Search

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.

PURPOSE OF REVIEW: Although vulnerable populations are disproportionately exposed to synthetic chemicals with endocrine disrupting properties, few recent reviews have summarized the impact of synthetic chemicals on cardiometabolic health among these groups. RECENT FINDINGS: Of 37 eligible epidemiological studies among vulnerable populations published between January 2018 and April 2019 in which over half were prospective, the most investigated populations were pregnant women and children. Racial/ethnic minorities, individuals of low socioeconomic status (SES), and those occupationally-exposed were studied the least. The most studied persistent organic pollutants (POPs) were per-/poly-fluoroalkyl substances (PFAS), and the most studied non-POPs were phenols. Across chemical classes, studies found certain POPs (e.g., PFAS) and non-POPs (i.e., phenols, phthalates, and parabens) to be associated with gestational diabetes and dysregulated glucose metabolism. Results for other cardiometabolic health outcomes were inconsistent but suggested certain chemicals may negatively affect cardiometabolic health. SUMMARY: Synthetic chemicals likely adversely affect cardiometabolic health, but current findings were inconclusive. Few recent studies focused on racial/ethnic minorities, low SES, and occupationally-exposed populations. To address poor cardiometabolic health and related disparities, more studies across vulnerable populations are warranted.

The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 μg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used globally at high volumes, primarily in the epoxy resin of circuit boards. It has been detected in the environment and in humans. The National Toxicology Program found that chronic oral TBBPA treatment of 250 mg/kg and higher caused an increased incidence of uterine lesions in female Wistar Han rats. The present laboratory has previously reported changes in gene expression associated with estrogen homeostasis in liver and uterine tissue of adult female Wistar Han rats after five days of gavage with 250 mg/kg of TBBPA. Microarray analysis of tissue from these same TBBPA-treated rats was performed to detect additional pathways perturbed by TBBPA. Microarray analysis of uterine tissue detected downregulation of genes in pathways of the immune response following TBBPA treatment. These results, along with validation of associated gene expression changes using droplet digital PCR, are reported here. Our findings suggest mechanisms that may be related to estrogen-mediated immunosuppression.

Background: In 2014, we conducted a longitudinal study [Anniston Community Health Survey (ACHS II)] 8 y after the baseline (ACHS I). Objectives: We investigated the relationship between persistent chlorinated compounds and hypertension in residents living around the former polychlorinated biphenyl (PCB) production plant in Anniston, Alabama. We also examined the potential role of inflammatory cytokines in those with hypertension. Methods: A total of 338 participants had their blood pressure measured and medications recorded, gave a blood sample, and completed a questionnaire. Prevalent hypertension was defined as taking antihypertensive medication or having systolic blood pressure >140 mmHg and/or diastolic pressure >90 mmHg; incident hypertension used similar criteria in those who developed hypertension since the baseline in 2005–2007. PCB congeners were categorized into structure–activity groups, and toxic equivalencies (TEQs) were calculated for dioxin-like compounds. Descriptive statistics, logistic and linear regressions, as well as Cox proportional hazard models, were used to analyze the associations between exposures and hypertension. Results: Prevalent hypertension (78%) in ACHS II showed statistically significant adjusted odds ratios (ORs) for PCBs 74, 99, 138, 153, 167, 177, 183, and 187, ranging from 2.18 [95% confidence interval (CI): 1.10, 4.33] to 2.76 (95% CI: 1.14, 6.73), as well as for two estrogenic-like PCB groups, and the thyroid-like group [ORs ranging from 2.25 (95% CI: 1.07, 4.75) to 2.54 (95% CI: 1.13, 5.74)]. Furthermore, analysis of quartiles demonstrated a monotonic relationship for dioxin-like non-ortho (non-o)-PCB TEQs [fourth vs. first quartile: 3.66 (95% CI: 1.40, 9.56)]. Longitudinal analyses of incident hypertension supported those positive associations. The results were strongest for the di-o-PCBs [hazard ratio (HR)=1.93 (95% CI: 0.93, 4.00)] and estrogenic II PCB group [HR=1.90 (95% CI: 0.96, 3.78)] but were weaker for the dioxin TEQs. Discussion: Findings supportive of positive associations were reported for dioxin-like mono-o- and non-o-PCBs as well as for nondioxin-like estrogenic and thyroid-like congeners with prevalent and incident hypertension, suggesting that multiple pathways may be involved in hypertension development. https://doi.org/10.1289/EHP5272

BACKGROUND: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals.OBJECTIVES: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease-Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden-both current and projected.METHODS: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment.DISCUSSION: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure-risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD's current methods do not fully account for lead's impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk-outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD's estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496.

2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%–94% in 24 h; 5% was recovered in feces; and 1%–2% in blood/tissues. TBP administered to female SD rats (0.1–1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%–27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.

2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB; MW 549.92 g/mol; CAS 183658-27-7) is a brominated component of flame retardant mixtures used as substitutes for some PBDEs. EH-TBB is added to various consumer products, including polyurethane foams, and has been detected in humans. The present study characterized the fate of EH-TBB in rodents. [14C]-labeled EH-TBB was absorbed, metabolized, and eliminated via the urine and feces following single administrations of 0.1–100 µmol/kg (∼0.05–55 mg/kg) or repeated administration (0.1 µmol/kg/day × 5–10 days) by gavage to female Hsd:Sprague DawleySD (SD) rats. Cumulative excretion via feces increased (39–60%) with dose (0.1–10 µmol/kg) with corresponding decreases in urinary excretion (54 to 37%) after 72 h. Delayed excretion of [14C]-radioactivity in urine and feces of a 100 µmol/kg oral dose was noted. Recovery was complete for all doses by 72 h. IV-injected rats excreted more of the 0.1 µmol/kg dose in urine and less in feces than did gavaged rats, indicating partial biliary elimination of systemically available compound. No tissue bioaccumulation was found for rats given 5 oral daily doses of EH-TBB. Parent molecule was not detected in urine whereas 2 metabolites, tetrabromobenzoic acid (TBBA), a TBBA-sulfate conjugate, and a TBBA-glycine conjugate were identified. EH-TBB and TBBA were identified in extracts from feces. Data from gavaged male B6C3F1/Tac mice indicated minimal sex- or species differences are likely for the disposition of EH-TBB. Approximately 85% of a 0.1 µmol/kg dose was absorbed from the gut. Overall absorption of EH-TBB is expected to be even greater at lower levels.

Background: Exposure to inorganic and organic arsenic compounds is a major public health problem that affects hundreds of millions of people worldwide. Exposure to arsenic is associated with cancer and noncancer effects in nearly every organ in the body, and evidence is mounting for health effects at lower levels of arsenic exposure than previously thought. Building from a tremendous knowledge base with > 1,000 scientific papers published annually with “arsenic” in the title, the question becomes, what questions would best drive future research directions? Objectives: The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines. Methods: The National Institutes of Health’s National Institute of Environmental Health Sciences Superfund Research Program convened a workshop to identify emerging issues and research needs to address the multi-faceted challenges related to arsenic and environmental health. This review summarizes information captured during the workshop. Discussion: More information about aggregate exposure to arsenic is needed, including the amount and forms of arsenic found in foods. New strategies for mitigating arsenic exposures and related health effects range from engineered filtering systems to phytogenetics and nutritional interventions. Furthermore, integration of omics data with mechanistic and epidemiological data is a key step toward the goal of linking biomarkers of exposure and susceptibility to disease mechanisms and outcomes. Conclusions: Promising research strategies and technologies for arsenic exposure and adverse health effect mitigation are being pursued, and future research is moving toward deeper collaborations and integration of information across disciplines to address data gaps. Citation: Carlin DJ, Naujokas MF, Bradham KD, Cowden J, Heacock M, Henry HF, Lee JS, Thomas DJ, Thompson C, Tokar EJ, Waalkes MP, Birnbaum LS, Suk WA. 2016. Arsenic and environmental health: state of the science and future research opportunities. Environ Health Perspect 124:890–899; http://dx.doi.org/10.1289/ehp.1510209

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30 kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)—the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4–39 years old and in Subcohort B, the 18 women were 3–17 years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20 years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations. Keywords: PBPK, Pharmacokinetics, Dioxin, TCDD, Developmental

Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 hours following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.

The 2014 follow-up of the Anniston Community Health Survey (ACHS II) consisted of 338 surviving participants from the 2005–2007 baseline study (ACHS) who had previous polychlorinated biphenyl (PCB) measurements, were not pregnant, and were not institutionalized. Questionnaires and blood samples provided the demographic, personal history, and chemical concentration data of the Anniston residents. Approximately 51% of participants were African American, 72% were female, and the mean age was 63 years old. The objectives of this study were to provide an exposure assessment of dioxin-like chemicals in the ACHS II participants and compare the measurements with the general United States (U.S.) population via the National Health and Nutrition Examination Survey (NHANES). Stratified analyses revealed significantly higher average total dioxin toxic equivalencies (TEQs) among African Americans compared to Whites (33.1 vs. 19.2 pg/g lipid), and in females compared to males (29.8 vs. 17.0 pg/g lipid). When adjusting for age, sex, and race in linear regression, we found ACHS II participants to have significantly higher total dioxin TEQ than the general 2014 U.S. population that we estimated for using half-life and NHANES 2003/04 data (most recent NHANES individual samples data), by 16.7 pg/g lipid. Principal component analyses showed that non-ortho and mono-ortho PCBs were separated from the other dioxin-like chemicals among the Anniston residents, whereas the chemicals were all clustered together for estimated NHANES 2014. The concentrations of dioxin-like chemicals, especially non-ortho and mono-ortho PCBs, in Anniston residents who resided near the former PCB production plant were higher than those in the general U.S. population. Although data strongly supported this difference, these inferences are limited because NHANES 2013/14 data were unavailable and we used estimated NHANES 2014 levels that we imputed from NHANES 2003/04 data in conjunction with half-life values estimated from Milbrath et al., 2009.

An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer’s disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) using inductively coupled plasma sector field mass spectrometry. All metals, with exception of equivalent Pb levels, were lower in the VF, compared to FC. Within-subject comparisons demonstrated that VF levels were not representative of levels within brain tissue. The essential metals Cu, Fe, and Zn were found highest in both compartments. Cd, Hg, and V levels in the VF were below the limit of quantification. In AD cases, FC levels of Fe were higher and As and Cd were lower than levels in controls, while levels of As in the VF were higher. Parameter estimates for FC metal levels indicated an association of Braak stage and higher Fe levels and an association of Braak stage and lower As, Mn, and Zn levels. The data showed no evidence of an accumulation of nonessential metals within the AD brain and, with the exception of As, showed no significant shift in the ratio of FC to VF levels to indicate differential clearance.

Tetrabromobisphenol A (TBBPA) is currently the world’s highest production volume brominated flame retardant. Humans are frequently exposed to TBBPA by the dermal route. In the present study, a parallelogram approach was used to make predictions of internal dose in exposed humans. Human and rat skin samples received 100 nmol of TBBPA/cm2 skin and absorption and penetrance were determined using a flow-through in vitro system. TBBPA-derived [14C]-radioactivity was determined at 6 hour intervals in the media and at 24 hours post-dosing in the skin. The human skin and media contained an average of 3.4% and 0.2% of the total dose at the terminal time point, respectively, while the rat skin and media contained 9.3% and 3.5%, respectively. In the intact rat, 14% of a dermally-administered dose of ~100 nmol/cm2 remained in the skin at the dosing site, with an additional 8% reaching systemic circulation by 24 hours post-dosing. Relative absorption and penetrance was less (10% total) at 24 hours following dermal administration of a ten-fold higher dose (~1,000 nmol/cm2) to rats. However, by 72 hours, 70% of this dose was either absorbed into the dosing-site skin or had reached systemic circulation. It is clear from these results that TBBPA can be absorbed by the skin and dermal contact with TBBPA may represent a small but important route of exposure. Together, these in vitro data in human and rat skin and in vivo data from rats may be used to predict TBBPA absorption in humans following dermal exposure. Based on this parallelogram calculation, up to 6% of dermally applied TBBPA may be bioavailable to humans exposed to TBBPA.

This review summarizes the report entitled: Breast Cancer and the Environment: Prioritizing Prevention, highlights research gaps and the importance of focusing on early life exposures for breast development and breast cancer risk.

Background: In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent. Objective: To evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE)] with male pubertal onset. Methods: In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8–9 year old boys with measured OCPs were enrolled during 2003–2005 and were followed annually for eight years. We evaluated three measures of pubertal onset: testicular volume (TV) > 3 mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with physician-assessed pubertal onset. Results: In adjusted models, boys with higher HCB concentrations had later mean ages of TV > 3 mL and P2+ (but not G2+). Mean age at attaining TV > 3 mL was delayed 3.6 (95% CI: −2.6, 9.7), 7.9 (95% CI: 1.7, 14.0), and 4.7 months (95% CI: −1.4, 10.9) for HCB Q2, Q3, and Q4, respectively, compared to Q1 (trend p: 0.06). Boys with higher HCB concentrations reached P2+ 0.1 months earlier (95% CI: −5.8, 5.6) for Q2, 4.7 months later (95% CI: −1.0, 10.3) for Q3 and 4.6 months later (95% CI: −1.1, 10.3) for Q4 compared to Q1 (trend p: 0.04). There were no associations of serum β-HCH and p,p′-DDE concentrations with age of pubertal onset. Conclusion: Higher prepubertal serum HCB concentrations were associated with later age of gonadarche and pubarche. Keywords: β-HCH, HCB, Organochlorine pesticides, Male puberty, p,p′-DDE

Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women. Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999–2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty–income ratio, and models were stratified by menopause status. Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P < 0.001; parous vs. nulliparous POR = 2.0; 95% CI, 1.2–3.4), but in parous women, ANA did not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16–20 vs. 10–12 years POR = 3.0; 95% CI, 1.6–5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence. Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women. Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women. Cancer Epidemiol Biomarkers Prev; 23(11); 2492–502. ©2014 AACR.

© 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved. Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Summary Understanding and preventing adverse impacts from chemicals in the environment is fundamental to protecting public health, and chemical risk assessments are used to inform public health decisions in the United States and around the world. Traditional chemical risk assessments focus on health effects of environmental contaminants on a chemical-by-chemical basis, largely based on data from animal models using exposures that are typically higher than those experienced by humans. Results from environmental epidemiology studies sometimes show effects that are not observed in animal studies at human exposure levels that are lower than those used in animal studies. In addition, new approaches such as Toxicology in the 21st Century (Tox21) and exposure forecasting (ExpoCast) are generating mechanistic data that provide broad coverage of chemical space, chemical mixtures, and potential associated health outcomes, along with improved exposure estimates. It is becoming clear that risk assessments in the future will need to use the full range of available mechanistic, animal, and human data to integrate multiple types of data and to consider nontraditional health outcomes and end points. This perspective was developed at the “Strengthening the Scientific Basis of Chemical Safety Assessments” workshop, which was cosponsored by the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences, where gaps between the emerging science and traditional chemical risk assessments were explored, and approaches for bridging the gaps were considered.

Background: Indoor air pollution (IAP) derived largely from the use of solid fuels for cooking and heating affects about 3 billion people worldwide, resulting in substantial adverse health outcomes, including cancer. Women and children from developing countries are the most exposed populations. A workshop was held in Arlington, Virginia, 9–11 May 2011, to better understand women’s and children’s potential health effects from IAP in developing countries. Workshop participants included international scientists, manufacturers, policy and regulatory officials, community leaders, and advocates who held extensive discussions to help identify future research needs. Objectives: Our objective was to identify research opportunities regarding IAP and cancer, including research questions that could be incorporated into studies of interventions to reduce IAP exposure. In this commentary, we describe the state of the science in understanding IAP and its associations with cancer and suggest research opportunities for improving our understanding of the issues. Discussion: Opportunities for research on IAP and cancer include studies of the effect of IAP on cancers other than lung cancer; studies of genetic factors that modify susceptibility; studies to determine whether the effects of IAP are mediated via germline, somatic, and/or epigenetic changes; and studies of the effects of IAP exposure via dermal and/or oral routes. Conclusions: IAP from indoor coal use increases the risk of lung cancer. Installing chimneys can reduce risk, and some genotypes, including GSTM1-null, can increase risk. Additional research is needed regarding the effects of IAP on other cancers and the effects of different types of solid fuels, oral and dermal routes of IAP exposure, genetic and epigenetic mechanisms, and genetic susceptibility.

Background: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes could provide insight into mechanistic pathways. This is one of the first studies to assess genetic susceptibility to dioxins. Objectives: We evaluated whether common polymorphisms in genes affecting either molecular responses to dioxin exposure or pubertal onset influence the association between peripubertal serum dioxin concentration and male pubertal onset. Methods: In this prospective cohort of Russian adolescent boys (n = 392), we assessed gene–environment interactions for 337 tagging single-nucleotide polymorphisms (SNPs) from 46 candidate genes and two intergenic regions. Dioxins were measured in the boys’ serum at age 8–9 years. Pubertal onset was based on testicular volume and on genitalia staging. Statistical approaches for controlling for multiple testing were used, both with and without prescreening for marginal genetic associations. Results: After accounting for multiple testing, two tag SNPs in the glucocorticoid receptor (GR/NR3C1) gene and one in the estrogen receptor-α (ESR1) gene were significant (q < 0.2) modifiers of the association between peripubertal serum dioxin concentration and male pubertal onset defined by genitalia staging, although not by testicular volume. The results were sensitive to whether multiple comparison adjustment was applied to all gene–environment tests or only to those with marginal genetic associations. Conclusions: Common genetic polymorphisms in the glucocorticoid receptor and estrogen receptor-α genes may modify the association between peripubertal serum dioxin concentration and pubertal onset. Further studies are warranted to confirm these findings.

Background: Over the past 20 years, knowledge of the genome and its function has increased dramatically, but risk assessment methodologies using such knowledge have not advanced accordingly. Objective: This commentary describes a collaborative effort among several federal and state agencies to advance the next generation of risk assessment. The objective of the NexGen program is to begin to incorporate recent progress in molecular and systems biology into risk assessment practice. The ultimate success of this program will be based on the incorporation of new practices that facilitate faster, cheaper, and/or more accurate assessments of public health risks. Methods: We are developing prototype risk assessments that compare the results of traditional, data-rich risk assessments with insights gained from new types of molecular and systems biology data. In this manner, new approaches can be validated, traditional approaches improved, and the value of different types of new scientific information better understood. Discussion and Conclusions: We anticipate that these new approaches will have a variety of applications, such as assessment of new and existing chemicals in commerce and the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. Additionally, results of the effort are likely to spur further research and test methods development. Full implementation of new approaches is likely to take 10–20 years.

Environmental health science is the study of the impact of the environment on human health. This paper introduces basic topics in environmental health, including clean air, clean water, and healthful food, as well as a range of current issues and controversies in environmental health. Conceptual shifts in modern toxicology have changed the field. There is a new understanding of the effects of exposure to chemicals at low doses, and in combination, and the impact on human growth and development. Other emerging topics include the role of epigenetics, or changes in genes and gene expression that can be brought about by chemical exposure; environmental justice; and potential effects of engineered nanomaterials and climate change. We review the important implications for public health policy and recommend a broad environmental health research strategy aimed at protecting and improving human health.

Childhood and adolescent rates of obesity and overweight are continuing to increase in much of the world. Risk factors such as diet composition, excess caloric intake, decreased exercise, genetics, and the built environment are active areas of etiologic research. The obesogen hypothesis, which postulates that prenatal and perinatal chemical exposure can contribute to risk of childhood and adolescent obesity, remains relatively underexamined. This review surveys numerous classes of chemicals for which this hypothesis has been explored. We focus on human data where they exist and also discuss the findings of rodent and cell culture studies. Organochlorine chemicals as well as several classes of chemicals that are peroxisome proliferator-activated receptor agonists are identified as possible risk factors for obesity. Recommendations for future epidemiologic and experimental research on the chemical origins of obesity are also given.

Toxicologists and pathologists worldwide will benefit from a new, website-based, and completely searchable Nonneoplastic Lesion Atlas just released by the U.S. National Toxicology Program (NTP). The atlas is a much-needed resource with thousands of high-quality, zoomable images and diagnostic guidelines for each rodent lesion. Liver, gallbladder, nervous system, bone marrow, lower urinary tract and skin lesion images, and diagnostic strategies are available now. More organ and biological systems will be added with a total of 22 chapters planned for the completed project. The atlas will be used by the NTP and its many pathology partners to standardize lesion diagnosis, terminology, and the way lesions are recorded. The goal is to improve our understanding of nonneoplastic lesions and the consistency and accuracy of their diagnosis between pathologists and laboratories. The atlas is also a useful training tool for pathology residents and can be used to bolster any organization’s own lesion databases. Researchers have free access to this online resource at www.ntp.niehs.nih.gov/nnl.

Developmental effects of polybrominated diphenyl ethers (PBDEs) have been suspected due to their structural similarities to polychlorinated biphenyls (PCBs). This study evaluated neurobehavioral, hormonal, and reproductive effects in rat offspring perinatally exposed to a widely used pentabrominated commercial mixture, DE-71. Pregnant Long-Evans rats were exposed to 0, 1.7, 10.2, or 30.6 mg/kg/day DE-71 in corn oil by oral gavage from gestational day 6 to weaning. DE-71 did not alter maternal or male offspring body weights. However, female offspring were smaller compared with controls from postnatal days (PNDs) 35-60. Although several neurobehavioral endpoints were assessed, the only statistically significant behavioral finding was a dose-by-age interaction in the number of rears in an open-field test. Developmental exposure to DE-71 caused severe hypothyroxinemia in the dams and early postnatal offspring. DE-71 also affected anogenital distance and preputial separation in male pups. Body weight gain over time, reproductive tissue weights, and serum testosterone concentrations at PND 60 were not altered. Mammary gland development of female offspring was significantly affected at PND 21. Congener-specific analysis of PBDEs indicated accumulation in all tissues examined. Highest PBDE concentrations were found in fat including milk, whereas blood had the lowest concentrations on a wet weight basis. PBDE concentrations were comparable among various brain regions. Thus, perinatal exposure to DE-71 leads to accumulation of PBDE congeners in various tissues crossing blood-placenta and blood-brain barriers, causing subtle changes in some parameters of neurobehavior and dramatic changes in circulating thyroid hormone levels, as well as changes in both male and female reproductive endpoints. Some of these effects are similar to those seen with PCBs, and the persistence of these changes requires further investigation.

Background Results from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk. Objectives Because both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility. Methods We exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 μg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed. Results We found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression. Conclusions Our data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans.

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches. These approaches are considered in this article for their potential to be extrapolated for the identification and assessment of other sensitive populations. Recommendations as to future research needs and/or alternate methodological considerations are also made.

Background Increased fat intake is associated with obesity and may make obese individuals uniquely susceptible to the effects of lipophilic aryl hydrocarbon receptor (AHR) ligands. Objectives We investigated the consequences of high-fat diet (HFD) and AHR ligands on body composition, mammary development, and hepatic P450 expression. Methods Pregnant C57BL/6J (B6) and DBA/2J (D2) dams, respectively expressing high- or low-responsive AHR, were dosed at mid-gestation with TCDD. At parturition, mice were placed on an HFD or a low-fat diet (LFD). Body fat of progeny was measured before dosing with 7,12-dimethylbenz[a]anthracene (DMBA). Fasting blood glucose was measured, and liver and mammary glands were analyzed. Results Maternal TCDD exposure resulted in reduced litter size in D2 mice and, on HFD, reduced postpartum survival in B6 mice. In D2 mice, HFD increased body mass and fat in off-spring, induced precocious mammary gland development, and increased AHR expression compared with mice given an LFD. Maternal TCDD exposure increased hepatic Cyp1a1 and Cyp1b1 expression in offspring on both diets, but DMBA depressed Cyp1b1 expression only in mice fed an HFD. In D2 progeny, TCDD exposure decreased mammary terminal end bud size, and DMBA exposure decreased the number of terminal end buds. Only in D2 progeny fed HFD did perinatal TCDD increase blood glucose and the size of mammary fat pads, while decreasing both branch elongation and the number of terminal end buds. Conclusions We conclude that despite having a low-responsive AHR, D2 progeny fed a diet similar to that consumed by most people are susceptible to TCDD and DMBA exposure effects blood glucose levels, mammary differentiation, and hepatic Cyp1 expression.

Previous studies demonstrated that perinatal exposure to polybrominated diphenyl ethers (PBDEs), a major class of brominated flame retardants, may affect thyroid hormone (TH) concentrations by inducing hepatic uridinediphosphate-glucoronosyltransferases (UGTs). This study further examines effects of the commercial penta mixture, DE-71, on genes related to TH metabolism at different developmental time points in male rats. DE-71 is predominately composed of PBDE congeners 47, 99, 100, 153, 154 with low levels of brominated dioxin and dibenzofuran contaminants. Pregnant Long-Evans rats were orally administered 1.7 (low), 10.2 (mid), or 30.6 (high) mg/kg/day of DE-71 in corn oil from gestational day (GD) 6 to postnatal day (PND) 21. Serum and liver were collected from male pups at PND 4, 21, and 60. Total serum thyroxine (T(4)) decreased to 57% (mid) and 51% (high) on PND 4, and 46% (mid) dose and 25% (high) on PND 21. Cyp1a1, Cyp2b1/2, and Cyp3a1 enzyme and mRNA expression, regulated by aryl hydrocarbon receptor, constitutive androstane receptor, and pregnane xenobiotic receptor, respectively, increased in a dose-dependent manner. UGT-T(4) enzymatic activity significantly increased, whereas age and dose-dependent effects were observed for Ugt1a6, 1a7, and 2b mRNA. Sult1b1 mRNA expression increased, whereas that of transthyretin (Ttr) decreased as did both the deiodinase I (D1) enzyme activity and mRNA expression. Hepatic efflux transporters Mdr1 (multidrug resistance), Mrp2 (multidrug resistance-associated protein), and Mrp3 and influx transporter Oatp1a4 mRNA expression increased. In this study the most sensitive responses to PBDEs following DE-71 exposure were CYP2B and D1 activities and Cyb2b1/2, d1, Mdr1, Mrp2, and Mrp3 gene expression. All responses were reversible by PND 60. In conclusion, deiodination, active transport, and sulfation, in addition to glucuronidation, may be involved in disruption of TH homeostasis due to perinatal exposure to DE-71 in male rat offspring.

Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M1dG, 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, DNA adducts after single dose or 1-year exposure to polyhalogenated aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M1dG adducts was explored initially in female mice exposed to a single dose of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M1dG adducts compared to the corn oil control group. The role of M1dG adducts in polychlorinated biphenyl (PCB)-induced toxicity and carcinogenicity was further investigated in rats exposed for a year to PCB 153, PCB 126, or a mixture of the two. PCB 153, at doses up to 3000 microg/kg/day, had no significant effect on the number of M1dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/day of PCB 126 resulted in M1dG adduct accumulation in the liver. More importantly, coadministration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M1dG adduct accumulation in the liver from 300 to 1000 ng/kg/day of PCB 126 with 300-1000 microg/kg/day of PCB 153. Interestingly, the coadministration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M1dG adduct accumulation with higher doses of PCB 153. These results are consistent with the results from cancer bioassays that demonstrated a synergistic effect between PCB 126 and PCB 153 on toxicity and tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.

Objective In this systematic review we evaluated the evidence on the association between dioxin exposure and cardiovascular disease (CVD) mortality in humans. Data sources and extraction We conducted a PubMed search in December 2007 and considered all English-language epidemiologic studies and their citations regarding dioxin exposure and CVD mortality. To focus on dioxins, we excluded cohorts that were either primarily exposed to polychlorinated biphenyls or from the leather and perfume industries, which include other cardiotoxic coexposures. Data synthesis We included results from 12 cohorts in the review. Ten cohorts were occupationally exposed. We divided analyses according to two well-recognized criteria of epidemiologic study quality: the accuracy of the exposure assessment, and whether the exposed population was compared with an internal or an external (e.g., general population) reference group. Analyses using internal comparisons with accurate exposure assessments are the highest quality because they minimize both exposure misclassification and confounding due to workers being healthier than the general population (“healthy worker effect”). The studies in the highest-quality group found consistent and significant dose-related increases in ischemic heart disease (IHD) mortality and more modest associations with all-CVD mortality. Their primary limitation was a lack of adjustment for potential confounding by the major risk factors for CVD. Conclusions The results of this systematic review suggest that dioxin exposure is associated with mortality from both IHD and all CVD, although more strongly with the former. However, it is not possible to determine the potential bias, if any, from confounding by other risk factors for CVD.

The toxic equivalency factor (TEF) approach was employed to compare immunotoxic potency of mixtures containing polychlorinated dibenzo- p -dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls relative to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), using the antibody response to sheep erythrocytes (SRBC). Mixture-1 (MIX-1) contained TCDD, 1,2,3,7,8-pentachlorodibenzo- p -dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,6,7,8,9-octachlorodibenzofuran (OCDF). Mixture-2 (MIX-2) contained MIX-1 and the following PCBs, 3,3′,4,4′-tetrachlorobiphenyl (IUPAC No. 77), 3,3′,4,4′,5-pentachlorobiphenyl (126), 3,3′,4,4′,5,5 N -hexachlorobiphenyl (169), 2,3,3′,4,4′-pentachlorobiphenyl (105), 2,3′,4,4′,5-pentachlorobiphenyl (118), and 2,3,3′,4,4′,5-hexachlorobiphenyl (156). The mixture compositions were based on relative chemical concentrations in food and human tissues. TCDD equivalents (TEQ) of the mixture were estimated using relative potency factors from hepatic enzyme induction in mice [DeVito, M.J., Diliberto, J.J., Ross, D.G., Menache, M.G., Birnbaum, L.S., 1997. Dose–response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I .CYP1A1 and CYP1A2 enzyme activity in liver, lung and skin. Toxicol. Appl. Pharmacol. 130, 197–208; DeVito, M.J., Menache, G., Diliberto, J.J., Ross, D.G., Birnbaum L.S., 2000. Dose–response relationships for induction of CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin in female mice following subchronic exposure to polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 167, 157–172] Female mice received 0, 1.5, 15, 150 or 450 ng TCDD/kg/day or approximately 0, 1.5, 15, 150 or 450 ng TEQ/kg/day of MIX-1 or MIX-2 by gavage 5 days per week for 13 weeks. Mice were immunized 3 days after the last exposure and 4 days later, body, spleen, thymus, and liver weights were measured, and antibody response to SRBCs was observed. Exposure to TCDD, MIX-1, and MIX-2 suppressed the antibody response in a dose-dependent manner. Two-way ANOVA indicated no differences in the response between TCDD and the mixtures for body weight, spleen/body weight and decreased antibody responses. The results support the use of the TEF methodology and suggest that immune suppression by dioxin-like chemicals may be of concern at or near background human exposures.

Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/kg/day, in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10 to 1,000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low-dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long-lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system.

Background Women have elevated rates of thyroid disease compared to men. Environmental toxicants have been implicated as contributors to this dimorphism, including polybrominated diphenyl ethers (PBDEs), flame retardant chemicals that disrupt thyroid hormone action. PBDEs have also been implicated in the disruption of estrogenic activity, and estrogen levels regulate thyroid hormones. Post-menopausal women may therefore be particularly vulnerable to PBDE induced thyroid effects, given low estrogen reserves. The objective of this study was to test for an association between serum PBDE concentrations and thyroid disease in women from the United States (U.S.), stratified by menopause status. Methods Serum PBDE concentrations (BDEs 47, 99, 100 and 153) from the National Health and Examination Survey (NHANES) and reports on thyroid problems were available in the NHANES 2003–2004 cycle. Odds ratios (ORs) were calculated using multivariate logistic regression models accounting for population-weighted survey techniques and controlling for age, body mass index (BMI), education, smoking, alcohol consumption and thyroid medication. Menopause status was obtained by self-reported absence of menstruation in the previous 12 months and declared menopause. Results Women in the highest quartile of serum concentrations for BDEs 47, 99, and 100 had increased odds of currently having thyroid disease (ORs: 1.5, 1.8, 1.5, respectively) compared to the reference group (1st and 2nd quartiles combined); stronger associations were observed when the analysis was restricted to postmenopausal women (ORs: 2.2, 3.6, 2.0, respectively). Conclusion Exposure to BDEs 47, 99, and 100 is associated with thyroid disease in a national sample of U.S. women, with greater effects observed post-menopause, suggesting that the disruption of thyroid signaling by PBDEs may be enhanced by the altered estrogen levels during menopause. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0141-0) contains supplementary material, which is available to authorized users.

There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span but potentially across several generations; and second, to initiate the discussion of how adoption of DOHaD can promote a more realistic, accurate, and integrative approach to understanding environmental disruption of developmental programming and better inform clinical and policy interventions. (Endocrinology 156: 3416–3421, 2015)

The developmental origin of health and disease hypothesis posits that early-life exposures, including prenatal, can influence disease outcomes throughout the entire lifespan of an organism. Over the past 30 years, scientific researchers have compiled robust epidemiological and mechanistic data showing the effects of early-life nutrition, chemical exposures, and stress on prenatal programing and toxicity. Using novel techniques in genomics and epigenetics, science is now establishing strong links between low-level early-life environmental exposures and the later development of noncommunicable diseases, such as cardiovascular disease, obesity, diabetes, neurodevelopmental and neurodegenerative disease, reproductive effects, immune system function and cancer. Now scientists must engage with communities, industry, policy makers, and clinicians to leverage our newfound understanding of prenatal programing and toxicity into better health outcomes across the lifespan.

The National Institute of Environmental Health Sciences (NIEHS) fully supports the development of “A community for disaster science” (M. McNutt, Editorial, 3 April, p. [11][1]). Almost 2 years ago, we created the NIH Disaster Research Response (DR2) Project to facilitate the incorporation of “disaster science” into national response and recovery efforts ([ 1 ][2]). Key components of this project include improving accessibility to health data collection tools and Institutional Review Board (IRB)–approved research protocols, proactive engagement of diverse public and private stakeholders, and fostering the development of a trained cadre of academic researchers who can collect critical information and function in the immediate post-disaster environment without interfering with the emergency response. The publicly accessible NIH DR2 website now includes more than 165 data collection tools and other information to support disaster science activities ([ 2 ][3]). We have also sponsored a national workshop and conducted two tabletop exercises that have brought together academia, local community representatives, private industry, emergency responders, and public health, emergency management, and volunteer organizations to discuss the challenges and benefits of conducting post-disaster research and the value of evidence-based decision-making ([ 3 ][4]). It is clear that disaster response and recovery require an interdisciplinary effort supported by the best evidence available. As such, we have begun to develop a national “Environmental Health Sciences Network for Disaster Response” composed of interested academic centers with diverse expertise to enhance our ability to identify human health threats, prioritize research needs, provide expert consultation, and conduct disaster research. Research and response organizations must work jointly with community partners, first responders, local public health departments, and policymakers to anticipate threats and develop innovative methods to prevent being overwhelmed by unexpected cascading events, such as those following the Great East Japan earthquake, tsunami, and nuclear reactor meltdown in 2011. For a sustained effort, there also needs to be a national framework that supports disaster science research, timely funding that supports a science response, and an interdisciplinary disaster science career path within academic institutions and government entities that nurtures the next generation of disaster researchers. 1. [↵][5] 1. N. Lurie, 2. T. Manolio, 3. A. P. Patterson, 4. F. Collins, 5. R. Frieden , N. Engl. J. Med. 368, 1251 (2013). [OpenUrl][6][CrossRef][7][PubMed][8][Web of Science][9] 2. [↵][10] NIH Disaster Research Response (DR2) ( ). 3. [↵][11] Institute of Medicine, “Enabling rapid and sustainable public health research during disasters: Summary of a Joint Workshop by the Institute of Medicine and the U.S. Department of Health and Human Services” (National Academies Press, Washington, DC, 2014). [1]: /lookup/doi/10.1126/science.aab2091 [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #xref-ref-1-1 "View reference 1 in text" [6]: {openurl}?query=rft.jtitle%253DN.%2BEngl.%2BJ.%2BMed.%26rft.volume%253D368%26rft.spage%253D1251%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMsb1209510%26rft_id%253Dinfo%253Apmid%252F23534565%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [7]: /lookup/external-ref?access_num=10.1056/NEJMsb1209510&link_type=DOI [8]: /lookup/external-ref?access_num=23534565&link_type=MED&atom=%2Fsci%2F348%2F6236%2F766.3.atom [9]: /lookup/external-ref?access_num=000316869000017&link_type=ISI [10]: #xref-ref-2-1 "View reference 2 in text" [11]: #xref-ref-3-1 "View reference 3 in text"

Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. Objective: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. Methods: We exposed six men and eight women to 100 μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. Results: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50 h. Unconjugated d6-BPA appeared in serum within 5–20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001–0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6 h, respectively. Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites within 24 h. Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24 h. Keywords: Deuterated bisphenol A, Endocrine disruptor, ADME, Bioavailability, Metabolism, Excretion

Theodora Colborn, research scientist and environmental activist, died 14 December 2014 at the age of 87. As the scientist who coined the term “endocrine disruptor,” Theo—as we had the privilege to call her—played a watershed role in the field of environmental health science, particularly in raising public awareness of the effects of chemical contaminants on human health and the environment. It is no exaggeration to say that endocrine disruption science brought about a sea change in how we consider chemical safety and that Theo was instrumental in bringing about this paradigm shift. The path to environmental health science was neither typical nor direct for Theo. After an early career as a pharmacist, she earned her PhD from the University of Wisconsin at age 58—and never stopped working in science. In the 1980s her research examined the effects of chemical pollutants on the health of Great Lakes wildlife. While synthesizing huge data sets from numerous scientific fields, she found that many Great Lakes species were suffering from health effects that included reproductive and immune system problems and behavioral, hormonal, and metabolic changes. Although the term “endocrine disruptor” was not yet in use, Theo’s descriptions mirrored what we now recognize as characteristics of endocrine disruptor exposures. Theo’s work helped bring us to our current understanding of the links between the environment and human health. It is now well recognized that environmental exposures to chemical contaminants, even at very low levels, can play a profound role in human health. It is also now understood that the environment plays an important role in most complex diseases. The ability of environmental chemicals to interfere with hormones—particularly the hormones critical to maintaining many vital body systems—may be responsible for many of these health effects. Today’s debates about chemicals such as bisphenol A, glyphosate, and phthalates, as well as ongoing discussions about the origins of diabetes, early-onset puberty, cancers, and neurological disorders, are all part of the science of endocrine disruption. Current conversations about these exposures and health effects, and the state of current scientific research, would not be the same without Theo’s work. Theo was prescient in recognizing that very low levels of exposure can have profound and lasting health effects, that timing plays a role in determining health outcomes, that environmental exposures can affect several generations, and that severity of a health effect does not always increase with dose in a linear fashion. With these discoveries, endocrine disruption science upset the age-old assumption that “the dose makes the poison.” In doing so it has posed considerable challenges to how we assess and prevent harmful chemical exposures. Throughout her career, Theo recognized that her ability to understand what was happening to both wildlife and human populations would be limited if she worked only as an individual research scientist. In 1991, as a fellow of the W. Alton Jones Foundation, she brought together a group of 21 scientists with diverse backgrounds to attend the first of a series of conferences at Racine, Wisconsin, that became known simply as “Wingspread.” The Wingspread Consensus Statement (1991), although simple in its wording, made a powerful contribution to the study of environmental contaminants, and the scientists at this meeting—whom Theo referred to as “experts, skeptics, and gurus”—would become the leaders of the field of endocrine disruption. While staunchly independent and path-breaking, Theo’s work was characterized by collaboration with scientists and researchers from a wide range of disciplines. In 2012 she coauthored an extensive review of the endocrine disruptor literature with 11 other scientists from fields including genetics, environmental epidemiology, neuroendocrinology, and developmental, cell, cancer, and molecular biology. The authorship of this paper included three generations of scientists, from postdocs to professors to Theo herself—a testament to Theo’s commitment to inclusiveness. At age 76 Theo founded The Endocrine Disruption Exchange (TEDX), a research organization devoted to understanding how environmental exposures to endocrine disruptors interfere with development and health. Her work with TEDX spanned fields including the developmental origins of health and disease, endocrinology, and toxicology. Most recently, her efforts focused on understanding the health effects of chemicals used in the hydraulic fracturing process used to liberate natural gas and oil. Among the other remarkable aspects of Theo’s work was her ongoing mentorship and encouragement of new scientists, particularly young women scientists. She shaped so many scientists, in so many positive ways. In a 2013 interview she noted her concern for the next generation of science. For those of us fortunate enough to work with her, she was a cheerleader and advisor; she pushed young scientists to look at “the big picture” and not just the data produced in the field or laboratory. Always available for a phone call or to send words of encouragement by e-mail, Theo provided insights and support that helped others achieve their goals. As her colleagues at TEDX noted in a recent message to their supporters, Theo often ended these conversations and e-mails with one word: Onward! For those of us on the receiving end of this word, we were both challenged and uplifted by her spirit and enthusiasm. The final chapter of her landmark book, Our Stolen Future (1996), coauthored with Dianne Dumanoski and John Peterson “Pete” Myers, described the twentieth century as a time of profound change in the relationship between humans and the Earth. “With that transformation, we have been altering the fundamental systems that support life,” they wrote. Given the high stakes, they concluded that solving this dilemma would require not only ingenuity but also courage and caution in the quest to create safer new chemicals and materials. In so many ways Theo’s work was about caring for the health of future generations. The news she brought us was not good, but it came with tremendous love for the world in all its messy complexities. Her love for science, passion for public health, and willingness to work with a wide diversity of “experts, skeptics, and gurus” has left a permanent mark on those who knew her and shaped the future for generations of scientists who will never have that opportunity.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.

One of the most sensitive and reproducible immunotoxic endpoints of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure is suppression of the antibody response to sheep red blood cells (SRBCs) in mice. Immunosuppression occurs in concert with hepatomegaly and associated induction of several hepatic cytochrome P450 enzymes, including CYP1A2 which is responsible for the hepatic sequestration of TCDD. In this study, TCDD-induced immunosuppression was evaluated in C57BL/6N CYP1A2 (+/+) wild-type and compared with that of age-matched CYP1A2 (-/-) knockout and CYP1A2 (+/-) heterozygous female mice. Groups of mice were given a single gavage dose of 0, 0.03, 0.1, 0.3, 1.0, 3.0 or 10.0microg TCDD/kg, followed 7 days later by immunization with SRBCs. Serum was obtained 5 days after immunization and body, spleen, thymus and liver weights were measured. sheep red blood cell (SRBC) antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA). Anti-SRBC titers were suppressed at 1.0, 1.0 and 0.3microg TCDD/kg for CYP1A2 (+/+), CYP1A2 (+/-), and CYP1A2 (-/-) mice, respectively, which indicated a three-fold increase in TCDD-induced immunosuppression for the CYP1A2 (-/-) mice. This increase in TCDD-induced immunosuppression may be due to the inability of CYP1A2 (-/-) mice to sequester TCDD in the liver leading to a higher dose to the immune system. In CYP1A2 (+/+) mice, a dose of 3.0microg TCDD/kg was sufficient to increase the liver weight, while in CYP1A2 (-/-) mice no increase in liver weight was observed. Application of analysis of variance and dose-response modeling approaches indicate that there is little evidence that the immunosuppression dose-response curves, for the three strains, differ in the lower part of the dose-response range. Thus, CYP1A2 is not required for TCDD-induced immunosuppression in the mouse.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and related polyhalogenated aromatic hydrocarbons (PHAHs) alter the reproductive development of laboratory animals. Therefore, we exposed animals to a mixture of dioxins, furans, and polychlorinated biphenyls (PCBs) that included TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), octachlorodibenzofuran (OCDF), 3,3',4,4'-tetrachlorobiphenyl (PCB77), 3,3',4,4',5-pentachlorobiphenyl (PCB126), and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169). The mixture composition approximated the relative abundance of these compounds in foodstuff (L. S. Birnbaum and M. J. DeVito, 1995, Toxicology Vol. 105, pp. 391-401). Following the work of Gray et al. with TCDD (1997, Toxicology and Applied Pharmacology Vol. 146, pp. 11-20), we exposed time-pregnant dams on gestation day (GD) 15 at doses up to 1.0 microgram TCDD toxic equivalency (TEQ)/kg and the development of offspring was monitored. This mixture significantly increased the time to puberty in both male and female offspring. At postnatal day (PND) 32 seminal vesicle weights were decreased; however, only ventral prostate weight was affected at PND 49 and no effects were seen at PND 63. In female offspring, the mixture caused dose-dependent increases in the incidence of vaginal thread. Ethoxyresorufin-O-deethylase (EROD) activity was higher than with TCDD the comparable TEQ exposure. Based on the slightly lowered responsiveness to the mixture, we used 2.0 microgram TEQ/kg to examine reproductive effects. This dose elicited the responses observed with 1.0 microgram TCDD/kg. Results indicate that the mixture causes a similar spectrum of effects seen with TCDD and the slightly lowered degree of response based on administered dose appears to be due to decreased transfer of mixture components to the offspring. Thus, the use of the WHO consensus TEFs (M. Van den Berg et al., 1998, Environ. Health Perspec. 106, 775-792) reasonably predicts the developmental toxicity of this mixture of dioxin-like PHAHs.

Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection.

Aging is associated with alterations in hepatic peroxisomal metabolism and susceptibility to hepatocarcinogenicity produced by agonists of peroxisome proliferator-activated receptor alpha (PPAR alpha). Mechanisms involved in these effects are not well understood. However, as a heterodimer with retinoid X receptor alpha (RXR alpha), PPAR alpha regulates transcription of genes involved in oxidative stress, cell proliferation and apoptosis. Modulating these important cell functions as a result of aging may be responsible for altered hepatic peroxisomal responses in the senescent liver. Therefore, we investigated hepatic apoptosis, and peroxisomal beta-oxidation activity, a major source of H(2)O(2), as well as the activity of the peroxisomal anti-oxidant enzyme catalase, in male Fischer-344 rats of four age groups (4, 10, 50 and 100 week old). We further quantified protein levels of both PPAR alpha and RXR alpha in these animals. Data show that peroxisomal beta-oxidation and catalase activities were significantly lower in livers of the 100 week old animals compared with other age groups, while percentage of apoptotic hepatocytes were identical in all animal age groups. However, aging had no effect on hepatic PPAR alpha protein levels. In the senescent group, the level of decline in both peroxisomal enzyme activities of 30% was surprisingly similar to the decline observed in the hepatic expression of the RXR alpha protein. Results from this study suggest that alterations in peroxisomal metabolism observed in the senescent liver may be a result of the decline in the availability of RXR alpha receptor, and not the primary PPAR alpha receptor. On the other hand, PPAR alpha-independent mechanisms appear to play a role in controlling apoptosis in the senescent liver.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure during gestation has revealed reproductive anomalies in rat offspring, including inconclusive reports of stunted mammary development in females (Brown et al., 1998, Carcinogenesis 19, 1623-1629; Lewis et al., 2001, TOXICOL: Sci. 62, 46-53). The current studies were designed to examine mammary-gland development in female offspring exposed in utero and lactationally to TCDD, and to determine a critical exposure period and cellular source of these effects. Long-Evans rats were exposed to 1 microg TCDD/kg body weight (bw) or vehicle on gestation day (GD) 15. TCDD-exposed females sacrificed on postnatal days (PND) 4, 25, 33, 37, 45, and 68 weighed significantly less than control litter mates, and peripubertal animals exhibited delayed vaginal opening and persistent vaginal threads, yet did not display altered estrous cyclicity. Mammary glands taken from TCDD-exposed animals on PND 4 demonstrated reduced primary branches, decreased epithelial elongation, and significantly fewer alveolar buds and lateral branches. This phenomenon persisted through PND 68 when, unlike fully developed glands of controls, TCDD-exposed rats retained undifferentiated terminal structures. Glands of offspring exposed to TCDD or oil on gestation days 15 and 20 or lactation days 1, 3, 5, and 10 were examined on PND 4 or 25 to discern that GD 15 was a critical period for consistent inhibition of epithelial development. Experiments using mammary epithelial transplantation between control and TCDD-exposed females suggested that the stroma plays a major role in the retarded development of the mammary gland following TCDD exposure. Our data suggest that exposure to TCDD prior to migration of the mammary bud into the fat pad permanently alters mammary epithelial development in female rat offspring.