Male-specific prolongation of prothombin time by industrial chemicals

Abstract

-Prolongation of prothrombin time (PT) induced by industrial chemicals was characterized using a database of repeated dose toxicity studies, HESS DB. Of the 685 chemicals in the DB, 20 chemicals markedly prolonged the PT by more than 150% of that of vehicle control. Prolonged PTs were detected in males for 20 chemicals but no significant prolongation of PT was observed in females for 19/20 chemicals, indicating that males are apparently more susceptible to PT prolongation than females. The effective dose of the chemicals for males were relatively high, in the range of 100 to 1,000 mg·kg -1 ·day -1 , compared to the dose range of 60 to 100 μg·kg -1 ·day -1 for warfarin, a typical anticoagulant. Since not all chemicals had severe hepatotoxic effects at these doses, the low protein synthesis capacity of the liver may not contribute to prolonged PT. The mechanism of PT prolongation by the chemicals was considered different from that of warfarin, which is a specific inhibitor of vitamin K epoxide reductase, because of large differences in their effective dose and lack of structural similarity between them. Herein, the possible mechanisms of PT prolongation by industrial chemicals in males are explored, with a focus on the action of estradiol and vitamin K.