Pharmacokinetics of multiple oral doses of selected polychlorinated biphenyls in mice

Abstract

The disposition of multiple oral doses of selected polychlorinated biphenyls, 4-chloro-, 4,4′-dichloro-, 2,4,5,2′,5′-pentachloro-, and 2,4,5,2′,4′,5′-hexachlorobiphenyl, were studied in mice. The rate of metabolism and excretion decreased with increasing chlorination but was most profoundly affected by the elimination of adjacent unsubstituted carbon atoms. Accumulation occurred mainly in adipose tissue, skin, and muscle. The tissue distribution for a particular polychlorinated biphenyl was found to be similar regardless of the route of administration and the number of doses. The fecal excretion rates of pentachloro- or hexachlorobiphenyl following multiple oral doses could be predicted from the excretion rates obtained after a single iv dose. Conservative lower limits and liberal upper limits of pentachloro- or hexachlorobiphenyl body burdens, following a single iv or multiple oral doses, were estimated by pharmacokinetic analysis of the fecal excretion rates observed after a single iv dose. Estimates of minimum body burden were based on a two-compartment open model, whereas estimates of the maximum body burden were based on a model that included a third, permanent retention, compartment. The experimental body burdens fell between the predicted upper and lower limit values. At a dose of 0.6 mg/kg/day, a steady state was obtained within 2 days with either monochloro- or dichlorobiphenyl, whereas pharmacokinetic analysis based on the two-compartment model predicted that it would require at least 15 days to reach steady state with the pentachlorobiphenyl and at least 7 weeks with the hexachlorobiphenyl.