“ch48” — 2008/6/2 — 18:18 — page 459 — #1 CHAPTER 48 Neurotoxicity of arsenic M.E. Gonsebatt, J. Limón-Pacheco, E. Uribe-Querol & G. Gutiérrez-Ospina Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico V.M. Rodríguez Environmental and Community Medicine, The University of Medicine and Dentistry of New Jersey and Rutgers, Piscataway, NJ, USA M. Giordano Instituto de Neurobiología, Universidad Nacional Autónoma de Mexico (UNAM), Querétaro, Mexico L.M. Del Razo & L.C. Sánchez-Peña Sección Externa de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City, Mexico ABSTRACT: Neurotoxicity by drinking well water contaminated with arsenic (As) or acciden- tally exposed to As compounds has been described in adults and infants by previous studies. Biomethylation of As generates toxic metabolites that could help explain the adverse effects observed following As exposure in human and in animal models. Here dose related accumula- tion of methylated As metabolites in mouse brain are studied and show that brain metabolizes arsenite to monomethyl arsonic acid (MMA) and dimethyl arsinic acid (DMA), being DMA the main metabolite in this tissue. Glutathione reductase activity was inhibited at the highest dose tested in liver and brain. 48.1 INTRODUCTION 48.1.1 Inorganic arsenic as a human neurotoxicant Inorganic arsenic (i-As) exposure via drinking water has been associated with cancer but also with peripheral neuropathy and diverse effects in the circulatory and nervous system (Rodriguez et al. 2003). During subacute or chronic exposure, i-As can occasionally result in subclinical or overt peripheral neuropathy (Yip et al. 2002). Diverse neurotoxic effects have been reported in children and adults receiving or exposed to different doses of As. Cerebellar symptoms and mental retardation associated with brain atrophy have been described in adults and infants drinking well water contaminated with diphenylarsinic compounds (Ishii et al. 2004). Children exposed to low levels of As during their whole-life showed hearing impairment (Bencko and Symon 1977) and lower scores in verbal intelligence quotient (IQ) (Calderon et al. 2001). Water i-As exposure was associated with reduced intellectual function, in a dose-dependent manner (Wasserman et al. 2004); children with water i-As levels >50 μg/l achieved significantly lower Performance and Full-Scale scores than did children with water i-As levels <5.5 μg/l. Adolescents exposed to high levels of i-As presented alterations in memory and attention processes (Tsai et al. 2003) or mental deterioration (Brower et al. 1992), while in adults acutely exposed to high amounts of i-As, impairments in learning, memory, and concentration and severe encephalopathy have been described (Bolla-Wilson and Bleecker 1987, Franzblau and Lilis 1989, Morton and Caron 1989, Berbel-Garcia et al. 2004). 459