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The purpose of this work was to estimate the degree of risk that might be associated with human exposure to low levels of the plasticizer di(2-ethylhexyl)phthalate (DEHP). DEHP is a common component, sometimes at high concentrations, of polyvinyl chloride (PVC) plastics and was recently reported by the National Toxicology Program (NTP) to be carcinogenic in rats and mice, inducing hepatocellular tumors in both species. This work was also designed to illustrate an approach to risk assessment that attempts to incorporate all available biological data. Based on the dose-response data generated by the NTP bioassays, we have performed extrapolations of risk to low dose levels using several procedures, including some that incorporate inferences from the available data that shed light on the likely relationship between dose level and risk at low dose levels. In drawing these inferences, consideration was given to such factors as genotoxicity, metabolism and pharmacokinetics, and physiological and biochemical effects of DEHP that might reveal its mechanism of action. The relative merits of each of the various risk estimates are described, based on current understanding of DEHP's mode of biological action. It is concluded that DEHP's mechanism of carcinogenicity in rodents most likely involves its ability to induce peroxisome proliferation and related enzymatic changes, although other mechanisms cannot be excluded. If humans and rodents are assumed to be at the same risk at the same daily dose level of DEHP, application of the various low dose extrapolation models leads to the prediction that the daily dose resulting in a lifetime risk of no more than 1 in 1 million would be between 1.5 and 791 mg/kg per day, with the most likely figure being 116 mg/kg per day. If the carcinogenicity of DEHP is dependent upon its pattern of metabolism, however, it would be inappropriate to extrapolate from rodents to man without qualification because of the major quantitative differences in metabolism in rats, mice, and primates, including man. One of the major differences in metabolism of DEHP between rats and mice and primates is in production of a metabolite whose level may be an indicator of the level of peroxisomal activity and, hence, if the peroxisome proliferation theory of DEHP carcinogenicity is correct, of carcinogenic risk. However, the substantial doubt that exists regarding the applicability of rodent carcinogenicity data to humans must be expressed in qualitative terms.

Assessment of Possible Carcinogenic Risk to Humans Resulting from Exposure to Di(2-ethylhexyl)phthalate (DEHP)