SUBCHRONIC DIETARY EXPOSURE TO AROCLOR-1254 IN RATS - ACCUMULATION OFPCBS IN LIVER, BLOOD, AND ADIPOSE-TISSUE AND ITS RELATIONSHIP TO INDUCTION OF VARIOUS HEPATIC DRUG-METABOLIZING-ENZYMES

Female F344/NCr rats were exposed continuously (7-84 days) or disconti nuously (7 days exposure/21 days control diet or 28 days exposure/56 d ays control diet) to various dietary concentrations (1-100 ppm) of Aro clor 1254. There were dose- and time-dependent increases in PCB levels in liver, blood, and adipose tissue. Following removal of the rats fr om diet containing Aroclor 1254, there was a relatively rapid decrease in PCB levels, particularly in rats exposed to higher concentrations of Aroclor 1254. In parallel with the alterations in PCB levels observ ed, the rats showed striking dose- and time-dependent increases in hep atic levels of CYP1A1 and CYP1A2, as determined by various methods [RN A analysis, immunochemical detection, or measurement of the O-dealkyla tion of methoxyresorufin (CYP1A2) or ethoxyresorufin (CYP1A1)]. In rat s removed from the Aroclor 1254 diet, catalytic activity for CYP1A1 as well as RNA levels for both CYP1A1 and CYP1A2 rapidly diminished. In contrast to the high levels of induction of CYP1A1 and CYP1A2 observed , limited induction (<5-fold) of epoxide hydrolase, quinone oxidoreduc tase, and aldehyde dehydrogenase was detected, even in rats exposed to the highest concentration of Aroclor (100 ppm) for up to 84 days. Fur thermore, induction of these non-CYP hepatic drug-metabolizing genes e xhibited distinctly different concentration-response curves. The ratio s of hepatic CYP1A1 activity to hepatic PCB burden were similar for ra ts exposed continuously to Aroclor in the diet for 7, 28, or 84 days, and for rats exposed discontinuously (7 days Aroclor/21 days control d iet or 28 days Aroclor/56 days control diet). Thus, hepatic PCB levels alone appeared to be reasonably predictive of CYP1A1 levels under a v ariety of modes of exposure. When the ratio of CYP1A1 activity to adip ose or blood PCB concentration was determined, similar ratios were obs erved for rats exposed continuously for 7, 28, or 84 days. However, lo wer ratios were observed for rats discontinuously exposed to Aroclor i n the diet. These results have important implications with respect to: (a) employing PCB levels in various tissues to predict biological eff ects, and (b) determining different concentration-response curves for the various biological effects induced by PCBs.