Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity.

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals is remarkably painstaking in conventional toxicological animal models and does not scale up to the number of chemicals present in our environment and requiring testing. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

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.

Development and evaluation of a novel dietary bisphenol A (BPA) exposure risk tool.

BACKGROUND: Exposure to endocrine disrupting chemicals such as bisphenol A (BPA) is primarily from the diet through canned foods. Characterizing dietary exposures can be conducted through biomonitoring and dietary surveys; however, these methods can be time-consuming and challenging to implement. METHODS: We developed a novel dietary exposure risk questionnaire to evaluate BPA exposure and compared these results to 24-hr dietary recall data from participants (n = 404) of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) study, a dietary clinical trial, to validate questionnaire responses. High BPA exposure foods were identified from the dietary recalls and used to estimate BPA exposure. Linear regression models estimated the association between exposure to BPA and questionnaire responses. A composite risk score was developed to summarize questionnaire responses. RESULTS: In questionnaire data, 65% of participants ate canned food every week. A composite exposure score validated that the dietary exposure risk questionnaire captured increasing BPA exposure. In the linear regression models, utilizing questionnaire responses vs. 24-hr dietary recall data, participants eating canned foods 1-2 times/week (vs. never) consumed 0.78 more servings (p < 0.001) of high BPA exposure foods, and those eating canned foods 3+ times/week (vs. never) consumed 0.89 more servings (p = 0.013) of high BPA exposure foods. Participants eating 3+ packaged items/day (vs. never) consumed 62.65 more total grams of high BPA exposure food (p = 0.036). CONCLUSIONS: Dietary exposure risk questionnaires may provide an efficient alternative approach to 24-hour dietary recalls to quantify dietary BPA exposure with low participant burden. TRIAL REGISTRATION: The trial was prospectively registered at clinicaltrials.gov as NCT01826591 on April 8, 2013.

Modelling the global economic costs of tobacco product waste.

Tobacco smoking continues to cause considerable premature mortality and morbidity worldwide. Most of the approximately six trillion cigarettes sold globally each year are discarded improperly as toxic environmental waste. Tobacco product waste, including cigarette butts, is the most commonly collected waste item worldwide. Of particular concern is the cellulose acetate filter, a poorly degradable plastic additive attached to most commercially manufactured cigarettes. This filter was introduced by the tobacco industry to reduce smokers' perception of harm and risk but it has no health benefit. To inform health policy and practice and improve public health outcomes, governments and society can benefit from cost estimates of preventing, properly disposing of and/or cleaning up tobacco product waste. Estimating the costs of tobacco product waste to communities and responsible authorities could encourage the development of health, environmental and fiscal policy interventions and shift accountability for the costs of tobacco product waste onto the global tobacco industry. To support health and environmental policy-making, we therefore propose an empirical approach to estimate the economic costs of tobacco product waste based on its negative environmental externalities. We first present general estimates for six representative countries and then identify data gaps that need to be addressed to develop global estimates. Interventions against tobacco product waste may be new channels to regulate tobacco products across sectors - for example, health, environment and finance - and consequently reduce overall tobacco use.

Le tabagisme continue à entraîner un taux de morbidité et de mortalité précoce considérable à travers le monde. La plupart des quelque six billions de cigarettes vendues chaque année à l'échelle planétaire ne sont pas correctement éliminées et deviennent une source de pollution environnementale toxique. Les déchets liés aux produits du tabac, notamment les mégots, sont les résidus les plus fréquemment collectés dans le monde. C'est surtout le filtre qui pose problème car il est composé d'acétate de cellulose, un additif plastique difficilement biodégradable que l'on retrouve dans la majorité des cigarettes commercialisées. Ce filtre a été introduit par l'industrie du tabac afin de donner aux fumeurs l'impression qu'ils courent moins de risques, alors qu'il n'a aucun effet bénéfique sur la santé. Les gouvernements et la société pourraient récolter les fruits d'une estimation des coûts engendrés par la prévention, l'élimination correcte et/ou le nettoyage des déchets liés aux produits du tabac, qui leur permettrait de mieux orienter les politiques et pratiques en la matière, mais aussi d'améliorer les résultats de santé publique. Estimer l'impact de ces déchets sur les communautés et les autorités compétentes pourrait encourager à adopter des mesures sanitaires, environnementales et fiscales, et pousser à responsabiliser davantage l'industrie mondiale du tabac vis-à-vis des coûts qu'ils entraînent. En vue de soutenir l'élaboration de politiques sanitaires et environnementales, nous proposons donc une approche empirique visant à déterminer les conséquences économiques des déchets générés par les produits du tabac en nous fondant sur l'influence néfaste qu'ils exercent sur l'environnement. Nous commençons par présenter des estimations globales pour six pays représentatifs, puis nous identifions les lacunes à combler dans les données afin de produire des estimations mondiales. Prendre des mesures de lutte contre ce type de déchets pourrait constituer un nouveau moyen de réglementer les produits du tabac dans différents secteurs comme la santé, l'environnement et les finances par exemple ­ et, par conséquent, faire diminuer la consommation de tabac en général.

El tabaquismo sigue causando una considerable tasa de mortalidad y morbilidad prematura en todo el mundo. La mayor parte de los casi seis billones de cigarrillos que se venden cada año en el mundo se desechan de forma inadecuada como residuos tóxicos para el medio ambiente. Los residuos de los productos del tabaco, incluidas las colillas, son los que más se recogen en todo el mundo. Un aspecto especialmente preocupante es el filtro de acetato de celulosa, un aditivo plástico poco degradable que se adhiere a la mayoría de los cigarrillos fabricados en el mercado. La industria del tabaco introdujo este filtro para reducir la percepción de daño y riesgo de los fumadores, pero no tiene ningún beneficio para la salud. A fin de fundamentar las políticas y prácticas sanitarias y mejorar los resultados en materia de salud pública, los gobiernos y la sociedad se pueden beneficiar de las estimaciones de costes de la prevención, la eliminación adecuada o la limpieza de los residuos de productos del tabaco. La estimación de los costes de los residuos de productos del tabaco para las comunidades y las autoridades responsables podría fomentar el desarrollo de intervenciones de política sanitaria, medioambiental y fiscal y trasladar la responsabilidad de los costes de los residuos de productos del tabaco a la industria del tabaco mundial. Para apoyar la elaboración de políticas sanitarias y medioambientales, se propone un enfoque empírico para estimar los costes económicos de los residuos de los productos del tabaco en función de sus consecuencias negativas para el medio ambiente. En primer lugar, se presentan estimaciones generales para seis países representativos y, a continuación, se identifican las deficiencias de información que se deben abordar para desarrollar estimaciones globales. Las intervenciones contra los residuos de productos del tabaco pueden constituir canales nuevos para regular los productos del tabaco en todos los sectores, por ejemplo, la salud, el medio ambiente y las finanzas, y, en consecuencia, reducir el consumo general de tabaco.

Development of an Evidence-Based Risk Assessment Framework.

Assessment of potential human health risks associated with environmental and other agents requires careful evaluation of all available and relevant evidence for the agent of interest, including both data-rich and data-poor agents. With the advent of new approach methodologies in toxicological risk assessment, guidance on integrating evidence from mul-tiple evidence streams is needed to ensure that all available data is given due consideration in both qualitative and quantitative risk assessment. The present report summarizes the discussions among academic, government, and private sector participants from North America and Europe in an international workshop convened to explore the development of an evidence-based risk assessment framework, taking into account all available evidence in an appropriate manner in order to arrive at the best possible characterization of potential human health risks and associated uncertainty. Although consensus among workshop participants was not a specific goal, there was general agreement on the key consider-ations involved in evidence-based risk assessment incorporating 21st century science into human health risk assessment. These considerations have been embodied into an overarching prototype framework for evidence integration that will be explored in more depth in a follow-up meeting.

Authors' rebuttal to Integrated Risk Information System (IRIS) response to "Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools".

This letter responds to the US Environmental Protection Agency's Integrated Risk Information System (IRIS) program letter by Radke et al. (2021) that was published in response to the application of the IRIS risk of bias tool in our recent study "Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools." Their letter stated that we misrepresented the IRIS approach. Here, we respond to their three points raised and how we did not misrepresent their tool and also identified areas for improvement: (1) why it should be expected that different reviewers could reach different conclusions with the IRIS tool, as ratings are subject to reviewer judgment; (2) why our interpretation that "low" or "uninformative" studies could be excluded from a body of evidence was reasonable; and (3) why we believe the use of a rating system that generates an overall rating based on an individual domain or a combination of identified deficiencies essentially acts as a score and assumes that we know empirically how much each risk of bias domain should contribute to the overall rating for that study. We have elaborated on these points in our letter.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

Low-calorie sweeteners and health outcomes: an evaluation of rapid versus traditional evidence mapping.

OBJECTIVE: Scientific evidence related to environmental exposures continues to mount. Tools such as evidence mapping support decision making, but can be resource- and time-intensive. We explored "rapid evidence mapping" to efficiently map scientific evidence using rigorous and transparent methodologies. We undertook a proof-of-concept case study on the topic of low-calorie sweeteners. Our intent was to conduct a traditional evidence map based on the same evidence base from a prior rapid evidence map case study to compare approaches, findings, and conclusions. We searched the literature, screened full text of studies, manually tagged and categorized articles, and created visualizations to map the evidence. RESULTS: We conducted full-text screening of studies from the prior rapid evidence map and identified 255 relevant studies. Our findings corroborated those of the rapid evidence map, identifying most studies as short-term conducted in healthy individuals studying outcomes of appetite, energy sensing and body weight. We identified gaps in research areas related to outcomes of appetite and dietary intake, particularly in study populations with diabetes. Our findings illustrate the promise of rapid evidence mapping as a rigorous approach that can summarize scientific evidence, identify knowledge gaps, and identify areas for a future systematic review in a time-efficient manner.

Investigating the Feasibility of a Restaurant Delivery Service to Improve Food Security among College Students Experiencing Marginal Food Security, a Head-to-Head Trial with Grocery Store Gift Cards.

Restaurant delivery services have gained in popularity among college students; however, students participating in the Supplemental Nutrition Assistance Program (SNAP) are not allowed to redeem their benefits via restaurant delivery services. This mixed-methods head-to-head crossover trial assessed whether college students experiencing marginal food security prefer benefits via a grocery store gift card (as a proxy for traditional SNAP benefits) or via a restaurant delivery service gift card of equivalent value, and which type of benefit is more effective at improving food security status. Thirty college students experiencing marginal food security were recruited to receive $80 in cash equivalent benefits to spend over a two-month period in the form of grocery store gift cards and restaurant delivery service gift cards. Participants completed surveys and interviews to measure their food security status and share their experiences with each benefit type. After four months of benefits, 48.3% of participants improved their food security status. However, neither type of benefit was statistically better at improving food security status. Most participants preferred grocery store benefits (89.7%) over restaurant delivery service benefits (10.3%). However, more research is needed to explore whether allowing SNAP recipients to redeem their benefits with restaurant delivery services is a viable mechanism to address food challenges among college students experiencing marginal food security.

A Protocol for the Use of Case Reports/Studies and Case Series in Systematic Reviews for Clinical Toxicology.

Introduction: Systematic reviews are routinely used to synthesize current science and evaluate the evidential strength and quality of resulting recommendations. For specific events, such as rare acute poisonings or preliminary reports of new drugs, we posit that case reports/studies and case series (human subjects research with no control group) may provide important evidence for systematic reviews. Our aim, therefore, is to present a protocol that uses rigorous selection criteria, to distinguish high quality case reports/studies and case series for inclusion in systematic reviews. Methods: This protocol will adapt the existing Navigation Guide methodology for specific inclusion of case studies. The usual procedure for systematic reviews will be followed. Case reports/studies and case series will be specified in the search strategy and included in separate sections. Data from these sources will be extracted and where possible, quantitatively synthesized. Criteria for integrating cases reports/studies and case series into the overall body of evidence are that these studies will need to be well-documented, scientifically rigorous, and follow ethical practices. The instructions and standards for evaluating risk of bias will be based on the Navigation Guide. The risk of bias, quality of evidence and the strength of recommendations will be assessed by two independent review teams that are blinded to each other. Conclusion: This is a protocol specified for systematic reviews that use case reports/studies and case series to evaluate the quality of evidence and strength of recommendations in disciplines like clinical toxicology, where case reports/studies are the norm.

Reviews in environmental health: How systematic are they?

BACKGROUND: Synthesizing environmental health science is crucial to taking action to protect public health. Procedures for evidence evaluation and integration are transitioning from "expert-based narrative" to "systematic" review methods. However, little is known about the methodology being utilized for either type of review. OBJECTIVES: To appraise the methodological strengths and weaknesses of a sample of "expert-based narrative" and "systematic" reviews in environmental health. METHODS: We conducted a comprehensive search of multiple databases and identified relevant reviews using pre-specified eligibility criteria. We applied a modified version of the Literature Review Appraisal Toolkit (LRAT) to three environmental health topics that assessed the utility, validity and transparency of reviews. RESULTS: We identified 29 reviews published between 2003 and 2019, of which 13 (45%) were self-identified as systematic reviews. Across every LRAT domain, systematic reviews received a higher percentage of "satisfactory" ratings compared to non-systematic reviews. In eight of these domains, there was a statistically significant difference observed between the two types of reviews and "satisfactory" ratings. Non-systematic reviews performed poorly with the majority receiving an "unsatisfactory" or "unclear" rating in 11 of the 12 domains. Systematic reviews performed poorly in six of the 12 domains; 10 (77%) did not state the reviews objectives or develop a protocol; eight (62%) did not state the roles and contribution of the authors, or evaluate the internal validity of the included evidence consistently using a valid method; and only seven (54%) stated a pre-defined definition of the evidence bar on which their conclusions were based, or had an author disclosure of interest statement. DISCUSSION: Systematic reviews produced more useful, valid, and transparent conclusions compared to non-systematic reviews, but poorly conducted systematic reviews were prevalent. Ongoing development and implementation of empirically based systematic review methods are required in environmental health to ensure transparent and timely decision making to protect the public's health.

Exposure to formaldehyde and asthma outcomes: A systematic review, meta-analysis, and economic assessment.

BACKGROUND: Every major federal regulation in the United States requires an economic analysis estimating its benefits and costs. Benefit-cost analyses related to regulations on formaldehyde exposure have not included asthma in part due to lack of clarity in the strength of the evidence. OBJECTIVES: 1) To conduct a systematic review of evidence regarding human exposure to formaldehyde and diagnosis, signs, symptoms, exacerbations, or other measures of asthma in humans; and 2) quantify the annual economic benefit for decreases in formaldehyde exposure. METHODS: We developed and registered a protocol in PROSPERO (Record ID #38766, CRD 42016038766). We conducted a comprehensive search of articles published up to April 1, 2020. We evaluated potential risk of bias for included studies, identified a subset of studies to combine in a meta-analysis, and rated the overall quality and strength of the evidence. We quantified economics benefit to children from a decrease in formaldehyde exposure using assumptions consistent with EPA's proposed formaldehyde rule. RESULTS: We screened 4,821 total references and identified 150 human studies that met inclusion criteria; of these, we focused on 90 studies reporting asthma status of all participants with quantified measures of formaldehyde directly relevant to our study question. Ten studies were combinable in a meta-analysis for childhood asthma diagnosis and five combinable for exacerbation of childhood asthma (wheezing and shortness of breath). Studies had low to probably-low risk of bias across most domains. A 10-µg/m3 increase in formaldehyde exposure was associated with increased childhood asthma diagnosis (OR = 1.20, 95% CI: [1.02, 1.41]). We also found a positive association with exacerbation of childhood asthma (OR = 1.08, 95% CI: [0.92, 1.28]). The overall quality and strength of the evidence was rated as "moderate" quality and "sufficient" for asthma diagnosis and asthma symptom exacerbation in both children and adults. We estimated that EPA's proposed rule on pressed wood products would result in 2,805 fewer asthma cases and total economic benefit of $210 million annually. CONCLUSION: We concluded there was "sufficient evidence of toxicity" for associations between exposure to formaldehyde and asthma diagnosis and asthma symptoms in both children and adults. Our research documented that when exposures are ubiquitous, excluding health outcomes from benefit-cost analysis can underestimate the true benefits to health from environmental regulations.

'Spending all this time stressing and worrying and calculating': marginal food security and student life at a Diverse Urban University.

OBJECTIVE: Food security status is a continuum ranging from high to very low food security. While marginal food security falls next to high food security on the spectrum, new quantitative research indicates marginal food security status is associated with negative health outcomes and poor academic performance among college students. Qualitative research focusing on college students experiencing marginal food security has not been conducted. The current study aims to qualitatively explore experiences of college students with marginal food security and to identify themes to better understand and provide context regarding how marginal food security impacts students. DESIGN: Students were recruited for semi-structured interviews with questions designed to study the challenges associated with students' food situations. All interviews were recorded and transcribed with themes identified via an inductive approach. SETTING: A large public university on the US west coast. PARTICIPANTS: Thirty college students. RESULTS: Key themes that emerged: purchasing cheap unhealthy foods, insufficient time to prepare and eat meals on a regular basis, stress and anxiety around the inability to eat healthy food and future health issues, self-perception of health when eating poorly along with physical symptoms and low academic motivation by not fully participating in their courses due to few healthy food options or missing meals. CONCLUSION: Marginal food security can potentially diminish students' health and their capacity to learn and succeed in their coursework. The results emphasise that students experiencing marginal food security should not be grouped with students experiencing high food security.

Application of the navigation guide systematic review methodology to evaluate prenatal exposure to particulate matter air pollution and infant birth weight.

Low birth weight is an important risk factor for many co-morbidities both in early life as well as in adulthood. Numerous studies report associations between prenatal exposure to particulate matter (PM) air pollution and low birth weight. Previous systematic reviews and meta-analyses report varying effect sizes and significant heterogeneity between studies, but did not systematically evaluate the quality of individual studies or the overall body of evidence. We conducted a new systematic review to determine how prenatal exposure to PM2.5, PM10, and coarse PM (PM2.5-10) by trimester and across pregnancy affects infant birth weight. Using the Navigation Guide methodology, we developed and applied a systematic review protocol [CRD42017058805] that included a comprehensive search of the epidemiological literature, risk of bias (ROB) determination, meta-analysis, and evidence evaluation, all using pre-established criteria. In total, 53 studies met our inclusion criteria, which included evaluation of birth weight as a continuous variable. For PM2.5 and PM10, we restricted meta-analyses to studies determined overall as "low" or "probably low" ROB; none of the studies evaluating coarse PM were rated as "low" or "probably low" risk of bias, so all studies were used. For PM2.5, we observed that for every 10 µg/m3 increase in exposure to PM2.5 in the 2nd or 3rd trimester, respectively, there was an associated 5.69 g decrease (I2: 68%, 95% CI: -10.58, -0.79) or 10.67 g decrease in birth weight (I2: 84%, 95% CI: -20.91, -0.43). Over the entire pregnancy, for every 10 µg/m3 increase in PM2.5 exposure, there was an associated 27.55 g decrease in birth weight (I2: 94%, 95% CI: -48.45, -6.65). However, the quality of evidence for PM2.5 was rated as "low" due to imprecision and/or unexplained heterogeneity among different studies. For PM10, we observed that for every 10 µg/m3 increase in exposure in the 3rd trimester or the entire pregnancy, there was a 6.57 g decrease (I2: 0%, 95% CI: -10.66, -2.48) or 8.65 g decrease in birth weight (I2: 84%, 95% CI: -16.83, -0.48), respectively. The quality of evidence for PM10 was rated as "moderate," as heterogeneity was either absent or could be explained. The quality of evidence for coarse PM was rated as very low/low (for risk of bias and imprecision). Overall, while evidence for PM2.5 and course PM was inadequate primarily due to heterogeneity and risk of bias, respectively, our results support the existence of an inverse association between prenatal PM10 exposure and low birth weight.

Risk and Protective Factors in the COVID-19 Pandemic: A Rapid Evidence Map.

Background: Given the worldwide spread of the 2019 Novel Coronavirus (COVID-19), there is an urgent need to identify risk and protective factors and expose areas of insufficient understanding. Emerging tools, such as the Rapid Evidence Map (rEM), are being developed to systematically characterize large collections of scientific literature. We sought to generate an rEM of risk and protective factors to comprehensively inform areas that impact COVID-19 outcomes for different sub-populations in order to better protect the public. Methods: We developed a protocol that includes a study goal, study questions, a PECO statement, and a process for screening literature by combining semi-automated machine learning with the expertise of our review team. We applied this protocol to reports within the COVID-19 Open Research Dataset (CORD-19) that were published in early 2020. SWIFT-Active Screener was used to prioritize records according to pre-defined inclusion criteria. Relevant studies were categorized by risk and protective status; susceptibility category (Behavioral, Physiological, Demographic, and Environmental); and affected sub-populations. Using tagged studies, we created an rEM for COVID-19 susceptibility that reveals: (1) current lines of evidence; (2) knowledge gaps; and (3) areas that may benefit from systematic review. Results: We imported 4,330 titles and abstracts from CORD-19. After screening 3,521 of these to achieve 99% estimated recall, 217 relevant studies were identified. Most included studies concerned the impact of underlying comorbidities (Physiological); age and gender (Demographic); and social factors (Environmental) on COVID-19 outcomes. Among the relevant studies, older males with comorbidities were commonly reported to have the poorest outcomes. We noted a paucity of COVID-19 studies among children and susceptible sub-groups, including pregnant women, racial minorities, refugees/migrants, and healthcare workers, with few studies examining protective factors. Conclusion: Using rEM analysis, we synthesized the recent body of evidence related to COVID-19 risk and protective factors. The results provide a comprehensive tool for rapidly elucidating COVID-19 susceptibility patterns and identifying resource-rich/resource-poor areas of research that may benefit from future investigation as the pandemic evolves.

Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools.

BACKGROUND: Systematic reviews are increasingly prevalent in environmental health due to their ability to synthesize evidence while reducing bias. Different systematic review methods have been developed by the US National Toxicology Program's Office of Health Assessment and Translation (OHAT), the US Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS), and by the US EPA under the Toxic Substances Control Act (TSCA), including the approach to assess risk of bias (ROB), one of the most vital steps which is used to evaluate internal validity of the studies. Our objective was to compare the performance of three tools (OHAT, IRIS, TSCA) in assessing ROB. METHODS: We selected a systematic review on polybrominated diphenyl ethers and intelligence quotient and/or attention deficit hyperactivity disorder because it had been endorsed by the National Academy of Sciences. Two reviewers followed verbatim instructions from the tools and independently applied each tool to assess ROB in 15 studies previously identified. We documented the time to apply each tool and the impact the ROB ratings for each tool had on the final rating of the quality of the overall body of evidence. RESULTS: The time to complete the ROB assessments varied widely (mean = 20, 32, and 40 min per study for the OHAT, IRIS, and TSCA tools, respectively). All studies were rated overall "low" or "uninformative" using IRIS, due to "deficient" or "critically deficient" ratings in one or two domains. Similarly, all studies were rated "unacceptable" using the TSCA tool because of one "unacceptable" rating in a metric related to statistical power. Approximately half of the studies had "low" or "probably low ROB" ratings across all domains with the OHAT and Navigation Guide tools. CONCLUSIONS: Tools that use overall ROB or study quality ratings, such as IRIS and TSCA, may reduce the available evidence to assess the harms of environmental exposures by erroneously excluding studies, which leads to inaccurate conclusions about the quality of the body of evidence. We recommend using ROB tools that circumvents these issues, such as OHAT and Navigation Guide. SYSTEMATIC REVIEW REGISTRATION: This review has not been registered as it is not a systematic review.

Differences in cytochrome p450 enzyme expression and activity in fetal and adult tissues.

INTRODUCTION: Human cytochrome p450 (CYP) enzyme expression and activity is lower in the fetus as compared to the adult; however, limited quantitative data exists regarding the specific differences in magnitude or the degree of inducibility due to environmental factors. METHODS: We utilized a combination of in silico- and molecular-based approaches to profile and compare CYP expression/activity in human adult liver and fetal tissues. Using public datasets, we evaluated human CYP expression between: 1) placenta vs. adult livers; 2) fetal vs. adult livers; or 3) five compartments of the human placenta. We generated new experimental data, characterizing expression levels of nine CYPs in placenta/fetal liver vs. adult liver. In a subset of samples, we evaluated CYP3A4 activity. Finally, we summarized evidence of human fetal CYP expression/activity and environmental exposures during pregnancy. RESULTS: In silico, CYPs were predominately expressed at higher levels in the adult liver vs. fetal tissues, with a few noted exceptions. Sixty percent of CYP enzymes were expressed at nominal levels in the placenta. In wet-lab analyses, we observed significant CYP-specific differences in expression/activity between adult and fetal tissues; CYP2E1 and -3A4 were expressed significantly lower in fetal vs. adult livers, while CYP2J2 levels were similar. DISCUSSION: We provide a qualitative review of the expression of the CYP enzyme family in critical sites of xenobiotic distribution during human pregnancy and novel quantitative data regarding fetal CYP expression and activity during mid-gestation. Data outputs may be a resource for modeling predictions of chemical distribution and sensitivity.