To allow for non-linear exposure-response relationships, we applied flexible non-parametric smoothing techniques to models of time to lung cancer mortality in two occupational cohorts with skewed exposure distributions. We focused on three different smoothing techniques in Cox models: penalized splines, restricted cubic splines, and fractional polynomials. We compared standard software implementations of these three methods based on their visual representation and criterion for model selection. We propose a measure of the difference between a pair of curves based on the area between them, standardized by the average of the areas under the pair of curves. To capture the variation in the difference over the range of exposure, the area between curves was also calculated at percentiles of exposure and expressed as a percentage of the total difference. The dose-response curves from the three methods were similar in both studies over the denser portion of the exposure range, with the difference between curves up to the 50th percentile less than 1 per cent of the total difference. A comparison of inverse variance weighted areas applied to the data set with a more skewed exposure distribution allowed us to estimate area differences with more precision by reducing the proportion attributed to the upper 1 per cent tail region. Overall, the penalized spline and the restricted cubic spline were closer to each other than either was to the fractional polynomial.

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 gm of fish (9 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 children's 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.

No abstract

Organochlorines are environmentally persistent contaminants that readily cross the placenta, posing a potential risk to the developing fetus. Evidence for neurodevelopmental effects at low levels of these compounds is growing, though few studies have focused on behavioral outcomes. The authors investigated the association between prenatal polychlorinated biphenyl (PCB) and p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) levels and behaviors associated with attention deficit hyperactivity disorder (ADHD), measured with the Conners' Rating Scale for Teachers (CRS-T), in a cohort of 607 children aged 7-11 years (median age, 8.2 years) born in 1993-1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. The median umbilical cord serum level of the sum of 4 prevalent PCB congeners (118, 138, 153, and 180) was 0.19 ng/g serum (range, 0.01-4.41 ng/g serum). The authors found higher risk for ADHD-like behaviors assessed with the CRS-T at higher levels of PCBs and p,p'-DDE. For example, the authors found higher risk of atypical behavior on the Conners' ADHD Index for the highest quartile of the sum of 4 PCB congeners versus the lowest quartile (risk ratio = 1.76, 95% confidence interval: 1.06, 2.92) and a similar relation for p,p'-DDE. These results support an association between low-level prenatal organochlorine exposure and ADHD-like behaviors in childhood.

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.