The US Environmental Protection Agency (EPA) has developed a framework for human health risk assessment to inform decision making. The National Research Council, in Science and Decisions, recommended that EPA adopt a framework for risk-based decision making, which maximises the utility of risk assessment. The framework considers the NRC's recommendations and builds upon existing agency guidance by emphasising the need to design risk assessments to provide information most applicable to the decision-making process. The framework ties together existing human health guidance, is flexible to accommodate the range of assessments conducted across the agency as well as future advances in risk assessment science, and considers overarching themes including environmental justice and susceptible lifestage risk. The framework integrates the concepts of planning and scoping and problem formulation and provides for incorporation of stakeholder involvement and peer review.

Summary:This article provides an overview of public health efforts by the U.S. Environmental Protection Agency (EPA) during the past two decades to protect children’s health from environmental hazards. It highlights examples of concrete steps and accomplishments toward improving environmental protection and health outcomes achieved through public policy, rules and regulations, increased scientific understanding, and public health messaging. Additionally, examples of future challenges for better understanding and improving children’s environmental health are discussed.

In this paper, we summarize exposure-related issues to consider in determining the most appropriate age ranges and life stages for risk assessment. We then propose a harmonized set of age bins for monitoring and assessing risks from exposures to chemicals for global use. The focus is on preconception through adolescence, though the approach should be applicable to additional life stages. A two-tiered set of early life age groups is recommended. The first tier involves the adoption of guidance similar to the childhood age groups recommended by the U.S. Environmental Protection Agency, whereas the second tier consolidates some of those age groups to reduce the burden of developing age-specific exposure factors for different regions. While there is no single "correct" means of choosing a common set of age groups to use internationally in assessing early life exposure and risk, use of a set of defined age groups is recommended to facilitate comparisons of potential exposures and risks around the globe, the collection of data and analyses of aggregate exposure and cumulative risk. Application of these age groups for robust assessment of exposure and risk for specific populations will require region-specific exposure factors as well as local environmental monitoring data.

In the 2007 report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences envisioned a major transition in toxicity testing from cumbersome, expensive, and lengthy in vivo testing with qualitative endpoints, to in vitro robotic high-throughput screening with mechanistic quantitative parameters. Recognizing the need for agencies to partner and collaborate to ensure global harmonization, standardization, quality control and information sharing, the U.S. Environmental Protection Agency is leading by example and has established an intra-agency Future of Toxicity Testing Workgroup (FTTW). This workgroup has produced an ambitious blueprint for incorporating this new scientific paradigm to change the way chemicals are screened and evaluated for toxicity. Four main components of this strategy are discussed, as follows: (1) the impact and benefits of various types of regulatory activities, (2) chemical screening and prioritization, (3) toxicity pathway-based risk assessment, and (4) institutional transition. The new paradigm is predicated on the discovery of molecular perturbation pathways at the in vitro level that predict adverse health effects from xenobiotics exposure, and then extrapolating those events to the tissue, organ, or whole organisms by computational models. Research on these pathways will be integrated and compiled using the latest technology with the cooperation of global agencies, industry, and other stakeholders. The net result will be that chemical toxicity screening will become more efficient and cost-effective, include real-world exposure assessments, and eliminate currently used uncertainty factors.

Children's susceptibility to environmental contaminants can vary significantly by life stage. The recent adoption by the US Environmental Protection Agency of a standard set of childhood age groups is proving instrumental in improving our ability to protect children by more consistently considering life-stage changes when assessing exposure, dose, and risk.

Increasing attention has been placed on inhalation dosimetry in children because of children's greater air intake rate and unique windows of vulnerability for various toxicants and health outcomes. However, risk assessments have not incorporated this information because dosimetric adjustments have focused upon extrapolation across species rather than across age groups within the human population. The objectives of this study were to synthesize information regarding child/adult intake and dosimetry differences for particles and gases for potential application to risk assessment. Data and models gathered at a 2006 workshop and more recent studies were reviewed to better understand lung development and inhaled dose in children. The results show that child/adult differences exist both on a chemical intake basis and on a deposited or systemic dose basis. These differences can persist for several years and are not captured by standard intraspecies uncertainty factors or by USEPA's reference concentration (RfC) methodology. Options for incorporating children's inhalation exposures into human risk assessments include (1) 3-fold default air intake adjustment for the first 3 years of life with a reduced factor for older children; (2) superseding this default via simplified dosimetry models akin to USEPA's RfC methodology modified for children; (3) utilizing more sophisticated models with better anatomical and air flow descriptions; (4) running these models with input distributions to reflect interchild variability; (5) developing more advanced approaches involving imaging techniques and computational fluid dynamic (CFD) models. These options will enable children's inhaled dose to have a quantitative role in risk assessment that has been lacking and will establish a basis for ongoing research.

Vol. 117, No. 7 PerspectivesOpen AccessThe Future of Toxicity Testing for Environmental Contaminants Melissa G. Kramer, Michael Firestone, Robert Kavlock, and Harold Zenick Melissa G. Kramer Search for more papers by this author , Michael Firestone Search for more papers by this author , Robert Kavlock Search for more papers by this author , and Harold Zenick Search for more papers by this author Published:1 July 2009https://doi.org/10.1289/ehp.12891Cited by:2AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Toxicity testing and assessment sit on the cusp of a transformational change brought about by the rapid emergence of tools and capabilities in molecular biology and computational and informational sciences. This transformation has the potential to dramatically reshape the philosophy and approaches underlying toxicity testing and the assessment of human health risks associated with exposure to environmental contaminants.Such a transformation is especially significant for agencies that are responsible for implementing congressionally mandated programs under which the risks of exposure to a wide variety of environmental pollutants are assessed and regulated. Most often, such regulatory decisions have relied on toxicity testing data obtained nearly exclusively from experimental animal models. This approach, however, presents challenges in accommodating the need for more efficient and cost-effective means to screen and prioritize chemicals for testing and addressing increasingly complex issues such as life-stage susceptibility and genetic variations in the human population, the risks of concurrent, cumulative exposure to multiple and diverse chemicals, and, fundamental to all, improved understanding of the mechanism through which toxicity occurs.The U.S. Environmental Protection Agency (EPA) has recognized the potential application of emerging science to improve toxicity testing and risk assessment (U.S. EPA 2002U.S. EPA 2004), notably by taking the lead in commissioning the National Research Council (NRC) in 2004 to review existing strategies (NRC 2006) and develop a long-range vision for toxicity testing and risk assessment (NRC 2007). Beyond EPA, other federal programs have also recognized the need for this transformative shift, as reflected in the National Toxicology Program’s (NTP) A National Toxicology Program for the 21st Century: Roadmap for the Future (NTP 2004) and the Food and Drug Administration’s FDA’s Critical Path Initiative (FDA 2008).To build on the NRC document, the U.S. EPA established an internal, cross-agency workgroup that produced The U.S. Environmental Protection Agency’s Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA 2009) to provide a framework for EPA to comprehensively move forward to incorporate this new scientific paradigm into future toxicity testing and risk assessment practices. The strategy is centered on three interrelated issues: a) the use of toxicity pathways information in screening and prioritization of chemicals for further testing; b) the use of toxicity pathways information in risk assessment; and c) organizational transition. The last element explicitly recognizes that regulatory offices within EPA will need to be actively involved in overseeing the significant transition to this new paradigm and the translation of the attendant data for regulatory application.Research to address the first issue will build on the efforts of EPA’s ToxCast program in identifying and developing simple, reliable screening models to predict chemical hazard (U.S. EPA 2008a). The second effort will seek to apply the toxicity pathways concept in a systems biology approach, to better delineate the molecular and cellular changes that perturb normal homeostatic mechanisms toward a given toxicity pathway or set of toxicity pathways. This information should reduce the uncertainty currently associated with dose–response models by increasing their biological plausibility.Recognizing the necessity and benefits of collaboration to achieve the NRC’s vision, EPA recently signed a Memorandum of Understanding with the NTP and the National Institutes of Health Chemical Genomics Center (U.S. EPA(2008b) to advance the high throughput screening and toxicity pathway profiling in risk assessment. This “Tox21” consortium is now actively coordinating efforts to identify chemicals, pathways, screening assays, and informatic approaches to assess the effects of thousands of chemicals (Kavlock et al. 2009). The U.S. EPA is also working with the European Commission and the Organization for Economic Cooperation and Development to facilitate global collaborations.As recognized by the NRC (2007), the development and implementation of a transformational paradigm will require a major commitment to new funding to sustain an iterative and long-term process that changes institutional toxicity testing and risk assessment practices. Regulators, stakeholders, and the public must be confident that the new types of data can be used to effectively assess risk and ultimately protect public health. As such, education and transparent communication will be critical. Ultimately, the testing paradigm must be evaluated via a comprehensive development and review process, involving public comment, expert peer review, and harmonization with other agencies and international organizations. EPA’s Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA 2009) lays the framework upon which the development, implementation, acceptance, and application of this transformative paradigm can be built.Melissa G. KramerMichael FirestoneRobert KavlockHarold ZenickFiguresReferencesRelatedDetailsCited by Trosko J and Upham B (2010) A Paradigm Shift is Required for the Risk Assessment of Potential Human Health After Exposure to Low Level Chemical Exposures, International Journal of Toxicology, 10.1177/1091581810371384, 29:4, (344-357), Online publication date: 1-Jul-2010. Kavlock R and Dix D (2010) Computational Toxicology as Implemented by the U.S. EPA: Providing High Throughput Decision Support Tools for Screening and Assessing Chemical Exposure, Hazard and Risk, Journal of Toxicology and Environmental Health, Part B, 10.1080/10937404.2010.483935, 13:2-4, (197-217), Online publication date: 17-Jun-2010. Vol. 117, No. 7 July 2009Metrics About Article Metrics Publication History Originally published1 July 2009Published in print1 July 2009 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering children's unique susceptibilities and exposure potential. Childhood is assessed as a sequence of life stages that reflects the fact that as humans develop, windows of susceptibility may appear that lead to enhanced sensitivity to exposure of environmental agents, while changes in behavior and physiology may increase exposure and dose. The U.S. EPA developed guidance in the past few years that addresses some aspects of increased susceptibility and exposure and dose. However, when it comes to considering inhalation exposure, dose, and risk, current U.S. EPA practice does not explicitly address children. The purpose here is to begin studying the adequacy of practice for children's health and to explore possible next steps in developing new methods to more accurately assess life-stage-specific differences. The existing guidelines and policies used to address potentially unique susceptibilities of children for inhaled environmental chemicals were considered, as well as what may be learned from examples of approaches that have been applied by state agencies (such as the California Environmental Protection Agency) or in the literature, to incorporate potentially unique susceptibilities and exposures to children. Finally, there is a discussion of possible approaches for considering inhalation exposure and susceptibility in U.S. EPA risk assessments.

Young children have a greater ventilation rate per body weight or pulmonary surface area as compared to adults. The implications of this difference for inhalation dosimetry and children's risk assessment were evaluated in runs of the U. S. Environmental Protection Agency ( U. S. EPA) 1994 reference concentration (RfC) methodology and the ICRP 1994 inhalation dosimetry model. Dosimetry estimates were made for 3-mo-old children and adults for particles and Category 1 and 2 reactive gases in the following respiratory-tract regions: extrathoracic ( ET), tracheobronchial ( BB), bronchioles (bb), and pulmonary (PU). Systemic dosimetry estimates were made for nonreactive ( Category 3) gases. Results suggest similar ET dosimetry for children and adults for all types of inhaled materials. BB dosimetry was also similar across age groups except that the dosimetry of ultrafine particles in this region was twofold greater in 3-mo-old children than in adults. In contrast, the bb region generally showed higher dosimetry of particles and gases in adults than in children. Particle dose in the PU region was two- to fourfold higher in 3-mo-old children, with the greatest child/adult difference occurring for submicron size particles. Particulate dosimetry estimates with the default RfC methodology were below those found with the ICRP model for both adults and children for submicrometer sized particles. There were no cases in which reactive gas dosimetry was substantially greater in the respiratory regions of 3-mo-old children. Estimates of systemic dose of Category 3 gases were greater in 3-mo-old children than in adults, especially for liver dose of metabolite for rapidly metabolized gases. These analyses support the approach of assuming twofold greater inhalation dose in children than adults, although there are cases in which this differential can be greater and others where it can be less.

Young children have a greater ventilation rate per body weight or pulmonary surface area as compared to adults. The implications of this difference for inhalation dosimetry and children's risk assessment were evaluated in runs of the U.S. Environmental Protection Agency (U.S. EPA) 1994 reference concentration (RfC) methodology and the ICRP 1994 inhalation dosimetry model. Dosimetry estimates were made for 3-mo-old children and adults for particles and Category 1 and 2 reactive gases in the following respiratory-tract regions: extrathoracic (ET), tracheobronchial (BB), bronchioles (bb), and pulmonary (PU). Systemic dosimetry estimates were made for nonreactive (Category 3) gases. Results suggest similar ET dosimetry for children and adults for all types of inhaled materials. BB dosimetry was also similar across age groups except that the dosimetry of ultrafine particles in this region was twofold greater in 3-mo-old children than in adults. In contrast, the bb region generally showed higher dosimetry of particles and gases in adults than in children. Particle dose in the PU region was two- to fourfold higher in 3-mo-old children, with the greatest child/adult difference occurring for submicron size particles. Particulate dosimetry estimates with the default RfC methodology were below those found with the ICRP model for both adults and children for submicrometer sized particles. There were no cases in which reactive gas dosimetry was substantially greater in the respiratory regions of 3-mo-old children. Estimates of systemic dose of Category 3 gases were greater in 3-mo-old children than in adults, especially for liver dose of metabolite for rapidly metabolized gases. These analyses support the approach of assuming twofold greater inhalation dose in children than adults, although there are cases in which this differential can be greater and others where it can be less.

Parents in all countries want and deserve safe and healthy environments for their children. Children in all countries need, as part of normal growth and development, regular and frequent opportunities to interact with their environments as they learn to crawl, run, climb, swim, and explore. Environmental scientists and regulators recognize that environmental hazards are not contained by international borders. This is of special concern for children, because they are intrinsically at greater risk, compared to adults. They have different opportunities for exposure, greater response to certain toxicants, and less empowerment to alter their environments. There is a growing awareness that adverse health effects in children can adversely affect a country's future productivity and well-being. Multiple government agencies, NGOs, and advocates are mobilizing to address these concerns. A sustained concerted effort will be needed to afford equitable and effective environmental health protection to the world's children, present and future.