Carcinogenic potential of o-nitrotoluene and p-nitrotoluene.
The potential of o-nitrotoluene and p-nitrotoluene to cause cancer in mammalian species was studied in male and female F344/N rats and B6C3F1 mice. These chemicals are on the EPA list of high production chemicals and there is potential for human exposure (High Production Volume Chemical List (2000) http://oaspub.cpa.gov/opptintr/chemrtk/volchall.htm.). o-Nitrotoluene, administered in the feed for up to 2 years, caused clear evidence for cancer at multiple sites in rats and mice. Male rats, receiving o-nitrotoluene in the feed ( approximately 0, 25, 50, or 90 mg/kg per day), developed treatment-related mesotheliomas, subcutaneous skin neoplasms, mammary gland fibroadenomas, and liver neoplasms. By 2 years, mesotheliomas, skin, liver, mammary gland and liver tumors also occurred in 'stop-study' male rats that received o-nitrotoluene at 125 or 315 mg/kg per day for only the first 3 months of study. These 'stop-studies' showed that the critical events leading to tumor formation occurred after 3 months of dosing, and these events were irreversible and eventually led to cancer at multiple sites. o-Nitrotoluene given in the feed to female rats (approximately 0, 30, 60, or 100 mg/kg per day) and to male and female mice (approximately 0, 150, 320, or 700 mg/kg per day) also caused a carcinogenic response. In female rats, treatment-related subcutaneous skin neoplasms and mammary gland fibroadenomas occurred. Hemangiosarcomas and carcinomas of the large intestine (cecum) were seen in treated male and female mice. In contrast to o-nitrotoluene, p-nitrotoluene given in the feed over approximately the same exposure levels caused only equivocal evidence of carcinogenic activity in male rats (subcutaneous skin neoplasms); some evidence of carcinogenic activity in female rats (clitoral gland neoplasms); equivocal evidence of carcinogenic activity in male mice (lung neoplasms); and no evidence of carcinogenic activity in female mice. Differences in the o-nitrotoluene and p-nitrotoluene carcinogenic activity may be due to differences in the metabolism of the parent compound to carcinogenic metabolites.
Dunnick
June K
JK
National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, P.O. Box 12233, Research Triangle Park, NC 27709, USA. dunnickj@niehs.nih.gov
Burka
Leo T
LT
Mahler
Joel
J
Sills
Robert
R
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344 / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*
D002273:Carcinogens; D014050:Toluene; C029955:2-nitrotoluene; C017572:4-nitrotoluene