CELL-PROLIFERATION IN THE LIVERS OF MALE-MICE AND RATS EXPOSED TO THECARCINOGEN P-DICHLOROBENZENE - EVIDENCE FOR THRESHOLDS

In a previous study, p-dichlorobenzene (pDCB), which is associated wit h tumorigenicity in merle rat kidney and livers of mice of both gender s, was found to produce acute increases in cell proliferation ill thos e tissues. To determine whether sustained cell proliferation in the li ver in susceptible species correlated with reported carcinogenic effec ts, we examined the effect of pDCB on cell proliferation in the livers and toxicity to the glutamine synthetase-expressing hepatocyte (GS(+) ) subpopulation of male B6C3F1C3F1 mice and F344 vats. Mice were expos ed for up to 4 weeks to 600, the maximally tolerated dose which increa sed liver tumors, 300 or 150 mg/kg. Rats were exposed to 300, 150 or 7 5 mg/kg for up to 4 weeks. In mice, the cumulative replicating fractio n (CRF) in the livers of the high dose animals was significantly incre ased 16-fold at 1 week and 4-fold at 4 weeks. The CRF was also increas ed at 300 mg/kg at 1 week, but this subsided at 4 weeks. No increase w as seen in the low dose group. In mts, the CRFs of the livers at 1 wee k were increased at 300 and 150 mg/kg, but returned to normal at 4 wee ks. The size of the hepatic GS(+) area was not affected in mice or in rats after 1 week of exposure, but comparable decreases were observed at all exposures at 4 weeks in mice. The data therefore suggest that s ustained increases of cell division in the mouse liver may contribute to the increases in liver tumors.