Diphenylarsinic acid (DPAA) is an environmental degradation product of diphenylarsine
chloride or diphenylarsine
cyanide, which were
chemical warfare agents produced by Japan during the World War II. DPAA is now considered a dangerous
environmental pollutant in Kamisu, Japan, where it is suspected of inducing health effects that include
articulation disorders (
cerebellar ataxia of the extremities and trunk),
involuntary movements (
myoclonus and
tremor), and
sleep disorders. In order to elucidate the toxic mechanism of DPAA, we focused on the distribution and metabolism of DPAA in rats. Systemic distribution of DPAA was determined by administering DPAA orally to rats at a single dose of 5.0 mg As/kg
body weight, followed by speciation analysis of selected organs and body fluids. Most of the total
arsenic burden was recovered in the urine (23% of the dose) and feces (27%), with the distribution in most other organs/tissues being less than 1%. However, compared with the typical distribution of inorganic dietary
arsenic, DPAA administration resulted in elevated levels in the brain, testes and pancreas. In contrast to urine, in which DPAA was found mostly in its unmodified form, the tissues and organs contained
arsenic that was mostly bound to non-soluble and soluble high molecular weight
proteins. These bound
arsenic species could be converted back to DPAA after oxidation with H(2)O(2), suggesting that the DPAA bound to
proteins had been reduced within the body and was in a trivalent oxidation state. Furthermore, we also detected two unknown
arsenic metabolites in rat urine, which were assumed to be hydroxylated
arsenic metabolites.