Interpreting biomonitoring data: Introducing the international human biomonitoring (i-HBM) working group's health-based guidance value (HB2GV) dashboard.

Human biomonitoring (HBM) data measured in specific contexts or populations provide information for comparing population exposures. There are numerous health-based biomonitoring guidance values, but to locate these values, interested parties need to seek them out individually from publications, governmental reports, websites and other sources. Until now, there has been no central, international repository for this information. Thus, a tool is needed to help researchers, public health professionals, risk assessors, and regulatory decision makers to quickly locate relevant values on numerous environmental chemicals. A free, on-line repository for international health-based guidance values to facilitate the interpretation of HBM data is now available. The repository is referred to as the "Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard". The Dashboard represents the efforts of the International Human Biomonitoring Working Group (i-HBM), affiliated with the International Society of Exposure Science. The i-HBM's mission is to promote the use of population-level HBM data to inform public health decision-making by developing harmonized resources to facilitate the interpretation of HBM data in a health-based context. This paper describes the methods used to compile the human biomonitoring health-based guidance values, how the values can be accessed and used, and caveats with using the Dashboard for interpreting HBM data. To our knowledge, the HB2GV Dashboard is the first open-access, curated database of HBM guidance values developed for use in interpreting HBM data. This new resource can assist global HBM data users such as risk assessors, risk managers and biomonitoring programs with a readily available compilation of guidance values.

Using the Matrix to bridge the epidemiology/risk assessment gap: a case study of 2,4-D.

BACKGROUND: The Matrix is designed to facilitate discussions between practitioners of risk assessment and epidemiology and, in so doing, to enhance the utility of epidemiology research for public health decision-making. The Matrix is comprised of nine fundamental "asks" of epidemiology studies, focusing on the types of information valuable to the risk assessment process. OBJECTIVE: A 2,4-dichlorophenoxyacetic acid (2,4-D) case study highlights the extent to which existing epidemiology literature includes information generally needed for risk assessments and proffers suggestions that would assist in bridging the epidemiology/risk assessment gap. METHODS: Thirty-one publications identified in the US Environmental Protection Agency 2,4-D epidemiology review were assessed. These studies focused on associations between 2,4-D exposure and non-Hodgkin lymphoma (NHL), respiratory effects, and birth outcomes. RESULTS: Many of the papers met one or more specific elements of the Matrix. However, from this case study, it is clear that some aspects of risk assessment, such as evaluating source-to-intake pathways, are generally not considered in epidemiology research. Others are incorporated, but infrequently (e.g. dose-response information, harmonization of exposure categories). We indicated where additional analyses or modifications to future study design could serve to improve the translation. DISCUSSION: Interaction with risk assessors during the study design phase and using the Matrix "asks" to guide the conversations could shape research and provide the basis for requests for funds to support these additional activities. The use of the Matrix as a foundation for communication and education across disciplines could produce more impactful and consequential epidemiology research for robust risk assessments and decision-making.

How Many Urine Samples Are Needed to Accurately Assess Exposure to Non-Persistent Chemicals? The Biomarker Reliability Assessment Tool (BRAT) for Scientists, Research Sponsors, and Risk Managers.

In epidemiologic and exposure research, biomonitoring is often used as the basis for assessing human exposure to environmental chemicals. Studies frequently rely on a single urinary measurement per participant to assess exposure to non-persistent chemicals. However, there is a growing consensus that single urine samples may be insufficient for adequately estimating exposure. The question then arises: how many samples would be needed for optimal characterization of exposure? To help researchers answer this question, we developed a tool called the Biomarker Reliability Assessment Tool (BRAT). The BRAT is based on pharmacokinetic modeling simulations, is freely available, and is designed to help researchers determine the approximate number of urine samples needed to optimize exposure assessment. The BRAT performs Monte Carlo simulations of exposure to estimate internal levels and resulting urinary concentrations in individuals from a population based on user-specified inputs (e.g., biological half-life, within- and between-person variability in exposure). The BRAT evaluates-through linear regression and quantile classification-the precision/accuracy of the estimation of internal levels depending on the number of urine samples. This tool should guide researchers towards more robust biomonitoring and improved exposure classification in epidemiologic and exposure research, which should in turn improve the translation of that research into decision-making.

Translation of Exposure and Epidemiology for Risk Assessment: A Shifting Paradigm.

Risk assessment is a well-established process used for various types of public health decision-making, such as setting chemical site clean-up levels, developing limits on exposures to chemicals in soil, water, air and food, and determining occupational exposure limits[...].

Environmental Chemicals in Breast Milk and Formula: Exposure and Risk Assessment Implications.

BACKGROUND: Human health risk assessment methods have advanced in recent years to more accurately estimate risks associated with exposure during childhood. However, predicting risks related to infant exposures to environmental chemicals in breast milk and formula remains challenging. OBJECTIVES: Our goal was to compile available information on infant exposures to environmental chemicals in breast milk and formula, describe methods to characterize infant exposure and potential for health risk in the context of a risk assessment, and identify research needed to improve risk analyses based on this type of exposure and health risk information. METHODS: We reviewed recent literature on levels of environmental chemicals in breast milk and formula, with a focus on data from the United States. We then selected three example publications that quantified infant exposure using breast milk or formula chemical concentrations and estimated breast milk or formula intake. The potential for health risk from these dietary exposures was then characterized by comparison with available health risk benchmarks. We identified areas of this approach in need of improvement to better characterize the potential for infant health risk from this critical exposure pathway. DISCUSSION: Measurements of chemicals in breast milk and formula are integral to the evaluation of risk from early life dietary exposures to environmental chemicals. Risk assessments may also be informed by research investigating the impact of chemical exposure on developmental processes known to be active, and subject to disruption, during infancy, and by analysis of exposure-response data specific to the infant life stage. Critical data gaps exist in all of these areas. CONCLUSIONS: Better-designed studies are needed to characterize infant exposures to environmental chemicals in breast milk and infant formula as well as to improve risk assessments of chemicals found in both foods. https://doi.org/10.1289/EHP1953.

Infant Dietary Exposures to Environmental Chemicals and Infant/Child Health: A Critical Assessment of the Literature.

BACKGROUND: The benefits of breastfeeding to the infant and mother have been well documented. It is also well known that breast milk contains environmental chemicals, and numerous epidemiological studies have explored relationships between background levels of chemicals in breast milk and health outcomes in infants and children. OBJECTIVES: In this paper, we examine epidemiological literature to address the following question: Are infant exposures to background levels of environmental chemicals in breast milk and formula associated with adverse health effects? We critically review this literature a) to explore whether exposure-outcome associations are observed across studies, and b) to assess the literature quality. METHODS: We reviewed literature identified from electronic literature searches. We explored whether exposure-outcome associations are observed across studies by assessing the quality (using a modified version of a previously published quality assessment tool), consistency, and strengths and weaknesses in the literature. The epidemiological literature included cohorts from several countries and examined infants/children either once or multiple times over weeks to years. Health outcomes included four broad categories: growth and maturation, morbidity, biomarkers, and neurodevelopment. RESULTS: The available literature does not provide conclusive evidence of consistent or clinically relevant health consequences to infants exposed to environmental chemicals in breast milk at background levels. CONCLUSIONS: It is clear that more research would better inform our understanding of the potential for health impacts from infant dietary exposures to environmental chemicals. A critical data gap is a lack of research on environmental chemicals in formula and infant/child health outcomes. https://doi.org/10.1289/EHP1954.

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches.

Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens. More research is needed to understand the mechanism of asthma induction and elicitation in the context of specific chemical exposures and exposure patterns, and the impact of population variability and patient phenotypes. Validated tools to predict respiratory sensitization and to translate irritancy assays to asthma potency are needed, in addition to diagnostic biomarkers that assess and differentiate allergy versus irritant-based asthmatic responses. Diagnostic methods that encompass the diverse etiologies of asthmatic responses and incorporate robust exposure measurements capable of capturing different temporal patterns of complex chemical mixtures are needed. In the absence of ideal tools, risk assessors apply hazard-based safety assessment methods, in conjunction with active risk management, to limit potential asthma concerns, proactively identify new concerns, and ensure deployment of approaches to mitigate asthma-related risks.

Lessons learned from the application of BEES-C: Systematic assessment of study quality of epidemiologic research on BPA, neurodevelopment, and respiratory health.

Epidemiologic studies evaluating associations between biomarkers of exposure to short-lived chemicals and health endpoints in humans face special challenges. Perhaps the most critical challenges are the need to determine the type and optimal number of samples, and the proper timing of specimen collection. Further, as many short-lived chemicals are ubiquitous in the environment, utmost care is required to avoid sample contamination. A separate set of challenges is associated with appropriate interpretation and reporting of results from multiple simultaneous analyses, which are becoming increasingly feasible. The Biomonitoring, Environmental Epidemiology, and Short-Lived Chemicals (BEES-C) instrument is specifically designed to evaluate the quality of epidemiologic studies that measure biomarkers of chemicals with short physiologic half-lives. The instrument provides systematic guidance for evaluating 14 different aspects of study quality divided into three broad categories: 1) biomarker selection and measurement, 2) strategy and execution of exposure assessment, and 3) general considerations of study design and reporting. We evaluated the utility of the BEES-C instrument using epidemiologic studies of exposure to bisphenol A and its association with neurodevelopmental and respiratory health indicators. Each BEES-C element was assessed with respect to needed modifications and concordance among reviewers using professional, scientific judgment. Based on this first use of the BEES-C instrument, we found that most of its elements were effective in comparing the quality of available studies, with reviews generally concordant and justifications consistent. However, we note that certain elements would be improved with slight adjustments and that one of the elements appeared redundant and should be removed.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.

Using systematic reviews and meta-analyses to support regulatory decision making for neurotoxicants: lessons learned from a case study of PCBs.

BACKGROUND: Epidemiologic weight-of-evidence reviews to support regulatory decision making regarding the association between environmental chemical exposures and neurodevelopmental outcomes in children are often complicated by lack of consistency across studies. OBJECTIVE: We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making. DATA EXTRACTION/SYNTHESIS: We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories. RESULTS: The current literature includes 11 cohorts of children for whom effects from prenatal or neonatal PCB exposures were assessed. The most consistently used tests included Brazelton's Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5-8 months of age, and the McCarthy Scales of Children's Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts. CONCLUSIONS: These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability. Our findings add support to previous calls for establishing consensus standards for the conduct, analysis, and reporting of epidemiologic studies in general, and for those evaluating the effects of potential neurotoxic exposures in particular.

The heart of the matter on breastmilk and environmental chemicals: essential points for healthcare providers and new parents.

Abstract The increasing number of environmental chemicals measured in breastmilk is a consequence of improved analytical capabilities and the increased interest in biomonitoring. It has been generally concluded that the benefits to the infant from breastfeeding outweigh potential risks associated with environmental chemical exposures associated with breastfeeding. However, there have been reports of subtle effects on infants associated with chemicals in breastmilk. Associations between concentrations of chemicals in breastmilk and a biochemical or other change in infants may signal the need for further study or regulatory action, whereas on an individual level, these changes may not be considered adverse. For healthcare providers, this distinction is critical, as many in the field are being asked for nuanced information on risks and benefits associated with breastfeeding, and this information is not readily available. Recognizing the challenge faced by healthcare providers, we have explored and developed a case study on dioxins in breastmilk. The essential conclusion for healthcare providers and new parents is that in studies of breastfed versus formula-fed infants across time, including times when levels of environmental chemicals such as dioxins were higher, beneficial effects associated with breastfeeding have been found. The current evidence does not support altering the World Health Organization recommendations promoting and supporting breastfeeding.

Derivation of biomonitoring equivalent (BE) values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds: a screening tool for interpretation of biomonitoring data in a risk assessment context.

Recent efforts by the U.S. Centers for Disease Control and Prevention and other researchers have resulted in a growing database of measured concentrations of dioxins and related compounds in blood samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring equivalent (BE) values are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments This study reviews available health based exposure guidance values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds from a variety of agencies including the World Health Organization Joint Expert Committee on Food Additives (JECFA), the European Commission Scientific Committee on Foods (ECSCF), the United Kingdom Committee on Toxicology (UKCOT), and the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) to estimate corresponding BE values for dioxin-like compounds in blood on a serum lipid-adjusted basis. Based on data from the animal studies underlying the exposure guidance values, a serum lipid-adjusted dioxin toxicity equivalent (TEQ) concentration of approximately 15 ppt is consistent with the ATSDR minimal risk level (MRL) for dioxins. Serum lipid-adjusted TEQ concentrations of approximately 31 to 74 ppt are consistent with the tolerable intakes estimated by the other three agencies. These values may be used as screening tools for evaluation of biomonitoring data for dioxins in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for dioxins.

Collection and use of exposure data from human milk biomonitoring in the United States.

Human milk is a unique biological matrix that can be used to estimate exposures in both the mother and the breastfed infant. In addition, the presence of environmental chemicals in human milk may act as a sentinel for exposures to a broader population. Several factors play a role in determining the quantity of chemicals transferred to milk and, subsequently, to the breastfeeding infant, including maternal, infant, and chemical characteristics. Exposure to certain environmental chemicals during critical periods can disrupt normal infant development, yet few data exist to quantify the hazards posed by environmental chemicals in human milk. Chemicals measured in human milk may also provide insights to agents suspect in altering breast development and breast-related disease risk. Carefully designed exposure assessment and toxicokinetic studies are needed to elucidate mechanisms and establish relationships between human milk and other biologic matrices. Data from human milk biomonitoring studies can be used to inform and validate models that integrate information about chemical properties, human metabolism, and biomarker concentrations. Additional research is needed to determine the degree to which environmental chemicals enter, are present in, and are excreted from human milk, their impact on the host (mother), and the extent of their bioavailability to breastfeeding infants. This article describes how the collection and use of exposure data from human milk biomonitoring in the United States can be designed to inform future research and policy.

Human milk biomonitoring data: interpretation and risk assessment issues.

Biomonitoring data can, under certain conditions, be used to describe potential risks to human health (for example, blood lead levels used to determine children's neurodevelopmental risk). At present, there are very few chemical exposures at low levels for which sufficient data exist to state with confidence the link between levels of environmental chemicals in a person's body and his or her risk of adverse health effects. Human milk biomonitoring presents additional complications. Human milk can be used to obtain information on both the levels of environmental chemicals in the mother and her infant's exposure to an environmental chemical. However, in terms of the health of the mother, there are little to no extant data that can be used to link levels of most environmental chemicals in human milk to a particular health outcome in the mother. This is because, traditionally, risks are estimated based on dose, rather than on levels of environmental chemicals in the body, and the relationship between dose and human tissue levels is complex. On the other hand, for the infant, some information on dose is available because the infant is exposed to environmental chemicals in milk as a "dose" from which risk estimates can be derived. However, the traditional risk assessment approach is not designed to consider the benefits to the infant associated with breastfeeding and is complicated by the relatively short-term exposures to the infant from breastfeeding. A further complexity derives from the addition of in utero exposures, which complicates interpretation of epidemiological research on health outcomes of breastfeeding infants. Thus, the concept of "risk assessment" as it applies to human milk biomonitoring is not straightforward, and methodologies for undertaking this type of assessment have not yet been fully developed. This article describes the deliberations of the panel convened for the Technical Workshop on Human Milk Surveillance and Biomonitoring for Environmental Chemicals in the United States, held at the Hershey Medical Center, Pennsylvania State College of Medicine, on several issues related to risk assessment and human milk biomonitoring. Discussion of these topics and the thoughts and conclusions of the panel are described in this article.