title: Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.
abstract: Risk assessments of arsenic have focused on skin, bladder, and lung cancers and skin lesions as the sensitive cancer and non-cancer health endpoints, respectively; however, an increasing number of epidemiologic studies that can inform risk assessment have examined neurodevelopmental effects in children. We conducted a systematic review and risk assessment based on the epidemiologic literature on possible neurodevelopmental effects at lower arsenic exposures. Twenty-four cross-sectional, case-control, and cohort studies were identified that report on the association between low-level arsenic exposure (i.e., largely <100 μg/L of arsenic in drinking water) and neurological outcomes in children. Although the overall evidence does not consistently show a causal dose-response relationship at low doses, the most rigorously conducted studies from Bangladesh indicate possible inverse associations with cognitive function, predominantly involving concurrent arsenic exposure as measured by biomarkers (i.e., arsenic in urine or blood) and raw verbal test scores at ages 5-11 years. Issues such as non-comparability of outcome measures across studies; inaccuracies of biomarkers and other measures of inorganic arsenic exposure; potential effect modification by cultural practices; insufficient adjustment for nutritional deficiencies, maternal IQ, and other important confounders; and presence of other neurotoxicants in foreign populations limit generalizability to U.S.
  
  
  METHODS
  Of the few U.S. studies available, the most rigorously conducted study did not find a consistent dose-response relationship between arsenic concentrations in tap water or toenails and decrements in IQ scores. Assuming that the strongest dose-response relationship from the most rigorous evidence from Bangladesh is generalizable to U.S. populations, possible reference doses were estimated in the range of 0.0004-0.001 mg/kg-day. These doses are higher than the U.S. Environmental Protection Agency reference dose for chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks.
authors.affiliation: Exponent, Center for Toxicology and Mechanistic Biology, Bellevue, WA, USA. Electronic address: tsujij@exponent.com.
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Tsuji
authors.affiliation: Exponent, Center for Toxicology and Mechanistic Biology, Bellevue, WA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garry
authors.affiliation: Exponent, Center for Epidemiology and Computational Biology, Chicago, IL, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Perez
authors.affiliation: Exponent, Center for Epidemiology and Computational Biology, Menlo Park, CA, USA.
authors.forename: Ellen T
authors.initials: ET
authors.lastname: Chang
mesh_terms: D000293:Adolescent; D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000473:pathology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000523:psychology; D011247:Pregnancy; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D001152:Arsenicals; D014874:Water Pollutants, Chemical; D001151:Arsenic
keywords: Arsenic; Children; Neurodevelopment; Neurotoxicity; Reference dose