| Non-Human Toxicity Excerpts | Four genotoxic rat carcinogens, previously reported as negative in the standard hepatocyte/DNA repair assay, were studied in hepatocyte cultures derived from the livers of rats pretreated with the hepatic mixed function oxidase inducers, Aroclor and 3-methylcholanthrene. Cytembena and dimethyl hydrogen phosphite induced positive dose dependent DNA repair responses in Aroclor and 3-methylcholanthrene pretreated cultures, while 2,4-, 2,6-toluene diisocyanate, and ziram were negative for unschedule synthesis in cultures from both pretreatments. The results from this study indicate that pretreatment with hepatic mixed function oxidase inducers lowers the false negative detection rate of various genotoxic rat carcinogens and other organ specific genotopins and significantly increases the sensitivity of the in vitro rat hepatocyte/DNA repair assay.The development of lung neoplasms following chronic dimethyl hydrogen phosphite administration was studied in rodents. Male Fischer 344 rats and B6C3F1 mice of both sexes received dimethyl hydrogen phosphite by oral gavage in doses of 0, 100, or 200 mg/kg body weight 5 days a week for 103 weeks, while female rats received dimethyl hydrogen phosphite via the same route in doses of 0, 50, or 100 mg/kg for an identical period of time. A dose related toxicity was observed in the lungs of dimethyl hydrogen phosphite treated male and female rats. Lung lesions were most prevalent among high dose male rats, which received twice the dimethyl hydrogen phosphite dose administered to high dose female rats. These pulmonary lesions included alevolar epithelial hyperplasia, chemically related pneumonia, alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and squamous cell carcinoma. Dimethyl hydrogen phosphite administration also caused the development of neoplastic and non neoplastic lesions in the forestomachs of male rats, with a similar but less pronounced effect being noted in female rats. The non neoplastic lesions associated with dimethyl hydrogen phosphite administration included mineralization of the cerebellum in male rats and focal calcification of the testes in male mice. The authors conclude that evidence of dimethyl hydrogen phosphite carcinogenicity is clear in male rats and equivocal in female rats, while no evidence exists to support dimethyl hydrogen phosphite carcinogenicity in mice of either sex.Pathological and biochemical effects induced by dimethyl hydrogen phosphite were studied in rats. Male Fischer 344 rats were administered 0 or 200 mg/kg dimethylhydrogen phosphite by oral gavage for 4, 5, or 6 wk. Some animals were treated for 4 wk and maintained for 1 or 2 wk of recovery. No overt signs of toxicity were seen in any animals. The weights of the forestomachs of treated rats were significantly increased. The other organ weights were not significantly affected by dimethyl hydrogen phosphite. Forestomach weights of rats treated for 4 wk returned to the control value after 1 wk of recovery. Epithelial hyperplasia, hyperkeratosis, subepithelial inflammation, and edema were seen in the forestomachs of rats given dimethyl hydrogen phosphite for 6 wk. No treatment related changes were seen in the glandular stomach or lungs. Serum angiotensin converting enzyme activity was increased in all treated rats. Angiotensin converting enzyme activity in rats treated for 4 wk decreased to near the control value after 2 wk recovery. The nonprotein sulfhydryl content of the forestomach was increased and carboxylesterase activity in the forestomach and lungs was reduced in rats given dimethyl hydrogen phosphite for 6 wk. In rats given a single oral or iv dose of 1000 mg/kg dimethyl hydrogen phosphite, and killed 0.5 to 8 hr later, nonprotein sulfhydryl content was significantly reduced in that dimethyl hydrogen phosphite, a known forestomach carcinogen for Fischer 344 rats, induces early and possibly preneoplastic changes in the forestomach.Dimethyl hydrogen phosphite, an intermediate in the production of insecticides or herbicides, was administered by oral gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. Dimethyl hydrogen phosphite also caused neoplastic and nonneoplastic lesions of the forestomach in male ratsa similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of dimethyl hydrogen phosphite included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. Dimethyl hydrogen phosphite caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program.In a chronic study by the National Toxicology Program, dimethyl hydrogen phosphite caused neoplastic and nonneoplastic changes in the lungs and forestomach of F344/N rats following gavage administration for 2 years. The current investigation was designed to study the effect of a short term exposure on a series of biochemical systems in target and nontarget tissues which may be involved in the metabolism and/or the manifestation of dimethyl hydrogen phosphite toxicity. Rats were treated daily with a dose similar to that used in the NTP study (200 mg/kg) for 4, 5, or 6 weeks. Two groups of animals were also treated for 4 weeks and then treatment was discontinued and the rats were allowed to recover for 1 or 2 weeks. An equal number of animals was treated similarly with the vehicle and used as control. The microsomal and soluble fractions were separated from liver, lungs kidneys, forestomach, and glandular stomach from the 6 week treatment group. Another group of rats treated for 6 weeks was prepared for pathology examination of the lungs, forestomach, and glandular stomach. There was a significant increase in the weight of the forestomach of rats treated for 4, 5, or 6 weeks relative to control animals, while no significant difference was observed in the weight of liver, lungs, kidneys, and glandular stomach. The forestomach weight of rats treated for 4 weeks returned to the control value after 1 week of recovery. Microscopic examination of the forestomach of rats treated for 6 weeks revealed a thickened stratified squamous epithelium characterized by hyperplasia, hyperkeratosis, and subepithelial inflammation and edema. There were no microscopic changes in the lungs or glandular stomach of animals treated for 6 weeks. The activity of angiotensin converting enzyme in the serum of rats treated for 4, 5, or 6 weeks was significantly increased over that of control animals. The activity of this enzyme returned to near levels seen in the control animals after 1 week of recovery following 4 weeks of treatment. No treatment related effect was observed in the activities of the microsomal p-nitroanisole demethylase, soluble glutathione S-transferase, and soluble superoxide dismutase in the five tissues studied. There was a significant increase in the level of nonprotein soluble sulfhydryls in the forestomach but in no other tissue of rats treated for 6 weeks. Also the activity of soluble carboxylesterase was significantly reduced in the lungs and forestomach, but not in any other tissue of the 6 week treated rats. |
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