Pathological and biochemical effects of dimethyl hydrogen phosphite in Fischer 344 rats.
In a chronic study by the National Toxicology Program (NTP), dimethyl hydrogen phosphite (DMHP) 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 DMHP 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.(ABSTRACT TRUNCATED AT 400 WORDS)
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Toxicology Research and Testing Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
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D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000633:toxicity*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017905:Phosphites; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000201:enzymology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D002273:Carcinogens; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D017905:Phosphites; D013438:Sulfhydryl Compounds; D003577:Cytochrome P-450 Enzyme System; D009575:Nitroanisole O-Demethylase; D002265:Carboxylic Ester Hydrolases; D007703:Peptidyl-Dipeptidase A; C047356:dimethyl hydrogen phosphite