HEPATIC AND ASSOCIATED RESPONSE OF RATS TO PREGNANCY, LACTATION AND SIMULTANEOUS TREATMENT WITH BUTYLATED HYDROXYTOLUENE

This paper describes changes in the livers of rats fed diets containin g butylated hydroxytoluene (BHT) over two generations in two separate studies. BHT did not produce tumours when tested for carcinogenicity i n several studies by the conventional way. However, when BHT was given to rats in a two-generation carcinogenicity study, a high incidence o f hepatic tumours was found in males but not in female rats of the F-1 generation. A sequential study has been carried out to gain an insigh t into this unexpected finding, paying particular attention to the per inatal period. In the dose-ranging study designed to assess the tolera nce of rats to BHT, groups of male and female rats (F-0 generation) we re fed diets calculated to deliver 0, 500, 750 and 1000 mg/kg body wei ght/day. Following a loading period of 5 wk the rats were mated. The B HT content of the diet was not adjusted during pregnancy and lactation . Owing to the normal increase in food consumption during lactation, i ntakes peaked at double the nominal value by 21 days after the birth o f pups. At this time the pups (F-1) were weaned onto control diet and maintained on it for 4 wk. At birth, the body weights of pups from the BHT-treated dams were comparable to those of the controls but at wean ing the body weights of the pups from all three dose levels were less than those of the controls. At the termination of the experiment (4 wk after weaning), the pups from BHT-treated dams still weighed less tha n those from untreated controls. In the main experiment the F-0 genera tion were fed 0, 25, 100 and 500 mg/kg body weight/day. Their offsprin g (F-1 generation) were weaned on diets containing the same amount of BHT as the respective parents, apart from the group given the highest dose level (500 mg/kg body weight/day). This dose level was reduced to 250 mg/kg body weight/day at weaning in order to conform with previou sly published findings. The pups from the dams given the highest dose level were maintained on a dietary concentration of 250 mg/kg body wei ght/day for the entire study. A group of age-matched non-pregnant fema les was also studied and the results obtained compared with those from pregnant dams. Pups from all groups were examined at day 20 of gestat ion, at weaning (21 days after birth), and at 4 and 22 wk post-weaning . There were no effects on fertility and no increase in foetal abnorma lities at any dose of BHT. Dams receiving BHT at a nominal dose of 500 mg/kg body weight/day showed liver enlargement accompanied by inducti on of pentoxyresorufin O-depentylase and glutathione S-transferase, an d proliferation of the endoplasmic reticulum, Pups from these dams wer e of the same weight at birth as controls but lost weight during the l actation period. This deficit was not recovered by the time the experi ment was terminated. Hence, in two independent studies, the only signi ficant finding in rats treated with BHT in utero and during lactation was that the weight gain of pups during lactation was less than expect ed when darns received at least 500 mg BHT/kg body weight/day. The bod y weight of pups did not return to normal following a return to a cont rol diet for 4 wk. It is postulated that the retardation in weight gai n of the pups could be due to inadequate milk production. (C) 1997 Els evier Science Ltd.