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

There is increasing concern for the potential adverse health effects o f human exposures to chemical mixtures. To better understand the compl ex interactions of chemicals within a mixture, it is essential to deve lop a research strategy which provides the basis for extrapolating dat a 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 dif ferences in carcinogenic/genotoxic response to BD. Knowledge regarding mechanisms of DD-induced carcinogenicity provides the basis for asses sing the potential effects of mixtures containing BD. BD is a multisit e 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 chemic al, a quantitative understanding of the balance of activation and inac tivation is essential for improving our understanding and assessment o f 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 exh ibited significant mutagenicity in the lung, a target organ for the ca rcinogenic effect of BD in mice. In vitro studies designed to assess i nterspecies differences in the activation of BD and inactivation of BD epoxides reveal that significant differences exist among mice, rats,a nd humans. In general, the overall activation/detoxication ratio for B D 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 ox idation compare favorably with the metabolic rate constants that were determined from the in vitro studies when the in vitro Values were adj usted 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 i nteractions of BD with other chemicals in the workplace (e.g., BD/styr ene), the environment (e.g., BD/benzene), or through certain-dietary i nfluences (e.g., BD/ethanol) were explored. The three examples of simu lations of BD chemical mixtures suggest two important general points r egarding chemical interactions. The first relates to extrapolations fr om high to low doses. Due to the saturable enzyme systems that metabol ize most toxic organic chemicals, it cannot be assumed that the inhibi tion effects demonstrated at high exposure concentrations will be prop ortional, 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 chemica l to the site of the enzyme chemical interaction may be, in some cases , the rate-limiting factor, rather than the quantity of the enzyme pre sent.