Immunotoxicity of Perfluorinated Alkylates: Calculation of Benchmark Doses Based on Serum Concentrations in Children

Background: Immune suppression may be a critical effect associated with exposure to perfluorinated compounds (PFCs), as indicated by recent data on vaccine antibody responses in children. Therefore, this information may be crucial when deciding on exposure limits. Methods: Results obtained from follow-up of a Faroese birth cohort were used. Serum-PFC concentrations were measured at age 5 years, and serum antibody concentrations against tetanus and diphtheria toxoids were obtained at age 7 years. Benchmark dose results were calculated in terms of serum concentrations for 431 children with complete data using linear and logarithmic curves, and sensitivity analyses were included to explore the impact of the low-dose curve shape. Results: Under different linear assumptions regarding dose-dependence of the effects, benchmark dose levels were about 1.3 ng/mL serum for perfluorooctane sulfonic acid and 0.3 ng/mL serum for perfluorooctanoic acid at a benchmark response of 5%. These results are below average serum concentrations reported in recent population studies. Even lower results were obtained using logarithmic dose–response curves. Assumption of no effect below the lowest observed dose resulted in higher benchmark dose results, as did a benchmark response of 10%. Conclusions:The benchmark dose results obtained are in accordance with recent data on toxicity in experimental models. When the results are converted to approximate exposure limits for drinking water, current limits appear to be several hundred fold too high. Current drinking water limits therefore need to be reconsidered

An estimating equations approach to fitting latent exposure models with longitudinal health outcomes

The analysis of data arising from environmental health studies which collect a large number of measures of exposure can benefit from using latent variable models to summarize exposure information. However, difficulties with estimation of model parameters may arise since existing fitting procedures for linear latent variable models require correctly specified residual variance structures for unbiased estimation of regression parameters quantifying the association between (latent) exposure and health outcomes. We propose an estimating equations approach for latent exposure models with longitudinal health outcomes which is robust to misspecification of the outcome variance. We show that compared to maximum likelihood, the loss of efficiency of the proposed method is relatively small when the model is correctly specified. The proposed equations formalize the ad-hoc regression on factor scores procedure, and generalize regression calibration. We propose two weighting schemes for the equations, and compare their efficiency. We apply this method to a study of the effects of in-utero lead exposure on child development.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS226 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Separation of Risks and Benefits of Seafood Intake

Background: Fish and seafood provide important nutrients but may also contain toxic contaminants, such as methylmercury. Advisories against pollutants may therefore conflict with dietary recommendations. In resolving this conundrum, most epidemiologic studies provide little guidance because they address either nutrient benefits or mercury toxicity, not both. Objectives: Impact on the same health outcomes by two exposures originating from the same food source provides a classical example of confounding. To explore the extent of this bias, we applied structural equation modeling to data from a prospective study of developmental methylmercury neurotoxicity in the Faroe Islands. Results: Adjustment for the benefits conferred by maternal fish intake during pregnancy resulted in an increased effect of the prenatal methylmercury exposure, as compared with the unadjusted results. The dietary questionnaire response is likely to be an imprecise proxy for the transfer of seafood nutrients to the fetus, and this imprecision may bias the confounder-adjusted mercury effect estimate. We explored the magnitude of this bias in sensitivity analysis assuming a range of error variances. At realistic imprecision levels, mercury-associated deficits increased by up to 2-fold when compared with the unadjusted effects. Conclusions: These results suggest that uncontrolled confounding from a beneficial parameter, and imprecision of this confounder, may cause substantial underestimation of the effects of a toxic exposure. The adverse effects of methylmercury exposure from fish and seafood are therefore likely to be underestimated by unadjusted results from observational studies, and the extent of this bias will be study dependent

Separation of Risks and Benefits of Seafood Intake

BACKGROUND: Fish and seafood provide important nutrients but may also contain toxic contaminants, such as methylmercury. Advisories against pollutants may therefore conflict with dietary recommendations. In resolving this conundrum, most epidemiologic studies provide little guidance because they address either nutrient benefits or mercury toxicity, not both. OBJECTIVES: Impact on the same health outcomes by two exposures originating from the same food source provides a classical example of confounding. To explore the extent of this bias, we applied structural equation modeling to data from a prospective study of developmental methylmercury neurotoxicity in the Faroe Islands. RESULTS: Adjustment for the benefits conferred by maternal fish intake during pregnancy resulted in an increased effect of the prenatal methylmercury exposure, as compared with the unadjusted results. The dietary questionnaire response is likely to be an imprecise proxy for the transfer of seafood nutrients to the fetus, and this imprecision may bias the confounder-adjusted mercury effect estimate. We explored the magnitude of this bias in sensitivity analysis assuming a range of error variances. At realistic imprecision levels, mercury-associated deficits increased by up to 2-fold when compared with the unadjusted effects. CONCLUSIONS: These results suggest that uncontrolled confounding from a beneficial parameter, and imprecision of this confounder, may cause substantial underestimation of the effects of a toxic exposure. The adverse effects of methylmercury exposure from fish and seafood are therefore likely to be underestimated by unadjusted results from observational studies, and the extent of this bias will be study dependent

Neurobehavioral deficits at age 7 years associated with prenatal exposure to toxicants from maternal seafood diet

To determine the possible neurotoxic impact of prenatal exposure to polychlorinated biphenyls (PCBs), we analyzed banked cord blood from a Faroese birth cohort for PCBs. The subjects were born in 1986–1987, and 917 cohort members had completed a series of neuropsychological tests at age 7 years. Major PCB congeners (118, 138, 153, and 180), the calculated total PCB concentration, and the PCB exposure estimated in a structural equation model showed weak associations with test deficits, with statistically significant negative associations only with the Boston Naming test. Likewise, neither hexachlorobenzene nor p,p'-dichlorodiphenyldichloroethylene showed clear links to neurobehavioral deficits. Thus, these associations were much weaker than those associated with the cord-blood mercury concentration, and adjustment for mercury substantially attenuated the regression coefficients for PCB exposure. When the outcomes were joined into motor and verbally mediated functions in a structural equation model, the PCB effects remained weak and virtually disappeared after adjustment for methylmercury exposure, while mercury remained statistically significant. Thus, in the presence of elevated methylmercury exposure, PCB neurotoxicity may be difficult to detect, and PCB exposure does not explain the methylmercury neurotoxicity previously reported in this cohort