Tracey J. Woodruff

Standardizing benchmark dose calculations to improve science-based decisions in human health assessments

Background: Benchmark dose (BMD) modeling computes the dose associated with a prespecified response level. While offering advantages over traditional points of departure (PODs), such as no-observed-adverse-effect-levels (NOAELs), BMD methods have lacked consistency and transparency in application, interpretation, and reporting in human health assessments of chemicals. Objectives: We aimed to apply a standardized process for conducting BMD modeling to reduce inconsistencies in model fitting and selection. Methods: We evaluated 880 dose–response data sets for 352 environmental chemicals with existing human health assessments. We calculated benchmark doses and their lower limits [10% extra risk, or change in the mean equal to 1 SD (BMD/L10/1SD)] for each chemical in a standardized way with prespecified criteria for model fit acceptance. We identified study design features associated with acceptable model fits. Results: We derived values for 255 (72%) of the chemicals. Batch-calculated BMD/L10/1SD values were significantly and highly correlated (R2 of 0.95 and 0.83, respectively, n = 42) with PODs previously used in human health assessments, with values similar to reported NOAELs. Specifically, the median ratio of BMDs10/1SD:NOAELs was 1.96, and the median ratio of BMDLs10/1SD:NOAELs was 0.89. We also observed a significant trend of increasing model viability with increasing number of dose groups. Conclusions: BMD/L10/1SD values can be calculated in a standardized way for use in health assessments on a large number of chemicals and critical effects. This facilitates the exploration of health effects across multiple studies of a given chemical or, when chemicals need to be compared, providing greater transparency and efficiency than current approaches. Citation: Wignall JA, Shapiro AJ, Wright FA, Woodruff TJ, Chiu WA, Guyton KZ, Rusyn I. 2014. Standardizing benchmark dose calculations to improve science-based decisions in human health assessments. Environ Health Perspect 122:499–505; http://dx.doi.org/10.1289/ehp.1307539

Environmental Chemicals in Pregnant Women in the United States: NHANES 2003–2004

Background Exposure to chemicals during fetal development can increase the risk of adverse health effects, and while biomonitoring studies suggest pregnant women are exposed to chemicals, little is known about the extent of multiple chemicals exposures among pregnant women in the United States. Objective We analyzed biomonitoring data from the National Health and Nutritional Examination Survey (NHANES) to characterize both individual and multiple chemical exposures in U.S. pregnant women. Methods We analyzed data for 163 chemical analytes in 12 chemical classes for subsamples of 268 pregnant women from NHANES 2003–2004, a nationally representative sample of the U.S. population. For each chemical analyte, we calculated descriptive statistics. We calculated the number of chemicals detected within the following chemical classes: polybrominated diphenyl ethers (PBDEs), perfluorinated compounds (PFCs), organochlorine pesticides, and phthalates and across multiple chemical classes. We compared chemical analyte concentrations for pregnant and nonpregnant women using least-squares geometric means, adjusting for demographic and physiological covariates. Results The percentage of pregnant women with detectable levels of an individual chemical ranged from 0 to 100%. Certain polychlorinated biphenyls, organochlorine pesticides, PFCs, phenols, PBDEs, phthalates, polycyclic aromatic hydrocarbons, and perchlorate were detected in 99–100% of pregnant women. The median number of detected chemicals by chemical class ranged from 4 of 12 PFCs to 9 of 13 phthalates. Across chemical classes, median number ranged from 8 of 17 chemical analytes to 50 of 71 chemical analytes. We found, generally, that levels in pregnant women were similar to or lower than levels in nonpregnant women; adjustment for covariates tended to increase levels in pregnant women compared with nonpregnant women. Conclusions Pregnant women in the U.S. are exposed to multiple chemicals. Further efforts are warranted to understand sources of exposure and implications for policy making.

Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing

OBJECTIVE To evaluate the possible role of endocrine-disrupting compounds (EDCs) on female reproductive disorders emphasizing developmental plasticity and the complexity of endocrine-dependent ontogeny of reproductive organs. Declining conception rates and the high incidence of female reproductive disruptions warrant evaluation of the impact of EDCs on female reproductive health. DESIGN Publications related to the contribution of EDCs to disorders of the ovary (aneuploidy, polycystic ovary syndrome, and altered cyclicity), uterus (endometriosis, uterine fibroids, fetal growth restriction, and pregnancy loss), breast (breast cancer, reduced duration of lactation), and pubertal timing were identified, reviewed, and summarized at a workshop. CONCLUSION(S) The data reviewed illustrate that EDCs contribute to numerous human female reproductive disorders and emphasize the sensitivity of early life-stage exposures. Many research gaps are identified that limit full understanding of the contribution of EDCs to female reproductive problems. Moreover, there is an urgent need to reduce the incidence of these reproductive disorders, which can be addressed by correlative studies on early life exposure and adult reproductive dysfunction together with tools to assess the specific exposures and methods to block their effects. This review of the EDC literature as it relates to female health provides an important platform on which womens health can be improved.

Environmental exposures and adverse pregnancy outcomes: a review of the science.

To better understand the science linking environmental contaminants exposures with adverse pregnancy outcomes, we reviewed the relevant epidemiologic literature. We searched PubMed (primarily 1995-2006) using the key word combinations for select environmental exposures and pregnancy outcomes. Environmental tobacco smoke is a risk factor for reduced birth weight and preterm delivery. Outdoor air pollution is associated with reduced term birth weight and preterm delivery. Suggestive evidence associates pesticides and polychlorinated biphenyls with decreased fetal growth and length of gestation. Stronger evidence, primarily occupational, links certain birth defects with exposure to organic solvents and chlorophenoxy herbicides. Evidence suggests dichlorodiphenyltrichloroethane and bisphenol-A could be associated with pregnancy loss. Exposures in utero can also increase the risk of developmental delays (ie, impaired neurological function), adult chronic illnesses (ie, heart disease, diabetes, cancer), and next generation effects (ie, reduced reproductive capacity). Further research, education, and improved public health policy are needed to reduce potentially adverse exposures.

Maternal exposure to particulate air pollution and term birth weight : a multi-country evaluation of effect and heterogeneity

Background: A growing body of evidence has associated maternal exposure to air pollution with adverse effects on fetal growth; however, the existing literature is inconsistent. Objectives: We aimed to quantify the association between maternal exposure to particulate air pollution and term birth weight and low birth weight (LBW) across 14 centers from 9 countries, and to explore the influence of site characteristics and exposure assessment methods on between-center heterogeneity in this association. Methods: Using a common analytical protocol, International Collaboration on Air Pollution and Pregnancy Outcomes (ICAPPO) centers generated effect estimates for term LBW and continuous birth weight associated with PM10 and PM2.5 (particulate matter ≤ 10 and 2.5 µm). We used meta-analysis to combine the estimates of effect across centers (~ 3 million births) and used meta-regression to evaluate the influence of center characteristics and exposure assessment methods on between-center heterogeneity in reported effect estimates. Results: In random-effects meta-analyses, term LBW was positively associated with a 10-μg/m3 increase in PM10 [odds ratio (OR) = 1.03; 95% CI: 1.01, 1.05] and PM2.5 (OR = 1.10; 95% CI: 1.03, 1.18) exposure during the entire pregnancy, adjusted for maternal socioeconomic status. A 10-μg/m3 increase in PM10 exposure was also negatively associated with term birth weight as a continuous outcome in the fully adjusted random-effects meta-analyses (–8.9 g; 95% CI: –13.2, –4.6 g). Meta-regressions revealed that centers with higher median PM2.5 levels and PM2.5:PM10 ratios, and centers that used a temporal exposure assessment (compared with spatiotemporal), tended to report stronger associations. Conclusion: Maternal exposure to particulate pollution was associated with LBW at term across study populations. We detected three site characteristics and aspects of exposure assessment methodology that appeared to contribute to the variation in associations reported by centers.

Temporal Trends in Phthalate Exposures: Findings from the National Health and Nutrition Examination Survey, 2001–2010

Background: Phthalates are ubiquitous environmental contaminants. Because of potential adverse effects on human health, butylbenzyl phthalate [BBzP; metabolite, monobenzyl phthalate (MBzP)], di-n-butyl phthalate [DnBP; metabolite, mono-n-butyl phthalate (MnBP)], and di(2-ethylhexyl) phthalate (DEHP) are being replaced by substitutes including other phthalates; however, little is known about consequent trends in population-level exposures. Objective: We examined temporal trends in urinary concentrations of phthalate metabolites in the general U.S. population and whether trends vary by sociodemographic characteristics. Methods: We combined data on 11 phthalate metabolites for 11,071 participants from five cycles of the National Health and Nutrition Examination Survey (2001–2010). Percent changes and least square geometric means (LSGMs) were calculated from multivariate regression models. Results: LSGM concentrations of monoethyl phthalate, MnBP, MBzP, and ΣDEHP metabolites decreased between 2001–2002 and 2009–2010 [percent change (95% CI): –42% (–49, –34); –17% (–23, –9); –32% (–39, –23) and –37% (–46, –26), respectively]. In contrast, LSGM concentrations of monoisobutyl phthalate, mono(3-carboxypropyl) phthalate (MCPP), monocarboxyoctyl phthalate, and monocarboxynonyl phthalate (MCNP) increased over the study period [percent change (95% CI): 206% (178, 236); 25% (8, 45); 149% (102, 207); and 15% (1, 30), respectively]. Trends varied by subpopulations for certain phthalates. For example, LSGM concentrations of ΣDEHP metabolites, MCPP, and MCNP were higher in children than adults, but the gap between groups narrowed over time (pinteraction < 0.01). Conclusions: Exposure of the U.S. population to phthalates has changed in the last decade. Data gaps make it difficult to explain trends, but legislative activity and advocacy campaigns by nongovernmental organizations may play a role in changing trends. Citation: Zota AZ, Calafat AM, Woodruff TJ. 2014. Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001–2010. Environ Health Perspect 122:235–241; http://dx.doi.org/10.1289/ehp.1306681

Dose-Response Relationship of Prenatal Mercury Exposure and IQ: An Integrative Analysis of Epidemiologic Data

Background Prenatal exposure to mercury has been associated with adverse childhood neurologic outcomes in epidemiologic studies. Dose–response information for this relationship is useful for estimating benefits of reduced mercury exposure. Objectives We estimated a dose–response relationship between maternal mercury body burden and subsequent childhood decrements in intelligence quotient (IQ), using a Bayesian hierarchical model to integrate data from three epidemiologic studies. Methods Inputs to the model consist of dose–response coefficients from studies conducted in the Faroe Islands, New Zealand, and the Seychelles Islands. IQ coefficients were available from previous work for the latter two studies, and a coefficient for the Faroe Islands study was estimated from three IQ subtests. Other tests of cognition/achievement were included in the hierarchical model to obtain more accurate estimates of study-to-study and end point–to–end point variability. Results We find a central estimate of −0.18 IQ points (95% confidence interval, −0.378 to −0.009) for each parts per million increase of maternal hair mercury, similar to the estimates for both the Faroe Islands and Seychelles studies, and lower in magnitude than the estimate for the New Zealand study. Sensitivity analyses produce similar results, with the IQ coefficient central estimate ranging from −0.13 to −0.25. Conclusions IQ is a useful end point for estimating neurodevelopmental effects, but may not fully represent cognitive deficits associated with mercury exposure, and does not represent deficits related to attention and motor skills. Nevertheless, the integrated IQ coefficient provides a more robust description of the dose–response relationship for prenatal mercury exposure and cognitive functioning than results of any single study.

Meeting Report: Atmospheric Pollution and Human Reproduction

Background There is a growing body of epidemiologic literature reporting associations between atmospheric pollutants and reproductive outcomes, particularly birth weight and gestational duration. Objectives The objectives of our international workshop were to discuss the current evidence, to identify the strengths and weaknesses of published epidemiologic studies, and to suggest future directions for research. Discussion Participants identified promising exposure assessment tools, including exposure models with fine spatial and temporal resolution that take into account time–activity patterns. More knowledge on factors correlated with exposure to air pollution, such as other environmental pollutants with similar temporal variations, and assessment of nutritional factors possibly influencing birth outcomes would help evaluate importance of residual confounding. Participants proposed a list of points to report in future publications on this topic to facilitate research syntheses. Nested case–control studies analyzed using two-phase statistical techniques and development of cohorts with extensive information on pregnancy behaviors and biological samples are promising study designs. Issues related to the identification of critical exposure windows and potential biological mechanisms through which air pollutants may lead to intrauterine growth restriction and premature birth were reviewed. Conclusions To make progress, this research field needs input from toxicology, exposure assessment, and clinical research, especially to aid in the identification and exposure assessment of feto-toxic agents in ambient air, in the development of early markers of adverse reproductive outcomes, and of relevant biological pathways. In particular, additional research using animal models would help better delineate the biological mechanisms underpinning the associations reported in human studies.

Estimated daily phthalate exposures in a population of mothers of male infants exhibiting reduced anogenital distance.

Phthalate diesters have been shown to be developmental and reproductive toxicants in animal studies. A recent epidemiologic study showed certain phthalates to be significantly associated with reduced anogenital distance in human male infants, the first evidence of subtle developmental effects in human male infants exposed prenatally to phthalates. We used two previously published methods to estimate the daily phthalate exposures for the four phthalates whose urinary metabolites were statistically significantly associated with developmental effects in the 214 mother–infant pairs [di-n-butyl phthalate (DnBP), diethyl phthalate (DEP), butylbenzyl phthalate (BBzP), diisobutyl phthalate (DiBP)] and for another important phthalate [di-2-ethylhexyl phthalate (DEHP)]. We estimated the median and 95th percentile of daily exposures to DBP to be 0.99 and 2.68 μg/kg/day, respectively; for DEP, 6.64 and 112.3 μg/kg/day; for BBzP, 0.50 and 2.47 μg/kg/day; and for DEHP, 1.32 and 9.32 μg/kg/day. The U.S. Environmental Protection Agency (EPA) reference doses for these chemicals are 100 (DBP), 800 (DEP), 200 (BBzP), and 20 (DEHP) μg/kg/day. The median and 95th percentile exposure estimates for the phthalates associated with reduced anogenital distance in the study population are substantially lower than current U.S. EPA reference doses for these chemicals and could be informative to any updates of the hazard assessments and risk assessments for these chemicals.

Methodological issues in studies of air pollution and reproductive health

In the past decade there have been an increasing number of scientific studies describing possible effects of air pollution on perinatal health. These papers have mostly focused on commonly monitored air pollutants, primarily ozone (O(3)), particulate matter (PM), sulfur dioxide (SO(2)), carbon monoxide (CO), and nitrogen dioxide (NO(2)), and various indices of perinatal health, including fetal growth, pregnancy duration, and infant mortality. While most published studies have found some marker of air pollution related to some types of perinatal outcomes, variability exists in the nature of the pollutants and outcomes associated. Synthesis of the findings has been difficult for various reasons, including differences in study design and analysis. A workshop was held in September 2007 to discuss methodological differences in the published studies as a basis for understanding differences in study findings and to identify priorities for future research, including novel approaches for existing data. Four broad topic areas were considered: confounding and effect modification, spatial and temporal exposure variations, vulnerable windows of exposure, and multiple pollutants. Here we present a synopsis of the methodological issues and challenges in each area and make recommendations for future study. Two key recommendations include: (1) parallel analyses of existing data sets using a standardized methodological approach to disentangle true differences in associations from methodological differences among studies; and (2) identification of animal studies to inform important mechanistic research gaps. This work is of critical public health importance because of widespread exposure and because perinatal outcomes are important markers of future child and adult health.