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The exposure-response relationship for airborne hexavalent chromium exposure and lung cancer mortality is well described by a linear relative rate model. However, categorical analyses have been interpreted to suggest the presence of a threshold. This study investigates nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis provided no improvement in fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30 μg/m3 CrO3 (16 μg/m3 as Cr+6) (one-sided 95% confidence limit, likelihood ratio test). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m3 (as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m3 CrO3 were excluded (two-sided upper 95% confidence limit, likelihood ratio test). A small departure from dose-rate linearity was observed, corresponding to (intensity)0.8 but was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Annotation: The Amphibole Hypothesis of Asbestos-Related Cancer--Gone But Not Forgotten," by M. R. Cullen in the 1996 issue.

A letter to the editor in response to an annotation and a paper about asbestos-related cancer and the amphibole hypothesis and a response by L. T. Stayner, D. A. Dankovic and R. A. Lemen are presented.

Opinion. Comments on the question on whether the carcinogenicity of TCDD in humans is quantitatively similar to that observed in animals. Disagreement with the interpretation of the authors results; Comparisons of toxicity at the highest dose levels; Views of the author in relation to the interpretation.

The excess (exposure-attributable) risks of certain respiratory diseases and outcomes were estimated for U.S. coal miners exposed to respirable coal mine dust for various durations and concentrations, including a 45-year working lifetime at the current 2-mg/m3 standard. Multiple linear and logistic regression models were used to compute predicted prevalence and excess risk of disease, using data andregression results from published epidemiological studies of U.S. coal miners. Disease outcomes evaluated include simple coal workers' pneumoconiosis, progressive massive fibrosis, and clinically significant deficits in lung function, measured as forced expiratory volume in 1 second of < 80% or < 65% of predicted normal values. Point estimates of excess risk of progressive massive fibrosis ranged from 1/1000 to 167/1000 among coal miners exposed to respirable coal mine dust at a mean concentration of 2 mg/m3 for 45 years. This range reflects coal rank and study differences. Point estimates for an excess risk of forced expiratory volume in 1 second of < 65% of predicted normal values ranged from 9/1000 to 188/1000 among miners with the same exposures noted above (the range reflects smoking status, geographical region, and study differences). Excess risks for all disease outcomes studied exceeded 1/1000 among miners exposed to mean concentrations as low as 0.5 mg/m3 and durations as low as 15 years (most coal ranks). Sources of uncertainty associated with these results were considered. Based on these and previous analyses, U.S. coal miners are predicted to have a substantial risk of developing occupational respiratory diseases from working lifetime exposures to respirable coal mine dust at the current 2-mg/m3 standard. To reduce this risk, the National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposures to respirable coal mine dust be kept below 1.0 mg/m3 during each work shift (as a ti [ABSTRACT FROM AUTHOR]

Prenatal nitrate exposure from household tap water has been associated with increased risk of fetal growth restriction, preterm birth, birth defects, and childhood cancer. We aim to examine the association between maternal consumption of drinking-water nitrate during pregnancy and small-for-gestational-age (SGA) in a nationwide study of Danish-born children, as only one prior study has examined this association. We linked individual-level household estimates of nitrate in tap water and birth registry data to all live singleton Danish births during 1991–2015 from Danish-born parents where the mother resided in Denmark throughout the pregnancy. Exposure was both binned into four categories and modeled as an ln-transformed continuous variable. SGA was defined as the bottom 10% of births by birth weight per sex and gestational week. Multiple logistic regression models with generalized estimating equations were used to account for siblings born to the same mother while controlling for relevant confounders. In the cohort of 1,078,892 births, the median pregnancy nitrate exposure was 1.9 mg/L nitrate. Compared to the reference group (≤2 mg/L), we found an increased risk of SGA in the second category (>2–5 mg/L) (OR = 1.04, 95% CI: 1.03–1.06) and third category (>5–25 mg/L) (OR = 1.02, 95% CI: 1.00–1.04) but not in the highest (>25 mg/L). There was strong (p = 0.002) evidence of an increase in SGA with nitrate in the model with continuous exposure (OR = 1.02, 95% CI: 1.01–1.04 per 10-fold increase in nitrate). Results were robust when restricting to households with nitrate levels at or below the current Danish and European Union regulatory drinking water standard (50 mg/L nitrate). Our findings suggest that exposure from nitrate in household tap water, even below current regulatory standards, may increase risk of SGA, raising concerns of whether current allowable nitrate levels in drinking water protect children from SGA. [ABSTRACT FROM AUTHOR]

• Residence near agriculture has been associated with childhood cancer risk. • Majority of Danish National Birth Cohort mothers lived within ½ kilometer of crops. • High area of crops within ½ kilometer increased risk of childhood leukemia. • High cattle density was associated with central nervous system tumors. • Novel findings - suggests agricultural exposures may increase childhood cancer risk. Living in an agricultural area or on farms has been associated with increased risk of childhood cancer but few studies have evaluated specific agricultural exposures. We prospectively examined residential proximity to crops and animals during pregnancy and risk of childhood leukemia and central nervous system (CNS) tumors in Denmark. The Danish National Birth Cohort (DNBC) consists of 91,769 pregnant women (96,841 live-born children) enrolled in 1996–2003. For 61 childhood leukemias and 59 CNS tumors <15 years of age that were diagnosed through 2014 and a ~10% random sample of the live births (N = 9394) with geocoded addresses, we linked pregnancy addresses to crop fields and animal farm locations and estimated the crop area (hectares [ha]) and number of animals (standardized by their nitrogen emissions) by type within 250 meters (m), 500 m, 1000 m, and 2000 m of the home. We also estimated pesticide applications (grams, active ingredient) based on annual sales data for nine herbicides and one fungicide that were estimated to have been applied to >30% of the area of one or more crop. We used Cox proportional hazard models (weighted to the full cohort) to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of childhood leukemia and CNS tumors with crop area, animals, and pesticide applications adjusted for gender and maternal age. Sixty-three percent of mothers had crops within 500 m of their homes during pregnancy; winter and spring cereals were the major crop types. Compared to mothers with no crops <500 m, we found increasing risk of childhood leukemia among offspring of mothers with increasing crop area near their home (highest tertile >24 ha HR: 2.0, CI:1.02–3.8), which was stronger after adjustment for animals (within 1000 m) (HR: 2.6, CI:1.02–6.8). We also observed increased risk for grass/clover (highest tertile >1.1 ha HR: 3.1, CI:1.2–7.7), peas (>0 HR: 2.4, CI: 1.02–5.4), and maize (>0 HR: 2.8, CI: 1.1–6.9) in animal-adjusted models. We found no association between number of animals near homes and leukemia risk. Crops, total number of animals, and hogs within 500 m of the home were not associated with CNS tumors but we observed an increased risk with >median cattle compared with no animals in crop-adjusted models (HR = 2.2, CI: 1.02–4.9). In models adjusted for total animals, the highest tertiles of use of three herbicides and one fungicide were associated with elevated risk of leukemia but no associations were statistically significant; there were no associations with CNS tumors. Risk of childhood leukemia was associated with higher crop area near mothers' homes during pregnancy; CNS tumors were associated with higher cattle density. Quantitative estimates of crop pesticides and other agricultural exposures are needed to clarify possible reasons for these increased risks. [ABSTRACT FROM AUTHOR]

Evidence is emerging that preterm birth (PTB, birth before 37 completed weeks of gestation), a risk factor for neonatal mortality and future morbidity, may be induced by maternal nitrate ( N O 3 - ) exposure from drinking water. The objective of this study is to assess the association between maternal exposure to nitrate and the risk of PTB in a nationwide study of liveborn singletons., Methods: We estimated maternal nitrate exposure from household tap water for 1,055,584 births in Denmark to Danish-born parents during 1991-2015 by linkage of individual home address(es) with nitrate concentrations from a national monitoring database. Nitrate exposure during pregnancy was modeled using four categories and continuously. Logistic models adjusted for sex, birth year, birth order, urbanicity, and maternal age, smoking, education, income, and employment, with generalized estimating equations were used to account for sibling clusters., Results: A total of 1,009,189 births were included, comprising 51,747 PTB. An increase in the risk of PTB was seen across categories of exposure ( P < 0.001) with an odds ratio (OR) in the uppermost category (>25 mg/L nitrate) of 1.05 (95% confidence interval [CI] = 1.00, 1.10). Evidence of an exposure-response relationship was observed in models using continuous nitrate (OR = 1.01 [95% CI = 1.00, 1.03] per 10 mg/L nitrate). In sensitivity analyses, results were robust to the addition of variables for short inter-pregnancy interval (<1 year between births), maternal pre-pregnancy body mass index, paternal socioeconomic status and age, season of birth, and inclusion of post-term births. Results were virtually unchanged when the analysis was restricted to women exposed to less than the current European Union standard of 50 mg/L., Conclusion: We observed an increasing risk of PTB with increases in nitrate in household tap water. These findings add to a growing body of evidence of adverse effects from nitrate in drinking water at levels below current regulatory levels., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further., (© 2019 UICC.)

Background: Ambient air pollution contains low concentrations of carcinogens implicated in the etiology of urinary bladder cancer (BC). Little is known about whether exposure to air pollution influences BC in the general population., Objective: To evaluate the association between long-term exposure to ambient air pollution and BC incidence., Design, Setting, and Participants: We obtained data from 15 population-based cohorts enrolled between 1985 and 2005 in eight European countries (N=303431; mean follow-up 14.1 yr). We estimated exposure to nitrogen oxides (NO 2 and NO x ), particulate matter (PM) with diameter <10μm (PM 10 ), <2.5μm (PM 2.5 ), between 2.5 and 10μm (PM 2.5-10 ), PM 2.5 absorbance (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project., Outcome Measurements and Statistical Analysis: We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and meta-analyses to estimate summary hazard ratios (HRs) for BC incidence., Results and Limitations: During follow-up, 943 incident BC cases were diagnosed. In the meta-analysis, none of the exposures were associated with BC risk. The summary HRs associated with a 10-μg/m 3 increase in NO 2 and 5-μg/m 3 increase in PM 2.5 were 0.98 (95% confidence interval [CI] 0.89-1.08) and 0.86 (95% CI 0.63-1.18), respectively. Limitations include the lack of information about lifetime exposure., Conclusions: There was no evidence of an association between exposure to outdoor air pollution levels at place of residence and risk of BC., Patient Summary: We assessed the link between outdoor air pollution at place of residence and bladder cancer using the largest study population to date and extensive assessment of exposure and comprehensive data on personal risk factors such as smoking. We found no association between the levels of outdoor air pollution at place of residence and bladder cancer risk., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans., Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed., Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed., Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

The exposure-response relationship for airborne hexavalent chromium exposure and lung cancer mortality is well described by a linear relative rate model. However, categorical analyses have been interpreted to suggest the presence of a threshold. This study investigates nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis provided no improvement in fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30 microg/m3 CrO3 (16 microg/m3 as Cr+6) (one-sided 95% confidence limit, likelihood ratio test). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m3 (as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m3 CrO3 were excluded (two-sided upper 95% confidence limit, likelihood ratio test). A small departure from dose-rate linearity was observed, corresponding to (intensity)0.8 but was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure.