METABOLISM AND DISPOSITION OF DIMETHYL HYDROGEN PHOSPHITE IN RATS ANDMICE

A study of dimethyl hydrogen phosphite (DMHP) by the National Toxicolo gy Program (NTP) indicated that chronic administration by oral gavage resulted in an increased incidence of neoplastic lesions in the lungs and forestomachs of Fischer 344 rats but not in B6C3F1 mice. The curre nt study was designed to evaluate the metabolic basis, if any, of this species selectivity by studying the metabolism and disposition of [C- 14]DMHP in the respective strains of rats and mice. Results of this st udy indicate that DMHP administered at a range of dose of 10-200 mg/kg was readily and near completely absorbed from the gastrointestinal tr acts of rats and mice. DMHP-derived radioactivity was eliminated prima rily as CO, in the expired air, 44-57%, and urine, 28-49%, and very li ttle was collected in feces, 1-2%, or as volatile organics, 2-3%. DMHP -derived radioactivity was widely distributed in tissues of rats and m ice, with the highest concentrations observed in the liver, kidneys, s pleen, lungs, and forestomach, and the lowest in brain, skeletal muscl e, and adipose tissue. The disappearance of radioactivity from mouse t issues was approximately twice as rapid as from rat tissues. In vitro, DMHP was metabolized to formaldehyde by the microsomal fractions of l iver, lungs, kidneys, forestomach, and glandular stomach. In vivo, DMH P was metabolized to the product of demethylation, monomethyl hydrogen phosphite (MMHP), which was excreted in urine. Results of this study indicate that the NTP carcinogenicity study with DMHP was carried out within the dose range in which the absorption, metabolism, and disposi tion of DMHP are linear in both species. Apparent species-dependent di fferences in the metabolism and disposition of DMHP are limited to the more rapid metabolism and elimination by the mouse. Therefore, the sp ecies-dependent variations in the carcinogenicity of DMHP are most lik ely attributable to factors other than metabolism and disposition.