THE USE OF TOXICOLOGIC DATA IN MECHANISTIC RISK ASSESSMENT - 1,3-BUTADIENE AS A CASE-STUDY

The National Research Council (NRC) recently published a report, Scien ce and Judgment in Risk Assessment, that critiqued the current approac hes to characterizing human cancer risks from exposure to chemicals. O ne issue raised in the report relates to the use of default options fo r quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interest ing case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as s ensitive as the most sensitive animal species, and (2) the rate of met abolism is a function of body surface area rather than inherent specie s differences in metabolic capacity. Butadiene, a major commodity chem ical used in the production of synthetic rubber, is listed as one of 1 89 hazardous air pollutants under the 1990 Clean Air Act Amendments. B utadiene is a carcinogen in rats and mice, with mice being substantial ly more sensitive than rats. The extent to which butadiene poses a can cer risk to humans exposed to this chemical is uncertain. Butadiene re quires metabolic activation to DNA-reactive epoxides to exert its muta genic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by e valuating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from h umans, rats, and mice as well as experimental data and physiological m odel predictions for butadiene in blood and butadiene epoxides in bloo d, lung, and liver after exposure of rats and mice to inhaled butadien e. The findings suggest that humans are more like rats and less like m ice regarding the formation of butadiene epoxides. The research approa ch employed can be a useful strategy for developing mechanistic and to xicokinetic data to supplant default options used in carcinogen risk a ssessments for butadiene.