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The recent long-term carcinogenesis bioassay of di(2-ethylhexyl) phthalate (DEHP) in rats and mice reported by the National Toxicology Program was the first such bioassay to implicate DEHP as a hepatocarcinogen. At the levels of DEHP fed (up to 1.2% of the diet for two years), the livers of the rats would have been exposed to unhydrolyzed diester; this would not have been the case at lower dosages. Extrapolation to lower dosages is therefore questionable. We do not have sufficient pharmacokinetic data in mice to evaluate the dose relationships as yet. Rodents differ conspicuously from primates in their manner of metabolizing DEHP, both in terms of the demand made on the oxidation potential of the liver and in the chemical properties of the major metabolites. The relevance of these differences must be determined before rodent species can be considered models for the effects of DEHP in humans. Radioactivity from carbonyl-labeled DEHP did not associate with purified protein, RNA or DNA from rat liver in vivo. Label from 2-ethyl-(1-14C)-hexyl-labeled DEHP or mono(2-ethylhexyl) phthalate (MEHP) did appear to associate strongly with purified DNA, but label from free 14C-labeled 2-ethylhexanol did not. The apparent binding from DEHP and MEHP was not exchangeable, but was not proven to be covalent. This phenomenon needs additional study.

Sterols are important lipid components that may contribute to phototoxicity. We have found that phototoxic response in earthworms is related to sterols extractable with lipophilic solvents. The photochemically active compounds in worm lipids are 5,7,9(11),22-ergostatetraen-3 beta-ol (9-DHE) and 5,7,9(11)-cholestartien-3 beta-ol (9-DDHC), respectively. Human skin lipids are known to contain 9-DHE. We have also found 9-DDHC in human skin, which is reported here for the first time. In the presence of an excess of the corresponding 5,7-dienes (ergosterol of 7-dehydrocholesterol), these photoactive sterols constitute a self-regenerating source of singlet molecular oxygen (1O2) during irradiation in vivo or in vitro with UVA (315-400 nm). The quantum yield for photosensitization of 1O2 by 9-DHE was estimated to be 0.09. The 1O2 is scavenged by the dienes and the rate constant for 1O2 quenching by ergosterol was found to be 1.2 x 10(7) M-1 s-1 in methyl t-butyl ether (MTBE). This scavenging ultimately leads to the production of 5,8-endoperoxide and hydrogen peroxide. Photochemically induced superoxide radical was also produced on irradiation of sterol 5,7,9-trienes and trapped with the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The production of singlet oxygen, peroxides and radicals by the sterols may be significant in the cell damaging and tumor promoting action of UVA light on skin.