Children's Health Scientific Journal Articles

Gary Ginsberg, Suryanarayana V Vulimiri, Yu-Sheng Lin, Jayaram Kancherla, Brenda Foos & Babasaheb Sonawane

Abstract:  Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children’s vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early life stages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child–adult differences in internal dose for a number of these chemicals.

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Julie Fitzpatrick; Rita Schoeny; Kathryn Gallagher; Kathleen Deener; Chris Dockins; Michael Firestone; William Jordan; Margaret McDonough; Deirdre Murphy; Marian Olsen; Kathleen Raffaele

Abstract: 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 maximizes the utility of risk assessment. The framework considers the NRC's recommendations and builds upon existing agency guidance by emphasizing 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 life stage risk. The framework integrates the concepts of planning and scoping and problem formulation and provides for incorporation of stakeholder involvement and peer review.

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Gary Ginsberg, Justine Ginsberg and Brenda Foos

Abstract:  Children’s exposure assessment is a key input into epidemiology studies, risk assessment and source apportionment. The goals of this article are to describe a methodology for children’s exposure assessment that can be used for these purposes and to apply the methodology to source apportionment for the case study chemical, diethylhexylphthalate (DEHP). A key feature is the comparison of total (aggregate) exposure calculated via a pathways approach to that derived from a biomonitoring approach. The 4-step methodology and its results for DEHP are: (1) Prioritization of life stages and exposure pathways, with pregnancy, breast-fed infants, and toddlers the focus of the case study and pathways selected that are relevant to these groups; (2) Estimation of pathway-specific exposures by life stage wherein diet was found to be the largest contributor for pregnant women, breast milk and mouthing behavior for the nursing infant and diet, house dust, and mouthing for toddlers; (3) Comparison of aggregate exposure by pathways vs biomonitoring-based approaches wherein good concordance was found for toddlers and pregnant women providing confidence in the exposure assessment; (4) Source apportionment in which DEHP presence in foods, children’s products, consumer products and the built environment are discussed with respect to early life mouthing, house dust and dietary exposure. A potential fifth step of the method involves the calculation of exposure doses for risk assessment which is described but outside the scope for the current case study. In summary, the methodology has been used to synthesize the available information to identify key sources of early life exposure to DEHP.

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Michael Firestone, Martha Berger, Brenda Foos, and Ruth Etzel

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.

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Rehr R., Miller G., & Foos B.

Abstract: Improving children’s environmental health is integral to achieving sustainability. Sustainability is often presented as the balance among three interdependent components—environment, economy, and social dynamics—the goal of which is to improve life for future generations. Traditionally rooted in resource conservation and management, sustainability efforts have focused on environmental and economic elements, at times neglecting human health as an important aspect of the social component. Improving quality of life for future generations requires protecting the environmental health and well-being of today’s children and women of childbearing age. During early stages of physiological development, from critical prenatal windows of development through infancy and childhood, people may be particularly sensitive to environmental hazards. Children also have higher exposure to certain factors, per unit of body mass, than adults. Consequently, environmental insults during development may increase the risks for adverse health outcomes at birth, during childhood, or later in life. Protecting children’s environmental health has overlapping environmental, economic, and social benefits. This research analyzes the intersections between children’s environmental health and sustainability and explores children’s environmental health indicators as quantitative metrics to evaluate existing sustainability initiatives in the United States. 

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Lesliam Quirós-Alcalá, Suril Mehta, and Brenda Eskenazi

Background: Usage of pyrethroid insecticides has increased dramatically over the past decade; however, data on their potential health effects, particularly on children, are limited.

Objective: We examined the cross-sectional association between postnatal pyrethroid exposure and parental report of learning disability (LD) and attention-deficit/hyperactivity disorder (ADHD) in children 6-15 years of age.

Methods: Using data from the National Health and Nutrition Examination Survey (1999-2002), we estimated associations of urinary metabolites of pyrethroid insecticides with parent-reported LD, ADHD, and both LD/ADHD in 1659-1680 children using logistic regression.

Results: The prevalence rates of parent-reported LD, ADHD, and both LD/ADHD were 12.7%, 10.0%, and 5.4%, respectively. Metabolite detection frequencies for 3-PBA [3-phenoxybenzoic acid], cis-DCCA [cis-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid], and trans-DCCA [trans-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid] were 77.1%, 35.6%, and 33.9%, respectively. The geometric mean 3-PBA concentration was 0.32 µg/L (Median = 0.31 µg/L; IQR = 0.10-0.89 µg/L). cis- and trans-DCCA 75th percentile concentrations were 0.21 µg/L and 0.68 µg/L, respectively. Log10-transformed 3-PBA concentrations were associated with an adjusted odds ratio (OR) of 1.18 (95% CI: 0.92, 1.51) for parent-reported LD, 1.16 (95% CI: 0.85, 1.58) for ADHD, and 1.45 (95% CI: 0.92, 2.27) for both LD/ADHD. Adjusted ORs remained non-significant and decreased after controlling for creatinine and other environmental chemicals previously linked to altered neurodevelopment. Similarly, no significant associations were observed for cis- and trans-DCCA.

Conclusions: Postnatal pyrethroid exposure was not associated with parental report of LD and/or ADHD. Given the widespread and increasing use of pyrethroids, future research should evaluate exposures at current levels, particularly during critical windows of brain development.

National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: Hubal.Elaine@epa.gov

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.

National Center for Environmental Assessment, U.S. Environmental Protection Agency (EPA), Washington, DC, USA

In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed a toxicological review of trichloroethylene (TCE) in September 2011, which was the result of an effort spanning > 20 years.  We summarized the key findings and scientific issues regarding the human health effects of TCE in the U.S. EPA's toxicological review methods: In this assessment we synthesized and characterized thousands of epidemiologic, experimental animal, and mechanistic studies, and addressed several key scientific issues through modeling of TCE toxicokinetics, meta-analyses of epidemiologic studies, and analyses of mechanistic data.  TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the central nervous system, kidney, liver, immune system, male reproductive system, and the developing embryo/fetus.

School of Community Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-6210, USA

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.

Office of Children's Health Protection, US Environmental Protection Agency, Washington, DC, USA

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.

Office of Children's Health Protection and Environmental Education, U.S. Environmental Protection Agency

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.

Tetrachloroethylene, also known as perchloroethylene or "perc", is a highly volatile and lipophilic solvent widely used in dry cleaning, textile processing, and metal-cleaning operations. The limited epidemiological and toxicological data available for exposure to perc during developmental lifestages, as well as the evidence for critical windows of exposure, highlight early life as a period of potential susceptibility. A literature search was performed to identify all peer-reviewed epidemiological and toxicological studies examining outcomes from early lifestage exposure to perc, and reviewed by developmental stage for both exposure and outcome. The limited evidence on early lifestage exposure to perc does not provide sufficient evidence of this sensitive period as being more or less important than exposure at a later lifestage, such as during adulthood. However, there are a number of adverse health effects observed uniquely in early lifestages, and increased sensitivity to visual system deficits is suggested in children. Other outcomes observed in adults may not have been adequately assessed in children to directly compare sensitivity.

Compared to adults, children maybe more highly exposed to toxic substances in drinking water because they consume more water per unit of body weight. The U.S. Environmental Protection Agency (USEPA) has developed new guidance for selecting age groups and age-specific exposure factors for assessing children's exposures and risks to environmental contaminants. Manganese, an essential nutrient and neurotoxicant, was selected as a case study and chemical of potential concern for children's health. A screening-level risk assessment was performed using age-specific drinking water intake rates and manganese concentrations from U.S. public drinking water systems. When age-specific drinking water intake rates are used to calculate dose, formula-fed infants receive the highest dose of manganese from drinking water compared to all other age groups. Estimated hazard quotients suggest adverse health effects are possible. Use of USEPA's standardized childhood age groups and childhood exposure factors significantly improves the understanding of childhood exposure and risks.

This overview paper provides the historical context for the incorporation of lifestage-specific concerns in human health risk assessment, briefly explains the process employed in a lifestage framework for risk assessment, and discusses the scientific rationale for how utilizing lifestage data will strengthen the overall risk assessment process. This risk assessment approach will add value by: (1) providing a more complete evaluation of the potential for vulnerability at different lifestages, including a focus on the underlying biological events and incorporation of mode of action information related to different critical developmental periods; (2) evaluating the potential for toxicity during all lifestages after early lifestage exposure; (3) reviewing the importance of integrating exposure information and adverse health effects across lifestages; and (4) serving as a basis to extend some aspects of the children's health risk assessment framework to all lifestages.

Substantial effort has been invested in improving children's health risk assessment in recent years. However, the body of scientific evidence in support of children's health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Children's inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within children's health, key issues for consideration include (1) epidemiological evidence of adverse effects following children's exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of children's inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand children's inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved children's health risk assessment.

Adults and children may have different reactions to inhalation exposures due to differences in target tissue doses following similar exposures, and/or different stages in lung growth and development. In the case of asthma and allergy both the developing immune system and initial encounters with common allergens contribute to this differential susceptibility. Asthma, the most common chronic childhood disease, has significant public health impacts and is characterized by chronic lung inflammation, reversible airflow obstruction, and immune sensitization to allergens. Animal studies described here suggest that air pollutants exacerbate asthma symptoms and may also play a role in disease induction. Changes characteristic of asthma were observed in rhesus monkeys sensitized to house dust mite antigen (HDMA) as infants and exposed repeatedly thereafter to ozone (O3) and HDMA. O3 exposure compromised airway growth and development and exacerbated the allergen response to favor intermittent airway obstruction and wheeze. In Brown Norway rats a variety of air pollutants enhanced sensitization to HDMA such that symptoms elicited in response to subsequent allergen challenge were more severe. Although useful for assessing air pollutants effects on initial sensitization, the rodent immune system is immature at birth relative to humans, making this model less useful for studying differential effects between adults and children. Because computational models available to address children's inhalation exposures are limited, default adjustments and their associated uncertainty will continue to be used in children's inhalation risk assessment. Because asthma is a complex (multiple genes, phenotypes, organ systems) disease, this area is ripe for systems biology approaches.

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.

The purpose of this article is to describe a standard set of age groups for exposure assessors to consider when assessing childhood exposure and potential dose to environmental contaminants. In addition, this article presents examples to show how the age groups can be applied in children's exposure assessments. A consistent set of childhood age groups, supported by an underlying scientific rationale, will improve the accuracy and comparability of exposure and risk assessments for children. The effort was undertaken in part to aid the U.S. Environmental Protection Agency (EPA) in implementing such regulatory initiatives as the 1997 Presidential Executive Order 13045, which required all federal agencies to ensure that their standards take into account special risks to children. The standard age groups include: birth to <1 month; 1 to <3 months; 3 to <6 months; 6 to <12 months; 1 to <2 years; 2 to <3 years; 3 to <6 years; 6 to <11 years; 11 to <16 years; and 16 to <21 years. These age groups reflect a consideration of developmental changes in various behavioral, anatomical, and physiological characteristics that impact exposure and potential dose. It is expected that the availability of a standard set of early-life age groups will inform future analyses of exposure factors data as well as guide new research and data collection efforts to fill knowledge gaps.

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.