The evidence that epigenomic modification by environmental factors can pose significant public health risks is substantial. Epigenomic modification can include a wide variety of health effects. Exposures during sensitive life stages (i.e., fetus, neonates and young children) may increase the incidence of early-life and later-in-life diseases with potential multigenerational effects. Despite these concerns, there is limited application of epigenetic information in risk assessments. Consequently, environmental health risks may go unaddressed. In this chapter, the risk assessment process is reviewed, and we propose a risk assessment framework to enhance characterization of risks posed by environmental exposures to epigenomic modifiers. Such improvements in risk assessment are anticipated to be useful to risk managers, risk assessors, and the public.

BACKGROUND:Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge. OBJECTIVES:Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied. METHODS:We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment. DISCUSSION:Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro, in silico, and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745.

Despite the many recent advances in the field of epigenetics, application of this knowledge in environmental health risk assessment has been limited. In this paper, we identify opportunities for application of epigenetic data to support health risk assessment. We consider current applications and present a vision for the future.

BACKGROUND:The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions. OBJECTIVE:Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures. METHODS:New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling. DISCUSSION:NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams. CONCLUSIONS:While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. Citation: Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study-highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671-1682; http://dx.doi.org/10.1289/EHP233.

Potosí, Bolivia, is the site of centuries of historic and present-day mining of the Cerro Rico, a mountain known for its rich polymetallic deposits, and was the site of large-scale Colonial era silver refining operations. In this study, the concentrations of several metal and metalloid elements were quantified in adobe brick, dirt floor, and surface dust samples from 49 houses in Potosí. Median concentrations of total mercury (Hg), lead (Pb), and arsenic (As) were significantly greater than concentrations measured in Sucre, Bolivia, a non-mining town, and exceeded US-based soil screening levels. Adobe brick samples were further analyzed for bioaccessible concentrations of trace elements using a simulated gastric fluid (GF) extraction. Median GF extractable concentrations of Hg, As, and Pb were 0.085, 13.9, and 32.2% of the total element concentration, respectively. Total and GF extractable concentrations of Hg, As, and Pb were used to estimate exposure and potential health risks to children following incidental ingestion of adobe brick particles. Risks were assessed using a range of potential ingestion rates (50–1000 mg/day). Overall, the results of the risk assessment show that the majority of households sampled contained concentrations of bioaccessible Pb and As, but not Hg, that represent a potential health risk. Even at the lowest ingestion rate considered, the majority of households exceeded the risk threshold for Pb, indicating that the concentrations of this metal are of particular concern. To our knowledge, this is the first study to quantify key trace elements in building materials in adobe brick houses and the results indicate that these houses are a potential source of exposure to metals and metalloids in South American mining communities. Additional studies are needed to fully characterize personal exposure and to understand potential adverse health outcomes within the community.

Between 1564 and 1810, nearly 17,000 metric tons of mercury (Hg) vapor was released to the environment during cinnabar refining in the small town of Huancavelica, Peru. The present study characterizes individual exposure to mercury using total and speciated Hg from residential samples, total Hg in hair, and self-reported questionnaire data regarding factors influencing exposure (e.g., frequency of fish consumption, occupation). Total Hg concentrations in hair from 118 participants ranged from 0.10 to 3.6 µg/g, similar to concentrations found in the USA and lower than concentrations in other Hg-exposed populations around the world. Pearson's correlation coefficients for data in this study suggest that there is a positive correlation between concentrations of total Hg in hair and concentrations of total Hg in adobe bricks, dirt floors, and surface dust; however, these correlations are not statistically significant. Results of a one-way analysis of variance (ANOVA) identified that total Hg concentrations in hair were significantly related to gender (p < 0.001), living in a neighborhood where smelters were previously located (p = 0.021), smoking status (p = 0.003), frequency of house cleaning (p = 0.019), and frequency of fish consumption (p = 0.046). These results highlight the need for further studies to better characterize Hg exposure in Huancavelica, particularly as related to residential contamination. A comprehensive analysis of residential Hg contamination and exposure in Huancavelica will guide the development and implementation of mitigation and remediation strategies in the community to reduce potential health risks from residential Hg exposure.

BACKGROUND:The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses. OBJECTIVE:We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization. METHODS:We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by the RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from international authorities. DISCUSSION:Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not find close agreement for lymphoma/leukemia of the respiratory tract or for neoplasms of the inner ear and cranium. Here we discuss a) the implications of the PWG findings, particularly lymphoma diagnostic issues; b) differences between RI studies and those from other laboratories that are relevant to evaluating RI cancer bioassays; and c) future work that may help resolve some concerns. CONCLUSIONS:We concluded that a) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia), as well as for neoplasms of the inner ear and cranium, and b) there is consistency and value in RI studies for identification of other chemical-related neoplasia.

This is the first study of adobe brick contamination anywhere in the world. Huancavelica, Peru is the site of historic cinnabar refining and one of the most mercury (Hg) contaminated urban areas in the world. Over 80% of homes in Huancavelica are constructed with adobe bricks made from Hg contaminated soil. In this study we measured total Hg concentrations in adobe brick, dirt floor, surface dust, and air samples from the interior of 60 adobe brick houses located in four neighborhoods. Concentrations of total Hg in adobe bricks, dirt floors, and surface dust ranged from 8.00 to 1070 µg/g, 3.06 to 926 µg/g, and 0.02 to 9.69 µg/wipe, respectively, with statistically significant differences between the four neighborhoods. Concentrations of Hg in adobe brick and dirt floor samples in Huancavelica were orders of magnitude higher than in Ayacucho, a non-mining town in Peru. A strong correlation exists between total Hg concentrations in adobe bricks and dirt floors which confirms that adobe bricks were being made on-site and not purchased from an off-site source. A strong correlation between surface dust and adobe bricks and dirt floors indicates that walls and floors serve as indoor sources of Hg contamination. Elemental Hg vapor concentrations were below detection (<0.5 µg/m3) in most homes; however in homes with detectable levels, concentrations up to 5.1 µg/m3 were observed. No statistically significant differences in Hg vapor measurements were observed between neighborhoods. This study demonstrates that building materials used widely in developing communities, such as adobe bricks, may be a substantial source of residential Hg exposure in silver or gold refining communities where Hg is produced or used for amalgamation in artisanal gold production.

Estimates of internal dosimetry for acrylamide (AA, 2-propenamide; CASRN: 79-06-1) and its active metabolite glycidamide (GA) were compared using either biomarkers of internal exposure (hemoglobin adduct levels in rats and humans) or a PBTK model (Sweeney et al., 2010). The resulting impact on the human equivalent dose (HED, oral exposures), the human equivalent concentration (HEC, inhalation), and final reference values was also evaluated. Both approaches yielded similar AA HEDs and HECs for the most sensitive noncancer effect of neurotoxicity, identical oral reference doses (RfD) of 2 × 10−3 mg AA/kg bw/d, and nearly identical inhalation reference concentrations (RfC = 0.006 mg/m3 and 0.007 mg/m3, biomarker and PBTK results, respectively). HED and HEC values for carcinogenic potential were very similar, resulting in identical inhalation unit risks of 0.1/(mg AA/m3), and nearly identical oral cancer slope factors (0.4 and 0.5/mg AA/kg bw/d), biomarker and PBTK results, respectively. The concordance in estimated HEDs, HECs, and reference values from these two diverse methods increases confidence in those values. Advantages and specific application of each approach are discussed. (Note: Reference values derived with the PBPK model were part of this research, and do not replace values currently posted on IRIS: http://www.epa.gov/iris/toxreviews/0286tr.pdf.)

Detailed Spanish records of cinnabar mining and mercury production during the colonial period in Huancavelica, Peru were examined to estimate historical health risks to the community from exposure to elemental mercury (Hg) vapor resulting from cinnabar refining operations. Between 1564 and 1810, nearly 17,000 metric tons of Hg were released to the atmosphere in Huancavelica from Hg production. AERMOD was used with estimated emissions and source characteristics to approximate historic atmospheric concentrations of mercury vapor. Modeled 1-hour and long-term concentrations were compared with present-day inhalation reference values for elemental Hg. Estimated 1-hour maximum concentrations for the entire community exceeded present-day occupational inhalation reference values, while some areas closest to the smelters exceeded present-day emergency response guideline levels. Estimated long-term maximum concentrations for the entire community exceeded the EPA Reference Concentration (RfC) by a factor of 30 to 100, with areas closest to the smelters exceeding the RfC by a factor of 300 to 1000. Based on the estimated historical concentrations of Hg vapor in the community, the study also measured the extent of present-day contamination throughout the community through soil sampling and analysis. Total Hg in soils sampled from 20 locations ranged from 1.75 to 698 mg/kg and three adobe brick samples ranging from 47.4 to 284 mg/kg, consistent with other sites of mercury mining and use. The results of the soil sampling indicate that the present-day population of Huancavelica is exposed to levels of mercury from legacy contamination which is currently among the highest worldwide, consequently placing them at potential risk of adverse health outcomes.

Background and Aims: Standard setting, science assessments, and research related to evaluating and reducing the human health effects of exposure to air pollutants have largely focused on single-pollutant approaches. Nonetheless, it has long been recognized that human populations are exposed to a complex mixture of air pollutants that varies in time and space. This work describes efforts of the U.S. Environmental Protection Agency (EPA) to move toward multipollutant approaches to evaluating the human health effects of exposure to air pollution. Methods: Scientists with EPA's National Center for Environmental Assessment (NCEA) are evaluating the feasibility of assessing the health effects of exposure to air pollutant mixtures as a part of ongoing reviews of the U.S. National Ambient Air Quality Standards (NAAQS). Overcoming the scientific and logistical challenges associated with conducting such an assessment will involve extensive collaboration with partners and stakeholders in government, industry, academia, and the broader research community. Results: EPA has developed plans to conduct a multipollutant science assessment whereby the health effects of exposures to mixtures of air pollutants may be systematically evaluated. While legally mandated schedules for completing reviews of the NAAQS somewhat complicates the simultaneous assessment of all air pollutants for which NAAQS have been established, there is a clear need to more explicitly address multipollutant issues in the NAAQS review process. Initial plans, scope and approaches related to the development of the proposed multipollutant science assessment will be presented and discussed. Conclusions: Although there are considerable scientific and regulatory challenges associated with adopting multipollutant approaches for the evaluation of air pollution-induced health effects, significant progress can be made in the near future through parallel advancements in multipollutant policy, health assessments and research. (Disclaimer: The views expressed are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA.)

A session entitled "Emerging Contaminants" was held in April 2009 in Cincinnati, OH at the 2009 Toxicology and Risk Assessment Conference. The purpose of the session was to share information on both programmatic and technical aspects associated with emerging contaminants. Emerging contaminants are chemicals or materials that are characterized by a perceived or real threat to human health or environment, a lack of published health standards or an evolving standard. A contaminant may also be "emerging" because of the discovery of a new source, a new pathway to humans, or a new detection method or technology. The session included five speakers representing the Department of Defense (DoD), the Environmental Protection Agency (EPA), and each of the military services. The DoD created the Emerging Contaminant Directorate to proactively address environmental, health, and safety concerns associated with emerging contaminants. This session described the scan-watch-action list process, impact assessment methodology, and integrated risk management concept that DoD has implemented to manage emerging contaminants. EPA presented emerging trends in health risk assessment. Researchers made technical presentations on the status of some emerging contaminates in the assessment process (i.e. manganese, RDX, and naphthalene).

Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde-exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta-analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde-induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde-DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia. Environ. Mol. Mutagen., 2010. Published 2009 Wiley-Liss, Inc.

Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde-exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta-analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde-induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde-DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia.

Detailed Spanish records of mercury use and silver production during the colonial period in Potosi, Bolivia were evaluated to estimate atmospheric emissions of mercury from silver smelting. Mercury was used in the silver production process in Potosi and nearly 32,000 metric tons of mercury were released to the environment. AERMOD was used in combination with the estimated emissions to approximate historical air concentrations of mercury from colonial mining operations during 1715, a year of relatively low silver production. Source characteristics were selected from archival documents, colonial maps and images of silver smelters in Potosi and a base case of input parameters was selected. Input parameters were varied to understand the sensitivity of the model to each parameter. Modeled maximum 1-h concentrations were most sensitive to stack height and diameter, whereas an index of community exposure was relatively insensitive to uncertainty in input parameters. Modeled 1-h and long-term concentrations were compared to inhalation reference values for elemental mercury vapor. Estimated 1-h maximum concentrations within 500 m of the silver smelters consistently exceeded present-day occupational inhalation reference values. Additionally, the entire community was estimated to have been exposed to levels of mercury vapor that exceed present-day acute inhalation reference values for the general public. Estimated long-term maximum concentrations of mercury were predicted to substantially exceed the EPA Reference Concentration for areas within 600 m of the silver smelters. A concentration gradient predicted by AERMOD was used to select soil sampling locations along transects in Potosi. Total mercury in soils ranged from 0.105 to 155 mg kg(-1), among the highest levels reported for surface soils in the scientific literature. The correlation between estimated air concentrations and measured soil concentrations will guide future research to determine the extent to which the current community of Potosi and vicinity is at risk of adverse health effects from historical mercury contamination. (C) 2010 Elsevier Ltd. All rights reserved.

BACKGROUND:Quantifying the benefits of reducing hazardous air pollutants (HAPs, or air toxics) has been limited by gaps in toxicological data, uncertainties in extrapolating results from high-dose animal experiments to estimate human effects at lower doses, limited ambient and personal exposure monitoring data, and insufficient economic research to support valuation of the health impacts often associated with exposure to individual air toxics. OBJECTIVES:To address some of these issues, the U.S. Environmental Protection Agency held the Workshop on Estimating the Benefits of Reducing Hazardous Air Pollutants (HAPs) in Washington, DC, from 30 April to 1 May 2009. DISCUSSION:Experts from multiple disciplines discussed how best to move forward on air toxics benefits assessment, with a focus on developing near-term capability to conduct quantitative benefits assessment. Proposed methodologies involved analysis of data-rich pollutants and application of this analysis to other pollutants, using dose-response modeling of animal data for estimating benefits to humans, determining dose-equivalence relationships for different chemicals with similar health effects, and analysis similar to that used for criteria pollutants. Limitations and uncertainties in economic valuation of benefits assessment for HAPS were discussed as well. CONCLUSIONS:These discussions highlighted the complexities in estimating the benefits of reducing air toxics, and participants agreed that alternative methods for benefits assessment of HAPs are needed. Recommendations included clearly defining the key priorities of the Clean Air Act air toxics program to identify the most effective approaches for HAPs benefits analysis, focusing on susceptible and vulnerable populations, and improving dose-response estimation for quantification of benefits.

The purpose of this article is to review approaches to air quality management (AQM) in the United States. To characterize AQM in the United States, four examples that addressed local, regional, and global scale air pollution are described. These examples include: (1) the Hazardous Air Pollutants (HAPs) program, (2) National Ambient Air Quality Standards (NAAQS) program, (3) "Cap & Trade" programs, and (4) U.S. global pollution control efforts. These four examples were chosen because each presents a different approach to AQM. This was not intended to be a comprehensive description of U.S. AQM programs, but rather representative of selected examples that highlight the themes of this program. Some general principles that are illustrated in the article and are considered important characteristics of U.S. AQM are:Ensure open access to information and transparency in decision making.Develop and sustain a well-trained workforce.Facilitate training, networking, and technology transfer among air quality managers.Integrate planning and coordination of efforts across jurisdictions (across federal, state, and local agencies).Educate and encourage participation of stakeholders.Balance of societal benefits and costs.Apply innovative approaches, where possible.Fund research to improve the scientific basis for problem identification and effective AQM strategy development.

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 on 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.