Assessment of the mutagenicity of phthalate esters

Abstract

The Ames assay was used to investigate the mutagenicity of several phthalate esters as an approximation of their carcinogenic potential. The ortho diesters, dimethyl phthalate (DMP) and diethyl phthalate (DEP) produced a positive dose-related mutagenic response with Salmonella TA100, but only in the absence of S-9 liver enzymes. Dibutyl, di(2-ethylhexyl), mono(2-ethylhexyl), and butyl benzyl phthalate as well as the dimethyl isophthalate and terephthalates and the trimethyl ester, trimellitate, were not mutagenic with TA100 or TA98 in the presence or absence of S-9. In a host-mediated assay, extracts of 24-hr urines of rats injected IP with DMP (2 g/kg) were not mutagenic to TA100 at levels up to 8 equivalent-ml of urine/plate (representing 30% of their daily urinary output). In vitro studies revealed that S-9 associated esterase hydrolyzed DMP to the monoester and methanol and eliminated its mutagenicity. Whole rat skin was shown to have about 1.5% of the DMP-esterase activity of liver, when compared on a wet weight basis. An in vitro binding study indicated that epidermal macromolecules bound DMP at a severalfold greater rate than hepatic macromolecules. Thus, both the mutagenicity and binding of DMP are inversely related to the metabolism of this compound. These results suggest that skin could be at high risk for a mutagenic/carcinogenic insult.