Sally W. Thurston

Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

Neurodevelopmental Effects of Maternal Nutritional Status and Exposure to Methylmercury from Eating Fish during Pregnancy

Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537 g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9 ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and childrens scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.

Are Environmental Levels of Bisphenol A Associated with Reproductive Function in Fertile Men

Background Rodent and in vitro studies have demonstrated the estrogenicity of bisphenol A (BPA). However, few studies have examined the relationship between human exposure to BPA and male reproductive function. Objectives We investigated the relationships between environmental BPA exposure and reproductive parameters, including semen quality and male reproductive hormones, in prospectively recruited fertile men. Methods Participants (n = 375) were partners of pregnant women who participated in the Study for Future Families in four U.S. cities, and all of the men provided blood, semen, and urine samples. BPA was measured in urine. Serum samples were analyzed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone (LH), testosterone, inhibin B, estradiol, and sex hormone–binding globulin (SHBG), as well as the free androgen index (FAI). Semen analyses were performed according to World Health Organization criteria. Pearson correlations were used for unadjusted analyses, and multiple linear regression analyses were used to examine associations controlling for age, body mass index, smoking, ethnicity, urinary creatinine concentration, time of sample collection, and duration of abstinence. Results After multivariate adjustment, we observed no significant associations between any semen parameter and urinary BPA concentration. However, a significant inverse association was found between urinary BPA concentration and FAI levels and the FAI/LH ratio, as well as a significant positive association between BPA and SHBG. Conclusions Our results suggest that, in fertile men, exposure to low environmental levels of BPA may be associated with a modest reduction in markers of free testosterone, but any effects on reproductive function are likely to be small, and of uncertain clinical significance.

Prenatal Exposure to Mercury and Fish Consumption During Pregnancy and Attention-Deficit/Hyperactivity Disorder-Related Behavior in Children

OBJECTIVE To investigate the association of prenatal mercury exposure and fish intake with attention-deficit/hyperactivity disorder (ADHD)-related behavior. METHODS For a population-based prospective birth cohort recruited in New Bedford, Massachusetts (1993-1998), we analyzed data for children examined at age 8 years with peripartum maternal hair mercury measures (n = 421) or maternal report of fish consumption during pregnancy (n = 515). Inattentive and impulsive/hyperactive behaviors were assessed using a teacher rating scale and neuropsychological testing. RESULTS The median maternal hair mercury level was 0.45 μg/g (range, 0.03-5.14 μg/g), and 52% of mothers consumed more than 2 fish servings weekly. In multivariable regression models, mercury exposure was associated with inattention and impulsivity/hyperactivity; some outcomes had an apparent threshold with associations at 1 μg/g or greater of mercury. For example, at 1 μg/g or greater, the adjusted risk ratios for mild/markedly atypical inattentive and impulsive/hyperactive behaviors were 1.4 (95% CI, 1.0-1.8) and 1.7 (95% CI, 1.2-2.4), respectively, for an interquartile range (0.5 μg/g) mercury increase; there was no confounding by fish consumption. For neuropsychological assessments, mercury and behavior associations were detected primarily for boys. There was a protective association for fish consumption (>2 servings per week) with ADHD-related behaviors, particularly impulsive/hyperactive behaviors (relative risk = 0.4; 95% CI, 0.2-0.6). CONCLUSIONS Low-level prenatal mercury exposure is associated with a greater risk of ADHD-related behaviors, and fish consumption during pregnancy is protective of these behaviors. These findings underscore the difficulties of balancing the benefits of fish intake with the detriments of low-level mercury exposure in developing dietary recommendations in pregnancy.

Postnatal Exposure to Methyl Mercury from Fish Consumption: a Review and New Data from the Seychelles Child Development Study

BACKGROUND Fish is an important source of nutrition worldwide. Fish contain both the neurotoxin methyl mercury (MeHg) and nutrients important for brain development. The developing brain appears to be most sensitive to MeHg toxicity and mothers who consume fish during pregnancy expose their fetus prenatally. Although brain development is most dramatic during fetal life, it continues for years postnatally and additional exposure can occur when a mother breast feeds or the child consumes fish. This raises the possibility that MeHg might influence brain development after birth and thus adversely affect childrens developmental outcomes. We reviewed postnatal MeHg exposure and the associations that have been published to determine the issues associated with it and then carried out a series of analyses involving alternative metrics of postnatal MeHg exposure in the Seychelles Child Development Study (SCDS) Main Cohort. METHODS The SCDS is a prospective longitudinal evaluation of prenatal MeHg exposure from fish consumption. The Main Cohort includes 779 subjects on whom recent postnatal exposure data were collected at the 6-, 19-, 29-, 66-, and 107-month evaluations. We examined the association of recent postnatal MeHg exposure with multiple 66- and 107-month outcomes and then used three types of alternative postnatal exposure metrics to examine their association with the childrens intelligence quotient (IQ) at 107 months of age. RESULTS Recent postnatal exposure at 107 months of age was adversely associated with four endpoints, three in females only. One alternative postnatal metric was beneficially associated with 9-year IQ in males only. CONCLUSIONS We found several associations between postnatal MeHg biomarkers and childrens developmental endpoints. However, as has been the case with prenatal MeHg exposure in the SCDS Main Cohort study, no consistent pattern of associations emerged to support a causal relationship.

Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6-10 years of age.

Background: There is concern over potential neurobehavioral effects of prenatal phthalate exposures, but available data are inconsistent. Objectives: We examined associations between prenatal urinary concentrations of phthalate metabolites and neurobehavioral scores among children. Methods: We measured phthalate metabolite concentrations in urine samples from 153 pregnant participants in the Study for Future Families, a multicenter cohort study. Mothers completed the Child Behavior Checklist when the children were 6–10 years of age. We estimated overall and sex-specific associations between phthalate concentrations and behavior using adjusted multiple regression interaction models. Results: In boys, concentrations of monoisobutyl phthalate were associated with higher scores for inattention (β = 0.27; 95% CI: 0.04, 0.50), rule-breaking behavior (β = 0.20; 95% CI: 0.01, 0.38), aggression (β = 0.34; 95% CI: 0.09, 0.59), and conduct problems (β = 0.39; 95% CI: 0.20, 0.58), whereas the molar sum of di(2-ethylhexyl) phthalate metabolites was associated with higher scores for somatic problems (β = 0.15; 95% CI: 0.03, 0.28). Higher monobenzyl phthalate concentrations were associated with higher scores for oppositional behavior (β = 0.16; 95% CI: 0.01, 0.32) and conduct problems (β = 0.21; 95% CI: 0.06, 0.37) in boys, but with reduced anxiety scores in girls (β = –0.20; 95% CI: –0.39, –0.01). In general, the associations reported above were close to the null among girls. Model coefficients represent the difference in the square root–transformed outcome score associated with a 1-unit increase in log-transformed metabolites. Conclusions: Our results suggest associations between exposure to certain phthalates in late pregnancy and behavioral problems in boys. Given the few studies on this topic and methodological and population differences among studies, additional research is warranted. Citation: Kobrosly RW, Evans S, Miodovnik A, Barrett ES, Thurston SW, Calafat AM, Swan SH. 2014. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6–10 years of age. Environ Health Perspect 122:521–528; http://dx.doi.org/10.1289/ehp.1307063

Prenatal bisphenol A exposure and maternally reported behavior in boys and girls.

Prenatal exposure to gonadal hormones plays a major role in the normal development of the male and female brain and sexually dimorphic behaviors. Hormone-dependent differences in brain structure and function suggest that exposure to exogenous endocrine disrupting chemicals may be associated with sex-specific alterations in behavior. Bisphenol A (BPA) is an environmental chemical that has been shown to alter estrogen, androgen, and thyroid hormone signaling pathways. Epidemiological and experimental studies suggest associations between prenatal exposure to BPA and child behavior, however data are inconsistent, and few studies have examined school age children. We examined BPA concentration in spot urine samples from women at mean 27 weeks of pregnancy in relation to child behavior assessed at age 6-10 years using the parent-completed Child Behavior Checklist (CBCL). We report associations between maternal BPA urinary concentrations and several CBCL scores in 153 children (77 boys and 76 girls). We observed a significant interaction between maternal urinary BPA and sex for several behaviors (externalizing, aggression, Anxiety Disorder, Oppositional/Defiant Disorder and Conduct Disorder traits), but no significant associations between BPA and scores on any CBCL scales. However in analyses restricted to children of mothers with detectable prenatal urinary BPA (n=125), BPA was associated with moderately increased internalizing and externalizing behaviors, withdrawn/depressed behavior, somatic problems, and Oppositional/Defiant Disorder traits in boys. In addition we observed a significant interaction between BPA and sex for several behaviors (externalizing, withdrawn/depressed, rule-breaking, Oppositional/Defiant Disorder traits, and Conduct Disorder traits). These results suggest that prenatal exposure to BPA may be related to increased behavior problems in school age boys, but not girls.

Neuropsychological measures of attention and impulse control among 8-year-old children exposed prenatally to organochlorines.

Background: We previously reported associations between organochlorines and behaviors related to attention deficit hyperactivity disorder among boys and girls at 8 years of age using a teacher’s rating scale for a birth cohort in New Bedford, Massachusetts (USA). Objectives: Our goal was to corroborate these findings using neuropsychological measures of inattentive and impulsive behaviors. Methods: We investigated the association between cord serum polychlorinated biphenyls (PCBs) and p,p´-dichlorodiphenyl dichloroethylene (p,p´-DDE) and attention and impulse control using a Continuous Performance Test (CPT) and components of the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III). Participants came from a prospective cohort of children born during 1993–1998 to mothers residing near a PCB-contaminated harbor in New Bedford. Median (range) cord serum levels for the sum of four prevalent PCBs [congeners 118, 138, 153, and 180 (ΣPCB4)] and p,p´-DDE were 0.19 (0.01–2.59) and 0.31 (0–14.93) ng/g serum, respectively. Results: We detected associations between PCBs and neuropsychological deficits for 578 and 584 children with CPT and WISC-III measures, respectively, but only among boys. For example, boys with higher exposure to ΣPCB4 had a higher rate of CPT errors of omission [rate ratio for the exposure interquartile range (IQR) = 1.12; 95% confidence interval (CI): 0.98, 1.27] and slower WISC-III Processing Speed (change in score for the IQR = –2.0; 95% CI: –3.5, –0.4). Weaker associations were found for p,p´-DDE. For girls, associations were in the opposite direction for the CPT and null for the WISC-III. Conclusions: These results support an association between organochlorines (mainly PCBs) and neuropsychological measures of attention among boys only. Sex-specific effects should be considered in studies of organochlorines and neurodevelopment.

On fitting generalized linear mixed‐effects models for binary responses using different statistical packages

The generalized linear mixed-effects model (GLMM) is a popular paradigm to extend models for cross-sectional data to a longitudinal setting. When applied to modeling binary responses, different software packages and even different procedures within a package may give quite different results. In this report, we describe the statistical approaches that underlie these different procedures and discuss their strengths and weaknesses when applied to fit correlated binary responses. We then illustrate these considerations by applying these procedures implemented in some popular software packages to simulated and real study data. Our simulation results indicate a lack of reliability for most of the procedures considered, which carries significant implications for applying such popular software packages in practice.

Smoothing in occupational cohort studies: an illustration based on penalised splines

Aims: To illustrate the contribution of smoothing methods to modelling exposure-response data, Cox models with penalised splines were used to reanalyse lung cancer risk in a cohort of workers exposed to silica in California’s diatomaceous earth industry. To encourage application of this approach, computer code is provided. Methods: Relying on graphic plots of hazard ratios as smooth functions of exposure, the sensitivity of the curve to amount of smoothing, length of the exposure lag, and the influence of the highest exposures was evaluated. Trimming and data transformations were used to down-weight influential observations. Results: The estimated hazard ratio increased steeply with cumulative silica exposure before flattening and then declining over the sparser regions of exposure. The curve was sensitive to changes in degrees of freedom, but insensitive to the number or location of knots. As the length of lag increased, so did the maximum hazard ratio, but the shape was similar. Deleting the two highest exposed subjects eliminated the top half of the range and allowed the hazard ratio to continue to rise. The shape of the splines suggested a parametric model with log hazard as a linear function of log transformed exposure would fit well. Conclusions: This flexible statistical approach reduces the dependence on a priori assumptions, while pointing to a suitable parametric model if one exists. In the absence of an appropriate parametric form, however, splines can provide exposure-response information useful for aetiological research and public health intervention.