1,3-BUTADIENE - LINKING METABOLISM, DOSIMETRY, AND MUTATION-INDUCTION

There is increasing concern for the potential adverse health effects of human exposures to chemical mixtures. To better understand the complex interactions of chemicals within a mixture, it is essential to develop a research strategy which provides the basis for extrapolating data from single chemicals to their behavior within the chemical mixture. 1,3-Butadiene (BD) represents an interesting case study in which new data are emerging that are critical for understanding interspecies differences in carcinogenic/genotoxic response to BD. Knowledge regarding mechanisms of DD-induced carcinogenicity provides the basis for assessing the potential effects of mixtures containing BD. BD is a multisite carcinogen in B6C3F1 mice and Sprague-Dawley rats. Mice exhibit high sensitivity relative to the rat to BD-induced tumorigenesis. Since it is likely that BD requires metabolic activation to mutagenic reactive epoxides that ultimately play a role in carcinogenicity of the chemical, a quantitative understanding of the balance of activation and inactivation is essential for improving our understanding and assessment of human risk following exposure to BD and chemical mixtures containing BD. Transgenic mice exposed to 625 ppm BD for 6 hr/day for 5 days exhibited significant mutagenicity in the lung, a target organ for the carcinogenic effect of BD in mice. In vitro studies designed to assess interspecies differences in the activation of BD and inactivation of BD epoxides reveal that significant differences exist among mice, rats,and humans. In general, the overall activation/detoxication ratio for BD metabolism was approximately 10-fold higher in mice compared to rats or humans. A preliminary physioiogical dosimetry model was developed for BD. The model simulations for the in vitro V-max and K-m for BD oxidation compare favorably with the metabolic rate constants that were determined from the in vitro studies when the in vitro Values were adjusted to account for microsomal content and liver weight in the intact animal. This favorable comparison suggests that in vitro biochemical parameters derived for BD could be used to predict in vivo metabolism. Using the physiological dosimetry model developed for BD, potential interactions of BD with other chemicals in the workplace (e.g., BD/styrene), the environment (e.g., BD/benzene), or through certain-dietary influences (e.g., BD/ethanol) were explored. The three examples of simulations of BD chemical mixtures suggest two important general points regarding chemical interactions. The first relates to extrapolations from high to low doses. Due to the saturable enzyme systems that metabolize most toxic organic chemicals, it cannot be assumed that the inhibition effects demonstrated at high exposure concentrations will be proportional, or even significant, at low exposure concentrations. Second, patterns of enzyme induction determined in vitro may not exhibit the same magnitude of effect in the intact animal. Delivery of the chemical to the site of the enzyme chemical interaction may be, in some cases, the rate-limiting factor, rather than the quantity of the enzyme present.