Species differences in kidney toxicitity and metabolic activation of tris(2,3-dibromopropyl)phosphate

Abstract

The flame retardant tris(2,3-dibromopropyl)phosphate(Tris-BP) was studied for nephrotoxicity and covalent protein binding in vivo to rat, mouse, hamster and guinea pig protein. In addition, Tris-BP mutagenicity to S. typhimurium TA 100 and covalent protein binding in vitro was determined with hepatic microsomes from rats, mice, hamsters, guinea pigs and humans. Tris-BP caused acute tubular renal necrosis in rats at doses of 100 mg/kg i.p. and higher, whereas no clear evidence of renal damage was found in mice, hamsters or guinea pigs at doses up to 500 – 1000 mg/kg. After administration of radiolabelled Tris-BP to the various laboratory animals, all species showed similar levels of covalent binding to proteins in liver and kidney, except for the rat which had much higher amounts of radiolabel bound to kidney proteins, correlating with the observed species differences in renal toxicity. Hepatic microsomes from all species, including man, activated Tris-BP to mutagenic products, constitutive mutagenic rates in mice microsomes being highest. Microsomes from animals pretreated with phenobarbital were considerably more active than control microsomes in mutagenic activation of Tris-BP. 3-Methylcholanthrene-pretreatment only increased Tris-BP mutagenicity with hamster and guinea pig liver microsomes. Clear interindividual differences in Tris-BP mutagenicity was noted with human hepatic microsomes. The rates of 3H-Tris-BP covalent protein binding in vitro were of the same magnitude with hepatic microsomes from laboratory animals and humans. Phenobarbital-pretreatment increased binding rates 7-fold with rat and 2–3 fold with hamster and guinea pig microsomes, respectively, whereas no increase was found with liver microsomes obtained from phenobarbital-pretreated mice. 3-Methylcholanthrene increased Tris-BP binding in vitro in hamsters and guinea pigs, but not in rats and mice. Covalent binding of radiolabel from 3H-Tris-BP varied over a 3-fold range using human hepatic microsomes.