Publications by authors named "Matthew P Longnecker"

131 Publications

Using quantitative modeling tools to assess pharmacokinetic bias in epidemiological studies showing associations between biomarkers and health outcomes at low exposures.

Environ Res 2021 Jun 20;197:111183. Epub 2021 Apr 20.

Ramboll US Consulting, Inc., Raleigh, NC, USA.

Biomarkers of exposure can be measured at lower and lower levels due to advances in analytical chemistry. Using these sensitive methods, some epidemiology studies report associations between biomarkers and health outcomes at biomarker levels much below those associated with effects in animal studies. While some of these low exposure associations may arise from increased sensitivity of humans compared with animals or from species-specific responses, toxicology studies with drugs, commodity chemicals and consumer products have not generally indicated significantly greater sensitivity of humans compared with test animals for most health outcomes. In some cases, these associations may be indicative of pharmacokinetic (PK) bias, i.e., a situation where a confounding factor or the health outcome itself alters pharmacokinetic processes affecting biomarker levels. Quantitative assessment of PK bias combines PK modeling and statistical methods describing outcomes across large numbers of individuals in simulated populations. Here, we first provide background on the types of PK models that can be used for assessing biomarker levels in human population and then outline a process for considering PK bias in studies intended to assess associations between biomarkers and health outcomes at low levels of exposure. After providing this background, we work through published examples where these PK methods have been applied with several chemicals/chemical classes - polychlorinated biphenyls (PCBs), perfluoroalkyl substances (PFAS), polybrominated biphenyl ethers (PBDE) and phthalates - to assess the possibility of PK bias. Studies of the health effects of low levels of exposure will be improved by developing some confidence that PK bias did not play significant roles in the observed associations.
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http://dx.doi.org/10.1016/j.envres.2021.111183DOI Listing
June 2021

Serum Concentration of Antibodies to Mumps, but Not Measles, Rubella, or Varicella, Is Associated with Intake of Dietary Fiber in the NHANES, 1999-2004.

Nutrients 2021 Mar 2;13(3). Epub 2021 Mar 2.

Ramboll U.S. Consulting, Inc., 3214 Charles B. Root Wynd, Suite 130, Raleigh, NC 27612, USA.

Treatment with prebiotics, a type of dietary fiber, was recently shown to increase antibody concentrations following influenza vaccination in a meta-analysis of clinical trials. In observational epidemiologic studies it is not possible to estimate intake of prebiotics, but quantifying intake of dietary fiber is routine. Our objective was to investigate the potential effect of dietary fiber on immunogenicity. We examined serum antibody concentrations (Measles, Mumps, Rubella, and Varicella) in relation to dietary fiber in more than 12,000 subjects in the U.S. National Health and Nutrition Examination Survey (NHANES) for the period 1999-2004. Data from one (1999-2002) or two (2003-2004) dietary recalls were used to calculate fiber intake. For Mumps the adjusted percentage difference in antibody concentration per interquartile range intake in energy-adjusted dietary fiber was 6.34% (95% confidence interval, 3.10, 9.68). Fiber from grain-based foods was more positively associated than fiber from other fiber-containing food groups. The association was slightly larger among subgroups with higher fiber intake, greater interquartile range in fiber intake, and less measurement error. Furthermore, based on the reliability of the diet recalls in 2003-2004, we calculated that the percentage difference per interquartile increment was substantially attenuated by measurement error. Dietary fiber may have a favorable influence on the immunogenicity of some vaccines or natural infections.
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http://dx.doi.org/10.3390/nu13030813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001807PMC
March 2021

Birth weight and perfluorooctane sulfonic acid: a random-effects meta-regression analysis.

Environ Epidemiol 2020 Jun 23;4(3):e095. Epub 2020 Apr 23.

Environment & Health, Ramboll, NC.

Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental contaminant. Most people in developed countries have detectable serum concentrations. Lower birth weight has been associated with serum PFOS in studies world-wide, many of which have been published only recently.

Methods: To facilitate a causal assessment of the birth weight and PFOS association, we updated previous meta-analyses of the association and employed a method that facilitated inclusion of all available data in one analysis. Our analysis was based on observations from 29 studies.

Results: The random effects summary was -3.22 g/ng/ml (95% confidence interval [CI] = -5.11, -1.33). In a subgroup analysis stratified by when in pregnancy the PFOS concentration was measured, the summary for the early group was -1.35 (95% CI = -2.33, -0.37) and for the later group was -7.17 (95% CI = -10.93, -3.41). In a meta-regression model including a term for timing of blood draw, the intercept was slightly positive but essentially zero (0.59 g/ng/ml, 95% CI = -1.94, 3.11). In other words, the model indicated that when blood was drawn at the very beginning of pregnancy, there was essentially no relation of birth weight to PFOS. The results from the subgroup analyses differed from those from the model because the average gestational age at blood draw in the early group was 14 weeks, when bias would still be expected. A stronger inverse association in Asian studies was not completely explained by their blood draws being from later in pregnancy.

Conclusions: The evidence was weakly or not supportive of a causal association.
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http://dx.doi.org/10.1097/EE9.0000000000000095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941775PMC
June 2020

The concentration of several perfluoroalkyl acids in serum appears to be reduced by dietary fiber.

Environ Int 2021 01 9;146:106292. Epub 2020 Dec 9.

Ramboll US Consulting, Inc., Raleigh, NC, USA.

Fiber-rich food intake has been associated with lower serum concentrations of perfluoroalkyl substances (PFAS) in some studies and dietary fiber was related to lower serum PFAS in a recent study. Given the previous epidemiologic data suggesting that fiber might decrease serum PFAS concentrations, we examined the relation of serum PFAS concentrations to intake of dietary fiber in National Health and Nutrition Examination Survey (NHANES) data. We examined the PFAS-fiber association among 6482 adults who participated in the NHANES, 2005-2016. Fiber intake was estimated based on two 24-hour diet recalls. We adjusted the models for determinants of PFAS and potentially confounding factors such as intake of foods reported to increase PFAS exposure. Results were expressed as the percent difference in PFAS concentration per interquartile range (IQR) increase in fiber (and 95 percent confidence interval), and the NHANES sampling parameters were used to make the results generalizable to the U.S. The adjusted percent difference in perfluorooctanoic acid (PFOA) per IQR increase in fiber was -3.64 (-6.15, -1.07); for perfluorooctane sulfonic acid (PFOS) was -6.69 (-9.57, -3.73), and for perfluorononanoic acid (PFNA) was -8.36 (-11.33, -5.29). These results suggest that dietary fiber increases the gastrointestinal excretion of PFOA, PFOS, and PFNA. Because fiber also lowers serum cholesterol, in some studies of the serum cholesterol-PFAS relationship confounding by fiber may be worth evaluating.
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http://dx.doi.org/10.1016/j.envint.2020.106292DOI Listing
January 2021

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

Environ Res 2020 12 14;191:110047. Epub 2020 Aug 14.

Erasmus MC, University Medical Center Rotterdam, Department of Child and Adolescent Psychiatry, Rotterdam, 3015 CN, the Netherlands; ISGlobal, Barcelona, 08003, Spain; Pompeu Fabra University, Barcelona, 08002, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, 28029, Spain. Electronic address:

Background: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years.

Method: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy.

Results: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations.

Conclusions: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.
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http://dx.doi.org/10.1016/j.envres.2020.110047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657967PMC
December 2020

Development of a physiologically based pharmacokinetic model of diisononyl phthalate (DiNP) in pregnant rat and human.

J Toxicol Environ Health A 2020 10 6;83(19-20):631-648. Epub 2020 Aug 6.

Health Sciences, Ramboll , Raleigh, NC, USA.

A physiologically based pharmacokinetic (PBPK) model for di-isononyl phthalate (DiNP) was developed by adapting the existing models for di(2-ethylhexyl) phthalate (DEHP) and di-butylphthalate (DBP). Both pregnant rat and human time-course plasma and urine data were used to address the hydrolysis of DiNP in intestinal tract, plasma, and liver as well as hepatic oxidative metabolism and conjugation of the monoester and primary oxidative metabolites. Data in both rats and humans were available to inform the uptake and disposition of mono-isononyl phthalate (MiNP) as well as the three primary oxidative metabolites including hydroxy (7-OH)-, oxo (7-OXO)-, and carboxy (7-COX)-monoisononyl phthalate in plasma and urine. The DiNP model was reliable over a wide range of exposure levels in the pregnant rat as well as the two low exposure levels in humans including capturing the nonlinear behavior in the pregnant rat after repeated 750 mg/kg/day dosing. The presented DiNP PBPK model in pregnant rat and human, based upon an extensive kinetic dataset in both species, may provide a basis for assessing human equivalent exposures based upon either rodent or points of departure.
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http://dx.doi.org/10.1080/15287394.2020.1798831DOI Listing
October 2020

Pharmacokinetic bias analysis of an association between clinical thyroid disease and two perfluoroalkyl substances.

Environ Int 2020 08 11;141:105784. Epub 2020 May 11.

Ramboll, Raleigh, NC, USA.

Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with the occurrence of thyroid disease in some epidemiologic studies. We hypothesized that in a specific epidemiologic study based on the National Health and Nutrition Examination Survey, the association of clinical thyroid disease with serum concentration of PFOA and PFOS was due to reverse causality. Thyroid hormone affects glomerular filtration, which in turn affects excretion of PFOA and PFOS. We evaluated this by linking a model of thyroid disease status over the lifetime to a physiologically based pharmacokinetic model of PFOA and PFOS. Using Monte Carlo methods, we simulated the target study population and analyzed the data using multivariable logistic regression. The target and simulated populations were similar with respect to age, estimated glomerular filtration rate, serum concentrations of PFOA and PFOS, and prevalence of clinical thyroid disease. The analysis showed little or no evidence of bias from the hypothesized mechanism. The largest bias was for the fourth quartile of PFOA in females, with an odds ratio of 0.93 (95% CI, 0.90, 0.97). The reported odds ratio of clinical thyroid disease for this group was 1.63 (1.07, 2.47), and if it were corrected for the bias would have been 1.74 (1.14, 2.65). Our results suggest that little of the reported association in the target study was due to reverse causality.
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http://dx.doi.org/10.1016/j.envint.2020.105784DOI Listing
August 2020

Neonatal thyroid-stimulating hormone and association with attention-deficit/hyperactivity disorder.

Paediatr Perinat Epidemiol 2020 09 18;34(5):590-596. Epub 2020 Feb 18.

Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.

Background: Normal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid-stimulating hormone (TSH) 48-72 hours after birth screens for congenital hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub-clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD).

Objectives: To estimate the association between neonatal TSH below threshold for potential congenital hypothyroidism and subsequent ADHD diagnosis using a population-based birth cohort.

Methods: Children with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD-10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003-2008) with available neonatal TSH concentrations below 10 mU/L (cut-off for potential congenital hypothyroidism) measured in dried blood spots sampled 48-72 hours after birth.

Results: In multivariable, quintile models the relationship appeared to follow a U-shaped pattern with elevated odds ratios (OR) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5-fold higher than children in the middle quintile (OR 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (P = 0.02; girls OR 3.10, 95% CI 1.53, 6.30; boys OR 1.16, 95% CI 0.73, 1.84).

Conclusions: ADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed.
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http://dx.doi.org/10.1111/ppe.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431377PMC
September 2020

Quantitative bias analysis of the association between subclinical thyroid disease and two perfluoroalkyl substances in a single study.

Environ Res 2020 03 9;182:109017. Epub 2019 Dec 9.

Ramboll, Raleigh, NC, USA.

Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with the occurrence of thyroid disease in some epidemiologic studies. We hypothesized that in a specific epidemiologic study based on the National Health and Nutrition Examination Survey, the association of subclinical thyroid disease with serum concentration of PFOA and PFOS was due to reverse causality. Thyroid hormone affects glomerular filtration, which in turn affects excretion of PFOA and PFOS. We evaluated this by linking a model of thyroid disease status over the lifetime to physiologically based pharmacokinetic models of PFOA and PFOS. Using Monte Carlo methods, we simulated the target study population and analyzed the data using multivariable logistic regression. The target and simulated populations were similar with respect to age, estimated glomerular filtration rate, serum concentrations of PFOA and PFOS, and prevalence of subclinical thyroid disease. Our findings suggest that in the target study the associations with subclinical hypothyroidism were overstated and the results for subclinical hyperthyroidism were, in general, understated. For example, for subclinical hypothyroidism in men, the reported odds ratio per ln(PFOS) increase was 1.98 (95% CI 1.19-3.28), whereas in the simulated data the bias due to reverse causality gave an odds ratio of 1.19 (1.16-1.23). Our results provide evidence of bias due to reverse causality in a specific cross-sectional study of subclinical thyroid disease with exposure to PFOA and PFOS among adults.
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http://dx.doi.org/10.1016/j.envres.2019.109017DOI Listing
March 2020

Organophosphate pesticide metabolite concentrations in urine during pregnancy and offspring attention-deficit hyperactivity disorder and autistic traits.

Environ Int 2019 10 29;131:105002. Epub 2019 Jul 29.

Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, USA. Electronic address:

Background: Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings.

Objective: The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands.

Method: Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18-25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders.

Results: Median DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18-25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected.

Conclusions: In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.
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http://dx.doi.org/10.1016/j.envint.2019.105002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939991PMC
October 2019

A model of functional thyroid disease status over the lifetime.

PLoS One 2019 18;14(7):e0219769. Epub 2019 Jul 18.

Ramboll, Research Triangle Park, North Carolina, United States of America.

Mathematical models of the natural history of disease can predict incidence rates based on prevalence data and support simulations of populations where thyroid function affects other aspects of physiology. We developed a Markov chain model of functional thyroid disease status over the lifetime. Subjects were in one of seven thyroid disease states at any given point in their lives [normal, subclinical hypothyroidism, overt hypothyroidism, treated thyroid disease (ever), subclinical hyperthyroidism, overt hyperthyroidism, and reverted to normal thyroid status]. We used a Bayesian approach to fitting model parameters. A priori probabilities of changing from each disease state to another per unit time were based on published data and summarized using meta-analysis, when possible. The probabilities of changing state were fitted to observed prevalence data based on the National Health and Nutrition Examination Survey 2007-2012. The fitted model provided a satisfactory fit to the observed prevalence data for each disease state, by sex and decade of age. For example, for males 50-59 years old, the observed prevalence of ever having treated thyroid disease was 4.4% and the predicted value was 4.6%. Comparing the incidence rates of treated disease predicted from our model with published values revealed that 82% were within a 4-fold difference. The differences seemed to be systematic and were consistent with expectation based on national iodine intakes. The model provided new and comprehensive estimates of functional thyroid disease incidence rates for the U.S. Because the model provides a reasonable fit to national prevalence data and predicts thyroid disease status over the lifetime, it is suitable for simulating populations, thereby making possible quantitative bias analyses of selected epidemiologic data reporting an association of thyroid disease with serum concentrations of environmental contaminants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638952PMC
March 2020

Organophosphate Pesticide Metabolite Concentrations in Urine during Pregnancy and Offspring Nonverbal IQ at Age 6 Years.

Environ Health Perspect 2019 01;127(1):17007

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services, Durham, North Carolina, USA.

Background: Susceptibility to organophosphate (OP) pesticide neurotoxicity may be greatest during the prenatal period; however, previous studies have produced mixed findings concerning OP pesticide exposure and child cognition.

Objectives: Our objective was to determine whether maternal urinary concentrations of OP pesticide metabolites are inversely associated with child nonverbal IQ at 6 y of age and to examine potential effect measure modification by the gene.

Methods: Data came from 708 mother–child pairs participating in the Generation R Study. Maternal urine concentrations of six dialkylphosphates (DAPs), collected at [Formula: see text], 18–25, and [Formula: see text] of gestation, were determined. Child nonverbal IQ was measured at 6 y of age using the Mosaics and Categories subtests from the Snijders-Oomen Nonverbal Intelligence Test-Revised. was determined in cord blood for 474 infants. Multiple linear regression models were fit to estimate the DAP-IQ associations and interactions.

Results: Overall, associations between child nonverbal IQ and maternal DAP concentrations were small and imprecise, and these associations were inconsistent across urine sampling periods. Howover, for a 10-fold difference in total DAP concentration for the [Formula: see text] of gestation samples, adjusted child nonverbal IQ was 3.9 points lower (95% CI: [Formula: see text], [Formula: see text]). Heterogeneity in the DAP–IQ association by gene allele status was not observed ([Formula: see text]).

Conclusions: Consistent evidence of an association between higher maternal urinary DAP concentrations and lower child IQ scores at 6 y of age was not observed. There was some evidence for an inverse relation of child nonverbal IQ and late pregnancy urinary DAPs, but the estimated association was imprecise. https://doi.org/10.1289/EHP3024.
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http://dx.doi.org/10.1289/EHP3024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381821PMC
January 2019

Maternal Thyroid Function During Pregnancy or Neonatal Thyroid Function and Attention Deficit Hyperactivity Disorder: A Systematic Review.

Epidemiology 2019 01;30(1):130-144

From the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits.

Methods: We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018.

Results: We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD.

Conclusions: The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in the measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing nonlinear dose-responses.
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http://dx.doi.org/10.1097/EDE.0000000000000937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359926PMC
January 2019

Household fuel use and biomarkers of inflammation and respiratory illness among rural South African Women.

Environ Res 2018 10 6;166:112-116. Epub 2018 Jun 6.

Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health in San Antonio, San Antonio, TX, USA; Southwest Center for Occupational and Environmental Health, UTHealth School of Public Health, Houston, TX, USA. Electronic address:

Though literature suggests a positive association between use of biomass fuel for cooking and inflammation, few studies among women in rural South Africa exist. We included 415 women from the South African Study of Women and Babies (SOWB), recruited from 2010 to 2011. We obtained demographics, general medical history and usual source of cooking fuel (wood, electricity) via baseline questionnaire. A nurse obtained height, weight, blood pressure, and blood samples. We measured plasma concentrations of a suite of inflammatory markers (e.g., interleukins, tumor necrosis factor-α, C-reactive protein). We assessed associations between cooking fuel and biomarkers of inflammation and respiratory symptoms/illness using crude and adjusted linear and logistic regression models. We found little evidence of an association between fuel-use and biomarkers of inflammation, pre-hypertension/hypertension, or respiratory illnesses. Though imprecise, we found 41% (95% confidence interval (CI) = 0.72-2.77) higher odds of self-reported wheezing/chest tightness among wood-users compared with electricity-users. Though studies among other populations report positive findings between biomass fuel use and inflammation, it is possible that women in the present study experience lower exposures to household air pollution given the cleaner burning nature of wood compared with other biomass fuels (e.g., coal, dung).
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http://dx.doi.org/10.1016/j.envres.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110960PMC
October 2018

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian Mother and Child Cohort (MoBa study).

Environ Res 2018 10 4;166:78-85. Epub 2018 Jun 4.

National Institute for Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, NC, USA.

Introduction: Perfluoroalkyl substances (PFASs) are fluorinated organic compounds that have been used in a variety of industrial and consumer applications. Menstruation is implicated as a possible route of elimination for PFASs in women. The overall purpose of this study was to examine menstrual cycle characteristics as determinants of plasma PFAS concentrations in women.

Methods: Our study sample consisted of 1977 pregnant women from the Norwegian Mother and Child Cohort (MoBa) study. The women were asked about menstrual cycle regularity in the year before the pregnancy and typical menstrual cycle length as well as other demographic and reproductive characteristics in a questionnaire completed during the pregnancy. Blood samples were collected around 17-18 weeks gestation and PFAS concentrations were measured in plasma. We examined the association between menstrual cycle characteristics and seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)) using multiple linear regression, adjusted for age, pre-pregnancy body mass index, smoking, education, income, parity, oral contraceptive use, inter-pregnancy interval, and breastfeeding duration.

Results: Irregular cycles were not associated with PFAS concentrations. Overall, we found no evidence of associations between menstrual cycle length and PFAS concentrations. In subgroup analyses we found some evidence, among parous women, of decreased PFHpS and PFOS with short menstrual cycles; we also found, among recent OC users (in the 12 months before the questionnaire) increased PFNA and PFUnDA with long cycle length. Limitations of our study include misclassification of menstrual cycle characteristics, small sample sizes in the sub-group analyses, and a lack of information on duration and volume of menses.

Conclusions: In the entire study sample, we found little evidence of menstrual cycle characteristics as determinants of PFAS concentrations. However, we observed some associations between cycle length and PFAS concentrations with some select PFAS compounds in subgroup analyses.
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http://dx.doi.org/10.1016/j.envres.2018.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174531PMC
October 2018

Secondary outcome analysis for data from an outcome-dependent sampling design.

Stat Med 2018 07 22;37(15):2321-2337. Epub 2018 Apr 22.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Outcome-dependent sampling (ODS) scheme is a cost-effective way to conduct a study. For a study with continuous primary outcome, an ODS scheme can be implemented where the expensive exposure is only measured on a simple random sample and supplemental samples selected from 2 tails of the primary outcome variable. With the tremendous cost invested in collecting the primary exposure information, investigators often would like to use the available data to study the relationship between a secondary outcome and the obtained exposure variable. This is referred as secondary analysis. Secondary analysis in ODS designs can be tricky, as the ODS sample is not a random sample from the general population. In this article, we use the inverse probability weighted and augmented inverse probability weighted estimating equations to analyze the secondary outcome for data obtained from the ODS design. We do not make any parametric assumptions on the primary and secondary outcome and only specify the form of the regression mean models, thus allow an arbitrary error distribution. Our approach is robust to second- and higher-order moment misspecification. It also leads to more precise estimates of the parameters by effectively using all the available participants. Through simulation studies, we show that the proposed estimator is consistent and asymptotically normal. Data from the Collaborative Perinatal Project are analyzed to illustrate our method.
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http://dx.doi.org/10.1002/sim.7672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130921PMC
July 2018

Placental Weight and Risk of Cryptorchidism and Hypospadias in the Collaborative Perinatal Project.

Am J Epidemiol 2018 07;187(7):1354-1361

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.
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http://dx.doi.org/10.1093/aje/kwy005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030958PMC
July 2018

Determinants of organophosphate pesticide exposure in pregnant women: A population-based cohort study in the Netherlands.

Int J Hyg Environ Health 2018 04 3;221(3):489-501. Epub 2018 Feb 3.

Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands. Electronic address:

Background: In the Netherlands organophosphate (OP) pesticides are frequently used for pest control in agricultural settings. Despite concerns about the potential health impacts of low-level OP pesticides exposure, particularly in vulnerable populations, the primary sources of exposure remain unclear. The present study was designed to investigate the levels of DAP metabolites concentrations across pregnancy and to examine various determinants of DAP metabolite concentrations among an urban population of women in the Netherlands.

Method: Urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined at <18, 18-25, and >25 weeks of pregnancy in 784 pregnant women participating in the Generation R Study (between 2004 and 2006), a large population-based birth cohort in Rotterdam, the Netherlands. Questionnaires administered prenatally assessed demographic and lifestyle characteristics and maternal diet. Linear mixed models, with adjustment for relevant covariates, were used to estimate associations between the potential exposure determinants and DAP metabolite concentrations expressed as molar concentrations divided by creatinine levels.

Results: The median DAP metabolite concentration was 311 nmol/g creatinine for the first trimester, 317 nmol/g creatinine for the second trimester, and 310 nmol/g creatinine for the third trimester. Higher maternal age, married/living with a partner, underweight or normal weight (BMI of <18.5 and 18.5-<25), high education, high income, and non-smoking were associated with higher DAP metabolite concentrations, and DAP metabolite concentrations tended to be higher during the summer. Furthermore, fruit intake was associated with increased DAP metabolite concentrations. Each 100 g/d difference in fruit consumption was associated with a 7% higher total DAP metabolite concentration across pregnancy. Other food groups were not associated with higher DAP metabolite concentrations.

Conclusions: The DAP metabolite concentrations measured in the urine of pregnant women in the Netherlands were higher than those in most other studies previously conducted. Fruit intake was the main dietary source of exposure to OP pesticides in young urban women in the Netherlands. The extent to which DAP metabolite concentrations reflect exposure to the active parent pesticide rather than to less toxic metabolites remains unclear. Further research will be undertaken to investigate the possible effects of this relatively high level OP pesticides exposure on offspring health.
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http://dx.doi.org/10.1016/j.ijheh.2018.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046212PMC
April 2018

Excretion of Di-2-ethylhexyl phthalate (DEHP) metabolites in urine is related to body mass index because of higher energy intake in the overweight and obese.

Environ Int 2018 04 6;113:91-99. Epub 2018 Feb 6.

Ramboll Environ, Research Triangle Park, NC 27709, USA.

A higher body mass index (BMI) has been positively associated with the rate of excretion of di-2-ethylhexyl phthalate (DEHP) metabolites in urine in data from the National Health and Nutrition Examination Survey (NHANES), suggesting an association between DEHP exposure and BMI. The association, however, may be due to the association between body mass maintenance and higher energy intake, with higher energy intake being accompanied by a higher intake of DEHP. To examine this hypothesis, we ran a Monte Carlo simulation with a DEHP physiologically-based pharmacokinetic (PBPK) model for adult humans. A realistic exposure sub-model was used, which included the relation of body weight to energy intake and of energy intake to DEHP intake. The model simulation output, when compared with urinary metabolite data from NHANES, supported good model validity. The distribution of BMI in the simulated population closely resembled that in the NHANES population. This indicated that the simulated subjects and DEHP exposure model were closely aligned with the NHANES population of interest. In the simulated population, the ordinary least squares regression coefficient for log(BMI) as a function of log(DEHP nmol/min) was 0.048 (SE 0.001), as compared with the reported value of 0.019 (SE 0.005). In other words, given our model structure, the higher energy intake in the overweight and obese, and the concomitant higher DEHP exposure, describes the reported relationship between BMI and DEHP.
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http://dx.doi.org/10.1016/j.envint.2018.01.023DOI Listing
April 2018

Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study.

Environ Int 2018 03 20;112:156-164. Epub 2017 Dec 20.

Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, School of Public Health in San Antonio, San Antonio, TX, USA; Southwest Center for Occupational and Environmental Health, The University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA. Electronic address:

Objective: Because oral contraceptives (OC) tends to lessen menstrual fluid loss - a route of excretion for perfluoroalkyl substances (PFASs) - we hypothesized that such use would be positively associated with PFAS concentrations.

Methods: This analysis was based on the Norwegian Mother and Child Cohort (MoBa) study. We included 1090 women from two previous substudies of women enrolled from 2003 to 2007. Characteristics of OC use were obtained at baseline: use in the past 12months, duration and recency of use, age at first use. We examined log-transformed plasma concentrations of seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)). Linear regression analyses, adjusted for maternal age, menstrual cycle length, parity, and education, were used to examine whether OC use characteristics were determinants of PFAS concentrations.

Results: Except for PFDA and PFUnDA, women who used OCs in the 12months preceding the baseline interview had 12.9-35.7% higher PFAS concentrations than never OC users. To a lesser extent, past OC use was positively associated with PFASs (estimates ranged from 7.2-32.1%). Compared with never users, using OCs for 10 or more years was associated with increased PFAS concentrations, except for PFDA and PFUnDA (estimates for other PFASs ranged from 18.9-46.2%). We observed little effect of age at first OC use.

Conclusions: This analysis shows that characteristics of OC use, and duration of use in particular, may be important considerations when investigating relationships between women's reproductive outcomes and PFASs.
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http://dx.doi.org/10.1016/j.envint.2017.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899038PMC
March 2018

In utero exposure to DDT and incidence of diarrhea among boys from tropical Mexico.

Environ Res 2017 11 18;159:331-337. Epub 2017 Sep 18.

Epidemiology Branch, National Institute of Environmental Health Sciences, NIH/DHHS/USA, Research Triangle Park, NC 27709, USA.

Background: A higher incidence rate (IR) of acute gastrointestinal (GI) infections associated with prenatal exposure to p,p'-DDE was suggested by the results in two studies. Given the high mortality rate due to childhood diarrhea in some countries with ongoing use of DDT, additional data on this association is relevant for those making decisions about vector-borne disease control.

Objective: To evaluate whether higher levels of prenatal exposure to p,p'-DDE and p,p'-DDT increase the risk of having diarrhea in a birth cohort of boys from tropical Mexico.

Methods: Our analysis was based on 747 boys whose exposure was measured in maternal serum collected at delivery (2002-2003). Mothers reported the number of diarrhea episodes of their children during in-person interviews. The median age of the children at their last interview was 21.4 months. Poisson regression models were fitted to estimate adjusted incidence rate ratios (aIRR) of diarrhea by levels of p,p'-DDE and p,p'-DDT.

Results: Overall, there were 1.7 episodes of diarrhea per child-year. Among those in the highest category of exposure (> 9µg DDE/g serum lipid), the aIRR for diarrhea was 1.14 (95% CI: 0.94, 1.30) compared to those in the lowest category of exposure (≤ 3µg/g). Among boys living in the urban area, the corresponding aIRR was 1.39 (95% CI: 1.07-1.80). Among rural boys, no associations emerged.

Conclusion: Although the results were consistent with a small positive association, the overall estimate was not precise. While urban boys in this study appeared to be more susceptible to DDE-associated diarrhea, a ready explanation for such increased susceptibility was not apparent.
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http://dx.doi.org/10.1016/j.envres.2017.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623652PMC
November 2017

Quantitative bias analysis of a reported association between perfluoroalkyl substances (PFAS) and endometriosis: The influence of oral contraceptive use.

Environ Int 2017 07 6;104:118-121. Epub 2017 Apr 6.

Department of Occupational and Environmental Health, Université de Montréal, 2375 chemin de la Cote-Sainte-Catherine, Montreal, QC H3T 1A8, Canada; Universite de Montreal Public Health Research Institute (IRSPUM), Université de Montréal, 7101, Parc Ave., Montreal, QC H3N 1X7, Canada. Electronic address:

An association between serum levels of perfluoroalkyl substances (PFAS) and endometriosis has recently been reported in an epidemiologic study. Oral contraceptive use to treat dysmenorrhea (pelvic pain associated with endometriosis) could potentially influence this association by reducing menstrual fluid loss, a route of excretion for PFAS. In this study, we aimed to evaluate the influence of differential oral contraceptive use on the association between PFAS and endometriosis. We used a published life-stage physiologically based pharmacokinetic (PBPK) model to simulate plasma levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from birth to age at study participation (range 18-44years). In the simulated population, PFAS level distributions matched those for controls in the epidemiologic study. Prevalence and geometric mean duration (standard deviation [SD]) of oral contraceptive use in the simulated women were based on data from the National Health and Nutrition Examination Survey; among the women with endometriosis the values were, respectively, 29% and 6.8 (3.1) years; among those without endometriosis these values were 18% and 5.3 (2.8) years. In simulations, menstrual fluid loss (ml/cycle) in women taking oral contraceptives was assumed to be 56% of loss in non-users. We evaluated the association between simulated plasma PFAS concentration and endometriosis in the simulated population using logistic regression. Based on the simulations, the association between PFAS levels and endometriosis attributable to differential contraceptive use had an odds ratio (95% CI) of 1.05 (1.02, 1.07) for a log unit increase in PFOA and 1.03 (1.02, 1.05) for PFOS. In comparison, the epidemiologic study reported odds ratios of 1.62 (0.99, 2.66) for PFOA and 1.25 (0.87, 1.80) for PFOS. Our results suggest that the influence of oral contraceptive use on the association between PFAS levels and endometriosis is relatively small.
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http://dx.doi.org/10.1016/j.envint.2017.03.023DOI Listing
July 2017

Effects of Sample Handling and Analytical Procedures on Thyroid Hormone Concentrations in Pregnant Women's Plasma.

Epidemiology 2017 05;28(3):365-369

From the aNorwegian Institute of Public Health, Mental and Physical Health, Oslo, Norway; bDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC; cNational Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC; dBiology Department, University of Massachusetts-Amherst, Amherst, MA; and eDivision of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Background: Maternal thyroid function is a critical mediator of fetal brain development. Pregnancy-related physiologic changes and handling conditions of blood samples may influence thyroid hormone biomarkers. We investigated the reliability of thyroid hormone biomarkers in plasma of pregnant women under various handling conditions.

Methods: We enrolled 17 pregnant women; collected serum and plasma were immediately frozen. Additional plasma aliquots were subjected to different handling conditions before the analysis of thyroid biomarkers: storage at room temperature for 24 or 48 hours before freezing and an extra freeze-thaw cycle. We estimated free thyroid hormone indices in plasma based on T3 uptake.

Results: High correlations between plasma and serum (>0.94) and intraclass correlation coefficients for plasma handling conditions (0.96 to 1.00) indicated excellent reliability for all thyroid hormone biomarkers.

Conclusion: Delayed freezing and freeze-thaw cycles did not affect reliability of biomarkers of thyroid function in plasma during pregnancy. See video abstract at, http://links.lww.com/EDE/B180.
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http://dx.doi.org/10.1097/EDE.0000000000000606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378640PMC
May 2017

Statistical inferences for data from studies conducted with an aggregated multivariate outcome-dependent sample design.

Stat Med 2017 03 14;36(6):985-997. Epub 2016 Dec 14.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, U.S.A.

Outcome-dependent sampling (ODS) scheme is a cost-effective sampling scheme where one observes the exposure with a probability that depends on the outcome. The well-known such design is the case-control design for binary response, the case-cohort design for the failure time data, and the general ODS design for a continuous response. While substantial work has been carried out for the univariate response case, statistical inference and design for the ODS with multivariate cases remain under-developed. Motivated by the need in biological studies for taking the advantage of the available responses for subjects in a cluster, we propose a multivariate outcome-dependent sampling (multivariate-ODS) design that is based on a general selection of the continuous responses within a cluster. The proposed inference procedure for the multivariate-ODS design is semiparametric where all the underlying distributions of covariates are modeled nonparametrically using the empirical likelihood methods. We show that the proposed estimator is consistent and developed the asymptotically normality properties. Simulation studies show that the proposed estimator is more efficient than the estimator obtained using only the simple-random-sample portion of the multivariate-ODS or the estimator from a simple random sample with the same sample size. The multivariate-ODS design together with the proposed estimator provides an approach to further improve study efficiency for a given fixed study budget. We illustrate the proposed design and estimator with an analysis of association of polychlorinated biphenyl exposure to hearing loss in children born to the Collaborative Perinatal Study. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291804PMC
March 2017

Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause.

Environ Int 2017 Feb 5;99:245-254. Epub 2016 Dec 5.

RAMBOLL ENVIRON, RTP, NC, USA. Electronic address:

An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported (Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42-51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26-1.40), whereas the reported OR was 1.4 (95% CI 1.1-1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.
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http://dx.doi.org/10.1016/j.envint.2016.11.030DOI Listing
February 2017

Pharmacokinetic bias analysis of the epidemiological associations between serum polybrominated diphenyl ether (BDE-47) and timing of menarche.

Environ Res 2016 10 16;150:541-548. Epub 2016 Jul 16.

Ramboll Environ, Research Triangle Park, NC, USA.

Background: Associations between serum levels of polybrominated diphenyl ether (PBDE) and timing of pubertal development in adolescent girls (e.g., menarche) have been reported in both a cross-sectional and in a longitudinal study. The associations may be biased by growth dilution and pharmacokinetic changes during pubertal development.

Objectives: To use a physiologically-based pharmacokinetic (PBPK) model to assess how much of the epidemiologic association between PBDE and altered timing of menarche might be attributable to growth dilution and pubertal maturation.

Methods: We developed a PBPK model of BDE-47, a major congener of PBDE, to perform Monte Carlo (MC) simulation of plasma BDE-47 levels in a hypothetical target population aged 2 to 22 years old. The model used realistic distributions of physiological parameters including timing of growth spurts and menarche. The simulated data were analyzed as if they had come from an epidemiologic study. We compared the results based on the simulated population to those reported.

Results: The population characteristics, including age and body mass index (BMI) were similar between the simulated and reported groups. In the cross-sectional study design, the association between proportion of subjects with menarche before age 12 years and BDE-47 serum concentration was inverse in our simulated population, whereas the reported association was positive. In the longitudinal study design, simulated data were not suggestive of an association, whereas a delay in pubertal onset with higher concentrations of BDE-47 was observed in the epidemiologic study.

Conclusion: Results of our simulation suggest that in the previous cross-sectional study there was a small negative bias due to pharmacokinetics in the reported relationship between BDE-47 and age at menarche. However, in the longitudinal study there was little evidence of bias. Our study showed how PBPK modeling can be used to quantify the potential bias in epidemiological studies and also suggested that further studies on the optimal approach to modeling exposure are warranted to better understand and quantify the potential bias in the epidemiological associations with BDE-47 due to pharmacokinetics.
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http://dx.doi.org/10.1016/j.envres.2016.07.004DOI Listing
October 2016

Brief Report: Plasma Concentrations of Perfluorooctane Sulfonamide and Time-to-pregnancy Among Primiparous Women.

Epidemiology 2016 09;27(5):712-5

From the aDepartment of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health at Houston, San Antonio Regional Campus, San Antonio, TX; bSouthwest Center for Occupational and Environmental Health, The University of Texas School of Public Health at Houston, Houston, TX; cNorwegian Institute of Public Health, Oslo, Norway; dDepartment of Health and Human Services, National Institute for Environmental Health Sciences, National Institutes of Health, Durham NC.

Background: A previous study reported a negative association between perfluorooctane sulfonamide (PFOSA) concentrations and fecundability.

Methods: We examined this association among women enrolled in the Norwegian Mother and Child Cohort Study (MoBa), in 2003-2004. This analysis was restricted to 451 primiparous women to avoid bias due to previous pregnancy. Self-reported time-to-pregnancy (TTP) and plasma were obtained around 18 weeks of gestation. Approximately half of the women had measurable PFOSA levels; missing values were multiply imputed. We used the logistic analogue of discrete-time survival analysis to examine the adjusted association between PFOSA, other perfluoroalkyl substances, and TTP.

Results: The median-measured PFOSA concentration was 0.03 ng/ml (interquartile range = 0.02, 0.07). The age and body mass index-adjusted association between an interquartile distance increase in PFOSA and TTP was 0.91 (95% confidence interval = 0.71, 1.17). Imputation of missing PFOSA resulted in similar estimates. No association was observed with other perfluoroalkyl substances.

Conclusion: Based on a weakly decreased fecundability odds ratio, we found only limited support for an association between plasma PFOSA concentrations and TTP among primiparous women. See Video Abstract at http://links.lww.com/EDE/B79.
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http://dx.doi.org/10.1097/EDE.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387409PMC
September 2016