Weight-of-evidence versus strength-of-evidence in toxicologic hazard identification: Di(2-ethylhexyl)phthalate (DEHP).
Toxicokinetic and mode of action data for DEHP reduce the concern for its potential carcinogenic hazard to human health. Chronic, high dose ingestion of DEHP and related peroxisome proliferators (PP) by mice and rats precipitate the following: activation of peroxisome proliferator activated receptor (PPARalpha) and its binding to peroxisome proliferator response elements (PPREs) within promoters of PP-responsive genes, peroxisome proliferation, increased microsomal fatty acid oxidation, increased hepatic hydrogen peroxide, hepatomegaly, hyperplasia and subsequent neoplasia. Neither peroxisome proliferation nor increased liver cancer occur in patients treated with pharmacologic doses of PP. Species differences in endogenous PPARalpha expression and differential activity of the peroxisome proliferator response element (PPRE) contribute to the failure of humans to respond in a manner qualitatively similar to that of rats or mice. Where it can be demonstrated that a mechanism for rodent tumor formation has no relevance for humans, then a substance which elicits a carcinogenic response in the test species via that mechanism should not be classified as anything other than an animal carcinogen. Systemic noncarcinogenic endpoints are available for definition of a DEHP reference dose. Considerable difficulty is encountered in the revision of promulgated regulations and in public risk communication when a material is no longer considered a carcinogenic hazard to humans.
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Department of Toxic Substances Control, State of California, 700 Heinz Street, Suite 200, Berkeley, CA 94710, USA.
D000818:Animals; D002273:Carcinogens / Q000145:classification*; D004051:Diethylhexyl Phthalate / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D020025:Peroxisome Proliferators / Q000493:pharmacokinetics* / Q000633:toxicity*; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D011640:Public Policy; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment / Q000331:legislation & jurisprudence / Q000379:methods*; D013045:Species Specificity; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014481:United States; D014484:United States Environmental Protection Agency
D002273:Carcinogens; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004051:Diethylhexyl Phthalate