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Human exposure to toluene diisocyanate (TDI) occurs mainly through inhalation of vapors in occupational settings where TDI is produced or used, but dermal exposure to TDI is also possible during some operations. Because of a recent epidemiology study reporting a possible association with lung cancer risk in workers with potential dermal exposure to TDI, we evaluated the evidence from epidemiological, toxicological, and toxicokinetic studies to assess whether it is likely that dermal exposure to TDI can cause human respiratory cancers. We found that the reported associations with respiratory cancers in the epidemiology studies do not support TDI as a causal factor, as there are other explanations that are more likely than causation, such as confounding by smoking and low socioeconomic status. Experimental animal and genotoxicity studies indicate that the carcinogenic potential of TDI depends on its conversion to toluene diamine (TDA), and there is no evidence of systemic availability of TDA after dermal or inhalation exposure to TDI. Also, systemic uptake of TDI is very low after dermal exposure, and any absorbed TDI is more likely to react with biomolecules on or below the skin surface than to form TDA. Even if some TDA formation occurred after dermal exposure to TDI, TDA does not induce respiratory tract tumors in experimental animals after either dermal or oral exposure. We conclude that the available evidence indicates that dermal TDI exposure does not cause respiratory cancers in humans., (Copyright © 2017 Gradient. Published by Elsevier Ltd.. All rights reserved.)

Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100μg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per μg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Short-term exposure to ozone has been associated with asthma hospital admissions (HA) and emergency department (ED) visits, but the shape of the concentration-response (C-R) curve is unclear., Methods: We conducted a time series analysis of asthma HAs and ambient ozone concentrations in six metropolitan areas in Texas from 2001 to 2013. Using generalized linear regression models, we estimated the effect of daily 8-hour maximum ozone concentrations on asthma HAs for all ages combined, and for those aged 5-14, 15-64, and 65+years. We fit penalized regression splines to evaluate the shape of the C-R curves., Results: Using a log-linear model, estimated risk per 10ppb increase in average daily 8-hour maximum ozone concentrations was highest for children (relative risk [RR]=1.047, 95% confidence interval [CI]: 1.025-1.069), lower for younger adults (RR=1.018, 95% CI: 1.005-1.032), and null for older adults (RR=1.002, 95% CI: 0.981-1.023). However, penalized spline models demonstrated significant nonlinear C-R relationships for all ages combined, children, and younger adults, indicating the existence of thresholds. We did not observe an increased risk of asthma HAs until average daily 8-hour maximum ozone concentrations exceeded approximately 40ppb., Conclusion: Ozone and asthma HAs are significantly associated with each other; susceptibility to ozone is age-dependent, with children at highest risk. C-R relationships between average daily 8-hour maximum ozone concentrations and asthma HAs are significantly curvilinear for all ages combined, children, and younger adults. These nonlinear relationships, as well as the lack of relationship between average daily 8-hour maximum and peak ozone concentrations, have important implications for assessing risks to human health in regulatory settings., (Copyright © 2017. Published by Elsevier Ltd.)

The inhalation unit risk (IUR) that currently exists in the United States Environmental Protection Agency's (US EPA's) Integrated Risk Information System was developed in 1984 based on studies examining the relationship between respiratory cancer and arsenic exposure in copper smelters from two US locations: the copper smelter in Anaconda, Montana, and the American Smelting And Refining COmpany (ASARCO) smelter in Tacoma, Washington. Since US EPA last conducted its assessment, additional data have become available from epidemiology and mechanistic studies. In addition, the California Air Resources Board, Texas Commission of Environmental Quality, and Dutch Expert Committee on Occupational Safety have all conducted new risk assessments. All three analyses, which calculated IURs based on respiratory/lung cancer mortality, generated IURs that are lower (i.e., less restrictive) than the current US EPA value of 4.3×10(-3) (μg/m(3))(-1). The IURs developed by these agencies, which vary more than 20-fold, are based on somewhat different studies and use different methodologies to address uncertainties in the underlying datasets. Despite these differences, all were developed based on a cumulative exposure metric assuming a low-dose linear dose-response relationship. In this paper, we contrast and compare the analyses conducted by these agencies and critically evaluate strengths and limitations inherent in the data and methodologies used to develop quantitative risk estimates. In addition, we consider how these data could be best used to assess risk at much lower levels of arsenic in air, such as those experienced by the general public. Given that the mode of action for arsenic supports a threshold effect, and epidemiological evidence suggests that the arsenic concentration in air is a reliable predictor of lung/respiratory cancer risk, we developed a quantitative cancer risk analysis using a nonlinear threshold model. Applying a nonlinear model to occupational data, we established points of departure based on both cumulative exposure (μg/m(3)-years) to arsenic and arsenic concentration (μg/m(3)) via inhalation. Using these values, one can assess the lifetime risk of respiratory cancer mortality associated with ambient air concentrations of arsenic for the general US population., (Copyright © 2014 Elsevier Ltd. All rights reserved.)