Frodi Debes

Cognitive Deficit in 7-Year-Old Children with Prenatal Exposure to Methylmercury

A cohort of 1022 consecutive singleton births was generated during 1986-1987 in the Faroe Islands. Increased methylmercury exposure from maternal consumption of pilot whale meat was indicated by mercury concentrations in cord blood and maternal hair. At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Neuropsychological tests included Finger Tapping; Hand-Eye Coordination; reaction time on a Continuous Performance Test; Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and California Verbal Learning Test (Children). Clinical examination and neurophysiological testing did not reveal any clear-cut mercury-related abnormalities. However, mercury-related neuropsychological dysfunctions were most pronounced in the domains of language, attention, and memory, and to a lesser extent in visuospatial and motor functions. These associations remained after adjustment for covariates and after exclusion of children with maternal hair mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on brain function associated with prenatal methylmercury exposure therefore appear widespread, and early dysfunction is detectable at exposure levels currently considered safe.

Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants.

Prenatal exposure to polychlorinated biphenyls (PCBs) was examined by analysis of cord tissue from 435 children from a Faroese birth cohort. Analysis of 50 paired cord blood samples showed excellent correlation with the cord tissue concentration (r=.90). Among 17 neuropsychological outcomes determined at age 7 years, the cord PCB concentration was associated with deficits on the Boston Naming Test (without cues, two-tailed P=.09 not adjusted for mercury; with cues, P=.03), the Continuous Performance Test reaction time (P=.03), and, possibly, on long-term recall on the California Verbal Learning Test (P=.15). The association between cord PCB and cord-blood mercury (r=.42) suggested possible confounding. While no PCB effects were apparent in children with low mercury exposure, PCB-associated deficits within the highest tertile of mercury exposure indicated a possible interaction between the two neurotoxicants. PCB-associated increased thresholds were seen at two of eight frequencies on audiometry, but only on the left side, and no deficits occurred on evoked potentials or contrast sensitivity. The limited PCB-related neurotoxicity in this cohort appears to be affected by concomitant methylmercury exposure.

Delayed evoked potentials in children exposed to methylmercury from seafood.

Methylmercury poisoning may cause constriction of visual fields and deafness, especially if exposure occurs prenatally. However, the risks associated with exposure from contaminated seafood is unclear. We examined 149 children attending first grade in a Madeiran fishing community. As maternal dietary habits were relatively unchanged, current maternal hair concentrations were used as indicator of the childs prenatal exposure to methylmercury (geometric average, 9.64 microg/g [48.2 nmol/g]). After adjustment for age and sex, the mean (+/-SD) latency of peak III of the brainstem auditory evoked potentials at 40 Hz was increased by 0.128+/-0.047 ms when maternal hair-mercury concentrations exceeded 10 microg/g (50 nmol/g) (p for association, 0.002), and the increase of the N145 pattern-reversal visual evoked potential latency at 15 minutes of arc was 3.16+/-1.57 ms (p for association, 0.002). No such relationships were seen with the childs own hair-mercury concentration, and other clinical examinations revealed no mercury-associated deficits. Neurophysiological evidence of adverse effects on brain function are relatively independent of confounders, and should be considered in the risk assessment of this seafood pollutant.

Pesticide Exposure and Stunting as Independent Predictors of Neurobehavioral Deficits in Ecuadorian School Children

OBJECTIVES. To examine possible effects on blood pressure, neurological function, and neurobehavioral tests in school-aged children with and without prenatal pesticide exposure in an area where stunting is common. METHODS. In a community of Northern Ecuador with intensive floriculture and a high female employment rate, we invited 79 children attending the 2 lowest grades of a public school for clinical examinations. In addition to a thorough physical examination, we administered simple reaction time, Santa Ana dexterity test, Stanford-Binet copying, and Wechsler Intelligence Scale for Children-Revised Digit Spans forward. Maternal interview included detailed assessment of occupational history to determine pesticide exposure during pregnancy. Recent and current pesticide exposure was assessed by erythrocyte acetylcholine esterase activity and urinary excretion of organophosphate metabolites. RESULTS. All eligible children participated in the study, but 7 children were excluded from data analysis due to other disease or age >9 years. A total of 31 of the remaining 72 children were classified as stunted based on their height for age. Maternal occupational history revealed that 37 children had been exposed to pesticides during development. After confounder adjustment, prenatal pesticide exposure was associated with a higher systolic blood pressure than in the controls. On neurological examination, 14 exposed children and 9 controls showed ≥1 abnormalities. Of 5 neurobehavioral tests, the Stanford-Binet copying test showed a lower drawing score for copying designs in exposed children than in controls. Stunting was associated with a lower score on this test only, and both risk factors remained statistically significant in a multiple regression analysis with adjustment for demographic and social confounders. Increased excretion of dimethyl and diethyl metabolites of organophosphates was associated with increased reaction time and no other outcomes. CONCLUSION. Prenatal pesticide exposure may cause lasting neurotoxic damage and add to the adverse effects of malnutrition in developing countries. The effects differ from those due to acute pesticide exposure.

Neurobehavioral deficits and increased blood pressure in school-age children prenatally exposed to pesticides.

Background The long-term neurotoxicity risks caused by prenatal exposures to pesticides are unclear, but a previous pilot study of Ecuadorian school children suggested that blood pressure and visuospatial processing may be vulnerable. Objectives In northern Ecuador, where floriculture is intensive and relies on female employment, we carried out an intensive cross-sectional study to assess children’s neurobehavioral functions at 6–8 years of age. Methods We examined all 87 children attending two grades in the local public school with an expanded battery of neurobehavioral tests. Information on pesticide exposure during the index pregnancy was obtained from maternal interview. The children’s current pesticide exposure was assessed from the urinary excretion of organophosphate metabolites and erythrocyte acetylcholine esterase activity. Results Of 84 eligible participants, 35 were exposed to pesticides during pregnancy via maternal occupational exposure, and 23 had indirect exposure from paternal work. Twenty-two children had detectable current exposure irrespective of their prenatal exposure status. Only children with prenatal exposure from maternal greenhouse work showed consistent deficits after covariate adjustment, which included stunting and socioeconomic variables. Exposure-related deficits were the strongest for motor speed (Finger Tapping Task), motor coordination (Santa Ana Form Board), visuospatial performance (Stanford-Binet Copying Test), and visual memory (Stanford-Binet Copying Recall Test). These associations corresponded to a developmental delay of 1.5–2 years. Prenatal pesticide exposure was also significantly associated with an average increase of 3.6 mmHg in systolic blood pressure and a slight decrease in body mass index of 1.1 kg/m2. Inclusion of the pilot data strengthened these results. Conclusions These findings support the notion that prenatal exposure to pesticides—at levels not producing adverse health outcomes in the mother—can cause lasting adverse effects on brain development in children. Pesticide exposure therefore may contribute to a “silent pandemic” of developmental neurotoxicity.

Prenatal exposure to lead and cognitive deficit in 7- and 14-year-old children in the presence of concomitant exposure to similar molar concentration of methylmercury.

Few studies have examined the effects of mixed metal exposures in humans. We have evaluated the effect of prenatal lead exposure in a Faroese birth cohort in the presence of similar molar-level exposure to methylmercury. A cohort of 1022 singleton births was assembled in the Faroe Islands during 1986-1987 from whom lead was measured in cord-blood. A total of 896 cohort subjects participated in a clinical examination at age 7 and 808 subjects in a second examination at age 14. We evaluated the association between cord-blood lead concentrations and cognitive deficits (attention/working memory, language, visuospatial, and memory) using multiple regression models. Overall, the lead concentration showed no clear pattern of association. However, in subjects with a low methylmercury exposure, after inclusion of statistical interaction terms, lead-associated adverse effects on cognitive functions were observed. In particular, higher cord-blood lead was associated with a lower digit span forward score on the Wechsler Intelligence Scale for Children-Revised (WISC-R) [beta=-1.70, 95% confidence interval (CI): -3.12 to -0.28] at age 7 and a lower digit span backward score on the WISC-R (beta=-2.73, 95%CI: -4.32 to -1.14) at age 14. Some interaction terms between lead and methylmercury suggested that the combined effect of the exposures was less than additive. The present study indicates that adverse effects of exposure may be overlooked if the effects of a co-pollutant are ignored. The present study supports the existence of adverse effects on cognitive functions at prenatal lead exposures corresponding to an average cord-blood concentration of 16 μg/L.

Cognitive deficits at age 22 years associated with prenatal exposure to methylmercury.

Prenatal exposure to mercury has been associated with adverse effects on child neurodevelopment. The present study aims to determine the extent to which methylmercury-associated cognitive deficits persist into adult age. In a Faroese birth cohort originally formed in 1986-1987 (N = 1,022), prenatal methylmercury exposure was assessed in terms of the mercury concentration in cord blood and maternal hair. Clinical examinations of 847 cohort members at age 22 years were carried out in 2008-2009 using a panel of neuropsychological tests that reflected major functional domains. Subjects with neurological and psychiatric diagnoses were excluded from the data analysis, thus leaving 814 subjects. Multiple regression analysis included covariates previously identified for adjustment. Deficits in Boston Naming Test (BNT) and other tests of verbal performance were significantly associated with the cord-blood mercury concentration. Deficits were also present in all other tests applied, although most were not statistically significant. Structural equation models were developed to ascertain the possible differences in vulnerability of specific functional domains and the overall association with general intelligence. In models for individual domains, all of them showed negative associations, with crystallized intelligence being highly significant. A hierarchical model for general intelligence based on all domains again showed a highly significant negative association with the exposure, with an approximate deficit that corresponds to about 2.2 IQ points at a 10-fold increased prenatal methylmercury exposure. Thus, although the cognitive deficits observed were smaller than at examinations at younger ages, maternal diets with contaminated seafood were associated with adverse effects in this birth cohort at age 22 years. The deficits affected major domains of brain functions as well as general intelligence. Thus, prenatal exposure to this marine contaminant appears to cause permanent adverse effects on cognition.

Neurotoxicity from prenatal and postnatal exposure to methylmercury

The extent to which postnatal methylmercury exposure contributes to neurobehavioral delays is uncertain. Confounding may occur because the childs dietary exposure likely correlates with the mothers. This conundrum was examined in the Faroese birth cohort 1 born in 1986-1987. Exposure parameters included mercury concentrations in maternal hair at parturition, cord blood, and child blood and hair at the age-7 clinical examination (N=923). In regression analyses, the childs current blood-mercury at age 7 (N=694) showed only weak associations with the neuropsychological test variables, but visuospatial memory revealed a significant negative association. Mutual adjustment caused decreases of the apparent effect of the prenatal exposure. However, such adjustment may lead to underestimations due to the presence of correlated, error-prone exposure variables. In structural equation models, all methylmercury exposure parameters were instead entered into a latent exposure variable that reflected the total methylmercury load. This latent exposure showed significant associations with neurodevelopmental deficits, with prenatal exposure providing the main information. However, postnatal methylmercury exposure appeared to contribute to neurotoxic effects, in particular in regard to visuospatial processing and memory. Thus, addition in the regression analysis of exposure information obtained at a different point in time was not informative and should be avoided. Further studies with better information on exposure profiles are needed to characterize the effects of postnatal methylmercury exposure.

Negative confounding by essential fatty acids in methylmercury neurotoxicity associations

BACKGROUND Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis. METHODS We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure. RESULTS A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (-18.9, 95% confidence interval [CI]=-36.3, -1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (-22.0, 95% confidence interval [CI]=-39.4, -4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (-1.94, 95% CI=-3.39, -0.49). CONCLUSIONS Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure.

Impact of contrast sensitivity performance on visually presented neurobehavioral tests in mercury-exposed children.

Presentation of neuropsychological tests on a computer screen may involve a visual challenge to the examinee. The possible need for adjustment for visual contrast sensitivity on test performance was therefore determined from data on 917 mercury-exposed children who were examined at age 7 years. Contrast sensitivity was found to be associated with performance on the computer-assisted Continuous Performance Test. However, it showed similar associations with performance on traditional pencil-and-paper tests, especially Bender Visual Motor Gestalt Test and Wechsler Intelligence Scale for Children-Revised (WISC-R) Block Designs. Contrast sensitivity was not associated with prenatal mercury exposure, and adjustment for visual function had only a negligible effect on the regression coefficients for mercury as predictor of neuropsychological deficits. The mercury-associated neurobehavioral deficits are therefore unlikely to be due to mercury-induced visual system dysfunction causing secondary deficits in cognitive domain testing. Visuospatial processing appears to be a determinant in contrast sensitivity performance, and careful consideration of whether to control for contrast sensitivity in future studies of neurotoxicant effects is therefore recommended.