TOXICOKINETIC AND TOXICODYNAMIC INFLUENCES ON ENDOCRINE DISRUPTION BY POLYCHLORINATED-BIPHENYLS

Polychlorinated biphenyl (PCB) mixtures and individual chlorobiphenyl (CB) congeners have various endocrine-disrupting effects, but ultimate responses may be altered by concurrent effects on enzyme levels and enzyme activities. The toxicodynamics of estrogenic PCBs and metabolites have been studied in vitro, but nonlinear dose-response relationships in vivo suggest that tests must integrate toxicokinetic parameters to explain whole-animal responses. To determine if any such interactions occurred, relatively large doses were subdivided into different treatment regimens for immature female Sprague-Dawley rats. Aroclor 1242 was uterotropic when 120 mg/kg (total) was administered (intraperitoneally) in two, three or five doses. CB 47 (2,2',4,4'-tetraCB) and CB 153 (2,2',4,4',5,5'-hexaCB) increased absolute uterine weights at 30 mg/kg on days 20 and 21. Results at 25 days in rats that received zero, two, three or five doses between days 20 and 24 were much more variable due to changes in tissue responsiveness and/or toxicokinetic interactions. In rats receiving treatment for 5 days, pentoxyresorufin O-dealkylase (PROD) activity was inversely related to CB serum residues; in rats receiving CB 153 for 2 days, PROD activity was directly related to serum residues. It was not clear whether PROD activity was the cause of or a reflection of lower serum residues; however, nonplanar CBs are better substrates for PROD than are planar CBs, and the longer-term dosing may enhance metabolism and excretion, changing the biological effects observed.