Abstract  We conducted an historical cohort study to investigate the mortality experience of industrial workers potentially exposed to chloroprene (CD) and other substances, including vinyl chloride (VC), with emphasis on cancer mortality, including respiratory system (RSC) and liver. In 1999, the International Agency for Research on Cancer (IARC) classified CD as a possible carcinogen (Group 2B); VC was classified in 1987 as a known human carcinogen (Group 1). Subjects were 12,430 workers ever employed at one of two U.S. industrial sites (Louisville, KY (n = 5507) and Pontchartrain, LA (n = 1357)) or two European sites (Maydown, Northern Ireland (n = 4849) and Grenoble, France (n = 717)), with earliest CD production dates ranging from 1942 (L) to 1969 (P). Two sites (L and M) synthesized CD with the acetylene process that produced VC exposures. We determined vital status through 2000 for 95% of subjects and cause of death for 95% of the deaths. Historical exposures for individual workers were estimated quantitatively for CD and VC. Workers ever exposed to CD ranged from 92.3% (M) to 100% (G); to VC from 5.5% (M) to 22.7% (L). We computed standardized mortality ratios (SMRs) (using national and regional standard populations) in relation to selected demographic, work history and exposure factors. We used worker pay type (white or blue collar) as a rough surrogate for lifetime smoking history. For the combined cohort, SMRs (95% CIs) for all causes combined, all cancers combined, RSC and liver cancer were, respectively, 0.72 (0.69–0.74), 0.73 (0.68–0.78), 0.75 (0.67–0.84) and 0.72 (0.43–1.13). Site-specific (L, M, P and G, respectively) SMRs were: for all cancers combined: 0.75 (0.69–0.80), 0.68 (0.56–0.80), 0.68 (0.47–0.95) and 0.59 (0.36–0.91); for RSC: 0.75 (0.66–0.85), 0.79 (0.58–1.05), 0.62 (0.32–1.09) and 0.85 (0.41–1.56); for liver cancer: 0.90 (0.53–1.44) (17 deaths), 0.24 (0.01–1.34) (1 death), 0.0 (0–2.39) (no deaths) and 0.56 (0.01–3.12) (1 death). Among all workers ever exposed to CD, SMRs were: for all cancers combined: 0.71 (0.66–0.76); for RSC: 0.75 (0.67–0.84); for liver cancer: 0.71 (0.42–1.14). We also observed no increased mortality risks among cohort subgroups defined by race, gender, worker pay type, worker service type (short/long term), time period, year of hire, age at hire, duration of employment, the time since first employment, and CD or VC exposure status (never/ever exposed). In summary, our study has many strengths and is the most definitive study of the human carcinogenic potential of exposure to CD conducted to date. We conclude that persons exposed to chloroprene or vinyl chloride at the levels encountered in the four study sites did not have elevated risks of mortality from any of the causes of death examined, including all cancers combined and lung and liver cancer, the cancer sites of a priori interest. This conclusion is corroborated by our detailed analyses of mortality in relation to qualitative and quantitative exposures to CD and VC at each of the four study sites, reported in our companion paper (Marsh et al., submitted for publication).

Abstract  As part of an historical cohort study to investigate the mortality experience of industrial workers exposed to chloroprene (CD) and other substances, including vinyl chloride monomer (VC), we analyzed mortality from all cancers combined, respiratory system (RSC) and liver cancer in relation to CD and VC exposures. Subjects were 12,430 workers ever employed at one of two U.S. sites (Louisville, KY (n = 5507) and Pontchartrain, LA (n = 1357)) or two European sites (Maydown, Northern Ireland (n = 4849) and Grenoble, France (n = 717)). Historical exposures for individual workers were estimated quantitatively for CD and VC. For sites L, M, P and G, respectively, average intensity of CD exposures (median value of exposed workers in ppm) were 5.23, 0.16, 0.028 and 0.149 and median cumulative exposures (ppm years) were 18.35, 0.084, 0.133 and 1.01. For sites L and M, respectively, average intensity of VC exposures (median value of exposed workers in ppm) was 1.54 and 0.03 and median cumulative exposures (ppm years) were 1.54 and 0.094. We performed relative risk (RR) regression modeling to investigate the dependence of the internal cohort rates for all cancers combined, RSC and liver cancer on combinations of the categorical CD or VC exposure measures with adjustment for potential confounding factors. We categorized exposure measures into approximate quartiles based on the distribution of deaths from all cancers combined. We also considered 5- and 15-year lagged exposure measures and adjusted some RR models for worker pay type (white/blue collar) as a rough surrogate for lifetime smoking history. All modeling was site-specific to account for exposure heterogeneity. We also computed exposure category-specific standardized mortality ratios (SMRs) to assess absolute mortality rates. With the exception of a one statistically significant association with duration of exposure to CD and all cancers combined in plant M, we observed no evidence of a positive association with all cancers, RSC or liver cancer and exposure to CD and/or VC using both the unlagged and lagged exposure measures: duration, average intensity or cumulative exposure to CD or VC; time since first CD or VC exposure; and duration of CD exposure or time since first CD exposure in presence or absence of VC exposure. We observed elevated and statistically significantly elevated RRs for some analysis subgroups, but these were due to inordinately low death rates in the baseline categories. With the possible exception of all cancer mortality in plant G, our additional adjustment of RRs for pay type revealed no evidence of positive confounding by smoking. We conclude that exposures to CD or VC at the levels encountered in the four study sites do not elevate mortality risks from all cancers, RSC or liver cancer. This conclusion is corroborated by our analysis of general mortality patterns among the CD cohort reported in our companion paper [G. Marsh, A. Youk, J. Buchanich, M. Cunningham, N. Esmen, T. Hall, M. Phillips, Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns, Chem.-Biol. Interact., submitted for publication].

Abstract  Beta-chloroprene (2-chloro-1,3-butadiene, CD) is carcinogenic by inhalation exposure to B6C3F1 mice and Fischer F344 rats but not to Wistar rats or Syrian hamsters. The initial step in metabolism is oxidation, forming a stable epoxide (1-chloroethenyl)oxirane (1-CEO), a genotoxicant that might be involved in rodent tumorigenicity. This study investigated the species-dependent in vitro kinetics of CD oxidation and subsequent 1-CEO metabolism by microsomal epoxide hydrolase and cytosolic glutathione S-transferases in liver and lung, tissues that are prone to tumor induction. Estimates for Vmax and Km for cytochrome P450-dependent oxidation of CD in liver microsomes ranged from 0.068 to 0.29 µ;mol/h/mg protein and 0.53 to 1.33 µ;M, respectively. Oxidation (Vmax/Km) of CD in liver was slightly faster in the mouse and hamster than in rats or humans. In lung microsomes, Vmax/Km was much greater for mice compared with the other species. The Vmax and Km estimates for microsomal epoxide hydrolase activity toward 1-CEO ranged from 0.11 to 3.66 µ;mol/h/mg protein and 20.9 to 187.6 µ;M, respectively, across tissues and species. Hydrolysis (Vmax/Km) of 1-CEO in liver and lung microsomes was faster for the human and hamster than for rat or mouse. The Vmax/Km in liver was 3 to 11 times greater than in lung. 1-CEO formation from CD was measured in liver microsomes and was estimated to be 2?5% of the total CD oxidation. Glutathione S-transferase-mediated metabolism of 1-CEO in cytosolic tissue fractions was described as a pseudo-second order reaction; rates were 0.0016?0.0068/h/mg cytosolic protein in liver and 0.00056?0.0022 h/mg in lung. The observed differences in metabolism are relevant to understanding species differences in sensitivity to CD-induced liver and lung tumorigenicity.

Abstract  The Environmental Protection Agency (EPA) is committed to providing public access to environmental information. This commitment is integral to our mission to protect human health and the environment. One of our goals is that all parts of society--including communities, individuals, businesses, State and local governments, Tribal governments--have access to accurate information sufficient to effectively participate in managing human health and environmental risks. To fulfill this and other important goals, EPA must rely upon information of appropriate quality for each decision we make.

Abstract  β-Chloroprene (chloroprene) is carcinogenic in inhalation bioassays with B6C3F1 mice and Fischer rats, but the potential effects in humans have not been adequately characterized. In order to provide a better basis for evaluating chloroprene exposures and potential effects in humans, we have explored species and tissue differences in chloroprene metabolism. This study implemented an in vitro-in vivo extrapolation (IVIVE) approach to parameterize a physiologically based pharmacokinetic (PBPK) model for chloroprene and evaluate the influence of species and gender differences in metabolism on target tissue dosimetry. Chloroprene metabolism was determined in vitro using liver, lung and kidney microsomes from male or female mice, rats, and humans. A two compartment PK model was used to estimate metabolism parameters for chloroprene in an in vitro closed vial system, which were then extrapolated to the whole body PBPK model. Two different strategies were used to estimate parameters for the oxidative metabolism of chloroprene: a deterministic point-estimation using the Nelder-Mead nonlinear optimization algorithm and probabilistic Bayesian analysis using the Markov Chain Monte Carlo technique. Target tissue dosimetry (average amount of chloroprene metabolized in lung per day) was simulated with the PBPK model using the in vitro-based metabolism parameters. The model-predicted target tissue dosimetry, as a surrogate for a risk estimate, was similar between the two approaches; however, the latter approach provided a measure of uncertainty in the metabolism parameters and the opportunity to evaluate the impact of that uncertainty on predicted risk estimates.

Abstract  A physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and human has been developed that relies solely on in vitro studies for the estimation of model parameters describing tissue metabolism and partitioning. The PBPK model accurately predicts in vivo pharmacokinetic data from a 6-hr, nose-only chloroprene inhalation study conducted with female B6C3F1 mice, the most sensitive species/gender for lung tumors in the 2-year bioassays conducted with chloroprene. This PBPK model has been developed to support an inhalation cancer risk assessment for chloroprene using in vitro data on the metabolism of chloroprene to reactive epoxides in the lung target tissue of mice and humans. The approach for calculating target tissue (lung) dose metrics was based on the PBPK modeling performed in support of the inhalation cancer risk assessment for methylene chloride and represents the best available science for determining the impact of species differences in metabolism of chloroprene.

Abstract  Background: Residents of census tract 708 in St. John Parish, Louisiana, face the highest nationwide cancer risk from air pollution due to chloroprene emissions from the Denka Performance Elastomer facility. The University Network for Human Rights worked with residents of this predominantly Black community in Cancer Alley to design and implement a survey-based health study of the area. The study aimed to (1) assess the relationship between household proximity to the facility and reported illness, and (2) advance the advocacy objectives of the community. Methods: The survey area consisted of households within a 2.5-km radius of the Denka facility. Sixty percent of the households within 1.5 km of the facility (“Zone 1”) and 20% of the households between 1.5 and 2.5 km from the facility (“Zone 2”) were randomly sampled. Survey implementers collected information on cancer diagnoses about all residents of each surveyed household. Information on chloroprene-linked medical symptoms was collected about respondents (those who took the survey) only. Results: Cancer prevalence among the survey sample is (1) significantly higher than what is considered likely using Monte Carlo simulations based on Surveillance, Epidemiology, and End Results prevalence data (p = 0.0306); and (2) associated with proximity to the facility, with significantly higher-than-likely prevalence in Zone 1 (p = 0.0032) and lower prevalence in Zone 2. Levels of medical symptoms among respondents are high and also associated with proximity to the facility. Discussion: Our findings highlight the need for action to compel Denka to reduce chloroprene emissions to Environmental Protection Agency-recommended limits. Conclusion: Our findings are consistent with Cancer Alley communities' lived experiences of the debilitating health consequences of the area's industrial emissions. The burden of proof must shift to polluting industries.

Abstract  beta-Chloroprene (2-chloro-1,3-butadiene; CD), which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance of the bioassay lung tumor findings to human health risk by developing a physiologically based toxicokinetic (PBTK) model and exploring a tissue specific exposure-dose-response relationship. Key steps included identification of the plausible genotoxic mode of action, experimental quantification of tissue-to-air partition coefficients, scaling of in vitro parameters of CD metabolism for input into the PBTK model, comparing the model with in vivo experimental gas uptake data, selecting an appropriate tissue dosimetric, and predicting a corresponding human exposure concentration. The total daily milligram amount of CD metabolized per gram of lung was compared with the animal bioassay response data, specifically combined bronchiolar adenoma/carcinoma. The faster rate of metabolism in mouse lung agreed with the markedly greater incidence of lung tumors compared with the other rodent species. A lung tissue dose was predicted for the combined rodent lung tumor bioassay data at a 10% benchmark response. A human version of the PBTK model predicted that the lung tissue dose in humans would be equivalent to continuous lifetime daily exposure of 23 ppm CD. PBTK model sensitivity analysis indicated greater dependence of model predictions of dosimetry on physiological than biochemical parameters. The combined analysis of lung tumor response across species using the PBTK-derived internal dose provides an improved alternative to default pharmacokinetic interspecies adjustments for application to human health risk assessment.

Abstract  Objectives: To update the U.S. portion of an historical cohort mortality study of workers with potential exposure to chloroprene (CD) and vinyl chloride (VC) with focus on lung and liver cancer. Methods: Subjects were 6864 workers from two sites with vital status determined through 2017 for 99% of subjects and cause of death for 97.2% of deaths. Historical exposures to CD and VC were estimated quantitatively. We performed external and internal mortality comparisons. Results: External comparisons revealed mostly deficits in deaths; internal comparisons revealed no consistent evidence of exposure-response relationships with CD or VC. Conclusions: Our update continues to support the conclusion that the risk of death from lung or liver cancer is unrelated to exposure to CD or VC at levels experienced by workers in the two U.S. sites.

Abstract  The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) program develops human health assessments that focus on hazard identification and dose-response analyses for chemicals in the environment. The ORD Staff Handbook for Developing IRIS Assessments (the handbook) provides guidance to scientists who perform the IRIS assessments in order to foster consistency in the assessments and enhance transparency about the IRIS assessment process. At the request of the EPA, this report reviews the procedures and considerations for operationalizing the principles of systematic reviews and the methods described in the handbook for determining the scope of the IRIS assessments, evidence integration, extrapolation techniques, dose-response analyses, and characterization of uncertainties.