Developmental Arsenic Neurotoxicity in Retrospect
Philippe Grandjean* and Katsuyuki Murata†
Developmental neurotoxicity is of crucial public health importance. The vulnerability of thebrain originates from the combination of immaturity and ongoing development; the damage incurred
is likely to be permanent. However, epidemiologic studies in this field must confront some serious
challenges. First of all, the functional deficits are likely to depend on the developmental stage at
which the exposure or the peak exposure occurred. Furthermore, neurobehavioral outcomes will beaffected by the age at examination and many other covariates. For example, nutritional deficiencies
may cause serious delays in mental development.1 The neurotoxicity literature on lead2 andmethylmercury3 contains ample demonstration that neurobehavioral responses vary among
populations and may be blurred by the effects of the covariates.
Causative exposures may occur during gestation or soon after birth, whereas valid assessment ofcognitive functions may require testing at school age several years later. Thus, the key study
parameters are often separated by a substantial time interval. Still, for feasibility reasons, mostepidemiologic studies are cross-sectional with some form of retrospective exposure assessment.
Estimates of past exposures from questionnaires and residence data are bound to be imprecise andgenerally tend to bias the findings toward the null. Although the amount of imprecision isunknown, it will likely exceed the substantial variability documented for exposure biomarkers, ie,contaminant concentrations in body fluids and tissues.4
The article by von Ehrenstein et al5 in this issue presents a valiant attempt to combine
measurements of arsenic in water with residence information to obtain a record of past arsenic
exposures in Bengali children. Although this effort failed to demonstrate impact of previous
arsenic exposure on measures of school-age cognitive function, the authors demonstrate that
information on past arsenic exposure may be obtained and applied in epidemiologic studies.
The authors chose to split the exposures into wide groupings according to regulatory limits.
Perhaps some different classification could have provided better separation of exposures. In
contrast, current exposure was based on both water intake and urine–arsenic concentrations and wastherefore likely to be more precise. Unexpectedly, the authors found that current exposure at age 5
to 15 years was associated with a cognitive deficit, whereas exposure during gestation was not.
This could be due to different degrees of imprecision of the exposure variables. This caveat isrecognized by the authors and needs emphasis, because the impact of confounders measured with
better precision (such as age) may increase the bias toward the null.6
In addition to the level of arsenic exposure (in this case, the concentration in drinking water), thetiming of exposure deserves careful consideration. Arsenic passes the placental barrier, but transfer
through human milk seems to be limited.7 The infant may therefore be relatively protected against
environmental arsenic exposure during the breast-feeding period. Future studies should, if possible,
take into account the time when postnatal water exposure began after the cessation of breast-feedingor the time of introduction of supplementary foods.
As von Ehrenstein et al5 note, several recent cross-sectional studies have reported links between
arsenic exposures and neurobehavioral deficits in school children. This evidence supports thenotion that arsenic is a developmental neurotoxicant. More substantial support derives fromevidence of severe clinical effects caused by arsenic contamination of milk powder used for
preparation of milk substitute for infants. The reports on this tragedy appeared in Japanese
language journals and have only been recently reviewed in English.8 Records show that theprepared milk contained arsenic concentrations of 2 mg/L or more. Clinical poisoning occurred
after total doses of approximately 60 mg within approximately 1 month. Limited follow-up of thechildren exposed to contaminated milk powder revealed neurologic diseases, neurobehavioral
dysfunction, and decreased cognitive skills.8
Judging from the Japanese study, some neurotoxicity would likely be present among the Bengali
children at the time of examination, at least among those with the highest exposure levels.
Furthermore, if the evidence on lead and methylmercury is of any guidance in regard to arsenic
neurotoxicity, subclinical effects might occur even at exposure levels that are 1/100 of the doses thatcause clinical poisoning. Accordingly, developmental arsenic exposure within the ranges studied
by von Ehrenstein et al could be associated with adverse neurobehavioral effects, although notdetected in this study. Given the current information on arsenic neurotoxicity, the absence ofsignificant associations in the Bengali study should therefore not be taken as evidence of safety ofthese arsenic exposure levels.
The issue of developmental neurotoxicity has been ignored in previous risk assessments ofenvironmental arsenic exposure. Thus, cancer risk has been the basis for current exposure
limits,9,10 whereas developmental neurotoxicity has not been considered at all. It would seem unwise
to overlook arsenic as a likely developmental neurotoxicant. This issue should be an importantpriority in environmental epidemiology research.
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Epidemiology 17: 25-26, 2007