Long-term accumulation of diphenylarsinic acid in the central nervous system of cynomolgus monkeys

Tomoyuki Masuda,Yasuo Seto,Ryuta Tanaka,Tomoko Hosoya,Nobuaki Iwasaki,Tomohiro Nakayama,Akira Tamaoka,Yasuyuki Shibata,Kazuhiro Ishii

doi:10.1007/s00204-016-1928-z

Abstract

Diphenylarsinic acid (DPAA) is an organic arsenic compound used for the synthesis of chemical weapons. We previously found that the residents of Kamisu city in Ibaraki Prefecture, Japan, were exposed to DPAA through contaminated well water in 2003. Although mounting evidence strongly suggests that their neurological symptoms were caused by DPAA, the dynamics of DPAA distribution and metabolism after ingestion by humans remain to be elucidated. To accurately predict the distribution of DPAA in the human body, we administrated DPAA (1.0 mg/kg/day) to cynomolgus monkeys (n = 28) for 28 days. The whole tissues from these monkeys were collected at 5, 29, 170, and 339 days after the last administration. The concentration of DPAA in these tissues was measured by liquid chromatography–mass spectrometry. We found that DPAA accumulated in the central nervous system tissues for a longer period than in other tissues. This finding would extend our knowledge on the distribution dynamics and metabolism of DPAA in primates, including humans. Furthermore, it may be useful for developing a treatment strategy for patients who are exposed to DPAA.

Highlights

Seaweed contains a large number of organic arsenic compounds, including non-toxic compounds, and many toxic compounds are synthesized as pharmaceutical and chemical warfare agents
At 5 days after the last administration, we found that the average concentrations of Diphenylarsinic acid (DPAA) in the tissues derived from the central nervous system (CNS) (600 ± 21.2 ng As/g), the emunctories (1033 ± 188 ng As/g), and the sciatic nerve (480 ± 50.0 ng As/g) were significantly higher than those derived from other tissues (Fig. 2; Table 1; p < 0.0001)
We examined the clearance of orally administrated DPAA in cynomolgus monkeys

Summary

Introduction

Seaweed contains a large number of organic arsenic compounds, including non-toxic compounds, and many toxic compounds are synthesized as pharmaceutical and chemical warfare agents. Diphenylarsinic acid (DPAA) is an organic arsenic compound that was used for the synthesis of chemical weapons during World War II (Kurata 1980). In 2003, several patients with illnesses of unknown origin were reported in Ibaraki Prefecture, Japan. Organic arsenic compounds that were found in the wells of Kamisu city in Ibaraki were identified as the cause of these symptoms (Ishii et al 2004). Contaminated water from one of the wells contained 4.5 mg As/L of DPAA, which is approximately 450 times higher than the concentration permitted by the drinking water quality standards in Japan (Kinoshita et al 2005; Shibata et al 2005). A total of 157 residents who were exposed to DPAA presented with progressive cerebellar and brain stem symptoms, including nystagmus, dizziness, ataxic gait, tremors, myoclonus and dysarthria, along with temporal and occipital lobe symptoms, including memory impairment, sleep disturbance, and visual disorders, as well as cerebral atrophy and mental retardation in

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Conclusion