Addressing systemic problems with exposure assessments to protect the public's health.

BACKGROUND: Understanding, characterizing, and quantifying human exposures to environmental chemicals is critical to protect public health. Exposure assessments are key to determining risks to the general population and for specific subpopulations given that exposures differ between groups. Exposure data are also important for understanding where interventions, including public policies, should be targeted and the extent to which interventions have been successful. In this review, we aim to show how inadequacies in exposure assessments conducted by polluting industries or regulatory agencies have led to downplaying or disregarding exposure concerns raised by communities; that underestimates of exposure can lead regulatory agencies to conclude that unacceptable risks are, instead, acceptable, allowing pollutants to go unregulated; and that researchers, risk assessors, and policy makers need to better understand the issues that have affected exposure assessments and how appropriate use of exposure data can contribute to health-protective decisions. METHODS: We describe current approaches used by regulatory agencies to estimate human exposures to environmental chemicals, including approaches to address limitations in exposure data. We then illustrate how some exposure assessments have been used to reach flawed conclusions about environmental chemicals and make recommendations for improvements. RESULTS: Exposure data are important for communities, public health advocates, scientists, policy makers, and other groups to understand the extent of environmental exposures in diverse populations. We identify four areas where exposure assessments need to be improved due to systemic sources of error or uncertainty in exposure assessments and illustrate these areas with examples. These include: (1) an inability of regulatory agencies to keep pace with the increasing number of chemicals registered for use or assess their exposures, as well as complications added by use of 'confidential business information' which reduce available exposure data; (2) the failure to keep assessments up-to-date; (3) how inadequate assumptions about human behaviors and co-exposures contribute to underestimates of exposure; and (4) that insufficient models of toxicokinetics similarly affect exposure estimates. CONCLUSION: We identified key issues that impact capacity to conduct scientifically robust exposure assessments. These issues must be addressed with scientific or policy approaches to improve estimates of exposure and protect public health.

Application of probabilistic methods to address variability and uncertainty in estimating risks for non-cancer health effects.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

Advancing the science on chemical classes.

BACKGROUND: Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators. OBJECTIVE AND METHODS: While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios. RESULTS: Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management. DISCUSSION AND CONCLUSION: Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Toxic Substances Control Act (TSCA) Implementation: How the Amended Law Has Failed to Protect Vulnerable Populations from Toxic Chemicals in the United States.

Exposures to industrial chemicals are widespread and can increase the risk of adverse health effects such as cancer, developmental disorders, respiratory effects, diabetes, and reproductive problems. The amended Toxic Substances Control Act (amended TSCA) requires the U.S. Environmental Protection Agency (EPA) to evaluate risks of chemicals in commerce, account for risk to potentially exposed and susceptible populations, and mitigate risks for chemicals determined to pose an unreasonable risk to human health and the environment. This analysis compares EPA's first 10 chemical risk evaluations under amended TSCA to best scientific practices for conducting risk assessments. We find EPA's risk evaluations underestimated human health risks of chemical exposures by excluding conditions of use and exposure pathways; not considering aggregate exposure and cumulative risk; not identifying all potentially exposed or susceptible subpopulations, and not quantifying differences in risk for susceptible groups; not addressing data gaps; and using flawed systematic review approaches to identify and evaluate the relevant evidence. We present specific recommendations for improving the implementation of amended TSCA using the best available science to ensure equitable, socially just safeguards to public health. Failing to remedy these shortcomings will result in continued systematic underestimation of risk for all chemicals evaluated under amended TSCA.

Preterm birth and economic benefits of reduced maternal exposure to fine particulate matter.

Preterm birth (PTB) is a predictor of infant mortality and later-life morbidity. Despite recent declines, PTB rates remain high in the United States. Growing research suggests a possible relationship between a mother's exposure to common air pollutants, including fine particulate matter (PM2.5), and PTB of her baby. Many policy actions to reduce exposure to common air pollutants require benefit-cost analysis (BCA), and it's possible that PTB will need to be included in BCA in the future. However, an estimate of the willingness to pay (WTP) to avoid PTB risk is not available, and a comprehensive alternative valuation of the health benefits of reducing pollutant-related PTB currently does not exist. This paper demonstrates an approach to assess potential economic benefits of reducing PTB resulting from environmental exposures when an estimate of WTP to avoid PTB risk is unavailable. We utilized a recent meta-analysis, county-level air quality data and county-level PTB prevalence data to estimate the potential health and economic benefits of a reduction in air pollution-related PTB, with PM2.5 as our case study pollutant. Using this method, a simulated nationwide 10% decrease from 2008 PM2.5 levels resulted in an estimated reduction of 5016 PTBs and benefits of at least $339 million, potentially reaching over one billion dollars when considering later-life effects of PTB.

Chemical Risk Assessment: Traditional vs Public Health Perspectives.

Preventing adverse health effects of environmental chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, chemical risk assessment enables risk management actions that minimize the incidence and effects of environmentally induced diseases related to chemical exposure. However, traditional chemical risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary risk assessment practices for protecting public health. It is becoming clear that to protect public health more effectively, future risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect the range of subtle effects and morbidities observed in human populations. Considering these factors, there is a need to reframe chemical risk assessment to be more clearly aligned with the public health goal of minimizing environmental exposures associated with disease.

Upstream adverse effects in risk assessment: a model of polychlorinated biphenyls, thyroid hormone disruption and neurological outcomes in humans.

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

Adverse effects in risk assessment: modeling polychlorinated biphenyls and thyroid hormone disruption outcomes in animals and humans.

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

The relationship between childhood blood lead levels below 5 µg/dL and childhood intelligence quotient (IQ): Protocol for a systematic review and meta-analysis.

BACKGROUND: The causal association between childhood lead (Pb) exposure and decrements in intelligence quotient (IQ) is well-established, and no safe blood lead level (BLL) in children has been identified. An international pooled analysis of seven prospective studies published by Lanphear et al. in 2005 quantified the relationship between childhood BLL and IQ. Further studies of Pb and IQ have been published more recently with mean BLLs generally lower than in the studies analyzed by Lanphear et al. In this article, we present the protocol for a systematic review to estimate an updated Pb-IQ relationship focusing on BLLs below 5 µg per deciliter (µg/dL). STUDY QUESTION: What is the quantitative relationship between childhood BLLs and IQ at ages 3-17 years at BLLs below 5 µg/dL? DATA SOURCES: A comprehensive search of the scientific literature will utilize citation mapping and key word searching. In the citation mapping approach, we will identify seed references that are relevant to our study question, and will then identify more recent references that have cited at least one of the seed references. The key word search will be conducted in the PubMed, Biosis Previews, Scopus, and Web of Science databases. We will also search electronic grey literature databases for conference proceedings, dissertations, and preprints. STUDY ELIGIBILITY CRITERIA, STUDY SCREENING AND DATA EXTRACTION: We will include studies that measured BLL in children at any age, assessed full-scale IQ of the same children (concurrent with or subsequent to BLL sample collection) at ages 3-17, and estimated a continuous quantitative relationship between BLL and IQ. We will consider only studies with a central tendency BLL < 10 µg/dL. The title and abstract of each record will be reviewed independently by two authors to determine whether the study in question satisfies the inclusion criteria. The full text of each article remaining after title-abstract screening will be reviewed independently by two authors to determine whether the study in question satisfies the inclusion criteria. Two authors will independently extract study characteristics and data from each included study. RISK OF BIAS ASSESSMENT: Studies meeting inclusion criteria will be evaluated for risk of bias (RoB) using the Navigation Guide method applied in a previous systematic review of neurodevelopmental effects (Lam et al., 2017), with adaptation to our study question. Each study will be independently evaluated by two review authors. DATA ANALYSIS AND SYNTHESIS: We intend to conduct a random-effects meta-analysis to summarize the effects of children's exposure to Pb on IQ scores. Additionally, we plan to perform sensitivity analyses using sub-group analyses and/or meta-regression techniques to assess the impact of study design and study population characteristics to examine potential heterogeneity of results across studies. We will assign a confidence level rating (high, moderate, low, or very low) to the effect estimate from the meta-analyses/meta-regressions.

Calculating summary statistics for population chemical biomonitoring in women of childbearing age with adjustment for age-specific natality.

The effects of chemical exposures during pregnancy on children's health have been an increasing focus of environmental health research in recent years, leading to greater interest in biomonitoring of chemicals in women of childbearing age in the general population. Measurements of mercury in blood from the National Health and Nutrition Examination Survey are frequently reported for "women of childbearing age," defined to be of ages 16-49 years. The intent is to represent prenatal chemical exposure, but blood mercury levels increase with age. Furthermore, women of different ages have different probabilities of giving birth. We evaluated options to address potential bias in biomonitoring summary statistics for women of childbearing age by accounting for age-specific probabilities of giving birth. We calculated median and 95th percentile levels of mercury, PCBs, and cotinine using these approaches: option 1: women aged 16-49 years without natality adjustment; option 2: women aged 16-39 years without natality adjustment; option 3: women aged 16-49 years, adjusted for natality by age; option 4: women aged 16-49 years, adjusted for natality by age and race/ethnicity. Among the three chemicals examined, the choice of option has the greatest impact on estimated levels of serum PCBs, which are strongly associated with age. Serum cotinine levels among Black non-Hispanic women of childbearing age are understated when age-specific natality is not considered. For characterizing in utero exposures, adjustment using age-specific natality provides a substantial improvement in estimation of biomonitoring summary statistics.

PCB body burdens in US women of childbearing age 2001-2002: An evaluation of alternate summary metrics of NHANES data.

An extensive body of epidemiologic data associates prenatal exposure to polychlorinated biphenyls (PCBs) with neurodevelopmental deficits and other childhood health effects. Neurological effects and other adverse health effects may also result from exposure during infancy, childhood, and adulthood. Although manufacture and use of PCBs were banned in the US in 1977, exposure to PCBs is a continuing concern due to the widespread distribution of these compounds in the environment and their persistence. The National Health and Nutrition Examination Survey provides PCB body burden measurements representative of the US population for the years 1999-2002. Interpretation of these data is challenging due to the large number of PCB congeners reported. We examined 6 PCB body burden metrics to identify an approach for summarizing the NHANES data and for characterizing changes over time in potential risks to children's health. We focused on women of childbearing age, defined here as 16-39 years, because in utero exposures have been associated with neurodevelopmental effects, and used only the 2001-2002 data because of higher detection rates. The 6 metrics, each consisting of different combinations of the 9 most frequently detected congeners, were as follows: total PCBs (all 9 congeners); highly chlorinated PCBs (2 congeners); dioxin-like PCBs (3 congeners, weighted by toxic equivalency factors); non-dioxin-like PCBs (6 congeners); a 4-congener metric (PCBs 118, 138, 153, and 180); and PCB-153 alone. The PCB metrics were generally highly correlated with each other. There was a strong association of PCB body burdens with age for all metrics. Median body burdens of Mexican American women were lower than those of non-Hispanic White and non-Hispanic Black women for 5 of the 6 metrics, and there were no significant differences in body burdens between the latter two groups. Body burdens of women with incomes above poverty level were greater than those for lower-income women at the median and 95th percentiles, but the differences were not statistically significant for any metric. We conclude that the 4-congener and total PCBs metrics are the most promising approaches for tracking changes in body burdens over time and for comparing body burdens of different subgroups in NHANES.

Methods for evaluating variability in human health dose-response characterization.

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as "a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point)." Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new database useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.

Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making.

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.

Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose-Response Assessments for Noncancer Effects.

BACKGROUND: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO). OBJECTIVES: Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDMI). METHODS: We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose-response workflow implementing the WHO framework. RESULTS: We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 HDMI values. Traditional RfDs are generally within an order of magnitude of the HDMI lower confidence bound for I=1% and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality. CONCLUSIONS: Overall, replacing RfDs with HDMI estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit-cost analysis, risk-risk tradeoffs, life-cycle impact analysis, and emergency response. https://doi.org/10.1289/EHP3368.

Dose-response relationship of prenatal mercury exposure and IQ: an integrative analysis of epidemiologic data.

BACKGROUND: Prenatal exposure to mercury has been associated with adverse childhood neurologic outcomes in epidemiologic studies. Dose-response information for this relationship is useful for estimating benefits of reduced mercury exposure. OBJECTIVES: We estimated a dose-response relationship between maternal mercury body burden and subsequent childhood decrements in intelligence quotient (IQ), using a Bayesian hierarchical model to integrate data from three epidemiologic studies. METHODS: Inputs to the model consist of dose-response coefficients from studies conducted in the Faroe Islands, New Zealand, and the Seychelles Islands. IQ coefficients were available from previous work for the latter two studies, and a coefficient for the Faroe Islands study was estimated from three IQ subtests. Other tests of cognition/achievement were included in the hierarchical model to obtain more accurate estimates of study-to-study and end point-to-end point variability. RESULTS: We find a central estimate of -0.18 IQ points (95% confidence interval, -0.378 to -0.009) for each parts per million increase of maternal hair mercury, similar to the estimates for both the Faroe Islands and Seychelles studies, and lower in magnitude than the estimate for the New Zealand study. Sensitivity analyses produce similar results, with the IQ coefficient central estimate ranging from -0.13 to -0.25. CONCLUSIONS: IQ is a useful end point for estimating neurodevelopmental effects, but may not fully represent cognitive deficits associated with mercury exposure, and does not represent deficits related to attention and motor skills. Nevertheless, the integrated IQ coefficient provides a more robust description of the dose-response relationship for prenatal mercury exposure and cognitive functioning than results of any single study.

Estimating risk from ambient concentrations of acrolein across the United States.

BACKGROUND: Estimated ambient concentrations of acrolein, a hazardous air pollutant, are greater than the U.S. Environmental Protection Agency (EPA) reference concentration throughout the United States, making it a concern for human health. However, there is no method for assessing the extent of risk under the U.S. EPA noncancer risk assessment framework. OBJECTIVES: We estimated excess risks from ambient concentrations of acrolein based on dose-response modeling of a study in rats with a relationship between acrolein and residual volume/total lung capacity ratio (RV/TLC) and specific compliance (sC(L)), markers for altered lung function. METHODS: Based on existing literature, we defined values above the 90th percentile for controls as "adverse." We estimated the increase over baseline response that would occur in the human population from estimated ambient concentrations of acrolein, taken from the U.S. EPA's National-Scale Air Toxics Assessment for 1999, after standard animal-to-human conversions and extrapolating to doses below the experimental data. RESULTS: The estimated median additional number of adverse sC(L) outcomes across the United States was approximately 2.5 cases per 1,000 people. The estimated range of additional outcomes from the 5th to the 95th percentile of acrolein concentration levels across census tracts was 0.28-14 cases per 1,000. For RV/TLC, the median additional outcome was 0.002 per 1,000, and the additional outcome at the 95th percentile was 0.13 per 1,000. CONCLUSIONS: Although there are uncertainties in estimating human risks from animal data, this analysis demonstrates a method for estimating health risks for noncancer effects and suggests that acrolein could be associated with decreased respiratory function in the United States.

Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis.

BACKGROUND: In the United States, one in six children are affected by neurodevelopmental disorders, and polybrominated diphenyl ethers (PBDEs) in flame-retardant chemicals are measured ubiquitously in children. OBJECTIVE: We conducted a systematic a systematic review regarding developmental exposure to PBDEs and intelligence or Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans. METHODS: We searched articles published up to 26 September 2016, and included original studies that quantified exposures to PBDEs incurred any time in proximity to conception or during in utero, perinatal, or childhood time periods. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide systematic review methodology. We established criteria in advance to identify studies that could be combined using random effects meta-analyses (DerSimonian-Laird method). RESULTS: Fifteen studies met the inclusion criteria; 10 studies met the criteria for intelligence and nine for attention-related problems. We rated studies generally with "low" to "probably low" risk of bias and rated the overall body of evidence as "moderate" quality with "sufficient" evidence for an association between Intelligence Quotient (IQ) and PBDEs. Our meta-analysis of four studies estimated a 10-fold increase (in other words, times 10) in PBDE exposure associated with a decrement of 3.70 IQ points (95% confidence interval: 0.83, 6.56). We concluded the body of evidence was of "moderate" quality for ADHD with "limited" evidence for an association with PBDEs, based on the heterogeneity of association estimates reported by a small number of studies and the fact that chance, bias, and confounding could not be ruled out with reasonable confidence. CONCLUSION: We concluded there was sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ. Preventing developmental exposure to PBDEs could help prevent loss of human intelligence. https://doi.org/10.1289/EHP1632.