A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat

Abstract

A mathematical model is presented to describe the kinetics of distribution, metabolism, and excretion of 4-chloro-, 4,4'-dichloro-, 2,2',4,5,5'-pentachloro-, and 2,2',4,4',5,5'-hexachlorobiphenyl in rats given an intravenols dose of 0.6 mg/kg. A modified flow-limited model simulates the penta- and hexachlorobiphenyl data for periods up to 96 hr but underestimates the mono- and dichlorobiphenyl data beyond 48 hr. The rate constant for metabolism by the liver decreases as degree of chlorination increases such that the rate constant is 200 times smaller for the hexachlorobiphenyl than for the monochlorobiphenyl. The value of the biliary clearance of metabolites is nearly the same for each chlorinated biphenyl, whereas the value of the urinary clearance decreases with increasing degree of chlorination, being 10 times smaller for hexachlorobiphenyl than for monochlorophenyl. The distribution coefficients between most tissues and blood are larger for each parent compound than for its metabolites. Hexachlorobiphenyl has the largest distribution coefficient of all the chlorinated biphenyls in each tissue, whereas the mono-, di-, and pentachlorobiphenyls show no consistent variation. For each compound the distribution coefficient is greater in the fat than in any other tissue. Changes in the fat volume of the growing rats were incorporated into the model in order to simulate the hexachlorobiphenyl concentrations in blood and fat for 42 days.