 |
|
Effects of Prenatal and Postnatal Methylmercury Exposure From Fish Consumption on Neurodevelopment
Outcomes at 66 Months of Age in the Seychelles Child Development Study
Philip W. Davidson, PhD;
Gary J. Myers, MD;
Christopher Cox, PhD;
Catherine Axtell, PhD;
Conrad Shamlaye, MB, ChB;
Jean Sloane-Reeves, MS;
Elsa Cernichiari, MS;
Larry Needham, PhD;
Anna Choi, MS;
Yining Wang, PhD;
Maths Berlin, MD;
Thomas W. Clarkson, PhD
JAMA. 1998;280:701-707.
ABSTRACT
| |
Context.— Human neurodevelopmental consequences of exposure to methylmercury (MeHg) from eating fish remain a question of public health concern.
Objective.— To study the association between MeHg exposure and the developmental outcomes of children in the Republic of Seychelles at 66 months of age.
Design.— A prospective longitudinal cohort study.
Participants.— A total of 711 of 779 cohort mother-child pairs initially enrolled in the Seychelles Child Development Study in 1989.
Setting.— The Republic of Seychelles, an archipelago in the Indian Ocean where 85% of the population consumes ocean fish daily.
Main Outcome Measures.— Prenatal and postnatal MeHg exposure and 6 age-appropriate neurodevelopmental tests: the McCarthy Scales of Children's Abilities, the Preschool Language Scale, the Woodcock-Johnson Applied Problems and Letter and Word Recognition Tests of Achievement, the Bender Gestalt test, and the Child Behavior Checklist.
Results.— The mean maternal hair total mercury level was 6.8 ppm and the mean child hair total mercury level at age 66 months was 6.5 ppm. No adverse outcomes at 66 months were associated with either prenatal or postnatal MeHg exposure.
Conclusion.— In the population studied, consumption of a diet high in ocean fish appears to pose no threat to developmental outcomes through 66 months of age.
INTRODUCTION
INORGANIC MERCURY (Hg) discharged into lakes, rivers, and oceans is converted to methylmercury (MeHg) by microorganisms and bioaccumulated up the aquatic food chain.1 Concern about the potential public health threat from MeHg arose in the United States in the early 1970s when elevated concentrations were found in fish in the Great Lakes. Today, recreational fishing is restricted in many states and Food and Drug Administration guidelines regulate interstate commerce of fish because of their MeHg content.
Mass health disasters in Minamata and Niigata, Japan, caused by consumption of fish highly contaminated with MeHg from an industrial source,2-3 and in Iraq following consumption of bread containing MeHg fungicide,4-6 confirmed that MeHg was neurotoxic and that the prenatal period was the most sensitive stage of the life cycle. For example, severe exposures in Iraq (up to 674 ppm of mercury in hair) were associated with microcephaly, seizures, mental retardation, and cerebral palsy. The Iraq outbreak also resulted in less severe outcomes typified by developmental delays and abnormal results of neurological examinations. A dose-response analysis suggested that effects may occur at maternal hair concentrations of mercury as low as 10 ppm,5-6 although there was considerable uncertainty in this estimate. This compares with an average in the US population of 1 ppm or less.7
All fish contain MeHg. Frequent consumption of ocean fish can lead to MeHg levels in excess of 10 ppm and as high as 50 ppm in hair.1 Epidemiological studies8-10 on populations consuming fish where Hg was biologically methylated failed to find clinical cases of MeHg poisoning. The possibility that prenatal MeHg exposure from maternal consumption of a fish diet may be associated with subtle changes in children's cognitive and neurological development has been examined in these studies with inconclusive results.1, 11
We have followed longitudinally12-13 a large inception cohort of mother-child pairs in the Republic of Seychelles, a westernized archipelago in the middle of the Indian Ocean where 85% of the population consumes marine fish daily.14 This article presents the results of the neurodevelopmental examination of the Seychelles Child Development Study (SCDS) cohort at 66 months, an age at which neuropsychological tests may be given that are sensitive enough to assess potential associations between developmental outcomes and MeHg dietary exposure. Our results also include examination of the role of postnatal exposure from fish consumption.
METHODS
Subjects
The cohort consisted of 711 mother-child pairs living in the Republic of Seychelles, representing 91% of the 779 pairs originally enrolled in the SCDS main study.11 Informed consent was obtained from the caregiver of every participating child. The protocol was approved by human subjects review boards at the University of Rochester, Rochester, NY, and the Ministry of Health, Victoria, Mahé, Republic of Seychelles, before enrollment began. The sample size was sufficient to detect a 5.7-point difference on any test with a mean (SD) of 100 (16) between low (0-3 ppm) and high (>12 ppm) MeHg groups for a 2-sided test ( =.05 at 80% power).
Twenty-eight mother-child pairs were excluded because of medical problems that might seriously affect development.13 An additional 16 pairs had insufficient maternal hair available to accurately recapitulate prenatal exposure, and 24 did not return for testing at 66 months.
Demographic characteristics of the Seychelles and the cohort were reported earlier.15 At enrollment, the mothers reported eating an average of approximately 12 marine fish meals per week. Sea mammals are not consumed in the Seychelles. We have previously documented that lead levels in whole blood are less than 0.48 µmol/L (10 µg/dL) in a representative group of Seychellois children and mothers.16
Procedure Test Battery
Each child was evaluated at 66 months (±6 months) at a child development center staffed by a team of specially trained Seychellois nurses blinded to MeHg levels and the results of testing during previous visits. Five children were tested between 72 months and 79 months of age. All evaluations were conducted between July 1994 and October 1995. The test battery assessed multiple developmental domains17 and was similar to those used to demonstrate adverse developmental effects of exposure to lead18 and polychlorinated biphenyls (PCBs)19 and to those used in earlier studies to measure MeHg exposure effects.9, 20 The tests are sufficiently sensitive and accurate to detect neurotoxicity in the presence of a number of confounding factors.21
The test battery included the following 6 primary measures: (1) the General Cognitive Index (GCI) of the McCarthy Scales of Children's Abilities22 to estimate cognitive ability; (2) the Preschool Language Scale23 (PLS) total score to measure both expressive and receptive language ability; (3) the Letter and Word Recognition and (4) the Applied Problems subtests of the Woodcock-Johnson (W-J) Tests of Achievement24 to measure reading and arithmetic achievement; (5) the Bender Gestalt test25 to measure visual-spatial ability; and (6) the total T score from the Child Behavior Checklist (CBCL)26 to measure the child's social and adaptive behavior. The CBCL questionnaire was completed by each child's primary caregiver. All tests were given in Creole, the language spoken by 98% of Seychellois at home.
Pure tone hearing thresholds were tested using a portable audiometer. Caregiver IQ was determined using the Raven Standard Progressive Matrices, a nonverbal test designed to minimize the effects of culture on measurement of IQ.27 When the children were between 42 and 56 months of age, the Home Observation for Measurement of the Environment (HOME) Inventory for Families of Preschool Age Children28 was administered during home visits. Following procedures described earlier,17 on-site test administration reliability was assessed by an independent scorer; percentage of disagreement ranged from 0% to 8%. Mean intraclass correlations for interscorer reliability were 0.96 to 0.97. Reliability of final scoring in Rochester was conducted by rescoring a sample of tests; the mean intraclass correlation coefficient was 0.96.
Mercury Exposure
Prenatal exposure was assessed by measuring the concentration of total mercury (THg) in a segment of maternal hair representing growth during pregnancy. Total Hg in maternal hair during pregnancy correlates well with blood levels of MeHg1 and with THg levels in fetal brain.29 Methylmercury accounts for over 80% of the THg in hair samples collected from fish-eating populations.16, 29 Maternal hair levels of THg have been the biological indicator of choice in nearly all previous epidemiological studies of fetal exposure to MeHg. There is considerable variation in the relationship between hair and blood THg in different individuals. However, the key relationship, that of hair levels and brain levels, may not show the same variability.29 Postnatal exposure was determined by measuring THg at 66 months of age from a 1-cm segment of the child's hair nearest the scalp. This age was chosen because it was coincident with the age of testing and all children were postweaning and eating a fish diet. In 25 children, hair samples taken during the HOME administration (at 48 months of age) were used to determine postnatal MeHg exposure because their hair sample at 66 months of age was insufficient for analysis.
Mercury in Fish
Total Hg was analyzed in 5 or more samples of species of fish caught and consumed in the Seychelles, including yellow fin tuna (Thunnus albacares), Indian mackerel (Rastrelleger kanagurta), brown spotted grouper (Epinephelus chlorustigma), green jobfish (Aprion virescens), bonito (Euthynnus affinis), bludger (Carangoides gymnostethus), and spangled emperor (Lethrinus nebulosus).
Maternal and Child Mercury Analysis
The analysis of hair samples and fish homogenates for THg and inorganic Hg was done by cold vapor atomic absorption spectrometry. The analysis technique and quality control procedure are given elsewhere.16
PCBs in Blood
Polychlorinated biphenyls are known to be present in some ocean fish and may be associated with developmental delays in children. Levels of PCBs in serum of 49 of the children at 66 months of age were analyzed at the laboratories of the US Centers for Disease Control and Prevention, Atlanta, Ga. The analytic method for measuring the PCBs involved deproteinization of the serum with formic acid, elution through a column containing octadodecyl (C18) packing material, elution through a column containing Florisil packing material, concentration of the organic eluents, and analysis by dual capillary column–gas chromatography with electron capture detection.30
Statistical Analysis
The effect of prenatal and postnatal MeHg on each outcome variable was adjusted for covariates, specified as part of the study design, and selected because of their potential to bias the assessment of the association between Hg and outcome.17 Covariates associated with the child included birth weight, birth order, sex, history of breast-feeding, hearing status, and the child's medical history. Covariates associated with the mother and family included maternal age, maternal smoking during pregnancy, maternal alcohol consumption during pregnancy, maternal medical history, caregiver intelligence, language spoken in the home, Hollingshead socioeconomic status (SES), and HOME score. Two multiple linear regression analyses (with 2-tailed significance tests using a significance level of P .05) including both prenatal and postnatal THg were performed for each of the 6 primary measures. The first involved all covariates (full model) and the second included only covariates believed to most likely influence child development in the Seychelles (reduced model), including sex, birth weight, child's medical history, maternal age, HOME score, caregiver IQ, SES, and hearing status. Each full and reduced model was run both with and without THg by sex interaction terms to test the hypothesis that males and females have different THg slopes.
All models were examined for statistical outliers and influential points.31 Each model was run first with outliers, then without outliers, and the results were compared. All of the results were essentially the same with or without outliers. The regression analyses for all 6 primary measures were also repeated without influential points to determine whether the original results were dependent on such points.31 The final analysis included influential points that were not also outliers. The results without influential points were consistent with the original analysis.
Secondary analyses tested the hypothesis that associations between developmental outcomes and THg exposure might be nonlinear. All regression analyses were repeated, first using the log of the prenatal and postnatal THg values, then classifying THg variables into 5 groups each for prenatal and postnatal exposure.
RESULTS
Mercury in Fish
A total of 350 samples of fish were analyzed. The median THg for each of the 25 species ranged from 0.004 ppm to 0.75 ppm, with most medians in the range of 0.05 to 0.25 ppm. These levels are comparable with fish in the US market. The lowest levels occurred in reef fish. Methylmercury accounted for over 90% of the THg in 34 fish homogenates analyzed by gas chromatography–atomic fluorescent detection. This finding confirms many previous observations.32
PCBs in Blood
Twenty-eight PCB congeners ranging from congener 28 to 206 were measured in each serum sample. All samples had no detectable levels of any PCB congeners. The detection limit for the PCB analysis was 0.2 ng/mL. These results are typical for persons with no known exposure to PCBs.33
Mercury Exposure
The mean (SD) maternal hair level of THg during pregnancy was 6.8 (4.5) ppm (n=711), and the mean child hair level at 66 months was 6.5 (3.3) ppm (n=708). The ranges (maternal hair, 0.5-26.7 ppm; child hair, 0.9-25.8 ppm) were sufficient to test for exposure effects using regression analysis. Maternal and child THg concentrations were not highly associated Pearson r=0.15, n=708, P<.001) as observed by others.20 The exposure levels found in the Seychelles are typical of populations that depend on fish as a major dietary source of protein and calories.34
Test Performance
Table 1 and Table 2 show test score means and SDs for prenatal and postnatal exposure levels. These results are similar to what would be expected from a healthy, well-developing US population. No test indicated a deleterious effect of MeHg exposure. Four of the 6 measures showed better scores in the highest MeHg groups compared with lower groups for both prenatal and postnatal exposure.
|
|
|
|
Table 1.—Neurodevelopmental Test Means (SDs) by Prenatal Exposure Levels*
|
|
|
|
|
|
|
Table 2.—Neurodevelopmental Test Means (SDs) by Postnatal Exposure Level*
|
|
|
Regression Analyses
Primary Analyses. The models with all covariates (full models) and limited covariates (reduced models) were both significant (ie, each model was able to describe the data) and yielded similar results for every measure. The THg by sex interaction test for prenatal exposure was not significant in any regression model. The THg by sex interaction was significant for postnatal exposure for the Bender Gestalt test; hence, we report the results of the reduced model with both interaction terms included. For all other analyses, we report the results for reduced models without THg by sex interactions.
The regression coefficients for all variables in the 6 sets of analyses are shown in Table 3. Figure 1 shows partial residual plots (end points adjusted for covariates) for prenatal and postnatal exposure for the McCarthy GCI, the PLS total score, and the W-J Applied Problems test score. For the McCarthy GCI analysis, the model (F [15, 628]=4.41, P<.001, R2 = 0.10) indicated that slopes for both THg exposures did not differ from 0 (P=.59 and .06 for prenatal and postnatal exposure, respectively). For the PLS analysis, the model (F [15, 590]=6.25, P<.001, R2 = 0.14) showed effects of both prenatal and postnatal THg exposure (P=.02 for both), but the effects were very small and in a direction of enhanced performance. The total increase in scores across the entire range of THg exposures was less than 4.5 points. The W-J Applied Problems model (F [15, 625]=5.38, P<.001, R2 = 0.11) indicated that the slope for prenatal exposure did not differ significantly from 0 (P=.41). There was a significant beneficial postnatal exposure effect (P=.05), but no evidence for an adverse effect. The postnatal exposure slope for the W-J Applied Problems test was 0.36 ppm, representing a 9.7-point increase over the full exposure range, or a 10% improvement in performance.
|
|
|
|
Table 3.—Multiple Regression Analysis of 66-Month Test Scores: Parameter Estimates for Reduced Models With Outliers Removed*
|
|
|
|
|
|
|
Figure 1.—Partial residuals for prenatal and postnatal exposure. The measures are the McCarthy Scales of Children's Abilities General Cognitive Index (GCI), the Preschool Language Scale (PLS) total score, and the Woodcock-Johnson (W-J) Applied Problems subtest. Each test score was adjusted for all reduced model predictors except the exposure value used in the plot. For graphical representation, the overall mean test score was added to the resulting partial residual. The slope of the line in the plot is the regression coefficient for the multiple regression model. Slopes are shown for the model with and without outliers. Black squares indicate outliers.
|
|
|
Figure 2 shows partial residual plots for the Bender Gestalt test, separating male from female subjects. The model (F [17, 613]=4.53, P<.001, R2 = 0.11] showed no significant association with prenatal exposure. The interaction of postnatal THg with sex was significant (P=.004). The slightly positive slope for female errors was not significant (P=.14). The regression coefficient of -0.16 ppm for male subjects was significant (P=.009), resulting in a reduction of 4.3 errors over the entire exposure range (a 40% performance improvement given that the average score for the lowest-exposure group was about 10 errors).
|
|
|
|
Figure 2.—Partial residuals for prenatal and postnatal exposure. The measures are Bender Gestalt error scores for male and female subjects. Each test score was adjusted for all reduced model predictors except the exposure value used in the plot. For graphical representation, the overall mean test score was added to the resulting partial residual. The slope of the line in the plot is the regression coefficient for the multiple regression model. Slopes are shown for the model with and without outliers. Black squares indicate outliers.
|
|
|
Although the models for the W-J Letter and Word Recognition achievement score and the CBCL yielded significant overall F statistics, none of these was significantly associated with either prenatal or postnatal exposure.
The data for covariate effects shown in Table 3 indicate that test scores were frequently influenced by sex (female subjects scored higher than male subjects), and were directly related to SES, quality of home stimulation, and caregiver IQ, as would be expected in westernized cultures. These data also indicate that performance by Seychellois children on these tests was similar to what would be expected of US children.
Table 4 gives the partial R2 values for the effects of prenatal and postnatal THg exposure on each developmental measure and the 95% confidence intervals for the effect of a 10-ppm increase in hair THg concentration. The small partial R2 values shown in Table 4 indicate that THg exposure accounted for little of the variance associated with each test. For the McCarthy GCI and the CBCL, the magnitude of the negative lower confidence limit might be of clinical significance, at least over a greater range of hair THg levels. However, the inclusion of 0 in the confidence intervals shows that the effects are not statistically significant.
|
|
|
|
Table 4.—Partial R2 Values for Total Mercury and 95% CIs for a 10-ppm Increase in Both Prenatal and Postnatal Total Mercury Hair Levels From the Regression Analysis of 66-Month End Points*
|
|
|
Secondary Analysis. Log transformations of the 2 THg variables did not alter the direction of any effects. In the categorical analyses, test scores for children with an MeHg exposure level greater than 12 ppm were not significantly different than for children with exposure levels of 3 ppm or less.
COMMENT
Results from this study are relevant for the United States and other countries with similar dietary intake of fish. The major source of MeHg in the Seychelles is ocean fish and the average fish levels are similar to those on the US market. Seychellois MeHg levels are 10 to 20 times higher than in the United States because the Seychellois consume more fish, not because they eat a few fish with abnormally high MeHg levels. Thus, any potential adverse effects of MeHg in fish should be detected in the Seychelles long before such effects would be seen in the United States. Our findings confirm our earlier report in which no adverse developmental effects were found in toddlers following prenatal MeHg exposure.12 Our data extend preliminary results from the SCDS Pilot Study,35 involving a less statistically powerful, less well-controlled developmental evaluation of 217 Seychellois children at 66 months using most of the same measures but lacking many of the covariates used here.
We applied multiple regression analysis to our data as has been done in other studies on the effects of mercury,9-13 lead,18, 36 or PCBs19 on child development. Although our models showed no negative associations between MeHg and outcome scores, our test procedures did detect other factors known to be associated with child development. The HOME test indicated that the quality of the home environment had a substantial impact on child performance, significantly affecting the results of all tests. The SES of the family, the caregiver's IQ, and the child's sex were all found to have an influence on performance scores, in keeping with the literature on child development.37-38 These results increase confidence in the sensitivity of our tests to child development functions. Postnatal exposure to MeHg at 66 months of age was associated with a small but statistically significant increase on several developmental outcomes. Our hypothesis did not predict positive effects, since there are no reasons to suppose that such effects are associated with exposure to MeHg. However, MeHg levels in hair are known to correlate closely with fish intake, and other factors or agents associated with fish, such as omega-3 fatty acids, may have beneficial effects. A large cohort study under way in the Faroe Islands found enhancement of developmental milestones in suckling infants exposed to MeHg in breast milk.39 They suggested that MeHg levels in the infant were a surrogate for the length of breast-feeding, which is reported to have a positive association with developmental outcomes.40
In contrast with the conclusions from this and our earlier studies of the main Seychellois cohort,12-13 the Faroe Islands study found evidence of cognitive deficits associated with prenatal exposure to THg when children were tested at 7 years of age.20 Important differences between the 2 populations may explain the divergent outcomes (eg, nutritional practices, housing, and lifestyle). However, the major difference between our study and the Faroe Islands study is the source of exposure. Ocean fish are the source of MeHg in the Seychelles, whereas pilot whales are the predominant source in the Faroe Islands.20 The average MeHg level in the meat of pilot whales sampled in the Faroe Islands was 1.6 ppm,41 approximately 10 times higher than the average level in fish consumed in the Seychelles. Approximately the same level of inorganic Hg is also present in whale meat.41 In addition, whale blubber is also consumed by the Faroese41 and is heavily contaminated with fat-soluble pollutants.42 The average PCB concentration in pilot whale blubber from Faroese waters is elevated (about 30 ppm).43 In general, fatty tissues of marine mammals in the North Atlantic also contain elevated levels of persistent organochlorine compounds including dibenzofurans and dioxins, DDT and its metabolites, and other pesticides. It is difficult to determine the relative toxicological impact of individual compounds. Some of these contaminants are believed to affect child development.44 The Faroese study may be relevant to populations consuming large, perhaps episodic, amounts of marine mammals, but its relevance to people consuming ocean fish remains to be established.
A Swedish expert group conducted the first extensive evaluation of human health risks from MeHg in fish in 1971.45 They concluded the lowest toxic level in hair was 50 ppm in adults. The World Health Organization (WHO) expert group46 subsequently reaffirmed the Swedish conclusion and applied a safety factor of 10 to cover risks to the most sensitive subgroup of the population, assumed to be those who are prenatally exposed. Thus, 5 ppm in hair was adopted as the international standard for the upper tolerable level of Hg in hair. Subsequent epidemiological studies of human populations prenatally exposed to MeHg from fish have given strong support to the WHO guideline.8, 10, 12-13 Our results add further support to the validity of this long-standing guideline.
In summary, the results of extensive performance tests conducted with cohort children at 66 months of age strongly support our findings reported at younger ages. The development of these children is proceeding well without any detectable adverse influence of MeHg. Our results support Egeland and Middaugh's observation47 that it would be inadvisable to forgo the health benefits of fish consumption to protect against a small risk of adverse effect at the levels of MeHg found in ocean fish on the US market.
AUTHOR INFORMATION
Reprints: Philip W. Davidson, PhD, Strong Center for Developmental Disabilities, Box 671, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642 (e-mail: pdavidson{at}cc.urmc.rochester.edu).
This research is supported by grants ES-05497, ES-01247, and ES-07271 from the National Institutes of Health, Bethesda, Md, by a grant from the Food and Drug Administration, US Department of Health and Human Services, Washington, DC, and by the Ministry of Health, Victoria, Mahé, Republic of Seychelles.
From the University of Rochester School of Medicine and Dentistry, Rochester, NY (Drs Davidson, Myers, Cox, Axtell, Wang, and Clarkson, and Mss Sloane-Reeves, Cernichiari and Choi); the Republic of Seychelles Ministry of Health, Victoria, Mahé, Seychelles (Dr Shamlaye); the Centers for Disease Control and Prevention, Atlanta, Ga (Dr Needham); and The University of Lund, Lund, Sweden (Dr Berlin).
REFERENCES
1. World Health Organization Environmental Health Criteria 101: Methylmercury. Geneva, Switzerland: World Health Organization; 1990.
2. Matsumoto H, Koya G, Takeuchi T. Fetal Minamata disease. J Neuropathol Exp Neurol. 1965;24:563-574.
ISI
| PUBMED
3. Takeuchi T. Pathology of Minamata disease. In: Study Group of Minamata Disease, ed. Minamata Disease. Kumamoto, Japan: Kumamoto University; 1968:141-228.
4. Marsh DO, Myers GJ, Clarkson TW, Amin-Zaki L, Tikriti S, Majeed M. Fetal methylmercury poisoning: clinical and toxicological data on 29 cases. Ann Neurol. 1980;7:348-353.
FULL TEXT
|
ISI
| PUBMED
5. Cox C, Clarkson TW, Marsh DO, Amin-Zaki L, Tikriti S, Myers GJ. Dose-response analysis of infants prenatally exposed to methylmercury: an application of a single compartment model to single-strand hair analysis. Environ Res. 1989;31:640-649.
6. Cox C, Marsh DO, Myers GJ, Clarkson TW. Analysis of data on delayed development from the 1971-72 outbreak of methylmercury poisoning in Iraq: assessment of influential points. Neurotoxicology. 1995;16:727-730.
ISI
| PUBMED
7. Smith JC, Allen PV, Von Burg R. Hair methylmercury levels in U.S. women. Arch Environ Health. 1997;52:476-480.
ISI
| PUBMED
8. McKeown-Eyssen G, Reudy J, Neims A. Methylmercury exposures in northern Quebec, II: neurologic findings in children. Am J Epidemiol. 1983;118:470-479.
FREE FULL TEXT
9. Kjellstrom T, Kennedy P, Wallis S, Mantell C. Physical and Mental Development of Children With Prenatal Exposure to Mercury From Fish, Stage I: Preliminary Tests at Age 4. Solna, Sweden: National Swedish Environmental Protection Board; 1986. Report 3080.
10. Kjellstrom T, Kennedy P, Wallis S, et al. Physical and Mental Development of Children With Prenatal Exposure to Mercury From Fish, Stage II: Interviews and Psychological Tests at Age 6. Solna, Sweden: National Swedish Environmental Protection Board; 1989. Report 3642.
11. Marsh D, Clarkson TW, Myers GJ, et al. The Seychelles study of methylmercury exposure and child development: introduction. Neurotoxicology. 1995;16:583-596.
ISI
| PUBMED
12. Myers GJ, Marsh DO, Davidson PW, et al. Main neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: outcome at six months. Neurotoxicology. 1995;16:653-664.
ISI
| PUBMED
13. Davidson PW, Myers GJ, Cox C, et al. Longitudinal neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from maternal fish ingestion: outcomes at 19 and 29 months. Neurotoxicology. 1995;16:677-688.
ISI
| PUBMED
14. Bovet P, Perret F, Shamlaye C, et al. The Seychelles Heart Study, II: methods and basic findings. Seychelles Med Dent J. 1997;1:8-24.
15. Shamlaye CF, Marsh DO, Myers GJ, et al. The Seychelles child development study on neurodevelopmental outcomes following in utero exposure to methylmercury from a maternal fish diet: background and demographics. Neurotoxicology. 1995;16:597-612.
ISI
| PUBMED
16. Cernichiari E, Toribara TY, Liang L, et al. The biological monitoring of mercury in the Seychelles study. Neurotoxicology. 1995;16:613-628.
ISI
| PUBMED
17. Davidson PW, Myers GJ, Cox C, et al. Neurodevelopmental test selection, administration, and performance in the main Seychelles Child Development Study. Neurotoxicology. 1995;16:665-676.
ISI
| PUBMED
18. Needleman HL, Gatsonis CA. Low level lead exposure and the IQ of children: a meta-analysis of modern studies. JAMA. 1990;263:673-678.
FREE FULL TEXT
19. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 1996;335:783-789.
FREE FULL TEXT
20. Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997;19:417-428.
FULL TEXT
|
ISI
| PUBMED
21. Amler RW, ed, Gibertini M, ed. Pediatric Environmental Neurobehavioral Test Battery. Atlanta, Ga: Agency for Toxic Substances and Disease Registry, US Dept of Health and Human Services; 1996.
22. McCarthy D. McCarthy Scales of Children's Abilities. New York, NY: The Psychological Corp; 1972.
23. Zimmerman I, Steiner V, Pond R. Preschool Language Scale. Rev ed. Columbus, Ohio: CE Merrill; 1979.
24. Woodcock R, Johnson M. Woodcock-Johnson Tests of Achievement. Allen, Tex: DLM; 1989.
25. Koppitz EM. The Bender Gestalt Test for Young Children. London, England: Grune & Stratton; 1963.
26. Achenbach TM. Manual for the Child Behavior Checklist and 1991 Child Behavior Profile. Burlington: University of Vermont Dept of Psychiatry; 1991.
27. Raven J. Standard Progressive Matrices. Cambridge, England: HK Lewis; 1958.
28. Caldwell B, Bradley R. Home Observation of Measurement of the Environment. Little Rock: University of Arkansas at Little Rock; 1984.
29. Cernichiari E, Brewer R, Myers G, et al. Monitoring methylmercury during pregnancy: maternal hair predicts fetal brain exposure. Neurotoxicology. 1995;16:705-710.
ISI
| PUBMED
30. Brock JW, Bruse VW, Ashley DL, et al. An improved analysis for chlorinated pesticides and polychlorinate biphenyls (PCBs) in human and bovine sera utilizing solid phase extraction. J Anal Toxicol. 1996;20:1-9.
ISI
| PUBMED
31. Cook RD, Weisberg S. Residuals and Influence in Regression (Monographs on Statistics and Applied Probability). New York, NY: Chapman & Hall; 1982.
32. Bloom NS. On the chemical form of mercury in the edible fish and marine invertebrate tissue. Can J Fish Aquatic Sci. 1992;49:1010-1017.
33. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Polychlorinated Biphenyis (Update). Atlanta, Ga: US Dept of Health and Human Services; 1997.
34. Airey D. Total mercury concentrations in human hair from 13 countries in relation to fish consumption and location. Sci Total Environ. 1983;31:157-180.
FULL TEXT
| PUBMED
35. Myers DJ, Davidson PW, Cox C, et al. Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot study. Neurotoxicology. 1995;16:639-652.
ISI
| PUBMED
36. Bellinger D, Leviton A, Waternaux C, Neddleman H, Rabinowitz M. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med. 1987;316:1037-1043.
ABSTRACT
37. Bendersky M, Lewis M. Environmental risk, biological risk, and developmental outcome. Dev Psychol. 1994;30:484-494.
FULL TEXT
|
ISI
38. Bendersky M, Lewis M. Effects of intraventricular hemorrhage and other medical and environmental risks on multiple outcomes at age three years. J Dev Behav Pediatr. 1995;16:89-96.
ISI
| PUBMED
39. Grandjean P, Weihe P, White RF. Milestone development in infants exposed to methylmercury from human milk. Neurotoxicology. 1995;16:27-33.
ISI
| PUBMED
40. Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breast milk and subsequent intelligence quotient in children born preterm. Lancet. 1992;339:261-264.
FULL TEXT
|
ISI
| PUBMED
41. Grandjean P, Weihe P, Jørgensen P, Clarkson T, Cernichiari E, Vider T. Impact of maternal seafood diet on fetal exposure to mercury, selenium, and lead. Arch Environ Health. 1992;47:185-195.
ISI
| PUBMED
42. Sanderson K. Marine mammals and the marine environment. Sci Total Environ. 1996;186:1-179.
FULL TEXT
| PUBMED
43. Weihe P, Grandjean P, Debes F, White R. Health implications for Faroe Islanders of heavy metals and PCBs from pilot whales. Sci Total Environ. 1996;186:141-148.
FULL TEXT
| PUBMED
44. Huisman M, Koopman-Esseboom C, Fidler V, et al. Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development. Early Hum Dev. 1995;41:111-127.
FULL TEXT
|
ISI
| PUBMED
45. Swedish Expert Group. Methylmercury in fish: a toxciological-epidemiological evaluation of risks. Nord Hyg Tidskr. 1971;suppl 4:1-333.
46. World Health Organization. Evaluation of Certain Food Additives and the Contaminants Mercury, Lead and Cadmium. Geneva, Switzerland: World Health Organization; 1972. Technical Report Series No. 505.
47. Egeland G, Middaugh J. Balancing fish consumption benefits with mercury exposure. Science. 1997;278:1904-1905.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED LETTER
Effects of Methylmercury Exposure on Neurodevelopment
Philippe Grandjean, Roberta F. White, Alan H. Stern, Michael Gochfeld, Philip W. Davidson, Gary J. Myers, Christopher Cox, Elsa Cernichiari, Thomas W. Clarkson, and Conrad Shamlaye
JAMA. 1999;281(10):896-897.
EXTRACT
| FULL TEXT
RELATED ARTICLE
Methylmercury Exposure and Neurotoxicity
Kathryn R. Mahaffey
JAMA. 1998;280(8):737-738.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Mercury, Vaccines, and Autism: One Controversy, Three Histories
Baker
Am. J. Public Health 2008;98:244-253.
ABSTRACT
| FULL TEXT
Role of Docosahexaenoic Acid in Modulating Methylmercury-Induced Neurotoxicity
Kaur et al.
Toxicol Sci 2007;100:423-432.
ABSTRACT
| FULL TEXT
Nutrient and Methyl Mercury Exposure from Consuming Fish
Myers et al.
J. Nutr. 2007;137:2805-2808.
ABSTRACT
| FULL TEXT
Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years
Thompson et al.
NEJM 2007;357:1281-1292.
ABSTRACT
| FULL TEXT
Risk assessment of dietary exposure to methylmercury in fish in the UK
Maycock and Benford
Hum Exp Toxicol 2007;26:185-190.
ABSTRACT
Interpreting Hair Mercury Levels in Individual Patients
Nuttall
Annals of Clinical & Laboratory Science 2006;36:248-261.
ABSTRACT
| FULL TEXT
The Effects of Methylmercury on Mitochondrial Function and Reactive Oxygen Species Formation in Rat Striatal Synaptosomes Are Age-Dependent
Dreiem et al.
Toxicol Sci 2005;87:156-162.
ABSTRACT
| FULL TEXT
Human Biomonitoring to Optimize Fish Consumption Advice: Reducing Uncertainty When Evaluating Benefits and Risks
Arnold et al.
Am. J. Public Health 2005;95:393-397.
ABSTRACT
| FULL TEXT
Spatial Alternation Deficits Following Developmental Exposure to Aroclor 1254 and/or Methylmercury in Rats
Widholm et al.
Toxicol Sci 2004;82:577-589.
ABSTRACT
| FULL TEXT
Mercury Exposure in Children With Autistic Spectrum Disorder: Case-Control Study
Ip et al.
J Child Neurol 2004;19:431-434.
ABSTRACT
Environmental toxins; their impact on children's health
Grigg
Arch. Dis. Child. 2004;89:244-250.
ABSTRACT
| FULL TEXT
Motor Impairment in Rats Exposed to PCBs and Methylmercury during Early Development
Roegge et al.
Toxicol Sci 2004;77:315-324.
ABSTRACT
| FULL TEXT
Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organization Databases
Verstraeten et al.
Pediatrics 2003;112:1039-1048.
ABSTRACT
| FULL TEXT
Nutritional Factors May Modify the Toxic Action of Methyl Mercury in Fish-Eating Populations
Clarkson and Strain
J. Nutr. 2003;133:1539S-1543.
ABSTRACT
| FULL TEXT
Blood Mercury Levels in US Children and Women of Childbearing Age, 1999-2000
Schober et al.
JAMA 2003;289:1667-1674.
ABSTRACT
| FULL TEXT
The impact of toxicology on public health policy and service: an update
De Rosa et al.
Toxicol Ind Health 2003;19:115-124.
ABSTRACT
Organic mercury compounds: human exposure and its relevance to public health
Risher et al.
Toxicol Ind Health 2002;18:109-160.
ABSTRACT
Commentary: Mercury, PCB, and now eicosapentaenoic acid: still another reason why pregnant women should be concerned about eating seafood?
Olsen
Int J Epidemiol 2001;30:1279-1280.
FULL TEXT
Technical Report: Mercury in the Environment: Implications for Pediatricians
Goldman et al.
Pediatrics 2001;108:197-205.
ABSTRACT
| FULL TEXT
An Assessment of Thimerosal Use in Childhood Vaccines
Ball et al.
Pediatrics 2001;107:1147-1154.
ABSTRACT
| FULL TEXT
Methylmercury and Neurodevelopment: Reanalysis of the Seychelles Child Development Study Outcomes at 66 Months of Age
Davidson et al.
JAMA 2001;285:1291-1293.
FULL TEXT
Cognitive Tests: Interpretation for Neurotoxicity? (Workshop Summary)
Slikker et al.
Toxicol Sci 2000;58:222-234.
ABSTRACT
| FULL TEXT
Limiting Infant Exposure to Thimerosal in Vaccines and Other Sources of Mercury
Halsey
JAMA 1999;282:1763-1766.
FULL TEXT
Prenatal and Postnatal Methylmercury Exposure and Neurodevelopmental Outcomes
Cox et al.
JAMA 1999;282:1333-1334.
FULL TEXT
Thimerosal in Vaccines---An Interim Report to Clinicians
Committee on Infectious Diseases and Committee on
Pediatrics 1999;104:570-574.
FULL TEXT
Effects of Methylmercury Exposure on Neurodevelopment
Grandjean et al.
JAMA 1999;281:896-897.
FULL TEXT
Methylmercury Exposure and Neurotoxicity
Mahaffey
JAMA 1998;280:737-738.
FULL TEXT
|
