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Background: Researchers have developed exposure assessment metrics for disinfection by-products (DBPs) utilizing drinking water monitoring data and accounting for spatial and temporal variability, water consumption, and showering and bathing time with an expectation of decreasing exposure misclassification compared to the use of measured concentrations at public water supply (PWS) monitoring locations alone., Objective: We used exposure data collected for a previous study of DBPs to evaluate how different sources of information impact trihalomethane (THM) exposure estimates., Methods: We compared gestational exposure estimates to THMs based on water utility monitoring data alone, statistical imputation of daily concentrations to incorporate temporal variability, and personal water consumption and use (bathing and showering). We used Spearman correlation coefficients and ranked kappa statistics to compare exposure classifications., Results: Exposure estimates based on measured or imputed daily THM concentrations, self-reported consumption, or bathing and showering differed substantially from estimates based solely on concentrations from PWS quarterly monitoring reports. Ranked exposure classifications, high to low quartiles or deciles, were generally consistent across each exposure metric (i.e., a subject with "high" exposure based on measured or imputed THM concentrations generally remained in the "high" category across exposure metrics.) The measured concentrations and imputed daily (i.e., spline regression) concentrations were highly correlated (r = 0.98). The weighted kappa statistics comparing exposure estimates using different exposure metrics ranged from 0.27 to 0.89, with the highest values for the ingestion + bathing/showering metrics compared to metrics for bathing/showering only (0.76 and 0.89). Bathing and showering contributed the most to "total" THM exposure estimates., Impact Statement: We compare exposure metrics capturing temporal variability and multiple estimates of personal THM exposure with THM concentrations from PWS monitoring data. Our results show exposure estimates based on imputed daily concentrations accounting for temporal variability were very similar to the measured THM concentrations. We observed low agreement between imputed daily concentrations and ingestion-based estimates. Considering additional routes of exposure (e.g., inhalation and dermal) slightly increased agreement with the measured PWS exposure estimate in this population. Overall, the comparison of exposure assessment metrics allows researchers to understand the added value of additional data collection for future epidemiologic analyses of DBPs., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: While epidemiologic evidence links higher levels of exposure to fine particulate matter (PM 2.5 ) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence., Objective: To evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO 2 ]) and late-life dementia incidence., Methods: We ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM 2.5 , and APOE genotype. We ran sensitivity analyses where we did not adjust for PM 2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others., Results: We identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92-1.05) for every 2000 pt/cm 3 increment in UFP, 0.95 (0.89-1.01) for every 100 ng/m 3 increment in BC, and 0.96 (0.91-1.02) for every 2 ppb increment in NO 2 . These findings were consistent across sensitivity and secondary analyses., Discussion: We did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Manganese (Mn) is neurotoxic in adults and children. Current assessments are based on the more extensive adult epidemiological data, but the potential for greater childhood susceptibility remains a concern. To better understand potential lifestage-based variations, we compared susceptibilities to neurotoxicity in children and adults using Mn biomarker data., Methods: We developed a literature search strategy based on a Population, Exposures, Comparators, and Outcomes statement focusing on inhalation exposures and neurological outcomes in humans. Screening was performed using DistillerSR. Hair biomarker studies were selected for evaluation because studies with air measurements were unavailable or considered inadequate for children. Studies were paired based on concordant Mn source, biomarker, and outcome. Comparisons were made based on reported dose-response slopes (children vs. adults). Study evaluation was conducted to understand the confidence in our comparisons., Results: We identified five studies evaluating seven pairings of hair Mn and neurological outcomes (cognition and motor effects) in children and adults matched on sources of environmental Mn inhalation exposure. Two Brazilian studies of children and one of adults reported intelligent quotient (IQ) effects; effects in both comparisons were stronger in children (1.21 to 2.03-fold difference). In paired analyses of children and adults from the United States, children exhibited both stronger and weaker effects compared to adults (0.37 to 1.75-fold differences) on postural sway metrics., Conclusion: There is limited information on the comparative susceptibility of children and adults to inhaled Mn. We report that children may be 0.37 to 2.03 times as susceptible as adults to neurotoxic effects of Mn, thereby providing a quantitative estimate for some aspects of lifestage variation. Due to the limited number of paired studies available in the literature, this quantitative estimate should be interpreted with caution. Our analyses do not account for other sources of inter-individual variation. Additional studies of Mn-exposed children with direct air concentration measurements would improve the evidence base., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKS, PR, CRK, PJL, PFL, AS, MT, MSB, JT, TAJ, LR, JM, AFK, RB, RS, SS, CL, KS, and BI report financial support provided by the US Environmental Protection Agency under Contract 68HERC19D0003 to ICF. PJL reports a relationship with Friedman Rubin Associates that includes: paid expert testimony. CRK reports a relationship with Bausch Health Companies Inc US that includes: employment and equity or stocks., (Published by Elsevier Inc.)

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

From the 1950s to the 1970s, three Superfund sites discharged polychlorinated biphenyl (PCB)-contaminated waste upstream of the Mohawk Nation at Akwesasne, resulting in PCB contamination of groundwater, soil, and sediment in the surrounding area. Given the persistence of PCBs in the environment and in human tissues, there are continued concerns regarding PCB exposures and the potential for adverse health effects in the community. We developed an evidence map of PCB research at Akwesasne in order to characterize the available data and to highlight potential research needs. Human health and exposure biomarker studies were identified from a literature search based on population, exposure, comparator, and outcome (PECO) criteria. Data extracted from references that met the inclusion criteria after full-text review included study characteristics (e.g., sample size, study design, sampling years), details on PCB measurements (e.g., analytical method, number of congeners analyzed, method detection limits), and results (e.g., PCB levels and summary of study conclusions). We identified 33 studies, conducted between 1986 and 2013, that examined PCB exposure characteristics and health effects in residents of the Akwesasne Mohawk Nation. Organizing this literature into an evidence map including information on study cohort, congener groupings, exposure biomarker characteristics, and health effects allowed us to identify research gaps and to suggest future research priorities for the community. We identified current PCB exposure levels and PCB source characterization as major uncertainties, both of which could be addressed by new studies of PCB concentrations in environmental media., (Published by Elsevier Ltd.)

Background: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest., Objectives: This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Lead exposure remains highly prevalent worldwide despite decades of research highlighting its link to numerous adverse health outcomes. In addition to well-documented effects on cognition, there is growing evidence of an association with antisocial behavior, including aggression, conduct problems, and crime. An updated systematic review on this topic, incorporating study evaluation and a developmental perspective on the outcome, can advance the state of the science on lead and inform global policy interventions to reduce exposure., Objectives: We aim to evaluate the link between lead exposure and antisocial behavior. This association will be investigated via a systematic review of human epidemiological and experimental nonhuman mammalian studies., Methods: The systematic review protocol presented in this publication is informed by recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER) and follows the study evaluation approach put forth by the U.S. EPA Integrated Risk Information System (IRIS) program., Data Sources: We will search the following electronic databases for relevant literature: PubMed, BIOSIS and Web of Science. Search results will be stored in EPA's Health and Environmental Research Online (HERO) database., Study Eligibility and Criteria: Eligible human epidemiological studies will include those evaluating any population exposed to lead at any lifestage via ingestion or inhalation exposure and considering an outcome of antisocial behavior based on any of the following criteria: psychiatric diagnoses (e.g., oppositional defiant disorder (ODD), conduct disorder (CD), disruptive behavior disorders (DBD)); violation of social norms (e.g., delinquency, criminality); and aggression. Eligible experimental animal studies will include those evaluating nonhuman mammalian studies exposed to lead via ingestion, inhalation, or injection exposure during any lifestage. The following outcomes will be considered relevant: aggression; antisocial behavior; and altered fear, anxiety, and stress response., Study Appraisal and Synthesis Methods: Screening will be conducted with assistance from an artificial intelligence application. Two independent reviewers for each data stream (human, animal) will screen studies with highest predicted relevance against pre-specified inclusion criteria at the title/abstract and full-text level. Study evaluation will be conducted using methods adapted from the U.S. EPA IRIS program. After data extraction, we will conduct a narrative review and quantitative meta-analysis on the human epidemiological studies as well as a narrative review of the experimental animal studies. We will evaluate the strength of each evidence stream separately and then will develop a summary evidence integration statement based on inference across evidence streams., Competing Interests: Declaration of Competing Interest All authors except H.H. declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Howard Hu reports a relationship with lead exposure litigation (various) that includes: consulting or advisory and paid expert testimony., (Published by Elsevier Ltd.)

Background: In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations., Objectives: We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods., Discussion: Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.

In the United States (U.S.), chemical evaluations and assessments are conducted by seven federal agencies responding to distinct statutory requirements and focusing on different exposure scenarios. While risk assessment is a fundamental concept in public health practice and policy, there is no clear, central, and concise summary of these processes. The novel infographic presented here depicts more than 30 different evaluation and assessment processes conducted by federal agencies for chemicals found in the environment, workplace, consumer products, hazardous waste sites, food, and/or cosmetics. The majority of these assessments are statutorily required. Most serve as sources of authoritative information to provide public health guidance or recommendations. Less than half directly result in risk management actions or regulations. Understanding these roles and processes can facilitate engagement from the broader community, including by highlighting priority areas for research to inform public health policy. This infographic also illustrates the opportunity and need for further intra- and interagency collaboration and coordination - including a particular focus on aggregate risk assessment, given that the population regularly experiences exposures from multiple sources crossing agency domains.

Background: Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States., Objectives: We evaluated the association between time-varying, 10-y average fine particulate matter ( PM 2.5 ) exposure and hazard of all-cause dementia. An additional goal was to understand how to adequately control for age and calendar-time-related confounding through choice of the time axis and covariate adjustment., Methods: Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based PM 2.5 exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-y average PM 2.5 exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time. Alternative models used calendar time as the time axis., Results: We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y average PM 2.5 was 10.1   ( ± 2.9 )   μ g / m 3 . Each 1 - μ g / m 3 increase in the moving average of 10-y PM 2.5 was associated with a 16% greater hazard of all-cause dementia [1.16 (95% confidence interval: 1.03, 1.31)]. Results using calendar time as the time axis were similar., Discussion: In this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to PM 2.5 was associated with increased hazard of all-cause dementia. We found that optimal control of age and time confounding could be achieved through use of either age or calendar time as the time axis in our study. Our results strengthen evidence on the neurodegenerative effects of PM 2.5 . https://doi.org/10.1289/EHP9018.

Background: Evidence links fine particulate matter (PM2.5) to Alzheimer's disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy., Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score)., Methods: We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score., Results: 10-year average (SD) PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3. Average age (SD) at death was 89 (7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47))., Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.

Background: The use of polypropylene prolapse mesh to treat pelvic organ prolapse has been limited by mesh-related complications. Gynemesh PS mesh, implanted via sacrocolpopexy in rhesus macaques, had a negative impact on the vagina with thinning of vaginal muscularis and decreased vaginal smooth muscle contractility. The negative effect was attenuated when a bioscaffold derived from urinary bladder extracellular matrix was used as a composite with Gynemesh PS., Objective: The objective of the study was to further elucidate the impact of Gynemesh PS polypropylene mesh and MatriStem extracellular matrix bioscaffolds on the vaginal smooth muscle in terms of micromorphology of vaginal smooth muscle (muscle bundles and individual myocytes), innervation, and nerve-mediated contractile function following their implantations in a rhesus macaque model via sacrocolpopexy., Study Design: Thirty-two middle-aged rhesus macaques were randomized to undergo either a sham surgery (sham, n = 8), or the implantation of Gynemesh PS alone (n = 8) vs composite mesh comprised of Gynemesh PS plus 2-ply MatriStem (n = 8) vs 6-ply MatriStem alone (n = 8) via sacrocolpopexy. The graft-vagina complexes were harvested 3 months later. Histomorphometrics of smooth muscle bundles and myocytes were performed by immunofluorescent labeling of alpha smooth muscle actin, caveolin-3 (membrane protein), and cell nuclei followed by confocal imaging. The cross-sectional diameters of smooth muscle bundles and individual myocytes were quantified using images randomly taken in at least 5 areas of each section of sample. Contractile proteins alpha smooth muscle actin and smoothelin were quantified by Western immunoblotting. Nerve density was measured by immunohistochemical labeling of a pan-neuron marker, PGP9.5. Nerve-mediated smooth muscle contractility was quantified using electrical field stimulation. One-way analysis of variance and appropriate post hoc tests were used for statistical comparisons., Results: Compared with sham, the implantation of Gynemesh PS alone resulted in a disorganized smooth muscle morphology with the number of small muscle bundles (cross-sectional diameter less than 20 μm) increased 67% (P = .004) and the myocyte diameter decreased 22% (P < .001). Levels of contractile proteins were all decreased vs sham with alpha smooth muscle actin decreased by 68% (P = .009), low-molecular-weight smoothelin by 51% (P = .014), and high-molecular-weight smoothelin by 40% (P = .015). Nerve density was decreased by 48% (P = .03 vs sham) paralleled by a 63% decrease of nerve-mediated contractility (P = .02). Following the implantation of composite mesh, the results of measurements were similar to sham (all P > .05), with a 39% increase in the myocyte diameter (P < .001) and a 2-fold increase in the level of alpha smooth muscle actin relative to Gynemesh (P = .045). Following the implantation of MatriStem alone, the number of small muscle bundles were increased 54% vs sham (P = .002), while the other parameters were not significantly different from sham (all P > .05)., Conclusion: The implantation of Gynemesh PS had a negative impact on the structural and functional integrity of vaginal smooth muscle evidenced by atrophic macro- and microscopic muscle morphology, decreased innervation, and impaired contractile property, consistent with a maladaptive remodeling response. The extracellular matrix bioscaffold (MatriStem), when used with Gynemesh PS as a composite (2 ply), attenuated the negative impact of Gynemesh PS; when used alone (6 ply), it induced adaptive remodeling as evidenced by an increased fraction of small smooth muscle bundles with normal contractility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals., Objectives: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease-Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden-both current and projected., Methods: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment., Discussion: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure-risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD's current methods do not fully account for lead's impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk-outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD's estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496.

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Phthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM)., Objective: We evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest., Study Design: We used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing., Results: In our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35)., Conclusion: In alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Despite the growing and widespread use of glyphosate, a broad-spectrum herbicide and desiccant, very few studies have evaluated the extent and amount of human exposure., Objective: We review documented levels of human exposure among workers in occupational settings and the general population., Methods: We conducted a review of scientific publications on glyphosate levels in humans; 19 studies were identified, of which five investigated occupational exposure to glyphosate, 11 documented the exposure in general populations, and three reported on both., Results: Eight studies reported urinary levels in 423 occupationally and para-occupationally exposed subjects; 14 studies reported glyphosate levels in various biofluids on 3298 subjects from the general population. Average urinary levels in occupationally exposed subjects varied from 0.26 to 73.5 μg/L; environmental exposure urinary levels ranged from 0.16 to 7.6 μg/L. Only two studies measured temporal trends in exposure, both of which show increasing proportions of individuals with detectable levels of glyphosate in their urine over time., Conclusions: The current review highlights the paucity of data on glyphosate levels among individuals exposed occupationally, para-occupationally, or environmentally to the herbicide. As such, it is challenging to fully understand the extent of exposure overall and in vulnerable populations such as children. We recommend further work to evaluate exposure across populations and geographic regions, apportion the exposure sources (e.g., occupational, household use, food residues), and understand temporal trends.

Background: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF)., Objective: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer's disease (AD) individuals., Methods: We collected CSF from 133 community volunteers at VA Puget Sound between 2001-2012. We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively., Results: Among cognitively normal individuals, a 5 μg/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5 μg/m3 increase in 1-year average PM2.5, but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals., Conclusions: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration.

Outdated federal and state occupational lead standards leave workers and their families vulnerable to the adverse effects of lead. Standards should be updated to reflect the best available scientific and medical evidence, which documents harm to multiple organ systems even at low levels of exposure. This commentary will review the inadequacies of existing policies, highlight susceptible populations, and briefly summarize state revision efforts to date. Federal policies must be strengthened to protect all workers and their families from this well-documented hazard., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Increasing scientific evidence suggests potential adverse effects on children's health from synthetic chemicals used as food additives, both those deliberately added to food during processing (direct) and those used in materials that may contaminate food as part of packaging or manufacturing (indirect). Concern regarding food additives has increased in the past 2 decades in part because of studies that increasingly document endocrine disruption and other adverse health effects. In some cases, exposure to these chemicals is disproportionate among minority and low-income populations. This report focuses on those food additives with the strongest scientific evidence for concern. Further research is needed to study effects of exposure over various points in the life course, and toxicity testing must be advanced to be able to better identify health concerns prior to widespread population exposure. The accompanying policy statement describes approaches policy makers and pediatricians can take to prevent the disease and disability that are increasingly being identified in relation to chemicals used as food additives, among other uses., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Our purposes with this policy statement and its accompanying technical report are to review and highlight emerging child health concerns related to the use of colorings, flavorings, and chemicals deliberately added to food during processing (direct food additives) as well as substances in food contact materials, including adhesives, dyes, coatings, paper, paperboard, plastic, and other polymers, which may contaminate food as part of packaging or manufacturing equipment (indirect food additives); to make reasonable recommendations that the pediatrician might be able to adopt into the guidance provided during pediatric visits; and to propose urgently needed reforms to the current regulatory process at the US Food and Drug Administration (FDA) for food additives. Concern regarding food additives has increased in the past 2 decades, in part because of studies in which authors document endocrine disruption and other adverse health effects. In some cases, exposure to these chemicals is disproportionate among minority and low-income populations. Regulation and oversight of many food additives is inadequate because of several key problems in the Federal Food, Drug, and Cosmetic Act. Current requirements for a "generally recognized as safe" (GRAS) designation are insufficient to ensure the safety of food additives and do not contain sufficient protections against conflict of interest. Additionally, the FDA does not have adequate authority to acquire data on chemicals on the market or reassess their safety for human health. These are critical weaknesses in the current regulatory system for food additives. Data about health effects of food additives on infants and children are limited or missing; however, in general, infants and children are more vulnerable to chemical exposures. Substantial improvements to the food additives regulatory system are urgently needed, including greatly strengthening or replacing the "generally recognized as safe" (GRAS) determination process, updating the scientific foundation of the FDA's safety assessment program, retesting all previously approved chemicals, and labeling direct additives with limited or no toxicity data., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Exposome-related efforts aim to document the totality of human exposures across the lifecourse. This field has advanced rapidly in recent years but lacks practical application to risk assessment, particularly for children's health., Objectives: Our objective was to apply the exposome to children's health risk assessment by introducing the concept of Lifestage Exposome Snapshots (LEnS). Case studies are presented to illustrate the value of the framework., Discussion: The LEnS framework encourages organization of exposome studies based on windows of susceptibility for particular target organ systems. Such analyses will provide information regarding cumulative impacts during specific critical periods of the life course. A logical extension of this framework is that regulatory standards should analyze exposure information by target organ, rather than for a single chemical only or multiple chemicals grouped solely by mechanism of action., Conclusions: The LEnS concept is a practical refinement to the exposome that accounts for total exposures during particular windows of susceptibility in target organ systems. Application of the LEnS framework in risk assessment and regulation will improve protection of children's health by enhancing protection of sensitive developing organ systems that are critical for lifelong health and well-being. https://doi.org/10.1289/EHP1250.

The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5-7days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4α and canaliculi structure, for up to 14days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B 1 , was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro., (Copyright © 2017. Published by Elsevier Ltd.)

As polybrominated diphenyl ethers are phased out, numerous compounds are emerging as potential replacement flame retardants for use in consumer and electronic products. Little is known, however, about the neurobehavioral toxicity of these replacements. This study evaluated the neurobehavioral effects of acute or developmental exposure to t-butylphenyl diphenyl phosphate (BPDP), 2-ethylhexyl diphenyl phosphate (EHDP), isodecyl diphenyl phosphate (IDDP), isopropylated phenyl phosphate (IPP), tricresyl phosphate (TMPP; also abbreviated TCP), triphenyl phosphate (TPHP; also abbreviated TPP), tetrabromobisphenol A (TBBPA), tris (2-chloroethyl) phosphate (TCEP), tris (1,3-dichloroisopropyl) phosphate (TDCIPP; also abbreviated TDCPP), tri-o-cresyl phosphate (TOCP), and 2,2-,4,4'-tetrabromodiphenyl ether (BDE-47) in zebrafish (Danio rerio) larvae. Larvae (n≈24 per dose per compound) were exposed to test compounds (0.4-120 μM) at sub-teratogenic concentrations either developmentally or acutely, and locomotor activity was assessed at 6 days post fertilization. When given developmentally, all chemicals except BPDP, IDDP and TBBPA produced behavioral effects. When given acutely, all chemicals produced behavioral effects, with TPHP, TBBPA, EHDP, IPP, and BPDP eliciting the most effects at the most concentrations. The results indicate that these replacement flame retardants may have developmental or pharmacological effects on the vertebrate nervous system., (Published by Elsevier Inc.)

Corneal tissue obtained at the Maryland Medical Examiners' Laboratory (Baltimore) from 47 cadaver donors was examined for the presence of potentially pathogenic fungi. Fifty-five percent of the donor corneas were positive for fungi consisting predominantly of Cladosporium spp. (11 isolates), Penicillium spp. (nine isolates), Rhodotorula spp. (six isolates), and Candida parapsilosis (four isolates). Exophiala jeanselmei (two isolates) and Wangiella dermatitidis were cultured from apparently healthy, normal corneas. Fifty-four percent of the fungi isolated from diabetic corneas were yeasts, as compared to 35% from the nondiabetic corneas. These fungi represent either normal fungal flora or opportunistic fungal pathogens, with the possible exceptions of E. jeanselmei and W. dermatitidis.