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Leukemia induced in rats but not mice by dimethyl morpholinophosphoramidate, a simulant anticholinesterase agent
1Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Abstract:
Dimethyl morpholinophosphoramidate (DMMPA), an organophosphate, caused leukemia in male and female Fischer 344/N rats. DMMPA was administered in corn oil by oral intubation to groups of 50 male and 50 female rats at 0, 150, 300, or 600 mg/kg body weight, five times per week for 2 years. B6C3F1 mice were given 0, 150 (males only), 300, and 600 (females only) mg/kg body weight under the same schedule. DMMPA induced a dose-related enhancement in the incidence of mononuclear cell leukemia in rats--males: controls = 14/50, 150 mg group = 21/50; 300 mg group = 19/50; 600 mg group = 25/50; females: controls = 9/50, 150 mg group = 13/50; 300 mg group = 12/49; 600 mg group = 18/50. Survival-adjusted rates strengthen the DMMPA effect: males--31%, 50%, 47%, and 63%; females--20%, 32%, 30%, 50%. Latent periods for mononuclear cell leukemia development in exposed rats were not shortened compared to controls. No carcinogenic effects in mice were detected. DMMPA was not mutagenic in Salmonella, was mutagenic for mouse lymphoma cells, and induced both chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells.
Insights
Dimethyl morpholinophosphoramidate (DMMPA), an organophosphate, significantly increased leukemia incidence in Fischer 344/N rats. This chemical did not show carcinogenic effects in mice but exhibited mutagenic properties in mammalian cells.
Area of Science:
- Toxicology
- Carcinogenesis
- Genotoxicity
Background:
- Organophosphates are a class of chemicals with diverse applications.
- Understanding the toxicological profile of specific organophosphates is crucial for risk assessment.
- Dimethyl morpholinophosphoramidate (DMMPA) is an organophosphate whose carcinogenic potential has been investigated.
Purpose of the Study:
- To evaluate the carcinogenic potential of DMMPA in Fischer 344/N rats and B6C3F1 mice.
- To assess the genotoxicity of DMMPA in bacterial and mammalian cell systems.
Main Methods:
- Rats and mice were administered DMMPA via oral intubation for 2 years at various dose levels.
- Tumor incidence, particularly mononuclear cell leukemia, was recorded.
- Genotoxicity assays included the Ames test, mouse lymphoma assay, and chromosomal aberration tests.
Main Results:
- DMMPA induced a dose-related increase in mononuclear cell leukemia in both male and female rats.
- Survival-adjusted rates confirmed the carcinogenic effect of DMMPA in rats.
- No carcinogenic effects were observed in mice, but DMMPA was mutagenic in mouse lymphoma cells and induced chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells.
Conclusions:
- DMMPA is a carcinogen in Fischer 344/N rats, specifically inducing leukemia.
- DMMPA exhibits genotoxic effects in mammalian cells, suggesting a potential mechanism for its carcinogenicity.
- DMMPA does not appear to be carcinogenic in B6C3F1 mice under the tested conditions.