Elsevier

Neurotoxicology and Teratology

Volume 28, Issue 5, September–October 2006, Pages 536-547
Neurotoxicology and Teratology

Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years

https://doi.org/10.1016/j.ntt.2006.02.005Get rights and content

Abstract

A cohort of 1022 consecutive singleton births was generated during 1987–1988 in the Faroe Islands, where increased methylmercury exposure occurs from traditional seafood diets that include pilot whale meat. The prenatal exposure level was determined from mercury analyses of cord blood, cord tissue, and maternal hair. At age 14 years, 878 of 1010 living cohort members underwent detailed neurobehavioral examination. Eighteen participants with neurological disorders were excluded. Blood and hair samples obtained from the participants were analyzed for mercury. The neuropsychological test battery was designed based on the same criteria as applied at the examination at age 7 years. Multiple regression analysis was carried out and included adjustment for confounders. Indicators of prenatal methylmercury exposure were significantly associated with deficits in finger tapping speed, reaction time on a continued performance task, and cued naming. Postnatal methylmercury exposure had no discernible effect. These findings are similar to those obtained at age 7 years, and the relative contribution of mercury exposure to the predictive power of the multiple regression models was also similar. An analysis of the test score difference between results at 7 and 14 years suggested that mercury-associated deficits had not changed between the two examinations. In structural equation model analyses, the neuropsychological tests were separated into five groups; methylmercury exposure was significantly associated with deficits in motor, attention, and verbal tests. These findings are supported by independent assessment of neurophysiological outcomes. The effects on brain function associated with prenatal methylmercury exposure therefore appear to be multi-focal and permanent.

Introduction

Methylmercury (MeHg) is a widespread contaminant of seafood and freshwater fish. The developing brain is considered the main target for MeHg toxicity, and the risk to consumers from MeHg exposure has been assessed by national and international agencies [11], [23], [28], [34]. Results from prospective epidemiological studies of birth cohorts from the Faroe Islands [14], [29] have contributed significantly to the data used for derivation of recommendations concerning human exposure limits, especially for pregnant women.

For the purposes of risk assessment, valid dose–effect relationships are essential, and the research in the Faroes has endeavored to represent both ends of the exposure–outcome relationship with the highest possible precision and sensitivity. Because of the need to obtain precise measures of the causative exposure [7], [14], the mercury concentration has been measured in cord blood and other biological samples from exposed participants. Detailed comparison of various prenatal exposure indices within the cohort has shown that the cord blood concentration is consistently the most precise predictor of nervous system deficits determined during postnatal follow-up [7], [14].

At the same time, valid outcome variables must be sensitive to MeHg neurotoxicity and relatively robust to impacts of confounders. In choosing feasible effect parameters, an important consideration includes suitability for the age group and culture. As confounder-independent outcomes, neurophysiological measurements have provided evidence that developmental MeHg neurotoxicity is detectable through age 14 years [26]. Clinical neurological tests have shown mercury-related adverse effects neonatally [29], but such tests may not be sensitive enough at school age [14]. Standardized neuropsychological tests are useful to gain insight into functional domains and overall cognitive functioning and have been widely applied as sensitive indicators of central nervous system (CNS) dysfunction associated with exposure to neurotoxicants in both environmental and occupational exposure settings [9], [40]. In choosing such measures for the study of children, it is important to consider the developmental stage of the child at both exposure and at the time of testing as well as cultural and psychometric parameters of the tests being administered [2], [40].

Risk assessments have so far been based on functional outcomes up to early school age obtained in three prospective epidemiological studies [11], [23], [28], [34]. Data from older children and adolescents have been available only from less informative cross-sectional studies. Developmental exposure to inorganic lead is known to cause permanent CNS damage, thus suggesting that deficits attributable to early developmental neurotoxicant exposure may be irreversible [2], [39]. However, long-term effects of prenatal and early childhood exposures to neurotoxicants may become more difficult to demonstrate with time, because an increasing number of other factors play a role in test performance and it may be difficult, if not impossible, to define and measure these covariates. Thus, the increasing complexity of confounder adjustment may cause problems in the statistical analysis of cognitive test data. Despite these potential problems, prospective assessment of cohorts with well defined exposures occurring early in development is essential to understanding how neuropsychological outcome measures can be utilized as long-term indicators of early neurotoxicant insults.

We have prospectively followed a birth cohort from the Faroe Islands for 14 years. The Faroes are located in the North Atlantic between Norway, Shetland, and Iceland. In this Nordic fishing community, excess exposure to MeHg is mainly due to the traditional habit of eating meat from the pilot whale, while baseline exposures are due to frequent intake of other types of seafood that contains lower MeHg concentrations [38]. In a study conducted when the cohort children were 7 years of age, the main finding was that decrements in specific functional domains were associated with prenatal MeHg exposure [14]. Tests assessing the domains of attention, language, and verbal memory showed the most robust effects, while measures of motor speed and visuospatial function showed less consistent effects. Among several measures of prenatal and postnatal exposure, the strongest associations were obtained with the cord blood mercury concentration as the exposure indicator [20], [14], [15]. These findings were robust in analyses controlled for age, sex and confounders, and they persisted after exclusion of high exposure participants (i.e., maternal hair–mercury concentrations above 10 μg/g) [14]. Ingestion of whale blubber causes exposure to lipophilic contaminants, notably polychlorinated biphenyls (PCBs), but the possible neurotoxic influence of this exposure did not explain the MeHg-associated neurobehavioral deficits [5], [17], [29]. The examination at age 14 years that is described in this paper included a clinical test battery similar to the one applied at age 7 years.

Section snippets

Materials and methods

The cohort was assembled in the Faroe Islands during a 21-month period in 1986–1987 [13]. The primary indicator of intrauterine exposure to MeHg was the mercury concentration in cord blood, and concentrations in maternal hair at parturition were also determined. Subsequently, mercury concentrations were measured in stored cord tissue (dry weight) from about half of the cohort members examined [17]. MeHg exposure was found to vary considerably: 15% of the mothers had hair–mercury concentrations

Results

The prenatal MeHg exposures of the participants of the 14-year examinations (Table 2) were similar to those of the cohort as a whole [13]. Exposure levels at age 14 years averaged about one-fifth of those experienced prenatally, although exposures at age 7 years were slightly higher [26].

Table 3 shows associations with potential confounders. Continuous variables were trichotomized for the purpose of this table only. The expected pattern of associations reflects dietary habits and local

Discussion

This study presents results on neuropsychological performance of adolescents with widely differing degrees of prenatal exposure to MeHg from maternal seafood diets during pregnancy and lower postnatal exposures to this neurotoxicant. Adverse effects were identified in regard to motor speed, attention, and language. These effects were apparent both in multiple regression analyses and in structural equation models that take into account multiple testing, exposure imprecision, and incomplete data.

Acknowledgments

This study was supported by grants from the US National Institute of Environmental Health Sciences (ES09797) and the Danish Medical Research Council. The contents of this paper are solely the responsibility of the authors and do not represent the official views of the NIEHS, NIH or any other funding agency. Advice on neurobehavioral test selection was contributed by the following members of the steering committee convened by NIEHS: David Bellinger, Kim Dietrich, Annette Kirshner, and David

References (41)

  • E. Budtz-Jørgensen et al.

    Estimation of health effects of prenatal mercury exposure using structural equation models

    Environ. Health

    (2002)
  • E. Budtz-Jørgensen et al.

    Adverse Mercury Effects in 7-Year-Old Children Expressed as Loss in ‘IQ’

    (2004)
  • E. Budtz-Jørgensen et al.

    Effects of exposure imprecision on estimation of the benchmark dose

    Risk Anal.

    (2004)
  • E. Budtz-Jørgensen, P. Grandjean, N. Keiding, Confounder selection in environmental epidemiology, Ann. Epidemiol....
  • L.J. Cronbach

    Essentials of Psychological Testing

    (1970)
  • C. Despres et al.

    Standardization of a neuromotor test battery: the CATSYS system

    Neurotoxicology

    (2000)
  • European Food Safety Authority

    Opinion of the Scientific Panel on Contaminants in the Food Chain on a request from the Commission related to mercury and methylmercury in food (EFSA-Q-2003-030)

    (2004)
  • W.A. Fuller

    Measurement Error Models

    (1987)
  • P. Grandjean et al.

    Impact of maternal seafood diet on fetal exposure to mercury, selenium, and lead

    Arch. Environ. Health

    (1992)
  • P. Grandjean et al.

    Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years

    Am. J. Epidemiol.

    (1999)
  • Cited by (0)

    DOI of original article: 10.1016/j.ntt.2006.02.004. Please note that this article was previously published in a recent regular issue and is being reprinted. Please cite this article as F. Debes et al, Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years, Neurotoxicology and Teratology, 28(2006), 363–375. It has been re-printed to appear alongside the Editorial “Editors’ Note: Methylmercury 2006, by Jane Adams and Susan L. Schantz" and the paper “Methylmercury and Neurodevelopment: Longitudinal Analysis of the Seychelles Child Development Cohort, by P.W. Davidson" appearing in this issue.

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