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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.

The ability of LTA of Streptococcus pyogenes to stimulate cell division or to kill tissue culture cells derived from human heart was investigated. Initial studies indicated that at low concentrations, ranging from 0.01 to 1.0 micrograms/ml, LTA stimulated cell division, whereas at higher concentrations, ranging from 10 to 1000 micrograms/ml, it killed the cells. Deacylated lipoteichoic acid, which lacked cell membrane binding activity, similarly stimulated or killed the heart cells depending on the concentration added to the tissue cultures. Fractionation of LTA after mild ammonia hydrolysis yielded a polyglycerophosphate and polar lipid fraction, both of which retained the glucose from the glycolipid moiety of the LTA molecule, and a neutral lipid fraction that was devoid of phosphorus or glucose. Toxic activity was present only in the fractions containing glucose. Oxidation of LTA or its deacylated derivative with sodium metaperiodate reduced the assayable glucose content without destroying the polyglycerophosphate backbone and resulted in a parallel loss of cytotoxicity, strongly suggesting that the glucose moieties of S. pyogenes LTA must be intact for the toxic activity against human heart cells to be expressed.