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Summary: Environmental exposures are ubiquitous and play a fundamental role in the development of complex human diseases. The exposome, which is defined as the totality of environmental exposures over the life course, allows for systematic evaluation of the relationship between exposures and associated biological consequences, and represents a powerful approach for discovery in environmental health research. However, implementing the exposome concept is challenged by the ability to accurately assess multiple exposures and the ability to integrate information across the exposure–disease continuum. On 14–15 January 2015, the National Institute of Environmental Health Sciences (NIEHS) held the Exposome Workshop where a group of international and U.S. scientists from different disciplines gathered to review the state of the science in research areas related to the exposome and to provide recommendations for incorporating the exposome concept into each research area. To move the field forward, the NIEHS is establishing a Children’s Health Exposure Analysis Resource (CHEAR) to provide infrastructure support for access to laboratory and statistical analyses to children’s health studies. It is recognized that incorporating the exposome concept into exposure and environmental health research will be a long journey and will require significant collaborative efforts from different scientific disciplines, nations, and stakeholders.

Within the past few decades, the concept of endocrine-disrupting chemicals (EDCs) has risen from a position of total obscurity to become a focus of dialogue, debate, and concern among scientists, physicians, regulators, and the public. The emergence and development of this field of study has not always followed a smooth path, and researchers continue to wrestle with questions about the low-dose effects and nonmonotonic dose responses seen with EDCs, their biological mechanisms of action, the true pervasiveness of these chemicals in our environment and in our bodies, and the extent of their effects on human and wildlife health. This review chronicles the development of the unique, multidisciplinary field of endocrine disruption, highlighting what we have learned about the threat of EDCs and lessons that could be relevant to other fields. It also offers perspectives on the future of the field and opportunities to better protect human health.

Environ Health Perspect 124(4):A59 (2016), http://dx.doi.org/10.1289/ehp.1611410 In the original article, the URL for the report titled “The Impacts of Climate Change on Human Health in the United States: A Scientific Assessment” was http://www.globalchange.gov/health-assessment. In this erratum, the authors provide the URL for the final version of this report, which is available at http://health2016.globalchange.gov.

International audience; From the lectures presented at the 2nd International Workshop on Obesity and Environmental Contaminants, which was held in Uppsala, Sweden, on 8-9 October 2015, it became evident that the findings from numerous animal and epidemiological studies are consistent with the hypothesis that environmental contaminants could contribute to the global obesity epidemic. To increase awareness of this important issue among scientists, regulatory agencies, politicians, chemical industry management, and the general public, the authors summarize compelling scientific evidence that supports the hypothesis and discuss actions that could restrict the possible harmful effects of environmental contaminants on obesity.

1. Bis(2-ethylhexyl)-tetrabromophthalate (BEH-TEBP; CAS No. 26040-51-7; PubChem CID: 117291; MW 706.15 g/mol, elsewhere: TeBrDEPH, TBPH, or BEHTBP) is used as an additive brominated flame retardant in consumer products. 2. Female Sprague Dawley rats eliminated 92-98% of [14C]-BEH-TEBP unchanged in feces after oral administration (0.1 or 10 μmol/kg). A minor amount of each dose (0.8-1%) was found in urine after 72 h. Disposition of orally administered BEH-TEBP in male B6C3F1/Tac mice was similar to female rats. 3. Bioaccumulation of [14C]-radioactivity was observed in liver and adrenals following 10 daily oral administrations (0.1 μmol/kg/day). These tissues contained 5- and 10-fold higher concentrations of [14C]-radioactivity, respectively, versus a single dose. 4. IV-administered [14C]-BEH-TEBP (0.1 μmol/kg) was slowly eliminated in feces, with >15% retained in tissues after 72 h. Bile and fecal extracts from these rats contained the metabolite mono-ethylhexyl tetrabromophthalate (TBMEHP). 5. BEH-TEBP was poorly absorbed, minimally metabolized and eliminated mostly by the fecal route after oral administration. Repeated exposure to BEH-TEBP led to accumulation in some tissues. The toxicological significance of this effect remains to be determined. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476).

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.

Almost 4 years ago, one of us (F.S.C.) wrote an Editorial ([ 1 ][1]) affirming the continued importance of basic research to the National Institutes of Health (NIH) mission. The Editorial emphasized that basic scientific discovery is the engine that powers the biomedical enterprise, and NIH

The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[(14)C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice was dosed and sacrificed 3 h postexposure to investigate tissue metabolite levels. Extractable and nonextractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine, and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to α-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, fecal extracts from mice exposed to γ-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene, while in liver and adipose tissues extracts only a single monohydroxy-pentabromocyclododecane metabolite was observed. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as suggested by high fecal nonextractables. The presence of tissue- and excreta-specific metabolic products after in vivo exposure to the two main HBCD stereoisomers supports previous toxicokinetic studies indicating that these two stereoisomers are biologically distinct. The distinct metabolic products identified in this study have the potential to aid in the identification of stereoisomer-specific HBCD exposures in future biomonitoring studies.

Background: Bisphenol A (BPA) is a high production volume chemical used to make polycarbonate plastic and is found in many consumer products. Some studies using animal models have suggested that BPA exposures may have adverse health effects. However, research gaps have precluded a full understanding of the effects of BPA in humans and engendered controversies surrounding the chemical’s potential toxicity. Objectives: The National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program (NTP) have developed an integrated, multipronged, consortium-based approach to optimize BPA-focused research investments to more effectively address data gaps and inform decision making. Discussion: NIEHS/NTP BPA research investments made over the past 4 years include extramural research grants, establishment of a BPA Grantee Consortium, intramural research activities on BPA’s mechanisms of action, the launch of two clinical studies and an occupational study, development of a round-robin experiment to validate BPA measurements in human serum, and, in collaboration with the Food and Drug Administration (FDA), formation of a consortium to design and execute a chronic toxicity study of BPA in rats. The NIEHS’s new consortium-based approach has led to more integrated, collaborative efforts and should improve our ability to resolve controversies over the potential human health effects of exposures to low levels of endocrine-active agents.

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.

Autoantibodies to cellular constituents are the serologic hallmarks of autoimmunity and are frequently seen in systemic autoimmune diseases, including systemic lupus erythematosus (SLE), scleroderma, and polymyositis/dermatomyositis (1). They also are detected in patients with organ-specific autoimmune diseases, such as autoimmune thyroiditis and hepatitis (1), certain infections and neoplasms (2), and in some individuals without diagnosed disease (2, 3). The most common autoantibodies are antinuclear antibodies (ANA), which are traditionally assessed by indirect immunofluorescence and include antibodies to both nuclear and cytoplasmic components (4). The cellular staining patterns and specific autoantibodies detected in those with ANA are clinically useful as they are strongly associated with particular autoimmune diseases, such as the nucleolar staining patterns that are often seen in scleroderma and anti-Sm autoantibodies that are included in SLE classification criteria (1). A variety of methods have been used to estimate ANA prevalence in selected populations, including blood donors (5, 6), hospital workers (6, 7), healthy volunteers (3, 8), or residents in small areas (9, 10), leading to a wide range of prevalence estimates (from 1.1% to 20%), which are difficult to compare. Factors associated with ANA production are largely unknown with the exception of some reports suggesting higher prevalence of ANA in females (8, 10–13) and older individuals (12, 14–16). A proportion of the ANA-positive population is thought to represent the preclinical stage of autoimmune diseases based on observations that autoantibodies are usually produced prior to clinical manifestations of disease (17). Thus, defining the prevalence and types of ANA, as well as characterizing factors associated with their production, may provide insight into the etiology of autoimmune diseases, which are thought to be increasing in frequency but are more difficult to characterize and study than ANA at the population level (18). Therefore, we evaluated serum samples from the United States (U.S.) National Health and Nutrition Examination Survey (NHANES) from 1999–2004 to estimate ANA prevalence, cellular patterns and specific autoantibody reactivities, and to identify sociodemographic and biobehavioral factors associated with their production. We specifically assessed selected systemic autoimmune disease risk factors including smoking (19) and alcohol use (20). We also evaluated C-reactive protein (21) and obesity, the former being a marker and the latter an underlying cause of chronic inflammation (22) and a growing public health concern.

Background: For > 50 years, polyfluoroalkyl compounds (PFCs) have been used worldwide, mainly as surfactants and emulsifiers, and human exposure to some PFCs is widespread. Objectives: Our goal was to report PFC serum concentrations from a convenience sample of Dallas, Texas, children from birth to < 13 years of age, and to examine age and sex differences in PFC concentrations. Methods: We analyzed 300 serum samples collected in 2009 for eight PFCs by online solid phase extraction–high performance liquid chromatography–isotope dilution–tandem mass spectrometry. Results: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in > 92% of participants; the other PFCs measured were detected less frequently. Overall median concentrations of PFOS (4.1 ng/mL) were higher than those for PFOA (2.85 ng/mL), PFNA (1.2 ng/mL), and PFHxS (1.2 ng/mL). For PFOS, PFOA, PFNA, and PFHxS, we found no significant differences (p < 0.05) by sex, significantly increasing concentrations for all four chemicals by age, and significantly positive correlations between all four compounds. Conclusions: We found no significant differences in the serum concentrations of PFOS, PFOA, PFNA, and PFHxS by sex, but increasing concentrations with age. Our results suggest that these 300 Texas children from birth through 12 years of age continued to be exposed to several PFCs in late 2009, years after changes in production of some PFCs in the United States.

Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (α), beta (β), and gamma (γ). γ-HBCD dominates the mixture (∼70%), and despite α-HBCD's minor contribution to global HBCD production and usage (∼10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both γ-HBCD and α-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of α-[(14)C]HBCD- and γ-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to α-HBCD had an overall higher body burden than γ-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the α-HBCD administered dose, whereas pups exposed to γ-HBCD retained 10%. Total body burden in infantile mice after exposure to γ-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to α-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice; whereas distribution patterns are similar, concentrations of each HBCD diastereomer's-derived radioactivity are higher in the pup's liver, fat, kidney, brain, blood, muscle, and lungs than in the adult's. This study suggests that developmental stage may be a risk factor for the harmful effects of α-HBCD and γ-HBCD, when developing animals may be more sensitive to effects and have increased body burden.

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.

Alpha-hexabromocyclododecane (α-HBCD) is an emerging persistent organic pollutant present in the hexabromocyclododecane (HBCD) commercial mixture. HBCD is used as an additive flame retardant in a wide variety of household consumer products. Three main stereoisomers, alpha (α), beta (β), and gamma (γ), comprise roughly 10, 10, and 80% of the mixture, respectively. Despite its small contribution to HBCD global production and usage, α-HBCD is the major stereoisomer found in wildlife and human tissues including breast milk and blood in North America, European Union, and Asia. No mammalian or human data are currently available regarding the toxicokinetics of α-HBCD. This study was conducted in an effort to fully characterize the absorption, distribution, metabolism, and elimination of α-HBCD following a single and repeated exposure with respect to dose, time, and route of administration in female C57BL/6 mice. Results indicate that ∼90% of the administered dose (3 mg/kg) was absorbed after oral exposure. Disposition was (1) dictated by lipophilicity, as adipose, liver, muscle, and skin were major depots and (2) was dose dependent with nonlinear accumulation at higher doses. Elimination, both whole-body and from individual tissues, was biphasic. α-HBCD-derived radioactivity was excreted in the feces as parent and metabolites, whereas urine only contained metabolites. Presence of polar metabolites in the blood and urine were a major factor in determining the rapid initial whole-body half-life after a single oral exposure. Initial half-lives were ∼1-3 days and much longer terminal half-lives of 17 days were observed, suggesting the potential for α-HBCD bioaccumulation. A 10-day repeated study supports α-HBCD bioaccumulation potential. Stereoisomerization previously observed after exposure to γ-HBCD was not seen after exposure of α-HBCD. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk of α-HBCD which is the major stereoisomer found in wildlife and people.

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.

Objectives Our aim was to report the first known incidence of U.S. butter contamination with extremely high levels of polybrominated diphenyl ethers (PBDEs). Methods Ten butter samples were individually analyzed for PBDEs. One of the samples and its paper wrapper contained very high levels of higher-brominated PBDEs. Dietary estimates were calculated using the 2007 U.S. Department of Agriculture Loss-Adjusted Food Availability data, excluding the elevated sample. Results The highly contaminated butter sample had a total upper bound PBDE level of 42,252 pg/g wet weight (ww). Levels of brominated diphenyl ether (BDE)-206, -207, and -209 were 2,000, 2,290, and 37,600 pg/g ww, respectively. Its wrapping paper contained a total upper-bound PBDE concentration of 804,751 pg/g ww, with levels of BDE-206, -207, and -209 of 51,000, 11,700, and 614,000 pg/g, respectively. Total PBDE levels in the remaining nine butter samples ranged from 180 to 1,212 pg/g, with geometric mean of 483 and median of 284 pg/g. Excluding the outlier, total PBDE daily intake from all food was 22,764 pg/day, lower than some previous U.S. dietary intake estimates. Conclusion Higher-brominated PBDE congeners were likely transferred from contaminated wrapping paper to butter. A larger representative survey may help determine how frequently PBDE contamination occurs. Sampling at various stages in food production may identify contamination sources and reduce risk.

A summation of new and novel findings presented at “The Fifth PCB Workshop: New Knowledge Gained from Old Pollutants” workshop is provided in this overview, along with discussion of data gaps and research needs in the future. Relative to the previous workshop, the scientific presentations had a decreased emphasis on toxicology; rather, more than half of the sessions dealt with environmental sources, fate and transport, or transformations. Approximately 100 presentations in the form of talks and posters were included in the workshop. The presentations were generally divided into: emissions and transport of PCBs in natural and urban settings; chiral aspects of PCB transport; metabolism and distribution; new aspects of environmental metabolism of PCBs – from microbes to plants to animals; reproduction, developmental and cardiovascular effects of PCBs; updates on Anniston – the most highly exposed PCB community in the U.S. to date; and new and novel approaches for evaluating PCB mixtures (e.g., PCB toxic equivalency factors, and TEFs) – and the implications of such for risk assessment. An overarching state-of-the-science view is important to the goal of preventing negative health consequences. Currently, there are still many roadblocks to evaluating risk associated with this large group of 209 congeners – all of which have different physiochemical properties, variable fate and transport mechanism in the environment, and a range of ability for persistence, bioaccumulation, and biological activity. Keywords: PCB, Workshop

Objectives The objective of this article is to extend our previous studies of persistent organic pollutant (POP) contamination of U.S. food by measuring perfluorinated compounds (PFCs), organochlorine pesticides, and polychlorinated biphenyls (PCBs) in composite food samples. This study is part of a larger study reported in two articles, the other of which reports levels of polybrominated diphenyl ethers and hexabromocyclododecane brominated flame retardants in these composite foods [Schecter et al. 2010. Polybrominated diphenyl ethers (PBDEs) and hexabromocyclodecane (HBCD) in composite U.S. food samples, Environ Health Perspect 118:357–362]. Methods In this study we measured concentrations of 32 organochlorine pesticides, 7 PCBs, and 11 PFCs in composite samples of 31 different types of food (310 individual food samples) purchased from supermarkets in Dallas, Texas (USA), in 2009. Dietary intake of these chemicals was calculated for an average American. Results Contamination varied greatly among chemical and food types. The highest level of pesticide contamination was from the dichlorodiphenyltrichloroethane (DDT) metabolite p,p′- dichlorodiphenyldichloroethylene, which ranged from 0.028 ng/g wet weight (ww) in whole milk yogurt to 2.3 ng/g ww in catfish fillets. We found PCB congeners (28, 52, 101, 118, 138, 153, and 180) primarily in fish, with highest levels in salmon (PCB-153, 1.2 ng/g ww; PCB-138, 0.93 ng/g ww). For PFCs, we detected perfluorooctanoic acid (PFOA) in 17 of 31 samples, ranging from 0.07 ng/g in potatoes to 1.80 ng/g in olive oil. In terms of dietary intake, DDT and DDT metabolites, endosulfans, aldrin, PCBs, and PFOA were consumed at the highest levels. Conclusion Despite product bans, we found POPs in U.S. food, and mixtures of these chemicals are consumed by the American public at varying levels. This suggests the need to expand testing of food for chemical contaminants.

Levels of polybrominated diphenyl ether (PBDE) flame retardants have been increasing in humans and the environment for the past few decades. Human levels are markedly higher in the US than Europe. Although food appears to be a significant route of intake, food PBDE levels are not substantially higher in the US than Europe. House and office dust appear to be major routes of exposure with air believed to usually provide a lesser route of intake. Because there are very few measurements of airborne PBDE that have been performed in relevant microenvironments in the US, increased efforts to assess airborne PBDE in the US as sources of exposure are needed. This study reports, for the first time from a Southwestern US city in Texas, the results of measurements of airborne PBDE in multiple locations, two outdoor and six indoor (residential and office) from active air sampling with collection of a combination of both vapor- and particulate-phase PBDE. Higher PBDE levels were measured in indoor than outdoor air, whi...

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.

Objectives The objectives of this study were to provide updated measurements of PBDEs in US food, to estimate possible difference in levels from differing geographical regions, and to provide an improved estimate of current dietary intake. Methods Thirty matched food samples for a total of 90 samples were collected from each of three cities (Los Angeles, California; Dallas, Texas; and Albany, New York) and were analyzed for 13 polybrominated diphenyl ether congeners (BDE 28, 47, 49, 66, 85, 99, 100, 138, 153, 154, 183, 203, and 209). Dietary intake of PBDEs was estimated by food type, age, and sex. Results In this pilot study, we did not note a statistically significant difference in total PBDE levels in food collected from the three locations. The median total PBDE levels (estimating non-detected values as half of the detection limit) in meat, dairy, eggs, and fish were 267 pg/g wet weight (ww) (range 102–3156 pg/g ww), 176 pg/g ww (range 41–954 pg/g ww), 637 pg/g ww (range 193–932 pg/g ww), and 243 pg/g ww (range 36–2161 pg/g ww). PBDE intake from food was estimated to range from 2.7 ng/kg/day for children 2 through 5 years of age to 0.8 ng/kg/day for women aged 60 years and older. This compares closely with our previous study where the intake estimate was 2.7 ng/kg/day for children 2 through 5 years of age and 0.9 ng/kg/day for women aged 60 years and older. Conclusion We did not find a decrease of PBDEs in food since our previous studies which we expected to find due to the declining use of PBDEs in the USA. These findings could be consistent with food contamination from depot sources of PBDEs. A larger, more representative sampling of the US food supply is indicated based on our findings.

Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consists of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.

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.

Objectives This study was designed to update previous U.S. market basket surveys of levels and polybrominated diphenyl ether (PBDE) dietary intake calculations. This study also quantifies hexabromocyclododecane (HBCD) levels in U.S.-purchased foods for the first time and estimates U.S. dietary intake of HBCD. This is part of a larger market basket study reported in two companion articles, of current levels of certain persistent organic pollutants (POPs) PBDEs, HBCD, perfluorinated compounds, polychlorinated biphenyls, and pesticides in composite food samples collected in 2008–2009. Methods In this study, we measured concentrations of 24 PBDE congeners and total HBCD in composite samples of 31 food types (310 samples). U.S. dietary intake of PBDEs and HBCD was estimated referencing the most current U.S. Department of Agriculture loss-adjusted food availability report. Results Total PBDE concentrations in food varied by food type, ranging from 12 pg/g wet weight (ww) in whole milk to 1,545 pg/g ww in canned sardines and 6,211 pg/g ww in butter. Total HBCD concentrations also varied substantially within and among food groups, ranging from 23 pg/g in canned beef chili to 593 pg/g in canned sardines. HBCD was not detected in any dairy samples. Dietary intake of all PBDE congeners measured was estimated to be 50 ng/day, mostly from dairy consumption but also from meat and fish. HBCD intake was estimated at 16 ng/day, primarily from meat consumption. Conclusion PBDEs and HBCDs currently contaminate some food purchased in the United States, although PBDE intake estimated in this study is lower than reported in our previous market basket surveys. HBCD is in food at higher levels than expected based on previously reported levels in milk and blood compared with PBDE levels and is comparable to European levels.

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.

Polybrominated diphenyl ethers (PBDEs) are a class of widely used flame retardants which have been found to persist, bioaccumulate, and potentially affect development in animals. Exposure to PBDEs can be through both diet and the environment and is generally estimated by measuring PBDEs in blood, adipose tissue, muscle, or milk samples. Using rats as a model, we investigated tissue distribution of PBDEs after oral administration and evaluated a suitable matrix for body burden estimation. Male rats were administered dust or corn oil containing 8 or 6 microg PBDEs kg(-1) body wt, respectively, in the diet for 21 days (N=4 rats per treatment), and the concentration of 15 PBDEs were measured in various tissues, plasma, and feces. PBDEs were found in all tissues, including the brain, and showed no difference in distribution patterns between treatments for most PBDEs. Tri- to hexa-BDEs comprised80% of the total PBDEs in the adipose, brain, kidney, lung, and residual carcass, but40% in the liver and plasma. The ratio of the lipid-weight concentration of tri- to hexa-BDEs in adipose tissue, residual carcass, and plasma was 1:1:2. For the hepta- to nona-BDEs, lipid-weight concentrations increased from adipose tissue to residual carcass to plasma in the ratio 0.3:1:4. BDE-209 was the dominant congener in the liver and plasma, but was not detected in the adipose tissue or carcass. In summary, the lower brominated congeners tended to distribute equally into lipids implying both adipose tissue and plasma would be suitable matrices for biomonitoring. Plasma was the best matrix for detection of the higher brominated congeners (especially BDE-209), although on a lipid-weight basis tended to overestimate the total body burdens.

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.

BACKGROUND: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links, between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. OBJECTIVES: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (Upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. DISCUSSION: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may, be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. CONCLUSIONS: For certain classes of early perturbations, Sufficient information oil the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will Support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population

The human body burden of polychlorinated biphenyls (PCBs) sharply declined after production was banned in the US in 1979. For the 10% of the US population that remains most exposed to PCBs, fish consumption is the primary source. National Health and Nutrition Examination Survey (NHANES) data indicates that the highest remaining PCB levels exist in a non-Hispanic black subpopulation. Our review suggests that catfish consumption may be a significant PCB source for the one million non-Hispanic black anglers who fish for catfish. In comparison to non-Hispanic white anglers, non-Hispanic black anglers consume more catfish, are more likely to eat the whole fish rather than just the fillets that contain less PCBs, and are more likely to fish in watersheds with high PCB contamination. Efforts to diminish potential racial disparities in PCB exposure are challenged by geographic, economic, cultural, and educational barriers. In response, we propose that a fish consumption survey be performed that identifies the extent of subsistence fishing by non-Hispanic black anglers for catfish in watersheds with PCB contamination, the type and quantity of catfish subsistence fishing provides, and what actions would help moderate PCB exposure due to subsistence fishing for catfish in such areas. Understanding the contamination and consumption factors that contribute to higher PCB body burdens will help identify and offer solutions to racial disparities in exposure to PCBs due to subsistence fishing while providing a model to prevent similar disparities in exposure to toxics ranging from mercury to polybrominated diphenyl ethers.

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.

Household dust has been implicated as a major source of polybrominated diphenyl ether (PBDE) exposure in humans. This finding has important implications for young children, who tend to ingest more dust than adults and may be more susceptible to some of the putative developmental effects of PBDEs. Absorption parameters of PBDEs from ingested dust are unknown; therefore, the objectives of this study were to determine and to compare the uptake of PBDEs from either household dust (NIST Standard Reference Material 2585) or a corn oil solution. Male rats were administered dust or corn oil doses at 1 or 6 microg of PBDEs kg(-1) body wt in the diet for 21 days (n = 4 rats per group). The concentrations of 15 PBDEs were measured in adipose tissue and liver from each treatment group and showed that bioconcentration was congener dependent, but for the majority of congeners, the concentrations did not differ with either dose level or dose vehicle. Hepatic Cyp2b1 and 2b2 mRNA expression increased in rats receiving the higher PBDE doses, suggesting potential effects on metabolic activity. Retention of PBDEs in tissues ranged from5% of the dose for BDE-209 to 70% for BDEs-47, 100, and 153 but generally did not differ between the high dust and high oil treatment groups. Excretion via the feces was significantly lower in the high oil dosed rats suggesting differences in absorption, excretion, and/or metabolism. The present study shows that PBDEs in dust are readily bioavailable and are biologically active, as indicated by increased transcription of hepatic enzymes.

Co-incident with the introduction of polybrominated diphenyl ethers (PBDEs) into household materials nearly 30 years ago, feline hyperthyroidism (FH) has increased dramatically. Risk of developing FH is associated with indoor living and consumption of canned catfood. We hypothesized that increases in FH were, in part, related to increased PBDE exposure, with key routes of exposure being diet and ingestion of house dust. This study was designed to determine whether body burdens of PBDEs in hyperthyroid (HT) cats were greater than that of young or sick non-HT cats. Serum samples and clinical information were collected from 23 cats. Serum and dry and canned cat food were analyzed for PBDEs. A spectrum of BDE congeners was detected in all cats, with BDE-47, 99, 207, and 209 predominating. Mean +/- standard error (and median) cumulative sigma PBDE serum concentrations of young, old non-HT, and HT cats were 4.3 +/- 1.5 (3.5), 10.5 +/- 3.5 (5.9), and 12.7 +/- 3.9 (6.2) ng/mL, respectively. Due to high variability within each group, no association was detected between HT cats and sigma PBDE levels. Indicative of age- or disease-dependent changes in PBDE metabolism, BDE-47/99 ratios were inversely correlated with age, and 47/99 and 100/ 99 ratios in HT cats were significantly lower than those in the other cats. Overall, sigma PBDE levels in cats were 20- to 100-fold greater than median levels in U.S. adults. Our results support the hypothesis that cats are highly exposed to PBDEs; hence, pet cats may serve as sentinels to better assess human exposure and adverse health outcomes related to low-level but chronic PBDE exposure.

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.

The Brief Communication by Langley et al. was exceptional in its presentation of genomics and epigenomics, the discussion of the extrinsic and intrinsic causes of disease, and its outline of why a paradigm shift to human-based research is needed. I was disappointed however, to find that the authors relied on largely empirical evidence and observation and failed to include the very strong theoretical reasons for the failure of the current paradigm. The theoretical grounding for the empirical evidence and observations cited by Langley et al. can be summarized as follows. A concept I developed called Trans-Species Modeling Theory (TSMT) states: “While trans-species extrapolation is possible when perturbations concern lower levels of organization or when studying morphology and function on the gross level, one evolved, complex system will not be of predictive value for another when the perturbation affects higher levels of organization” (Greek and Hansen 2013). Humans and animals are examples of complex systems, which differ from simple systems in various important features. Complex systems exhibit a hierarchy of organization, with higher levels developing out of lower levels. Disease and drug responses occur at higher levels of organization and thus are difficult to model. Complex systems are highly dependent on initial conditions, demonstrate emergent properties, and are more than the sum of their parts. This limits the amount that we can learn about complex systems by using reductionism alone. The initial conditions that concern biomedical research revolve around the genome of the patient. Genomes vary among individual humans and lead to important variation in drug response and disease susceptibility. Even monozygotic twins with their very minimal variation in genomes can respond differently to drugs and disease (Alexanderson and Borga 1972; Bell and Spector 2011; Czyz et al. 2012). The same has been demonstrated among ethnicities (Haiman et al. 2006) and between the sexes (Simon 2005). Even different strains of mice can respond dramatically differently to perturbations (Morange 2001, Belmaker et al. 2012). The striking divergence of responses to perturbations because of very small changes in initial conditions is illustrated by the divergence of weather outcomes demonstrated by Lorenz in his model of chaotic systems (Lorenz 1963) and has been reproduced in living systems (West 2006). Interspecies genome variation, including variation of the regulatory genome, is even more dramatic than the interindividual variations we are accustomed to observing (Romero et al. 2012). Sir Arthur Eddington (2014) stated, “It is also a good rule not to put overmuch confidence in the observational results that are put forward until they have been confirmed by theory.” TSMT places the position of Langley et al. in the context of science in general and explains why animal models will continue to fail as predictive models for humans: Evolved, complex systems will continue to respond differently to perturbations like drugs and disease regardless of additions or deletions in the genome.

I would certainly never have predicted that I would become the director of the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP) when I was a Jewish girl growing up in Teaneck, New Jersey. My family stressed the importance of education. Yet for a girl there were many not-so-subtle suggestions that the appropriate careers were in teaching or nursing, and the most important thing was to be a wife and mother. Well, I can't disagree with the latter, although I would have to add grandmother to that list of achievements. My parents were both college graduates, but my mom only taught high school English for one year before leaving the field to start our family. My dad returned from World War II and joined his brother in accounting. After my first sister was born, my father joined my mother's family jewelry business and helped to open a second retail store. My mother helped my dad out during the busy times—Christmas and wedding season—but otherwise focused on our growing family of three girls and one boy. This became increasingly challenging when it became clear that my little brother was severely retarded and would require extra care.

Background: Hexabromocyclododecane (HBCD) is a high production volume brominated flame retardant added to building insulation foams, electronics, and textiles. HBCD is a commercial mixture (CM-HBCD) composed of three main stereoisomers: α-HBCD (10%), β-HBCD (10%), and γ-HBCD (80%). A shift from the dominant stereoisomer γ-HBCD to α-HBCD is detected in humans and wildlife. Objectives: Considering CM-HBCD has been implicated in neurodevelopment and endocrine disruption, with expected metabolism perturbations, we performed metabolomics on mice serum obtained during a window-of-developmental neurotoxicity to draw correlations between early-life exposures and developmental outcomes and to predict health risks. Methods: Six female C57BL/6 mice at postnatal day (PND) 10 were administered a single gavage dose of α-, γ-, or CM-HBCD at 3, 10, and 30 mg/kg. Nuclear magnetic resonance metabolomics was used to analyze 60 μL serum aliquots of blood collected 4 days post-oral exposure. Results: Infantile mice exposed to α-, γ-, or CM-HBCD demonstrated differences in endogenous metabolites by treatment and dose groups, including metabolites involved in glycolysis, gluconeogenesis, lipid metabolism, citric acid cycle, and neurodevelopment. Ketone bodies, 3-hydroxybutyrate, and acetoacetate, were nonstatistically elevated, when compared with mean control levels, in all treatment and dose groups, while glucose, pyruvate, and alanine varied. Acetoacetate was significantly increased in the 10 mg/kg α-HBCD and was nonsignificantly decreased with CM-HBCD. A third ketone body, acetone, was significantly lower in the 30 mg/kg α-HBCD group with significant increases in pyruvate at the same treatment and dose group. Metabolites significant in differentiating treatment and dose groups were also identified, including decreases in amino acids glutamate (excitatory neurotransmitter in learning and memory) and phenylalanine (neurotransmitter precursor) after α-HBCD and γ-HBCD exposure, respectively. Conclusions: We demonstrated that 4 days following a single neonatal oral exposure to α-, γ-, and CM-HBCD resulted in different serum metabolomic profiles, indicating stereoisomer- and mixture-specific effects and possible mechanisms of action. Citation: Szabo DT, Pathmasiri W, Sumner S, Birnbaum LS. 2017. Serum metabolomic profiles in neonatal mice following oral brominated flame retardant exposures to hexabromocyclododecane (HBCD) alpha, gamma, and commercial mixture. Environ Health Perspect 125:651–659; http://dx.doi.org/10.1289/EHP242

Introduction: Leukocyte telomere length (LTL) is considered a measure of cellular aging and is associated with chronic disease, including cancer. Exposure to environmental chemicals may influence L...

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"

Poly- and perfluoroalkyl acids (PFASs) are ubiquitous in our lives. These chemicals are used as surfactants and as water and oil repellents in a variety of consumer products such as cosmetics, food packaging, furnishings, and clothing. Since their initial marketing more than 60 years ago, extensive research has demonstrated that the long-chain PFASs are highly persistent, bioaccumulative, and toxic (Buck et al. 2011). As a result, they are being phased out in many countries. However, controversy has emerged regarding the safety of the most common alternatives, the short-chain PFASs. In the Madrid Statement on Poly- and Perfluoroalkyl Substances (PFASs), Blum et al. (2015) question the use of the entire class of PFASs, including short-chain fluorinated alternatives. Authored by 14 experts on the health effects, environmental fate, and policy issues concerning PFASs, the Madrid Statement documents the scientific consensus about the extreme environmental persistence, bioaccumulation, and potential toxicity of the overall class of PFASs (Blum et al. 2015). The statement defines a roadmap for scientists, governments, product manufacturers, purchasing organizations, and consumers to work together to limit the production and use of PFASs globally and to develop safer alternatives. Since it was presented at the 34th International Symposium on Halogenated Persistent Organic Pollutants, held 31 August–5 September 2014 in Madrid, Spain, 206 scientists and professionals from 40 countries have signed the Statement (Blum et al. 2015). In a response to the Madrid Statement in this issue of EHP, the FluoroCouncil, which represents the world’s leading fluorotechnology companies, agrees that it “could support many of these policy recommendations if they were limited to long-chain PFASs” (Bowman 2015). The FluoroCouncil supports the call to action from the scientific and professional community to limit the production and environmental release of long-chain PFASs but states that “the short-chain PFAS substances studied to date are not expected to harm human health or the environment,” as they “are eliminated more rapidly from the body and are less toxic than long-chain substances” (Bowman 2015). Although there is agreement regarding the shorter human half-lives of short-chain PFASs, the Helsingor Statement on PFASs (Scheringer et al. 2014) and other recent publications (Gomis et al. 2015; Wang et al. 2013, 2015) expressed concerns that fluorinated replacements are similar to the PFASs they replaced in terms of their chemical structure, environmental persistence, and hazardous potential for both the environment and humans. Given the fact that research raised concern about the long-chain PFASs for many years before action was taken and that global contamination and toxicity have been documented in the general population (Grandjean and Clapp 2014), potential risks of the short-chain PFASs should be taken into account when choosing replacements for the longer-chain compounds. There are numerous similar examples of replacements for other chemical classes, in which banned or phased-out chemicals have been replaced with structurally similar chemicals. For example, polychlorinated biphenyls were replaced with chlorinated paraffins (National Toxicology Program 2014), polybrominated diphenyl ethers were replaced with other halogenated flame retardants (Birnbaum and Staskal 2004), and bisphenol A has been replaced with bisphenol S, at least in some applications (Rochester and Bolden 2015). Such straightforward replacement strategies may be cost effective in the short term. However, manufacturers may yet incur costs if the closely related alternative is later found to be as toxic as its predecessor. In fact, there are now multi-stakeholder efforts to improve the choice of alternatives to chemicals of concern (Birnbaum 2013; National Research Council 2014). It has been difficult to find substitutes that match the function and performance level of PFASs. The chemical and thermal stability of PFASs as well as their hydrophobic and oleophobic properties provide unique material benefits (Buck et al. 2011). Significant innovation is thus required to find functional nonfluorinated alternatives to PFASs. The U.S. Environmental Protection Agency (EPA) recently recognized such innovation by awarding its 2014 Designing Greener Chemicals Award to a halogen-free firefighting foam (U.S. EPA 2014). The growing global field of chemical alternatives assessment (CAA) provides tools and strategies for identifying compounds, materials, or product designs to substitute for the use of hazardous chemicals (Lavoie et al. 2010). For example, the California Department of Toxic Substances Control is using CAA in its Safer Consumer Products Program, whose objective is to remove toxic chemicals from products (California Department of Toxic Substances Control 2010). Many CAAs have already been conducted, and many more are in progress (e.g., Substitution in Practice of Prioritized Fluorinated Chemicals to Eliminate Diffuse Sources 2015). Conducting CAAs may prove valuable in clarifying the state of the science among potential alternatives to PFASs and providing guidance for future research and innovation. Nevertheless, finding an optimal alternative substance or technology is not straightforward, and CAAs may not always offer solutions. For instance, suitable nonfluorinated alternatives for certain functions of PFASs, such as stain resistance, appear to be lacking or underdeveloped. Research is needed to understand the potential for adverse health effects from exposure to the short-chain PFASs, especially regarding low-dose endocrine disruption and immunotoxicity. In parallel, research is needed to find safe alternatives for all current uses of PFASs. The question is, should these chemicals continue to be used in consumer products in the meantime, given their persistence in the environment? And, in the absence of indisputably safe alternatives, are consumers willing to give up certain product functionalities, such as stain resistance, to protect themselves against potential health risks? These conundrums cannot be resolved by science alone but need to be considered in an open discussion informed by the scientific evidence.