Carcinogenicity and chronic toxicity of para-chloronitrobenzene in rats and mice by two-year feeding.
Carcinogenicity and chronic toxicity of para-chloronitrobenzene (p-CNB) were examined by feeding diets containing p-CNB to rats and mice of both sexes for two years. The dietary concentration of p-CNB was 0 (control), 40, 200, or 1000 ppm (w/w) for rats and 0, 125, 500, or 2000 ppm for mice. Survival rates of the high-dosed male rats and male mice were significantly decreased compared with those of the respective controls, and this was attributed to the increased number of cancer deaths. Therefore, the high-dose levels were considered not to exceed the maximum tolerated dose. Significant decreases in red blood cell counts and hematocrit value and an increase in mean corpuscular volume were noted in the p-CNB-fed rats and mice. Nonneoplastic splenic lesions were characterized by capsule hyperplasia, fibrosis, fatty metamorphosis, and increased extramedullary hematopoiesis in rats, and congestion, increased extramedullary hematopoiesis, hemosiderin deposition, and ossification in mice. Incidences of fibromas, fibrosarcomas, osteosarcomas, sarcomas (NOS), and hemangiosarcomas in males and fibrosarcomas in females were significantly increased in the spleen of high-dosed rats. The most frequently observed splenic tumor was fibrosarcomas, followed by fibromas. The tumor incidences were increased in a dose-related manner and were more prevalent in males than in females. The malignant tumors metastasized mainly to the liver, peritoneum, and pancreas. Adrena/medullary hyperplasia and pheochromocytomas were significantly increased in the p-CNB-fed females. No tumor was induced in any of the p-CNB-fed mice of either sex except hepatic hemangiosarcomas in the 2000 ppm-fed females. Causative factors of p-CNB-induced carcinogenicity and chronic toxicity are discussed in light of the subchronic and chronic hematotoxicity reported in our present and previous studies and in the literature.
Matsumoto
Michiharu
M
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hirasawa, Hadano, Kanagawa, Japan. m-matsumoto@jisha.or.jp
Aiso
Shigetoshi
S
Senoh
Hideki
H
Yamazaki
Kazunori
K
Arito
Heihachiro
H
Nagano
Kasuke
K
Yamamoto
Seigo
S
Matsushima
Taijiro
T
D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D004906:Erythrocyte Count; D004909:Erythrocyte Indices / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005350:Fibroma / Q000139:chemically induced / Q000473:pathology; D006400:Hematocrit; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009578:Nitrobenzenes / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D011919:Rats, Inbred Strains; D012509:Sarcoma / Q000139:chemically induced / Q000473:pathology; D013160:Splenic Neoplasms / Q000139:chemically induced* / Q000473:pathology; D036401:Toxicity Tests, Chronic
D002273:Carcinogens; D009578:Nitrobenzenes; C010407:4-chloronitrobenzene