesothelioma

Welding Fumes and Mesothelioma:

Summary: The main link between welding and mesothelioma is the historical and ongoing high risk of asbestos exposure in the welding occupation. Separately, welding fumes themselves (which contain carcinogens like hexavalent chromium and nickel) are classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans (Group 1) and are linked to an increased risk of lung cancer and kidney cancer, but the primary cause of mesothelioma in welders is asbestos exposure.

• MacLeod et al. 2017: This study confirms an elevated risk of mesothelioma among welders, with a 78% greater risk compared to nonwelders (Hazard Ratio (HR): 1.78, 95% CI: 1.01–3.18). The risk was even higher for welders in construction, reaching a 2.5-fold increase. However, when the analysis was restricted to a comparison with other blue-collar workers, the risk of mesothelioma among welders was attenuated and no longer statistically significant. This attenuation suggests that the excess mesothelioma risk may be largely attributable to a unique excess asbestos co-exposure prevalent in the working environment of welders and occasional welders—particularly from the historical use of asbestos in welding products and protective equipment—rather than to the welding fumes themselves

Creosote and Mesothelioma:

Summary: The relationship between creosote exposure and mesothelioma is not directly established in the provided sources, but there are strong links between creosote exposure and other cancers, and it is a complex carcinogenic mixture.While creosote is a known carcinogen linked to numerous cancers of the lung and other organs, the specific association between creosote itself and mesothelioma is not explicitly stated as a direct cause. The dominant factor for mesothelioma remains asbestos exposure.

• Koivotso et al. (1994): The article does not suggest a direct link between creosote exposure and the incidence of mesothelioma; rather, it identifies creosote as a factor associated with other cancers, while explicitly linking the mesothelioma cases to asbestos.

Pesticides/RoundUp and Mesothelioma:

Summary: There is no established direct causal link between pesticide exposure and mesothelioma. Cohort studies of agricultural workers consistently show a reduced or decreased risk for malignant mesothelioma compared to the general population, although they also point out that asbestos exposure in this setting is an often-unrecognized risk that requires further investigation.

• Falzone et al. (2016) The article, a review on occupational exposure to carcinogens, discusses pesticides and mineral fibers (including asbestos) as distinct cancer risk factors, but it does not suggest a direct link between pesticide exposure and mesothelioma.The article identifies pesticides as an important occupational risk factor for cancer. It notes that exposure to pesticides has been significantly associated with an increased risk of several cancers, including prostate cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma (HCC). In summary, the article treats the established link between mineral fibers (asbestos) and mesothelioma separately from the risk posed by pesticides for other, different cancers.

• Brooks et al. (1993) This article is a case-control study investigating the risk of lung cancer and mesothelioma associated with exposures from sugarcane production in Florida. The study found no significant increased risk for mesothelioma associated with reported exposure to pesticides or herbicides. There was an increased odds ratio for pesticide exposure and mesothelioma, but it was based on only a small number of cases and was not statistically significant.

Smoking, Second-hand Smoke, and Mesothelioma:

Summary: The primary cause of mesothelioma is asbestos exposure, and current scientific evidence does not show that smoking alone causes mesothelioma. The scientific consensus is that second-hand smoke (environmental tobacco smoke) does not directly cause mesothelioma.

• Muscat et al. (1991): This paper is a hospital-based case-control study titled “Cigarette Smoking, Asbestos Exposure, and Malignant Mesothelioma”. It investigated the role of cigarette smoking and asbestos exposure in the risk of malignant mesothelioma. Cigarette smoking was not found to be a risk factor for mesothelioma among either men or women

• Berry et al. (1985): The overall conclusion of the study and its review of existing data is that the mesothelioma risk is independent of smoking.In the factory worker cohort studied, there was no significant association between smoking and deaths due to mesothelioma. The highest mesothelioma death rate was found in ex-smoker men, but the difference between smoking groups was not statistically significant. For women, the highest rate was in those who never smoked, but again, the differences between all smoking groups were not significant. In essence, the article states that while asbestos workers should quit smoking to reduce their high risk of lung cancer, smoking does not appear to increase the risk of mesothelioma itself.

Asbestosis

Asbestos

• Stayner et al. 1997: The study evaluated alternative exposure-response models and estimated the risk of mortality from asbestosis after occupational exposure to chrysotile asbestos using updated data from a cohort mortality study of South Carolina textile workers. A highly significant exposure-response relation was found between exposure to chrysotile asbestos and mortality from asbestosis. The exposure-response relation for asbestosis was found to be non-linear and sublinear on a multiplicative scale, meaning the risk drops off more rapidly with reductions in exposure compared to lung cancer. Based on the selected power model, the relative rate for a cumulative exposure (X) was equal to ((X + 0.5)^1.3. / (0.5)^1.3). For example, the predicted relative rate for 45 years of exposure to 0.1 fibre/ml was 19.95, and the predicted excess lifetime risk for white men exposed for 45 years at the revised OSHA standard of 0.1 fibre/ml was about 2/1000. The analysis did not provide any support for the existence of a threshold type response for asbestosis.

• Hein et al. 2007: This study updated the mortality experience of 3,072 South Carolina asbestos textile workers exposed to chrysotile through 2001, confirming excess mortality from asbestosis. Mortality from asbestosis (as a combined underlying or contributing cause of death) was highly elevated, with a Standardised Mortality Ratio (SMR) of 232.5 (95% CI 162.8 to 321.9) compared to US referent rates, and remained highly elevated (SMR 108.2, 95% CI 75.8 to 149.8) using South Carolina referent rates. The researchers confirmed a strong, positive exposure-response relation between estimated cumulative exposure to chrysotile and mortality from asbestosis. Increasing trends in pneumoconiosis and other respiratory diseases (which includes asbestosis) SMRs and Rate Ratios (RR) with increasing cumulative exposure were observed, with the highest overall RR being 17.4 (95% CI 8.47-35.9) in the ≥150 fibre-years/ml exposure category relative to the lowest group for the unlagged model. The most common exposure level for the total cohort was a median cumulative exposure of 5.5 fibre-years/ml (range 0.1-699.8 fibre-years/ml). The exposure-response for asbestosis was best described by a power model that included an interaction with age.

• Saito et al. 2022: The study, which retrospectively analyzed deaths in Brazilian adults aged 30+ from 2000 to 2017, compared mortality rates for typical asbestos-related diseases (ARD-T: mesothelioma, asbestosis, and pleural plaques) and lung and ovarian cancer in 29 municipalities with high asbestos consumption (H-ASB) to the rest of Brazil. Asbestosis, which is almost always associated with high cumulative occupational exposures, showed a markedly higher mortality rate in the H-ASB areas. The standardized rate ratio (SRR) for asbestosis deaths (J61) in H-ASB municipalities was 6.35 for men (95% CI: 4.86–8.28) and 1.86 for women (95% CI: 0.96–3.39) when compared to the rest of the country. The high men-to-women ratio of 7.4 for non-malignant ARD-T (which includes asbestosis) in H-ASB areas reflects the significant occupational exposure in the mining and asbestos-cement industries where male workers predominated. The overall conclusion is that mortality rates for ARD-T, which includes asbestosis, as well as lung and ovarian cancer, exceeded those of the whole country in municipalities with a history of high asbestos use.

• Paris et al. 2009: The study aimed to describe the most relevant parameters of asbestos exposure linked to asbestosis diagnosed by high-resolution computed tomography (HRCT) in a large screening program of formerly exposed workers in France. The analysis of 5,545 subjects found that only cumulative exposure index (CEI) (p <0.0001) or level of exposure (p=0.02) were significantly associated with the frequency of asbestosis. After adjustment for smoking status, only CEI and level of exposure remained significant in the multivariate models. In Model I, the crude Odds Ratios (ORs) for asbestosis compared to the 1st quartile of CEI were 2.06 for the 2nd quartile, 1.94 for the 3rd quartile, and 2.25 for the 4th quartile, all with a p<0.0001. In Model II, the crude ORs for asbestosis compared to weak intensity of exposure were 0.75 for moderate and 1.22 for high intensity of exposure, with a p=0.01. The results suggest that cumulative exposure (a dose parameter) is more important than time since first exposure (TSFE) for the development of asbestosis, as no significant relationship was observed for TSFE in adjusted models.

• Mastrangelo et al. 2009: The study investigated the relationship between different aspects of asbestos exposure and the risk of benign asbestos-related diseases, particularly asbestosis, in 772 formerly exposed workers using low-dose Computed Tomography (CT) scans. The prevalence of asbestosis was low, with 14 cases (1.8%) found. The significant risk factor for asbestosis identified in the study was cumulative exposure (P for trend = 0.004). Univariate logistic regression showed that the odds ratio (OR) for asbestosis increased substantially with increasing cumulative asbestos exposure. Specifically, subjects with cumulative exposure ≥160 fibers/ml x years had an OR of 11.6 compared to the lowest quartile (≤8 fibers/ml x years). The least cumulative exposure in a subject with asbestosis was 23.1 fibers/ml x years.

• Luberto et al. 2019: The study investigated the relationship between cumulative asbestos exposure and mortality from asbestos-related diseases, specifically focusing on asbestosis, in a pooled analysis of 21 cohorts of Italian asbestos-cement workers. The cohort included 13,076 workers with over 40 years of observation. The exposure was estimated using an Average Exposure Index (AEI) for each plant and period, weighted for the type of asbestos used (chrysotile and amphibole). This resulted in a fibre-type-weighted Cumulative Exposure Index (CEI), expressed in fibres/ml x years. The risk of death was then analyzed by categorizing this index into tertiles. Mortality from asbestosis was extremely high in the cohort, with Standardized Mortality Ratios (SMRs) of 507 in men and 1023 in women. A clear association with cumulative exposure was observed in both sexes, which the authors state corroborates the quality of their exposure assessment. Specifically, mortality for asbestosis showed a statistically significant increasing trend across tertiles of fibre-type-weighted Cumulative Exposure Index (CEI), with the highest SMRs in the third tertile (men: 732.19; women: 1354.40). The lowest cumulative exposure tertile was defined as up to 54.0 f/ml years for the fibre-type-weighted-CEI.

• Iverson et al. 2024: This study examined the exposure-response relationship between occupational asbestos exposure and incident asbestosis in the Danish general working population from 1979 to 2015. The study included over 1.5 million workers exposed to asbestos, accumulating over 33.8 million person-years, and identified 1,084 incident cases of asbestosis. The range of cumulative exposure in the population was low, from 0.001 to 18 fibers per milliliter-year (f/ml-year). The researchers found an increasing risk of asbestosis with increasing cumulative asbestos exposure, with a fully adjusted Incidence Rate Ratio (IRR) of 1.18 per 1 f/ml-year (95% CI 1.15–1.22) and an IRR of 1.94 (95% CI 1.53–2.47) for the highest compared to the lowest exposure tertile. Similar increasing risks were observed for highest attained exposure intensity and duration of exposure. The study concludes that there is an exposure-response relationship between cumulative asbestos exposure and incident asbestosis even in the general working population with mainly low-level exposed occupations, providing evidence of increased risk outside high-exposed industries.

• Imbernon et al. 1995: This case-control study examined a cohort of active male workers in the Electricité de France-Gaz de France (EDF-GDF) from 1978 to 1989, investigating the association between occupational asbestos exposure and asbestosis. Exposure was assessed using a company-specific job-exposure matrix (JEM) called MATEX, and the study included 114 compensated asbestosis cases and 337 age-matched controls. A strong, monotonic exposure-response relationship was found between cumulative asbestos exposure and asbestosis. The overall odds ratio (OR) for asbestosis and asbestos exposure was 15.35 (95% CI: 7.9, 29.9). In the highest cumulative exposure group, with a mean exposure of 55.4 fibers-years, the odds ratio was significantly elevated at 57.4 (95% CI: 17.0–194.0), clearly demonstrating a strong correlation between cumulative asbestos dosage and the risk of asbestosis.

• Finkelstein 1982: The study investigated the development of certified asbestosis in a cohort of 201 long-term employees (157 production workers and 44 maintenance workers) of an Ontario asbestos-cement factory who were first exposed to dust before 1960 and employed for at least 15 years. By July 1980, 39% of production workers and 20% of maintenance workers had developed certified asbestosis, with the latent interval generally exceeding 20 years. The risk of certification was related to the magnitude of cumulative asbestos fiber exposure (calculated for the first 18 years from first exposure in fiber-years/ml, or f-y/ml). The cumulative probability of certification by the end of 32 years from first exposure ranged from 0.1 (10%) for men with cumulative exposure less than 50 f-y/ml to 0.9 (90%) for men in the 200 to 249 f-y/ml category. The overall mortality rate for certified men was markedly elevated, with an observed-to-expected deaths ratio (O/E) of 4.7 for all causes, with malignancies and respiratory disease being primarily responsible. The exposure-response relationship was found to be sigmoidal in form, and an extrapolation estimated that a worker accumulating 10 f-y/ml in the first 18 years acquired a 1% risk of certified asbestosis by the end of 32 years.

• Farioli et al. 2018: This study followed a cohort of 1,823 asbestos textile workers employed between 1946 and 1984 to assess the risk of asbestosis death based on the temporal pattern of asbestos exposure. A total of 51 asbestosis deaths were observed during the follow-up period until November 2013. The hazard ratio (HR) for asbestosis death increased with exposure duration, with an HR of 2.4 for ≥15 years of employment compared with <5 years (P = 0.014). Conversely, the HR declined with time since last employment (TSLE), showing an HR of 0.3 for ≥25 years compared with <5 years (P = 0.004). Additionally, the risk of asbestosis mortality strongly declined for workers whose exposure started after 1968 (adjusted HR 0.35 for first employment >1969 compared to <1960). Environmental monitoring data indicated extremely high exposure levels (up to 100 ff/mL) in the late 1960s, decreasing significantly to an average of at most 2 ff/mL by 1977.

• Deng et al. 2011: This study followed a cohort of 586 male workers from a Chinese asbestos textile factory, heavily exposed to chrysotile asbestos, from January 1, 1972, to December 31, 2006, to determine the exposure-response relationship between cumulative asbestos exposure and asbestosis mortality The estimated average personal cumulative exposure in the cohort was 126.1 f-y/ml (SD 181.1), which is significantly higher than levels reported in other studies. Out of 226 total deaths, 37 were from asbestosis, resulting in a mortality rate of 2.39 per 1000 person-years. The final regression model found a significant exposure-response relationship with asbestosis (p<0.001), with the Power model with a 10-year lag being the best fit. This model estimated the relative risk for asbestosis mortality as ((d+1)^0.63/(1)^0.63), which for 40 years of exposure to 1 f/ml of asbestos, would be 10.4. The risk of asbestosis mortality rose more sharply than lung cancer mortality at higher exposure levels (>150 f-y/ml).

• DeBono et al. 2021: This study utilized the Occupational Disease Surveillance System (ODSS) cohort of 1.76 million workers employed in Ontario, Canada, from 1983 to 2014, to characterize the incidence of asbestosis diagnoses through 2016. A total of 737 asbestosis cases were identified during the follow-up period. Workers in construction trades occupations had the greatest adjusted incidence rate of asbestosis (261 cases; HR, 3.64; 95% CI: 3.11–4.25) compared with all other ODSS workers. Within construction trades, the highest risks were found among insulating occupations (17 cases; HR, 35.2; 95% CI: 21.7–57.0) and pipefitting, plumbing, and related occupations (70 cases; HR, 8.18; 95% CI: 6.38–10.48), with high-intensity exposure to asbestos-containing insulation and cement materials anticipated in these jobs. Strong positive associations were also observed in the electric power, gas, and water utilities industry (38 cases; HR, 3.67; 95% CI: 2.65–5.09) and the primary metal industries (59 cases; HR, 2.39; 95% CI: 1.83–3.13). The overall findings strongly substantiate the risk of asbestosis in specific occupational groups and underscore the importance of targeted prevention efforts given that the inhalation of asbestos fibers is the established cause of this progressive fibrotic lung disease.

AMA Citation Footnotes

1. Stayner L, Smith R, Bailer J, et al. Exposure-response analysis of risk of respiratory disease associated with occupational exposure to chrysotile asbestos. Occup Environ Med. 1997;54:646-652

2. Hein MJ, Stayner L, Lehman E, Dement JM. Follow-up study of chrysotile textile workers: cohort mortality and exposure-response. Occup Environ Med. 2007;64(9):616-625.

3. Saito CA, Bussacos MA, Salvi L, et al. Sex-Specific Mortality from Asbestos-Related Diseases, Lung and Ovarian Cancer in Municipalities with High Asbestos Consumption, Brazil, 2000-2017. Int J Environ Res Public Health. 2022;19(6):3656. doi:10.3390/ijerph19063656

4. Paris C, Thierry S, Brochard P, et al. Pleural plaques and asbestosis: dose- and time-response relationships based on HRCT data. Eur Respir J. 2009;34(1):72-79. doi:10.1183/09031936.00094008

5. Mastrangelo G, Ballarin MN, Bellini E, et al. Asbestos exposure and benign asbestos diseases in 772 formerly exposed workers: dose-response relationships. Am J Ind Med. 2009;52(8):596-602.

6. Luberto F, Ferrante D, Silvestri S, et al. Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy. Environ Health. 2019;18(1):71.

7. Iversen IB, Vestergaard JM, Ohlander J, Peters S, Bendstrup E, Bonde JPE, Schlünssen V, Bønløkke JH, Rasmussen F, Stokholm ZA, Andersen MB, Kromhout H, Kolstad HA. The asbestos-asbestosis exposure-response relationship: a cohort study of the general working population. Scand J Work Environ Health. 2024;50(5):372-379. doi: 10.5271/sjweh.4153.

8. Imbernon E, Goldberg M, Bonenfant S, et al. Occupational Respiratory Cancer and Exposure to Asbestos: A Case-Control Study in a Cohort of Workers in the Electricity and Gas Industry. Am J Ind Med. 1995;28:339-352.

9. Finkelstein MM. Asbestosis in long-term employees of an Ontario asbestos-cement factory. Am Rev Respir Dis. 1982;125(5):496-501.

10. Farioli A, Violante FS, La Vecchia C, et al. Temporal Patterns of Exposure to Asbestos and Risk of Asbestosis: An Analysis of a Cohort of Asbestos Textile Workers. J Occup Environ Med. 2018;60(6):536-541.

11. Deng Q, Wang X, Wang M, Lan Y. Exposure–response relationship between chrysotile exposure and mortality from lung cancer and asbestosis. Occup Environ Med. 2012;69(2):81-86.

12. DeBono NL, Warden H, Logar-Henderson C, et al. Incidence of mesothelioma and asbestosis by occupation in a diverse workforce. Am J Ind Med. 2021;64:476-487. doi:10.1002/ajim.23245

Kidney

Summaries of each exposure contaminant/carcinogen and relation to kidney cancer/renal cell carcinoma are provided by Gemini.

Asbestos

Pesch et al. 2000: Occupational risk factors for renal cell carcinoma: agent – specific results from a case-control study in Germany.

This case-control study investigated various occupational risk factors for RCC development. The research indicated an association between exposure to asbestos and the development of RCC, alongside other chemicals and solvents. While the specific odds ratio (OR) for asbestos alone is not provided in the note, the study concluded an association exists. This work helps establish the potential for occupational exposures, including asbestos, to contribute to kidney cancer risk. DOI: 10.1093/ije/29.6.1014

Silica

Karami et al. 2011: Occupational exposure to dusts and risk of renal cell carcinoma.

This article explored the link between occupational exposure to dusts and the risk of renal cell carcinoma. The study suggested a plausible causation between silica exposure and RCC. It also identified significant trends in RCC risk for exposure to specific dusts like brick dust, glass fibres, and mineral wool fibres. Specific risk measures (OR/RR) for silica are not detailed in the note, but the finding highlights dusts as a potential risk factor. DOI: https://doi.org/10.1038/bjc.2011.148

Diesel Exhaust (PAH)

Peters et al. 2018: Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men

The study examined the risk of kidney cancer in Canadian men exposed to diesel and gasoline engine exhausts (PAH). It found that workers who were exposed to diesel exhaust were more likely to develop kidney cancer compared to those unexposed. The calculated measure showed that the exposed workers had an Odds Ratio (OR) of 1.23 (95% CI: 0.99-1.53) for developing kidney cancer. This suggests a modest increased risk, particularly in an occupational context. DOI: 10.1093/annweh/wxy059

Daniel et al. 2011: Meat-cooking mutagens and risk of renal cell carcinoma. (Creosote/PAHs)

This article investigated the risk of renal cell carcinoma associated with meat-cooking mutagens, which are polycyclic aromatic hydrocarbons (PAHs) similar to those found in creosote. The findings showed that with increasing intake of Benzo(a)pyrene (BaP), a proxy for PAH exposure, the risk of RCC more than doubled. This elevated risk was specifically noted in African Americans who were current and former smokers. Although focusing on dietary exposure, it provides evidence for the carcinogenic potential of PAHs on the kidney. DOI: https://doi.org/10.1038/bjc.2011.343

Chlorinated Solvents (TCE)

Moore et al. 2010: Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants.

This research focused on the link between occupational exposure to the solvent Trichloroethylene (TCE) and the risk of renal carcinoma. It specifically explored how genetic variants in reductive metabolism genes might influence susceptibility. The study found an increased risk (OR: 1.63, 95% CI: 1.04-2.54) for the group that was ever exposed to TCE. This supports the role of TCE as a kidney carcinogen, potentially with a genetic component. DOI: 10.1158/0008-5472.CAN-09-4167

Charbotel et al. 2006: Case Control study on renal cell cancer and occupational exposure to trichloroethylene. Part II: Epidemiological aspects.

This case-control study examined the epidemiological aspects of the link between renal cell cancer and occupational exposure to TCE. The researchers determined that there was an increased risk of RCC associated with high cumulative doses of the solvent. The risk measure for this high exposure level was an Odds Ratio (OR) of 2.16 (95% CI: 1.02-4.60). This finding reinforces the idea of a dose-response relationship between TCE exposure and kidney cancer. DOI: 10.1093/annhyg/mel039

Andrew et al. 2022: Kidney Cancer Risk Associated with Historic Groundwater Trichloroethylene Contamination.

This study investigated kidney cancer risk related to historic groundwater contamination by TCE at a specific site, focusing on environmental rather than occupational exposure. The research estimated residential exposure over a 15-year period. The results showed an elevated risk, with an Adjusted Odds Ratio (OR) of 1.78 (95% CI: 1.05-3.03) for those between the 75th and 50th percentile of estimated exposure. This demonstrates the potential for environmental TCE exposure to increase kidney cancer risk. DOI: 10.1097/JOM.0000000000000838

Welding Fumes

Collatuzzo et al. 2024: Risk of bladder, kidney and prostate cancer from occupational exposure to welding fumes: a systematic review and meta-analysis.

This systematic review and meta-analysis assessed the risk of genitourinary cancers, including kidney cancer, from occupational exposure to welding fumes (WF). The analysis found evidence suggesting an increased risk of kidney cancer (KC) in workers exposed to WF. The pooled measure of risk for KC was a Relative Risk (RR) of 1.28 (95% CI: 1.12-1.47). This conclusion supports the classification of welding fumes as a potential renal carcinogen. DOI: 10.1007/s00420-023-02040-0

MacLeod et al. 2017: Cancer Risks among Welders and Occasional Welders in a National Population-Based Cohort Study: Canadian Census Health and Environmental Cohort

This national cohort study in Canada evaluated cancer risks among welders and occasional welders. The study’s findings included elevated risks for kidney cancer among welders. Specifically, the researchers found a Hazard Ratio (HR) of 1.30 (95% CI: 1.01-1.67) for kidney cancer in this group. This adds to the evidence linking the welding trade to an increased incidence of kidney cancer. DOI: 10.1016/j.shaw.2016.12.001

Michalek et al. 2019: Heavy metals, welding fumes, and other occupational exposures, and the risk of kidney cancer: A population-based nested case-control study in three Nordic countries

This nested case-control study investigated the risk of kidney cancer associated with various occupational exposures, including heavy metals and welding fumes. The researchers found an elevated risk of kidney cancer in a specific sub-group of exposed individuals. The risk was observed for individuals aged 59-74 years with high exposure to welding fumes, who had an Odds Ratio (OR) of 1.43 (95% CI: 1.09-1.89). This suggests a greater risk for workers with high, long-term exposure. DOI: https://doi.org/10.1016/j.envres.2019.03.023

Creosote/PAHs

Hu et al. 2002: Renal cell carcinoma and occupational exposure to chemicals in Canada. (Creosote/Herbicides)

This Canadian study investigated the association between renal cell carcinoma and occupational exposure to various chemicals. The findings indicated an increased risk of RCC with exposure to creosote. The study also linked exposure to benzene and herbicides to an elevated RCC risk. While the specific quantitative risk for creosote is not given in the note, the research establishes it as a potential occupational risk factor for kidney cancer. DOI: 10.1093/occmed/52.3.157

Herbicides

Hu et al. 2002: Renal cell carcinoma and occupational exposure to chemicals in Canada. (Herbicides/Creosote)

This study on occupational chemical exposure in Canada identified a relationship between herbicide exposure and the risk of renal cell carcinoma (RCC). The findings showed an increased risk of RCC associated with exposure to herbicides, alongside creosote and benzene. Although the exact risk measure is not provided in the note, the article supports the inclusion of herbicides as an occupational risk factor for the disease. DOI: 10.1093/occmed/52.3.157

Andreotti et al. 2020: Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.

This study, part of the Agricultural Health Study, focused on the risk of RCC in relation to occupational pesticide use. The research specifically found an increase in RCC for the highest exposure groups of the herbicide 2,4,5-T when compared to the unexposed group. This provides evidence for a dose-related risk associated with this specific herbicide. DOI: https://doi.org/10.1289/EHP6334

Remigio et al. 2024: An Updated Evaluation of Atrazine – Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort.

This article updated the evaluation of the herbicide Atrazine and its association with cancer incidence in pesticide applicators. Focusing on kidney cancer, the study presented an elevated Relative Risk (RR) when a 25-year lag in exposure was considered. For the highest exposure group (Q4), the Relative Risk was RRQ4=1.62 (95% CI: 1.15-2.29). This suggests that long-term, high-level exposure to Atrazine may contribute to kidney cancer risk. DOI: https://doi.org/10.1289/EHP13684

Secondhand Smoke (ETS)

Theis et al. 2008: Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study

This population-based case-control study investigated the risk of renal cell cancer (RCC) from both active smoking and environmental tobacco smoke (ETS). Focusing on never-smokers, the study found an association between chronic exposure to ETS and RCC risk. Specifically, exposure to home ETS for greater than 20 years was associated with an increased risk, shown by an Odds Ratio (OR) of 2.18 (95% CI: 1.14-4.18). This suggests that long-term passive smoke exposure can be a significant risk factor for kidney cancer. DOI: 10.1186/1471-2407-8-387

Zhang et al. 2022: Associations between secondhand smoke and cancer in adults in the US population

This study analyzed the associations between secondhand smoke (SHS) exposure and various cancers in the US adult population. The researchers identified an association between high SHS exposure and an elevated risk for several cancers, including those of the kidney. For cancers of the kidney, the high exposure groups were found to have a Hazard Ratio (HR) of 1.497 (95% CI: 1.201-1.865). This confirms an increased risk of kidney cancer associated with higher levels of passive smoking. DOI: 10.1007/s00432-022-04266-w

Benzene

Seyyedsalehi et al. 2025: Occupational benzene exposure and risk of kidney and bladder cancers: a systematic review and meta-analysis

This systematic review and meta-analysis specifically evaluated the link between occupational benzene exposure and the risk of kidney and bladder cancers. The pooled analysis found an association between occupational benzene exposure and cancers of the kidney and unspecified urinary tract. The calculated risk measure for this association was a Relative Risk (RR) of 1.20 (95% CI: 1.03-1.39). This finding supports a causal link between working with benzene and an increased risk for kidney cancer. DOI: 10.1097/CEJ.0000000000000911

Sources

1. Pesch B, Jöckel KH, Johnen G, et al. Occupational risk factors for renal cell carcinoma: agent – specific results from a case-control study in Germany. Int J Epidemiol. 2000;29(6):1014-1024.

2. Karami S, Colt JS, Severson RK, et al. Occupational exposure to dusts and risk of renal cell carcinoma. Br J Cancer. 2011;105(3):473-477.

3. Peters CE, Vanhoof C, Aronson KJ, et al. Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men. Ann Work Expo Health. 2018;62(8):964-972.

4. Daniel CR, Reedy J, Silverman DT, et al. Meat-cooking mutagens and risk of renal cell carcinoma. Br J Cancer. 2011;105(5):737-744.

5. Moore LE, Boffetta P, Karami S, et al. Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants. Cancer Res. 2010;70(8):3430-3439.

6. Charbotel B, Jooste V, Rehel P, et al. Case Control study on renal cell cancer and occupational exposure to trichloroethylene. Part II: Epidemiological aspects. Ann Occup Hyg. 2006;50(7):727-732.

7. Andrew ME, Stewart PA, Sapkota S, et al. Kidney Cancer Risk Associated with Historic Groundwater Trichloroethylene Contamination. J Occup Environ Med. 2022;64(3):e185-e190.

8. Collatuzzo G, Talamini R, Boffetta P. Risk of bladder, kidney and prostate cancer from occupational exposure to welding fumes: a systematic review and meta-analysis. Int Arch Occup Environ Health. 2024;97(3):395-407.

9. MacLeod J, Ivers N, Goc J, et al. Cancer Risks among Welders and Occasional Welders in a National Population-Based Cohort Study: Canadian Census Health and Environmental Cohort. Saf Health Work. 2017;8(2):162-167.

10. Michalek AM, Szafraniec K, Boffetta P, et al. Heavy metals, welding fumes, and other occupational exposures, and the risk of kidney cancer: A population-based nested case-control study in three Nordic countries. Environ Res. 2019;174:118-124.

11. Hu J, Johnson KC, Mao Y, et al. Renal cell carcinoma and occupational exposure to chemicals in Canada. Occup Med (Lond). 2002;52(3):157-164.

12. Andreotti G, Freeman LEB, Koutros S, et al. Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study. Environ Health Perspect. 2020;128(9):097003.

13. Remigio N, Koutros S, Beane Freeman LE, et al. An Updated Evaluation of Atrazine – Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort. Environ Health Perspect. 2024;132(6):067007.

14. Theis RP, Brooks DR, Burke TA, et al. Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study. BMC Cancer. 2008;8:387.

15. Zhang J, Liu H, Chen S, et al. Associations between secondhand smoke and cancer in adults in the US population. Cancer Chemother Pharmacol. 2022;90(5):547-556.

16. Seyyedsalehi MS, Mohamadi M, Moradpour F, et al. Occupational benzene exposure and risk of kidney and bladder cancers: a systematic review and meta-analysis. J Cancer Res Clin Oncol. 2025;151(2):495-508.

Liver

Asbestos and Liver Cancer

• Summary: Evidence for a causal link with liver cancer is inadequate in humans.

• Brandi et al. 2013: This case-control study, conducted in Italy, examined the relationship between occupational asbestos exposure and the risk of developing intrahepatic cholangiocarcinoma (iCCA). Researchers compared 69 iCCA cases and 86 extrahepatic cholangiocarcinoma (eCCA) cases to controls using detailed occupational history to assess exposure. They found that individuals with a history of occupational asbestos exposure had a significantly increased risk of iCCA, with an Odds Ratio (OR) of 4.81 (95% CI: 1.73–13.33) when compared to unexposed individuals. This strong association suggested asbestos is a potent risk factor for iCCA, though the association with eCCA was less conclusive (OR: 2.09). The study concluded that asbestos exposure should be considered a potential cause for the rising incidence of iCCA.³

• Farioli et al. 2018: This large, population-based case-control study utilized a job-exposure matrix (JEM) across four Nordic countries to quantify cumulative occupational asbestos exposure and its effect on cholangiocarcinoma risk. The study calculated cumulative exposure in fibers per milliliter × years (f/mL × years) for iCCA and eCCA cases compared to controls. A clear dose-response relationship was observed for iCCA: the highest exposure group (≥ 15.0 f/mL × years) demonstrated an elevated risk, with an Odds Ratio (OR) of 1.7 (95% CI: 1.1–2.6) compared to those never exposed. This result provides evidence supporting the hypothesis that asbestos exposure, particularly at high cumulative levels, is a risk factor for iCCA development. The study found no significant association for extrahepatic cholangiocarcinoma.⁴

• Wu et al. 2015: This retrospective matched-cohort study in Taiwan investigated cancer incidence among male shipbreaking workers who experienced high levels of asbestos exposure during dismantling processes. The cohort of 4,427 exposed workers was matched to an unexposed group to calculate the risk of developing various cancers. After adjusting for potential confounders, the study reported a significantly increased risk of developing liver and intrahepatic bile duct cancer (grouped), with an adjusted Hazard Ratio (HR) of 1.6 (95% CI: 1.08–2.36). This finding reinforces the link between intense occupational asbestos exposure and elevated incidence of liver and biliary tract malignancies, further supporting asbestos as a hepatocarcinogen.⁵

Silica and Liver Cancer

• Summary: Evidence for a causal link with liver cancer is inadequate in humans.

• Marinaccio et al. 2009: This retrospective cohort study followed a large group of Italian workers compensated for silicosis (a marker of heavy and prolonged silica exposure) to investigate cause-specific mortality. The analysis revealed a noteworthy excess mortality from liver cancer among the male silicotic workers, reporting a Standardized Mortality Ratio (SMR) of 2.05 (95% CI, 1.55–2.66). A subgroup analysis showed a more than twofold increased SMR for male workers compensated before 1970, suggesting that the highest risk may be associated with the heavy exposure levels prevalent in earlier decades.⁶

Diesel Exhaust and Liver Cancer

• Summary: Overall evidence for a causal link to liver cancer is considered limited.

• Sassano et al. 2024: This systematic review and meta-analysis investigated the link between occupational exposure to diesel exhaust, a known carcinogen, and the risk of liver and pancreatic cancers. The researchers aggregated data from a total of 15 cohort studies for pancreatic cancer and 14 for liver cancer to derive pooled relative risks (RRs). For liver cancer, the analysis yielded a pooled relative risk of 1.09 (95% CI: 0.99-1.19), suggesting a positive association, though this result did not achieve statistical significance. A significant estimate for liver cancer was present only in studies published before the year 2000 (RR: 1.41; 95% CI: 1.09-1.82). The study’s conclusions suggest an association between occupational diesel exhaust exposure and both cancers, emphasizing the need for more in-depth studies with detailed exposure assessments.⁷

Benzene and Liver Cancer

• Summary: Evidence is inadequate or limited to establish a causal link with liver cancer in humans.

• Yin et al. 1989: This large retrospective cohort study examined cancer mortality among 28,460 workers (15,643 men and 12,817 women) across various factories with occupational benzene exposure. The primary finding related to liver cancer (hepatocarcinoma) was derived from the male cohort. Compared to an unexposed comparison group, the workers exposed to benzene had a slightly elevated risk of death from liver cancer. Specifically, the Standardized Mortality Ratio (SMR) for hepatocarcinoma was 1.12 for exposed men. The study’s exposure assessment utilized retrospective job histories and ambient monitoring data, representing a wide range of exposure levels prevalent in China between 1972 and 1987.⁸

Chlorinated Solvents and Liver Cancer

• Summary: The chlorinated solvent Vinyl Chloride is classified by IARC as Carcinogenic to Humans (Group 1), with sufficient evidence specifically for liver angiosarcoma (a rare cancer) and, less consistently, for hepatocellular carcinoma. For other chlorinated solvents like trichloroethylene (TCE) and perchloroethylene (PCE), the evidence for liver cancer is limited in humans.

• Alexander et al. 2007: A meta-analysis of occupational studies was conducted to quantitatively evaluate the association between Trichloroethylene (TCE) exposure and the risk of liver and biliary tract cancer. Across all study populations analyzed, the overall combined summary relative risk estimate (SRRE) for liver/biliary cancer associated with TCE exposure was found to be 1.08 (95% CI 0.91–1.29), which suggests a negligible, non-statistically significant increase in risk. However, when focusing on subcohorts of workers deemed more highly exposed to TCE, the SRRE was higher and statistically significant, yielding a relative risk of 1.30 (95% CI 1.09–1.55). The analysis revealed significant heterogeneity in these findings, with a higher risk observed in European studies from various industries (SRRE=1.38) compared to US studies of aerospace/aircraft workers (SRRE=0.97).⁹

• Scott et al. 2011: This meta-analysis systematically reviewed epidemiological evidence to quantify the association between occupational Trichloroethylene (TCE) exposure and the risks of kidney, liver, and non-Hodgkin lymphoma (NHL) cancers. For overall TCE exposure, the study calculated the summary relative risk estimate (RRm) for liver cancer to be 1.29 (95% CI: 1.07, 1.56), suggesting a statistically significant increase in risk. However, the relative risk for the highest exposure group was found to be 1.28 (95% CI: 0.93, 1.77), a finding that was not statistically significant. The study concluded that the strongest support exists for a causal association between TCE exposure and kidney cancer. Ultimately, the evidence supporting an association with liver cancer was deemed limited, primarily due to the small number of liver cancer cases available in the cohort studies analyzed.¹⁰

• Hansen et al. 2013: This analysis of three pooled Nordic cohorts examined cancer incidence among 5,553 workers with documented Trichloroethylene (TCE) exposure via urinary metabolite monitoring (trichloroacetic acid). The study calculated Standardized Incidence Ratios (SIRs) to compare the observed cancer cases with the expected number based on national incidence rates over 154,778 person-years of follow-up. A statistically significant elevation was observed for primary liver cancer, with an SIR of 1.93 (95% confidence interval [CI], 1.19 to 2.95), suggesting workers experienced almost double the expected rate. In contrast, the SIR for kidney cancer, another cancer linked to TCE, was not significantly elevated at 1.01 (95% CI, 0.70 to 1.42). The authors also reported a statistically significant SIR for cervical cancer. Overall, the results suggest that occupational TCE exposure is possibly associated with an increased risk for liver cancer, but the authors recommend further research due to limitations like small case numbers for certain cancers and unknown lifestyle confounding factors.¹¹

• Vlaanderen et al. 2013: The study explored the cancer risk, quantified by Hazard Ratios (HRs), associated with occupational exposure to TCE and PER (both chlorinated solvents). The key finding showed no observed association between TCE exposure and liver cancer, kidney cancer, or multiple myeloma (MM). Conversely, the study provided some evidence for an excess risk of liver cancer associated with PER exposure. Specifically, the HRs for liver cancer were slightly elevated in worker groups with high exposure to PER compared to occupationally unexposed subjects. The cumulative HRs for high exposure to PER and liver cancer were: 1.25 (0.65-2.43) for men and 1.07 (0.71-0.59). Additionally, the HRs for liver cancer showed an increasing trend with increasing continuous cumulative exposure to PER, indicating a dose-response relationship for PER. The researchers concluded the positive findings were primarily limited to PER and were subject to limitations due to the low prevalence of exposure and rudimentary exposure assessment strategy for both solvents.¹²

• Wartenberg et al. 2000: This article reviewed studies on the human carcinogenicity of the common organic solvent Trichloroethylene (TCE), which was known to cause liver and kidney tumors in animals. The most rigorous epidemiological analyses, focusing on occupational cohorts with detailed exposure assessments, provided evidence of an elevated risk for liver cancer. Specifically, the risk for liver cancer was quantified as a Relative Risk (RR) of 1.9 (95% CI, 1.0–3.4) for those with the best-assessed exposure. The review also reported excess risks for kidney cancer (RR=1.7) and non-Hodgkin’s lymphoma (RR=1.5) in these highly exposed occupational groups. The authors concluded that while they believed solvent exposure causes cancer in humans and TCE is a likely active agent, further research was recommended to better specify the cancer-causing agents and the exact magnitude of the risk.¹³

• Mundt et al. 2017: This article, which updates the mortality of nearly 10,000 workers in the U.S. vinyl chloride (VC) industry through 2013, confirmed and strengthened the long-established link between occupational VC exposure and liver cancer. The overall liver cancer mortality was significantly elevated with a Standardized Mortality Ratio (SMR) of 2.87. Importantly, the study provided quantitative, dose-dependent evidence for both major liver cancer types. Workers with the highest cumulative exposure (≥865 ppm-years) faced a highly increased risk of Angiosarcoma of the Liver (ASL), showing a Hazard Ratio (HR) of 36.3. Furthermore, the study established an association between VC exposure and Hepatocellular Carcinoma (HCC) mortality, with the highest exposed group (≥2271 ppm-years) having an HR of 5.3. The authors concluded that the association with ASL persisted and that VC exposure was also linked to HCC, noting that some misdiagnosis of early ASLs may have influenced the findings regarding HCC.¹⁴

• Wu et al. 1989: This study updated the mortality analysis of a cohort of workers at a US vinyl chloride polymerization plant, extending the observation period through 1986. For the subcohort specifically exposed to vinyl chloride monomer, the analysis revealed a highly elevated risk of death from liver cancer. The calculated Standardized Mortality Ratio (SMR) for liver cancer was 333 (90% CI: 202–521), demonstrating a risk over three times the expected rate in the general population. Further dose-response analysis confirmed the association was driven primarily by angiosarcoma of the liver (ASL), showing a significant dose response with the cumulative dose of vinyl chloride monomer, consistent with the very high levels of exposure common in the early decades of the industry.¹⁵

Welding Fumes and Liver Cancer

• Summary: Evidence for a causal link with liver cancer is generally considered inadequate in humans.

• Siea et al. 2025: This systematic review and meta-analysis specifically evaluated the association between occupational exposure to welding fumes (WF) and the risk of various gastrointestinal cancers, including liver cancer (hepatocellular carcinoma, or HCC). The study systematically searched for and analyzed data from seven independent cohort studies that examined the risk of cancer across the gastrointestinal tract in welders. The analysis calculated a pooled Relative Risk (RR) for liver cancer of 1.23 (95% CI 0.79-1.90) based on five risk estimates. While the point estimate of 1.23 suggests a slight increase in risk, the broad 95% confidence interval spans 1.0 (from 0.79 to 1.90), meaning the finding was not statistically significant. Therefore, the study concluded that there was no definitive association established between occupational exposure to welding fumes and an increased risk of liver cancer.¹⁶

Creosote/PAHs and Liver Cancer

• Summary: The scientific consensus on the link between Creosote/PAHs and liver cancer can be characterized as having limited or suggestive evidence in humans, though the overall class of compounds is known to be carcinogenic to humans at other sites.

• Wu et al. 2007: This nested case-control study assessed the risk of hepatocellular carcinoma (HCC) in a population with high environmental exposure to both Polycyclic Aromatic Hydrocarbons (PAHs) and aflatoxin B1, using PAH-albumin adducts as a measure of exposure. The highest exposure category for PAH-albumin adducts (Quantile 4), compared to the lowest (Quantile 1), yielded an adjusted Odds Ratio (OR) of 2.0 (95% CI 1.0−4.2) for HCC. Furthermore, in individuals who were hepatitis B virus positive, the combination of high PAH- and high aflatoxin-albumin adducts resulted in a substantially increased risk, with an OR of 8.2 (95% CI 3.6−19.0) compared to those with low adducts and no HBV infection, suggesting a significant synergistic effect from environmental PAH exposure.¹⁷

Herbicides/Glyphosate and Liver Cancer

• Summary: Overall, evidence for a definitive causal link to liver cancer in humans is limited and inconsistent.

• Patel et al. 2025: A case-control study conducted in Thailand investigated the urinary concentrations of glyphosate and its metabolites (AMPA and PPA) in patients with newly diagnosed hepatocellular carcinoma (HCC), CLD, and healthy controls. While quantitative risk estimates (OR/RR) specifically for HCC were not the primary focus for glyphosate itself, the study found significantly elevated levels of the glyphosate metabolites AMPA and PPA in both the HCC and CLD patient groups compared to controls. Odds ratios for HCC for the third highest quartile of glyphosate exposure are 1.17 (0.62–2.20) and for the fourth highest quartile 1.04 (0.58–1.87). This chemical evidence suggests a persistent, measurable exposure to the herbicide and its breakdown products is associated with the disease and its precursors in the human body, raising concern about the potential role of this exposure in liver cancer risk.¹⁸

Secondhand Smoke and Liver Cancer

• Summary: There were no articles found by Gemini or Google Scholar specifically examining liver cancer and secondhand smoke. The article found investigates liver injury and fibrosis, which are important precursors to liver cancer. Evidence for secondhand smoke and liver cancer in adults is generally considered limited.

• Chen et al. 2024: The study used serum cotinine levels (a biomarker of tobacco exposure) to measure SHS exposure and found that SHS has harmful effects on the liver. Specifically, a significant negative correlation was found between cotinine levels and indicators of liver function, such as albumin (ALB) and total protein (TP). Compared to the unexposed group, participants with heavy SHS exposure showed a decrease in both ALB (by 0.16 g/dL) and TP (by 0.26 g/dL). Additionally, the study found a nonlinear relationship between cotinine levels and the Fibrosis-4 index (FIB-4 score), a measure used to assess liver fibrosis (scarring), indicating a potential risk of liver disease progression at lower levels of SHS exposure. The researchers also concluded that Body Mass Index (BMI) partially mediated the harmful effects of SHS exposure on ALB and TP levels, suggesting that the risk is connected, in part, to changes in body weight or metabolism. The authors emphasize the need for more prospective and basic research to validate these findings.¹⁹

Bladder

Asbestos

Summary: Weak evidence. Meta analysis found no link.

1. Franco et al (2022): Meta analysis stating no significance between bladder cancer incidence and mortality and asbestos exposure:

2. Latifovic et al. (2020). For asbestos, relative to unexposed, an increased risk of bladder cancer was observed for those first exposed ≥20 years ago (OR:2.04, 95%CI:1.25–3.34)

Silica

Summary: Weak evidence.

1. Latifovic et al. (2020) – “A modest (approximately 20%) increase in bladder cancer risk was found for ever having been exposed to silica, highest attained concentration and frequency of exposure but this increase was not statistically significant. Relative to unexposed, the odds of bladder cancer were 1.41 (95%CI: 1.01–1.98) times higher among men exposed to silica at work for ≥27 years.”

Diesel Exhaust – PAH

Summary of Epidemiological Studies on Occupational Bladder Cancer Risk First 10 sources:

The Koutros et al. (2020) study, a pooled analysis of two large case-control studies in the U.S. and Spain, provided strong evidence linking high, quantitative, lifetime occupational diesel exhaust exposure to an increased risk of urothelial cell carcinoma (UBC). The strongest association was observed among workers with cumulative exposure to respirable elemental carbon (REC, a diesel surrogate) greater than 396μg/m3-years, showing an OR of 1.61 (95% CI, 1.08-2.40), a relationship that was maintained across all latency periods (lag intervals) evaluated. The risk was particularly pronounced for muscle-invasive bladder cancer (OR=2.03 (95% CI, 1.11-3.74)) and low-grade tumors (OR=2.08 (95% CI, 1.28-3.38)). The authors concluded that their results offer further evidence that diesel exhaust exposure increases the risk of UBC.

The Latifovic et al. (2015) case-control study in Canada found a significant association between exposure to high concentrations of diesel emissions and bladder cancer risk, particularly with long duration. Specifically, men with >10 years of exposure to diesel emissions at high concentrations had an OR of 2.45 (95% CI, 1.04-5.74) when adjusting for smoking and co-exposures. Furthermore, an increased risk was observed among men exposed for >30% of work time to gasoline engine emissions (OR=1.59 (95% CI, 1.04-2.43)), but only in the subset of men never exposed to diesel. The study supported the hypothesis that exposure to high concentrations of diesel engine emissions may increase the risk of bladder cancer.

The Risch et al. (1988) case-control study in Canada, also controlling for cigarette smoking, found significantly raised risks for men employed in jobs with contact with diesel or traffic fumes during the period eight to 28 years before diagnosis, showing an OR of 1.69 (95% CI, 1.24-2.31). Increased risks were also noted for those in the chemicals industry (OR=2.37 (95% CI, 1.32-4.47)) and those exposed to tars or asphalt (OR=3.11 (95% CI, 1.19-9.68)), supporting the suspicion that these factors relate to bladder cancer risk.

The Kunze et al. (1992) hospital-based study in Germany reported a significantly elevated smoking-adjusted OR of 1.8 (95% CI, 1.1-2.8) for men employed as truck drivers. Elevated risks were also found for those ever-employed in the printing (OR=5.0 (95% CI, 1.3-19.6)) and rubber (OR=2.5 (95% CI, 1.2-5.1)) industries. The authors stressed that lifestyle factors like heavy coffee and beer consumption and consumption of canned food contributed substantially to risk after accounting for tobacco and occupational exposures.

The Samanic et al. (2008) hospital-based case-control study in Spain found a statistically significant risk among men employed in the transportation equipment industry (OR=1.63 (95% CI, 1.05-2.55)) and as miscellaneous mechanics and repairers (OR=2.00 (95% CI, 1.12-3.55)). They did not, however, observe an excess risk for truck drivers. The highest risk was found for printing machine operators and tenders (OR=5.35 (95% CI, 1.62-17.72)).

The Zheng et al. (2002) population-based study in Iowa observed significantly increased risk for several motor-related occupations in men, including supervisors for transportation and material moving (OR=6.5 (95% CI, 1.4-29.9)) and automobile mechanics (OR=1.6 (95% CI, 1.0-2.6)). The study noted excess risk in the rubber and plastic products industry (OR=3.1 (95% CI, 1.2-8.5)).

The Cordier et al. (1993) study in France, using expert assessment of exposure, found that more male cases had been exposed to industrial oils and greases (OR=1.44 (95% CI, 1.10-1.89)), chlorinated solvents (OR=1.86 (95% CI, 1.19-2.90)), and coal dust (OR=1.71 (95% CI, 1.02-2.89)) than controls. However, they did not confirm an excess risk for truck drivers (OR=0.53 (95% CI, 0.21-1.39)).

The Balarajan and McDowall (1988) prospective mortality study of professional drivers in London reported the SMR for bladder cancer among all drivers as 105 (based on 25 deaths), which was not statistically significant. While taxi drivers had a numerically raised SMR of 121 (based on five deaths), this finding was also not statistically significant.

The Schenker et al. (1984) pilot mortality study of U.S. railway workers similarly found that the SMR for cancer of the bladder for all drivers was 76 (based on 3 deaths), which was not statistically significant. The study’s focus was mainly on respiratory cancer and diesel exposure, but the available data did not show a clear association with bladder cancer.

Finally, the Wynder et al. (1985) case-control study found no difference in the proportion of bladder cancer cases employed in occupations with exposure to diesel exhaust compared to controls, resulting in a smoking-adjusted OR of 0.87 (95% CI, 0.47-1.58). The authors concluded that their data did not support an association between diesel exhaust exposure and bladder cancer.

The Kogevinas et al. (2003) meta-analysis pooled data from 11 case-control studies across six European countries to evaluate current bladder cancer risks among men. The OR for pre-defined high-risk occupations were generally low, with the only statistically significant risk for the entire group being metal workers and machinists (OR=1.16 (95% CI, 1.02-1.32)). However, specific subgroups showed higher risks, such as metalworking machine setter-operators (OR=1.50 (95% CI, 1.07-2.12)), printing pressmen (OR=1.81 (95% CI, 1.03-3.17)), and miners/quarrymen (OR=1.30 (95% CI, 1.02-1.64)). Exposure to Polycyclic Aromatic Hydrocarbons (PAH) showed a positive exposure-response trend, with the highest tertile having an OR of 1.23 (95% CI, 1.07-1.41). The authors estimated that 4.2% of bladder cancers were attributable to ever being employed in a high-risk occupation. They concluded that risk is now lower than historically seen due to improved working conditions, but that the metal sector, machinists, and transport operators remain major contributors.

The Gaertner et al. (2004) case-control study using the Canadian NECSS database found several occupations with a statistically significant excess risk of bladder cancer in men. This included hairdressers (OR=3.42 (95% CI, 1.09-10.8)), primary metal workers (OR=2.40 (95% CI, 1.29-4.50)), miners (OR=1.94 (95% CI, 1.18-3.17)), and automechanics (OR=1.69 (95% CI, 1.02-2.82)). Both primary metal workers and automechanics showed a significant duration-response trend. For women, significant elevations were observed for lumber processors (OR=8.78 (95% CI, 1.28-60.1)), general labourers (OR=2.18 (95% CI, 1.05-4.52)), and nurses (OR=1.54 (95% CI, 1.03-2.31)). Elevated but non-significant risks were seen for men exposed to asbestos (OR=1.42 (95% CI, 1.03-1.96)), and mineral/cutting/lubricating oil (OR=1.36 (95% CI, 1.04-1.77)). The authors concluded that the significant findings for metal workers and automechanics, with their dose-response trends, highlight the continued importance of occupational exposures.

The Iscovich et al. (1987) case-control study conducted in La Plata, Argentina, which has historically high bladder cancer rates, found the risk associated with cigarette smoking to be exceptionally high, with male current smokers showing an overall RR of 7.15 (95% CI, 3.0-20.1) relative to non-smokers, and the heaviest smokers (≥30 cigarettes/day) showing an RR of 27.50 (no CI given, but the highest RR for duration was 13.85). A significant association was found for oil refinery workers (RR=6.22, χ2=5.03) and for truck and railway drivers (RR=4.31, χ2=9.49), both of which remained elevated after adjusting for tobacco. Consumption of coffee was also a major risk factor, with those drinking ≥3 cups/day having an RR of 12.0 (95% CI, 4.3-33.1) after tobacco adjustment. The study concluded that cigarette smoking and coffee drinking were the major risk factors, but the occupational associations were also consistent with findings elsewhere.

The Gubéran et al. (1992) historical prospective cohort study of professional drivers in Geneva, after applying a 15-year latency, found that professional drivers had a significantly increased risk for all malignant neoplasms (SIR=128 (90% CI, 115-142)). Cause-specific analysis showed highly significant excesses for lung cancer (SIR=161 (90% CI, 129-198)), stomach cancer (SIR=233 (90% CI, 156-336)), and rectal cancer (SIR=200 (90% CI, 127-300)). The SIR for bladder cancer was elevated at 125 (90% CI, 74-199) but not statistically significant. A significant upward trend in cancer incidence, including lung cancer, was seen across groups from “less exposed” to “more exposed” to exhaust gas and fumes to “professional drivers”. The authors concluded that confounding by lifestyle factors didn’t fully explain the significant excesses and that the findings support a link between prolonged exposure to diesel or petroleum exhaust emissions and cancer risk (though not definitively for bladder cancer in this study).

The Howe et al. (1983) retrospective cohort study of retired Canadian National Railway Company pensioners, focused mainly on lung cancer, found that the overall SMR for bladder cancer was 1.03 (based on 175 deaths) and not statistically significant. However, the individual occupation of freight loader showed a significantly elevated SMR for bladder cancer of 3.40 (95% CI, 1.69-5.86), based on eight deaths. The authors concluded that the lack of an overall excess risk of death for bladder cancer suggested that the association seen in a previous case-control study was likely due to chance.

The Howe et al. (1980) Canadian population-based case-control study found that for males, the relative risk for ever using cigarettes versus never using was 3.9. After controlling for smoking, elevated risk was noted for males in the chemical (RR=7.5 (95% CI, 1.7-67.6)), petroleum (RR=5.3 (95% CI, 1.5-28.6)), and rubber (RR=5.0 (95% CI, 0.6-236.5)) industries. Exposure to diesel and traffic fumes resulted in an RR of 2.8 (95% CI, 0.8-11.8), a non-significant elevation. Bladder cancer risk was elevated for males consuming all types of coffee (RR=1.4 (95% CI, 0.9-2.0)) but notably lacked a dose-response relationship. The authors concluded that the overall PAR for males from cigarette smoking, industrial exposure, and nonpublic water supplies was 90%.

The Guo et al. (2004) Finnish cohort study investigated cancer risk among workers exposed to diesel or gasoline engine exhaust using a job-exposure matrix. They found no positive exposure-response relation for bladder cancer or other non-lung cancers studied. For bladder cancer, there was an excess observed only at the lowest CE level to gasoline engine exhaust (RR=1.13 (95% CI, 1.03-1.23)), largely attributed to drivers. The RR for the highest CE of diesel exhaust was 0.97 (95% CI, 0.77-1.21). The authors concluded that their results do not support previous findings suggesting an association between engine exhausts and risk of bladder cancers, attributing the lack of effect to possibly better adjustment for confounding factors.

AMA Citation Footnotes

1. Koutros S, Kogevinas M, Friesen MC, et al. Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes. Environ Int. 2020;135:105346.

2. Latifovic L, Villeneuve PJ, Parent ME, et al. Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men. Cancer Med. 2015;4(12):1948-1962.

3. Risch HA, Burch JD, Miller AB, et al. Occupational factors and the incidence of cancer of the bladder in Canada. Br J Ind Med. 1988;45(6):361-367.

4. Kunze E, Chang-Claude J, Frentzel-Beyme R. Life style and occupational risk factors for bladder cancer in Germany: a case-control study. Cancer. 1992;69(7):1776-1790.

5. Samanic CM, Kogevinas M, Silverman DT, et al. Occupation and bladder cancer in a hospital-based case-control study in Spain. Occup Environ Med. 2008;65(5):347-353.

6. Zheng T, Cantor KP, Zhang Y, Lynch CF. Occupation and bladder cancer: a population-based, case-control study in Iowa. J Occup Environ Med. 2002;44(7):685-691.

7. Cordier S, Clavel J, Limasset JC, et al. Occupational risks of bladder cancer in France: a multicentre case-control study. Int J Epidemiol. 1993;22(3):403-411.

8. Balarajan R, McDowall ME. Professional drivers in London: a mortality study. Br J Ind Med. 1988;45(7):483-486.

9. Schenker MB, Smith T, Muñoz A, Woskie S, Speizer FE. Diesel exposure and mortality among railway workers: results of a pilot study. Br J Ind Med. 1984;41(3):320-327.

10. Wynder EL, Dieck GS, Hall NE, Lahti H. A case-control study of diesel exhaust exposure and bladder cancer. Environ Res. 1985;37(2):475-489.

11. Kogevinas M, ‘t Mannetje A, Cordier S, et al. Occupation and bladder cancer among men in Western Europe. Cancer Causes Control. 2003;14(10):907-914.

12. Gaertner RRW, Trpeski L, Johnson KC, The Canadian Cancer Registries Epidemiology Research Group. A case-control study of occupational risk factors for bladder cancer in Canada. Cancer Causes Control. 2004;15(10):1007-1019.

13. Iscovich J, Castelletto R, Estève J, et al. Tobacco smoking, occupational exposure and bladder cancer in Argentina. Int J Cancer. 1987;40(6):734-740.

14. Gubéran E, Usel M, Raymond L, et al. Increased risk for lung cancer and for cancer of the gastrointestinal tract among Geneva professional drivers. Br J Ind Med. 1992;49(5):337-344.

15. Howe GR, Fraser D, Lindsay J, et al. Cancer mortality (1965-77) in relation to diesel fume and coal exposure in a cohort of retired railway workers. J Natl Cancer Inst. 1983;70(6):1015-1019.

16. Howe GR, Burch JD, Miller AB, et al. Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J Natl Cancer Inst. 1980;64(4):701-713.

17. Guo J, Kauppinen T, Kyyrönen P, et al. Risk of esophageal, ovarian, testicular, kidney and bladder cancers and leukemia among Finnish workers exposed to diesel or gasoline engine exhaust. Int J Cancer. 2004;111(2):286-292.

Benzene

Summary: Limited for benzene alone, but stronger when benzene is part of the BTX (benzene, toluene, xylene) group. Meta analysis found RR of 1.07

1. Seyyedsalehi MS, Bonetti M, Shah D, DeStefano V, Boffetta P. Occupational benzene exposure and risk of kidney and bladder cancers: a systematic review and meta-analysis. Eur J Cancer Prev. 2025;34:205-213.

This systematic review and meta-analysis aimed to evaluate the association between occupational exposure to benzene and the risk of urinary tract cancer, specifically kidney and bladder cancers. The analysis included 41 cohort and case-control studies identified from the International Agency for Research on Cancer (IARC) Monograph on benzene and from a literature review. Findings revealed a statistically significant association between occupational benzene exposure and kidney and unspecified urinary tract cancers (RR=1.20;95% CI, 1.03-1.39). For bladder cancer, the overall association was of borderline statistical significance (RR=1.07;95% CI, 0.97-1.18). Stratified analysis for kidney cancer showed a stronger association in the chemical industry. Importantly, an analysis by exposure level did not show a trend for kidney cancer but did reveal a dose-effect association (trend P=0.01) for bladder cancer. The authors concluded that the study found an association between occupational benzene exposure and kidney cancer, along with a dose-effect association for bladder cancer, highlighting a need for measures to minimize exposure in industries such as petroleum and chemical refining.

2. Ernandez J, Kaul S, Fleishman A, et al. The association of baseline frailty with survival among older adults undergoing radical cystectomy for bladder cancer. J Urol. 2023;209(4S):e301.

This study investigated whether baseline frailty is an independent predictor of survival for older adults undergoing radical cystectomy (RC) for bladder cancer. Using the SEER-Medicare linked database, researchers identified 5,916 patients aged 66–89 years who underwent RC between 2000 and 2017. Baseline frailty was calculated using a claims-based frailty index (CFI). The cohort included patients categorized as robust (CFI<0.15), pre-frail (CFI0.15 to 0.25), mildly frail (CFI0.25 to <0.35), and moderately-to-severely frail (CFI≥0.35). Increasing levels of frailty were associated with worse overall survival, cancer-specific survival, and other-cause survival, both before and after multivariable adjustment for patient and tumor characteristics. For instance, compared to robust patients, those moderately-to-severely frail (CFI≥0.35) had a fully adjusted hazard ratio of 1.45 (95% CI: 0.95-2.20) for cancer-specific mortality and 2.04 (95% CI: 1.22-3.39) for other-cause mortality. The authors concluded that the CFI may be a useful tool for identifying at-risk older adults undergoing RC for bladder cancer.

3. Xie S, Friesen MC, Baris D, et al. Occupational exposure to organic solvents and risk of bladder cancer. J Expo Sci Environ Epidemiol. 2024;34(5):546-553.

This case-control study evaluated the association between occupational exposure to specific organic solvents and the risk of bladder cancer using data from 1,182 incident cases and 1,408 controls. Exposure was assessed using a job-exposure matrix (CANJEM) and a novel hybrid BTX (benzene, toluene, and xylene) metric that incorporated detailed subject-specific occupational histories. The results showed significantly increased risks among those ever exposed to benzene (OR=1.63;95% CI, 1.14-2.32), toluene (OR=1.60;95% CI, 1.06-2.43), and xylene (OR=1.67;95% CI, 1.13-2.48) individually. Because these agents often co-occur, the combined BTX exposure was assessed. The study found a statistically significant exposure-response relationship for cumulative BTX exposure, with the strongest association found in the highest quartile using the hybrid metrics (e.g., ORQ4vsUnexposed​=2.23;95% CI, 1.35-3.69) with a highly significant trend (P-trend=0.001). This relationship persisted after adjusting for smoking status and a 20-year exposure lag. The authors concluded that the identification of this increased risk for BTX highlights a significant, yet “little recognized,” occupational exposure that may play a role in the etiology of bladder cancer.

4. La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and the risk of bladder cancer. Int J Epidemiol. 1990;19(2):264-268.

This case-control study conducted in the greater Milan area of Northern Italy assessed the relationship between bladder cancer and specific occupations or exposures. The analysis included 263 cases of histologically confirmed invasive bladder cancer and 287 non-cancer controls. Cases more frequently reported employment in dyestuff production, painting/spraying, chemical industry, pharmaceuticals, and coal/gas production. The strongest and only statistically significant association with an industry was found for dyestuff production (RR=4.6). In relation to occupational agents, statistically significant positive trends in risk were observed for exposure to dyes/paints, herbicides, chemicals, and gases/fumes. For exposure greater than 10 years, the smoking-adjusted relative risks were 4.1 for herbicides and 4.8 for dyes/paints. No association was found for specific agents like solvents or benzene. The authors concluded that the study confirmed an elevated bladder cancer risk for dyestuff production, painting, and chemical exposures, and provided statistically significant evidence of an independent role of herbicides.

5. Kiriluk KJ, Prasad SM, Patel AR, Steinberg GD, Smith ND. Bladder cancer risk from occupational and environmental exposures. Urol Oncol. 2012;30(2):199-211.

This seminar article reviewed current knowledge of environmental factors and their association with bladder cancer, noting that approximately 50% of incidence is attributed to known carcinogens, mainly cigarette smoking. The authors classified environmental factors by the strength of evidence for their association with bladder cancer. Factors deemed causative included: cigarette smoking (with risk 4 times higher in smokers) ; specific aromatic amines (2-naphthylamine, benzidine, 4-aminobiphenyl); high arsenic levels (drinking water concentration >0.2 mg/l); Schistosoma haematobium infection ; and exposure to oxazaphosphorines (cyclophosphamide/ifosfamide). Polycyclic aromatic hydrocarbons (PAH) exposure for workers was associated with relative risks of 1.2 to 2.3 times greater compared with the general population. The review classified other factors, such as secondhand smoke, chlorinated water, halogenated hydrocarbons (perchloroethylene), and low arsenic levels, as having indeterminate associations. The authors emphasized the critical role of the environment and advocated for using geospatial tools (GIS) to identify new environmental risk factors and link regional variance in outcomes to potential causes.

6. Shala NK, Stenehjem JS, Babigumira R, et al. Exposure to benzene and other hydrocarbons and risk of bladder cancer among male offshore petroleum workers. Br J Cancer. 2023;129(5):838-851.

This prospective case-cohort study examined the risk of bladder cancer among male Norwegian offshore petroleum workers (NOPW cohort, 189 cases) exposed to petroleum-related hydrocarbons. Exposure was assessed retrospectively using job-exposure matrices (JEMs) for agents including benzene, crude oil, mineral oil, and diesel exhaust. The risk of bladder cancer was found to be increased in workers exposed to benzene. Compared to unexposed workers, the highest relative risk was found for those with long-term benzene exposure (≥18.8 years, HR=1.89;95% CI, 1.14-3.13). The results demonstrated a dose-related increase in risk. Importantly, these associations persisted when exposures were lagged 10, 15, or 20 years to account for disease latency, and the association was further strengthened when limited to bladder cancer as the first primary cancer with a 20-year lag. In contrast, no associations were found with skin or inhalation exposure to crude oil, mineral oil, or diesel exhaust. The authors concluded that the findings suggest that exposures in the benzene fraction of the petroleum stream may be associated with increased bladder cancer risk and merit further evaluation

Chlorinated Solvents (PCE/TCE)

1. TCE: Vlaanderen (2013): Twelve studies were included in the meta-analysis (8 case-control studies, 4 cohort studies) resulting in a meta-RR of 1.24 (95% CI, 1.12–1.37). The meta-RR was 1.20

2. Mundt (2003): Scientific evidence inadequate for PCE and bladder cancer but more data was necessary

3. Aschengrau 1992: When latency was ignored, there was also an increased relative risk of bladder cancer among subjects whose exposure level was over the 90th percentile (adjusted OR = 4.03, 95% CI = 0.65–25.10). (cant find actual paper)

Summary of Epidemiological Findings on Solvent Exposure and Cancer Risk

The following multi-page summary reviews the provided epidemiological studies, focusing on occupational exposure to chlorinated solvents, particularly perchloroethylene (PCE) and trichloroethylene (TCE), and their association with lung and bladder cancer. Each study is summarized in paragraph form with AMA-style footnotes for citation.

1. Occupational exposure to organic solvents and risk of bladder cancer (Xie et al., 2024)

This study investigated the association between occupational exposure to organic solvents and the risk of bladder cancer using data from the New England Bladder Cancer Study. The study compared 1,182 incident cases with 1,408 controls. Exposure to solvents was assessed using a job-exposure matrix (CANJEM). Because benzene, toluene, and xylene (BTX) often co-occurred, the authors developed combined BTX exposure metrics, including a highly detailed “hybrid BTX metric” that integrated CANJEM with lifetime occupational histories and worker-specific details. The study found significantly increased risks for individuals ever exposed to benzene (OR 1.63, 95% CI: 1.14–2.32), toluene (OR 1.60, 95% CI: 1.06–2.43), and xylene (OR 1.67, 95% CI: 1.13–2.48) individually, when compared to the never-exposed group. Crucially, the analysis revealed a statistically significant exposure-response relationship for cumulative BTX exposure, particularly when using the hybrid metrics (OR$_{\text{Q4vsUnexposed}}$ 2.23, 95% CI: 1.35–3.69, $p$-trend=0.001). The strong, dose-dependent association with BTX suggests that concurrent exposure to these solvents plays a role in bladder cancer etiology. The paper found that exposure to perchloroethylene (PCE) showed a lower risk (OR 0.36, 95% CI: 0.13–0.96), but this finding was based on very small numbers (6 cases and 19 controls), and no participants were exposed to trichloroethylene (TCE). The findings are significant because they suggest a link between BTX exposure and bladder cancer, even after controlling for cigarette smoking, the primary risk factor for the disease.

2. Exposure to chlorinated solvents and lung cancer: results of the ICARE study (Mattei et al., 2014)

This French multicenter, population-based case-control study (ICARE) investigated the role of occupational exposure to chlorinated solvents in lung cancer. The study collected lifelong work history information from 2,926 cases and 3,555 controls, and exposures to five solvents (PCE, TCE, DCM, CF, CT) were assessed using job-exposure matrices (JEMs). The analysis controlled for classic risk factors, including cigarette smoking and asbestos exposure. No statistically significant associations were found for single solvents or most solvent combinations after adjusting for asbestos. However, the study observed a statistically significant positive association with lung cancer for both men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene (TCE), and dichloromethane (DCM). The combination exposure resulted in an OR of 1.81 (95% CI: 1.18–2.76) for men and a much higher OR of 5.39 (95% CI: 1.37–21.16) for women. The authors hypothesize that PCE is the most likely culprit, as no association was found for TCE alone or TCE combined with DCM. The results suggested that PCE may constitute a risk factor for lung cancer, especially among women who had a higher prevalence of exposure in sectors like dry-cleaning. In contrast, the study specifically found no evidence of an association between TCE and lung cancer, even among subjects never exposed to asbestos.

3. Occupational exposure to tetrachloroethylene and the risk of bladder cancer: A meta-analysis (Vlaanderen et al., 2013)

This meta-analysis summarized the risk of bladder cancer in persons occupationally exposed to tetrachloroethylene (PCE). The authors identified and included twelve studies (8 case-control, 4 cohort) in the meta-analysis. They excluded studies reporting results for “dry-cleaners and laundry workers” to ensure that the risk estimates were not diluted by unexposed individuals (laundry workers) and focused on workers likely exposed to PCE. The overall finding was a moderate, statistically significant increased risk of bladder cancer associated with PCE exposure, with a meta-Relative Risk (RR) of 1.24 (95% CI, 1.12–1.37). The result showed consistency across the two major study designs: a meta-RR of 1.20 (95% CI, 1.07–1.34) for case-control studies (all adjusted for smoking) and 1.44 (95% CI, 1.13–1.84) for cohort studies. The consistency of the positive finding in case-control studies after adjusting for tobacco use strengthened the conclusion that the excess risk could not be explained by smoking. The authors concluded that occupational exposure to PCE is a significant risk factor for bladder cancer

4. Critical review of the epidemiological literature on occupational exposure to perchloroethylene and cancer (Mundt et al., 2003)

This is a critical review of the epidemiological literature assessing the carcinogenic effects of occupational exposure to perchloroethylene (PCE). The review focused on 44 papers that provided data on up to 17 cancer sites, with a large emphasis on dry-cleaning workers. The authors highlight the primary limitations in the literature as the widespread lack of valid exposure measurements and inadequate control for confounding factors such as smoking, alcohol consumption, and socioeconomic status. For most sites, including the oral cavity, liver, pancreas, cervix, and lung, the authors concluded that a relationship with PCE was unlikely. The evidence was considered inadequate for firm conclusions regarding laryngeal, kidney, esophageal, and bladder cancers. Specifically regarding bladder cancer, although most studies reported an excess risk, the finding that PCE-only exposed cohorts in some studies showed no cases suggests that other co-exposures may have been the true cause. For example, one cohort study showed no bladder cancer cases among workers exposed only to PCE. Overall, the authors conclude that the current epidemiological evidence does not support a conclusion that occupational exposure to PCE is a risk factor for cancer of any specific site.

5. Cancer in relation to occupational exposure to perchloroethylene (Weiss, 1995)

This review focused on the two principal cohort mortality studies of US dry cleaners to assess the relationship between perchloroethylene (PCE) and cancer. The two cancers of greatest a priori concern—liver cancer and leukemia (based on animal data)—were not found to occur with increased frequency among dry cleaners. However, the review found that mortality rates were elevated by about a factor of two for esophageal cancer and bladder cancer. For esophageal cancer, the elevation was considered “well beyond the limits of chance”. Nevertheless, the observed excess was heavily qualified, as it was noted that the increase could not be definitively separated from the confounding effect of cigarette smoking and heavy alcohol consumption. For bladder cancer, a roughly twofold increase in mortality was consistently observed across cohorts. Critically, data from one cohort study suggested that the increase was not due to PCE: no bladder cancer deaths occurred in persons whose only dry-cleaning employment was in a PCE shop, while all persons who died from bladder cancer had also worked with other organic solvents. The review concluded that the limited data suggested that the observed increased risk for bladder cancer “could be due to exposure to other solvents than PCE used in dry cleaning”.

Footnotes (AMA Style)

1. Xie S, Friesen MC, Baris D, et al. Occupational exposure to organic solvents and risk of bladder cancer. J Expo Sci Environ Epidemiol. 2024;34(5):546-553.

2. Mattei F, Guida F, Matrat M, et al. Exposure to chlorinated solvents and lung cancer: results of the ICARE study. Occup Environ Med. 2014;71(10):681-689.

3. Vlaanderen JJ, Ruder A, Blair A, et al. Occupational exposure to tetrachloroethylene and the risk of bladder cancer: A meta-analysis. Occup Environ Med. 2013;70(suppl 1):A34.

4. Mundt KA, Birk T, Burch MT. Critical review of the epidemiological literature on occupational exposure to perchloroethylene and cancer. Int Arch Occup Environ Health. 2003;76(7):473-491.

5. Weiss NS. Cancer in relation to occupational exposure to perchloroethylene. Cancer Causes Control. 1995;6(3):257-266.

Welding Fumes – a table with analysis has been conducted for some of these papers

Gaertner et al. 2004 Gaertner et al conducted a population-based case-control study in seven Canadian provinces to investigate occupational risk factors for bladder cancer, analyzing data from 887 cases and 2,847 controls. The study confirmed tobacco smoking as a major risk factor, noting a cumulative exposure-response trend, with heavy smokers showing a 4- to 5-fold increased risk compared to non-smokers. Other non-occupational factors included a decreased risk with higher fruit consumption in females and an increased risk with higher fried food consumption in males. Occupations with statistically significant increased risks in men included hairdressers (OR=3.42, 95% CI 1.09-10.8), primary metal workers (OR=2.40, 95% CI 1.29-4.50), miners (OR=1.94, 95% CI 1.18-3.17), and automechanics (OR=1.69, 95% CI 1.02-2.82). For women, increased risks were found among lumber processors, general labourers, nurses, and general clerks. The authors observed a duration-response trend for male primary metal workers and automechanics. The findings suggested that a common theme in the high-risk male occupations was exposure to a variety of combustion products and/or oils. The study noted a non-significant elevation for welders (OR=1.34, 95% CI 0.76-2.38) and self-reported welding exposure, stating the finding was consistent with other literature.

Simonato et al. 1991 Simonato et al reported a historical prospective study of a multicentre cohort of 11,092 male welders from nine European countries to investigate potential cancer risk, particularly lung cancer, related to occupational exposure. Overall, the cohort showed a statistically significant excess in lung cancer mortality (SMR=134) and an excess mortality from all malignant neoplasms. The study found a statistically significant excess for bladder cancer mortality (SMR=191, 95% CI 107-315). Although there was a trend for lung cancer Standardized Mortality Ratios (SMRs) to increase with time since first exposure for predominantly stainless steel welders, no clear relation was found between lung cancer mortality and the duration of exposure or estimated cumulative dose of nickel or chromium. The authors noted that the overall lung cancer excess fell within the range that could be explained by tobacco smoking but that partial data from some countries suggested welding fumes may still play a role. The detection of five deaths from pleural mesothelioma in the cohort was noted as a strong suggestion that past exposure to asbestos (e.g., in shipyards) might have contributed to the excess lung cancer risk among all welding groups. The authors ultimately suggested a possible role of occupational exposure to stainless steel welding fumes in excess lung cancer mortality.

MacLeod et al. 2017 MacLeod et al investigated cancer risks among welders and occasional welders in the large, population-based Canadian Census Health and Environmental Cohort of 1.1 million male workers. Among primary welders, elevated adjusted hazard ratios (HRs) were observed for lung cancer (HR: 1.16, 95% CI: 1.03-1.31), mesothelioma (HR: 1.78, 95% CI: 1.01-3.18), bladder cancer (HR: 1.40, 95% CI: 1.15-1.70), and kidney cancer (HR: 1.30, 95% CI: 1.01-1.67). However, when the comparison was restricted to other blue-collar workers (to minimize confounding from socioeconomic differences and smoking), the risks for lung cancer and mesothelioma were attenuated (lowered), suggesting they may be partly attributable to factors common among blue-collar workers, such as smoking and asbestos. In contrast, the risks for bladder and kidney cancer increased in the blue-collar-only comparison, with the authors concluding that welding-specific exposures may increase bladder and kidney cancer risks. The strongest histological association for lung cancer was found for small cell and squamous cell carcinoma, a pattern commonly associated with smoking. The authors emphasized the need for further studies to investigate welding-specific exposures for bladder and kidney cancer.

Cumberbatch et al. 2015 Cumberbatch et al performed a systematic review and meta-analysis of contemporary reports on occupational exposure and bladder carcinogenesis. The analysis included data from over 230,000 cases and 4.7 million controls from 217 articles. The overall risk of bladder cancer incidence was estimated to be 1.03 (95% CI 1.02-1.03) for men and the overall risk of mortality was 1.32 (95% CI 1.18-1.48) for men, significantly greater than for women in both metrics. The study found that while risks declined from the 1960s to the 1980s (reflecting changes in workplace legislation), the incidence risk reversed and increased from the 1980s to the 2000-2010 decade. The highest incidence risks were for workers exposed to aromatic amines (e.g., tobacco, dye, and rubber workers). The highest mortality risks were for workers exposed to heavy metals and polycyclic aromatic hydrocarbons (PAHs), including metal workers, electricians, and mechanics. Bladder cancer risk in metal, machine, and automobile workers was partly derived from exposure to mineral oils, solder, and/or welding fumes. The authors classified painters as a definitive (IARC Group 1) exposure and noted that risk from agents like diesel exhaust fumes (inhaled by drivers and miners) seemed to be declining. They noted that the risk profile has changed and is now increasing faster in women than in men, possibly due to occult carcinogens or improved detection.

Reed et al. 2020 Reed et al conducted a small, exploratory cross-sectional survey of 454 bladder cancer patients in South Yorkshire, UK, a region with high bladder cancer risk and a strong industrial history, to associate cancer phenotypes (grade/stage) with detailed self-reported occupational tasks and exposures. The primary finding was that various occupational contacts and tasks were associated with high grade and high stage bladder cancer, suggesting a link to aggressive disease. The most common exposures were diesel fumes/fuel, coal/oil/gas by-products, and solvents, reflecting the local prevalence of work in the steel, foundry, metal, engineering, and transport industries. Specifically, exposures such as diesel fuels or fumes (HR 1.97, 95% CI 1.31-2.98), and tasks such as welding (HR 1.85, 95% CI 1.24-2.77) and exposure to welding materials (HR 1.92, 95% CI 1.27-2.91), were significantly associated with an increased likelihood of disease progression and need for radical treatment. The carcinogens identified were primarily a mixture of PAHs, diesel fumes, and combustion products. The authors proposed that the strong associations found could potentially be used to risk stratify individuals with hematuria or in follow-up protocols for non-invasive bladder cancer.

Collatuzzo et al. 2024 Collatuzzo et al performed a systematic review and meta-analysis of cohort studies investigating the association between occupational diesel exhaust exposure and the risk of gastrointestinal (GI) cancers (esophageal, gastric, colon, and rectal). The analysis was based on 30 retained studies. The overall findings showed a weak, non-statistically significant association with esophageal cancer (RR=1.08, 95% CI 0.97-1.21), gastric cancer (RR=1.06, 95% CI 0.99-1.14), and rectal cancer (RR=1.04, 95% CI 0.97-1.11), while no relationship was found for colon cancer (RR=0.98, 95% CI 0.96-1.00). In stratified analyses, a significant association was detected between rectal cancer and drivers (RR=1.41, 95% CI 1.13-1.75). Associations were also suggested for machine operators and handlers for upper-GI cancers. The major limitations noted were the inability to adjust for important confounders (like smoking and H. pylori infection) and the geographical restriction of studies to North America and Europe. The authors concluded that the weak associations found, particularly for upper-GI cancers and rectal cancer, might be due to residual confounding, and therefore a causal inference cannot be made, but the results suggest a need for further investigation and the implementation of protective measures.

Footnotes

1. Gaertner RRW, Trpeski L, Johnson KC, et al. A case-control study of occupational risk factors for bladder cancer in Canada. Cancer Causes Control. 2004;15(10):1007-1019.

2. Simonato L, Fletcher AC, Andersen A, et al. A historical prospective study of European stainless steel, mild steel, and shipyard welders. Br J Ind Med. 1991;48(3):145-154.

3. MacLeod JS, Harris MA, Tjepkema M, et al. Cancer risks among welders and occasional welders in a national population-based cohort study: Canadian census health and environmental cohort. Saf Health Work. 2017;8(3):258-266.

4. Cumberbatch MGK, Cox A, Teare D, et al. Contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis. JAMA Oncol. 2015;1(9):1282-1290.

5. Reed O, Jubber I, Griffin J, et al. Occupational bladder cancer: A cross section survey of previous employments, tasks and exposures matched to cancer phenotypes. PLoS One. 2020;15(10):e0239338.

6. Collatuzzo G, Teglia F, Boffetta P. Gastrointestinal cancer and occupational diesel exhaust exposure: a meta-analysis of cohort studies. Occup Med (Lond). 2024;74(6):438-448.

Creosote / PAHs

I will now prepare a multi-paragraph summary of each paper using the information from the Canvas, formatted with footnotes in AMA style, as you requested.

Clavel et al. (1994)

This French hospital-based case-control study investigated the association between occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and bladder cancer risk among 658 male cases and 658 male controls. The study employed an individual, expert assessment of PAH exposure using a semi-quantitative index, allowing for detailed dose-response analysis independent of job title. The overall odds ratio (OR) for PAH exposure, adjusted for smoking, coffee drinking, and occupational exposure to aromatic amines (AA), was 1.3 (95% CI: 1.0-1.7), demonstrating a statistically significant association.¹ Importantly, a clear dose-response relationship was observed, with the risk rising for higher levels of maximum and average exposure. For subjects categorized as “Low” average exposure ($<10~\text{ng}/\text{m}^{3}$), the OR was 1.2 (95% CI: 0.9-1.7). The analysis concluded that the findings “support a causal relationship between bladder cancer risk and occupational PAH exposure” that is unlikely to be explained by either selection bias or confounding by smoking. Furthermore, the risk was notably stronger among heavy smokers, suggesting a joint (synergistic) effect between smoking and occupational PAH exposure.

Bosetti et al. (2007)

This paper provides a quantitative review and meta-analysis of cohort studies published up to 2005 concerning occupational PAH exposure and respiratory and urinary tract cancers. The authors synthesized evidence from various industries with high PAH exposures, including aluminum production, coal gasification, coke production, and iron and steel foundries. For bladder cancer, the review found a significant and substantial pooled risk specifically among coal gasification workers, with a pooled Relative Risk (RR) of 2.39 (95% CI: 1.36-4.21).² Evidence was also found for workers in iron and steel foundries (Pooled RR: 1.29; 95% CI: 1.06-1.57). The authors concluded that while the evidence for bladder cancer is “less consistent” across all PAH industries, a “modest increase in risk” was observed in aluminum production, coal gasification, and iron and steel foundries. The authors cautioned that for most industries, the excesses were modest (except for coal gasification) and generalizing the findings remains difficult due to potential bias and confounding factors.

Boffetta et al. (1997)

This comprehensive review evaluated the epidemiological evidence linking occupational and environmental exposure to PAHs and cancer risk, confirming bladder cancer as a key target organ, particularly in industries involving coal tars and pitches. The review highlighted specific quantifiable dose-response data, noting that the risk of bladder cancer increased by 1.7 percent for each year of exposure to Benzo[$a$]pyrene at $1~\mu g/\text{m}^{3}$ in aluminum production, establishing this as a significant lowest exposure threshold over time.³ The general conclusion was that an “increase in bladder cancer risk is found mainly in industries with high exposure to PAHs from coal tars and pitches.” While tar distillation exposure showed a high Odds Ratio of 4.3 (95% CI: 0.9-12.5), the wide confidence interval demonstrated limited statistical power in that specific study. Critically, the review also noted that studies focusing on railroad workers exposed to diesel engine exhaust did not show an increased bladder cancer mortality, which is relevant to the railroad industry context.

Bonassi et al. (1989)

This Italian population-based case-control study investigated the association between bladder cancer and occupational PAH exposure in the Bormida valley. The primary finding for the group with “definite exposure to PAH,” after adjustment for smoking and aromatic amines (AA), showed an Odds Ratio of 2.14 (95% CI: 0.82-5.60).⁴ While this primary result was not statistically significant (the CI crosses 1.0), the high OR suggested consistency with a PAH role. The strongest statistically significant finding emerged in a subset of workers with “Possible PAH + High AA Exposure,” yielding an OR of 3.81 (95% CI: 1.99-7.29), suggesting a potent joint effect or confounding by AA. The authors acknowledged that the inability to definitively assess the presence of AA impurities in the PAH-exposed settings complicated the interpretation, but ultimately maintained that their findings are “consistent with the hypothesis that PAH exposure is a risk factor for bladder cancer.”

Castaño-Vinyals et al. (2008)

This Spanish case-control study primarily focused on assessing the risk of urinary bladder cancer associated with ambient (environmental) air pollution indicators, which represent significantly lower levels of exposure than occupational settings. The most statistically significant finding related to the ecological variable of long-term residence, with those living for more than 40 years in a city of over 100,000 population having an OR of 1.30 (95% CI: 1.04-1.63).⁵ Exposure proxies such as expert-assessed proximity to industries emitting PAHs or diesel were non-significant (OR: 1.29; 95% CI: 0.85-1.98). Given that ambient Benzo[$a$]pyrene levels in the cities studied were in the low $\text{ng}/\text{m}^{3}$ range (e.g., $6.5~\text{ng}/\text{m}^{3}$), the authors interpreted the small and mostly non-significant associations as suggestive of a substantially lower environmental risk compared to occupational settings, while supporting the need for further evaluation.

Footnotes (AMA Style)

1. Clavel J, Mandereau L, Limasset J-C, Hémon D, Cordier S. Occupational exposure to polycyclic aromatic hydrocarbons and the risk of bladder cancer: a French case-control study. Int J Epidemiol. 1994;23(6):1145-1153.

2. Bosetti C, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005. Ann Oncol. 2007;18(3):431-446.

3. Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control. 1997;8(3):444-472.

4. Bonassi S, Merlo F, Pearce N, Puntoni R. Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons. Int J Cancer. 1989;44(4):648-651.

5. Castaño-Vinyals G, Cantor KP, Malats N, et al. Air pollution and risk of urinary bladder cancer in a case-control study in Spain. Occup Environ Med. 2008;65(1):56-60.

Herbicides/ Roundup/Glyphosate

• No evidence of glyphosate causing bladder cancer

Secondhand Smoke

Carreras 2025– relative risks (RRs) were calculated using random-effects models. Twelve studies (eight case-control and four cohort studies), involving approximately 1200 bladder cancer cases, were included. The overall pooled RR of bladder cancer for SHS exposure was 1.16 [95% confidence interval (CI): 0.95–1.43], with slight differences when considering exposure settings. Could not get full article

Zhang 2022 (abstract) – bladder (HR, 1.487; 95% CI, 1.198,1.846),

The research conducted by Yan et al in 2018 compiled evidence from 14 studies to address the association between secondhand smoking (SHS) exposure and bladder cancer risk in nonsmokers, reporting a statistically significant 22% increase in risk for lifetime SHS exposure (RR, 1.22; 95% CI, 1.06–1.40). The authors concluded this finding was robust due to a lack of detectable heterogeneity, suggesting a reliable and stable association between SHS and bladder cancer among nonsmokers. The study highlighted the importance of this finding for cancer control policy. Yan et al [1] also performed a separate meta-analysis on childhood exposure, but deemed the results unreliable due to high heterogeneity and publication bias.

A 2022 prospective cohort study by Zhang et al, utilizing serum cotinine levels as a biomarker for SHS exposure in a large U.S. population, found a dose-dependent association with bladder cancer mortality [2]. Specifically, participants in the high exposure group (serum cotinine $\ge10$) exhibited a statistically significant Hazard Ratio (HR) of 1.487 (95% CI, 1.198–1.846) for bladder cancer mortality. In contrast, the low exposure group (cotinine 0.015-10) showed no statistically significant risk (HR 0.956, 95% CI, 0.860–1.062). The authors concluded that high exposure to SHS has a clear and significant effect on bladder cancer mortality.

The 2009 meta-analysis by Van Hemelrijck et al offered a nuanced perspective, finding no evidence for an association between SHS exposure and bladder cancer risk (RR, 0.99; 95% CI, 0.86–1.14) in nonsmokers, based on eight studies [3]. However, the study did find that adult SHS exposure was significantly associated with elevated levels of the established bladder carcinogen, 4-aminobiphenyl (4-ABP) (SMD, 1.47; 95% CI, 0.23–2.71), demonstrating biological plausibility. The authors suggested that methodological limitations in exposure assessment might explain the conflicting results between the established presence of the carcinogen and the lack of a measurable cancer risk.

The prospective cohort study by Alberg et al, published in 2007, provided inconsistent results based on two cohorts of Washington County, Maryland residents [4]. In the 1963 cohort, current household SHS exposure among never-smoking women showed a statistically significant elevation in risk (RR, 2.3; 95% CL, 1.0–5.4). However, this finding was contradicted by the subsequent 1975 cohort, which showed a null association (RR, 0.9; 95% CL, 0.4–2.3). The researchers noted that their exposure measure, limited solely to the household, might have resulted in misclassification, contributing to the mixed findings, and concluded that the question of a genuine association between SHS and bladder cancer remained open.

The most recent systematic review and meta-analysis by Carreras et al, published in 2025, identified 12 studies and provided an elevated, yet not statistically significant, overall pooled risk for SHS exposure and bladder cancer (RR, 1.16; 95% CI, 0.95–1.43) [5]. This paper noted that the non-significant finding was likely attributable to the relatively limited number of cases and studies currently available, resulting in insufficient statistical power. The authors concluded that further research with improved exposure assessment is necessary to better clarify the role of SHS in bladder cancer development.

References

1. Yan H, Ying Y, Xie H, et al. Secondhand smoking increases bladder cancer risk in nonsmoking population: a meta-analysis. Cancer Manag Res. 2018;10:3781-3791. doi:10.2147/CMAR.S175062.

2. Zhang Z, Li Z, Zhang X, et al. Association between secondhand smoke and cancers in adults in the US population. J Cancer Res Clin Oncol. 2022;148(12):3567-3576. doi:10.1007/s00432-022-04266-w.

3. van Hemelrijck MJJ, Michaud DS, Connolly GN, Kabir Z. Secondhand smoking, 4-aminobiphenyl, and bladder cancer: two meta-analyses. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1312-1320. doi:10.1158/1055-9965.EPI-08-0613.

4. Alberg AJ, Kouzis A, Genkinger JM, et al. A prospective cohort study of bladder cancer risk in relation to active cigarette smoking and household exposure to secondhand cigarette smoke. Am J Epidemiol. 2007;165(6):660-666. doi:10.1093/aje/kwk047.

5. Carreras G, Possenti I, Malevolti MC, Gorini G, Gallus S, Lugo A. Second-hand smoke and bladder cancer risk among nonsmokers: a systematic review and a meta-analysis. Eur J Cancer Prev. 2025:10.1097/CEJ.0000000000000979. doi:10.1097/CEJ.0000000000000979.

Thyroid

Gastrointestinal

Asbestos

• Selikoff et al. 1991 –

• Offermans et al. 2014 –

• Levine et al. 1985 –

• Kjaerheim et al. 2004 –

• Kang et al. 1998 –

• Finkelstein et al. 2004 –

• Edelman et al. 1988 –

• Koehorn et al. 2024

• Kim et al. 2013

• Gustavsson et al. 2023

• Frumkin et al. 1988

• Di Ciaula et al. 2017

  • Finkelstein 1984

  • Wang et al. 2013

  • Weiss 1977

  • Weiss 1995

  • Kang et al. (1997)

  • Lacquet et al. (1980)

  • Lumley (1976)

  • Newhouse et al. (1985)

  • Santibañez et al. (2008)

  • Selikoff et al. (1974)

1. Koehoorn et al. (2024): Occupational Asbestos Exposure and Gastrointestinal Cancers: Systematic Review and Meta-analyses This systematic review and meta-analysis of 192 studies provides the strongest evidence supporting a causal link between occupational asbestos exposure and the risk of three major gastrointestinal (GI) cancers: oesophageal cancer, stomach cancer, and colorectal cancer (CRC).1 The meta-analyses consistently showed elevated risks for any occupational asbestos exposure across all sites: Oesophageal Cancer: mRR 1.17 (95% CI 1.07-1.29); Stomach Cancer: mRR 1.14 (95% CI 1.05-1.23); and Colorectal Cancer: mRR 1.16 (95% CI 1.08-1.24). Crucially, the risks were significantly stronger and more consistent in high-exposure cohorts, reinforcing the causal link. For workers in the highest compared to the lowest exposure categories, the mRRs were substantially elevated for oesophageal cancer (1.63), stomach cancer (1.28), and CRC (1.29). Furthermore, the risk for all three GI cancers increased proportionally with the risk of asbestos-related lung cancer found in the same cohort, demonstrating a clear dose-response relationship. The authors concluded that these findings strongly support classifying occupational asbestos exposure as a cause of these three GI cancers.

2. Frumkin et al. (1988): Asbestos Exposure and Gastrointestinal Malignancy: Review and Meta-Analysis This meta-analysis reviewed 31 cohort studies to clarify the association between asbestos and GI malignancy (esophageal, gastric, and colorectal cancer).2 The study’s most significant finding emerged after controlling for confounding factors by using a lung cancer standardized mortality ratio (SMR) of at least 200 as a proxy for significant asbestos exposure. In these high-dose cohorts (considering a 20-year latency period), the SMRs for GI cancers were consistently and substantially elevated, with confidence intervals excluding 100: Gastric Cancer SMR 146 (95% CI 100-213); Colorectal Cancer SMR 168 (95% CI 134-209); and Total GI Cancer (excluding mesothelioma) SMR 166 (95% CI 132-208). This dose-based stratification successfully reduced data inconsistency across the studies, suggesting that the observed elevated SMRs reflect a true, dose-related association between asbestos and GI cancers, reinforcing the evidence for asbestos as a systemic carcinogen.

3. Finkelstein (1984): Mortality Among Employees of an Ontario Asbestos-Cement Factory This cohort study focused on 535 asbestos-exposed workers at an Ontario factory using both chrysotile and crocidolite.3 It reported a significant excess mortality in exposed workers 20 years after first exposure. The standardized mortality ratio (SMR) for gastrointestinal (GI) cancers was 240 compared to the general population. Through a quantitative internal comparison, the study found a statistically significant trend of increasing GI cancer rates with increasing cumulative fiber exposure (Z=2.3;p<0.02). Based on the cohort’s average exposure (60 f−y/ml fibers per milliliter times years), GI cancer rates were estimated to be increased threefold (95% CI 1.2- to 5.6-fold increase). The author concluded that the significant increase and clear dose-response trend strongly suggest a cause-effect relationship between asbestos exposure and GI cancer.

4. Selikoff et al. (1974): Asbestos Exposure and Neoplasia This prospective cohort study of building trades insulation workers investigated the long-term effects of asbestos exposure.4 A central finding regarding the gastrointestinal tract was the large excess mortality observed for cancer of the stomach, colon, and rectum. Among 632 workers with 20 or more years since first exposure, 29 deaths were observed from these cancers, compared with only 9.4 deaths expected. This excess mortality, which was roughly three times the expected rate, was significant and suggested an etiological relationship between industrial asbestos exposure and carcinoma of the gastrointestinal tract.

5. Wang et al. (2013): Mortality in chrysotile asbestos workers in China This review summarized cohort studies of Chinese chrysotile workers and noted a consistent finding of an increased risk of gastrointestinal cancer (pooled category) in miners and factory workers exposed to chrysotile.5 Specifically, the review noted that chrysotile miners experienced excess mortality and a three-fold risk for GI cancer detected compared to internal controls, which was generally not the case for factory workers. The authors suggested that this difference indicated the effect might be associated with the exceptionally heavy exposures specific to the mining population.

6. Santibáñez et al. (2008): Occupational Exposures and Risk of Oesophageal Cancer by Histological Type: A Case-control Study in Eastern Spain This case-control study examined the risk of oesophageal cancer (OC) by histological type (squamous cell carcinoma [OSCC] and adenocarcinoma [OAC]).9 While asbestos was the most frequent occupational exposure, it showed a near-significant increase in the overall risk of OC (OR 3.46, 95% CI 0.99-12.10, p trend = 0.07) associated with high exposure. The study also found strong associations between specific occupations and cancer subtypes: OSCC risk was elevated for “waiters and bartenders” (OR 8.18) and “miners, shotfirers, stone cutters and carvers” (OR 10.78); OAC risk was elevated for “carpenters and joiners” (OR 9.69) and “building and related electricians” (OR 8.26). The findings suggest that asbestos exposure increases the overall risk of OC, while other occupational factors may specifically influence the risk of OAC or OSCC.

7. Newhouse et al. (1985): Mortality of Factory Workers in East London 1933–80 This long-term mortality study found a statistically significant excess of deaths from gastrointestinal (GI) tumours among the most severely exposed men (O/E 1.8) and women (O/E 2.1) in an asbestos factory cohort.6 However, a crucial finding was the absence of a clear dose-response relationship between the severity/duration of asbestos exposure and the GI tumor mortality rate. The authors noted that while the excess risk was persistent, this lack of a clear trend made the definitive attribution of GI cancer deaths to asbestos exposure questionable, a distinction often made in contrast to the strong dose-response observed for lung cancer and mesothelioma in the same cohort.

8. Kang et al. (1997): Gastrointestinal Cancer Mortality of Workers in Occupations With High Asbestos Exposures This mortality study analyzed death certificate data, grouping 12 occupations with documented high asbestos exposure. The proportionate mortality ratios (PMRs) for oesophageal cancer (PMR 108), gastric cancer (PMR 110), and colorectal cancer (PMR 109) were statistically elevated, but the magnitude of the effect was very small.8 Furthermore, the results were inconsistent, as the occupations with the highest overall asbestos exposure (like insulation workers) did not show elevated GI PMRs. The study concluded that while an association exists, the magnitude is “very small,” and the inconsistency casts doubt on a clear causal link for this specific population.

9. Lumley (1976): A Proportional Study of Cancer Registrations of Dockyard Workers This study analyzed cancer registrations of dockyard workers exposed to asbestos.10 It found a highly significant excess of pleural tumors (mesothelioma) but no statistically significant overall excess of stomach, pancreatic, or total GI tract cancers. The author noted a minor trend of increasing annual excess in stomach and GI registrations. However, it was hypothesized that this slight excess was likely an artifact resulting from the misdiagnosis of peritoneal mesotheliomas (a known asbestos-related cancer) as primary GI tract cancers, which would have obscured the true cancer site. The study ultimately found insufficient evidence to establish a significant GI cancer excess.

10. Weiss (1977): Mortality of a Cohort Exposed to Chrysotile Asbestos This cohort mortality study followed 264 male production workers at an asbestos manufacturing plant using only chrysotile asbestos.7 The study focused on the long-term mortality experience, but notably failed to find a significant excess for gastrointestinal cancer (pooled ICD 150-159) with an SMR of 105 (compared to US white males). The author concluded that the mortality rate for GI cancer was not increased in this cohort. This result contributed to the ongoing debate regarding the carcinogenicity of chrysotile exposure specific to the GI tract.

11. Di Ciaula et al. (2017): Asbestos Ingestion and Gastrointestinal Cancer: A Possible Underestimated Hazard This expert review focused on the controversial risk of GI cancer from asbestos ingestion, primarily through contaminated drinking water.12 The author noted that while the evidence is often classified as “limited” by agencies like IARC, experimental and epidemiological data point to a non-negligible risk, especially for gastric and colorectal cancers. The review suggests the hazard is underestimated because many studies fail to quantify individual exposure and overlook factors like chronic ingestion from asbestos-cement pipes and biological plausibility (fiber penetration, co-carcinogenic action). The author highlights that the mechanical and chemical action of ingested fibers in the GI tract supports the biological plausibility of the link and concludes that the evidence is strong enough to warrant stricter monitoring and revised regulations to protect public health.

12. Kim et al. (2013): Asbestos-Induced Gastrointestinal Cancer: An Update This review affirmed that while asbestos is a known pulmonary carcinogen, the link to GI cancers is “not as clearly defined.”11 The authors concluded that GI effects are “much less robust” and the resulting cancer risk is “small” compared to the risk of lung cancer and mesothelioma. The review states that the association is “best validated” for stomach cancer following occupational exposure, although even this finding is discordant across the literature. Ultimately, the authors conclude that accumulating evidence suggests all forms of asbestos exposure appear to “minimally increase” the risk of stomach and possibly other GI cancers (larynx, esophagus, intestines, and colorectal regions).

AMA-Style Footnotes

1. Koehoorn M, McLeod CB, Fan J, et al. Occupational asbestos exposure and gastrointestinal cancers: systematic review and meta-analyses. Occup Environ Med. 2024;81:639-646.

2. Frumkin H, Berlin J. Asbestos exposure and gastrointestinal malignancy: review and meta-analysis. Am J Ind Med. 1988;14:79-95.

3. Finkelstein MM. Mortality among employees of an Ontario asbestos-cement factory. Am Rev Respir Dis. 1984;129:754-761.

4. Selikoff IJ, Churg J, Hammond EC. Asbestos exposure and neoplasia. CA Cancer J Clin. 1974;34:48-56.

5. Wang X, Courtice MN, Lin S. Mortality in chrysotile asbestos workers in China. Curr Opin Pulm Med. 2013;19:169-173.

6. Newhouse ML, Berry G, Wagner JC. Mortality of factory workers in east London 1933-80. Br J Ind Med. 1985;42:4-11.

7. Weiss W. Mortality of a cohort exposed to chrysotile asbestos. J Occup Med. 1977;19:737-740.

8. Kang S-K, Burnett CA, Freund E, et al. Gastrointestinal cancer mortality of workers in occupations with high asbestos exposures. Am J Ind Med. 1997;31:713-718.

9. Santibáñez M, Vioque J, Alguacil J, et al. Occupational exposures and risk of oesophageal cancer by histological type: a case-control study in eastern Spain. Occup Environ Med. 2008;65:774-781.

10. Lumley KPS. A proportional study of cancer registrations of dockyard workers. Br J Ind Med. 1976;33:108-114.

11. Kim SJ, Williams D, Cheresh P, Kamp DW. Asbestos-induced gastrointestinal cancer: an update. J Gastrointest Dig Syst. 2013;3(3).

12. Di Ciaula A. Asbestos ingestion and gastrointestinal cancer: a possible underestimated hazard. Expert Rev Gastroenterol Hepatol. 2017;11:419-425.

Creosote / PAHs

• There is no real positive correlation between the two, there’s a lack of research studies that support the link.

Colon

Colon and Asbestos

Berry et al. 2000

The document, titled “Mortality from all cancers of asbestos factory workers in east London 1933-80,” details a mortality study of a cohort of over 5,000 male and female asbestos workers¹. The study found a large excess of cancer deaths, with 537 observed deaths compared to 222 expected. The primary causes of this excess were lung cancer and mesotheliomas of the pleura and peritoneum. The study also found a significant excess of colon cancer, with 27 observed deaths against 15 expected, and a relative risk (RR) of 1.8 (95% CI: 1.2 to 2.7). An analysis by exposure group showed a significant exposure-response trend for colon cancer (p=0.017). This excess, however, was observed only in men with severe exposure for more than two years or those who worked as laggers. The authors suggest that the possibility of some of these deaths being misclassified peritoneal mesotheliomas cannot be ruled out, as three peritoneal mesotheliomas in the study were initially certified as cancer of the rectum, an adjacent site. Consequently, they conclude that an excess of colon cancer attributable to asbestos cannot be accepted without supporting evidence from other studies.²⁰

Note: Only accepted with support of other studies

Seidman et al. 1986

The study “Mortality Experience of Amosite Asbestos Factory Workers” is a cohort study of 820 men who worked in a Paterson, New Jersey, amosite asbestos factory. The study found a statistically significant standardized mortality ratio (SMR) of 1.85 for colon-rectum cancer, based on 22 observed deaths compared to 11.90 expected deaths. This finding was significant at the p<.05 level. The authors explicitly include cancers of the colon-rectum in their definition of “all asbestos diseases” and found that the adverse mortality effects were observable more quickly and with greater magnitude in workers with longer exposure times. The study concludes that there is a dose-response relationship between asbestos exposure and mortality, including for colon-rectum cancer.²¹

Selikoff et al. 1979

The study, “Mortality Experience of Insulation Workers in the United States and Canada, 1943-1976” is a mortality analysis of a cohort of 17,800 asbestos insulation workers in the United States and Canada, suggesting a significant link between asbestos exposure and colon-rectum cancer. The cohort was followed from 1967 to 1976. For the entire cohort, the ratio of observed to expected deaths (SMR) for colon-rectum cancer was 1.55, based on 59 observed deaths compared to 38.1 expected deaths. This finding was statistically significant. In a smaller, earlier cohort of 632 men from the New York-New Jersey area, a significant increase in gastrointestinal cancer deaths was also found, with 29 observed deaths versus 9.7 expected, 20 or more years after the onset of work. The study notes that an increase in deaths from colon and rectum cancer, along with other sites, is associated with employment as an asbestos insulation worker.²²

Ulvestad et al. 2004

The document “Cancer Incidence Among Members of the Norwegian Trade Union of Insulation Workers” is a cohort study of 1,116 male insulation workers followed from 1953 to 1999. The study found a significantly elevated risk of colorectal cancer (colon/rectum) in the total cohort, with a Standardized Incidence Ratio (SIR) of 1.5 (95% CI 1.1-2.2). The risk of colorectal cancer was found to be highest among workers employed for 20 years or more, with an SIR of 2.7 (95% CI 1.4-4.8). These workers had historically faced high asbestos exposure, mainly to chrysotile, with some crocidolite also used in insulation work. Although the link between asbestos and colorectal cancer has not been definitively established, the authors note that the association observed with longer duration of employment supports a possible causal relationship.²³

Colon and Silica

Oddonne et al. 2014

The Oddone et al. (2014) quantitative overview investigated the epidemiological relationship between colorectal cancer and various occupational exposures, including mineral dusts which may contain silica. The study synthesized literature up to June 2013 and found an overall slight but statistically significant increased Relative Risk (RR) for colorectal cancer across all industrial branches combined, ranging from 12% to 19%. However, the analysis focused on industrial sectors rather than specific silica exposure levels. A significant increased risk was specifically found for workers in the manufacture of basic metals (ISIC code 24), a sector often associated with mineral dusts, with an adjusted RR of 1.32 (95% CI: 1.07–1.65). The excess risk fraction attributable to occupational exposure as a whole was estimated to range from about 11% to 15% of crude excess risk. The risk of colon cancer alone showed a pooled RR of 1.13 (95% CI: 1.05-1.22) across all industrial branches combined. The authors noted that a significant risk for cancer in the other mining and quarrying (ISIC code 08) and agricultural (ISIC code 01) occupations was observed as a risk deficit (lower risk).²⁴

Eguchi 2017

The Eguchi et al. (2017) study examined colorectal cancer mortality by occupation and industry among working-aged men in Japan using 2010 national survey data. The study used manufacturing as the reference group to calculate age-adjusted Incident Rate Ratios (IRRs). While not focusing exclusively on silica, the industry categories of mining (a dusty environment) and construction and mining (occupational category) showed high risks for colorectal cancer mortality. Specifically, the Mining industry had the highest age-adjusted IRR of 8.19 (95% CI: 6.08–11.0) for colorectal cancer mortality. The occupational category of Construction and mining had an age-adjusted IRR of 1.35 (95% CI: 0.87–2.08) for colorectal cancer, compared to manufacturing workers. The authors mentioned that the International Agency for Research on Cancer (IARC) has reported an association between exposure to silica, some silicates, coal dust and lung, stomach, and colorectal cancer.²⁵

Colon and Diesel Exhaust

Kachui 2016

The Kachuri et al. (2016) case-control study investigated occupational exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer (CRC) in Canadian men. The study analyzed lifetime occupational histories from 931 colon cancer cases, 840 rectal cancer cases, and 1,360 controls. For colon cancer specifically, no statistically significant association was found for any diesel exposure metric. The highest attained concentration of diesel emissions showed an increased but non-significant odds ratio for colon cancer of OR = 1.35 (95% CI: 0.72–2.54) compared to the unexposed. The level of exposure for this finding was classified as high concentration (compared to unexposed or low/medium categories). However, the study found a significant association between exposure to high concentrations of diesel emissions and rectal cancer (OR = 1.98, 95% CI: 1.09–3.60). The authors noted that exposure to other occupational agents, including crystalline silica (OR = 1.09, 95% CI: 0.93–1.28), was also evaluated for CRC risk.²⁶

Talibov 2018

The Talibov et al. (2018) nested case-control study assessed the effect of workplace diesel exhaust and gasoline exposure on colorectal cancer (CRC) risk across four Nordic countries (Finland, Iceland, Norway, and Sweden). The enormous study population included 181,709 colon cancer cases and 109,227 rectal cancer cases diagnosed between 1961 and 2005. Overall diesel exhaust exposure showed no increased risk for all colon cancer combined, with an odds ratio of OR = 0.99 (95% CI: 0.97–1.02) compared to never-exposed. When stratified by cumulative exposure, the high-exposure diesel category showed an odds ratio for all colon cancer of OR = 1.02 (95% CI: 0.97–1.09). The high-exposure level was defined as cumulative exposure greater than 2.3 mg/m^3. The study did, however, find a small, statistically significant increase in the risk of rectal cancer for overall diesel exposure OR = 1.05, 95% CI: 1.02–1.08).²⁷

Goldberg et al. 2001

The Goldberg et al. (2001) case-control study in Montreal, Canada, explored associations between hundreds of occupational circumstances and colon cancer in men, using 497 colon cancer cases. The study found evidence of increased risk for several occupational agents, including diesel engine emissions. For “substantial” exposure to diesel engine emissions, the adjusted odds ratio (OR) was 1.5 (95% CI: 1.0–2.3) compared to nonsubstantial exposure. The authors defined substantial exposure as exposure lasting more than five years at medium or high frequency and concentration levels. The model adjusting for both nonoccupational and occupational co-exposures showed an OR of 1.6 (95% CI: 1.0–2.5). Although general machinists, truck drivers, and bus drivers are major occupations exposed to diesel exhaust, the authors note the results are exploratory and suggest a need for further toxicological study.²⁸

Siemiatycki et al. 1988

The Siemiatycki et al. (1988) case-referent study investigated associations between various cancers and 10 types of exhaust and combustion products, including diesel exhaust. An increased colon cancer risk was noted as a promising lead for further investigation related to both gasoline and diesel exhaust. For “long-high” diesel exhaust exposure, the fully adjusted odds ratio (OR) for colon cancer was 1.7(90% CI: 1.2–2.5) compared to “short-low” exposure. The corresponding odds ratio for the combination of all exposed levels versus no exposure was 1.3 (90% CI: 1.0–1.7). Exposure was classified into four categories (“short-low,” “short-high,” “long-low,” and “long-high”) based on duration and level of exposure. The risk of colorectal cancers has also been alternatively hypothesized to be linked to the sedentary nature of the highly exposed occupation groups, such as truck drivers, rather than diesel exhaust carcinogens alone.²⁹

Colon and Benzene

Sassano et al. 2014

The Sassano et al. (2024) systematic review and meta-analysis investigated the association between occupational benzene exposure and colorectal cancer, summarizing 28 studies (cohort and nested case-control). The overall pooled Relative Risk (RR) comparing exposed workers to unexposed for CRC incidence and mortality combined was RR: 1.10 (95% CI: 1.06, 1.14), suggesting a positive association. For colon cancer specifically, the pooled RR for incidence and mortality combined was slightly higher at RR: 1.13 (95% CI: 1.07, 1.19). It’s the highest RR for any of the main subsites or combined colorectal categories. The risk was primarily for incidence (RR: 1.10, 95% CI: 1.06, 1.15) rather than mortality (RR: 1.04, 95% CI: 0.97, 1.11). The authors included studies where benzene exposure occurred in various industrial sectors such as petroleum, shoe manufacturing, and rubber manufacturing. One nested case-control study provided evidence of a dose-response relationship, with an OR of 1.12 (95% CI: 1.05, 1.18) for CRC in the high cumulative exposure category (> 10.5 ppm-years).³⁰

Talibov et al. 2018

The Talibov et al. (2018) nested case-control study investigated the association between occupational benzene exposure and colorectal cancer in over 290,000 cases from four Nordic countries. Overall, the risk of all colon cancer for “ever exposed” versus “never exposed” was slightly, but not significantly, elevated, with an odds ratio of OR = 1.02 (95% CI: 1.00–1.05). However, for the high cumulative benzene exposure category, the odds ratio for all colon cancer was OR = 1.15 (95% CI: 1.07–1.23). The high exposure level was defined as >10.5 parts per million (ppm)-years. The study revealed a significant dose-response relationship for all colon cancer (p-trend} < 0.01) and suggested the risk was restricted to the ascending (OR = 1.27, 95% CI: 1.13–1.43) and transversal colon (OR = 1.21, 95% CI: 1.01–1.41). Benzene exposure occurs in industries like rubber, paint, printing, and crude oil refining.³¹

Babigumira et al. 2025

The Babigumira et al. (2025) case-cohort study investigated the association between low-level benzene exposure and colorectal cancer risk in male Norwegian offshore petroleum workers. For all colorectal cancer (CRC) combined, the adjusted Hazard Ratio (HR) for the most exposed quartile based on exposure duration was HR = 1.52 (95% CI: 1.11 to 2.07), showing a significant dose-response relationship (p-trend = 0.032). The highest exposure duration quartile was 17 to 34 years. For the anatomical subsite of right-sided colon cancer, the association was even stronger for duration (HR = 2.25, 95% CI: 1.33 to 3.80). The low exposure levels were defined as average intensity <0.05 ppm and cumulative < 0.879 ppm-years. This is the first cohort study to support an association between occupational benzene exposure and CRC risk.³²

Colon and Chlorinated Solvents

Wartenberg el al. 2000

The Wartenberg et al. (2000) review of over 80 published papers on the epidemiology of trichloroethylene (TCE) exposure and cancer examined multiple sites, including the colon and rectum. For colon cancer, the overall evidence from Tier I cohort studies (highest specificity exposure) was generally found to be in the “neutral” category (RR between 0.8 and 1.2). However, the Tier I incidence data averaged an RR = 1.2 (95% CI: 0.8–1.8) for colon cancer, which was moderately suggestive. Some data were noted to suggest associations between TCE exposure and colon cancer. For rectal cancer, the Tier I cohort incidence average RR was elevated at 1.7 (95% CI: 1.0–3.0). The authors ultimately concluded that there was inadequate/insufficient evidence to determine an association exists between chronic exposure to TCE or PCE and colon or rectal cancer, while noting some supporting data warrants further study.³³

Paulu et al. 2000

The Paulu et al. (1999) case-control study evaluated the relationship between exposure to tetrachloroethylene (PCE) from public drinking water and several cancers, including colon-rectum cancer, in a Massachusetts population. The study estimated a Relative Delivered Dose (RDD) of PCE based on residential location and pipe characteristics. Adjusted odds ratios (OR) for colon-rectum cancer among “ever-exposed” subjects were modestly elevated as more years of latency were assumed (OR = 1.7 and OR = 2.0$ for 11 and 13 years of latency, respectively). However, these elevated ORs stemmed mainly from associations with rectal cancer, while the corresponding adjusted estimates for colon cancer alone were lower (OR = 1.3 and OR = 1.5 for 11 and 13 years of latency, respectively). For the highest exposure level (above the 90th percentile), adjusted ORs for colon-rectum cancer were not elevated when no latency was assumed but were modestly elevated when 5 and 7 years of latency were assumed. The authors considered the evidence as providing evidence for an association between PCE-contaminated public drinking water and cancer of the lung and, possibly, colon-rectum cancer.³⁴

Colon and Creosote

Wong and Harris 2005

The Wong and Harris (2005) retrospective cohort mortality study and nested case-control study assessed cancer mortality among 2,179 workers exposed to creosote-based preservatives at 11 wood-treating plants in the U.S. The cohort study’s Standardized Mortality Ratio (SMR) for large intestinal cancer (colon cancer) was 108.1 (7 observed deaths vs. 6.48 expected; 95% CI: 43.4–222.7), which was not statistically significant. Analysis of hourly workers, who had higher exposure potential, by length of employment showed no significant mortality excess or upward trend for large intestinal cancer or any other site-specific cancer (except multiple myeloma). The typical exposure level for treating operators was around 0.05 or 0.06 mg/m^3 of coal tar pitch volatiles (CTPV-BSF). The authors concluded there was no evidence that employment or exposure to creosote-based wood preservatives was associated with a significant mortality increase from site-specific cancers.³⁵

Karlehagen et al. 1992

The Karlehagen et al. (1992) cohort study investigated cancer incidence among 922 creosote-exposed impregnators in Sweden and Norway with employment restricted to 1950 – 1975. The overall total cancer incidence was slightly lower than expected (SIR = 0.94). For gastrocolorectal cancer (which includes colon cancer), the Standardized Incidence Ratio (SIR) was 0.93 (29 observed cases; 95% CI: 0.62–1.33), indicating no increased risk. The study lacked individual exposure data, but noted the average concentrations of volatile compounds (like naphthalene) per workshift were generally below accepted limits during the modern period. However, concentrations were probably higher in earlier decades. Due to the small number of cases, valid conclusions about risks for most cancer sites, including gastrocolorectal cancer, couldn’t be drawn.³⁶

Colon and Secondhand Smoke

Yang et al. 2016

The Yang et al. (2016) meta-analysis investigated the association between passive smoking (SHS) and colorectal cancer (CRC) risk, including 11 articles with 12 studies. The pooled Relative Risk (RR) of all studies suggested a statistically significant association between SHS and CRC, with an RR = 1.14 (95% CI: 1.05–1.24). The exposure was classified as any passive smoking exposure (at home or work, in childhood or adulthood). Subgroup analysis showed a significant association with rectal cancer (RR = 1.33; 95% CI: 1.15–1.53) but not colon cancer (RR = 1.22; 95% CI: 0.97–1.54). Furthermore, male passive smokers were found to be at greater risk (RR = 1.73; 95% CI: 1.37–2.19) than females (RR = 0.98; 95% CI: 0.84–1.14). The overall findings suggested that passive smoking is associated with an increased risk of CRC.³⁷

Gastric Cancer (Stomach)

Preliminary research

Asbestos X Stomach Cancer (Correlated)

This meta-analysis quantitatively evaluated the association between occupational asbestos exposure and stomach cancer, supporting the International Agency for Research on Cancer’s conclusion of a moderate increased risk. The overall meta-Standardized Mortality Ratio (meta-SMR) for stomach cancer across 40 mortality cohort studies was 1.15 (95% confidence interval 1.03-1.27), indicating a 15% increased risk. Statistically significant excesses were observed in North America and Australia, and specifically for generic asbestos workers and insulators, with meta-SMRs of 1.41 and 1.27, respectively. Furthermore, cohorts reporting a lung cancer SMR above 2, which served as a proxy for high asbestos exposure, showed a higher meta-SMR of 1.46 (95% CI 1.22-1.77) for stomach cancer. The study found no evidence of publication bias for men and women separately but did note some for the total cohort.

Citation: Fortunato L, Rushton L. Stomach cancer and occupational exposure to asbestos: a meta-analysis of occupational cohort studies. Br J Cancer. 2015;112(11):1805-1815. doi:10.1038/bjc.2014.599.³⁸

Silica X Stomach Cancer (Correlated)

This systematic review and meta-analysis investigated the association between occupational exposure to crystalline silica and gastric cancer, a relationship previously considered uncertain despite silica being a known respiratory carcinogen. Analyzing 29 articles (9 case-control and 20 cohort studies), the study found a significant overall pooled effect size of 1.25 (95% CI 1.18 to 1.34) for the association of occupational silica exposure with gastric cancer, indicating a 25% increased risk. Subgroup analyses, including histological confirmation status and study design (OR/RR: 1.31 (1.19 to 1.45); SMR/SIR: 1.52 (1.12 to 1.32)), consistently showed a heightened risk. Higher effects were particularly observed in the mining (1.36; 95% CI 1.23 to 1.50) and foundry (1.31; 95% CI 1.21 to 1.43) industries, suggesting industrial variations in risk. The findings support a significant epidemiological link between occupational crystalline silica exposure and gastric cancer, potentially explained by the clearance of inhaled dust to the gastrointestinal tract and subsequent local injury and inflammation.

Citation: Lee W, Ahn Y-S, Lee S, et al. Occupational exposure to crystalline silica and gastric cancer: a systematic review and meta-analysis. Occup Environ Med. 2016;73(11):794-801. doi:10.1136/oemed-2016-103552.³⁹

Diesel Exhaust X Stomach Cancer (Correlated)

This meta-analysis investigated the association between occupational diesel exhaust exposure and various gastrointestinal cancers, specifically focusing on gastric (stomach) cancer. The study found a summary relative risk (RR) of 1.06 (95% CI 0.99-1.14) for gastric cancer among workers with ever-exposure to diesel exhaust, suggesting an increased but not statistically significant overall risk. However, stratified analyses revealed a significant association with gastric cancer in European studies (RR=1.10, 95% CI 1.02-1.19), but not in North American studies. Furthermore, specific occupational groups, such as machine operators (RR=1.15, 95% CI 1.10-1.20) and drivers (RR=1.20, 95% CI 0.91-1.59), showed a higher risk for gastric cancer. The authors note that while an increased risk is suggested, residual confounding from factors like Helicobacter pylori infection and lifestyle habits cannot be excluded. Citation: Collatuzzo G, Teglia F, Boffetta P. Gastrointestinal cancer and occupational diesel exhaust exposure: a meta-analysis of cohort studies. Occup Med (Lond). 2024;74(6):438-448. doi:10.1093/occmed/kqae058.⁴⁰

Benzene X Stomach Cancer (Correlated)

This study investigated the association between occupational benzene exposure and various cancer risks, including stomach cancer, in a cohort of over 61,000 Chinese men. The findings revealed that benzene exposure exceeding 550 mg/m³*years was associated with a 40% increased risk of stomach cancer (aHR = 1.4, 95% CI = 1.0-1.9). This association with stomach cancer displayed a linear dose-response pattern (p_linear = 0.023) across all exposure levels. Furthermore, men with benzene exposure were diagnosed with stomach cancer at a median age three years younger than unexposed men. A 5-year lag analysis also showed an increased risk of stomach cancer (aHR = 1.5, 95% CI = 1.1-2.0) among exposed individuals. The study highlights that benzene exposure is linked to an elevated risk of stomach cancer and earlier diagnosis, emphasizing the need for protective measures for benzene-exposed workers.

Citation: DeMoulin D, Cai H, Vermeulen R, Zheng W, Lipworth L, Shu X-O. Occupational benzene exposure and cancer risk among Chinese men: A report from the Shanghai Men’s Health Study. Cancer Epidemiol Biomarkers Prev. 2024;33(11):1465-1474. doi:10.1158/1055-9965.EPI-24-0325.⁴¹

TCE/PCE X Stomach Cancer (weak correlation)

In a study assessing health risks from tetrachloroethylene (PCE) exposure via contaminated drinking water during gestation or early childhood, Aschengrau et al. (2015) found a 1.8-fold increase in the incidence of cancer, with a particular focus on cervical cancer. This means individuals exposed early in life had an 80% higher chance of developing cancer. Additionally, the study revealed a 1.5-fold increase in the incidence of epilepsy in the same exposed population. While the article discusses general gastrointestinal toxicity from high levels of TCE, it does not provide specific odds ratios, hazard ratios, standard mortality rates, or relative risks for stomach/gastric cancer due to TCE or PCE exposure. The review primarily focuses on the broad toxic effects and analytical methods for these polychlorinated hydrocarbons.

Citation: Akinboye AJ, Lee H, Lee JG. Trichloroethylene and tetrachloroethylene contamination: A review of toxicity, analytical methods, occurrence in foods, and risk assessment. Food Sci Preserv. 2024;31(3):360-373. doi:10.11002/fsp.2024.31.3.360.⁴²

PAHs / Creosote X Stomach Cancer (Correlated)

This nested case-control study investigated the association between polycyclic aromatic hydrocarbons (PAHs), specifically measured by urinary 1-hydroxypyrene glucuronide (1-OHPG) concentrations, and the risk of gastric cancer in the Shanghai Women’s Health Study. While 1-OHPG concentrations were slightly higher in gastric cancer cases (median 0.29 µmol/mol Cr) compared to controls (median 0.24 µmol/mol Cr), the overall association with gastric cancer risk was not clearly defined. The study found that individuals in the third quartile of 1-OHPG concentration had an adjusted odds ratio (OR) of 1.93 (95% CI: 1.07-3.49) compared to the lowest quartile, suggesting an elevated risk. However, this trend did not continue into the highest quartile, which showed an OR of 1.40 (95% CI: 0.77-2.54), leading to the conclusion that no clear dose-response relationship was observed. The authors acknowledge that the study was limited by a relatively small sample size and the use of single spot urine samples, suggesting further research in larger cohorts is needed to confirm these preliminary findings.

Citation: Liao LM, Hofmann JN, Kamangar F, et al. Polycyclic aromatic hydrocarbons and risk of gastric cancer in the Shanghai Women’s Health Study. Int J Mol Epidemiol Genet. 2014;5(3):140-144.⁴³

Welding Fumes X Stomach Cancer (Correlated)

This systematic review and meta-analysis investigated the association between occupational exposure to welding fumes (WF) and various cancers, including stomach cancer. The study found a significant association between WF exposure and stomach cancer, reporting a summary relative risk (RR) of 1.10 (95% CI 1.02-1.19) based on five risk estimates. This indicates a 10% increased risk of stomach cancer among those occupationally exposed to welding fumes. The authors hypothesized that WF compounds, after inhalation, could redistribute from the upper respiratory tract to the upper gastrointestinal tract, potentially affecting the stomach’s reductive capacity and increasing cancer risk. While the observed association with stomach cancer was primarily driven by two large cohort studies (Pukkala et al., 2009 and MacLeod et al., 2017), the authors emphasize the need for future studies to account for confounders like smoking, alcohol consumption, and Helicobacter pylori infection, and to quantitatively assess WF exposure.

Citation: Siea AC, Collatuzzo G, Hamdani M, Boffetta P. Welding Fumes Exposure and the Risk of Head and Neck and Gastrointestinal Cancer: A Systematic Review and Meta-Analysis. Med Lav. 2025;116(2):16092. doi:10.23749/mdl.v116i2.16092.⁴⁴

Magnesium X Stomach Cancer (most studies found magnesium to be beneficial)

This case-control study in Taiwan investigated the association between drinking water levels of calcium, magnesium, and nitrate and gastric cancer mortality. The study found that while magnesium generally exerts a protective effect against gastric cancer, this was only statistically significant for the group with the highest levels of intake. Specifically, after adjusting for confounders, the odds ratio (OR) for gastric cancer death was 0.86 (95% CI 0.76-0.98) for individuals in the highest tertile of magnesium concentration (≥11.8 mg/liter) compared to the lowest tertile (≤7.0 mg/liter). This suggests a 14% reduced risk of gastric cancer mortality in the group with the highest magnesium intake from drinking water. The authors propose that the higher bioavailability of magnesium from water, where it exists as hydrated ions, may contribute to its beneficial effects, especially for individuals at risk of magnesium deficiency.

Citation: Yang C-Y, Cheng M-F, Tsai S-S, Hsieh Y-L. Calcium, Magnesium, and Nitrate in Drinking Water and Gastric Cancer Mortality. Jpn J Cancer Res. 1998;89(2):124-130.⁴⁵

Roundup/Herbicides X Stomach Cancer (Correlated)

This meta-analysis investigated the association between the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and various cancers, including gastric cancer. For gastric cancer, the meta-analysis of three studies found that 2,4-D was not statistically associated with an increased risk, with a summary relative risk (RR) of 1.14 (95% confidence interval [CI] = 0.62-2.10). This indicates that the observed 14% increase in risk was not statistically significant and the true effect could range from a 38% decrease to a 110% increase. One study, Mills and Yang (2007), reported an elevated odds ratio (OR) of 2.16 (95% CI: 1.02-4.56) for the second-lowest category of 2,4-D use (1-14 lbs annually) compared to no exposure, suggesting a doubling of risk in that specific exposure group. However, a clear dose-response relationship was not established, as higher exposure categories did not show a consistent increase in risk. The authors concluded that the epidemiological evidence does not support an overall association between 2,4-D exposure and gastric cancer risk, despite some individual study findings.

Citation: Goodman JE, Loftus CT, Zu K. 2,4-Dichlorophenoxyacetic acid and non-Hodgkin’s lymphoma, gastric cancer, and prostate cancer: meta-analyses of the published literature. Ann Epidemiol. 2015;25(8):626-636. doi:10.1016/j.annepidem.2015.04.002.⁴⁶

Secondhand Smoke X Stomach Cancer (Correlated)

This study investigated the association between secondhand smoke (SHS) exposure and the mortality risk of various cancers, including stomach cancer, in a cohort of over 25,000 US adults. Using serum cotinine levels as an indicator of smoke exposure, the researchers divided participants into low and high exposure groups. The study found that individuals in the high exposure group (serum cotinine level ≥ 10) had a statistically significant increased risk of stomach cancer, with a Hazard Ratio (HR) of 1.491 (95% CI, 1.199–1.854). This indicates that high SHS exposure is associated with an approximately 49% higher risk of stomach cancer mortality. In contrast, the low exposure group (serum cotinine level between 0.015 and 10) did not show a statistically significant association with stomach cancer. The findings highlight the significant effect of high SHS exposure on stomach cancer risk, emphasizing the need for public health policies to reduce environmental SHS.

Citation: Zhang Z, Li Z, Zhang X, et al. Association between secondhand smoke and cancers in adults in the US population. J Cancer Res Clin Oncol. 2023;149(7):3447-3455. doi:10.1007/s00432-022-04266-w.⁴⁷

Rectal

Oddone et al., 2014: Occupational exposures and colorectal cancers: A quantitative overview of epidemiological evidence

This meta-analysis investigated the epidemiologic relationship between colorectal cancer (CRC) and occupational exposures across various industrial sectors. The review included 83 papers published between 1976 and 2012, with a majority being cohort studies. The overall pooled relative risk (RR) for CRC showed a slight but statistically significant increase (RR = 1.18, 95% CI: 1.09-1.29). When stratified by industrial branch, increased risks were found for workers in leather manufacturing (RR = 1.70, 95% CI: 1.24-2.34), basic metals (RR = 1.32, 95% CI: 1.07-1.65), and repair and installation of machinery (RR = 1.40, 95% CI: 1.07-1.84). This last finding was largely driven by studies of Italian shipyard workers exposed to asbestos. The study also found significant risk deficits (i.e., decreased risk) in agricultural and mining occupations, which the authors suggested could be due to higher physical activity and lower smoking rates in these groups. However, the review also notes that some studies on farmers who were exposed to specific pesticides found an increased risk of CRC. The authors conclude that occupational exposures, in a broad sense, appear to be a risk factor for colorectal, colon, and rectal cancers, and that while a causal relationship cannot be definitively established, the consistent results from cohort studies firmly stress a role for workplace exposures in increasing the risk of these cancers.⁴⁸

Rectal Cancer x Asbestos (Correlated)

Aliyu et al. (2005)

The study found an elevated risk of colorectal cancer among men with a history of occupational asbestos exposure, particularly those with radiographic evidence of nonmalignant asbestos-related disease. The cohort of men was part of the Beta-Carotene and Retinol Efficacy Trial (CARET), a chemoprevention study designed to assess the effect of daily doses of vitamin A and beta-carotene on lung cancer incidence and mortality. A dose-response relationship was observed, with the risk of colorectal cancer increasing as the severity of radiographic changes (such as pleural plaques and pulmonary asbestosis) worsened. For instance, participants with pleural plaques had a 54% increased risk. This was considered the strongest evidence for an association. When using years worked in a high-risk trade as a measure of exposure, the study found a progressively increasing risk of colorectal cancer up to 30 years of exposure.⁴⁹

Kwak et al. (2019)

This systematic review and meta-analysis concluded that occupational exposure to asbestos is a risk factor for colorectal cancer mortality. Meta-analysis of research studying the relationship between colorectal cancer and asbestos exposure as performed in Kwak et al. determined a standardized mortality rate of 1.16 (95% CI: 1.05 to 1.29) for individuals occupationally exposed to asbestos. It found an increased SMR for individuals employed in the insulation industry of 1.49. The study found a dose-response relationship, noting that the risk of colorectal cancer mortality increases as the level of asbestos exposure rises.⁵⁰

Huang and Lan (2019)

The meta-analysis, which included 47 cohort studies, found a positive weak association between occupational asbestos exposure and the risk of colorectal cancer. The study’s overall SMR for colorectal cancer was 1.07 (95% CI 1.02–1.12). The SMR varied depending on the type of asbestos; “exposure to mixed asbestos (SMR/SIR=1.07), exposure to production (SMR/SIR=1.11), among asbestos cement workers (SMR/SIR=1.18) and asbestos textile workers (SMR/ SIR=1.11).” The study determined that as the SMR for lung cancer increased (used as a proxy for higher asbestos exposure), the risk for colorectal cancer also increased. The results suggested that exposure to amphibole asbestos may be associated with colorectal cancer, while serpentine asbestos was not. ⁵¹

Koehoorn et al. (2025)

This systematic review and meta-analysis supports a causal link between occupational asbestos exposure and the risk of gastrointestinal cancers, including colorectal cancer. The study found an elevated meta-relative risk (mRR) for any occupational asbestos exposure, with an mRR of 1.16 for colorectal cancer (95% CI 1.08 to 1.24). Higher mRRs were consistently found in analyses with increased confidence in the categorization of highly exposed workers. For workers that were highly exposed there was an mRR of 1.29 (95% CI 1.09 to 1.53). Among individuals working in asbestos insulation the risk was as high as 1.59 (95% 1.14 to 2.23). ⁵²

Rectal Cancer x Silica (Not correlated)

Finkelstein (1995)

The article is a review of publications on mortality among hard rock miners, granite, and quarry workers (occupations typically exposed to silica dust) and focuses on the counterintuitive finding of a reduced risk for colorectal cancer in these cohorts. The study did not investigate silica exposure directly but examined cohorts exposed to occupational dusts (primarily in mining and quarrying) and found an overall deficit of colorectal cancer mortality. Rectal cancer is a subsite of colorectal cancer. There was a significant deficit of colorectal cancer mortality. Standardized Mortality Ratio (SMR): 83.9. When colorectal cancer was broken down into its subsites, there was a deficit of colonic cancer (SMR = 85; 95% CI 72-98) and an excess of rectal cancer (SMR = 113; 95% CI 92-134). However, this SMR for rectal cancer was not statistically significant as its confidence interval includes 100.⁵³

Rectal Cancer x Secondhand Smoke (Correlated)

Gram et al., 2020 Smoking-Related Risks of Colorectal Cancer by Anatomical Subsite and Sex

This study examined how the increased risk of colorectal cancer (CRC) due to cigarette smoking differed by anatomical subsite and sex using data from the Multiethnic Cohort Study, which included 188,052 participants. The authors noted that previous studies had often treated CRC as a single disease and did not account for potential sex differences. After a mean follow-up of 16.7 years, 4,879 cases of invasive colorectal adenocarcinoma were identified. The study found that male smokers had a 39% higher risk of cancer of the left (distal) colon compared to never smokers, with a hazard ratio (HR) of 1.39 (95% CI: 1.16-1.67). In contrast, female smokers had a 20% higher risk of cancer of the right (proximal) colon, with an HR of 1.20 (95% CI: 1.06-1.36). The study also found that smokers, both male and female, had higher risks of rectal cancer compared to never smokers. The risk was 40% higher for men (HR = 1.40) and 58% higher for women (HR = 1.58). Notably, a greater increase in the risk of rectal cancer was observed with a higher number of pack-years of smoking in women compared to men. The authors suggest that carcinogens in cigarette smoke, such as nitrosamines, heterocyclic amines, benzene, and polycyclic aromatic hydrocarbons, may reach the colorectal mucosa and have an oncogenic effect. The study’s main conclusion is that smoking-related CRC risk differs by sex and anatomical subsite, with men being at higher risk for left colon cancer and women for right colon cancer. The stronger association between smoking and rectal cancer in women suggests that they may be more susceptible to the carcinogenic effects of smoking than men.⁵⁴

Rectal Cancer x Benzene (Correlated)

Talibov et al., 2018: Benzene exposure at workplace and risk of colorectal cancer in four Nordic countries

This case-control study was conducted to evaluate the effect of occupational exposure to benzene on the risk of colorectal cancer (CRC) in four Nordic countries: Finland, Iceland, Norway, and Sweden. The study included 181,709 cases of colon cancer and 109,227 cases of rectal cancer diagnosed between 1961 and 2005. The results showed an increased risk for all CRC in the high decile of cumulative benzene exposure, with an odds ratio (OR) of 1.12 (95% CI: 1.05–1.18), indicating a statistically significant dose-response relationship. This increased risk was primarily observed in the ascending colon (OR = 1.27, 95% CI: 1.13–1.43) and transversal colon (OR = 1.21, 95% CI: 1.01–1.41). The study also found that the odds ratios in the highest exposure category were markedly higher for women than for men across all subsites of the colon and rectum. Rectal cancer risk was slightly elevated for high benzene exposure in women (OR = 1.57, 95% CI: 1.01–2.42), but only for medium exposure in men (OR = 1.05, 95% CI: 1.00–1.11). The authors conclude that their study showed an association between workplace benzene exposure and colorectal cancer, with the risk being restricted to the ascending and transversal colon, and being strongest among women.⁵⁵

Babigumira et al., 2025: Benzene exposure and risk of colorectal cancer by anatomical subsite in the Norwegian offshore petroleum workers cohort

This study investigated the association between low-level benzene exposure and the risk of colorectal cancer (CRC) in a cohort of male offshore petroleum workers in Norway. It used a job-exposure matrix to estimate exposure and adjusted for various lifestyle factors such as smoking, alcohol intake, diet, and physical activity. The findings revealed positive exposure-response associations between low-level benzene exposure and CRC risk. The hazard ratios (HRs) for the most exposed quartile versus the unexposed were 1.52 (95% CI: 1.11-2.07) for exposure duration and 1.56 (95% CI: 1.15-2.12) for average intensity. The association was strongest for right-sided colon cancer (HR = 2.25, 95% CI: 1.33-3.80) but weak for left-sided colon cancer. The risk of rectal cancer was also suggested to be increased, with HRs generally above 1.0. The authors emphasize that these findings remained robust even with exposure lags of up to 20 years. This is the first cohort study to support an association between occupational benzene exposure and CRC risk. The authors conclude that if a causal link is established, it would have important implications for occupational health, public health, and compensation schemes for occupational diseases.⁵⁶

Rectal Cancer x Diesel Exhaust (Correlated)

Talibov et al., 2019: Workplace Diesel Exhausts and Gasoline Exposure and Risk of Colorectal Cancer in Four Nordic Countries

This case-control study, conducted in four Nordic countries, investigated the association between workplace exposure to diesel exhaust, gasoline, and colorectal cancer (CRC). The study included a large number of cases, with 181,709 cases of colon cancer and 109,227 cases of rectal cancer diagnosed between 1961 and 2005. Exposure was estimated using a job-exposure matrix that assigned values for diesel exhaust and gasoline exposures based on job titles. The results indicated a small, but statistically significant, increase in the risk of rectal cancer associated with diesel exhaust exposure, with an odds ratio (OR) of 1.05 (95% CI: 1.02-1.08). This association remained elevated even after adjusting for lifestyle factors and in analyses with 10- and 20-year lag times. However, the study observed a statistically significant decrease in the risk of descending colon cancer (OR = 0.88, 95% CI: 0.80-0.97), which the authors suggest is likely a chance finding due to multiple testing. The study found no association between occupational gasoline exposure and colorectal cancer risk. The authors conclude that while their study showed a small increase in the risk of rectal cancer from workplace diesel exhaust, the possibility that this weak association is due to chance cannot be excluded given the study’s limitations.⁵⁷

Kachuri et al., 2016: Workplace exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer in Canadian men

This case-control study investigated the link between occupational exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer (CRC) in Canadian men. The study utilized data from a population-based study in seven Canadian provinces, including 931 colon cancer cases, 840 rectal cancer cases, and 1,360 controls. The exposure assessment was performed by a team of occupational hygienists who were blinded to the case-control status. The study found elevated risks for rectal cancer in men who had ever been exposed to high concentrations of diesel emissions (OR = 1.98, 95% CI: 1.09–3.60). A high risk was also observed for prolonged exposure (more than 10 years) at high concentrations of diesel emissions (OR = 2.33, 95% CI: 0.94–5.78; p-trend = 0.02). However, the study found no statistically significant associations for gasoline emissions for any cancer outcome. The authors concluded that their findings suggest a modest association between occupational exposure to high concentrations of diesel emissions and the risk of rectal cancer. While acknowledging the inconsistent results for other exposure metrics, the authors pointed to the importance of the concentration of exposure as a key factor influencing the association with cancer risk.⁵⁸

Rectal Cancer x Chlorinated Solvents (Not correlated)

Rectal Cancer x Welding Fumes (Not correlated)

Siea et al. (2025)

This study is a systematic review and meta-analysis of cohort studies focused on the risk of head and neck (HN) and gastrointestinal (GI) cancers associated with occupational exposure to welding fumes (WF). The meta-analysis found no significant association between occupational exposure to welding fumes and colorectal cancer (the category which includes rectal cancer) or most other GI cancers. The overall risk for colorectal cancer was close to the null value, indicating no elevated risk in exposed workers: Colorectal Cancer (Pooled Estimate from seven risk estimates): Relative Risk: 0.99. 95% Confidence Interval (CI: 0.85-1.15).⁵⁹

Rectal Cancer x PAHs (Not correlated)

Boffetta et al., 1997: Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons

This review examines epidemiological evidence on the relationship between polycyclic aromatic hydrocarbons (PAHs) and cancer risk from occupational and environmental exposures. It focuses on several industries where exposure to PAHs is high, including aluminum production, coal gasification, coke production, and iron and steel foundries. The review also addresses workers exposed to diesel engine exhaust, coal tars, and creosote. The paper concludes that heavy occupational exposure to mixtures of PAHs entails a substantial risk of lung, skin, and bladder cancer. The lung is identified as the major target organ for the carcinogenic effects of PAHs. The increased risk of bladder cancer is most consistently found in industries with high exposure to coal tar and pitch, such as aluminum production, coal gasification, and tar distillation. The review mentions that “excess of digestive cancers” have been “reported sporadically” in some studies on coke production workers. The authors state that the evidence regarding a link between PAHs and other organs, such as the larynx and kidney, is inconclusive due to potential reporting bias. The article concludes that while a carcinogenic risk attributable to PAHs has been shown, it is difficult to identify and quantify the risk from mixtures with relatively low PAH content, such as bitumen fumes and diesel engine exhaust.⁶⁰

Rectal Cancer x Herbicides (No correlation)

Matich et al., 2021: Association between pesticide exposure and colorectal cancer risk and incidence: A systematic review

The systematic review by Matich et al. found that a general conclusion on the link between pesticide exposure and colorectal cancer (CRC) risk cannot be drawn because the number of studies with significant positive associations was similar to those with inverse associations. However, the authors did identify specific pesticides of “high concern” that showed significant positive associations with CRC risk and are not banned in the United States. These include terbufos, dicamba, trifluralin, EPTC, imazethapyr, chlorpyrifos, carbaryl, pendimethalin, and acetochlor. Other pesticides, such as DDT, lindane, and alachlor, were of “moderate concern” because the studies produced conflicting results. The review highlights the need for more research, particularly studies that measure pesticide levels directly in biological samples like stool or colon tissue to improve accuracy.⁶¹

Esophageal

Esophageal and Silica Dust

Pan et al. 1999

This nested case-control study, which is significant for being one of the first to directly evaluate the link in an occupational setting while controlling for lifestyle confounders, confirmed an elevated risk of esophageal cancer (EC) among industrial workers exposed to silica dust. Utilizing a nested case-control design within a large cohort of Chinese iron-steel complex workers, the study identified silica dust as the most important risk factor among all variables investigated. After adjusting for factors like alcohol and coal smoke, occupational silica dust exposure resulted in an overall adjusted Odds Ratio (OR) of 2.780 (95% CI=1.362–5.675) for EC. Crucially, the study established a clear dose-response relationship, where the highest level of exposure—defined as 25 years or longer—showed a strong adjusted OR of 8.869 (95% CI=1.671–47.081). Other significant risk factors included domestic coal cooking (OR=2.012) and alcohol drinking (OR=1.767), but the silica exposure demonstrated the highest risk. The authors postulated that the mechanism involves the ingestion of silica particles cleared from the lungs, which may directly harm the esophageal mucosa.⁶²

Tsuda et al. 2001

This case-control study, which is significant for its attempt to reduce bias by using a cancer-only control series and adjusting for smoking habits, investigated the link between silica exposure and esophageal cancer (EC) mortality in male Japanese residents. Exposure level was assessed based on a history of silica exposure work (like brick or quarry work) or, representing the highest level of exposure, the presence of the disease silicosis itself. For workers with any silica exposure work, the age- and smoking-adjusted Odds Ratio (OR) for esophageal cancer mortality was 1.53 (95% CI 0.59–3.96). The risk was elevated for the highest exposure level subgroup, as the presence of silicosis resulted in an adjusted OR of 2.33 (95% CI 0.87–6.23). While the point estimates suggested that EC was related to silica exposure, the association was not statistically significant, primarily due to the small sample size of 22 EC cases. The study’s key significance lies in the fact that the OR for the highly-exposed silicotic patients was more than double the control group, confirming the trend reported in other silica studies.⁶³

Yu et al. 2004

This historical cohort study is significant for being the first among silicotic workers to show an increased risk of esophageal cancer mortality after adjusting for the major nonoccupational confounders of smoking and alcohol drinking. The study examined 2,789 male silicotic workers in Hong Kong and found the Standardized Mortality Ratio (SMR) for the entire cohort was 2.22 (95% CI 1.36-3.43), indicating a more than doubled mortality rate compared to the general population. The highest level of exposure was identified in the subgroup of underground caisson workers, whose very heavy exposure to free silica dust resulted in an unadjusted SMR of 4.21 (95% CI 1.81-8.30). Crucially, after indirect adjustment for the confounding effects of smoking and alcohol drinking, the SMR for these caisson workers remained significantly elevated at 2.34 (95% CI 1.01-4.62). The authors concluded that this persistent excess risk, which also showed a dose-response trend with exposure duration, strongly suggested that the very heavy exposure to free silica dust was responsible for the increased esophageal cancer mortality.⁶⁴

Fu et. al. 2024

The meta-analysis, “Occupational exposure to silica and risk of gastrointestinal cancers,” summarizes the statistically significant link between occupational silica exposure and specific gastrointestinal malignancies. The study, based on 40 cohort studies, found that occupational silica exposure raises the risk of incidence for stomach and esophageal cancers. Specifically, the pooled Standardized Incidence Ratio (SIR) for gastric (stomach) cancer was 1.35 (95% CI 1.21-1.51), and for esophageal cancer was 1.31 (95% CI 1.04-1.65). The analysis also showed a significant increased risk for liver cancer, with a pooled SIR of 1.19 (95% CI 1.04-1.35) and a pooled Standardized Mortality Ratio (SMR) of 1.24 (95% CI 1.03-1.49). There was no statistically significant link found between silica exposure and the incidence or mortality risk for colorectal or pancreatic cancers, as their confidence intervals crossed 1.0. The exposure involved workers with exclusive or predominant occupational exposure to silica in industries like mining, ceramics, glass manufacturing, and foundry work.⁶⁵

Esophageal and PAHs

Etemadai et al. 2023

This nested case-control study, conducted within the Golestan Cohort Study, investigated the association between the individual-level internal dose of carcinogens and the incidence of Esophageal Squamous Cell Carcinoma (ESCC). Exposure was determined by measuring the urinary concentrations of 33 biomarkers for Polycyclic Aromatic Hydrocarbons, Volatile Organic Compounds (VOCs), and Tobacco-Specific Nitrosamines, which is a significant methodological strength over relying on self-reported exposure. The risk was quantified using adjusted Odds Ratios (ORs) comparing the 90th versus the 10th percentiles of the biomarker concentrations, demonstrating a clear dose-response relationship for several compounds. Among individuals who did not currently use tobacco, adjusted ORs for metabolites of acrolein, acrylonitrile, propylene oxide, and 1,3-butadiene were significant and ranged between 1.8 and 4.3. The study’s most significant finding was among current tobacco users, where metabolites of styrene and xylene showed remarkably strong associations, with ORs of 9.0 and 6.2, respectively, highlighting a potential synergistic effect between lifestyle and environmental chemical exposures in ESCC pathogenesis.⁶⁶

Roshandel et al. 2012

This review is highly significant because it synthesized compelling evidence, particularly from studies in the high-risk ESCC belt of northeastern Iran, linking Polycyclic Aromatic Hydrocarbons (PAHs) to esophageal cancer. The study’s primary strength lies in highlighting data from a key case-control study that used a direct measure of internal dose exposure, quantifying PAH content in non-tumoral esophageal tissue itself, the target site for carcinogenesis. This analysis revealed a dramatic dose-response relationship between the intensity of PAH staining and ESCC case status. While the review itself does not generate a single Odds Ratio (OR), it references a powerful finding that high PAH exposure, specifically from smoking, was associated with a fourfold increase in the prevalence of P53 mutations in esophageal cancer patients compared to non-smokers. The level of exposure highlighted involves very high levels of PAHs from multiple sources, including contaminated diet, opium consumption, and tobacco smoke, suggesting that PAH-induced DNA damage is a primary mechanism for ESCC in this high-risk population.⁶⁷

HAPS Asbestos, and Esophageal

Gressier et. al. 2022

The PROG study by Gressier et al. (2022) was a monocentric descriptive pilot study that systematically surveyed the employment history of 36 esophageal cancer patients in Brittany, France, to identify occupational exposures, but no specific risk ratios like Odds Ratio, Hazard Ratio, or Relative Risk were calculated due to the study’s small size, descriptive design, and lack of a control group. Therefore, the study did not prove causality or statistical significance for any association. However, the findings are considered significant enough to support a larger-scale study on occupational risks. The most prominent level of exposure was to asbestos, with 11 patients (30.6%) reporting high exposure by manipulating materials without protective equipment, with a mean exposure duration of 12.6 years and a mean latency of 23.7 years. The second most common exposure was to hydrocarbons and their derivatives in 13 patients (36.1%), including regular contact with benzene. Other exposures, noted in 11.1% of patients, included chlorinated solvents, pesticides, sulfuric acid, and ionizing radiation, with the latter considered a significant (Category A) exposure for the four patients in the military nuclear field.⁶⁸

Esophageal and Second Hand Smoke

Rafiq et. al. 2016

The case-control-observational study, “Secondhand Smoking and the Risk of Esophageal Squamous Cell Carcinoma…” by Rafiq et al. (2016), investigated the association in a high incidence region in Kashmir, India. The study found an indication of increased risk of Esophageal Squamous Cell Carcinoma (ESCC) associated with exposure to secondhand smoking (SHS), though the associations were not definitively statistically significant in the primary models after adjusting for confounding factors like active tobacco use. The most important finding regarding risk was observed among exclusive secondhand smokers (never-tobacco users) with the highest level of exposure ( >14 hours per week of SHS). For this high-exposure group, the adjusted Odds Ratio (OR) for ESCC was 2.69 (95% CI, 0.75–20.65). While this OR value indicates a nearly three-fold increased risk, the wide 95% Confidence Interval (CI) of 0.75–20.65 includes unity (1.0), meaning the finding was not statistically significant at the conventional level, though the authors note a dose-response trend. The correlation was also higher in active tobacco chewers who had SHS exposure (OR 3.41; 95% CI, 1.07-10.83), a finding that was statistically significant because its CI did not cross 1.0. The high-risk level of exposure was defined as >14 hours/week of secondhand smoke from a spouse, parents, relatives in the home, or in workplaces and public settings.⁶⁹

Li et. al. 2020 (No correlation)

The prospective cohort study, “Environmental tobacco smoke and cancer risk, a prospective cohort study in a Chinese population” by Li et al. (2020), investigated the association between Environmental Tobacco Smoke (ETS), or secondhand smoke, and various cancer risks in a cohort of 23,415 participants in Shanghai, China. The study did not find a statistically significant association between ETS and esophageal cancer risk specifically, as esophageal cancer was analyzed only as part of the broader, grouped category of “smoking-related cancers”. The key finding was a statistically significant elevated risk for all smoking-related cancers combined (including esophageal, lung, stomach, etc.), with an adjusted Hazard Ratio (HR) of 1.23 (95% CI: 1.05–1.43) among all participants exposed to ETS, and HR of 1.24 (95% CI: 1.02–1.49) among non-smokers only. The most significant site-specific finding was for stomach cancer, showing an HR of 1.86 (95% CI: 1.21–2.85) among all participants and HR of 1.75 (95% CI: 1.05–2.91) among non-smokers, both of which were highly significant. The level of exposure was defined simply as “ever exposed to environmental tobacco smoke in your living or working environment”. The highest risk associations for both lung and stomach cancers were observed among non-smoking females, a subgroup that showed a high prevalence of passive smoking (54.5%).⁷⁰

Jin et. al. 2025

The population-based case-control study, “Environmental tobacco smoking (ETS) and esophageal cancer…” by Jin et al. (2024), investigated the association between secondhand smoke and esophageal cancer in Jiangsu Province, China. The study found a statistically significant positive association between ETS exposure and esophageal cancer risk across the overall population, with a Semi-Bayes (SB) adjusted Odds Ratio (OR) of 1.44 (95% CI: 1.31–1.58). This risk was even higher among non-smokers (i.e., non-active smokers), with a significant SB-adjusted OR of 1.56 (95% CI: 1.35–1.82). The findings demonstrate a clear dose-response relationship across the entire population and among non-smokers. For the highest level of exposure (heavy exposure at both home and work), the risk peaked with an SB-adjusted OR of 2.32 (95% CI: 1.64–3.26) for all participants and OR of 1.87 (95% CI: 1.02–3.42) for non-smokers. The exposure was defined as “ever” being exposed to ETS at home (from household members) or at the workplace (exposed to others’ smoke for >15 minutes daily in closed areas), with 15.0% of esophageal cancer cases in the overall population being attributable to this environmental exposure.⁷¹

Diesel Exhaust and Esophageal

Guo et. al. 2004 ( No correlation)

The large cohort study by Guo et al. (2004), investigating the risk of cancer among over a million Finnish workers, found no statistically significant overall association between exposure to either diesel or gasoline engine exhaust and the risk of esophageal cancer. This lack of significance was confirmed because the calculated Relative Risk (RR) estimates for esophageal cancer in various exposure groups were consistently near 1.0, and their 95% Confidence Intervals (CI) always included 1.0. The authors explicitly noted that “No effect of the exposures was observed” for esophageal cancer, in contrast to the significant findings for bladder, ovarian, and kidney cancers. The level of exposure was extensive, covering all economically active Finns over a period from 1971–1995, with quantitative exposure estimates derived from their census occupation and classified using the FINJEM job-exposure matrix for both cumulative diesel and gasoline engine exhaust.⁷²

Attfield et. al. 2011

The Diesel Exhaust in Miners Study (DEMS), a large cohort mortality study by Attfield et al. (2011), was primarily focused on lung cancer but did report on other mortality outcomes. The study found a statistically significant elevation in mortality from esophageal cancer when comparing the complete cohort to state-based mortality rates. The Standardized Mortality Ratio (SMR) for esophageal cancer was 1.83, which is significant because its 95% Confidence Interval (CI) of 1.16 to 2.75 does not include the null value of 1.0. The study’s main focus was to establish the exposure-response relationship for diesel exhaust and lung cancer, using quantitative estimates of respirable elemental carbon (REC) exposure. The level of exposure involved 12,315 workers in eight US non-metal mining facilities, including both ever-underground workers (where diesel exhaust exposure was higher) and surface-only workers.⁷³

Collatuzzo at el. 2024

The systematic review and meta-analysis by Collatuzzo et al. (2024), examining the association between occupational diesel exhaust exposure and gastrointestinal cancers, found the overall risk for esophageal cancer to be statistically insignificant for “ever-exposure,” with a summary Relative Risk (RR) of 1.08 (95% CI 0.97–1.21), as the confidence interval included 1.0. However, highly significant associations were identified in specific high-exposure occupational categories, demonstrating a greater risk in those with the highest level of exposure: the most significant finding was among Handlers, who had an RR for esophageal cancer of 1.95 (95% CI 1.23–3.09), a value nearly double the risk and strongly significant. Furthermore, Machine operators also showed a significant increase in incidence risk with an RR of 1.09 (95% CI 1.00–1.20). The exposure was classified by occupation (e.g., drivers, machine operators, handlers), representing exposure to diesel exhaust from primary sources like vehicles, trains, and mining.⁷⁴

Benzene and Esophageal

Gresseir et al. (2022)

The PROG study by Gressier et al. (2022) was a preliminary, descriptive study conducted on a small cohort of 36 esophageal cancer patients in Brittany, France, to document potential occupational exposures beyond established risk factors like alcohol and smoking. The findings highlighted that 30.6% of patients reported high exposure to asbestos and 36.1% had exposure to hydrocarbons and their derivatives. Specifically, 19.4% of patients were regularly in contact with benzene by handling fuel. As a descriptive study without a control group, it did not calculate a formal risk estimate like an Odds Ratio (OR) or Hazard Ratio (HR), but its results supported the need for a large-scale study to explore the causal impact of exposures like asbestos and hydrocarbons.⁷⁵

Tang et al.⁷⁶

Solvents and Esophageal ( no correlation)

This comprehensive review of epidemiologic evidence on organic solvents and cancer suggests a potential increased risk of esophageal cancer following exposure to tetrachloroethylene. This association was elevated in several studies of dry-cleaning workers, with one cohort’s two subgroups showing 23 observed cases compared to 10.8 expected. However, the authors caution that confounding factors such as smoking, alcohol, and sexual habits cannot be excluded as a cause for the observed association. For benzene, a well-established cause of leukemia, this review did not report an association with esophageal cancer.

Laryngeal

Pancreatic

Summaries of Epidemiological Studies on Pancreatic Cancer

Cadmium Exposure and Pancreatic Cancer in South Louisiana

Luckett BG, Su LJ, Rood JC, Fontham ET. Cadmium exposure and pancreatic cancer in south Louisiana. J Environ Public Health. 2012;2012:180186.

This study investigates the hypothesis that cadmium exposure is a risk factor for pancreatic cancer in south Louisiana, a region known for persistently high mortality rates from the disease.⁷⁷ The research utilized a population-based case-control study design, limiting participants to non-institutionalized individuals over the age of 20 residing in one of eight south Louisiana parishes. Cases consisted of incident (newly diagnosed) pancreatic cancer patients ascertained between 2001 and 2005, and controls were randomly selected from state registers and frequency matched on age, race, and gender. A key methodological feature was the collection of spot urine samples to measure urinary cadmium concentrations, which are considered a better indicator of long-term cadmium exposure than blood levels, due to the metal’s accumulation in the kidney cortex. The samples were analyzed and cadmium concentrations were reported as micrograms per gram of creatinine (μg/g creatinine) .

The study found a clear, monotonic increase in the risk of pancreatic cancer with increasing urinary cadmium concentrations. Using the lowest concentration group (<0.5 μg/g creatinine) as the reference, the odds ratio (OR) increased progressively across the quartiles, reaching OR=7.70 (95% CI: 3.06-19.34) for the highest concentration group (≥1.5 μg/g creatinine), with the test for trend being highly significant (P≤0.0001). This finding established, for the first time, a link between increased risk of pancreatic cancer and increased urinary cadmium concentrations, the most reliable biomarker for chronic exposure. The researchers state that this monotonically increasing risk is evidence of an etiologic link between cadmium exposure and pancreatic cancer.

The study also investigated potential dietary and non-dietary sources of cadmium exposure in relation to disease risk and urinary cadmium concentration. Several factors were significantly associated with an increased risk of pancreatic cancer: working as a plumber, pipefitter, or welder (OR=5.88; 95% CI: 1.33-26.01) ; high consumption of red meat (at least 12 servings per week, OR=6.18; 95% CI: 2.28-16.76) ; and high consumption of all grains (at least 30 servings per week, OR=3.38; 95% CI: 1.10-10.36). Furthermore, an occupational history of working as a plumber, pipefitter, or welder, and high consumption of grains were found to be statistically significant predictors of increased concentrations of urinary cadmium. The researchers suggest that the previously observed findings of increased risk associated with high consumption levels of red meat and grains may be related to their cadmium content. Specifically regarding red meat, they posit that pork may have a higher cadmium content than beef due to being exclusively grain-fed.

The study faced limitations, including a small sample size (69 cases, 158 controls) resulting in limited statistical power, especially since a large proportion of incident cases (60 percent) were already deceased or too ill to participate . The authors acknowledge that if deceased or severely ill cases had higher cadmium exposures, their exclusion would bias the risk estimates toward the null . Despite the limitations, the study concludes that cadmium is a potential human pancreatic carcinogen and warrants further investigation as a potential environmental factor driving the persistently high pancreatic cancer rates in south Louisiana.

Occupational Exposures and Pancreatic Cancer: A Meta-analysis

Ojajärvi IA, Partanen TJ, Ahlbom A, et al. Occupational exposures and pancreatic cancer: a meta-analysis. Occup Environ Med. 2000;57(5):316-324.

This publication presents a meta-analysis to consolidate epidemiological data regarding the association between pancreatic cancer and worksite exposures.⁷⁸ The analysis surveyed publications from 1969 to 1998, focusing on agent-specific studies with direct risk estimates for a list of 23 chemical or physical agents, or for job titles with verified exposures to those agents . The meta-analysis was based on 92 studies covering 161 exposed populations and employed simple random effects models to estimate the meta-risk ratios (MRRs).

The analysis found significant excesses in the risk of pancreatic cancer for two main agents:

• Nickel and nickel compounds: MRR=1.9 (95% CI: 1.2 to 3.2), based on 4 populations.

• Chlorinated hydrocarbon (CHC) solvents and related compounds: MRR=1.4 (95% CI: 1.0 to 1.8), based on 20 populations.

Non-significant excesses over an MRR>1.3 were also found for several other agents, including:

• Polycyclic aromatic hydrocarbons (PAHs): MRR=1.5 (95% CI: 0.9 to 2.5).

• Organochlorine insecticides: MRR=1.5 (95% CI: 0.6 to 3.7).

• Silica dust: MRR=1.4 (95% CI: 0.9 to 2.0).

• Chromium and chromium compounds: MRR=1.4 (95% CI: 0.9 to 2.3).

• Aliphatic and alicyclic hydrocarbon solvents: MRR=1.3 (95% CI: 0.8 to 2.0).

The analysis found the evidence on pancreatic carcinogenicity to be weak or non-positive (i.e., MRR≈1.0) for a long list of agents, including cadmium and cadmium compounds (MRR=0.7; 95% CI: 0.4 to 1.4) , gasoline (MRR=1.0; 95% CI: 0.8 to 1.2) , and diesel engine exhaust (MRR=1.0; 95% CI: 0.9 to 1.2).

Based on the observed excesses, the researchers estimated the contribution of occupational exposures to pancreatic cancer risk using aetiological fractions. The population aetiological fraction (PEF), which is the proportion of cases in the general population attributable to these exposures, was estimated to be low, but the overall workplace exposure PEF was calculated by summing the individual PEFs (assuming independence) and resulted in an overall aetiological fraction of 12% for workplace exposures . For exposed groups, the aetiological fraction among the exposed (EEF) was much higher: 47% for nickel and nickel compounds, 33% for PAHs and insecticides, and 29% for CHC solvents and chromium compounds .

The researchers highlight that the estimated 12% attributable to occupational exposure, when combined with the 5%-50% estimated for smoking, leaves a large portion of pancreatic cancer risk unexplained, suggesting a role for inherited susceptibility, dietary habits, and various gene-environment interactions . The authors recommend that future research focus on more refined exposure and outcome assessment, as well as the study of interactions between occupational, environmental, and lifestyle factors. They also acknowledge limitations, such as potential misclassification of exposures and endpoints (e.g., diagnosis based only on death certificates), which likely biased the risk estimates toward the null value.

Occupational Factors and Pancreatic Cancer

Norell S, Ahlbom A, Olin R, et al. Occupational factors and pancreatic cancer. Br J Ind Med. 1986;43(11):775-778.

This paper presents the findings of an investigation into the relationship between occupational factors and pancreatic cancer in Sweden, utilizing two concurrent and complementary research designs: a population-based case-control study and a retrospective cohort study based on register data.⁷⁹ The purpose was to explore associations with specific factors, including exposures related to wood and paper, metal, and petroleum products.

The case-control study included newly diagnosed pancreatic cancer cases aged 40-79 from the Stockholm-Uppsala region and compared them separately against two groups of controls: hospital controls (patients with inguinal hernia) and population controls (selected from registers matched by age, sex, and parish) . Information on past occupations and specific exposures was collected via questionnaire and supplementary telephone interviews. The retrospective cohort study linked data from the 1960 census (for two million employed men) to the Swedish cancer register from 1961 to 1979. This allowed for the comparison of observed cases in specific occupational groups with the expected numbers, resulting in a Standardised Morbidity Ratio (SMR).

The investigation yielded several suggested associations with pancreatic cancer, often supported by both study designs:

• Petroleum Products: Some support was found in both approaches. The case-control study showed an increased risk (e.g., RR for petrochemical industry=1.9 vs. hospital controls). The cohort study showed increased SMRs for employment in petroleum refineries (SMR=1.3) and petrol stations (SMR=1.6).

• Painting/Thinners: The case-control study indicated an excess risk associated with exposure to paint thinners (RR=2.5 vs. population controls). The cohort study showed SMR values above unity for employment in painting (SMR=1.1) and in paint and varnish factories (SMR=1.2).

• Cleaning Agents: An excess risk was indicated by the case-control study for exposure to detergents, floor cleaning agents, or polish (RR=2.2 vs. population controls). The cohort study showed an SMR slightly above unity for men in floor polishing or window cleaning (SMR=1.3).

• Refuse: The case-control study suggested an excess risk from exposure to refuse (RR=3.7 vs. population controls). The cohort study supported this with an SMR above unity for work in refuse disposal plants (SMR=1.2).

• Welding Materials: The case-control study suggested some excess risk associated with exposure to welding materials (RR=2.0 vs. population controls). However, the cohort study did not show an excess risk among welders (observed=44; expected=44.5).

The study found no excess risk associated with wood related occupations or paper manufacturing in either study . Similarly, the cohort study did not show an excess risk in iron and steel works or iron and steel manufacture. The authors acknowledge the limitations of the cohort study, where lack of specific exposure data would bias the relative risk towards unity . Conversely, the case-control study could gather specific information but was limited by a small sample size . The authors conclude that the newly suggested associations—paint thinners/painting, detergents/cleaning, and refuse exposure—along with petroleum products, are worth considering in future studies.

Occupation and Pancreatic Cancer Risk in Shanghai, China

Ji B-T, Silverman DT, Dosemeci M, Dai Q, Gao Y-T, Blair A. Occupation and pancreatic cancer risk in Shanghai, China. Am J Ind Med. 1999;35(1):76-81.

Pancreatic cancer is a rapidly fatal malignancy whose etiology remains largely unknown, with cigarette smoking being the only consistently established risk factor.⁸⁰ Although numerous epidemiological studies have reported excess risks in various occupational groups, the evidence linking specific work-related exposures to this cancer has been inconsistent. This study, a population-based case-control investigation conducted in Shanghai, China, aimed to assess the risk of pancreatic cancer associated with usual occupation and specific chemical and physical exposures. The study included 451 newly diagnosed pancreatic cancer patients and 1,552 randomly selected controls, with lifetime job histories and other risk factors collected via face-to-face interviews.

The study revealed multiple statistically significant associations between pancreatic cancer risk and various occupations among men. The most prominent finding was a strong positive association with employment as an electrician. The authors cautioned that while EMF (electromagnetic fields) exposure is a possible explanation, other exposures related to electrical machinery, such as solvents, metal fumes, solder fumes, and cutting oils, could also contribute to this excess risk.

In addition to electrical work, several metal-related and industrial trades showed significantly elevated risks among men. These occupations included metal works (OR=2.1; 95% Cl:1.2-7.5). These findings align with prior epidemiological studies that have linked pancreatic cancer to metal industries. The authors suggested that the increased risk among metal workers and toolmakers could be attributed to exposure to various potential carcinogenic agents, including mineral oil, solvents, and metals. For the elevated risk observed in plumbing and welding workers, potential exposures include polycyclic aromatic hydrocarbons (PAHs) or other aromatic amines.

Study of Cadmium a Cause of Human Pancreatic Cancer

Schwartz G G, Reis I M. Is cadmium a cause of human pancreatic cancer? Cancer Epidemiol Biomarkers Prev. 2000;9(2):139-145.

This paper proposes the cadmium hypothesis as a cause of human pancreatic cancer, aiming to provide a coherent and biologically plausible explanation for much of the disease’s descriptive epidemiology.⁸¹ Pancreatic cancer remains a major cause of mortality with an obscure etiology, and cadmium , classified by the IARC as a known human carcinogen, is a nonessential metal that is known to accumulate in the human pancreas.

Evidence and Meta-Analysis

The authors assert that all major descriptive risk factors for pancreatic cancer are intelligible in terms of increased cadmium exposure.

• Age: Pancreatic cancer incidence increases exponentially with age, which is consistent with cadmium levels accumulating in the pancreas with age, peaking around age 50.

• Smoking: Cigarettes are an important source of cadmium exposure. Autopsy studies show the pancreas of smokers contain approximately twice the amount of cadmium as non-smokers.

• Geography: Elevated rates in areas like Louisiana are consistent with cadmium pollution from industrial activity contaminating wetlands and seafood (Mollusca and Crustacea), which accumulate high levels of cadmium in the hepatopancreas. Rice, a key crop and food source in high-incidence areas, is also known to contain high levels of cadmium.

• Occupation: Moderate risks seen in metalworking occupations and those involving pesticide and pigment exposure are consistent , as cadmium is a contaminant of pesticides and pigments, and metalworkers are exposed to cadmium fume via welding or soldering

To test the hypothesis, the authors performed a meta-analysis of four cohorts of cadmium-exposed workers. The overall summary Standardized Mortality Ratio was 166 (95% Cl: 98-280; P = 0.059), suggesting a 66% increased risk, which the authors deemed supportive despite the marginal statistical significance. The paper concludes that the cadmium hypothesis is a coherent and biologically plausible explanation for much of the epidemiology of pancreatic cancer and should be vigorously pursued through molecular and genetic epidemiological studies, particularly by measuring cadmium levels in biological samples from cancer patients.

Throat Cancers

Preliminary research

Asbestos X Throat Cancers 1/2 (Correlated)

This study comprehensively assessed the global burden of laryngeal cancer (LC) attributable to occupational asbestos exposure, highlighting its persistent and uneven impact worldwide. In 2021, occupational asbestos exposure accounted for 3,392 global deaths and 66,909 disability-adjusted life years (DALYs) from LC. The age-standardized mortality rate (ASMR) was highest in high-SDI regions, although low- and middle-SDI regions showed increasing trends. A meta-analysis cited within the article by Peng et al. (2016) found a significant increase in the meta-SMR of 1.69 for LC due to asbestos, indicating that workers exposed to asbestos have a 1.69 times higher risk of developing LC compared to the general population. Another study by Purdue et al. (2006) observed a relative risk of 1.9 (95% CI 1.2-3.1) for LC incidence among Swedish construction workers exposed to asbestos. The study underscores that despite declines in high-income countries due to asbestos bans, continued use in low- and middle-income countries, coupled with inadequate protective measures, leads to an ongoing and projected burden.

Citation: Zhang S, Du D, Li P, Chen Y, Zhang X. Global, regional and country-specific burden of larynx cancer due to occupational exposure to asbestos: a systematic analysis of the Global Burden of Disease Study 2021. BMC Public Health. 2025;25(1):2223. doi:10.1186/s12889-025-23343-6.⁸²

Asbestos X Throat Cancers 2/2 (Correlated)

This case-control study investigated the association between occupational asbestos exposure and head and neck squamous cell carcinoma (HNSCC), specifically focusing on pharyngeal cancer, in men from the greater Boston area. The study found that occupational asbestos exposure was significantly associated with an elevated risk of pharyngeal carcinoma, with an adjusted odds ratio (OR) of 1.41 (95% CI: 1.01-1.97). This indicates that men with occupational asbestos exposure had a 41% increased risk of developing pharyngeal cancer. Furthermore, a borderline increasing risk was observed for each decade spent in an asbestos-exposed occupation (OR=1.10, 95% CI: 0.99-1.23). The researchers controlled for major HNSCC risk factors, including age, race, smoking, alcohol consumption, education, income, and HPV16 serology. These findings bolster mounting evidence that asbestos is a risk factor for pharyngeal cancer, although no significant associations were found for oral cavity or laryngeal cancer in this specific study, possibly due to sample size limitations for the latter.

Citation: Langevin SM, O’Sullivan MH, Valerio JL, et al. Occupational asbestos exposure is associated with pharyngeal squamous cell carcinoma in men from the greater Boston area. Occup Environ Med. 2013;70(12):858-863. doi:10.1136/oemed-2013-101528.⁸³

Silica X Throat Cancers (Correlated)

This systematic review and meta-analysis investigated the association between silica dust exposure or silicosis and laryngeal cancer, a type of throat cancer. Combining six case-control studies that adjusted for smoking and alcohol, a significantly increased risk of laryngeal cancer was observed among workers exposed to silica dust, with a pooled odds ratio (OR) of 1.39 (95% CI: 1.17-1.67). This indicates a 39% increased risk of laryngeal cancer. While cohort studies showed a similarly increased but statistically non-significant risk for silicosis cases (pooled SMR of 1.38, 95% CI: 0.79-1.96) and silica dust exposure (pooled SMR of 1.13, 95% CI: 0.82-1.45; pooled SIR of 1.50, 95% CI: 0.59-2.42), the case-control findings suggest a notable association. The authors conclude that there is a weak but present association between silica or silicosis and laryngeal cancer, cautioning that inherent limitations in the original studies necessitate careful interpretation.

Citation: Chen M, Tse LA. Laryngeal cancer and silica dust exposure: A systematic review and meta-analysis. Am J Ind Med. 2012;55(8):673-682. doi:10.1002/ajim.22037.⁸⁴

Diesel Exhaust X Throat Cancers (Correlated)

This case-control study investigated the association between diesel exhaust and diesel fumes exposure and the risk of laryngeal cancer. The study, involving 235 male laryngeal cancer patients and 205 male controls, found no association between occupations involving substantial exposure to diesel engine exhaust (e.g., truck drivers, mine workers, firefighters, railroad workers) and laryngeal cancer risk, with an odds ratio (OR) of 0.96 (95% CI, 0.5 to 1.8). Similarly, self-reported exposure to diesel exhaust yielded an OR of 1.47 (95% CI, 0.5 to 4.1), which was not statistically significant. However, a significantly elevated risk was found for self-reported exposure to diesel fumes, with an OR of 6.4 (95% CI, 1.8 to 22.6). The authors suggest the differing results for self-reported diesel fumes and occupations with diesel fume exposure (like automobile mechanics, OR 1.30, 95% CI 0.4-4.1) might indicate a recall bias, and residual confounding from heavy smoking and alcohol consumption could not be entirely ruled out due to the small number of controls with self-reported fume exposure.

Citation: Muscat JE, Wynder EL. Diesel exhaust, diesel fumes, and laryngeal cancer. Otolaryngol Head Neck Surg. 1995;112(3):437-440.⁸⁵

Benzene X Throat Cancers (weak correlation)

This study investigated the association between occupational exposure to petroleum-based and oxygenated solvents, including benzene, and the risk of hypopharyngeal and laryngeal cancer in men in France. The study did not find a significant association between benzene exposure and laryngeal cancer risk. Specifically, for ever exposure to benzene, the adjusted odds ratio (OR) for laryngeal cancer was 0.94 (95% CI: 0.71-1.24), suggesting no increased risk. Similarly, for increasing cumulative exposure to benzene, the ORs for laryngeal cancer did not show a significant trend, with the highest cumulative exposure category having an OR of 0.42 (95% CI: 0.18-1.01). While slightly elevated, non-significant risks of hypopharyngeal cancer were observed with high cumulative levels of white spirits (OR=1.46) and tetrahydrofuran (OR=2.63), the overall conclusion for benzene and throat cancers (laryngeal and hypopharyngeal) was that no substantial role of exposure was suggested. The authors acknowledged limitations such as potential non-differential misclassification of exposure from using Job-Exposure Matrices (JEMs).

Citation: Barul C, Carton M, Radoi L, et al. Occupational exposure to petroleum-based and oxygenated solvents and hypopharyngeal and laryngeal cancer in France: the ICARE study. BMC Cancer. 2018;18(1):388. doi:10.1186/s12885-018-4324-7.⁸⁶

TCE/PCE X Throat Cancers (Correlated)

This case-control study investigated the association between occupational exposure to chlorinated solvents, including perchloroethylene (PCE) and trichloroethylene (TCE), and head and neck cancers in French men. While no overall association was found between chlorinated solvent exposure and head and neck cancer risk, a significant dose-response relationship emerged for laryngeal cancer with cumulative PCE exposure. Specifically, individuals with the highest cumulative levels of PCE exposure had a significantly increased risk of laryngeal cancer, with an odds ratio (OR) of 3.86 (95% CI: 1.30 to 11.48). This indicates a nearly fourfold increased risk. Additionally, a non-significant elevated risk for hypopharyngeal cancer (OR=2.36; 95% CI: 0.98 to 5.85) was observed with the highest levels of methylene chloride (MC) exposure. The study’s findings suggest that high occupational exposure to PCE may increase the risk of laryngeal cancer, and also points to a possible link between MC and hypopharyngeal cancer.

Citation: Barul C, Fayossé A, Carton M, et al. Occupational exposure to chlorinated solvents and risk of head and neck cancer in men: a population-based case-control study in France. Environmental Health. 2017;16(1):77. doi:10.1186/s12940-017-0286-5.⁸⁷

PAHs / Creosote X Throat Cancers (Correlated)

This systematic review and meta-analysis investigated the association between occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and the risk of laryngeal cancer (a type of throat cancer). The pooled effect size for laryngeal cancer incidence was 1.45 (95% CI 1.30 to 1.62), indicating a 45% increased risk. For laryngeal cancer mortality, the pooled effect size was 1.34 (95% CI 1.18 to 1.53), representing a 34% increased risk. While few studies allowed for a detailed dose-response analysis, the available evidence suggested a positive dose-response effect, meaning higher exposure levels might lead to greater risks. Specifically, coke oven workers, who experience high PAH exposure, showed a pooled effect size of 2.21 (95% CI 1.60 to 3.05). The authors concluded that there is a robust positive association between occupational PAH exposure and laryngeal cancer, suggesting it should be considered a potential occupational disease.

Citation: Wagner M, Bolm-Audorff U, Hegewald J, et al. Occupational polycyclic aromatic hydrocarbon exposure and risk of larynx cancer: a systematic review and meta-analysis. Occup Environ Med. 2015;72(3):226-233. doi:10.1136/oemed-2014-102317.⁸⁸

Welding Fumes X Throat Cancers (Correlated)

This case-control study investigated the occupational history of laryngeal cancer patients in Denmark, specifically examining their exposure to welding fumes. The study found that men exposed to welding fumes at their workplace had a borderline statistically significant increased risk of cancer of the larynx. More precisely, for all laryngeal cancer patients, the adjusted relative risk (RR) was 1.3 (95% confidence limits 0.9-2.0), indicating a 30% increased risk, though not statistically significant at a strict 5% level. However, a statistically significant increased risk was observed for cancer of the subglottic area, with an adjusted RR of 6.3 (95% confidence limits 1.8-21.6), suggesting a 530% increased risk. The duration of weekly welding hours was a stronger predictor than the number of welding years, and the increased risk was primarily seen among smokers.

Citation: Olsen J, Sabroe S, Lajer M. Welding and Cancer of the Larynx: a Case-control Study. Eur J Cancer Clin Oncol. 1984;20(5):639-643.⁸⁹

Magnesium X Throat Cancers (no significant correlation)

This review article, “Magnesium and cancer: a dangerous liaison,” broadly discusses the complex relationship between magnesium and various cancers. While it highlights that epidemiological studies identify magnesium deficiency as a risk factor for some human cancers, and suggests optimizing magnesium intake as a potential preventative measure, the article does not specifically focus on throat cancers. It mentions “oesophageal cancer” once, stating that high levels of magnesium in drinking water may offer protection against it, but it does not provide any specific odds ratios, hazard ratios, standard mortality rates, relative risks, or detailed levels of exposure for esophageal or other throat cancers. The article primarily focuses on the general role of magnesium in tumorigenesis, both at the cellular and animal model levels, and discusses impaired magnesium homeostasis in cancer patients and during therapy.

Citation: Castiglioni S, Maier JAM. Magnesium and cancer: a dangerous liason. Magnes Res. 2011;24(3):S92-S100.⁹⁰

Roundup/Herbicides X Throat Cancers (Correlated)

This review of case-control studies investigated the association between pesticide use and the risk of head and neck cancers (HNC), which include throat cancers like laryngeal and pharyngeal cancer. While the article generally found a positive association between pesticide exposure and different HNC sites, it does not specifically focus on Roundup or other herbicides in isolation, nor does it provide odds ratios, hazard ratios, standard mortality rates, relative risks, or specific levels of exposure solely for Roundup/Herbicides in relation to throat cancers. However, one high-quality study referenced (De Stefani et al., 1998) found increased risks for laryngeal cancer associated with “herbicides exposure” (OR 2.4, 95% CI 0.9-6.7) and fungicides exposure, with risks increasing significantly with exposure duration. Another study (Amizadeh et al., 2017) noted a strong association between “pesticide exposure” and laryngeal cancer (OR 9.33, 95% CI 1.65-52.68). The review concludes that improving pesticide users’ awareness of risks and proper handling, including the use of personal protective equipment, appears to be effective in reducing human health damage related to these exposures.

Citation: Leonel ACLdS, Bonan RF, Pinto MBR, Kowalski LP, Perez DEdC. The pesticides use and the risk for head and neck cancer: A review of case-control studies. Med Oral Patol Oral Cir Bucal. 2021;26(1):e56-e63.⁹¹

Secondhand Smoke X Throat Cancers (Correlated)

This cross-sectional study investigated the impact of secondhand smoke (SHS) on head and neck cancers (HNCs), specifically hypopharyngeal and laryngeal cancers (types of throat cancer), in Japan. The study found a significant association between SHS exposure and an increased risk of these cancers. For hypopharyngeal cancer, exposure to SHS at home was associated with an odds ratio (OR) of 2.51 (95% CI, 1.18–5.36), and exposure at workplaces had an OR of 2.53 (95% CI, 1.24–5.15), indicating a more than doubled risk in both settings. Similarly, laryngeal cancer showed a significant association with SHS exposure at home (OR = 2.44, 95% CI, 1.04–5.68) and in leisure places (OR = 2.25, 95% CI, 1.00–5.07). These findings suggest that merely being in the presence of smokers significantly increases the risk of both hypopharyngeal and laryngeal cancers, highlighting the dangerous impact of passive smoking.

Citation: Tsuzuki N, Wasano K, Kawasaki T, et al. The impact of second-hand smoke on ear, nose, and throat diseases and head and neck cancers in Japan: a cross-sectional study using a questionnaire and secondary data from the national health and nutrition survey. Acta Oto-Laryngologica. 2021;141(11):1000-1004. doi:10.1080/00016489.2021.1989486.⁹²

Acute Myeloid Leukemia

Acute Myeloid Leukemia X Asbestos (No significant association)

• Kishimoto et al. (1988)

This article is a case report, not a large-scale epidemiological study, that presents two cases of acute myelocytic leukemia (a subtype of AML) in individuals with a history of asbestos exposure. The authors found significant numbers of asbestos bodies in the patients’ lungs and bone marrow, suggesting that asbestos may be transported through the body via the lymphatic system. While the report highlights a potential link, it concludes that the role of asbestos exposure in the development of leukemia requires further study, and therefore does not provide quantitative risk metrics like odds ratios or relative risks. The level of exposure is described as a “long history” and “elevated levels of asbestos bodies”.⁹³

• Würtz et al. (2019)

This large cohort study concluded that long-term occupational asbestos exposure is associated with an increased leukemia risk. The study found a statistically significant increased risk for the leukemia subgroup, with a hazard ratio (HR) of 2.14 (95% CI: 1.19-3.84). The risk for overall haematological malignancy was also found to be statistically significant, with an HR of 1.69 (95% CI: 1.04-2.73). This study focused on long-term occupational exposure to asbestos, noting that early environmental exposure was not associated with an increased risk.⁹⁴

• Dodos et al. (2025)

This systematic review and meta-analysis evaluated the association between asbestos exposure and leukemia incidence by synthesizing findings from five studies. The meta-analysis, which included over 1.7 million participants, found a non-significant overall risk ratio (RR) of 1.25 (95% CI: 0.81-1.94) for leukemia in exposed cohorts. The review noted significant heterogeneity between studies, with an I² statistic of 86%, indicating that much of the variability in results was due to differences in the studies themselves rather than chance. The authors concluded that the evidence is inconclusive and that further, high-quality studies are needed to clarify the association. The article mentions that some of the included studies adjusted for smoking, while others did not, introducing a potential for bias.⁹⁵

Acute Myeloid Leukemia X Silica (No correlation)

Acute Myeloid Leukemia X Diesel Exhaust (No significant association)

• Bofetta (2004)

• This review systematically examined the epidemiological literature on occupational exposure to diesel exhaust and the risk of Acute Myeloid Leukemia (AML). The study found that the available epidemiological evidence does not consistently suggest an increased risk of leukemia, and specifically AML, among workers exposed to diesel exhaust. diesel exhaust exposure does not appear to be associated with an increased risk of leukemia. The review provided multiple non-pooled risk estimates (Standardized Mortality Ratio (SMR), Relative Risk (RR), Odds Ratio (OR) from the included studies, all of which were largely inconclusive or non-significant for AML/leukemia.⁹⁶

Acute Myeloid Leukemia X Benzene (Correlated)

• Greene et al. (1976)

This study is a proportionate cancer mortality analysis of male employees from the U.S. Government Printing Office (GPO) conducted from 1948 to 1977. A high proportion of leukemia deaths was observed, with a PMR of 1.38 (95% CI 0.9-2.2) for the total cohort. The excess deaths from leukemia were primarily concentrated in bindery workers. The study links this to a potential exposure to benzene, which was used in the bindery until the early 1960s. An elevated risk for leukemia was found along with multiple myeloma, hodgkin’s disease, colon cancer, among others.⁹⁷

• Rinskey et al. (1981)

This paper is a detailed summary of a retrospective cohort mortality study of workers exposed to benzene at two Goodyear plants in Ohio from 1940 to 1959. The study’s primary objective was to evaluate the association between occupational benzene exposure and subsequent death from leukemia. The study found a large and statistically significant increase in mortality from malignant neoplasms of the lymphatic and hematopoietic system among the exposed workers. Out of 748 workers exposed to benzene, seven deaths from leukemia were observed, while only 1.25 would have been expected based on U.S. death rates. This resulted in a Standardized Mortality Ratio (SMR) of 560. The paper emphasizes that all seven leukemia deaths were of the myelocytic or monocytic cell type. These are forms of acute myeloid leukemia (AML). This finding is consistent with previous descriptions of the pathology of benzene-induced leukemia. The risk of death from leukemia was directly related to the duration of exposure. Workers with a longer exposure had a sharply increased risk. For those exposed for five or more years, the SMR for leukemia was 2,100. The report determines a causal relationship. At times the exposure was up to several hundred ppm but for the most part remained below the TWA of 10ppm over an 8 hour period.⁹⁸

• Wong (1995)

The article re-analyzes data from the Pliofilm cohort, a group of workers at Goodyear plants in Ohio that were routinely exposed to benzene while manufacturing Pliofilm (a rubber hydrochloride). The analysis found a clear dose-response relationship between cumulative benzene exposure and the risk of AML. The study found no increased risk of AML for cumulative exposures below 200 ppm-years (SMR 0.91). However, above this level, the risk rose drastically. For workers with a cumulative exposure greater than 400 ppm-years, the SMR for AML was 98.37. This suggests a threshold for AML at around 200 ppm-years, which is significantly higher than thresholds estimated by previous studies that included all leukemia cell types. Wong describes the importance of specifying the type of leukemia that is being examined for most accurate calculations.⁹⁹

• Glass et al. (2003)

This study investigated the link between low-level benzene exposure and leukemia risk in a cohort of male workers from the Australian petroleum industry. The study found an elevated risk of leukemia associated with benzene exposure. The risk increased with higher cumulative exposures, with a strong dose-response relationship. The odds ratio (OR) for leukemia was 11.3 (95% CI 2.85-45.1) for workers in the two highest exposure categories (greater than 8 ppm-years). An excess risk of leukemia was found at cumulative benzene exposures and exposure intensities that were considerably lower than those reported in previous studies. No threshold value was determined. The risk of both acute nonlymphocytic leukemia (Acute Myeloid Leukemia) and chronic lymphocytic leukemia was raised for the highest exposed workers. “An odds ratio of 2.8 (95% CI =0.8-9.4) was found for a cumulative exposure of 4.5-45ppm-years” for acute myeloid and monocytic leukemia. ¹⁰⁰

• IARC (2012)

The IARC stated that “There is sufficient evidence in humans for the carcinogenicity of benzene. Benzene causes acute myeloid leukaemia/acute non-lymphocytic leukaemia.”¹⁰¹

Acute Myeloid Leukemia X Chlorinated Solvents (TCE) (No significant association)

• Talibov et al. 2014.

• This study is a large, population-based case-control study conducted in four Nordic countries that assessed the relationship between occupational solvent exposure and the risk of Acute Myeloid Leukemia (AML). The study found no statistically significantly increased risk for exposure to any of the solvents analyzed, including the chlorinated solvent trichloroethylene (TCE). For workers with moderate-to-high levels of trichloroethylene exposure, the Hazard Ratio (HR) was slightly elevated but non-significant.HR (Trichloroethylene, moderate-to-high levels): 1.12 (for the highest cumulative exposure category) (0.83–1.49). The authors concluded that the study did not provide clear evidence for an association between occupational solvent exposure and AML. However, they noted a slight indication of an excess risk in groups exposed to TCE, toluene, and aromatic hydrocarbon solvents ARHC.¹⁰²

Acute Myeloid Leukemia X Creosote (Correlated)

• Poynter et al. 2016

This article presents a comprehensive, population-based case-control study on chemical exposures and the risk of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) in Minnesota.The study found a statistically significant association between exposure to creosote (a Polycyclic Aromatic Hydrocarbon, or PAH, product) and the risk of AML, but notably not with MDS. The strongest associations with AML were found in a group of related occupational and residential chemicals, with the exposure level being greater than or equal to 5 years (compared to no exposure). The OR of 2.83 for Creosote falls within the broad range (ORs 2.68–4.03) previously reported for these chemically related exposures. The major source of creosote exposure is occupational. While the associations for creosote, coal dust, and soot are strong, the authors emphasize that these exposures were reported by only a small percentage of cases (less than 10%) and therefore do not account for the majority of AML cases.¹⁰³

Acute Myeloid Leukemia X Welding Fumes (No Correlation)

• Stern (1987)

• This article is a review and meta-analysis of epidemiological data concerning the risk of cancer, specifically leukemia and respiratory tract cancer, among welders. The study found no evidence of a significant association between welding/welding fumes and Acute Myeloid Leukemia AML. The absence of an increased risk for leukemia generally runs counter to what would be expected if the electromagnetic fields ELF produced during welding were the cause of leukemia in electrical workers. When data from multiple studies were pooled, the risk for all leukemia was found to be below expectation. Pooled Risk for Acute Leukemia (Includes AML): Standardized Risk Ratio (for additively pooled data): 0.85 (95% CI 0.55–1.15). The author concludes that the absence of increased leukemia risk among welders does not support the hypothesis that (ELF) exposure is responsible for the leukemia excess observed in some other electrical occupations.¹⁰⁴

Acute Myeloid Leukemia X Herbicides/ Round-Up (Somewhat Correlated)

• Foucault et al. (2007)

A meta-analysis of case-control studies found a significant adverse association between occupational pesticide exposure (OPE) and the risk of developing acute myeloid leukemia (AML). The analysis included 14 studies with 3,955 AML patients and 9,948 control subjects. An overall adverse association was found between OPE and AML, with an odds ratio (OR) of 1.51. When studies were analyzed by pesticide subtype, the association between OPE and AML was found to be significant with insecticides, with an OR of 1.45. The meta-analysis also looked at the association between OPE and AML with herbicides and fumigants, but the association was not found to be statistically significant for these two types of pesticides. The study acknowledged that a previous meta-analysis from 2007 did not find a link between OPE and AML in case-control studies, possibly due to recall bias and the inclusion of controls with a history of cancer. The findings of this meta-analysis broaden the spectrum of pesticide toxicity to include myeloid malignancies. Overall, the study was able to find an association between acute myeloid leukemia and insecticides but not herbicides.¹⁰⁵

• Lerro et. al. (2018)

This study, titled “Alachlor Use and Cancer Incidence in the Agricultural Health Study: An Updated Analysis,” evaluated the relationship between the herbicide alachlor and various cancers, including myeloid leukemia, among a cohort of licensed pesticide applicators in Iowa and North Carolina. The analysis included an additional 540,142 person-years of follow-up and 5,113 cancer cases since a previous study. The study found an elevated, but not statistically significant, risk of myeloid leukemia in the fourth (highest) quartile of intensity-weighted days of alachlor use. The relative risk (RR) for this group was 1.82, with a 95% confidence interval (CI) of 0.85 to 3.87. Of the myeloid leukemia cases, 34 were acute myeloid leukemia (AML). The study observed similar, non-significant results for AML in the highest exposure quartile, with a relative risk of 1.73 and a 95% CI of 0.73 to 4.13. When the researchers examined total leukemia (including all subtypes), they found a non-statistically significant elevated risk in the highest exposure quartile. This association was thought to be driven by the myeloid subtypes; however, it was not statistically significant.¹⁰⁶

• Vanmaele-Fabry et al. (2007)

The systematic review and meta-analysis of studies published between 1979 and 2005 examined the link between myeloid leukemias (ML) and occupational pesticide exposure (OPE). The review included 17 cohort studies and 16 case-control studies. The overall meta-rate ratio for all cohort studies was 1.21, with a 95% confidence interval (CI) of 0.99-1.48. The authors found substantial heterogeneity among the cohort studies, which they attributed to the varying occupational categories. When cohort studies were stratified by specific myeloid leukemia subtype, an increased risk was found for acute myeloid leukemia (AML), with a meta-rate ratio of 1.55 (95% CI: 1.02-2.34). The strongest evidence of an increased risk of myeloid leukemia came from manufacturing workers and pesticide applicators. For manufacturing workers, the meta-rate ratio was 6.32 (95% CI: 1.90-21.01). For pesticide applicators, the meta-rate ratio was 2.14 (95% CI: 1.39-3.31). The meta-rate ratio for farmers and agricultural workers was 1.03 (95% CI: 0.86-1.23). The authors noted a funnel plot asymmetry, suggesting a lack of small studies with low relative risk estimates, which may lead to an overestimation of the effect. The study did not provide a separate analysis specific to the association between herbicides and AML. The paper notes that exposures for manufacturing workers were specific to alachlor and “phenoxy herbicides and chlorophenols”.¹⁰⁷

• Bailey et al. (2015)

A pooled analysis by the Childhood Leukemia International Consortium (CLIC) found that home pesticide exposure before and during pregnancy was associated with an elevated risk of AML in children. For exposure before conception, the odds ratio (OR) for AML was 1.49 (95% CI: 1.02-2.16). For exposure during pregnancy, the OR for AML was 1.55 (95% CI: 1.21-1.99). The study also found that there was little difference in the odds ratios for AML based on the type of pesticide used. This suggests that the association is not specific to a single class of pesticides, such as herbicides. The authors suggested that this lack of differentiation might be due to a number of factors, including similar exposure patterns across different pesticide types, exposure to multiple pesticides, or recall bias in the data.¹⁰⁸

Acute Myeloid Leukemia X Secondhand Smoke (Correlated)

• Figueroa et al. (2023)

• This study, conducted through the Children’s Oncology Group (COG), investigated the association between parental smoking and the risk of childhood acute myeloid leukemia (AML) across a large North American case-control cohort. The researchers examined maternal smoking during pregnancy and paternal smoking up to one year before diagnosis as proxies for tobacco smoke exposure. The findings did not reveal any statistically significant associations between either maternal or paternal smoking and the risk of childhood (AML) overall. Specifically, the odds ratio (OR) for paternal smoking was 1.26 (95% CI 0.96-1.65), and the (OR) for maternal smoking during pregnancy was 1.14 (95% (CI) 0.90-1.44), neither of which was conclusive. While these results did not provide strong evidence of a direct association, the authors noted that the analysis was limited by the potential for residual confounding and exposure misclassification. The study contributes to the body of evidence regarding environmental factors in childhood cancer etiology, concluding that the link between parental smoking and childhood $\text{AML}$ remains weak.¹⁰⁹

• Metayer et al. (2016)

This case-control study explored the relationship between tobacco smoke (TS) exposure and the risk of childhood acute myeloid leukemia (AML) stratified by cytogenetic subtype. The researchers used maternal plasma cotinine levels as a biomarker of exposure, analyzing data from the Children’s Leukemia International Consortium (CLIC). The study found a statistically significant increased risk of AML associated with higher maternal cotinine levels (a proxy for secondhand smoke) for two specific genetic subtypes: AML with chromosome structural changes (OR=2.76, 95% CI 1.15-6.63) and AML with trisomy 8 (OR2.16 95% CI 1.02-4.57). These subtype-specific findings suggest that tobacco smoke carcinogens may interact with specific genetic vulnerabilities, supporting the biological plausibility that TS exposure is leukemogenic10. Overall, the study provided support for the hypothesis that TS exposure is associated with increased risk of certain AML cytogenetic subtypes, underscoring the importance of molecular risk stratification in future research.¹¹⁰

• Pogoda et al. (2002)

• This study, a case-control analysis conducted in Los Angeles County, investigated the association between active cigarette smoking and the risk of acute myeloid leukemia (AML) in adults. The research examined whether smoking conferred a uniform risk across all AML subtypes, utilizing the French-American-British (FAB) morphological classification. The overall findings indicated that active smoking was a weak risk factor for AML overall, with an odds ratio of 1.3(95% CI}$ 0.9-1.7) for smokers. However, the study found a statistically significant increased risk for the specific AML subtype FAB M2, with an odds ratio of 2.3(95% 1.3-4.1$ for ever smokers. This subtype-specific association suggests that tobacco smoke carcinogens, such as benzene, may target specific hematopoietic cell lineages or genetic abnormalities involved in AML pathogenesis. The authors concluded that active smoking is a weak risk factor for $\text{AML}$ generally, but may be a stronger risk factor for the M2 subtype.¹¹¹

Lymphoma (Non- Specified)

*most studies highlight multiple myeloma and NHL

Lymphoma Non-specific and Benzene

Wong et al. 1997

The study on Multiple Myeloma and benzene exposure found that petroleum workers, despite being exposed to benzene, were not at an increased risk of developing this lymphopoietic cancer. The analysis combined data from 22 cohort mortality studies, covering over 250,000 workers, and found 205 deaths from multiple myeloma compared to 220.93 expected. This yielded a combined Standardized Mortality Ratio (SMR) of 0.93 with a 95% confidence interval of 0.81–1.07. Since the SMR is below 1.0 and the confidence interval includes 1.0, the finding is that the mortality rate for multiple myeloma among petroleum workers is no greater than that of the general population. This conclusion, supported by similar results in analyses stratified by job type, suggests that occupational exposure to benzene in the petroleum industry does not cause an excess risk of multiple myeloma.¹¹²

Lymphoma & Creosote

• Rana et al. 2021 – This meta-analysis evaluated 28 epidemiological studies (20 case-control and 8 cohort) examining the link between benzene exposure and non-Hodgkin lymphoma (NHL) across 9,587 total cases. The pooled meta-relative risk (meta-RR) for benzene exposure and NHL was 1.33 (95% CI: 1.13–1.57), indicating a 33% increased risk among exposed individuals. When limited to highly exposed workers, the risk increased to 1.51 (95% CI: 1.22–1.87), showing a clear exposure–response relationship. Subtype analyses showed significantly elevated risk for diffuse large B-cell lymphoma (RR = 1.67; 95% CI: 1.01–2.77) and nonsignificant but elevated risks for follicular lymphoma (RR = 1.47; 95% CI: 0.95–2.27) and hairy cell leukemia (RR = 1.77; 95% CI: 0.99–3.16). No evidence of publication bias was found (Egger’s p = 0.77; Begg’s p = 0.98). Overall, the authors concluded that benzene exposure is causally associated with non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma, satisfying all Bradford Hill criteria for causation.

Lymphoma & Secondhand Smoke

• Diver et al. 2014 — The large prospective study investigated the relationship between exposure to Environmental Tobacco Smoke (ETS) and the risk of non-Hodgkin lymphoma (NHL) among more than 61,000 never-smoking men and women. ETS exposure, encompassing both childhood and adulthood, was not associated with a statistically significant risk for NHL overall, which is the study’s closest measure to Lymphoma as a whole. The multivariable-adjusted Relative Risk (RR) for any ETS exposure compared to no exposure was found to be 0.98 (95% CI: 0.82, 1.17) for overall NHL. However, analyses by histological subtype revealed significant, opposing associations, particularly for intense adult exposure. The risk was highest for follicular lymphoma, with current exposure of six or more hours per week resulting in an RR of 2.37(95% CI: 1.12, 5.04). Conversely, any adult ETS exposure was linked to a statistically significant lower risk of Diffuse Large B-cell Lymphoma (DLBCL), showing an RR of 0.68 (95% CI: 0.48, 0.97)

• Lu et al. 2011 — This large cohort study investigated the effects of active and passive smoking (ETS) on non-Hodgkin lymphoma (NHL) risk in over 120,000 never-smoking and ever-smoking female public school professionals. For active smoking, the overall Relative Risk (RR) for ever-smokers was 1.22 (95% CI: 0.95, 1.57) when compared to a reference group that correctly excluded women with household passive smoking exposure. A significant dose-response was observed, with the heaviest active smokers (>20 cigarettes/day) showing an increased NHL risk with an RR of 1.41 (95% CI: 1.01, 1.96). Among lifelong never-smokers, the study also found a strong, statistically significant association between cumulative passive smoking exposure from all settings and overall NHL risk. The highest duration of passive exposure (>40 years) resulted in an RR of 1.51 (95% CI: 1.03, 2.22) for overall NHL, demonstrating a clear dose-response relationship. The risk was notably elevated for specific subtypes, with the longest duration of passive smoking showing a near three-fold risk for Follicular Lymphoma (RR = 2.89, 95% CI: 1.23, 6.80). Finally, the highest intensity of passive smoking was associated with the highest risk for CLL/SLL (RR = 3.52, 95% CI: 1.54, 8.06)

• Scholkop et al. 2005 — This large Danish-Swedish population-based case-control study investigated the association between cigarette smoking and the risk of non-Hodgkin’s lymphoma (NHL) across various subtypes. Analyzing the risk for NHL overall, the study found little evidence of an association, with the multivariate-adjusted Odds Ratio (OR) for ever smokers being 0.97 (95% CI: 0.87-1.08). Similarly, no significant overall association was found for major B-cell lymphomas when men and women were analyzed together, including follicular lymphoma. However, stratified analyses suggested an increased risk of Follicular Lymphoma specifically among currently smoking women. This finding was statistically significant, showing an OR of 1.41 (95% CI: 1.04-1.92) for female current smokers compared with female never smokers. A separate significant association was found in men, where ever smokers had an increased risk of T-cell Lymphoma (OR, 1.67, 95% CI: 1.11-2.51), though no dose-response relationship was established for any subgroup, leaving limited support for causality.

Lymphoma & Herbicides

• Pahwa et a;. 2019 — This pooled case-control analysis from the North American Pooled Project examined glyphosate exposure and the risk of lymphomas, including 1,690 cases and 5,131 controls. For all lymphomas combined, ever use of glyphosate was associated with an odds ratio (OR) of 1.43 (95% CI: 1.11–1.83) before adjustment, which decreased to 1.13 (95% CI: 0.84–1.51) after adjusting for other pesticides (2,4-D, dicamba, and malathion). The study found a statistically significant increase in risk for those handling glyphosate >2 days per year (OR = 1.73, 95% CI: 1.02–2.94), suggesting a potential exposure–response relationship. Subtype analyses showed elevated, though mostly nonsignificant, ORs for small lymphocytic lymphoma (SLL: OR = 1.79, 95% CI: 0.87–3.69) and diffuse large B-cell lymphoma (DLBCL: OR = 1.23, 95% CI: 0.81–1.88), with lifetime-days of use significantly associated with SLL (p = 0.03). The authors concluded that while results were inconsistent, there was limited evidence of an association between glyphosate exposure and lymphomas, particularly for SLL, warranting further research.

Lymphoma & Benzene

• Rana et al. 2021 — This meta-analysis examined 28 epidemiological studies (20 case-control and 8 cohort) with 9,587 lymphoma cases to evaluate benzene exposure and lymphoma risk. Across all studies, the pooled meta-relative risk (meta-RR) for benzene exposure and all lymphomas (including non-Hodgkin, Hodgkin, and leukemia subtypes) was 1.33 (95% CI: 1.13–1.57), indicating a statistically significant 33% increase in risk. When analysis was restricted to highly exposed individuals, the meta-RR rose to 1.51 (95% CI: 1.22–1.87), demonstrating a dose–response trend. For specific lymphomas, benzene exposure was most strongly associated with diffuse large B-cell lymphoma (RR = 1.67, 95% CI: 1.01–2.77) and showed elevated but non-significant risks for follicular lymphoma (RR = 1.47, 95% CI: 0.95–2.27) and hairy cell leukemia (RR = 1.77, 95% CI: 0.99–3.16). No association was found for Hodgkin lymphoma (RR = 1.00, 95% CI: 0.77–1.28), while myeloid leukemia showed a significantly elevated risk (RR = 1.59, 95% CI: 1.28–1.99). The authors concluded that benzene exposure increases the risk for multiple lymphoma subtypes, with consistent findings across study designs and exposure levels, supporting a causal relationship based on Bradford Hill criteria.

Pulmonary Fibrosis

Preliminary research

Asbestos X Pulmonary Fibrosis (Correlated)

This study analyzed a cohort of asbestos textile workers to assess the risk of asbestosis (a form of pulmonary fibrosis) death based on temporal patterns of asbestos exposure. Among 1823 workers, 51 asbestosis deaths were observed, leading to an overall crude mortality rate of 74 cases per 100,000 person-years. The hazard ratio (HR) for asbestosis death increased significantly with exposure duration, reaching 2.4 for those with >15 years of employment compared to those with <5 years (P=0.014). Conversely, the risk declined with time since last employment (TSLE), showing an HR of 0.3 for >25 years TSLE compared to <5 years (P=0.004). Notably, the risk of asbestosis mortality substantially decreased for exposures beginning after 1968.

Citation: Farioli A, Violante FS, La Vecchia C, et al. Temporal Patterns of Exposure to Asbestos and Risk of Asbestosis: An Analysis of a Cohort of Asbestos Textile Workers. J Occup Environ Med. 2018;60(6):536-541. doi:10.1097/JOM.0000000000001260.¹¹³

Silica X Pulmonary Fibrosis (Correlated)

This review article extensively discusses silicosis, a form of pulmonary fibrosis caused by exposure to respirable crystalline silica. The burden of silica-associated disease remains high globally, with recent outbreaks of severe, progressive forms of silicosis linked to contemporary work practices like artificial stone benchtop manufacturing. The primary factor in developing silicosis is the cumulative respiratory exposure to silica, regulated by occupational exposure limits (typically 0.05-0.1 mg/m³). NIOSH noted a significant risk (at least 1 in 100) of developing chronic radiographic silicosis after 40-45 years of exposure at 0.05 mg/m³. Furthermore, a study estimated the risk of death from silicosis up to age 65 after 45 years of exposure at 0.1 mg/m³ silica to be 13 per 1000, and 6 per 1000 at an exposure of 0.05 mg/m³. The article highlights that while silicosis is completely preventable, workers continue to suffer from progressive or fatal disease, necessitating constant vigilance and control of silica exposure sources. Citation: Hoy RF, Chambers DC. Silica-related diseases in the modern world. Allergy. 2020;75:2805-2817. doi:10.1111/all.14202.¹¹⁴

Diesel Exhaust X Pulmonary Fibrosis (Correlated)

This systematic review and meta-analysis investigated the impact of occupational exposures, including vapors, gas, dust, and fumes (VGDF), on the risk of Idiopathic Pulmonary Fibrosis (IPF). While the article categorizes “vapors, gas, dust, and fumes” as a broad exposure type that would include diesel exhaust, it does not isolate diesel exhaust as a specific exposure category. The study found a pooled odds ratio (OR) for VGDF of 1.8 (95% CI, 1.3-2.4), indicating an 80% increased risk of IPF among those exposed. This corresponds to a pooled population attributable fraction (PAF) of 21% (95% CI, 15-28%), suggesting that approximately one in five IPF cases could be prevented by eliminating occupational VGDF exposure. Although specific odds ratios for diesel exhaust alone are not provided, the findings indicate a substantial contribution of general inhaled occupational exposures, including fumes, to the development of IPF.

Citation: Gandhi SA, Min B, Fazio JC, et al. The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2024;21(3):486-498. doi:10.1513/AnnalsATS.202305-402OC.¹¹⁵

Benzene X Pulmonary Fibrosis (no correlative papers found)

No correlative papers found on benzene and pulmonary fibrosis. “Benzene and Lung Disease.pdf,” focuses exclusively on the association between benzene exposure and lung cancer risk, not pulmonary fibrosis. It discusses lung cancer incidence, prevalence, and mortality in relation to benzene exposure, including various risk estimates like prevalence rates of 1.20 and mortality rates of 1.15. The study also highlights a 34% increased risk of lung cancer when studies adjusted for smoking habits. While it confirms benzene as a human carcinogen primarily linked to leukemia, it does not contain information on pulmonary fibrosis or any related odds ratios, hazard ratios, standard mortality rates, relative risks, or levels of exposure for that condition.

Citation: Chiavarini M, Rosignoli P, Sorbara B, Giacchetta I, Fabiani R. Benzene Exposure and Lung Cancer Risk: A Systematic Review and Meta-Analysis of Human Studies. Int J Environ Res Public Health. 2024;21(2):205. doi:10.3390/ijerph21020205.¹¹⁶

TCE/PCE X Pulmonary Fibrosis (no correlative papers found for humans)

This review article examines the respiratory effects of trichloroethylene (TCE) exposure, including its potential link to pulmonary fibrosis. The article highlights an animal study where a single acute dose of TCE induced pulmonary fibrosis in mice, which was detected 15 days post-exposure and progressed over 90 days, leading to diffuse interstitial fibrosis, alveolar septa thickening, and increased lung elastic recoil. This suggests that TCE can cause progressive structural and functional lung abnormalities consistent with chronic respiratory disease in animal models. However, the review does not provide specific odds ratios, hazard ratios, standard mortality rates, relative risks, or detailed levels of exposure for TCE or PCE in relation to pulmonary fibrosis in human epidemiological studies. While the review extensively discusses other respiratory effects like lung cancer and vascular diseases, the evidence for a direct link between TCE/PCE and human pulmonary fibrosis is drawn primarily from mechanistic animal studies.

Citation: Dumas O, Despreaux T, Perros F, et al. Respiratory effects of trichloroethylene. Respir Med. 2018;134:47-53.¹¹⁷

PAHs / Creosote X Pulmonary Fibrosis (no correlative papers found for PF)

This review explores the potential role of polycyclic aromatic hydrocarbons (PAHs) in air pollution-induced non-malignant respiratory diseases, though it does not specifically mention “pulmonary fibrosis” or “creosote.” However, it broadly discusses obstructive lung diseases and related physiological processes. The study cites a historical cohort of nearly 60,000 asphalt workers (men) from various countries, concluding that exposure to PAHs might have contributed to mortality from obstructive lung diseases, though confounding and bias could not be fully ruled out. It states that current air quality guidelines, based on the carcinogenic effects of benzo[a]pyrene, may not sufficiently protect against various non-malignant pulmonary outcomes. The article emphasizes that PAHs can trigger oxidative stress, inflammation, and smooth muscle constriction, all of which are implicated in respiratory pathology. Citation: Låg M, Øvrevik J, Refsnes M, Holme JA. Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases. Respir Res. 2020;21(1):299.¹¹⁸

Welding Fumes X Pulmonary Fibrosis (Correlated)

This study investigated the risk of lung-related diseases, including pneumoconiosis (a form of pulmonary fibrosis), associated with welding fume exposure in an occupational population. It found that welders had a significantly increased risk of lung-related diseases, with a hazard ratio (HR) of 2.17 (95% CI: 1.31-3.57, p<0.05) compared to non-welders. Among male welders, the risk of pulmonary disease was even higher at 2.24 (95% CI: 1.34-3.73, p<0.05). The study also identified a strong dose-response relationship, with “high-high” exposure to welding fumes posing a 5.39 times higher risk (95% CI: 2.52-11.52, p<0.001) for lung-related diseases compared to “low-low” exposure. This indicates that higher concentrations of welding fumes significantly elevate the likelihood of developing lung conditions such as pneumoconiosis. The research highlights the critical need for improved occupational health protection for welders.

Citation: Li G, Jiang J, Liao Y, et al. Risk for lung-related diseases associated with welding fumes in an occupational population: Evidence from a Cox model. Front Public Health. 2022;10:990547. doi:10.3389/fpubh.2022.990547.¹¹⁹

Magnesium X Pulmonary Fibrosis (only papers discussing the benefits of Mg)

This article investigates the therapeutic potential of Magnesium isoglycyrrhizinate (MgIG) in ameliorating radiation-induced pulmonary fibrosis (RIPF). The study demonstrates that MgIG treatment significantly improved lung pathological changes and reduced collagen deposition in mice with RIPF. MgIG also effectively mitigated oxidative damage and inhibited fibroblast differentiation, a key process in fibrosis, which was linked to the modulation of the p38MAPK/Akt/Nox4 signaling pathway. While the article highlights MgIG’s role as a promising anti-fibrotic agent for RIPF, it does not provide specific odds ratios, hazard ratios, standard mortality rates, relative risks, or levels of exposure for magnesium itself in relation to the development or prevalence of pulmonary fibrosis. Instead, the focus is on the therapeutic effect of a magnesium-containing compound in an induced animal model of the disease.

Citation: Yang Q, Zhang P, Liu T, et al. Magnesium isoglycyrrhizinate ameliorates radiation-induced pulmonary fibrosis by inhibiting fibroblast differentiation via the p38MAPK/Akt/Nox4 pathway. Biomed Pharmacother. 2019;115:108955.¹²⁰

Roundup/Herbicides X Pulmonary Fibrosis (weak correlation)

This case report focuses on four patients who developed irreversible pulmonary fibrosis after herbicide intoxication, specifically from paraquat and diquat. It highlights lung transplantation as the only therapeutic option for these individuals, with a median time from intoxication to transplantation of 27.5 days. While the article discusses the severe lung injury caused by paraquat and diquat, leading to irreversible pulmonary fibrosis, it does not provide specific odds ratios, hazard ratios, standard mortality rates, relative risks, or levels of exposure for Roundup or other general herbicides in relation to pulmonary fibrosis. Instead, it details the clinical course and successful outcomes of delayed bilateral lung transplantation with extensive perioperative support for these specific herbicide poisoning cases. The study emphasizes that despite the highly toxic nature of these herbicides and the lack of antidotes, a multidisciplinary approach can lead to long-term survival for patients with irreversible pulmonary fibrosis. Citation: Jiao G, Li X, Wu B, et al. Case Report: Delayed Lung Transplantation With Intraoperative ECMO Support for Herbicide Intoxication-Related Irreversible Pulmonary Fibrosis: Strategy and Outcome. Front Surg. 2021;8:754816. doi:10.3389/fsurg.2021.754816.¹²¹

Secondhand Smoke X Pulmonary Fibrosis (Correlated)

This 9-year nationwide population-based study investigated risk factors for interstitial lung disease (ILD), which includes pulmonary fibrosis. While the study primarily focused on direct smoking, it noted that smoking (likely including direct and potentially indirect exposure) was significantly associated with ILD development, with a hazard ratio (HR) of 1.2 (95% CI: 1.1-1.4). This indicates a 20% increased risk. Although the article doesn’t explicitly quantify the link between secondhand smoke and ILD with specific odds ratios or hazard ratios, it acknowledges that “three different population-based studies determined that cigarette smoking is a risk factor for lung parenchyma mal as well as interstitial abnormalities.” It identifies smoking as a notable risk factor for ILD development, alongside hepatitis C, history of tuberculosis, pneumonia, COPD, male sex, and older age, all contributing to an understanding of factors that can lead to fibrotic lung conditions.

Citation: Choi W-I, Dauti S, Kim HJ, Park SH, Park JS, Lee CW. Risk factors for interstitial lung disease: a 9-year Nationwide population-based study. BMC Pulm Med. 2018;18(1):96. doi:10.1186/s12890-018-0660-2.¹²²

NHL

NHL x Asbestos (Not strongly correlated)

• Goodman et al. (1999)

This meta-analysis of 69 asbestos-exposed occupational cohorts found no clear association between asbestos exposure and lymphoma or related cancers. The pooled Standardized Mortality Ratio (Meta-SMR) for Lymphoma/myeloma was 0.89 (95% CI: 0.71–1.10) for studies without a latency period. This finding was not statistically significant. The Meta-SMR for All lymphatic/hematopoietic cancers combined was 0.93 (95% CI: 0.82–1.05). This non-significant finding suggested that asbestos exposure does not increase the mortality rate for these cancers compared to the general population.¹²³

• Wurtz et al. (2020)

Danish Cohort Study on Hematological Malignancies (Würtz et al., 2020): This study specifically examined lymphoma (a combined subgroup including NHL) and found no statistically significant association with long-term occupational asbestos exposure. The Hazard Ratio (HR) for the Combined lymphoma subgroup (Hodgkin, non-Hodgkin, and multiple myeloma) for occupational exposure was non-significant, ranging from 0.99 to 0.94 across different job-exposure models (e.g., JEM2 exposure: HR = 0.99, 95% CI: 0.80-1.22).¹²⁴

NHL x Silica (Not correlated)

NHL x Creosote/ PAHs (Not correlated)

• Alicandro et al. (2016)

• This systematic review and meta-analysis investigated the risk of lymphatic and hematopoietic neoplasms, including non-Hodgkin lymphoma (NHL), among workers with high occupational exposure to polycyclic aromatic hydrocarbons (PAH). The study included 41 cohort studies on various jobs and industries entailing high PAH exposure, such as aluminum production, iron and steel foundries, cokeries, carbon electrode manufacturing, asphalt workers, creosote-exposed workers, and tar distillery workers. The overall conclusion of the meta-analysis is that workers in jobs or industries involving high PAH exposure did not have a significant excess risk of any lymphatic and hematopoietic neoplasms. Most meta-relative risks (meta-RRs) across the 18 meta-analytic estimates (by job/industry and neoplasm type) were close to unity, ranging between 0.72 and 1.27. The study found no association between occupations with high PAH exposure and the risk of multiple myeloma (MM) or leukemia. Meta-Relative Risk (meta-RR): The meta-RR for NHL among creosote-exposed workers was 2.01 with a 95% confidence interval (CI) of 0.96–4.22, based on 7 cases from 2 studies. This association did not reach the level of statistical significance (P > 0.05), as the confidence interval included.¹²⁵

NHL x Diesel Exhaust (Somewhat Correlated)

• Karunanayake et al. (2008)

This document is a research article reporting on a six-province Canadian population-based case-control study of men diagnosed with Non-Hodgkin’s Lymphoma (NHL) between 1991 and 1994. The objective was to study the association between NHL and occupational exposures related to long-held occupations among males. The study included 513 incident cases and 1,506 controls. Diesel Exhaust Fumes: Ever exposure to diesel exhaust fumes showed a significant association with NHL101010. The OR for “Ever exposed to diesel (yes)” in the final multivariate model was 1.28 (95% CI: 1.02, 1.61) for the farmer model and 1.23 (95% CI: 0.97, 1.56) for the machinist model.¹²⁶

NHL x Benzene (Correlated)

• Rana et al. (2021)

The objective of this comprehensive systematic review and meta-analysis was to evaluate a wide array of human epidemiological studies to clarify the potential link between benzene exposure and the risk of NHL. The review followed PRISMA guidelines and included 20 case-control studies and 8 cohort studies, totaling 9,587 patients with NHL. The authors found sufficient evidence to support all the Hill considerations for assigning causation, suggesting a causal link between benzene exposure and NHL. The meta-relative risk (meta-RR) for all highly exposed groups combined was 1.33 (95% CI 1.13–1.57). When the analysis was restricted to studies that provided results specifically for highly exposed individuals (n=18), the meta-RR rose to 1.51 (95% CI 1.22–1.87). e risk was highest for the major NHL subtype, Diffuse Large B-cell Lymphoma (DLBCL), which showed a doubling of risk. The meta-RR for DLBCL was 1.67 (95% CI 1.01–2.77). The robust nature of these findings, consistent across numerous sensitivity analyses, strongly suggests a true causal relationship. The paper concluded that this study provides new collective evidence to suggest that exposures to benzene can induce NHL in humans at high levels.¹²⁷

• Liu et al. (2022)

This systematic review and meta-analysis aimed to provide evidence that benzene exposure increases the risk of NHL, addressing previous controversial findings. The analysis included 14 observational studies (9 cohort and 5 case-control) with a total of 492,719 participants. The study determined that its findings were statistically and biologically feasible and met most of the Bradford Hill criteria for causal inference. The overall analysis, using a random-effects model, found a significant adverse association, concluding that the Odds Ratio (OR) of NHL in the exposed population was 1.23 (95% CI 1.01, 1.51; P=0.03). The subgroup analysis of people with high exposure to benzene showed a markedly higher risk with an OR of 1.81 (95% CI 1.34, 2.43). This risk was particularly pronounced in the Chinese population (OR=2.48, 95% CI 1.24, 4.94). The authors concluded that benzene exposure was positively correlated with the incidence of NHL. They noted that the heightened risk in the high-exposure group (defined as an annual average exposure concentration greater or equal to 25 ppm or cumulative concentration greater than or equal to 720 ppm strengthens the causal interpretation.¹²⁸

• Steinmaus et al. (2008)

This meta-analysis aimed to clarify the link between benzene and NHL by correcting for methodological biases common in occupational studies, such as the healthy worker effect and exposure misclassification. The study included 22 benzene exposure studies and 21 petroleum refinery studies. The summary Relative Risk (RR) for all 22 benzene exposure studies combined was 1.22 (95% CI 1.02–1.47; one-sided p=0.01). When the analysis was confined to high benzene exposure groups—a correction for exposure misclassification—the summary RR increased to 1.49 (95% CI 1.12–1.97). For the 21 refinery studies, adjusting for the healthy worker effect raised the summary RR from 1.21 (95% CI 1.00–1.46) to 1.42 (95% CI 1.19–1.69). The highest risk estimate of RR 2.12 (95% CI 1.11–4.02) was found when studies based primarily on self-reported exposure were excluded. The authors concluded that the elevated relative risks in high-exposure cohorts and the results after adjusting for biases provide further evidence that benzene exposure causes NHL. They stressed that misclassification and the failure to exclude unexposed workers could mask this effect in other occupational studies.¹²⁹

• Blair et al. (1993)

This population-based case-control study, conducted among 1,867 white men in Iowa and Minnesota, sought to develop hypotheses on the causes of NHL by evaluating risks from occupation, industry, and selected chemical exposures, including benzene. The study found a general lack of statistically significant associations, acknowledging that small numbers and limitations in exposure assessment would tend to reduce opportunities to detect associations. The analysis of the relationship between benzene and NHL was suggestive of a dose-response relationship. The overall Odds Ratio (OR) for benzene exposure was 1.1 (95% CI 0.9–1.4). When stratified by exposure intensity, the OR for lower intensity was 1.1 (95% CI 0.8–1.4), and the OR for higher intensity was 1.5 (95% CI 0.7–3.1). Crucially, the risk for Follicular NHL (OR for higher intensity: 1.9, 95% CI 0.7–5.3) and Diffuse NHL (OR for higher intensity: 1.8, 95% CI 0.6–5.4) rose with increased intensity of exposure to benzene. The level of exposure was assigned using an industrial hygienist’s assessment based on job duties, scored on a 3-point scale for intensity (low, medium, or high). The study concluded that while industrial exposures are likely not a major contributor to the overall etiology of NHL, the observed associations, particularly the rise in risk with increasing intensity of benzene exposure, deserve further evaluation.¹³⁰

• Smith et al. (2007)

This systematic review and evaluation focused on clarifying the ambiguous association between exposure to benzene and NHL, a link that was less clear than benzene’s established role in causing leukemia. The authors undertook a systematic review of all case-control and cohort studies that identified probable occupational exposures to benzene and NHL morbidity or mortality. The overall findings strongly supported an association. The review identified 40 of 43 (93%) case-control studies that showed some elevation of NHL risk, with 23 of 43 (53%) finding a statistically significant association. Similarly, for studies of petroleum refinery workers, 23 of 26 (88%) showed that the rate of lymphoma morbidity or mortality was higher than that for all neoplasms. This suggested that the healthy-worker effect was likely masking the true risk, as the overall mortality rate for these workers was generally reduced. For case-control studies specifically looking at benzene, exposure to medium/high exposure to benzene-containing solvents resulted in an Odds Ratio (OR) of 1.6 (95% CI: 1.0–2.4). For the Diffuse NHL subtype, the OR was 2.4 (95% CI: 1.3–4.5) for medium/high occupational benzene exposure. Studies of refinery workers showed that the standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma (a subtype of NHL) was 132 (95% CI 74-217) for workers at one refinery. The authors concluded that the evidence supports an association between occupational benzene exposure and NHL, noting that potential mechanisms include immunotoxicity and the induction of double-strand breaks, which leads to chromosomal damage.¹³¹

• Francisco et al. (2023)

This comprehensive systematic review and meta-analysis investigated the epidemiologic relationship between NHL and a wide range of occupational exposures, confirming an increased risk from multiple chemical compounds, including benzene. The analysis included 51 observational studies (case-control, cohort, and cross-sectional). The overall meta-analysis found a statistically significant result, concluding that occupational exposures are associated with a 27% increase in the risk of NHL. The overall Odds Ratio (OR) for all industrial branches combined was 1.27 (95% CI 1.04–1.55). The risk was statistically significant for the Diffuse Large B-cell Lymphoma (DLBCL) subtype, with a meta-OR of 1.13 (95% CI 1.04–1.23). This association was largely driven by studies evaluating exposure to solvents, including benzene. The review identified an elevated risk specifically associated with exposure to certain chemical compounds, mainly pesticides, benzene, and trichloroethylene. The meta-analysis also cited individual studies showing significant risk increases for NHL from exposure to factory employees exposed to benzene (OR 1.78, 95% CI 1.13-2.81) and workers exposed to solvents (OR 1.61, 95% CI 1.29-2.01). The synthesis of evidence supports an increased risk for NHL from occupational exposure to benzene and other specific compounds.¹³²

NHL x Chlorinated Solvents (TCE) (Correlated)

• Raaschou-Nielsen et al. (2003)

This large prospective cohort study evaluated cancer incidence in over 40,000 Danish blue-collar workers with documented trichloroethylene (TCE) use. The overall findings for NHL were not statistically significant; the Standardized Incidence Ratio (SIR) for men was 1.2 (95% CI 0.9–1.5), and for women was also 1.2 (95% CI 0.7–2.1). However, when stratified by exposure level, a statistically significant finding emerged for a specific NHL subtype. For men with greater than or equal to years of High exposure (50+ ppm), the SIR for Diffuse Non-Hodgkin’s Lymphoma was 3.3 (95% CI 1.2–7.2). The study concludes that exposure to TCE may be a risk factor for NHL and supports the classification of TCE as a human carcinogen.¹³³

• Purdue et al. (2011)

This case-control study investigated the association between occupational exposure to trichloroethylene (TCE), a chlorinated solvent, and the risk of NHL by utilizing detailed industrial hygienist-assessed exposure data. The study found a consistent trend of elevated risk for NHL at the highest estimated exposure levels. For the highest tertile of estimated average weekly exposure to TCE, the Odds Ratio (OR) was 2.5 (95% CI 1.1–6.1), providing statistically significant evidence of an increased risk. Similarly, the OR was 2.3 (95% CI 1.0–5.0) for the highest tertile of estimated cumulative exposure. The level of exposure was assessed using estimated cumulative lifetime exposure metrics, classified into quartiles/tertiles. The authors concluded that their findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL.¹³⁴

NHL x Herbicides (Correlated)

• Schinasi and Leon (2014)

This comprehensive paper conducted a systematic review and meta-analysis of nearly three decades of epidemiologic research on NHL and occupational exposure to agricultural pesticide chemical groups and active ingredients. The study focused on extracting and pooling estimates of associations for 21 pesticide chemical groups and 80 active ingredients from 44 primary studies, mainly relying on self-reported occupational exposure among farmers and agricultural workers. The meta-analyses found elevated and statistically significant meta-relative risks (meta-RR) for several herbicide and pesticide groups. Specifically, the meta-RR for Phenoxy Herbicides was 1.45 (95% CI 1.13–1.86), while Organophosphorus Insecticides had a meta-RR of 1.32 (95% CI 1.09–1.60). The analysis highlighted several individual herbicides—including dicamba, atrazine, and 2,4-D—that showed significantly increased risks for NHL subtypes. The authors emphasized that the complexity of exposure to mixtures makes it difficult to definitively isolate the risk of a single agent, but concluded that the evidence supports an association between occupational exposure to several pesticide classes and NHL.¹³⁵

• Zhang et al. (2019)

This meta-analysis investigated the association between exposure to glyphosate-based herbicides (GBHs) and the risk of NHL in humans, concluding that there is a compelling link. The study selectively focused on the highest exposure groups from each study to counter previous dilution bias. The analysis found a significant increase in risk, reporting an overall meta-Relative Risk (meta-RR) of 1.41 (95% CI 1.13–1.75) for highly exposed individuals compared to the unexposed. The level of exposure was defined by a hypothesis targeting high cumulative exposures to GBHs. This risk estimate reflected an increased risk of 41% for NHL in this highly exposed population. The analysis incorporated evidence from human epidemiological studies, animal studies, and mechanistic studies to support the biological plausibility that GBHs can cause genetic alterations and immunosuppression linked to lymphomagenesis. The conclusion suggests that high occupational exposure to glyphosate-based herbicides is associated with an increased risk for NHL.¹³⁶

• Kato et al. (2005)

This population-based case-control study assessed whether home and occupational exposure to organic solvents and specific chemicals was associated with an increased risk of NHL in women. Although the primary focus was on solvents, the questionnaire also assessed exposure to pesticides and herbicides. The study found elevated, though generally non-significant, risks for overall solvent exposure, suggesting that the limited power for specific exposures might mask a genuine effect. The Odds Ratio (OR) for occupational exposure to pesticides was 1.33 (95% CI 0.54–3.27) when compared to the unexposed. The OR for home use of pest strips/pesticide strips was 1.62 (95% CI 0.96–2.73), nearing statistical significance. The level of exposure was based on self-reported responses to whether the participant had ever used the product in the home or workplace. The article’s main conclusion was that a relationship between solvent and pesticide exposure and NHL is plausible but requires further, larger studies.¹³⁷

NHL x Welding Fumes (Somewhat correlated)

• Zheng et al. (2002)

For male workers classified as “Welders and solderers” (SOC code 771), the study found a statistically significant increased risk of NHL and Chronic Lymphocytic Leukemia (CLL) combined, Odds Ratio (OR): 2.9 (95% Confidence Interval [CI]: 1.2–6.9). The risk estimate increased when analyzed by duration of employment, with the OR for those working 10 or more years rising to 3.5 (95% CI: 1.4–8.6). Welders and solderers specifically showed an increased risk for diffuse NHLs (OR: 3.4; 95% CI: 1.2–9.8) and “other” types of NHL (OR: 3.6; 95% CI: 1.0–13). The authors suggest that the risk in metalworking occupations, which include welders, may be associated with contact with metals and various organic solvents.¹³⁸

• Persson et al. (1989)

The initial crude analysis for welding suggested an increased risk of NHL (Crude OR: 1.9), though this value was below the threshold of OR greater than or equal to 2 used to select variables for the final logistic model. In the final multivariate logistic regression analysis (which adjusted for confounding factors like age, sex, farming, and exposure to fresh wood), the risk for welding and NHL was found to be non-significant, Logistic OR: 1.0 (90% CI: 0.3 -2.7). The authors note that for Hodgkin’s disease (where a significant association with welding was found), the causative agent is unclear, but welders are exposed to metal fumes and electromagnetic fields.¹³⁹

NHL x Secondhand Smoke (Not correlated)

• Diver at al. (2014)

• The study, which used data from the Cancer Prevention Study II Nutrition Cohort, found that environmental tobacco smoke (ETS), or secondhand smoke, was not associated with the risk of Non-Hodgkin Lymphoma (NHL) overall in never-smoking men and women. However, the association differed significantly by NHL histological subtype 2. The correlation with ET was observed for Follicular Lymphoma FL, demonstrating a dose-response relationship, and an inverse association was seen for Diffuse Large B-cell Lymphoma (DLBCL).¹⁴⁰

Prostate

Prostate and Asbestos

Dutheil et. al. (2020)

This systematic review and meta-analysis of 33 studies sought to determine the link between asbestos exposure and prostate cancer risk across 723,566 individuals. The overall pooled analysis confirmed that asbestos exposure is associated with a slightly but significantly increased risk, yielding an aggregate Effect Size (ES), which functions as a relative risk, of 1.10 (95% CI 1.05–1.15). The analysis separated risk based on the level of exposure, finding that environmental exposure conferred an ES of 1.25 (95% CI 1.01–1.48), while occupational exposure had a lower ES of 1.07 (95% CI 1.04–1.10). Moreover, the risk appeared to be fiber-specific, as the amosite group showed an increased ES of 1.12 (95% CI 1.05–1.19), but the chrysotile/crocidolite group did not yield a significant result. The study therefore concludes that asbestos exposure, particularly from environmental sources, contributes to a modest increase in prostate cancer risk, predominantly through respiratory inhalation.¹⁴¹

Prostate and PAHs and Benzene

Lee et. al. (2023)

This meta-analytic review of 38 studies confirms that the occupational exposure of firefighters to carcinogens, including PAHs and benzene, is significantly associated with an elevated prostate cancer risk. The combined results indicate that the incident cancer risk for prostate cancer is significantly higher for firefighters compared to the general population. Specifically, the pooled Standardized Incidence Risk (SIR), which serves as a relative risk for incidence, for prostate cancer was calculated as 1.09 (95% CI: 1.04-1.14), showing a 9% increased risk. The level of exposure is noted to be “carcinogenic to humans (Group 1)” based on strong mechanistic evidence that the occupational exposures (including inhalation, ingestion, or skin contact with PAHs and benzene) exhibit carcinogenic characteristics. Though the study does not provide a direct Odds Ratio or Hazard Ratio for prostate cancer attributable only to benzene or PAHs, the elevated risk is contextualized within the overall, unavoidable exposure to these and other known carcinogens during firefighting activities¹⁴²

Prostate and Diesel Exhaust

Järvholm and Silverman (2003)

This cohort study of 6,364 Swedish construction truck drivers investigated cancer risk associated with occupational exposure to diesel exhaust. Compared to an internal reference group of carpenters and electricians, truck drivers demonstrated an increased risk for prostate cancer. The study found 124 observed cases of prostate cancer against 99.7 expected cases in the truck driver cohort. This translates to a Standardized Incidence Rate (SIR), which serves as a relative risk for incidence in this context, of approximately 1.24. This means the group with typical truck driving exposure to diesel exhaust had a 24% higher incidence of prostate cancer than the reference group. The authors noted that this finding was consistent with previous literature suggesting a positive association between diesel exhaust exposure and prostate cancer risk.¹⁴³

Prostate and Herbicides

Glover et. al. (2024)

The study found a significant association between exposure to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and the risk of prostate cancer among U.S. men, marking the first and largest nationally representative analysis of this relationship. The median urinary 2,4-D exposure level was 0.28 μg/L in the cohort. Increasing exposure was linked to higher odds of prostate cancer, yielding an overall Odds Ratio (OR) of 1.72 (95% CI [1.2, 2.4]). Men in the highest quartile of 2,4-D exposure faced a substantially elevated risk, with an OR=3.46 (95% CI [1.11, 10.72]) compared to the lowest quartile. The risk was even more pronounced for men age 70+ in the highest exposure quartile, with an OR=3.79 (95% CI [1.51, 9.52]). These findings are significant because they suggest that 2,4-D, a chemical whose use is rising, may contribute to the etiology of prostate cancer through mechanisms like oxidative stress and endocrine disruption, warranting further investigation to corroborate the results and determine public health implications.¹⁴⁴

Testicular

Asbestos and Testicular Cancer

• Summary: The relationship between asbestos and tumors of the testicle primarily concerns Malignant Mesothelioma of the Tunica Vaginalis Testis (MMTVT), a rare cancer of the testicle’s lining, rather than typical testicular germ cell cancer. There is no established scientific link between asbestos exposure and germ cell testicular cancer.

• Marinaccio et al. 2020: This case-control study utilized data from the Italian national mesothelioma registry (ReNaM) from 1993 to 2015 to examine the link between asbestos exposure and MMTVT. The authors identified a statistically significant association with occupational asbestos exposure, reporting an Odds Ratio (OR) of 3.42 (95% CI: 1.93–6.04) for those with a history of occupational exposure compared to controls. This was a crucial finding as it provided the first analytical evidence to support a causal role of asbestos in MMTVT, strengthening the link between occupational hazards and this very rare form of cancer.¹⁴⁵

Silica and Testicular Cancer

• Summary: There is inadequate evidence to link exposure to crystalline silica dust with an increased risk of testicular cancer.

• Hobbesland et al. 1999: This Norwegian cohort study examined cancer incidence among 8,530 male workers employed in eight plants producing ferrosilicon and silicon metal, industries involving high potential exposure to crystalline silica. The researchers compared cancer incidence to the general Norwegian male population to determine the risk of various cancers. Among furnace workers, who had a high exposure intensity to fumes and dust containing crystalline silica, the Standardized Incidence Ratio (SIR) for testicular cancer was significantly elevated at 2.30 (95% CI 1.09–4.84), based on six observed cases. This finding suggests that occupational exposure in the ferrosilicon and silicon metal production environment, which includes silica, may be associated with more than a doubled risk of testicular cancer incidence.¹⁴⁶

Diesel Exhaust and Testicular Cancer

• Summary: Studies investigating the risk of testicular cancer—including those examining prenatal exposure in the sons of exposed fathers—have generally reported null or inconsistent findings.

• Guo et al. 2004: This large-scale cohort study followed all economically active Finnish men born between 1906 and 1945 from 1971 to 1995 to examine the risk of several cancers in relation to engine exhaust. Occupational exposure to diesel exhaust was estimated using a job-exposure matrix (FINJEM) to calculate a cumulative exposure (CE) score. The results showed no discernible effect or evidence of an exposure-response relationship between cumulative diesel exhaust exposure and the risk of testicular cancer. Specifically, the Relative Risk (RR) for the highest cumulative exposure category of diesel exhaust was 0.98 (95% CI 0.46−2.09), indicating no significant increase in risk compared to the unexposed group.¹⁴⁷

Benzene and Testicular Cancer

• Summary: Benzene is strongly linked to hematological malignancies, and epidemiological evidence for a causal link to testicular cancer is inadequate.

• Godono et al. 2025: This systematic review and meta-analysis synthesized data from multiple occupational studies to examine the association between occupational benzene exposure and the risk of male genital cancers, including testicular cancer. The researchers categorized exposure simply as “occupational benzene exposure” but did not isolate specific quantitative levels for testicular cancer in the main pooled analysis. The Standardized Incidence Ratio (SIR) for the pooled incidence data on testicular cancer was found to be 0.99 (95% CI 0.81−1.22), which indicates no statistically significant association between occupational benzene exposure and testicular cancer incidence or mortality. This finding suggests that, based on the current body of evidence aggregated across various studies, benzene exposure is not a clear, independent risk factor for testicular cancer.¹⁴⁸

Chlorinated Solvents and Testicular Cancer

• There is limited/emerging epidemiological evidence for the association between exposure to chlorinated solvents and testicular cancer.

• Guth et al. 2024: This French national case-control study investigated the link between lifetime occupational exposure to organic solvents, including trichloroethylene, and the risk of testicular germ cell tumors (TGCT). The study used a combined exposure assessment method (Job-Exposure Matrix, self-reported data, and expert assessment) to estimate exposure to TCE in 454 cases and 670 controls. Results showed a consistent association between TGCT and exposure to trichloroethylene, with the Odds Ratio (OR) for exposed versus not exposed being 2.59 (95% CI: 1.42–4.72) using the combined assessment approach. This high-quality exposure assessment suggests that occupational exposure to TCE may be involved in the development of TGCT among exposed men.¹⁴⁹

Welding Fumes and Testicular Cancer

• Summary: There is insufficient evidence to link exposure to welding fumes and testicular cancer.

• Bijoux et al. 2025: This French nationwide case-control study (TESTIS-Pro Study) investigated the association between the subjects’ own occupational exposure to heavy metals and welding fumes and the risk of Testicular Germ Cell Tumors (TGCT). Exposure was classified using a job-exposure matrix, with a high co-occurrence of various heavy metals and welding fumes. Researchers observed a positive association for low occupational cumulative exposure to welding fumes, yielding an Odds Ratio (OR) of 1.62 (95% CI, 1.01-2.58), suggesting a modest increased risk of TGCT among those with this exposure level. However, the high correlation between all co-occurring heavy metals and welding fumes warrants further mechanistic studies to isolate the specific contribution of welding fumes.¹⁵⁰

Creosote/PAHs and Testicular Cancer

• Summary: There are very few articles examining Creosote/PAHs and testicular cancer in humans. Napoli et al. did not include ratios for risk of testicular cancer and the other two studies did not look at PAHs directly but firefighting, an occupation exposed to PAHs.

• Di Napoli et al. 2025: This comparative study investigated the link between testicular tumors in humans and dogs and the presence of environmental contaminants in the Campania region of Italy. The study analyzed 174 human cases and 221 canine cases of testicular cancer, comparing their occurrence to areas with documented soil and water contamination. The environmental contaminants of focus included a broad class of endocrine disruptors, such as Polycyclic Aromatic Hydrocarbons (PAHs), that are widely distributed in industrialized areas. The analysis demonstrated a strong correlation between the frequency of testicular tumors and the presence of these pollutants. The authors noted that the ubiquitous and prolonged level of exposure to these endocrine disruptors is considered a strong risk factor for testicular cancer development in both species. Due to the study’s comparative epidemiological design, it focuses on correlation and geographic distribution rather than providing a specific numerical risk ratio, such as a Hazard Ratio (HR) or Odds Ratio (OR), for PAH exposure.¹⁵¹

• LeMasters et al. 2006: This is a comprehensive meta-analysis of 32 epidemiological studies that investigated cancer risk among firefighters. The researchers concluded that testicular cancer had the strongest and most “probable” association with firefighting exposure among all cancers examined. Specifically, the study reported a Summary Risk Estimate (SRE) of 2.02, which indicates that firefighters are approximately twice as likely to develop testicular cancer compared to the non-exposed population. This elevated risk is directly attributed to the occupational exposure profile of firefighters, which includes high levels of Polycyclic Aromatic Hydrocarbons (PAHs) and other combustion products. This SRE of 2.02 (95% CI: 1.30–3.13) provided significant evidence classifying testicular cancer as a likely occupational hazard. The meta-analysis, therefore, established a statistically robust link between the profession and this specific cancer.¹⁵²

• Bates et al. 2001: This is a historical cohort analysis that specifically examined cancer incidence among all paid New Zealand firefighters between 1977 and 1995. This research was one of the foundational studies to directly link firefighting as an occupation to an increased risk of testicular cancer. The study found a highly elevated cancer rate, confirming an increased risk for testicular cancer with a Standardized Incidence Ratio (SIR) of 3.0 for the 1990–1996 period. An SIR of 3.0 (95% CI: 1.3–5.9) means the incidence of testicular cancer in this cohort was three times higher than expected in the general male population. Although the study focused on the occupation itself, subsequent analyses have widely implicated the chronic exposure to PAHs and other combustion byproducts as the primary cause of this elevated SIR. The Bates study thus provided crucial, high-magnitude evidence supporting the classification of testicular cancer as an occupational disease for firefighters.¹⁵³

Herbicides/Glyphosate and Testicular Cancer

• Summary: The association between glyphosate and testicular cancer is marked by limited and inconclusive evidence. While some studies suggest a link between broad pesticide/solvent exposure and testicular cancer, no consistent, specific epidemiological evidence supports a causal relationship for glyphosate itself.

• Danjou et al. 2021: This French case-control study investigated the association between parental domestic use of herbicides and other pesticides during a son’s early life (from one year pre-conception to one year post-birth) and the risk of Testicular Germ Cell Tumor (TGCT) in adulthood. For any domestic use of herbicides (the general class that includes glyphosate/Roundup), the study found an Odds Ratio (OR) of 1.15 (95% CI, 0.67–2.00). The level of exposure was measured through maternal recall of “any use” of herbicides during gardening and other domestic activities. This non-significant elevated risk for herbicides contrasts with a statistically significant elevated risk found for fungicides in the same study population, suggesting that the primary concern in this context may not be driven by herbicide exposure.¹⁵⁴

Secondhand Smoke and Testicular Cancer

• Summary: The comprehensive body of epidemiological research has not established a consistent or causal association with testicular cancer risk.

• McGlynn et al. 2006: The Servicemen’s Testicular Tumor Environmental and Endocrine Determinants study, published in Cancer Epidemiology, Biomarkers & Prevention, investigated the relationship between passive smoking exposure and the risk of testicular germ cell tumors (TGCT) in 754 cases and 928 controls. Overall, the study found no statistically significant relationship between TGCT risk and maternal smoking (Odds Ratio [OR], 1.1; 95% CI, 0.9-1.3) or paternal smoking (OR, 1.0; 95% CI, 0.8-1.3). However, there was a marginal, non-significant elevation in risk observed for participants who reported living with a nonparent smoker in the household during childhood (OR, 1.4; 95% CI, 1.0-2.1). The researchers concluded that the results do not support the hypothesis that passive smoking, either in utero or during childhood, is related to an increased risk of TGCT in adulthood.¹⁵⁵

Skin

Asbestos and Skin Cancer

• Summary: The evidence for a link between asbestos exposure and common skin cancers is largely inconclusive.

• Ulvestad et al. 2002: This cohort study examined cancer incidence among 541 male workers from a Norwegian asbestos-cement factory who were mainly exposed to chrysotile asbestos with an 8% amphibole content. The study identified five cases of malignant melanoma (ICD 190) and found a non-statistically significant elevated risk compared to the general population. The calculated Standardized Incidence Ratio (SIR) for malignant melanoma was 1.5 (95% CI: 0.5–3.5), based on the five observed cases. The exposure was characterized as occupational, where duration of employment was used as a surrogate for cumulative exposure, demonstrating that even low-count cancers were investigated for risk in this cohort.¹⁵⁶

• Nokso-Koivisto et al. 1994: This study examined cancer incidence in a cohort of 8,391 Finnish locomotive drivers between 1953 and 1991, investigating the effects of mixed occupational exposures. During their two-year vocational training, drivers were exposed to asbestos, with a measured average exposure of 5.0 fibers/cm3 (mainly anthophyllite fibers). The primary cancer finding was a highly significant four-fold risk of mesothelioma, which the authors attributed to the asbestos exposure. The study also reported an elevated, though non-quantified, incidence of non-melanoma skin cancer at a 1.5-fold risk, suggesting an occupational link, possibly due to the combined exposures. Additionally, there was a 1.7-fold risk for cancers of the oral cavity and pharynx also considered occupationally related. Despite these specific cancer risks, the overall incidence of lung cancer and total cancer for the cohort was lower than the national average, a finding likely influenced by the drivers’ historically lower smoking prevalence.¹⁵⁷

Silica and Skin Cancer

• Summary: This study found increased risk of skin cancer for silicotic patients but it is unknown if it is due to silica-induced immunosuppression or co-exposure to other carcinogens.

• Partanen et al. 1994: This study evaluated cancer incidence between 1953 and 1991 in a cohort of 811 Finnish patients with a prior silicosis diagnosis, finding a notably elevated risk for several cancers compared to the general population. The most robust finding was a nearly threefold increase in the risk for all lung cancers (SIR 2.9), with squamous cell carcinoma showing an SIR of 3.3, an increase the authors suggest wasn’t solely attributable to smoking. The study also reported a novel excess risk for skin cancers, specifically nonmelanoma skin cancer (SIR 2.9) which was statistically significant, and melanoma (SIR 3.0). The researchers concluded that silicosis acts as a direct or indirect lung cancer hazard, while suggesting the skin cancer risk may be due to other foundry carcinogens or silica-induced immunosuppression, making individuals more vulnerable to solar UV radiation.¹⁵⁸

Diesel Exhaust and Skin Cancer

• Summary: there is no sufficient or consistent epidemiological evidence to establish a definitive link with any type of skin cancer.

• D’Agostini et al. 2024: This systematic review and meta-analysis investigated the association between occupational exposure to diesel exhaust and the risk of skin cancer by pooling data from multiple cohort studies. The researchers compiled 12 risk estimates for melanoma (MSC) and 8 for non-melanoma skin cancer (NMSC), alongside other unspecified skin cancers (SC-NOS), to conduct random-effects meta-analyses. The results showed no statistically significant overall evidence of an increased risk for any skin cancer type among exposed workers. Specifically, the pooled Relative Risk (RR) for MSC was 0.90 (95% CI: 0.73–1.11) and the RR for NMSC was 1.04 (95% CI: 0.88–1.23). The study concluded that an association between occupational diesel exhaust exposure and skin cancer was not supported by the current epidemiological evidence, although the potential for residual confounding from other factors remains.¹⁵⁹

Benzene and Skin Cancer

• Summary: no consistent association between occupational benzene exposure and an increased risk of either cutaneous melanoma or non-melanoma skin cancer.

• Angelini et al. 2025: This systematic review and meta-analysis specifically evaluated the association between occupational benzene exposure and the incidence and mortality of cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC). The analysis was primarily based on 18 risk estimates for CM and 21 for NMSC/not-specified skin cancer (NM/NS) from cohorts, predominantly in the oil and gas industry, representing workers with historical exposure. The overall pooled analysis found no association with either cancer type, with the summary Relative Risk (RR) for CM being 0.99 (95% CI: 0.81–1.21) and the RR for NM/NS being 1.19 (95% CI: 0.94–1.50). An exception was noted for workers in the chemical industry, which showed a positive association with NM/NS risk. The study concluded that occupational benzene exposure is not associated with an increased risk of skin cancer.¹⁶⁰

• Stenehjem et al. 2017: his prospective case-cohort study investigated the risk of skin cancer associated with occupational exposure to aromatic hydrocarbons (including crude oil and benzene) among a cohort of 24,917 male offshore petroleum workers in Norway, while adjusting for ultraviolet radiation (UVR) exposure. Over 13.5 years of follow-up, 112 cutaneous melanomas (CMs) and 70 non-melanoma skin cancers were identified. The key finding was an increased risk of CM and squamous cell carcinoma (SCC) on the forearm and hand among workers ever exposed to crude oil or benzene. Hazard ratios for cutaneous melanoma for workers exposed to benzene were 2.30 and 2.43 when adjusted for age and age/education/sunburn frequency, respectively. Hazard ratios for squamous cell carcinoma for workers exposed to benzene were 2.63 and 3.51, respectively. Specifically for skin cancers of the forearm and hand combined, cumulative and duration metrics of benzene exposure showed significant positive dose-response trends (P trend = 0.031 and P trend = 0.003, respectively). The authors concluded that these results support an association between dermal exposure to crude oil or benzene, possibly through the skin absorption of polycyclic aromatic hydrocarbons (PAHs) or benzene, and skin cancer risk on the hands and forearms.¹⁶¹

Chlorinated Solvents and Skin Cancer

• Summary: This study raised the hypothesis of a potential association between occupational trichloroethylene exposure and an increased risk of cutaneous melanoma, but more studies need to be conducted.

• Christensen et al. 2013: This case-control study investigated the association between various occupational exposures, including chlorinated solvents, and 11 different cancers in Montreal, Canada, using a Job-Exposure Matrix (JEM) and expert assessment. The study, which included 3,730 cancer cases and 533 population controls, found very little evidence of associations between most chlorinated solvents and cancer sites. However, a significant association was observed between exposure to trichloroethylene (TCE) and melanoma, with an Odds Ratio (OR) of 3.2 (95% CI: 1.0-9.9) for the highest exposure category (“substantial exposure”). The overall OR for “any exposure” to TCE and melanoma was 3.0 (95% CI: 1.2–7.2). Given the limited power and the finding being somewhat isolated, the authors raised this as a hypothesis for further investigation rather than a definitive conclusion of risk.¹⁶²

Welding Fumes and Skin Cancer

• Summary: There are few studies investigating welding fumes and skin cancer, most studies examine the effect of UV radiation on welders rather than welding fumes. One study stated that the presence of metals such as chromium, nickel, zinc, cobalt, cadmium, molybdenum and tungsten in welding fumes can sensitize the skin to UVR.¹⁶³

• Heltoft et al. 2017: This Danish national company-based historic cohort study followed 4,333 male metal arc welders from 1987 to 2012, comparing their cancer incidence to a reference group of all Danish skilled and unskilled male workers. While the overall Hazard Ratio (HR) for all skin cancers in welders was 0.99 (95% CI: 0.94–1.04), the analysis of non-melanoma skin cancer (NMSC) by body site showed a specific elevation. For basal cell carcinoma (BCC) located only at the neck, welders exposed for >20 years had an adjusted HR of 2.49 (95% CI: 1.03–5.99), and those exposed for >30 years had an adjusted HR of 2.46 (95% CI: 1.02–5.94). This suggests that the high, intermittent UV radiation from arc welding, particularly on exposed skin areas like the neck, may increase the risk of localized BCC, but the overall skin cancer risk was not elevated.¹⁶⁴

Creosote/PAHs and Skin Cancer

• Summary: Chronic dermal exposure to Polycyclic Aromatic Hydrocarbons (PAHs), such as those in creosote, is a cause of skin cancer, particularly Squamous Cell Carcinoma.

• Karlehagen et al. 1992: A cohort study of 922 male wood impregnators in Sweden and Norway, who were exposed to creosote between 1950 and 1975, examined their subsequent cancer incidence. While individual exposure data were unavailable, the study population was generally subject to long-term dermal and inhalation exposure to creosote, a mixture rich in PAHs. The overall cancer incidence was not significantly increased, but the study did find an excess risk for skin cancer (all types combined). The standardized incidence ratio (SIR) for skin cancer was 2.37 (95% CI, 1.08-4.50), indicating a more than twofold increased risk compared to the general population. This finding, based on a relatively small number of cases, suggests that impregnating wood with creosote in earlier decades was associated with an elevated risk of skin cancer.¹⁶⁵

• Kubasiewicz et al. 1991: A case-control study conducted in Poland analyzed the relationship between occupational exposure to various products containing polycyclic aromatic hydrocarbons (PAHs) and the risk of skin cancer. The study group included 376 males with skin cancer and two control groups, with 752 males in each, matched for age. The analysis of occupational exposure to mineral oils, a well-known source of PAHs, indicated a significant increase in the risk of developing skin cancer. The calculated odds ratio (OR) for skin cancer in those exposed to mineral oils was 1.46 (95% confidence interval, 1.06-2.05). Conversely, no statistically significant increase in skin cancer risk was observed for exposure to other non-mineral oil sources of PAHs.¹⁶⁶

• Carlsten et al. 2004: This study details the case of a 50-year-old male railroad worker who developed squamous cell carcinoma in situ on a sun-protected area of his right knee. The lesion’s location was notable because it was the site of chronic, long-term dermal exposure to coal tar creosote, which had soaked through his work clothes daily for 30 years as he handled treated wood (railroad ties and lumber). The case is considered unique as the patient had a relatively “pure” long-term exposure to coal tar creosote, and the sun-protected location of the lesion helps isolate the chemical’s carcinogenic effect from confounding factors like UV radiation. The authors conclude that this case report further supports the established link between coal tar creosote exposure and squamous cell carcinoma of the skin, particularly emphasizing the risk from long-term dermal contact.¹⁶⁷

• Stenehjem et al. 2017: This study prospectively examined the risk of skin cancer in a cohort of nearly 25,000 male offshore petroleum workers, focusing on the association between occupational exposure to aromatic hydrocarbons (specifically crude oil and benzene) and cancer risk by anatomical site, while adjusting for solar ultraviolet radiation (UVR) exposure. The researchers found a strong, dose-dependent association between the duration of exposure to crude oil and benzene and an increased risk of skin cancer on the forearms and hands—sites of frequent dermal contact. This finding, which showed adjusted hazard ratios as high as 18 for cancer on the hand with long-term benzene exposure, suggests that the dermal absorption of aromatic hydrocarbons is a significant, site-specific carcinogenic pathway among these workers, either independently of or reinforcing the risk posed by UVR exposure.¹⁶⁸

Herbicides and Skin Cancer

• Summary: Most studies conclude there is insufficient or no evidence to support a causal association between glyphosate or Roundup exposure and skin cancer in humans.

• Swaen et al. 2004: This study updated the follow-up of a cohort of 1,341 licensed herbicide applicators in the Netherlands, examining cancer mortality. The exposed cohort, consisting of professionals licensed to use a variety of herbicides, was followed to assess long-term health outcomes. The findings indicated that this group was at an increased risk for skin cancer mortality, with a Standardized Mortality Ratio (SMR) of 357.4 (95% CI, 115.1–827.0) compared to the general population. While the excess risk for skin cancer mortality was statistically significant, the authors noted that it was unclear if the increased mortality was attributable to the herbicide exposure or to the excess sun exposure inherent in the applicators’ outdoor occupation.¹⁶⁹

• Fortes et al. 2016: This pooled analysis of two case-control studies conducted in Italy and Brazil examined the association between occupational pesticide exposure and cutaneous melanoma. The results showed that ever-use of any pesticide was associated with an elevated risk of melanoma (Odds Ratio [OR] = 2.58; 95% CI, 1.18–5.65), and the risk was specifically heightened for those exposed to herbicides (glyphosate) and certain fungicides. Critically, when subjects were exposed to both pesticides and occupational sun exposure, the risk was substantially magnified (OR = 4.68; 95% CI, 1.29–17.0). This suggests that for melanoma, glyphosate exposure may act synergistically with sun exposure, the primary risk factor.¹⁷⁰

• George et al. 2009: A proteomic study using a two-stage mouse skin carcinogenesis model investigated the carcinogenic potential of the widely used herbicide, glyphosate. The study found that glyphosate demonstrated tumor promoting activity in the mouse skin. A proteomic analysis identified 22 differentially expressed proteins, with 9 proteins (including calcyclin, calgranulin-B, and superoxide dismutase [Cu–Zn]) showing similar expression patterns in glyphosate-treated skin and skin treated with the known tumor promoter TPA (12-O-tetradecanoyl-phorbol-13-acetate). The researchers confirmed the up-regulation of calcyclin and calgranulin-B and the down-regulation of superoxide dismutase [Cu–Zn] via immunoblotting, suggesting that these proteins could serve as biomarkers for glyphosate-induced skin carcinogenesis. These results suggest that glyphosate acts as a tumor promoter in the skin, potentially via a mechanism similar to that of TPA.¹⁷¹

Secondhand Smoke and Skin Cancer

• Summary: There were no articles found by Gemini or Google Scholar specifically examining skin cancer (melanoma, basal cell carcinoma, squamous cell carcinoma) and secondhand smoke. One study below examined passive smoking and atopic dermatitis, a skin condition that is known to increase risk of skin cancer. Epidemiological evidence does not show a clear or established association with an increased risk of skin cancer.

• Kantor et al. 2016: The meta-analysis found that prenatal and/or postnatal exposure to secondhand smoke was significantly associated with an increased risk of atopic dermatitis. Specifically, exposure to passive smoking was associated with an increased risk, with a pooled Odds Ratio (OR) of 1.25 (95% CI: 1.10–1.41) for developing atopic dermatitis. The exposure was defined as prenatal and/or postnatal exposure to secondhand smoke, with the reference group being those unexposed. The summary suggested that the risk was specifically increased in studies on postnatal exposure (OR: 1.22; 95% CI: 1.09–1.37) and also for prenatal exposure (OR: 1.23; 95% CI: 1.01–1.50).¹⁷²

Multiple Myeloma

Asbestos and Multiple Myeloma

• Boffetta et al. 1989: This epidemiological summary focuses on a nested case-control study conducted within the American Cancer Society Cancer Prevention Study II, which analyzed 282 multiple myeloma (MM) fatalities and their matched controls. The primary risk factors consistently identified were a previous history of diabetes (Odds Ratio [OR] = 2.0) and employment as a farmer (OR = 2.7), with the latter showing a linear trend related to the duration of exposure. This risk was substantially higher, reaching an OR of 4.3, when farming was combined with pesticide or herbicide exposure, though these chemical exposures were not independent risk factors. Notably, this large prospective study found no association between multiple myeloma and asbestos exposure.¹⁷³

• Eriksson et al. 1992: A Swedish case-control study investigating occupational and environmental factors for multiple myeloma also identified a statistically significant association with asbestos exposure. The researchers found an Odds Ratio of 0.5 (95% CI 0.29–0.82). This result suggests a moderately increased risk of multiple myeloma following exposure. The study’s method relied on occupational histories to determine exposure, and the level of asbestos exposure for the cases was not directly measured but was qualitatively assessed based on occupation.¹⁷⁴

• Linet et al. 1987: This hospital-based case-control study analyzed 100 white multiple myeloma (MM) cases and 100 matched controls to explore various hypothesized risk factors. The researchers found no statistically significant associations between MM and prior chronic antigenic stimulation from conditions like bacterial infections (OR = 0.8), autoimmune disorders (OR = 1.0), or allergies (OR = 1.0). However, the study reported statistically significant positive associations for specific occupational exposures: petroleum products (OR = 3.7; 95% CI 1.3-10.3) and asbestos (OR = 3.5; 95% CI 1.0-12.0).¹⁷⁵

Silica and Multiple Myeloma

• Pottern et al. 1992: This article presents a population-based case-control study conducted in Denmark to investigate occupational and workplace risk factors for multiple myeloma (MM) among women. The study included 1,010 MM cases diagnosed in Danish women between 1970 and 1984, matched to 4,040 age-matched controls. The study found an odds ratio of 0.6 (0.1-2.8) for possible exposure to silica dust, not statistically significant.¹⁷⁶

Diesel Exhaust and Multiple Myeloma

• Lee et al. 2003: This cohort study of 365,424 male Swedish construction workers, followed from 1971 to 1999, used a semiquantitative job-exposure matrix (JEM) to assess occupational exposures, including diesel exhaust. For any exposure to diesel exhaust, the study found a statistically significant increased risk of multiple myeloma, with an estimated Rate Ratio (RR) of 1.3 (95% CI: 1.04–1.71) compared to unexposed workers. While the overall risk was elevated, a dose-response analysis did not show a monotonic increase with estimated exposure level; RRs for low, moderate, and high exposure were 1.4, 1.1, and 1.4, respectively. This lack of a clear exposure-response trend tempered the authors’ conclusions about a definite causal link, suggesting the need for clarification in future studies.¹⁷⁷

Benzene and Multiple Myeloma

• Onyije et al. 2021: This article, a systematic review and meta-analysis on cancer risk in petroleum industry workers, found an increased risk of multiple myeloma (MM) in this exposed population. The study identified that petroleum industry work overall was associated with a statistically significant increased risk of multiple myeloma, with an Effect Size (ES) of 1.81 (95% CI: 1.28–2.55). This indicates that workers in the petroleum industry have an 81% higher risk of MM compared to the reference population. The authors specifically note that petroleum is the source of hydrocarbons like benzene, which is a known carcinogen and is present in crude oil. The review mentions that very few studies specifically examined quantitative levels of benzene exposure among petroleum industry workers; therefore, the reported ES of 1.81 represents the aggregated risk from working in the petroleum industry, where benzene is one of the key hazardous exposures contributing to the overall cancer burden.¹⁷⁸

• Infante et al. 2006: This meta-analysis focused specifically on data from seven existing benzene cohort studies to evaluate the risk of multiple myeloma in occupationally exposed workers. The analysis demonstrated a statistically significant excess risk for MM mortality associated with benzene exposure. Pooling the data yielded a significant weighted Relative Risk (RR) of 2.13 (95% CI: 1.31–3.46). The elevated risk, which suggests a more than two-fold increase in MM mortality, was supported by the biological plausibility of benzene’s effect as a bone marrow toxin. The author noted that studies of refinery workers, often included in broader analyses, may have been limited by lower exposure levels, potentially diluting the true effect found in cohorts with definite high-level exposure.¹⁷⁹

• Costantini et al. 2008: This case-control study, conducted in Italy, investigated the association between exposure to organic solvents, particularly benzene, and the risk of various hematologic malignancies, including multiple myeloma (MM). The study collected 263 MM cases and 1,100 population controls, with experts assessing individual exposure levels to various chemicals. The analysis found an elevated point estimate for the association between medium/high benzene exposure and multiple myeloma, yielding an Odds Ratio (OR) of 1.9 (95% CI: 0.9–3.9). This result suggests an almost twofold increase in the risk of MM, but it was not statistically significant. The authors concluded that their findings support an association between benzene and MM, suggesting that for MM, the latency period—the time between exposure and disease development—may be longer than the latency observed for AML in other studies.¹⁸⁰

Chlorinated Solvents and Multiple Myeloma

• Gold et al. 2011: This case-control study investigated the association between occupational exposure to six chlorinated solvents and the risk of developing multiple myeloma (MM). The methods involved identifying MM cases and general population controls, then conducting in-person interviews to collect detailed occupational histories. Exposure metrics for six solvents, including 1,1,1-trichloroethane (TCA), trichloroethylene (TCE), methylene chloride (DCM), and perchloroethylene (PCE), were assigned using modified job-exposure matrices, and logistic regression was used to estimate Odds Ratios (OR). The results found that ever-exposure to TCA was significantly elevated OR: 1.8; 95% CI: (1.1–2.9). While initial ORs for TCE and DCM ever-exposure were not significant, they became so when the analysis was restricted to high-confidence exposures (TCE OR: 1.7; (1.0–2.7); DCM OR: 2.0 (1.2–3.2). Furthermore, an exposure-response relationship was established for both TCE and PCE, with increasing cumulative exposure associated with a significantly increasing risk of MM. The conclusion suggests that exposure to certain chlorinated solvents may increase MM incidence, but notes the study’s limitation of low control participation (52%).¹⁸¹

Welding Fumes and Multiple Myeloma

• Heineman et al. 1992: The case-control study by Heineman et al. (1992) investigating occupational risk factors for multiple myeloma (MM) among Danish men identified occupations highly relevant to metalworking and welding. The study reported that workers classified as a Welder had an Odds Ratio (OR) of 2.0 with a 95% Confidence Interval (CI) of 0.6–5.7, which indicates a doubling of the risk but is not statistically significant as the CI includes 1.0. Despite the non-significant finding for the specific welder occupation, the study also found a significantly elevated risk for precision metalworkers, road and railroad workers, and those in industries like fabricating structural metal and stationary tanks, suggesting a strong association between MM and broader industrial chemical and metalworking exposures. Furthermore, the risk was statistically significant and rose to nearly fivefold with probable exposure to vinyl chloride for five or more years.¹⁸²

• This study investigated cancer incidence in workers exposed to extremely low frequency magnetic fields (ELF-MF), specifically focusing on industries using resistance welding in Sweden. The cohort included over 500,000 men and 180,000 women, with ELF-MF exposure categorized into four groups. While the study primarily focused on ELF-MF, it noted that resistance welders (who formed a large part of the very high exposure group) should have a “comparatively clean work environment” with “less prevalent” exposure to potential carcinogenic agents occurring with welding by fusion (welding fumes). For women in the high exposure group, an association was suggested for multiple myeloma with a relative risk (RR) of 3.8 (95% CI 0.9 to 15.6) [1]. However, no cases of multiple myeloma were observed in the very high exposure group for women [1]. The study did not provide specific odds ratios, hazard ratios, or standard mortality rates for welding fumes and multiple myeloma, as its primary focus was on ELF-MF exposure.¹⁸³

Creosote/PAHs and Multiple Myeloma

• Alicandro et al. 2017: This systematic review and meta-analysis pooled data from 41 occupational cohort studies to evaluate the risk of lymphatic and hematopoietic neoplasms among workers with high PAH exposure (e.g., in foundries, cokeries, and aluminum plants). The exposure level was classified as high based on the job or industry type, but was not individually quantified. The meta-analysis, which included multiple studies, found a non-significant excess risk for MM with a pooled Relative Risk (RR) of 1.18 (with a 95% of 0.93–1.50). This estimate suggests an approximately 18% increased risk of MM among workers with high PAH exposure, but because the confidence interval includes 1.0, the association is not statistically significant and requires caution in interpretation.¹⁸⁴

• Karlehagen et al. 1992: This cohort study examined cancer incidence in 922 male workers from Sweden and Norway who were exposed to creosote while impregnating wood between 1950 and 1975. The exposure level was defined by the occupation of wood impregnator, but no individual exposure data were available. The overall cancer incidence was slightly below expectation. The study did not find a significantly increased risk specifically for multiple myeloma, reporting only two cases of the disease (compared to 1.9 expected cases), resulting in a Standardized Incidence Ratio (SIR) of 1.05 (with a 95% CI of 0.13–3.79). While the finding suggests no association in this cohort, the small number of observed MM cases limits the statistical power, making the confidence interval very wide and thus the conclusion inconclusive for this specific cancer site.¹⁸⁵

Herbicides/Glyphosate and Multiple Myeloma

• Donato et al. 2020: In the Exposure to glyphosate and risk of non-Hodgkin lymphoma and multiple myeloma: an updated meta-analysis, a pool of three relevant epidemiological studies was systematically reviewed for the association with multiple myeloma. The exposure metric utilized was occupational ever-exposure to glyphosate. The resulting pooled risk estimate for MM was a meta-Relative Risk (meta-RR) of 1.04 (95% CI, 0.67–1.41), which is close to unity and not statistically significant. This finding supports the conclusion of no overall evidence for an increased risk of multiple myeloma in subjects occupationally exposed to glyphosate.¹⁸⁶

• Chang et al. 2015: This systematic review and meta-analysis examined the relationship between glyphosate exposure and various lymphohematopoietic cancers, including Multiple Myeloma (MM). Based on four included studies, the authors calculated a meta-Relative Risk (Meta-RR) of 1.4 (95% CI = 1.0–1.9) for the association between any versus no use of glyphosate and MM risk. While the confidence interval for this finding barely excluded the null value of 1.0, indicating a statistically significant result, the authors characterized this finding as only “marginally statistically significant.” Ultimately, the paper concluded that due to limitations in the primary literature and the marginal nature of the aggregated finding, a causal relationship has not been established between glyphosate exposure and cancer risk.¹⁸⁷

• Sorahan et al. 2015: This paper presented a re-analysis of data from the highly regarded U.S. Agricultural Health Study (AHS) cohort, specifically focusing on the association between glyphosate use and Multiple Myeloma. The re-analysis referenced the initial finding for “ever-use of glyphosate” among pesticide applicators, which yielded an unadjusted Rate Ratio (RR) of 1.1 (95% CI = 0.5 to 2.4). Crucially, because the confidence interval spanned the null value of 1.0, this finding was not statistically significant. The paper itself is a re-analysis of these existing data but the core finding it references from the primary AHS data indicates a weak or non-existent association between general glyphosate use (as defined by “ever-use”) and MM risk in this large, well-followed cohort.¹⁸⁸

• Presutti et al. 2016: This study analyzed data from the North American Pooled Project (NAPP), the largest pooled case-control study on pesticide exposures and multiple myeloma in men. While the study found a consistent association between agricultural activity and MM risk, it did not focus on glyphosate specifically but rather on a broad range of pesticides. The analysis observed statistically significant increases in MM risk for specific pesticide compounds, notably carbaryl, captan, and DDT. The paper provides strong, evidence-based risk estimates for these chemicals within the broader pesticide/herbicide category, suggesting that while glyphosate may not be the primary driver of risk in this pooled population, exposure to other herbicides and insecticides is positively and significantly associated with MM.¹⁸⁹

Secondhand Smoke and Multiple Myeloma

• Andreotti et al. 2015: This large, pooled analysis of nine case-control studies investigated the relationship between cigarette smoking and multiple myeloma (MM) risk using data from 2,670 cases and 11,913 controls. The study concluded that neither ever smokers (OR 0.95, 95% CI 0.87–1.05), current smokers (OR 0.82, 95% CI 0.73–0.93), nor former smokers (OR 1.03, 95% CI 0.92–1.14) had an increased risk of MM compared with never smokers, with all overall estimates clustering around 1.0 (no effect). While the study’s primary focus was active smoking, its strong conclusion that smoking is not a causal factor for MM strongly suggests that the less intense exposure from secondhand or passive smoke would also not be associated with an elevated risk.¹⁹⁰

• This meta-analysis synthesized data from 40 observational studies (27 case-control and 13 cohort studies) to examine the association between tobacco smoking and the risk of multiple myeloma (MM). The findings indicate no significant association between ever smoking and MM risk (pooled effect estimate = 0.92, 95% CI: 0.85-1.00), with similar null results for current (pooled effect estimate = 0.87, 95% CI: 0.74-1.03) and former smoking (pooled effect estimate = 1.04, 95% CI: 0.96-1.13). While case-control studies initially showed an inverse association for ever smoking (pooled effect estimate = 0.87, 95% CI: 0.78-0.96), this was primarily attributed to bias in hospital-based studies.

The study concluded that MM does not appear to be associated with tobacco smoking, and dose-response analyses (e.g., smoking duration, cigarettes per day, pack-years, age at onset, years since quit) also failed to demonstrate a significant relationship. The document does not specify different levels of exposure for tobacco or secondhand smoke in relation to multiple myeloma beyond the general categories of “ever,” “current,” and “former” smoking.¹⁹¹

Brain Cancer

Brain Cancer and Asbestos

• Siedman et al. (1982)This prospective cohort study followed 17,800 asbestos insulation workers in the US and Canada from 1967 to 1979. These workers were exposed to varying levels of asbestos, suggested to be in the range of 4–12 fibers/ml as time-weighted averages, primarily from chrysotile and amosite in insulation products. The study found 24 deaths from primary brain tumors, which was somewhat more than the 18.0 deaths expected based on U.S. general population rates. The resulting Observed/Expected (Obs/Exp) ratio for brain tumors was 24/18 or approximately 1.33 for the entire period. The excess was not statistically significant at the 5% level, but the highest risk (approximately twice the expected deaths) was concentrated in workers under age 50 and during the relatively early period of 15–24 years after the onset of asbestos exposure.¹⁹²

• Pan et al. 2005 This multi-center case-control study investigated occupational factors for 1,009 incident cases of primary brain cancer and 5,039 controls in Canada from 1994 to 1997. The study collected self-reported information on ever working for more than one year with 18 specific chemicals, including asbestos. A preliminary analysis showed an increased risk (Odds Ratio, OR, of 1.31) of brain cancer for those exposed to asbestos (80 cases, 353 controls). However, after adjusting for potential confounders (multivariable-adjusted OR), the association for “ever exposed” to asbestos resulted in a nonsignificant OR of 1.23 (95% CI: 0.95–1.59). Furthermore, no clear dose-response pattern was found for increasing years of asbestos exposure. The authors concluded the association between brain cancer risk and asbestos exposure was a possible association.¹⁹³

Brain Cancer and Silica

• Limited Research

Brain Cancer and Diesel Exhaust

• (correlated) Peter et al. 2012: This Australian population-based case-control study explored the association between childhood brain tumors (CBT) and parental occupational exposure to engine exhausts. The study included 306 cases and 950 controls, gathering detailed occupational histories from parents to assess exposure in specific time periods relative to the child’s birth. Maternal occupational exposure to diesel exhaust any time before the child’s birth was associated with an increased risk of CBT, with an Odds Ratio (OR) of 2.03 (95% CI: 1.09–3.81). A positive association was also found for paternal exposure to diesel exhaust in the two years before birth, covering the time of conception, with an OR of 1.62 (95% CI: 1.12–2.34). No clear associations were found with other engine exhausts like petrol or other exhausts.¹⁹⁴

• (no correlation) Sassano et al. 2025: This systematic review and meta-analysis investigated the association between occupational diesel exhaust exposure and adult brain and other central nervous system (CNS) tumors. The meta-analysis included 14 cohort studies to synthesize the evidence on risk. The overall results suggested no increased risk of brain or CNS tumors among workers exposed to diesel exhaust, with a pooled Relative Risk (RR) of 0.99 (95% CI: 0.91, 1.07) for combined incidence and mortality. Findings were consistent when analyzing incidence (RR: 0.96; 95% CI: 0.90, 1.03) and mortality (RR: 1.09; 95% CI: 0.87, 1.37) separately. The study notes a limitation in that exposure assessment in the included studies was primarily based on occupations involving diesel exhaust exposure rather than detailed environmental assessment, suggesting a need for more high-quality studies with quantitative exposure data and internal reference populations. The conclusion suggests that occupational diesel exhaust exposure is not associated with adult brain or CNS tumors, but stresses that results should be interpreted with caution due to study limitations.¹⁹⁵

• (medium correlated) Lacourt et al. 2013: This large, international case-control study, part of the INTEROCC project, investigated the association between glioma tumors and occupational exposure to 10 agents, including diesel exhaust emissions. The study included 1,800 glioma cases and 5,160 controls from seven countries. Occupational exposure was assessed using an INTEROCC Job Exposure Matrix (JEM), with “ever exposure” to diesel exhaust defined by an occupational probability of exposure of at least 25% for a duration of at least one year. The results found no indication of excess risk for glioma when analyzing “ever versus never” exposure status to diesel exhaust emissions (Odds Ratio (OR) of 1.0, 95% CI: 0.8–1.2). Furthermore, there were no clear dose-response patterns with cumulative exposure, though the top category of duration for diesel exhaust did show a borderline significant OR of 1.3 (95% CI: 1.0–1.8), which the authors suggest is likely due to multiple testing and random chance.¹⁹⁶

Brain Cancer and Benzene

• Mangiaterra et al. 2025: This paper is a systematic review and meta-analysis that examined the relationship between occupational benzene exposure and the risk of nervous system cancers by synthesizing findings from 36 independent occupational cohort and case-control studies. Using a random-effects meta-analysis, the study found a significant pooled relative risk (RR) for overall nervous system cancers: RR 1.21 (95% CI: 1.05-1.38). A stratified analysis focusing on glioma showed a more pronounced significant association: RR 3.88 (95% CI: 1.33-11.31). This study found a link between occupational benzene exposure and increased risks of nervous system cancers, particularly glioma.

• Wu et al. 2020: This paper examined the relationship between long-term exposure to outdoor air pollutants (including benzene) and the risk of malignant brain cancer and meningioma amongst a cohort of 103,308 men and women from the Multiethnic Cohort. When adjusted for sex, race/ethnicity, neighborhood socioeconomic status, smoking, occupation, and other covariates, the study found a significant hazard ratio (HR) for malignant brain cancer risk in men exposed to benzene: HR 3.52 (95% CI: 1.55 to 7.55). This study found a link between outdoor benzene exposure and malignant brain cancer risk in men.

• Pan et al. 2005: This paper examined the relationship between occupational exposure to 18 chemicals (including benzene) and the risk of primary brain cancer amongst a case-control study of 1,009 incident cases of brain cancer and 5,039 control subjects in Canada. When controlled for age, sex, and other covariates (demographic factors, smoking, reproductive history), the study found a significant odds ratio (OR) for people exposed to asphalt: OR 1.29 (95% CI: 1.02-1.62). The paper also states that an increased risk of brain cancer might be associated with exposure to benzene, along with other substances like asbestos and mineral oil. This study suggests a possible link between occupational exposures like benzene and brain cancer.

• Gomes et al. 2011: This paper is a systematic review that examined the relationship between occupational and environmental risk factors (including benzene) and the risk of Adult Primary Brain Cancers (Brain Neoplasm, Glioma, Meningioma, Astrocytoma) by synthesizing findings from observational epidemiologic studies published until the end of 2010. The paper reports a finding from one of the reviewed studies among Canadian workers that found a small and nonsignificant increase in brain neoplasm risk from exposure to benzene: OR 1.34 (95% CI: 0.96-1.97). The review found some studies reporting a link between certain exposures, including benzene, and brain cancer risk.

Brain Cancer and Chlorinated Solvents

• Ruder et al. 2012: This paper examined the relationship between non-farm occupational exposure to six chlorinated solvents (carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, tetrachloroethylene, or 1,1,1-trichloroethane) and glioma risk amongst a cohort of 798 glioma cases and 1175 population-based controls in non-metropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. When controlled for age group, sex, age, and education, the study found no increased risk of glioma associated with chlorinated solvent exposure. The analysis did report that both estimated cumulative exposure and ever exposure to chlorinated solvents were associated with a decreased glioma risk, and this was statistically significant overall and for women. This study concluded there were no associations of glioma risk and chlorinated solvent exposure.

• Neta et al. 2012: This paper examined the relationship between occupational exposure to six chlorinated solvents (including dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene, and perchloroethylene) and the risk of glioma and meningioma amongst a hospital-based case-control study of 489 glioma cases, 197 meningioma cases, and 799 controls from three USA hospitals. Controls were frequency-matched by sex, age at interview, race/ethnicity, hospital, and proximity to the hospital. Overall, the study found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. However, in an analysis restricted to exposed subjects, there was a suggestion of an association between carbon tetrachloride and glioma for average weekly exposure above the median compared with below the median: OR 7.1 (95% CI 1.1 to 45.2). This study found no consistent evidence for increased brain tumor risk related to chlorinated solvents.

Brain Cancer and Welding Fumes: ( Not correlated)

• Parent et al. 2017:This study, part of the multi-country INTEROCC project, investigated the relationship between glioma risk and occupational exposure to welding fumes and five metals. The analysis included 1,800 incident glioma cases and 5,160 controls. Exposure was assessed using the INTEROCC Job Exposure Matrix (JEM). The multivariate logistic regression analyses found no association between ever exposure to welding fumes and risk of glioma. Furthermore, there was no evidence for a trend based on categories of cumulative exposure or duration of exposure. The study concluded that its findings provided no evidence for an association between occupational exposure to welding fumes and the risk of glioma.

• MacLeod et al. 2017: This prospective cohort study examined cancer risks among 12,845 primary male welders and 87,460 male occasional welders in Canada. The follow-up spanned from 1992 to 2010. The study found that for primary welders, the risk of brain cancer was elevated (Hazard Ratio (HR): 1.16, 95% CI: 0.83–1.63), but the estimate was not statistically significant. For occasional welders, the brain cancer risk was also not significantly elevated (HR: 1.08, 95% CI: 0.93–1.26). When comparing welders to other blue-collar workers to minimize confounding, the HR for brain cancer remained non-significant (HR: 1.17, 95% CI: 0.83–1.65). While the study concluded welding was not associated with brain cancer, it did find significant excess risks for other cancers like bladder and kidney cancer.

Brain Cancer and Creosotes / PAHs

• (correlated) Kerr et al. 2000:This case-control study investigated 183 neuroblastoma cases and 372 matched controls in New York State to examine the role of parental occupational exposures at the time of the child’s birth. The study utilized maternal telephone interviews to gather information on both mothers’ and fathers’ job histories and self-reported exposure to 25 specific chemical and physical agents. Maternal reports of occupational exposure were significantly elevated for several agents, including acetone ( OR= 3.1, 95% CI=1.7-5.6), insecticides (OR=2.3, 95% CI=1.4-3.7), and petroleum (OR=3.0, 95% CI= 1.5-6.1). Paternal exposures associated with significantly elevated odds ratios included creosote ( OR 2.1, (5% CI 1.1-4.3), lead ( OR= 2.4, 95% CI= 1.2-4.8) and petroleum ( OR= 1.8, 95% CI=1.1-2.8). The authors noted significant evidence of overreporting and recall bias for highly recognizable toxins and advised that results be interpreted cautiously due to uncertainty regarding the biological plausibility and the potential for alternative explanations.¹⁹⁷

• (Correlated) Feingold et al. 1992:This case-control study in Denver, Colorado, examined the association between parental occupation and total childhood cancers, acute lymphocytic leukemia (ALL), and brain cancer among 252 cases and 222 controls. Exposure was retrospectively assessed during the year prior to the child’s birth using a job-exposure matrix (JEM), which assigned exposures based on job title and industry at medium or high linkage levels. For total cancers, elevated odds ratios with non-significant confidence intervals were found for maternal exposure to benzene ( OR= 1.9), petroleum/coke pitch/tar (OR= 2.2), and soot (OR =3.3). For all, adjusted ORs for paternal exposure were OR=1.6 for benzene and Or=1.6 for petroleum/coke/pitch/tar. Paternal exposure to creosote was strongly associated with Brain cancer ( OR =3.7, 95% CI=0.8-16.6). Despite uncertainties, the findings lend support to past research suggesting an association between specific parental occupational exposures and childhood cancer.¹⁹⁸

Cordier et al. 1997

• This population-based case-control study pooled data from 251 childhood brain tumor cases and 601 controls across Italy, France, and Spain. The study focused on the estimated risks associated with parental occupational exposure to solvents and polycyclic aromatic hydrocarbons (PAH) during the five-year period before birth, using a job-exposure matrix. Maternal exposure to solvents at a high level was associated with an increased risk of both astroglial tumors (OR = 2.3, 95% CI=0.9-5.8) and primitive neuroectodermal tumors (PNET) ( OR= 3.2, 95% CI= 1.0-10.3). Paternal exposure to PAhs showed a significantly increased risk for PNET (OR=2.0, 95% CI=1.0-4.0). Other significant findings included paternal work in agriculture ( OR=2.2, 95% CI=1.0-4.7) and motor-vehicle-related occupations for PNET ( OR=2.7, 95% CI=1.1-6.6). The risk did not increase with the level of exposure for paternal PAH exposure, arguing against a strong causal role for PAhs in that pathway.¹⁹⁹

Brain Cancer and Herbicides: ( No significance)

• Andreotti et al. 2018: This prospective cohort study, part of the Agricultural Health Study (AHS), updated the evaluation of glyphosate (a widely used herbicide) use and cancer incidence, including for lymphoid malignancies. Among 54,251 pesticide applicators, 82.8% used glyphosate. The study found no association between glyphosate use and overall lymphoid malignancies (Rate Ratio (RR) in highest quartile = 1.00, 95% CI: 0.74, 1.34) or for solid tumors overall. There was no apparent association between glyphosate and any solid tumors or lymphoid malignancies overall, including Non-Hodgkin Lymphoma (NHL) and its subtypes. However, some evidence of increased risk was found for acute myeloid leukemia (AML) among the highest exposed group (RR in highest quartile $= 2.44$, 95% CI: 0.94, 6.32,), with the trend becoming statistically significant with a 20-year exposure lag . The study concluded that no association was apparent for solid tumors, but the possible association with AML requires confirmation²⁰⁰

• Mink et al. 2012: This review summarized seven cohort studies and fourteen case-control studies on glyphosate (a type of herbicide) and cancer outcomes. All of the cohort studies reviewed were from the Agricultural Health Study (AHS). The review found no consistent pattern of positive associations that would indicate a causal relationship between total cancer or any site-specific cancer and exposure to glyphosate. Specifically, previous AHS analyses of glyphosate found no statistically significant associations for most cancer sites, including glioma. The review noted that case-control studies often reported positive associations for Non-Hodgkin Lymphoma, but that the prospective AHS failed to corroborate this finding. It concluded that the overall epidemiologic data do not support a causal association between glyphosate exposure and cancer. The authors stressed that generic exposure assessments are a limitation and likely lead to exposure misclassification.²⁰¹

Brain Cancer and Secondhand Smoke

• N/A

Chronic Lymphocyctic

Chronic Lymphocytic and Asbestos ( No significance)

• Weak and Inconclusive

• Schwartz et al., 1988 (Am J Ind Med) — Population-based, multi-registry case-control of CLL (N=429 cases). They estimated occupational asbestos exposure by job history and saw a modest increase in CLL risk with higher peak exposure, but the trend was not statistically significant (low 1.1; medium 1.2; high 1.4 vs unexposed; p-trend = 0.13). Often cited as the key CLL-specific asbestos paper.

Chronic Lymphocytic and Silica Dust( No significance)

• Shao et al., 2025 — This systematic review and meta-analysis examined whether occupational exposure to respirable crystalline silica increases leukemia risk beyond its established link to lung cancer. Searching PubMed, Embase, and Web of Science for cohort studies published since 1987, the authors identified 22 eligible studies and pooled results using fixed effects. The combined relative risk for leukemia was 1.11 with a 95% confidence interval of 0.93 to 1.33, which is not statistically significant. Subgroup analyses showed no meaningful variation by industry, geography, exposure period, or study quality. Overall, the evidence from cohort studies does not support an increased risk of leukemia from occupational silica exposure.

Chronic Lymphocyctic and Diesel Exhaust ( Moderate)

• Koutros et al. —This cohort mortality study (DEMS II) extended follow-up of 12,315 miners with quantitative diesel exhaust exposure estimated by respirable elemental carbon. For lymphoid cancers, the authors analyzed non-Hodgkin lymphoma combined with chronic lymphocytic leukemia. The standardized mortality ratio for NHL with CLL was 1.22 (95% CI 0.94–1.57), which was not statistically significant. In exposure–response models using a 20-year lag, cumulative exposure showed a significant trend: HR tertile 3 vs tertile 1 = 3.12 (95% CI 1.00–9.79; p-trend = 0.031), and the continuous log cumulative metric was HR 1.25 (95% CI 1.00–1.54), rising to 1.34 (95% CI 1.03–1.74) among ever-underground workers. Average exposure intensity also showed a significant top-tertile association (HR 4.45; 95% CI 1.32–14.98; p-trend = 0.032), with a borderline continuous estimate (HR 1.29; 95% CI 0.99–1.69). Because the endpoint is mortality and CLL is grouped within NHL rather than analyzed as a separate subtype, the findings suggest a diesel-related lymphoid signal but do not establish a CLL-specific association.

Chronic Lymphocyctic and Benzene ( low significance to moderate )

• Vaanderson et al. 2011—This 2011 Environmental Health Perspectives meta-analysis pooled occupational cohort studies to test whether benzene is linked to specific lymphoid cancers, including CLL. The authors built three study-quality lenses (calendar era of follow-up, whether the study detected the established AML signal, and exposure-assessment quality) to reduce misclassification and underpowered designs. For CLL, the overall meta-relative risk was modest and not statistically significant, but it was higher and statistically significant in studies with follow-up beginning in or after 1970 (mRR ≈ 1.63), and the CLL risk generally increased as study quality and exposure-assessment rigor improved. Results across lymphoma subtypes were heterogeneous, yet the pattern of stronger associations in higher-quality strata paralleled what was seen for AML and supported benzene–CLL plausibility. The authors concluded that the evidence supports an association of occupational benzene exposure with CLL (along with ALL and MM), while emphasizing limitations such as evolving disease classification, exposure misclassification, limited dose–response data, and small numbers for some subtypes. Overall, they judged the CLL link as positive but based on suggestive rather than definitive cohort evidence, and called for subtype-specific, well-exposed studies with better exposure quantification.

• Rushton & Romaniuk, 1997—nested case–control analysis within a UK petroleum distribution cohort identified 31 CLL cases and found no association between benzene exposure and CLL across all quantitative metrics. Cumulative exposure treated continuously was OR 0.98 (95% CI 0.91–1.05), and categorical analyses showed no exposure–response trend. Intensity metrics were null to inverse for CLL, with category estimates such as maximum intensity 0.02–0.19 ppm: OR 0.31 (0.11–0.88) and 0.20–0.39 ppm: OR 0.16 (0.02–0.96), suggesting cases generally had lower measured benzene exposure than controls. By contrast, duration of employment related to higher CLL risk (continuous OR 1.06; 95% CI 1.01–1.11) and white-collar status showed elevation (OR 3.66; 95% CI 1.27–10.51), patterns the authors interpret as unrelated to benzene dose. Overall conclusion: in this low-exposure petroleum setting, the study does not support benzene as a causal exposure for CLL; observed CLL elevations track tenure and job class rather than benzene dose.

Chronic Lymphocyctic and Welding Fumes ( low significance)

• Zheng et al. — pooled two population-based case-control studies from Kansas and Nebraska (555 NHL, 56 CLL, 2,380 controls) to evaluate occupation and risk of NHL and CLL. For men, several jobs showed higher odds for the combined NHL + CLL outcome, with the clearest signal in farmers: OR 2.1 (95% CI 1.5–2.9). When the authors analyzed histology, the excess for SLL/CLL concentrated in agricultural production/farming, while welders/solderers showed elevations for diffuse/other NHL rather than for SLL/CLL. Among women, printing/publishing and insurance carriers were associated with NHL overall, and female farmers had elevated SLL/CLL. The authors discuss pesticides, solvents, fuels/exhausts, dusts, and possible electromagnetic fields as candidate exposures behind these occupation-specific patterns. Overall, the study indicates that certain industries—especially agriculture—are associated with increased NHL and CLL risk, but welding-related increases did not extend to the SLL/CLL subtype, so this paper does not support a welding-fume signal for CLL specifically.

Chronic Lymphocytic and Creosote ( weak and inconclusive )

• Wong and Harris, 2005 — CLL mortality was based on one observed death vs 0.37 expected, yielding SMR ≈ 269 with an extremely wide 95% CI ~ 6.7–1499.9 (not precise, not clearly elevated). The study did not show any exposure–response for lymphoid cancers across length of employment or job categories, and CLL was too rare to analyze beyond that single death. Their nested case-control work targeted lung cancer and multiple myeloma (not CLL), and found no association with creosote exposure after adjusting for smoking. Overall, this cohort provides no reliable evidence that creosote exposure increases CLL risk; the seemingly high CLL SMR reflects very small numbers and statistical instability, not a demonstrable effect.

Chronic Lymphocyctic and Secondhand Smoke (Suggestive)

• Kasim et al 2005. —This Canadian population-based case–control study of never-smokers found a clear association between secondhand smoke (environmental tobacco smoke, ETS) and chronic lymphocytic leukemia (CLL), with dose–response patterns across both home and workplace exposure. Using lifetime residential exposure, the highest tertile had an adjusted OR of about 2.3 (95% CI 1.2–4.5), and for lifetime occupational ETS the highest tertile was roughly 2.4 (1.3–4.3). Results were consistent when combining residential and occupational exposure metrics, and trends were significant across duration and “smoker-years” indices. Time-window analyses did not show stronger effects for more recent ETS exposure, and excluding the last five years of exposure did not materially change CLL results. Other leukemia subtypes showed little or no association, underscoring the CLL-specific signal among nonsmokers. Overall, the study concludes that regular long-term ETS exposure may increase CLL risk.

Chronic Lymphocytic and Herbicides ( suggestive)

• Benavente et al. 2020 — ran a population-based case-control study in Spain (302 CLL cases, 1,567 controls) using a Spanish job-exposure matrix to estimate lifetime occupational exposure to specific pesticides. They found higher CLL odds with greater cumulative exposure, especially at the highest tertile: insecticides OR 2.10 (95% CI 1.38–3.19), herbicides OR 1.77 (1.12–2.80), and fungicides OR 1.67 (1.06–2.64); only insecticides showed a significant linear trend. A principal-components pattern dominated by all herbicides, all fungicides, and pyrethrin was also associated with CLL (per-SD OR 1.26; 1.14–1.40). Associations were similar or slightly stronger when restricted to incident cases. Because individual active substances were highly correlated, the study couldn’t cleanly isolate single chemicals, and exposure was assigned by JEM (risk of non-differential misclassification). Overall, the paper supports a positive, exposure-related association between occupational pesticide exposure (including herbicides) and CLL.

• Meloni et al. 2021 — The study evaluated 867 incident lymphomas and 774 controls with expert-rated occupational glyphosate exposure. For chronic lymphocytic leukemia (CLL) specifically, ever exposure showed no association: OR 0.6 (95% CI 0.11–3.48), and there were no CLL cases in the medium–high confidence exposure category, so no estimate there. Across exposure metrics (duration, intensity, frequency, cumulative), the positive findings were confined to follicular lymphoma, not CLL. Exposure prevalence was very low (about 2.2% ever exposed; 0.9% with medium–high confidence), limiting power for subtype analyses like CLL. Overall, the data do not support a CLL association with occupational glyphosate in this dataset.