Kazuhiro Ishii1, Yasunori Itoh2, Nobuaki Iwasaki3, Yasuyuki Shibata2, Akira Tamaoka4. 1. Faculty of Medicine, Department of the Neurology Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: kazishii@md.tsukuba.ac.jp. 2. Environmental Chemistry Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan. 3. Department of Pediatrics, Ibaraki Prefectural University of Health Sciences, 4669-2, Ami, Ibaraki 300-0331, Japan. 4. Faculty of Medicine, Department of the Neurology Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
Abstract
BACKGROUND: Residents (n=157) of Kamisu City, Ibaraki, Japan, were orally exposed to diphenylarsinic acid (DPAA) via the ingestion of contaminated underground water. Subsequently, a clinical syndrome associated with a variety of cerebellar and brainstem symptoms, was observed in 20 of the 30 residents who consumed high concentrations of DPAA in the contaminated well water. While the clinical symptoms of DPAA were defined, the toxicokinetics of DPAA remained unclear. METHODS: In order to investigate the underlying toxicokinetics of DPAA, we collected serum and cerebrospinal fluid (CSF) samples from 5 patients with DPAA intoxication, and attempted to estimate the half-life of serum DPAA and the CSF/serum ratio of DPAA. RESULTS: DPAA, and its derivatives, such as phenylmethylarsinic acid (PMAA) and phenylarsinic acid (PAA), were detected in serum from residents exposed to DPAA. Serum DPAA was observed for >200 days after the last ingestion of contaminated water. The half-life of serum DPAA was 22.5 days in children and 39.4 days in youths and adults, which was nearly double that observed in children. DPAA was found in CSF, and the CSF/serum ratios of DPAA in 2 patients were 3.0% and 3.7%, respectively, suggesting that this toxicant is able to cross the blood-brain barrier. CONCLUSION: An established animal model of DPAA intoxication was examined regarding the toxicokinetics, distribution and direct DPAA accumulation in the cerebrum. On the basis of existing animal data, and the present results arising from human subjects, the development of new therapies for DPAA intoxication should be enhanced, such as accelerated DPAA excretion.
BACKGROUND: Residents (n=157) of Kamisu City, Ibaraki, Japan, were orally exposed to diphenylarsinic acid (DPAA) via the ingestion of contaminated underground water. Subsequently, a clinical syndrome associated with a variety of cerebellar and brainstem symptoms, was observed in 20 of the 30 residents who consumed high concentrations of DPAA in the contaminated well water. While the clinical symptoms of DPAA were defined, the toxicokinetics of DPAA remained unclear. METHODS: In order to investigate the underlying toxicokinetics of DPAA, we collected serum and cerebrospinal fluid (CSF) samples from 5 patients with DPAA intoxication, and attempted to estimate the half-life of serum DPAA and the CSF/serum ratio of DPAA. RESULTS:DPAA, and its derivatives, such as phenylmethylarsinic acid (PMAA) and phenylarsinic acid (PAA), were detected in serum from residents exposed to DPAA. Serum DPAA was observed for >200 days after the last ingestion of contaminated water. The half-life of serum DPAA was 22.5 days in children and 39.4 days in youths and adults, which was nearly double that observed in children. DPAA was found in CSF, and the CSF/serum ratios of DPAA in 2 patients were 3.0% and 3.7%, respectively, suggesting that this toxicant is able to cross the blood-brain barrier. CONCLUSION: An established animal model of DPAA intoxication was examined regarding the toxicokinetics, distribution and direct DPAA accumulation in the cerebrum. On the basis of existing animal data, and the present results arising from human subjects, the development of new therapies for DPAA intoxication should be enhanced, such as accelerated DPAA excretion.