HEPATOCARCINOGENIC POTENTIAL OF DI(2-ETHYLHEXYL)PHTHALATE IN RODENTS AND ITS IMPLICATIONS ON HUMAN RISK

The plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and m ice. DEHP is potentially set free from objects made of synthetic mater ials (e.g., those used in medicine). Chronically, the greatest amounts are transferred to persons undergoing hemodialysis (up to 3.1 mg/kg b .w. per day) who would thus be considered the individuals most endange red by tumorigenesis. Although toxicokinetics seem to play a certain u nclear role in the course of DEHP-related toxicity, toxicodynamic fact ors appear more decisive. DEHP is a representative of ''peroxisome pro liferators'' (PP), a distinct group of substances that, in rodents, do not only induce peroxisomes but also specific enzymes in other organe lles, organ growth, and DNA synthesis. The cluster of the characterist ic effects of PP is generally, although perhaps not quite appropriatel y summarized as ''peroxisome proliferation,'' and is strongest in the liver. The lowest observed effect level (LOEL) and the no observed eff ect level (NOEL) of peroxisome proliferation in the rat, as determined by the induction of specific enzymes (peroxisomal beta-oxidation, car nitine-acetyl-transferase, cytochrome P-452), DNA synthesis, and hepat omegaly, may be assumed as 50 and 25 mg/kg b.w. per day, respectively. DEHP and other carcinogenic PP are neither genotoxic nor tumor initia tors, but they appear to be tumor promoters, also implicating a thresh old level for the carcinogenic effect. Although a causal relationship between a particular effect of peroxisome proliferation and hepatocarc inogenesis is as yet unknown, peroxisome proliferation as a whole phen omenon appears to be associated with the potential of tumor induction, as shown by comparison of the relative strength of individual PP and by comparison of species and organ specificities. Likewise, LOLL and N OEL of rodent carcinogenesis, that is, 300 and 50 to 100 mg/kg b.w. pe r day, respectively, are above but not too far from the corresponding values for the investigated parameters of peroxisome proliferation. Th us, with respect to dose alone, worst-case exposure in hemodialysis pa tients is at least 16-fold below the LOEL of any characterized PP-spec ific effect of DEHP and approximately 100-fold below that of DEHP-rela ted tumorigenesis. Also, primates are less responsive to PP than rats with respect to the investigated biochemical and morphological paramet ers. If this lower primate responsiveness is extrapolated to estimate carcinogenicity in humans, we might thus arrive at an even larger safe ty margin than when based on exposure alone. Doses of PP hypolipidemic s that had clearly induced several indicators of peroxisome proliferat ion in rats did not cause any clear-cut enhancements in the peroxisome s of patients, even though most of these hypolipidemics were considera bly stronger PP than DEHP. Thus, an actual threat to humans by DEHP se ems rather unlikely. Accordingly, hepatocarcinogenesis was neither enh anced in workers exposed to DEHP nor in patients treated with hypolipi demics.