Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.
Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.(ABSTRACT TRUNCATED AT 400 WORDS)
Huff
J E
JE
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Haseman
J K
JK
DeMarini
D M
DM
Eustis
S
S
Maronpot
R R
RR
Peters
A C
AC
Persing
R L
RL
Chrisp
C E
CE
Jacobs
A C
AC
D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D004305:Dose-Response Relationship, Drug; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D008297:Male; D051379:Mice; D009153:Mutagens; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009153:Mutagens; D001554:Benzene