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

Heritability of Tpeak-Tend interval and T-wave amplitude: a twin study

Background— Tpeak-Tend interval (TpTe) and T-wave amplitude (Tamp) carry diagnostic and prognostic information regarding cardiac morbidity and mortality. Heart rate and QT interval are known to be heritable traits. The heritability of T-wave morphology parameters such as TpTe and Tamp is unknown. TpTe and Tamp were evaluated in a large sample of twins. Methods and Results— Twins from the GEMINAKAR study (611 pairs, 246 monozygotic, 365 dizygotic; mean age, 38±11 years; 49% men) who had an ECG performed during 1997 to 2000 were included. Tamp was measured in leads V1 and V5. Duration variables (RR interval, QTpeak and QTend interval) were measured and averaged over 3 consecutive beats in lead V5. TpTe was calculated as the QTend- and QTpeak-interval difference. Heritability was assessed using structural equation models adjusting for age, sex, and body mass index. All models were reducible to a model of additive genetics and unique environment. All variables had considerable genetic components. Adjusted heritability estimates were as follows: TpTe, 46%; Tamp lead V1, 34%; Tamp lead V5, 47%; RR interval, 55%; QT interval, 67%; and Bazett-corrected QT interval, 42%. Conclusions— RR interval, QT interval, Tamp, and TpTe interval are heritable ECG parameters. </jats:sec

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

Underestimation of risk due to exposure misclassification

Exposure misclassification constitutes a major obstacle when developing dose-response relationships for risk assessment. A non-differentional error results in underestimation of the risk. If the degree of misclassification is known, adjustment may be achieved by sensitivity analysis. The purpose of this study was to examine the full magnitude of measurement error in determining the prenatal exposure to methylmercury. We used data from a prospective study of a Faroese birth cohort. Two biomarkers of methylmercury exposure were available, i.e., the mercury concentrations in cord blood and in maternal hair (sampled at the time of parturition). The laboratory imprecision on both chemical analyses was thought to be below 5% coefficient of variation (CV). As a third exposure parameter, we used the dietary questionnaire response on frequency of whale meat dinners. Factor analysis and structural equation analysis were applied to assess the full extent of the imprecision. The calculated total imprecision much exceeded the known laboratory variation: the CV was 28-30% for the cord-blood concentration and 52-55% for the maternal hair concentration. The dietary questionnaire response was even more imprecise. These findings illustrate that measurement error may be greatly underestimated if judged solely from reproducibility or laboratory quality data. Adjustment by sensitivity analysis is meaningful only if realistic measurement errors are applied. When exposure measurement errors are overlooked or underestimated, decisions based on the precautionary principle will not appropriately reflect the degree of precaution that was intended