Coumarin metabolism, toxicity and carcinogenicity: Relevance for human risk assessment

The metabolism toxicity and results of tests for carcinogenicity have been reviewed with respect to the safety for humans of coumarin present in foods tuffs and from fragrance use in cosmetic products Coumarin is a natural pro duct which exhibits marked species differences in both metabolism and toxic ity. The majority of tests for mutagenic and genotoxic potential suggest th at coumarin is not a genotoxic agent. The target organs for toxicity and ca rcinogenicity in the rat and mouse are primarily the liver and lung. Moreov er. the doss-response relationships for coumarin-induced toxicity and carci nogenicity are non-linear, with tumour formation only being observed at hig h doses which are associated with hepatic and pulmonary toxicity. Other spe cies, including the Syrian hamster, are seemingly resistant to coumarin-ind uced toxicity. There are marked differences in coumarin metabolism between susceptible rodent species and other species including humans. It appears t hat the 7-hydroxylation pathway of coumarin metabolism, the major pathway i n most human subjects but only a minor pathway in the rat and mouse, is a d etoxification pathway. In contrast, the major route of coumarin metabolism in the rat and mouse is by a 3,4-epoxidation pathway resulting in the forma tion of toxic metabolites. The maximum daily human exposure to coumarin fro m dietary sources for a 60-kg consumer has been estimated to be 0.02 mg/kg/ day. From fragrance use in cosmetic products, coumarin exposure has been es timated to be 0.04 mg/kg/day. The total daily human exposure From dietary s ources together with fragrance use in cosmetic products is thus 0.06 mg/kg/ day. No adverse effects of coumarin have been reported in susceptible speci es in response to doses which are more than 100 rimes the maximum human dai ly intake. The mechanism of coumarin-induced tumour formation in rodents is associated with metabolism-mediated, toxicity and it is concluded that exp osure to coumarin From food and/or cosmetic products poses no health risk t o humans. (C) 1999 Elsevier Science Ltd. All rights reserved.