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.

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.

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals.

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n = 45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

High-throughput in Vitro Data To Inform Prioritization of Ambient Water Monitoring and Testing for Endocrine Active Chemicals.

The presence of industrial chemicals, consumer product chemicals, and pharmaceuticals is well documented in waters in the U.S. and globally. Most of these chemicals lack health-protective guidelines and many have been shown to have endocrine bioactivity. There is currently no systematic or national prioritization for monitoring waters for chemicals with endocrine disrupting activity. We propose ambient water bioactivity concentrations (AWBCs) generated from high throughput data as a health-based screen for endocrine bioactivity of chemicals in water. The U.S. EPA ToxCast program has screened over 1800 chemicals for estrogen receptor (ER) and androgen receptor (AR) pathway bioactivity. AWBCs are calculated for 110 ER and 212 AR bioactive chemicals using high throughput ToxCast data from in vitro screening assays and predictive pathway models, high-throughput toxicokinetic data, and data-driven assumptions about consumption of water. Chemical-specific AWBCs are compared with measured water concentrations in data sets from the greater Denver area, Minnesota lakes, and Oregon waters, demonstrating a framework for identifying endocrine bioactive chemicals. This approach can be used to screen potential cumulative endocrine activity in drinking water and to inform prioritization of future monitoring, chemical testing and pollution prevention efforts.

Lead exposure to children from consumption of backyard chicken eggs.

Backyard chicken ownership is rapidly increasing in urban areas in the United States, largely as a way to provide eggs for household consumption. Despite elevated levels of environmental lead contamination in many US cities, the role of backyard chicken eggs as a pathway for lead exposure, particularly for children, has received limited scrutiny. To characterize lead exposure from consumption of backyard chicken eggs for children and predict related effects on blood lead level (BLL), we conducted a cross-sectional study of backyard chicken owners in the Greater Boston area (n = 51). We interviewed participants regarding egg consumption by household members and collected backyard eggs (n = 201) and coop soil samples (n = 48) for analysis. Inductively coupled plasma mass spectrometry (ICP-MS) was used to evaluate lead concentration in homogenized eggs and an X-ray fluorescence (XRF) portable device was used to assess soil lead levels in the laboratory. We used the USEPA's Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK) to assess the relative contribution of backyard egg consumption to aggregate BLL in children. Four scenarios were developed in the IEUBK model to address variability in egg consumption rates and egg lead contamination. Lead was detected in egg samples from 98% of the households that provided egg samples. Mean household lead concentration was 0.10 µg/g (SD: 0.18). Egg lead concentrations ranged from below the limit of detection (0.0014 µg/g) to 1.798 µg/g (<1.4-1198 ppb). Egg lead levels were strongly positively correlated with lead concentration in coop soil (r = 0.64; p < 0.001). In modeled scenarios where a child < 7 years frequently ate eggs highly contaminated with lead, BLLs are predicted to increase by 0.9-1.5 µg/dL. In three other scenarios reflecting more moderate egg lead contamination and consumption rates, BLLs were predicted to increase from 0.1 to 0.8 µg/dL. Consumption of backyard chicken eggs can contribute to lead exposure in children. Soil lead remediation prior to chicken ownership may reduce lead exposure from backyard eggs.

Modeling variability in air pollution-related health damages from individual airport emissions.

In this study, we modeled concentrations of fine particulate matter (PM2.5) and ozone (O3) attributable to precursor emissions from individual airports in the United States, developing airport-specific health damage functions (deaths per 1000t of precursor emissions) and physically-interpretable regression models to explain variability in these functions. We applied the Community Multiscale Air Quality model using the Decoupled Direct Method to isolate PM2.5- or O3-related contributions from precursor pollutants emitted by 66 individual airports. We linked airport- and pollutant-specific concentrations with population data and literature-based concentration-response functions to create health damage functions. Deaths per 1000t of primary PM2.5 emissions ranged from 3 to 160 across airports, with variability explained by population patterns within 500km of the airport. Deaths per 1000t of precursors for secondary PM2.5 varied across airports from 0.1 to 2.7 for NOx, 0.06 to 2.9 for SO2, and 0.06 to 11 for VOCs, with variability explained by population patterns and ambient concentrations influencing particle formation. Deaths per 1000t of O3 precursors ranged from -0.004 to 1.0 for NOx and 0.03 to 1.5 for VOCs, with strong seasonality and influence of ambient concentrations. Our findings reinforce the importance of location- and source-specific health damage functions in design of health-maximizing emissions control policies.

Petroleum contaminated water and health symptoms: a cross-sectional pilot study in a rural Nigerian community.

BACKGROUND: The oil-rich Niger Delta suffers from extensive petroleum contamination. A pilot study was conducted in the region of Ogoniland where one community, Ogale, has drinking water wells highly contaminated with a refined oil product. In a 2011 study, the United Nations Environment Programme (UNEP) sampled Ogale drinking water wells and detected numerous petroleum hydrocarbons, including benzene at concentrations as much as 1800 times higher than the USEPA drinking water standard. UNEP recommended immediate provision of clean drinking water, medical surveillance, and a prospective cohort study. Although the Nigerian government has provided emergency drinking water, other UNEP recommendations have not been implemented. We aimed to (i) follow up on UNEP recommendations by investigating health symptoms associated with exposure to contaminated water; and (ii) assess the adequacy and utilization of the government-supplied emergency drinking water. METHODS: We recruited 200 participants from Ogale and a reference community, Eteo, and administered questionnaires to investigate water use, perceived water safety, and self-reported health symptoms. RESULTS: Our multivariate regression analyses show statistically significant associations between exposure to Ogale drinking water and self-reported health symptoms consistent with petroleum exposure. Participants in Ogale more frequently reported health symptoms related to neurological effects (OR = 2.8), hematological effects (OR = 3.3), and irritation (OR = 2.7). CONCLUSIONS: Our results are the first from a community relying on drinking water with such extremely high concentrations of benzene and other hydrocarbons. The ongoing exposure and these pilot study results highlight the need for more refined investigation as recommended by UNEP.

Manganese in residential drinking water from a community-initiated case study in Massachusetts.

BACKGROUND: Manganese (Mn) is a metal commonly found in drinking water, but the level that is safe for consumption is unknown. In the United States (U.S.), Mn is not regulated in drinking water and data on water Mn concentrations are temporally and spatially sparse. OBJECTIVE: Examine temporal and spatial variability of Mn concentrations in repeated tap water samples in a case study of Holliston, Massachusetts (MA), U.S., where drinking water is pumped from shallow aquifers that are vulnerable to Mn contamination. METHODS: We collected 79 residential tap water samples from 21 households between September 2018 and December 2019. Mn concentrations were measured using inductively coupled plasma mass spectrometry. We calculated descriptive statistics and percent of samples exceeding aesthetic (secondary maximum containment level; SMCL) and lifetime health advisory (LHA) guidelines of 50 µg/L and 300 µg/L, respectively. We compared these concentrations to concurrent and historic water Mn concentrations from publicly available data across MA. RESULTS: The median Mn concentration in Holliston residential tap water was 2.3 µg/L and levels were highly variable (range: 0.03-5,301.8 µg/L). Mn concentrations exceeded the SMCL and LHA in 14% and 12% of samples, respectively. Based on publicly available data across MA from 1994-2022, median Mn concentration was 17.0 µg/L (N = 37,210; range: 1-159,000 µg/L). On average 40% of samples each year exceeded the SMCL and 9% exceeded the LHA. Samples from publicly available data were not evenly distributed between MA towns or across sampling years. IMPACT STATEMENT: This study is one of the first to examine Mn concentrations in drinking water both spatially and temporally in the U.S. Findings suggest that concentrations of Mn in drinking water frequently exceed current guidelines and occur at concentrations shown to be associated with adverse health outcomes, especially for vulnerable and susceptible subpopulations like children. Future studies that comprehensively examine exposure to Mn in drinking water and its associations with children's health are needed to protect public health.

Association between Combined Sewer Overflow Events and Gastrointestinal Illness in Massachusetts Municipalities with and without River-Sourced Drinking Water, 2014-2019.

BACKGROUND: Combined sewer overflow (CSO) events release untreated wastewater into surface waterbodies during heavy precipitation and snowmelt. Combined sewer systems serve ∼40 million people in the United States, primarily in urban and suburban municipalities in the Midwest and Northeast. Predicted increases in heavy precipitation events driven by climate change underscore the importance of quantifying potential health risks associated with CSO events. OBJECTIVES: The aims of this study were to a) estimate the association between CSO events (2014-2019) and emergency department (ED) visits for acute gastrointestinal illness (AGI) among Massachusetts municipalities that border a CSO-impacted river, and b) determine whether associations differ by municipal drinking water source. METHODS: A case time-series design was used to estimate the association between daily cumulative upstream CSO discharge and ED visits for AGI over lag periods of 4, 7, and 14 days, adjusting for temporal trends, temperature, and precipitation. Associations between CSO events and AGI were also compared by municipal drinking water source (CSO-impacted river vs. other sources). RESULTS: Extreme upstream CSO discharge events (>95th percentile by cumulative volume) were associated with a cumulative risk ratio (CRR) of AGI of 1.22 [95% confidence interval (CI): 1.05, 1.42] over the next 4 days for all municipalities, and the association was robust after adjusting for precipitation [1.17 (95% CI: 0.98, 1.39)], although the CI includes the null. In municipalities with CSO-impacted drinking water sources, the adjusted association was somewhat less pronounced following 95th percentile CSO events [CRR= 1.05 (95% CI: 0.82, 1.33)]. The adjusted CRR of AGI was 1.62 in all municipalities following 99th percentile CSO events (95% CI: 1.04, 2.51) and not statistically different when stratified by drinking water source. DISCUSSION: In municipalities bordering a CSO-impacted river in Massachusetts, extreme CSO events are associated with higher risk of AGI within 4 days. The largest CSO events are associated with increased risk of AGI regardless of drinking water source. https://doi.org/10.1289/EHP14213.

Flame retardant exposure among collegiate United States gymnasts.

Gymnastics training facilities contain large volumes of polyurethane foam, a material that often contains additive flame retardants such as PentaBDE. While investigations of human exposure to flame retardants have focused on the general population, potentially higher than background exposures may occur in gymnasts and certain occupational groups. Our objectives were to compare PentaBDE body burden among gymnasts to the general United States population and characterize flame retardants levels in gym equipment, air, and dust. We recruited 11 collegiate female gymnasts (ages 18-22) from one gym in the eastern United States. The geometric mean (GM) concentration of BDE-153 in gymnast sera (32.5 ng/g lipid) was 4-6.5 times higher than in the general United States population groups. Median concentrations of PentaBDE, TBB, and TBPH in paired handwipe samples were 2-3 times higher after practice compared to before, indicating the gymnasts contacted these flame retardants during practice. GM concentrations of PentaBDE, TBB, and TBPH were 1-3 orders of magnitude higher in gym air and dust than in residences. Our findings suggest that these collegiate gymnasts experienced higher exposures to PentaBDE flame retardants compared to the general United States population and that gymnasts may also have increased exposure to other additive flame retardants used in polyurethane foam such as TBB and TBPH.

Sewer Gas: An Indoor Air Source of PCE to Consider During Vapor Intrusion Investigations.

The United States Environmental Protection Agency (USEPA) is finalizing its vapor intrusion guidelines. One of the important issues related to vapor intrusion is background concentrations of volatile organic chemicals (VOCs) in indoor air, typically attributed to consumer products and building materials. Background concentrations can exist even in the absence of vapor intrusion and are an important consideration when conducting site assessments. In addition, the development of accurate conceptual models that depict pathways for vapor entry into buildings is important during vapor intrusion site assessments. Sewer gas, either as a contributor to background concentrations or as part of the site conceptual model, is not routinely evaluated during vapor intrusion site assessments. The research described herein identifies an instance where vapors emanating directly from a sanitary sewer pipe within a residence were determined to be a source of tetrachloroethylene (PCE) detected in indoor air. Concentrations of PCE in the bathroom range from 2.1 to 190 ug/m3 and exceed typical indoor air concentrations by orders of magnitude resulting in human health risk classified as an "Imminent Hazard" condition. The results suggest that infiltration of sewer gas resulted in PCE concentrations in indoor air that were nearly two-orders of magnitude higher as compared to when infiltration of sewer gas was not known to be occurring. This previously understudied pathway whereby sewers serve as sources of PCE (and potentially other VOC) vapors is highlighted. Implications for vapor intrusion investigations are also discussed.

Potential Policy and Community Implications of Equitable Organic Waste, Compost, and Urban Agricultural Systems in the United States.

BACKGROUND: Urban organic waste diverted from landfills for use as compost feedstock may help mitigate and adapt to the effects of our changing climate. Yet, compost produced from urban food and yard waste is often a source of contaminants harmful to human and environmental health. Efforts by multiple municipalities are increasing residential and commercial food and yard waste collection; however, finished, tested compost is typically unavailable to those contributing the waste and whose gardens would benefit. OBJECTIVES: This commentary evaluates the relative equity and safety of U.S. organic waste cycles in relation to urban and peri-urban agriculture (UA) and waste stewardship. We a) explore historical structures that have led to siloed food and waste systems and b) provide recommendations to promote safer compost production from urban organic waste inputs. The engagement of intersectional partners in the creation of equitable policies and contracts that integrate food and waste justice is crucial to this work. METHODS: A 15-y relationship between community, academic, and government partners in Boston, Massachusetts, has increased access to health-promoting community gardens. Historical concerns raised by gardeners resulted in improvement to the quality of compost sourced from municipal organic waste and motivated a case study of Boston and three other cities (Seattle, Washington; San Francisco, California; New York, New York). This case study provides the approaches used to source, collect, process, test, and deliver urban organic waste as compost for UA. It informed recommendations to improve the safety and equity of organic waste-to-compost cycles. DISCUSSION: Strict feedstock regulation and required compost safety testing are essential to produce safe, city-sourced compost. Balancing the needs of landfill diversion with equitable distribution to all contributors, particularly low-income and food-insecure people, will help concentrate UA benefits within marginalized communities. Adoption of a public health lens may help ensure the safety of nutrient-rich compost available for urban growers through legislation at state and local levels, along with explicit industry contracts. https://doi.org/10.1289/EHP12921.

Unknown Organofluorine Mixtures in U.S. Adult Serum:Contribution from Pharmaceuticals?

Organofluorines occur in human serum as complex mixtures of known and unidentified compounds. Human biomonitoring traditionally uses targeted analysis to measure the presence of known and quantifiable per- and polyfluoroalkyl substances (PFAS) in serum, yet characterization of exposure to and quantification of PFAS are limited by the availability of methods and analytical standards. Studies comparing extractable organofluorine (EOF) in serum to measured PFAS using organofluorine mass balance show that measurable PFAS only explain a fraction of EOF in human serum and that other sources of organofluorine may exist. The gap in fluorine mass balance has important implications for human biomonitoring because the total body burden of PFAS cannot be characterized and the chemical species that make up unidentified EOF are unknown. Many highly prescribed pharmaceuticals contain organofluorine (e.g., Lipitor, Prozac) and are prescribed with dosing regimens designed to maintain a therapeutic range of concentrations in serum. Therefore, we hypothesize organofluorine pharmaceuticals contribute to EOF in serum. We use combustion ion chromatography to measure EOF in commercial serum from U.S. blood donors. Using fluorine mass balance, we assess differences in unexplained organofluorine (UOF) associated with pharmaceutical use and compare them with concentrations of organofluorine predicted based on the pharmacokinetic properties of each drug. Pharmacokinetic estimates of organofluorine attributable to pharmaceuticals ranged from 0.1 to 55.6 ng F/mL. Analysis of 44 target PFAS and EOF in samples of commercial serum (n = 20) shows the fraction of EOF not explained by Σ44 PFAS ranged from 15% to 86%. Self-reported use of organofluorine pharmaceuticals is associated with a 0.36 ng F/mL (95% CL: -1.26 to 1.97) increase in UOF, on average, compared to those who report not taking organofluorine pharmaceuticals. Our study is the first to assess sources of UOF in U.S. serum and examine whether organofluorine pharmaceuticals contribute to EOF. Discrepancies between pharmacokinetic estimates and EOF may be partly explained by differences in analytical measurements. Future analyses using EOF should consider multiple extraction methods to include cations and zwitterions. Whether organofluorine pharmaceuticals are classified as PFAS depends on the definition of PFAS.

Methodological limitations may prevent the observation of non-Hodgkin's lymphoma in bioassays of polychlorinated biphenyls.

Epidemiological studies increasingly indicate that polychlorinated biphenyls (PCBs) contribute to the risk of non-Hodgkin's lymphoma (NHL). In rodent bioassays, PCBs have long been demonstrated to be liver carcinogens, and excess tumors in the thyroid, lung, and other organs have been observed in more recent studies. Leukemias and lymphomas now classified as NHL were observed in one bioassay in which a concurrent infection was also reported. Clinical and epidemiological studies show immunosuppression and inflammation are strong risk factors for NHL, and both epidemiology and toxicology studies show that PCBs are immunosuppressive and cause inflammation. We reviewed published carcinogenesis bioassays conducted using commercial PCB products, individual congeners, and congener mixtures, with a focus on bioassay protocols and immune-related observations. Based on a mode-of-action framework for PCBs, we suggest that an immune challenge in conjunction with PCB exposure may be necessary for the observation of NHL. We conclude that the lack of concordance between human epidemiology and animal bioassays with respect to NHL may simply be the result of the bioassay methodology used, and not a difference in underlying biology. The lack of concordance should not be construed as evidence that PCBs do not contribute to the risk of NHL.

Predictors of tetrabromobisphenol-A (TBBP-A) and hexabromocyclododecanes (HBCD) in milk from Boston mothers.

Tetrabromobisphenol-A (TBBP-A) and hexabromocyclododecanes (HBCDs) are brominated flame retardants that have been found in human milk and serum throughout the world, but have received comparatively little attention in the United States. The objective of this study is to determine concentrations of these analytes in samples of breast milk collected from first-time mothers in the Greater Boston, Massachusetts area and to explore predictors of exposure. Human milk samples were analyzed by LC-ESI-MS/MS for TBBP-A, HBCDs (the α, ß, and γ diastereomers), and HBCD degradation products: pentabromocyclododecanes (PBCDs) and tetrabromocyclododecadienes (TBCDs). HBCD diastereomers were detected in all samples with α-HBCD present in the highest proportion. TBBP-A, PBCDs, and TBCDs were detected in 35%, 42%, and 56% of the analyzed samples, respectively. Self-reported demographic, dietary and behavioral data were examined as predictors of HBCD levels. Levels of HBCD were significantly, positively associated with the number of stereo and video electronics in the home (17% increase/item; 95% Confidence Interval (CI) = 4-31%) and reduced in participants who regularly chose organic foods compared to those who did not (0.51, 95% CI = 0.32-0.82). These results suggest that lifestyle factors are related to body burdens of HBCD and that domestic electronics may be an important source of HBCD exposure in the indoor environment.

Implications of PFAS definitions using fluorinated pharmaceuticals.

There are 9,000+ per- and polyfluoroalkyl substances (PFAS) in existence, which makes studying and regulating PFAS individually, or even as small mixtures, infeasible. Multiple PFAS definitions based on structure have been proposed, yet these definitions do not consider the implications for the full suite of organofluorine chemicals. For example, organofluorine pharmaceuticals, whose use may be essential and are found in human serum and wastewater, are not uniformly identified across all definitions. Using nine definitions prepared by various stakeholders, we screened the 360 organofluorine pharmaceuticals approved and used globally between 1954 and 2021. Definitions ranged in their inclusion of organofluorine pharmaceuticals (1%-100%). The most inclusive definitions include several top prescribed pharmaceuticals, e.g., Prozac and Lipitor. This analysis provides a framework against which organizations can make decisions about how best to proceed when defining PFAS.

Predicting the effects of per- and polyfluoroalkyl substance mixtures on peroxisome proliferator-activated receptor alpha activity in vitro.

Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes.

Multiple metals in children's deciduous teeth: results from a community-initiated pilot study.

BACKGROUND: Characterizing retrospective exposure to toxicants during multiple early-life developmental periods is challenging, yet critical for understanding developmental effects. OBJECTIVE: To characterize early-life metal exposure using deciduous teeth in a community concerned about past exposures. METHODS: Naturally shed teeth were collected from 30 children ages 5-13 years who resided in Holliston, Massachusetts since conception. We estimated weekly prenatal and postnatal (up to 1 year of age) exposure to 12 metals by measuring dentine concentrations using laser ablation-inductively coupled plasma-mass spectrometry. Multivariable linear mixed models were used to explore sociodemographic, dietary, and behavioral correlates of dentine metal concentrations. RESULTS: Temporal trends in dentine levels differed by metal. Source of milk during the first year of life was associated with dentine barium (Ba) levels, where being fed predominantly breastmilk was associated with 39% (95% CI: -57%, -13%) lower dentine Ba compared to predominantly formula use. Females had higher prenatal and postnatal dentine Mn and Pb, compared to males (e.g., % difference, postnatal Mn: 122% (17%, 321%); postnatal Pb: 60% (95% CI: -8%, 178%)). SIGNIFICANCE: Deciduous teeth provide retrospective information on dose and timing of early-life metals exposure at high resolution. We demonstrate their utility in a community-based study with known past contamination of drinking water. IMPACT STATEMENT: We conducted a community-initiated pilot study in a community concerned with historical exposure to multiple metals. Using deciduous teeth, a novel noninvasive biomarker, we characterized early-life exposure to 12 metals in approximately weekly increments during sensitive developmental periods, thus demonstrating the utility of this biomarker in communities concerned with past exposures.

Balancing incomplete COVID-19 evidence and local priorities: risk communication and stakeholder engagement strategies for school re-opening.

In the midst of the COVID-19 pandemic, United States (U.S.) educational institutions must weigh incomplete scientific evidence to inform decisions about how best to re-open schools without sacrificing public health. While many communities face surging case numbers, others are experiencing case plateaus or even decreasing numbers. Simultaneously, some U.S. school systems face immense infrastructure challenges and resource constraints, while others are better positioned to resume face-to-face instruction. In this review, we first examine potential engineering controls to reduce SARS-CoV-2 exposures; we then present processes whereby local decision-makers can identify and partner with scientists, faculty, students, parents, public health officials, and others to determine the controls most appropriate for their communities. While no solution completely eliminates risks of SARS-CoV-2 exposure and illness, this mini-review discusses engaged decision and communication processes that incorporate current scientific knowledge, school district constraints, local tolerance for health risk, and community priorities to help guide schools in selecting and implementing re-opening strategies that are acceptable, feasible, and context-specific.