Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Agricultural crop density and risk of childhood cancer in the midwestern United States: an ecologic study.

BACKGROUND: There is limited evidence for an association between agricultural pesticide exposure and certain types of childhood cancers. Numerous studies have evaluated exposure to pesticides and childhood cancer and found positive associations. However, few studies have examined the density of agricultural land use as a surrogate for residential exposure to agricultural pesticides and results are mixed. We examined the association of county level agricultural land use and the incidence of specific childhood cancers. METHODS: We linked county-level agricultural census data (2002 and 2007) and cancer incidence data for children ages 0-4 diagnosed between 2004 and 2008 from cancer registries in six Midwestern states. Crop density (percent of county area that was harvested) was estimated for total agricultural land, barley, dry beans, corn, hay, oats, sorghum, soybeans, sugar beets, and wheat. Rate ratios and 95% confidence intervals were estimated using generalized estimating equation Poisson regression models and were adjusted for race, sex, year of diagnosis, median household income, education, and population density. RESULTS: We found statistically significant exposure-response relationships for dry beans and total leukemias (RR per 1% increase in crop density = 1.09, 95% CI = 1.03-1.14) and acute lymphoid leukemias (ALL) (RR = 1.10, 95% CI = 1.04-1.16); oats and acute myeloid leukemias (AML) (RR = 2.03, 95% CI = 1.25, 3.28); and sugar beets and total leukemias (RR = 1.11, 95% CI = 1.04, 1.19) and ALL (RR = 1.11, 95% CI = 1.02, 1.21). State-level analyses revealed some additional positive associations for total leukemia and CNS tumors and differences among states for several crop density-cancer associations. However, some of these analyses were limited by low crop prevalence and low cancer incidence. CONCLUSIONS: Publicly available data sources not originally intended to be used for health research can be useful for generating hypotheses about environmental exposures and health outcomes. The associations observed in this study need to be confirmed by analytic epidemiologic studies using individual level exposure data and accounting for potential confounders that could not be taken into account in this ecologic study

Lung cancer risk at low cumulative asbestos exposure: meta-regression of the exposure–response relationship

Purpose: Existing estimated lung cancer risks per unit of asbestos exposure are mainly based on, and applicable to, high exposure levels. To assess the risk at low cumulative asbestos exposure, we provide new evidence by fitting flexible meta-regression models, a notably new and more robust method. Methods: Studies were selected if lung cancer risk per cumulative asbestos exposure in at least two exposure categories was reported. From these studies (n = 19), we extracted 104 risk estimates over a cumulative exposure range of 0.11-4,710 f-y/ml. We fitted linear and natural spline meta-regression models to these risk estimates. A natural spline allows risks to vary nonlinearly with exposure, such that estimates at low exposure are less affected by estimates in the upper exposure categories. Associated relative risks (RRs) were calculated for several low cumulative asbestos exposures. Results: A natural spline model fitted our data best. With this model, the relative lung cancer risk for c umulative exposure levels of 4 and 40 f-y/ml was estimated between 1.013 and 1.027, and 1.13 and 1.30, respectively. After stratification by fiber type, a non-significant three- to fourfold difference in RRs between chrysotile and amphibole fibers was found for exposures below 40 f-y/ml. Fiber-type-specific risk estimates were strongly influenced by a few studies. Conclusions: The natural spline regression model indicates that at lower asbestos exposure levels, the increase in RR of lung cancer due to asbestos exposure may be larger than expected from previous meta-analyses. Observed potency differences between different fiber types are lower than the generally held consensus. Low-exposed industrial or population-based cohorts with quantitative estimates of asbestos exposure a required to substantiate the risk estimates at low exposure levels from our new, flexible meta-regression

Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C)

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

Asbestos and its lethal legacy

Asbestos has become the leading cause of occupationally related cancer death, and the second most fatal manufactured carcinogen (after tobacco). In the public's mind, asbestos has been a hazard since the 1960s and 1970s. However, the knowledge that the material was a mortal health hazard dates back at least a century, and its carcinogenic properties have been appreciated for more than 50 years