Tumorigenic potential of carbaryl in the heterozygous p53 knockout mouse model.
The heterozygous p53 knockout mouse model was used to assess whether vascular tumors noted in a 2-year carcinogenicity study in CD-1 mice with carbaryl were induced through a genotoxic mechanism. This knockout mouse model was selected for carbaryl because of the high sensitivity of this model to genotoxic events and its low spontaneous incidence of tumors until 9-12 months of age. Carbaryl was administered continuously via the diet to groups of 20 male heterozygous p53 knockout mice at concentrations of 0, 10, 30, 100, 300, 1000 and 4000 ppm for 180 days. Histopathological examinations revealed no evidence of carbaryl-induced neoplasms of any type. In particular, no neoplastic or preneoplastic changes were noted in the vascular tissue of any of the organs examined. Only neoplasms, recognized as those that occur spontaneously in untreated mice of this strain, were sporadically observed in a few animals from the intermediate dose groups with no evidence of a dose- or treatment-related effect. Therefore, under the conditions of this study, the no-observed-effect level (NOEL) of carbaryl for neoplastic changes in male mice was 4000 ppm (around 716 mg/kg body weight/day). We conclude: (1) carbaryl does not appear to be a genotoxic carcinogen at least in male mice; (2) if the vascular tumors observed in the CD-1 mice are treatment-related, they could have been induced by a non-genotoxic mechanism; (3) the response in transgenic animals may provide useful complementary results to better assess carbaryl's potential genotoxic hazard to humans.
Bigot-Lasserre
D
D
Bayer CropScience, Centre de Recherche, Sophia Antipolis, France. dominique.lasserre-bigot@bayercropscience.com
Chuzel
F
F
Debruyne
E L M
EL
Bars
R
R
Carmichael
N G
NG
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D012721:Carbaryl / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53 / Q000235:genetics*; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects; D019043:Vascular Neoplasms / Q000139:chemically induced* / Q000209:etiology / Q000235:genetics
D002273:Carcinogens; D007306:Insecticides; D012721:Carbaryl