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 containing butylated hydroxytoluene (BHT) over two generations in two separate studies. BHT did not produce tumours when tested for carcinogenicity in several studies by the conventional way. However, when BHT was given to rats in a two-generation carcinogenicity study, a high incidence of hepatic tumours was found in males but not in female rats of the F1 generation. A sequential study has been carried out to gain an insight into this unexpected finding, paying particular attention to the perinatal period. In the dose-ranging study designed to assess the tolerance of rats to BHT, groups of male and female rats (F0 generation) were fed diets calculated to deliver 0, 500, 750 and 1000 mg/kg body weight/day. Following a loading period of 5 wk the rats were mated. The BHT content of the diet was not adjusted during pregnancy and lactation. Owing to the normal increase in food consumption during lactation, intakes peaked at double the nominal value by 21 days after the birth of pups. At this time the pups (F1) 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 weaning 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 than those from untreated controls. In the main experiment the F0 generation were fed 0, 25, 100 and 500 mg/kg body weight/day. Their offspring (F1 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 previously published findings. The pups from the dams given the highest dose level were maintained on a dietary concentration of 250 mg/kg body weight/day for the entire study. A group of age-matched non-pregnant females was also studied and the results obtained compared with those from pregnant dams. Pups from all groups were examined at day 20 of gestation, 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 abnormalities at any dose of BHT. Dams receiving BHT at a nominal dose of 500 mg/kg body weight/day showed liver enlargement accompained by induction of pentoxyresorufin O-depentylase and glutathione S-transferase, and proliferation of the endoplasmic reticulum. Pups from these dams were of the same weight at birth as controls but lost weight during the lactation period. This deficit was not recovered by the time the experiment was terminated. Hence, in two independent studies, the only significant finding in rats treated with BHT in utero and during lactation was that the weight gain of pups during lactation was less than expected when dams received at least 500 mg BHT/kg body weight/day. The body weight of pups did not return to normal following a return to a control diet for 4 wk. It is postulated that the retardation in weight gain of the pups could be due to inadequate milk production.
McFarlane
M
M
Robens Institute of Health and Safety, University of Surrey, Guildford, UK.
Price
S C
SC
Cottrell
S
S
Grasso
P
P
Bremmer
J N
JN
Bomhard
E M
EM
Hinton
R H
RH
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000201:enzymology; D005520:Food Preservatives / Q000633:toxicity*; D007774:Lactation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D015383:Zona Fasciculata / Q000187:drug effects / Q000473:pathology
D005520:Food Preservatives; D002084:Butylated Hydroxytoluene; D003577:Cytochrome P-450 Enzyme System