Susceptibility of newborn rats to hepatotoxicity of 1,3-dibromopropane and 1,1,2,2-tetrabromoethane, compared with young rats.
Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.
Hirata-Koizumi
Mutsuko
M
National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
Kusuoka
Osamu
O
Nishimura
Nobuo
N
Wada
Hajime
H
Ogata
Hidehiro
H
Fukuda
Naemi
N
Ito
Yoshihiko
Y
Kamata
Eiichi
E
Ema
Makoto
M
Hasegawa
Ryuichi
R
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D005260:Female; D006842:Hydrocarbons, Brominated / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006842:Hydrocarbons, Brominated; D011407:Propane; C037530:1,1,2,2-tetrabromoethane; C032699:1,3-dibromopropane