Toxicokinetics of bisphenol A in rats, monkeys and chimpanzees by the LC-MS/MS method

Abstract

We examined the toxicokinetics of bisphenol A (BPA) in F344 rats, cynomolgus monkeys and chimpanzees. Serum BPA levels were quantified using the LC-MS/MS method. After oral administration at 10 mg/kg, the maximum concentration in the serum (C(max)) and the area under the serum concentration curve (AUC) of BPA in cynomolgus monkeys and chimpanzees were greater than in rats. After oral administration at 100 mg/kg, AUC during the first 4h (AUC(0-->4h)) in cynomolgus monkeys was greater than in rats. In rats, the serum BPA levels were increased again 6h or later after oral administration at each dose, which suggested the enterohepatic circulation of BPA in rats. After subcutaneous administration at 10 mg/kg, the AUCs were ranked in the following order: cynomolgus monkeys>chimpanzees>rats, and C(max) in cynomolgus monkeys was greater than in rats and chimpanzees. After subcutaneous administration at 100 mg/kg to cynomolgus monkeys and rats, both the C(max) and AUCs in cynomolgus monkeys were greater than in rats. In all species, the oral administration of BPA resulted in much lower C(max) and AUCs than subcutaneous administration at the corresponding doses, indicating the low bioavailability of oral administration. This result suggests that BPA undergoes an extensive first-pass metabolism in these animal species. AUCs of subcutaneous administration and the AUC (0-->4h) of oral administration in the two primates were greater than that in rats. Because the systemic clearance for BPA is assumed to be dependent on the hepatic blood flow-rate, the high AUCs in primates are considered to be due to the lower systemic clearance by a lower hepatic blood flow-rate in primates than in rats. In addition, the toxicokinetics of the metabolites of BPA were examined. After the oral administration of 10 mg/kg BPA, both C(max) and AUCs of BPA metabolites were ranked in the following order: cynomolgus monkeys>chimpanzees>rats, and the terminal elimination half-life (T(1/2)) in rats was greater than that in cynomolgus monkeys and chimpanzees, suggesting the enterohepatic circulation of BPA in rats. From these results, the systemic clearance of BPA in primates is considered to be close to that in humans due to the similarity of the hepatic blood flow-rate. Furthermore, the major elimination route of BPA metabolites in primates is assumed to be renal excretion, as in humans, because the enterohepatic circulation that was observed in rats was not observed. In conclusion, primates are thought to be served as a valuable surrogate model for the toxicokinetics of BPA in humans.