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 micromol/h/mg protein and 0.53 to 1.33 microM, 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 micromol/h/mg protein and 20.9 to 187.6 microM, 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.
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.
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