CELL-PROLIFERATION IN THE LIVER AND THYROID OF C57B1/10J MICE AFTER DIETARY ADMINISTRATION OF CHLORDANE

Chlordane is a polychlorinated hydrocarbon that causes liver enlargement and induces mixed-function oxidases similar to those induced by phenobarbitone in the mouse. We have assessed the hepatocarcinogenicity (after 2 years) and the time course (over 6 months) of liver and thyroid cell proliferation in C57B1/10J mice exposed to chlordane at 50 ppm in the diet, using the same batch of food for both carcinogenicity and cell proliferation studies. In the bioassay, 15/39 survivors had hepatocellular adenomas and a further 5/59 had carcinomas, compared with less than 5% incidence of primary hepatic tumors in concurrent controls. Among unscheduled deaths, 1/40 adenomas and 2/40 carcinomas were recorded. There were no macroscopically observed thyroid lesions. In the proliferation study, mice were killed on days 4, 5, 8, 15, 29, 99, and 190 after the start of dosing. Withdrawal groups were included from days 29 to 99 and from days 190 to 247. Replicating cells were labeled via bromodeoxyuridine delivered by osmotic minipump for 3 days before necropsy. In the thyroid, the peak labeling index (LI) was seen on day 5 (LI = 5.99 +/- 2.90% versus 1.00 +/- 20% in controls), while in the liver the peak was on day 8 (9.0 +/- 1.6% versus 0.5 +/- 0.4% in controls). Both organs had an elevated LI for the first month of dosing, but while the thyroid follicular LI was similar to control at 99 and 190 days, the liver LI was significantly elevated at all time points except in the withdrawal groups. However, there appeared to be a trend toward the control LI at longer time points, suggesting that elevated hepatocyte replication may not have occurred throughout the duration of the oncogenicity study.