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BackgroundDespite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus.ObjectiveThe aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood.MethodsWe collected experimental values of the concentration ratio between cord and maternal blood (RCM) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred. Weused the compiled database to, train and test an artificial neural network (ANN). And then applied the best performing model to predict RCM for a large dataset of PFAS chemicals (n = 7982). We, finally, examined the calculatedphysicochemical descriptors of the chemicals to identify which properties correlated significantly with RCM.ResultsWe determined that 7855 compounds were within the applicability domain and 127 compounds are outside the applicability domain of our model. Our predictions of RCM for PFAS suggested that 3623 compounds had a log RCM > 0 indicating preferable partitioning to cord blood. Some examples of these compounds were bisphenol AF, 2,2-bis(4-aminophenyl)hexafluoropropane, and nonafluoro-tert-butyl 3-methylbutyrate.SignificanceThese observations have important public health implications as many PFAS have been shown to interfere with fetal development.In addition, asthese compounds are highly persistent and many of them can readilycross the placenta,they are expected to remain in the population for a long time as they are being passed from parent to offspring.ImpactUnderstanding the behavior of chemicals in the human body during pregnancy is critical in preventing harmful exposures during critical periods of development. Many chemicals can cross the placenta and expose the fetus, however, the mechanism by which this transport occurs is not well understood. In our study, we developed a machine learning model that describes the transplacental transfer of chemicals as a function of their physicochemical properties. The model was then used to make predictions for a set of 7982 per-and polyfluorinated alkyl substances that are listed on EPA's CompTox Chemicals Dashboard.The model can be applied to make predictions for other chemical categories of interest, such as plasticizers and pesticides. Accurate predictions of RCMcan help scientists and regulators to prioritize chemicals that have the potential to cause harm by exposing the fetus.

BackgroundKey characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents.ObjectivesThe goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs.MethodsA committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity.DiscussionKCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800.

On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and ΔWhile the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III).Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. ΔIn reaching its decision to list cannabis and Δ

This review focuses on neurodevelopmental effects observed in animal studies of cannabis smoke and Δ

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ

Background: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. Objectives: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. Methods: An expert working group was convened to discuss mechanisms associated with CV toxicity. Results: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1–4 below), the vascular system (5–7), or both (8–12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. Discussion: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA's ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n = 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of-concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams.

BackgroundPeople are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design.ObjectivesThe objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches.MethodsA working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development.Results and discussionThree approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. https://doi.org/10.1289/EHP8525.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro. We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention. See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach., In this Expert Consensus Statement, the authors define 10 key characteristics (KCs) for endocrine-disrupting chemicals. They further describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs.

BackgroundIdentification of female reproductive toxicants is currently based largely on integrated epidemiological and invivo toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.ObjectiveWe sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.MethodsA working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell–cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways; and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics.DiscussionFuture efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use. https://doi.org/10.1289/EHP4971.

Background: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. Objectives: The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. Discussion: The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045

Background: There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Objective: Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? Methods: We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. Results: We found 4282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: −0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: −0.38, −0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall, we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a “moderate/low” quality rating to the body of evidence for human thyroid hormone alterations and a “moderate” quality rating to the body of evidence for non-human thyroid hormone alterations. Conclusion: Based on this application of the Navigation Guide systematic review methodology, we concluded that there was “sufficient” non-human evidence and “inadequate” human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is “possibly toxic” to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated. Keywords: Soap, Personal care, Antibacterial, Thyroid, Policy, Risk assessment

Author(s): Vesterinen, Hanna M; Morello-Frosch, Rachel; Sen, Saunak; Zeise, Lauren; Woodruff, Tracey J | Abstract: BackgroundAdverse effects of prenatal stress or environmental chemical exposures on fetal growth are well described, yet their combined effect remains unclear.ObjectivesTo conduct a systematic review on the combined impact and interaction of prenatal exposure to stress and chemicals on developmental outcomes.MethodsWe used the first three steps of the Navigation Guide systematic review. We wrote a protocol, performed a robust literature search to identify relevant animal and human studies and extracted data on developmental outcomes. For the most common outcome (fetal growth), we evaluated risk of bias, calculated effect sizes for main effects of individual and combined exposures, and performed a random effects meta-analysis of those studies reporting on odds of low birthweight (LBW) by smoking and socioeconomic status (SES).ResultsWe identified 17 human- and 22 animal-studies of combined chemical and stress exposures and fetal growth. Human studies tended to have a lower risk of bias across nine domains. Generally, we found stronger effects for chemicals than stress, and these exposures were associated with reduced fetal growth in the low-stress group and the association was often greater in high stress groups, with limited evidence of effect modification. We found smoking associated with significantly increased odds of LBW, with a greater effect for high stress (low SES; OR 4.75 (2.46-9.16)) compared to low stress (high SES; OR 1.95 (95% CI 1.53-2.48)). Animal studies generally had a high risk of bias with no significant combined effect or effect modification.ConclusionsWe found that despite concern for the combined effects of environmental chemicals and stress, this is still an under-studied topic, though limited available human studies indicate chemical exposures exert stronger effects than stress, and this effect is generally larger in the presence of stress.

Summary: Regulatory agencies face daunting challenges identifying emerging chemical hazards because of the large number of chemicals in commerce and limited data on exposure and toxicology. Evaluating one chemical at a time is inefficient and can lead to replacement with uncharacterized chemicals or chemicals with structural features already linked to toxicity. The Office of Environmental Health Hazard Assessment (OEHHA) has developed a process for constructing and assessing chemical groups for potential biomonitoring in California. We screen for chemicals with significant exposure potential and propose possible chemical groups, based on structure and function. To support formal consideration of these groups by Biomonitoring California’s Scientific Guidance Panel, we conduct a detailed review of exposure and toxicity data and examine the likelihood of detection in biological samples. To date, 12 chemical groups have been constructed and added to the pool of chemicals that can be selected for Biomonitoring California studies, including p,p´-bisphenols, brominated and chlorinated organic compounds used as flame retardants, non-halogenated aromatic phosphates, and synthetic polycyclic musks. Evaluating chemical groups, rather than individual chemicals, is an efficient way to respond to shifts in chemical use and the emergence of new chemicals. This strategy can enable earlier identification of important chemicals for monitoring and intervention.

Global climate change (GCC) is likely to alter the degree of human exposure to pollutants and the response of human populations to these exposures, meaning that risks of pollutants could change in the future. The present study, therefore, explores how GCC might affect the different steps in the pathway from a chemical source in the environment through to impacts on human health and evaluates the implications for existing risk-assessment and management practices. In certain parts of the world, GCC is predicted to increase the level of exposure of many environmental pollutants due to direct and indirect effects on the use patterns and transport and fate of chemicals. Changes in human behavior will also affect how humans come into contact with contaminated air, water, and food. Dietary changes, psychosocial stress, and coexposure to stressors such as high temperatures are likely to increase the vulnerability of humans to chemicals. These changes are likely to have significant implications for current practices for chemical assessment. Assumptions used in current exposure-assessment models may no longer apply, and existing monitoring methods may not be robust enough to detect adverse episodic changes in exposures. Organizations responsible for the assessment and management of health risks of chemicals therefore need to be more proactive and consider the implications of GCC for their procedures and processes. Environ. Toxicol. Chem. 2013;32:62–78. © 2012 SETAC

US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern.

Copyright © 2016 by Annual Reviews. All rights reserved. Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces. Environmental exposures may interact with social stressors, thereby worsening health outcomes. Age, genetic characteristics, and preexisting health conditions increase the risk of adverse health effects from exposure to pollutants. There are existing approaches for characterizing cumulative exposures, cumulative risks, and cumulative health impacts. Although such approaches have merit, they also have significant constraints. New developments in exposure monitoring, mapping, toxicology, and epidemiology, especially when informed by community participation, have the potential to advance the science on cumulative impacts and to improve decision making.

Bisphenol A (BPA) exposure has been documented in pregnant women, but consequences for development are not yet widely studied in human populations. This review presents research on the consequences for offspring of BPA exposure during pregnancy. Extensive work in laboratory rodents has evaluated survival and growth of the conceptus, interference with embryonic programs of development, morphological sex differentiation, sex differentiation of the brain and behavior, immune responsiveness, and mechanism of action. Sensitive measures include RAR, aryl hydrocarbon receptor, and Hox A10 gene expression, anogenital distance, sex differentiation of affective and exploratory behavior, and immune hyperresponsiveness. Many BPA effects are reported at low doses (10-50 µg/kg d range) by the oral route of administration. At high doses (>500,000 µg/kg d) fetal viability is compromised. Much of the work has centered around the implications of the estrogenic actions of this agent. Some work related to thyroid mechanism of action has also been explored. BPA research has actively integrated current knowledge of developmental biology, concepts of endocrine disruption, and toxicological research to provide a basis for human health risk assessment.

Objectives There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. Data sources For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. Data extraction Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. Data synthesis Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. Conclusions Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

At the request of the U.S. Environmental Protection Agency (EPA), the National Research Council (NRC) recently completed a major report, Science and Decisions: Advancing Risk Assessment, that is intended to strengthen the scientific basis, credibility, and effectiveness of risk assessment practices and subsequent risk management decisions. The report describes the challenges faced by risk assessment and the need to consider improvements in both the technical analyses of risk assessments (i.e., the development and use of scientific information to improve risk characterization) and the utility of risk assessments (i.e., making assessments more relevant and useful for risk management decisions). The report tackles a number of topics relating to improvements in the process, including the design and framing of risk assessments, uncertainty and variability characterization, selection and use of defaults, unification of cancer and noncancer dose-response assessment, cumulative risk assessment, and the need to increase EPA's capacity to address these improvements. This article describes and summarizes the NRC report, with an eye toward its implications for risk assessment practices at EPA.

At the request of the Environmental Protection Agency, the National Research Council (NRC) recently completed a major report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The terms of reference for this report were to develop a long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental agents. The report describes how current and anticipated scientific advances can be expected to transform toxicity testing to permit broader coverage of the universe of potentially toxic chemicals to which humans may be exposed, using more timely and more cost-effective methods for toxicity testing. The report envisages greatly expanded use of high- and medium-throughput in vitro screening assays, computational toxicology, and systems biology, along with other emerging high-content testing methodologies, such as functional genomics and transcriptomics. When fully implemented, the vision will transform the ways toxicity testing and chemical risk assessment are conducted, moving away from measuring apical health endpoints in experimental animals toward identification of significant perturbations of toxicity pathways using in vitro tests in human cells and cell lines. Population-based studies incorporating relevant biomarkers will also be useful in identifying pathway perturbations directly in humans and in interpreting the results of in vitro tests in the context of human health risk assessment. The present article summarizes and extends the NRC report and examines its implications for risk assessment practice.

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23–24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.

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

In 1987 investigators in Liaoning Province China reported that mortality rates for all cancer stomach cancer and lung cancer in 1970-1978 were higher in villages with hexavalent chromium (Cr/+6)-contaminated drinking water than in the general population. The investigators reported rates but did not report statistical measures of association or precision. Using reports and other communications from investigators at the local Jinzhou Health and Anti-Epidemic Station we obtained data on Cr/+6 contamination of groundwater and cancer mortality in 9 study regions near a ferrochromium factory. We estimated: (1) person-years at risk in the study regions based on census and population growth rate data (2) mortality counts based on estimated person-years at risk and previously reported mortality rates and (3) rate ratios and 95% confidence intervals. The all-cancer mortality rate in the combined 5 study regions with Cr/+6-contaminated water was negligibly elevated in comparison with the rate in the 4 combined study regions without contaminated water (rate ratio = 1.13; 95% confidence interval = 0.86-1.46) but was somewhat more elevated in comparison with the whole province (1.23; 0.97-1.53). Stomach cancer mortality in the regions with contaminated water was more substantially elevated in comparison with the regions without contaminated water (1.82; 1.11-2.91) and the whole province (1.69; 1.12-2.44). Lung cancer mortality was slightly elevated in comparison with the unexposed study regions (1.15; 0.62-2.07) and more strongly elevated in comparison with the whole province (1.78; 1.03-2.87). Mortality from other cancers combined was not elevated in comparison with either the unexposed study regions (0.86; 0.53-1.36) or the whole province (0.92; 0.58-1.38). While these data are limited they are consistent with increased stomach cancer risk in a population exposed to Cr/+6 in drinking water. (authors)

The USEPA risk assessment practices for high to low dose extrapolation have evolved in response to scientific developments, regulatory need, stakeholder concerns and to further the Agency's mission...

Background Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk. Methods Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC. Results The HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist. Conclusions This approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases. Citation Schwarzman MR, Ackerman JM, Dairkee SH, Fenton SE, Johnson D, Navarro KM, Osborne G, Rudel RA, Solomon GM, Zeise L, Janssen S. 2015. Screening for chemical contributions to breast cancer risk: a case study for chemical safety evaluation. Environ Health Perspect 123:1255–1264; http://dx.doi.org/10.1289/ehp.1408337

Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates.

Author(s): Vesterinen*, Hanna; Morello-Frosch, Rachel; Sen, Saunak; Zeise, Lauren; Safdir, Hira; Woodruff, Tracey

Background: Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Objective: Our goal was to explore how next-generation human health risk assessments may better characterize variability in the context of the conceptual framework for the source-to-outcome continuum. Methods: This review was informed by a National Research Council workshop titled “Biological Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications for Decision-Making.” We considered current experimental and in silico approaches, and emerging data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of information and models relevant for assessing interindividual variability for application to human health risk assessments of environmental chemicals. Discussion: One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is that each particular pair of health outcomes and chemical exposures involves combinations of these sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, other exogenous chemical exposures). A third challenge is that different decision contexts present distinct needs regarding the identification—and extent of characterization—of interindividual variability in the human population. Conclusions: Despite these inherent challenges, opportunities exist to incorporate evidence from emerging data streams for addressing interindividual variability in a range of decision-making contexts.

We investigate, through modeling, the impact of interindividual heterogeneity in the metabolism of 4-aminobiphenyl (ABP) and in physiological factors on human cancer risk: A physiological pharmacokinetic model was used to quantify the time course of the formation of the proximate carcinogen, N-hydroxy-4-ABP and the DNA-binding of the active species in the bladder. The metabolic and physiologic model parameters were randomly varied, via Monte Carlo simulations, to reproduce interindividual variability. The sampling means for most parameters were scaled from values developed by Kadlubar et al. (Cancer Res., 51: 4371, 1991) for dogs; variances were obtained primarily from published human data (e.g., measurements of ABP N-oxidation, and arylamine N-acetylation in human liver tissue). In 500 simulations, theoretically representing 500 humans, DNA-adduct levels in the bladder of the most susceptible individuals are ten thousand times higher than for the least susceptible, and the 5th and 95th percentiles differ by a factor of 160. DNA binding for the most susceptible individual (with low urine pH, low N-acetylation and high N-oxidation activities) is theoretically one million-fold higher than for the least susceptible (with high urine pH, high N-acetylation and low N-oxidation activities). The simulations also suggest that the four factors contributing most significantly to interindividual differences in DNA-binding of ABP in human bladder are urine pH, ABP N-oxidation, ABP N-acetylation and urination frequency.

The statutory language of the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65; California Health and Safety Code 25249.5 et seq.) encourages rapid adoption of "no significant risk levels" (NSRLs), intakes associated with estimated cancer risks of no more than 1 in 100,000. Derivation of an NSRL for a carcinogen listed under Proposition 65 requires the development of a cancer potency value. This paper discusses the methodology for the derivation of cancer potencies using an expedited procedure, and provides potency estimates for a number of agents listed as carcinogens under Proposition 65. To derive expedited potency values, default risk assessment methods are applied to data sets selected from an extensive tabulation of animal cancer bioassays according to criteria used by regulatory agencies. A subset of these expedited values is compared to values previously developed by regulatory agencies using conventional quantitative risk assessment and found to be in good agreement. Specific regulatory activities which could be facilitated by adopting similar expedited procedures are identified.

There is a growing need for quantitative approaches to extrapolate relationships between chemical exposures and early biological perturbations from animals to humans given increasing use of biological assays to evaluate toxicity pathways. We have developed such an approach using polychlorinated biphenyls (PCBs) and thyroid hormone (TH) disruption as a case study. We reviewed and identified experimental animal literature from which we developed a low-dose, linear model of PCB body burdens and decrements in free thyroxine (FT 4) and total thyroxine (TT 4), accounting for 33 PCB congeners; extrapolated the dose-response from animals to humans; and compared the animal dose-response to the dose-response of PCB body burdens and TH changes from eleven human epidemiological studies. We estimated a range of potencies for PCB congeners (over 4 orders of magnitude), with the strongest for PCB 126. Our approach to developing toxic equivalency models produced relative potencies similar to the toxicity equivalency factors (TEFs) from the World Health Organization (WHO). We generally found that the dose-response extrapolated from the animal studies tends to under-predict the dose-response estimated from human epidemiological studies. A quantitative approach to evaluating the relationship between chemical exposures and TH perturbations, based on animal data can be used to assess human health consequences of thyroid toxicity and inform decision-making. © 2012 Elsevier Inc.

Polluting facilities and hazardous sites are often concentrated in low-income communities of color already facing additional stressors to their health. The influence of socioeconomic status is not considered in traditional models of risk assessment. We describe a pilot study of a screening method that considers both pollution burden and population characteristics in assessing the potential for cumulative impacts. The goal is to identify communities that warrant further attention and to thereby provide actionable guidance to decision- and policy-makers in achieving environmental justice. The method uses indicators related to five components to develop a relative cumulative impact score for use in comparing communities: exposures, public health effects, environmental effects, sensitive populations and socioeconomic factors. Here, we describe several methodological considerations in combining disparate data sources and report on the results of sensitivity analyses meant to guide future improvements in cumulative impact assessments. We discuss criteria for the selection of appropriate indicators, correlations between them, and consider data quality and the influence of choices regarding model structure. We conclude that the results of this model are largely robust to changes in model structure.

The California Environmental Protection Agency (Cal/EPA) Environmental Justice Action Plan calls for guidelines for evaluating “cumulative impacts.” As a first step toward such guidelines, a screening methodology for assessing cumulative impacts in communities was developed. The method, presented here, is based on the working definition of cumulative impacts adopted by Cal/EPA [1]: “Cumulative impacts means exposures, public health or environmental effects from the combined emissions and discharges in a geographic area, including environmental pollution from all sources, whether single or multi-media, routinely, accidentally, or otherwise released. Impacts will take into account sensitive populations and socio-economic factors, where applicable and to the extent data are available.” The screening methodology is built on this definition as well as current scientific understanding of environmental pollution and its adverse impacts on health, including the influence of both intrinsic, biological factors and non-intrinsic socioeconomic factors in mediating the effects of pollutant exposures. It addresses disparities in the distribution of pollution and health outcomes. The methodology provides a science-based tool to screen places for relative cumulative impacts, incorporating both the pollution burden on a community- including exposures to pollutants, their public health and environmental effects- and community characteristics, specifically sensitivity and socioeconomic factors. The screening methodology provides relative rankings to distinguish more highly impacted communities from less impacted ones. It may also help identify which factors are the greatest contributors to a community’s cumulative impact. It is not designed to provide quantitative estimates of community-level health impacts. A pilot screening analysis is presented here to illustrate the application of this methodology. Once guidelines are adopted, the methodology can serve as a screening tool to help Cal/EPA programs prioritize their activities and target those communities with the greatest cumulative impacts.

Background Increasing data on early biological changes from chemical exposures requires new interpretation tools to support decision-making. Objectives To test the possibility of applying a quantitative approach using human data linking chemical exposures and upstream biological perturbations to overt downstream outcomes. Methods Using polychlorinated biphenyl (PCB) exposures and maternal thyroid hormone (TH) perturbations as a case study, we model three relationships: (1) prenatal PCB exposures and TH changes, using free T 4 (FT 4 ); (2) prenatal TH and childhood neurodevelopmental outcomes; and (3) prenatal PCB exposures and childhood neurodevelopmental outcomes (IQ). We surveyed the epidemiological literature; extracted relevant quantitative data; and developed models for each relationship, applying meta-analysis where appropriate. Results For relationship 1, a meta-analysis of 3 studies gives a coefficient of −0.27 pg/mL FT 4 per ln(sum of PCBs) (95% confidence interval [CI] −0.82 to 0.27). For relationship 2, regression coefficients from three studies of maternal FT 4 levels and cognitive scores ranged between 0.99 IQ points/(pg/mL FT 4 ) (95% CI −0.31 to 2.2) and 7.6 points/(pg/mL FT 4 ) (95% CI 1.2 to 16.3). For relationship 3, a meta-analysis of five studies produces a coefficient of −1.98 IQ points (95% CI −4.46 to 0.50) per unit increase in ln(sum of PCBs). Combining relationships 1 and 2 yields an estimate of −2.0 to −0.27 points of IQ per unit increase in ln(sum of PCBs). Conclusions Combining analysis of chemical exposures and early biological perturbations (PCBs and FT 4 ) with analysis of early biological perturbations and downstream overt effects (FT 4 and IQ) yields estimates within the range of studies of exposures and overt effects (PCBs and IQ). This is an example approach using upstream biological perturbations for effect prediction.

Protecting the health of the public—particularly the most vulnerable groups, such as children—requires rethinking current approaches to reducing environmental risks. We review the evolving understanding of the relationship between exposure to chemicals in the environment and disease, as well as the current state of managing those chemicals. We present recommendations to improve current approaches, including a renewed focus on health and acknowledging the contribution of the environment, flipping the burden of proof so that chemicals are not presumed safe in the absence of scientific data, and modernizing approaches to assessing health risks.

At the request of the U.S. Environmental Protection Agency (EPA), the National Research Council (NRC) recently completed a major report, Science and Decisions: Advancing Risk Assessment, that is intended to strengthen the scientific basis, credibility, and effectiveness of risk assessment practices and subsequent risk management decisions. The report describes the challenges faced by risk assessment and the need to consider improvements in both the technical analyses of risk assessments (i.e., the development and use of scientific information to improve risk characterization) and the utility of risk assessments (i.e., making assessments more relevant and useful for risk management decisions). The report tackles a number of topics relating to improvements in the process, including the design and framing of risk assessments, uncertainty and variability characterization, selection and use of defaults, unification of cancer and noncancer dose-response assessment, cumulative risk assessment, and the need to increase EPA's capacity to address these improvements. This article describes and summarizes the NRC report, with an eye toward its implications for risk assessment practices at EPA.