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Rodent inhalation studies indicate styrene is a mouse lung-specific carcinogen. Mode-of-action (MOA) analyses indicate that the lung tumors cannot be excluded as weakly quantitatively relevant to humans due to shared oxidative metabolites detected in rodents and humans. However, styrene also is not genotoxic following in vivo dosing. The objective of this review was to characterize occupational and general population cancer risks by conservatively assuming mouse lung tumors were relevant to humans but operating by a non-genotoxic MOA. Inhalation cancer values reference concentrations for respective occupational and general population exposures (RfC car-occup and RfC car-genpop ) were derived from initial benchmark dose (BMD) modeling of mouse inhalation tumor dose-response data. An overall lowest BMDL 10 of 4.7 ppm was modeled for lung tumors, which was further duration- and dose-adjusted by physiologically based pharmacokinetic (PBPK) modeling to derive RfC car-occup/genpop values of 6.2 ppm and 0.8 ppm, respectively. With the exception of open-mold fiber reinforced composite workers not using personal protective equipment (PPE), the RfC car-occup/genpop values are greater than typical occupational and general population human exposures, thus indicating styrene exposures represent a low potential for human lung cancer risk. Consistent with this conclusion, a review of styrene occupational epidemiology did not support a conclusion of an association between styrene exposure and lung cancer occurrence, and further supports a conclusion that the conservatively derived RfC car-occup is lung cancer protective.

Over the past several decades, there have been many epidemiology studies on talc and cancer published in the scientific literature, and several reviews and meta-analyses of talc and respiratory, female reproductive, and stomach cancers, specifically. To help provide a resource for the evaluation of talc as a potential human carcinogen, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the association between talc exposure (by various routes) and cancers (of various types). We identified 30 cohort, 35 case-control, and 12 pooled studies that evaluated occupational, medicinal, and personal-care product talc exposure and cancers of the respiratory system, the female reproductive tract, the gastrointestinal tract, the urinary system, the lymphohematopoietic system, the prostate, male genital organs, and the central nervous system, as well as skin, eye, bone, connective tissue, peritoneal, and breast cancers. We tabulated study characteristics, quality, and results in a systematic manner, and evaluated all cancer types for which studies of at least three unique populations were available in a narrative review. We focused on study quality aspects most likely to impact the interpretation of results. We found that only one study, of medicinal talc use, evaluated direct exposure measurements for any individuals, though some used semi-quantitative exposure metrics, and few studies adequately assessed potential confounders. The only consistent associations were with ovarian cancer in case-control studies and these associations were likely impacted by recall and potentially other biases. This systematic review indicates that epidemiology studies do not support a causal association between occupational, medicinal, or personal talc exposure and any cancer in humans.

The potential carcinogenicity of talc has been evaluated in many studies in humans and experimental animals published in the scientific literature over the last several decades, with a number of these studies reporting no associations between talc exposure and any type of cancer. In order to fully understand the current state of the science regarding the potential for talc to induce human cancers, we conducted a comprehensive and systematic review of the available experimental animal and mechanistic evidence (in conjunction with a systematic review of the epidemiology evidence in a companion analysis) to evaluate whether it supports talc as being carcinogenic to humans. We considered study quality and its impact on the interpretation of results and evaluated all types of cancer and all exposure routes. We also evaluated the evidence on the potential for talc to migrate in the body to potential tumor sites. We identified seven experimental animal carcinogenicity studies and 11 mechanistic studies of talc to systematically review. We found that several of the experimental animal carcinogenicity studies of talc have limitations that preclude their sensitivity to detect increases in tumor incidence. Regardless, the studies cover multiple exposure routes, species, and exposure durations, and none indicate that talc is a carcinogen in experimental animals except in rats under conditions of extremely high exposure that likely resulted in lung particle overload, a nonspecific effect of high exposures to poorly soluble particles, and not from any carcinogenic properties of talc. Lung particle overload leading to lung tumor formation has only been observed in rats and not in any other species, including humans. The mechanistic studies indicate that talc is not genotoxic or mutagenic, but can induce some effects that could be events on a possible pathway to carcinogenicity, mainly at high exposures or in in vitro studies with exposures of unclear relevance in vivo , but these effects are not consistent across studies and cell types. This systematic review of the experimental animal carcinogenicity and mechanistic evidence for talc indicates that an association between talc exposure and cancer is not expected in humans. Talc carcinogenicity is not plausible in any species except rats, and only when the exposure conditions are high enough to induce lung particle overload, which is not relevant to human exposures.

Exposure to ambient particulate matter (PM) has been associated with respiratory and cardiovascular outcomes, and nickel has been more frequently associated with these outcomes than other metal constituents of ambient PM. Because of this, we evaluated whether the evidence to date supports causal relationships between exposure to nickel in ambient PM and respiratory or cardiovascular outcomes. We critically reviewed 38 studies in human populations published between 2012 and 2022. Although a large variety of respiratory and cardiovascular outcomes were examined, data were sparse for many. As a result, we focused our evaluation on seven respiratory outcomes and three cardiovascular outcomes that were each examined in ≥3 studies. Of these health outcomes, exposure to nickel in ambient PM has been statistically significantly associated with respiratory mortality, respiratory emergency hospital visits, asthma, lung function (i.e., forced expiratory volume in 1 s, forced vital capacity), cardiovascular mortality, and ischemic heart disease mortality. Studies of the health outcomes of focus are subject to multiple methodological limitations, primarily ecological fallacy (short-term exposure studies), exposure measurement error, confounding, model misspecification, and multiple comparisons issue. While some statistically significant associations were reported, they were not strong, precise, or consistent. Statistically significant findings for long-term exposure to nickel in PM were largely reported in studies that could not establish temporality, despite their cohort study design. Statistically significant findings for short-term exposure to nickel in PM were largely reported in studies that could establish temporality, although this cannot inform causal inference at the individual level due to the aggregate level data used. The biological plausibility of the associations is only supported at high concentrations not relevant to ambient exposures. Overall, the literature to date does not provide adequate support for a causal relationship between nickel in ambient PM and respiratory or cardiovascular outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All of the authors are empoyed by Gradient, an independent risk science consulting firm. The work reported in this paper was conducted by the authors during their normal course of employment, with financial support by NiPERA, Inc., and a draft of this paper was reviewed by members of NiPERA, Inc. at the request of the authors. This paper is the professional work product of the authors, and the opinions and conclusions within are not necessarily those of their employers or the financial sponsor of the work., (Copyright © 2024 GradCo LLC dba Gradient. Published by Elsevier Ltd.. All rights reserved.)

The European Food Safety Authority (EFSA) recently derived a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.2 ng/kg bw/day. There are several issues with EFSA's hazard assessment review process, including that it was based on a limited subset of relevant studies. Multiple public commenters on EFSA's draft evaluation of BPA, including several European regulatory agencies, noted these issues, yet they were not adequately addressed by EFSA in the final evaluation. The TDI for BPA was based on an intermediate immunotoxicity endpoint in mice that has not been observed in other species; there is no evidence that it is a precursor event to any downstream pathological outcome. The TDI is several orders of magnitude lower than estimates of safe doses of BPA established by agencies worldwide, including EFSA's temporary TDI (t-TDI) for BPA established in 2015. Overall, the EFSA hazard assessment review process has led to a conclusion that there are low-dose effects of BPA based on very few, lower quality experimental animal studies. This conclusion is not supported by the totality of the available evidence, which includes multiple high-quality studies not considered by EFSA and indicates that the t-TDI established in 2015 is protective of human health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)

Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors were employed by Gradient, a private environmental consulting firm, during the drafting of this manuscript. Gradient has conducted work on talc in general, and this topic specifically, in the context of litigation and regulatory comments to Health Canada. That work informed this analysis but did not influence the work presented here. The Cosmetics Alliance Canada (CA Canada) and Essential Minerals Association (EMA) (formerly Industrial Minerals Association – North America) provided funding for some initial research, but were not involved with the conception or drafting of this paper.

Competing Interests: All authors are employed by Gradient, a private environmental consulting firm. The commentary was solely conceived by the authors. The American Gas Association (AGA) provided funding for this commentary, but was not involved in either its conception or drafting. This work was conducted during the authors' normal course of employment. The authors had sole responsibility for the writing and content of this paper, which represents the professional opinions of the authors and not necessarily those of AGA. Gradient has worked with several other organizations in the past that have an interest in gas stoves and NO2 science. None were involved with the conception or drafting of this commentary.

Objectives: Mortality from respiratory and cardiovascular health conditions contributes largely to the total mortality that has been associated with exposure to PM 2.5 in epidemiology studies. A mode of action (MoA) for these underlying morbidities has not been established, but it has been proposed that some effects of PM 2.5 occur through activation of neural reflexes., Materials and Methods: We critically reviewed the experimental studies of PM 2.5 (including ambient PM 2.5 , diesel exhaust particles, concentrated ambient particles, diesel exhaust, and cigarette smoke) and neural reflex activation, and applied the principles of the International Programme on Chemical Safety (IPCS) MoA/human relevance framework to assess whether they support a biologically plausible and human-relevant MoA by which PM 2.5 could contribute to cardiovascular and respiratory causes of death. We also considered whether the evidence from these studies supports a non-threshold MoA that operates at low, human-relevant PM 2.5 exposure concentrations., Results and Discussion: We found that the proposed MoA of neural reflex activation is biologically plausible for PM 2.5 -induced respiratory effects at high exposure levels used in experimental studies, but further studies are needed to fill important data gaps regarding the relevance of this MoA to humans at lower PM 2.5 exposure levels. A role for the proposed MoA in PM 2.5 -induced cardiovascular effects is plausible for some effects but not others., Conclusions: Further studies are needed to determine whether neural reflex activation is the MoA by which PM 2.5 could cause either respiratory or cardiovascular morbidities in humans, particularly at the ambient concentrations associated with total mortality in epidemiology studies.

Air pollution accountability studies examine the relationship(s) between an intervention, regulation, or event and the resulting downstream impacts, if any, on emissions, exposure, and/or health. The sequence of events has been schematically described as an accountability chain. Here, we update the existing framework to capture real-life complexities and to highlight important factors that fall outside the linear chain. This new "accountability web" is intended to convey the intricacies associated with conducting an accountability study to various audiences, including researchers, policy makers, and stakeholders. We also identify data considerations for planning and completing a robust accountability study, including those relevant to novel and innovative air pollution and exposure data. Finally, we present a series of recommendations for the accountability research community that can serve as a guide for the next generation of accountability studies., Competing Interests: Support for the Workshop was provided by the 10.13039/100011253American Petroleum Institute (API). API was not involved in the Workshop deliberations nor in the preparation or approval of the manuscript. The authors retain sole responsibility for the writing and content of this paper, which represent the professional opinions of the authors and not necessarily those of API or its member companies. As Workshop facilitators, CJB, JEG, and JSL received compensation and travel support from 10.13039/100011253API. Travel support was also provided to all authors except AMR, HSE, and SL. Honoraria were provided to SE, LRFH, MN, AGR, and JWH. JSL, JEG, JWH, and CJB consult to governmental and private organizations, including API, on issues related to air pollution epidemiology. The views expressed in this manuscript are those of the authors and do not necessarily represent the views or policies of EPA, API (or its member companies), or co-authors' employers., (© 2023 The Authors. Published by Elsevier Inc.)

Aspartame is a dipeptide non-sugar sweetener that was first marketed in the US in carbonated beverages in 1983, before gaining prominence globally. The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) and the WHO International Agency for Research on Cancer (IARC) completed evaluations of aspartame and cancer in July 2023. JECFA reaffirmed the safety of aspartame, stating that epidemiology evidence is "not convincing," and that there are no consistent associations between aspartame and cancer (JECFA/IARC, 2023; JECFA, 2023). JECFA also noted "reverse causality, chance, bias and confounding by socioeconomic or lifestyle factors, or consumption of other dietary components, could not be completely ruled out" in relevant epidemiology studies (JECFA/IARC, 2023). In contrast, IARC stated that there are three "high quality" studies on liver cancer (Riboli, 2023), but that the evidence is limited because "chance, bias or confounding could not be ruled out as an explanation for the positive findings" (JECFA/IARC, 2023). IARC does not provide an explanation as to how these studies can be both high quality and have these weaknesses, most notably potential exposure misclassification, or how inconsistent associations from studies with these weaknesses constitute limited evidence. Further, when IARC concludes an agent has limited or inadequate human evidence (and no sufficient animal or strong mechanistic evidence), it classifies that agent as either Group 2B, a possible human carcinogen, or Group 3, not classifiable as to its carcinogenicity. Ultimately, the interpretations of Group 2B and Group 3 classifications are intended to be similar. However, a Group 2B designation may make it appear to scientists and non-scientists alike that the evidence is pointing in the direction of causality. This can lead to unnecessary confusion with respect to the evidence, as well as a perception of a disagreement within WHO regarding aspartame. This apparent contradiction could have been avoided by assigning the IARC classification most consistent with the conclusion that the human evidence for cancer is inadequate: Group 3., Competing Interests: MMJ is an employee of ABA. She serves as Chief Science and Regulatory Officer in that role. JEG and DNB are employees of Gradient, a private environmental consulting firm. Work on this paper was conducted during the authors' normal course of employment. The authors had sole responsibility for the writing and content of this paper, which represents the professional opinions of the authors and not necessarily those of ABA., (© 2023 Gradco LLC dba Gradient.)

Bisphenol A (BPA) is a synthetic chemical to which humans are exposed through a variety of environmental sources. We have conducted a comprehensive, systematic review of 29 epidemiology studies and 27 experimental animal studies, published through May 2022, evaluating the potential carcinogenicity of BPA to contribute to the understanding of whether BPA is carcinogenic in humans. We conducted this review according to best practices for systematic reviews and incorporating established frameworks for study quality evaluation and evidence integration. The epidemiology studies have many limitations that increase the risk of biased results, but overall, the studies do not provide clear and consistent evidence for an association between BPA exposure and the development of any type of cancer. The experimental animal studies also do not provide strong and consistent evidence that BPA is associated with the induction of any malignant tumor type. Some of the proposed mechanisms for BPA carcinogenicity are biologically plausible, but the relevance to human exposures is not clear. We conclude that there is inadequate evidence to support a causal relationship between BPA exposure and human carcinogenicity, based on inadequate evidence in humans, as well as evidence from experimental animal studies that suggests a causal relationship is not likely., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All of the authors are employees of Gradient, an independent environmental and risk science consulting firm. The work reported in this paper was conducted during the normal course of employment. Two of the authors (JEG and RLP) have previously provided consulting on BPA-related issues and have given testimony on topics related to BPA at meetings with regulatory agencies, with funding provided by the American Chemistry Council (ACC). All other authors declare that they have not been involved in any regulatory activities related to the contents of this paper. This manuscript is the professional work product of the authors, and the opinions and conclusions offered within are not necessarily those of their employers or the financial sponsor of the work., (Copyright © 2023 Gradient. Published by Elsevier Inc. All rights reserved.)

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:JG, SS, BC, DB, AN, and GG have served as experts in asbestos and/or talc litigation. JG and GG are members of the Scientific Advisory Board of NSSGA and received a honorarium for time spent on organizing the conference. They, and most other participants, are grateful to NSSGA for covering travel and accommodation costs. The time spent by the authors in the preparation of this manuscript was at their own expense or of their employers. The National Mesothelioma Virtual Bank (NMVB) section of this workshop summary is funded and supported by the Centers for Disease Control and Prevention (CDC) in association with the National Institute for Occupational Safety and Health (NIOSH) Grant U24OH009077., (Copyright © 2022 Gradco LLC dba Gradient. Published by Elsevier Inc. All rights reserved.)

Toews et al. [1] and the World Health Organization (WHO) [2] reviewed observational epidemiology studies of non-sugar sweeteners (NSSs) and various health effects. The former used the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool and the latter used both the ROBINS-I tool and the Newcastle-Ottawa Scale to evaluate study quality. Both reviews concluded that there were no associations between NSS or aspartame consumption and cancer (except possibly between saccharin and bladder cancer) but indicated that the certainty of the evidence for all cancer types was "very low." While we agree with this conclusion, the support for the confidence in the evidence generally was not transparently documented, as the results of the study quality assessment were only provided in scores or ratings. An examination of illustrative case studies shows that some important aspects of study quality domains specific for NSSs generally or aspartame specifically (i.e., issues with the exposure and outcome assessments, the consideration of confounding/covariates, and selection bias) may have been overlooked or not given appropriate consideration, while other aspects that were less likely to have a large impact on overall study quality dominated the results in the two assessments. Our review of other studies published after the WHO [2] review further demonstrates this point. While this may not seem important given the overall lack of associations, it impacts the degree to which evidence supports a lack of effects as opposed to not being adequate to evaluate associations. In the future, aspartame and cancer outcome reviews should focus on those study quality domains that are most likely to impact the interpretation of results and discuss them in a transparent, systematic manner. If there is very low certainty in the evidence as a result of low study quality, reviewers should conclude the evidence is inadequate for making a causal determination., Competing Interests: 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., (© 2023 Gradco LLC dba Gradient.)

The most recent meta-analysis of gas cooking and respiratory outcomes in children was conducted by Lin et al. [93] in 2013. Since then, a number of epidemiology studies have been published on this topic. We conducted the first systematic review of this epidemiology literature that includes an in-depth evaluation of study heterogeneity and study quality, neither of which was systematically evaluated in earlier reviews. We reviewed a total of 66 relevant studies, including those in the Lin et al. [93] meta-analysis. Most of the studies are cross-sectional by design, precluding causal inference. Only a few are cohort studies that could establish temporality and they have largely reported null results. There is large variability across studies in terms of study region, age of children, gas cooking exposure definition, and asthma or wheeze outcome definition, precluding clear interpretations of meta-analysis estimates such as those reported in Lin et al. [93]. Further, our systematic study quality evaluation reveals that a large proportion of the studies to date are subject to multiple sources of bias and inaccuracy, primarily due to self-reported gas cooking exposure or respiratory outcomes, insufficient adjustment for key confounders (e.g., environmental tobacco smoke, family history of asthma or allergies, socioeconomic status or home environment), and unestablished temporality. We conclude that the epidemiology literature is limited by high heterogeneity and low study quality and, therefore, it does not provide sufficient evidence regarding causal relationships between gas cooking or indoor NO 2 and asthma or wheeze. We caution against over-interpreting the quantitative evidence synthesis estimates from meta-analyses of these studies., Competing Interests: Gradient has worked with several organizations in the past that have an interest in gas stoves and NO2 science. None of these clients was involved with the conception or drafting of this paper., (© 2023 Gradco LLC dba Gradient.)

Competing Interests: The authors are employed by Gradient, a private environmental consulting firm. The work reported in this paper was conducted during the normal course of employment, with no financial support. Gradient has conducted work on PCE in general, and this topic specifically, in the context of litigation and TSCA assessment reviews. That work informed this manuscript; however, it did not influence the work presented here. The authors have the sole responsibility for the writing, content, and conclusions in this article.

We used a transparent systematic review framework based on best practices for evaluating study quality and integrating evidence to conduct a review of the available epidemiology studies evaluating associations between long-term exposure to ambient concentrations of PM 2.5 and mortality (all-cause and non-accidental) conducted in North America. We found that while there is some consistency across studies for reporting positive associations, these associations are weak and several important methodological issues have led to uncertainties with regard to the evidence from these studies, including potential confounding by measured and unmeasured factors, exposue measurement error, and model misspecification. These uncertainties provide a plausible, alternative explanation to causality for the weakly positive findings across studies. Using a causality framework that incorporates best practices for making causal determinations, we concluded that the evidence for a causal relationship between long-term exposure to ambient PM 2.5 concentrations and mortality from these studies is inadequate.

We conducted a systematic review of epidemiology studies that evaluated the association between perchloroethylene (PCE) and non-Hodgkin's lymphoma (NHL). This included an independent detailed assessment of a few critical aspects of study quality (i.e., study design, exposure measurement, exposure levels, and potential confounding), and a consideration of other aspects of quality less formally. Of the identified 18 cohort studies of 15 unique cohorts, 17 case-control studies of 14 unique population groups, and 3 ecological studies, none was high quality for all four critical quality elements and each study also had other major methodological study limitations. Reported risk estimates were mostly null, ranged widely from below to above 1, and often had extremely wide confidence intervals (CIs), indicating unstable risk estimates. In addition, there was no consistent evidence of dose-response. Overall, given the low quality of the available epidemiology studies, the evidence does not support an association between PCE exposure and NHL., Competing Interests: The authors are employed by Gradient, a private environmental consulting firm. The work reported in this paper was conducted during the normal course of employment, with no financial support. Gradient has conducted work on PCE in general, and this topic specifically, in the context of litigation and TSCA assessment reviews. That work informed this manuscript; however, it did not influence the work presented here. The authors have the sole responsibility for the writing, content, and conclusions in this article. This review has not been registered and no protocol was prepared., (© 2022 Gradco llc dba Gradient.)

In many ways, plumbing is essential to life support. In fact, the advance of humankind on Earth is directly linked to the advance of clean, healthy, reliable plumbing solutions. Shouldn't this also be true for the advancement of humankind in space? Unfortunately, the reliability of even the simplest plumbing element aboard spacecraft is rarely that of its terrestrial counterpart. This state of affairs is due entirely to the near-weightless "low-g" state of orbiting and coast spacecraft. But the combined passive capillary effects of surface tension, wetting, and system geometry in space can be exploited to replace the passive role of gravity on earth, and thus achieve similar outcomes there. In this paper, we review a selection of experiments conducted in low-g environments (i.e., ISS and drop towers) that focus on capillary fluidic phenomena. The results of each experiment are highly applicable to subsequent advances in spacecraft plumbing. With examples ranging from spurious droplet ejections to passive bubble coalescence, to droplet bouncing, to complex container wicking, we show how simple low-g demonstrations can lead to significant reliability improvements in practical passive plumbing processes from pipetting to liquid-gas separations, to wastewater transport, to drinking in space., (© 2022. The Author(s).)

Background: In epidemiology studies, ambient measurements of PM 2.5 are often used as surrogates for personal exposures. However, it is unclear the degree to which ambient PM 2.5 reflects personal exposures., Objective: In order to examine potential sources of bias in epidemiology studies, we conducted a review and meta-analysis of studies to determine the extent to which short-term measurements of ambient PM 2.5 levels are related to short-term measurements of personal PM 2.5 levels., Methods: We conducted a literature search of studies reporting both personal and ambient measurements of PM 2.5 published in the last 10 years (2009-2019) and incorporated studies published prior to 2009 from reviews., Results: Seventy-one studies were identified. Based on 17 studies reporting slopes, a meta-analysis revealed an overall slope of 0.56 μg/m 3 (95% CI: [0.39, 0.73]) personal PM 2.5 per μg/m 3 increase in ambient PM 2.5 . Slopes for summer months were higher (slope = 0.73, 95% CI: [0.64, 0.81]) than for winter (slope = 0.46, 95% CI: [0.36, 0.57]). Based on 44 studies reporting correlations, we calculated an overall personal-ambient PM 2.5 correlation of 0.63 (95% CI: [0.55, 0.71]). Correlations were stronger in studies conducted in Canada (r = 0.86, 95% CI: [0.67, 0.94]) compared to the USA (r = 0.60, 95% CI: [0.49, 0.70]) and China (r = 0.60, 95% CI: [0.46, 0.71]). Correlations also were stronger in urban areas (r = 0.53, 95% CI: [0.43, 0.62]) vs. suburban areas (r = 0.36, 95% CI: [0.21, 0.49])., Significance: Our results suggest a large degree of variability in the personal-ambient PM 2.5 association and the potential for exposure misclassification and measurement error in PM 2.5 epidemiology studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Controlled human inhalation exposure ( CHIE) studies provide a unique opportunity to conduct formal experiments to examine the human health effects of airborne pollutants. Lung function, easily measured using spirometry, is a common physiological variable often utilized in these studies. By design, CHIE studies only induce mild and reversible acute effects, which may or may not predict adverse effects that may develop under chronic exposure conditions. There is substantial inter- and intra-individual variability in functional capacity and symptoms such as chest tightness and dyspnea, which are complex variables that are affected by individual perception, physiological lung impairment, and other variables (e.g., concomitant health conditions, and level of conditioning/fitness). Thus, the design of the CHIE study and physiological and environmental factors of study participants can affect each CHIE study's results. Researchers can address many of these critical issues in the problem formulation phase of CHIE studies, utilizing existing information on the expected effects of the substance of interest and possible modes of action. Thoughtful design and interpretation of CHIE studies will increase their utility for evaluating and setting environmental health policy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The United States Environmental Protection Agency (US EPA) is currently refining its approach for risk assessments conducted under the amended Toxic Substances Control Act (TSCA), largely based on recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM). We identified several issues with the current TSCA risk assessment approach that were not addressed by NASEM in its recommendations. Here, we demonstrate these issues with a case study of the 'Risk Evaluation for Asbestos, Part 1: Chrysotile Asbestos,' which US EPA released in December 2020. In this evaluation, US EPA found that occupational and some consumer uses of automotive brakes and clutches that contain asbestos result in unreasonable risks. These risks were calculated from estimated exposures during brake work and an inhalation unit risk (IUR) developed for chrysotile asbestos. We found that US EPA overestimated risk as a result of unrealistic inputs to both the exposure and toxicity components of the risk equation, and because the Agency did not fully consider relevant epidemiology and toxicity evidence in its systematic review. Our evaluation demonstrates areas in which the TSCA risk assessment approach could be improved to result in risk evaluations that are supported by the available scientific evidence.

We utilized a practical, transparent approach for systematically reviewing a chemical-specific evidence base. This approach was used for a case study of ozone inhalation exposure and adverse metabolic effects (overweight/obesity, Type 1 diabetes [T1D], Type 2 diabetes [T2D], and metabolic syndrome). We followed the basic principles of systematic review. Studies were defined as "Suitable" or "Supplemental." The evidence for Suitable studies was characterized as strong or weak. An overall causality judgment for each outcome was then determined as either causal, suggestive, insufficient, or not likely. Fifteen epidemiologic and 33 toxicologic studies were Suitable for evidence synthesis. The strength of the human evidence was weak for all outcomes. The toxicologic evidence was weak for all outcomes except two: body weight, and impaired glucose tolerance/homeostasis and fasting/baseline hyperglycemia. The combined epidemiologic and toxicologic evidence was categorized as weak for overweight/obesity, T1D, and metabolic syndrome,. The association between ozone exposure and T2D was determined to be insufficient or suggestive. The streamlined approach described in this paper is transparent and focuses on key elements. As systematic review guidelines are becoming increasingly complex, it is worth exploring the extent to which related health outcomes should be combined or kept distinct, and the merits of focusing on critical elements to select studies suitable for causal inference. We recommend that systematic review results be used to target discussions around specific research needs for advancing causal determinations.

Causal inference regarding exposures to ambient fine particulate matter (PM 2.5 ) and mortality estimated from observational studies is limited by confounding, among other factors. In light of a variety of causal inference frameworks and methods that have been developed over the past century to specifically quantify causal effects, three research teams were selected in 2016 to evaluate the causality of PM 2.5 -mortality association among Medicare beneficiaries, using their own selections of causal inference methods and study designs but the same data sources. With a particular focus on controlling for unmeasured confounding, two research teams adopted an instrumental variables approach under a quasi-experiment or natural experiment study design, whereas one team adopted a structural nested mean model under the traditional cohort study design. All three research teams reported results supporting an estimated counterfactual causal relationship between ambient PM 2.5 and all-cause mortality, and their estimated causal relationships are largely of similar magnitudes to recent epidemiological studies based on regression analyses with omitted potential confounders. The causal methods used by all three research teams were built upon the potential outcomes framework. This framework has marked conceptual advantages over regression-based methods in addressing confounding and yielding unbiased estimates of average treatment effect in observational epidemiological studies. However, potential violations of the unverifiable assumptions underlying each causal method leave the results from all three studies subject to biases. We also note that the studies are not immune to some other common sources of bias, including exposure measurement errors, ecological study design, model uncertainty and specification errors, and irrelevant exposure windows, that can undermine the validity of causal inferences in observational studies. As a result, despite some apparent consistency of study results from the three research teams with the wider epidemiological literature on PM 2.5 -mortality statistical associations, caution seems warranted in drawing causal conclusions from the results. A possible way forward is to improve study design and reduce dependence of conclusions on untested assumptions by complementing potential outcomes methods with structural causal modeling and information-theoretic methods that emphasize empirically tested and validated relationships., (© 2021 Gradco LLC dba Gradient.)

The inhalation of dust containing certain nickel compounds has been associated with an increased risk of lung and nasal cancers in occupational studies of workers who process or refine sulfidic nickel ores and are exposed to relatively high levels of mixtures of water-soluble, sulfidic, oxidic, and/or metallic forms of nickel. We conducted a systematic review of the potential carcinogenicity of metallic nickel, focusing on cancers of the respiratory tract. We evaluated the quality and risk of bias (RoB) of the relevant epidemiology, experimental animal, and in vitro mechanistic studies using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) RoB Rating Tool. We then used a systematic review protocol based on the OHAT approach to critically assess whether metallic nickel should be considered a human respiratory carcinogen. Our evaluation of the epidemiology studies indicates that there is no substantive evidence of increased respiratory cancer risk in workers exposed predominantly to metallic nickel. Animal evidence indicates that metallic nickel does not increase the incidence of respiratory tumors in rodents exposed by inhalation. The in vitro studies are limited in value, as they bypass normal clearance mechanisms. Nevertheless, the mechanistic evidence indicates that metallic nickel is not mutagenic but can induce DNA strand breaks under certain conditions. Based on a standard framework for assessing causality, we conclude that the evidence does not support a causal relationship between metallic nickel exposure and respiratory cancer in humans.

Both toxicology and epidemiology are used to inform hazard and risk assessment in regulatory settings, particularly for pesticides. While toxicology studies involve controlled, quantifiable exposures that are often administered according to standardized protocols, estimating exposure in observational epidemiology studies is challenging, and there is no established guidance for doing so. However, there are several frameworks for evaluating the quality of published epidemiology studies. We previously developed a preliminary list of methodology and reporting standards for epidemiology studies, called Good Epidemiology Practice (GEP) guidelines, based on a critical review of standardized toxicology protocols and available frameworks for evaluating epidemiology study quality. We determined that exposure characterization is one of the most critical areas for which standards are needed. Here, we propose GEP guidelines for pesticide exposure assessment based on the source of exposure data (i.e., biomonitoring and environmental samples, questionnaire/interview/expert record review, and dietary exposures based on measurements of residues in food and food consumption). It is expected that these GEP guidelines will facilitate the conduct of higher-quality epidemiology studies that can be used as a basis for more scientifically sound regulatory risk assessment and policy making.

The association between perineal talc use and ovarian cancer has been evaluated in several epidemiology studies. Some case-control studies reported weak positive associations, while other case-control and three large prospective cohort investigations found this association to be null. A weight-of-evidence evaluation was conducted of the epidemiology, toxicity, exposure, transport, in vitro , and mechanistic evidence to determine whether, collectively, these data support a causal association. Our review of the literature indicated that, while both case-control and cohort studies may be impacted by bias, the possibility of recall and other biases from the low participation rates and retrospective self-reporting of talc exposure cannot be ruled out for any of the case-control studies. The hypothesis that talc exposure induces ovarian cancer is only supported if one discounts the null results of the cohort studies and the fact that significant bias and/or confounding are likely reasons for the associations reported in some case-control investigations. In addition, one would need to ignore the evidence from animal experiments that show no marked association with cancer, in vitro and genotoxicity studies that did not indicate a carcinogenic mechanism of action for talc, and mechanistic and transport investigations that did not support the retrograde transport of talc to the ovaries. An alternative hypothesis that talc does not produce ovarian cancer, and that bias and confounding contribute the reported positive associations in case-control studies, is better supported by the evidence across all scientific disciplines. It is concluded that the evidence does not support a causal association between perineal talc use and ovarian cancer.

Inflammasomes are a family of pro-inflammatory signaling complexes that orchestrate inflammatory responses in many tissues. The NLRP3 inflammasome has been implicated in several diseases associated with chronic inflammation. In this paper, we present an Adverse Outcome Pathway (AOP) for NLRP3-induced chronic inflammatory diseases that demonstrates how NLRP3 can cause a transition from acute to chronic inflammation, and ultimately the onset of disease. We present a simple graphical description of the main features of internal dose time courses that are important when pharmacodynamics are governed by an activation threshold. Similar considerations hold for other AOPs that are rate-limited by processes with activation thresholds. The risk analysis implications of AOPs with threshold or threshold-like pharmacodynamic responses include the need to consider how cumulative dose per unit time is distributed over time and the possibility that safe, or virtually safe, exposure concentrations can be defined for such processes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors had complete control over the design, conduct, interpretation, and composition of this manuscript. The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views or policies of their employers. J. Goodman and A. Engel received support from the George Washington University (GWU) for developing this manuscript. Dr. Goodman has served as an expert in multiple litigation matters involving asbestos-containing products. None of the underlying research or analysis for this paper was performed during the context of those engagements or was sponsored by any of the defendants. Dr. Cox's work on the risk modeling approach reported here was supported by his employer, Cox Associates LLC, which has received research funding in 2018–2020 from the following sources: (1) a research contract from the National Stone, Sand, and Gravel Association to develop and apply risk models and machine learning methods and causal analytics to risk assessment for mineral dusts and fibers; (2) a research project with the GWU Regulatory Studies Center to investigate and explain the role of the NLRP3 inflammasome in risk analysis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In 2019, the International Agency for Research on Cancer (IARC) "Preamble to the IARC Monographs" expanded guidance regarding the scientific approaches that should be employed in its monographs. These amendments to the monograph development process are an improvement but still fall short in several areas. While the revised Preamble lays out broad methods and approaches to evaluate scientific evidence, there is a lack of specificity with regard to how IARC Working Groups will conduct consistent evaluations in a standardized, objective, and transparent manner; document systematic review and evidence integration actions, and substantiate how these actions and decisions inform the ultimate classifications. Furthermore, no guidance is provided to ensure Working Groups consistently incorporate mechanistic evidence in a robust manner using a defined approach in the context of 21st century knowledge of modes of action. Nor are the conclusions of the working groups subjected to outside, independent scientific peer review. Continued improvements and modernization of the procedures for evaluating, presenting, and communicating study quality, and in the methods used to conduct and peer-review evidence-based decision making will benefit the Working Group members, the IARC Monographs Programme overall, and the international regulatory community and public who rely upon the monographs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors had complete control over the design, conduct, interpretation, and composition of this manuscript. The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views or policies of their employers. J. Goodman and D. Mayfield received support from the American Chemistry Council (ACC) for developing this manuscript. R. Becker, S. Hartigan, and N. Erraguntla are employed by the ACC, a trade association of chemical manufacturers. This work was supported by funding from the ACC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In 2016, the American Conference of Governmental Industrial Hygienists (ACGIH) lowered the 8-hr Threshold Limit Value - time-weighted average (TLV-TWA) for toluene diisocyanate (TDI) from 5 ppb to 1 ppb, and the 15-min short-term exposure limit (STEL) from 20 ppb to 5 ppb. We evaluated ACGIH's basis for lowering these values. It is our opinion that the ACGIH's evaluation of the evidence for occupational asthma and respiratory effects from TDI exposure does not fully integrate the results of all the available human and animal studies. We found that some studies reported occupational asthma cases at TWAs less than 5 ppb, but these cases were likely caused by peak exposures above 20 ppb. Advances in industrial hygiene have reduced peak exposures and the incidence of upset conditions, such as spills and accidents, in modern TDI facilities. Taken together, the human evidence indicates that adherence to the previous 8-hr TLV-TWA and 15-min STEL (5 ppb and 20 ppb, respectively) prevents most, if not all, cases of occupational asthma, and eliminates or reduces the risk of lung function decrements and other respiratory effects. While limited, the animal literature supports the human evidence and indicates that TDI-induced asthma is a threshold phenomenon. We conclude that ACGIH's decision to lower the TLV-TWA and STEL values for TDI is not adequately supported., (Copyright © 2018 Gradco LLC dba Gradient. Published by Elsevier Inc. All rights reserved.)

Of adolescents in the United States, 20% have obesity and current treatment options prioritize intensive lifestyle interventions that are largely ineffective. Bariatric surgery is increasingly being offered to obese adolescent patients; however, large-scale effectiveness data is lacking. We used MEDLINE, Embase, and Cochrane databases, and a manual search of references to conduct a systematic review and meta-analysis on overall weight loss after gastric band, gastric sleeve, and gastric bypass in obese adolescent patients (age ≤19) and young adults (age ≤21) in separate analyses. We provided estimates of absolute change in body mass index (BMI, kg/m 2 ) and percent excess weight loss across 4 postoperative time points (6, 12, 24, and 36 mo) for each surgical subgroup. Study quality was assessed using a 10 category scoring system. Data were extracted from 24 studies with 4 having multiple surgical subgroups (1 with 3, and 3 with 2 subgroups), totaling 29 surgical subgroup populations (gastric band: 16, gastric sleeve: 5, gastric bypass: 8), and 1928 patients (gastric band: 1010, gastric sleeve: 139, gastric bypass: 779). Mean preoperative BMI (kg/m 2 ) was 45.5 (95% confidence interval [CI]: 44.7, 46.3) in gastric band, 48.8 (95%CI: 44.9, 52.8) in gastric sleeve, and 53.3 (95%CI: 50.2, 56.4) in gastric bypass patients. The short-term weight loss, measured as mean (95%CI) absolute change in BMI (kg/m 2 ) at 6 months, was -5.4 (-3.0, -7.8) after gastric band, -11.5 (-8.8, -14.2) after gastric sleeve, and -18.8 (-10.9, -26.6) after gastric bypass. Weight loss at 36 months, measured as mean (95%CI) absolute change in BMI (kg/m 2 ) was -10.3 (-7.0, -13.7) after gastric band, -13.0 (-11.0, -15.0) after gastric sleeve, and -15.0 (-13.5, -16.5) after gastric bypass. Bariatric surgery in obese adolescent patients is effective in achieving short-term and sustained weight loss at 36 months; however, long-term data remains necessary to better understand its long-term efficacy., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Asthma, a chronic respiratory disorder with complex etiology and various phenotypes, is a considerable public health concern in the USA and worldwide. While there is evidence suggesting ambient ozone exposure may exacerbate asthma, information regarding the potential role of ozone in asthma development is more limited. Thus, we conducted a critical review of observational epidemiology studies to determine whether long-term ambient ozone exposure is a risk factor for asthma development. We identified 14 relevant studies; 11 evaluated asthma development in children, while three studies, based on a single cohort, assessed this outcome in adults. Studies of childhood asthma and long-term ozone exposure - including exposure in utero, during the first year of life and during early childhood - reported inconsistent findings, which were further weakened by critical methodological limitations in statistical analyses and in exposure and outcome assessments, such as exposure measurement error and a lack of adjustment for key confounders. For adult-onset asthma, long-term ozone exposure was associated with an increased risk in men but not women. In addition to considerable uncertainties due to potential exposure measurement error and a lack of adjustment for key confounders, this study has limited generalizability to the US general population. While experimental evidence indicates that it may be biologically plausible that long-term ozone exposure could contribute to asthma development, it does not provide insight regarding an established mode of action. Future research is needed to address the uncertainties regarding the role of long-term ambient ozone exposure in asthma development.

To determine whether evidence indicates that short-term exposure to ambient concentrations of ozone in the United States can affect asthma severity, we systematically reviewed published controlled human exposure, epidemiology, and animal toxicity studies. The strongest evidence for a potential causal relationship came from epidemiology studies reporting increased emergency department visits and hospital admissions for asthma following elevated ambient ozone concentrations. However, while controlled exposure studies reported lung function decrements and increased asthma symptoms following high ozone exposures 160-400 parts per billion [ppb]), epidemiology studies evaluating similar outcomes reported less consistent results. Animal studies showed changes in pulmonary function at high ozone concentrations (> 500ppb), although there is substantial uncertainty regarding the relevance of these animal models to human asthma. Taken together, the weight of evidence indicates that there is at least an equal likelihood that either explanation is true, i.e., the strength of the evidence for a causal relationship between short-term exposure to ambient ozone concentrations and asthma severity is "equipoise and above.", (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140μg/m 3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human exposure to toluene diisocyanate (TDI) occurs mainly through inhalation of vapors in occupational settings where TDI is produced or used, but dermal exposure to TDI is also possible during some operations. Because of a recent epidemiology study reporting a possible association with lung cancer risk in workers with potential dermal exposure to TDI, we evaluated the evidence from epidemiological, toxicological, and toxicokinetic studies to assess whether it is likely that dermal exposure to TDI can cause human respiratory cancers. We found that the reported associations with respiratory cancers in the epidemiology studies do not support TDI as a causal factor, as there are other explanations that are more likely than causation, such as confounding by smoking and low socioeconomic status. Experimental animal and genotoxicity studies indicate that the carcinogenic potential of TDI depends on its conversion to toluene diamine (TDA), and there is no evidence of systemic availability of TDA after dermal or inhalation exposure to TDI. Also, systemic uptake of TDI is very low after dermal exposure, and any absorbed TDI is more likely to react with biomolecules on or below the skin surface than to form TDA. Even if some TDA formation occurred after dermal exposure to TDI, TDA does not induce respiratory tract tumors in experimental animals after either dermal or oral exposure. We conclude that the available evidence indicates that dermal TDI exposure does not cause respiratory cancers in humans., (Copyright © 2017 Gradient. Published by Elsevier Ltd.. All rights reserved.)

The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight., (Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.)

The current 100 ppb short-term National Ambient Air Quality Standard for NO 2 , and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO 2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens. These include an exercise-induced refractory period; partial reversal of bronchospasm from use of forced expiration maneuvers; and greater airway responsiveness of participants exposed to NO 2 at rest. We reviewed the scientific evidence to determine whether there is biological support for these factors and found that none sufficiently explained the lack of an effect during exercise or after exposure to allergens. In the absence of either a consistent concentration-response or a plausible explanation for the paradoxical AHR findings, the biological significance of these findings is uncertain and provides equivocal support for NO 2 as a causal factor of AHR at these exposure levels., (Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.)

Background: Many studies have evaluated associations between asthma emergency department (ED) visits, hospital admissions (HAs), and ambient ozone (O 3 ) across the US, but not in Texas. We investigated the relationship between O 3 and asthma HAs, and the potential impacts of outdoor pollen, respiratory infection HAs, and the start of the school year in Texas., Methods: We obtained daily time-series data on asthma HAs and ambient O 3 concentrations for Dallas, Houston, and Austin, Texas for the years 2003-2011. Relative risks (RRs) and 95% confidence intervals (CIs) of asthma HAs per 10-ppb increase in 8-h maximum O 3 concentrations were estimated from Poisson generalized additive models and adjusted for temporal trends, meteorological factors, pollen, respiratory infection HAs, day of the week, and public holidays. We conducted a number of sensitivity analyses to assess model specification., Results: We observed weak associations between total asthma HAs and O 3 at lags of 1 day (RR 10 ppb  = 1.012, 95% CI: 1.004-1.021), 2 days (RR 10 ppb  = 1.011, 95% CI: 1.002-1.019), and 0-3 days (RR 10 ppb  = 1.017, 95% CI: 1.005-1.030). The associations were primarily observed in children aged 5-14 years (e.g., for O 3 at lag 0-3 days, RR 10 ppb  = 1.037, 95% CI: 1.011-1.064), and null in individuals 15 years or older. The effect estimates did not change significantly with adjustment for pollen and respiratory infections, but they attenuated considerably and lost statistical significance when August and September data were excluded. A significant interaction between time around the start of the school year and O 3 at lag 2 day was observed, with the associations with pediatric asthma HAs stronger in August and September (RR 10 ppb  = 1.040, 95% CI: 1.012-1.069) than in the rest of the year (October-July) (RR 10 ppb  = 1.006, 95% CI: 0.986-1.026)., Conclusions: We observed small but statistically significant positive associations between total and pediatric asthma HAs and short-term O 3 exposure in Texas, especially in August and September. Further research is needed to determine how the start of school could modify the observed association between O 3 and pediatric asthma HAs.

Background: Epidemiology studies have shown that ambient concentrations of ozone and fine particulate matter (PM2.5) are associated with increased emergency department (ED) visits and hospital admissions (HAs) for asthma., Objective: Evaluate the impact of outdoor pollen, respiratory infections, and socioeconomic status (SES) on the associations between ambient ozone and PM2.5 and asthma HAs in New York City., Methods: Daily ozone, PM2.5, meteorological factors, pollen, and hospitalization records during 1999 to 2009 were obtained for New York City residents. Daily counts of HAs for asthma and respiratory infections were calculated for all-age and specific age groups, and for high- and low-SES communities. Generalized additive models were used to examine ambient concentrations of ozone and PM2.5 and asthma HAs, potential confounding effects of outdoor pollen and HAs for respiratory infections, and potential effect modification by neighborhood SES., Results: Both ozone and PM2.5 were statistically significantly associated with increased asthma HAs in children aged 6-18 years (per 10 ppb increase in ozone: RR = 1.0203, 95% CI: 1.0028-1.0382; per 10 μg/m3 increase in PM2.5: RR = 1.0218, 95% CI: 1.0007-1.0434), but not with total asthma HAs, or asthma HAs in other age groups. These associations were stronger for children living in the high-SES areas. Adjustment for respiratory infection HAs at various lags did not result in changes greater than 10% in the risk estimates for either ozone or PM2.5. In contrast, adjustment for outdoor pollen generally attenuated the estimated RRs for both ozone and PM2.5., Conclusions: Ambient ozone and PM2.5 are associated with asthma HAs in school-age children, and these associations are not modified by SES. HAs for respiratory infections do not appear to be a confounder for observed ozone- and PM2.5-asthma HAs associations, but pollen may be a weak confounder.

Background: Short-term exposure to ozone has been associated with asthma hospital admissions (HA) and emergency department (ED) visits, but the shape of the concentration-response (C-R) curve is unclear., Methods: We conducted a time series analysis of asthma HAs and ambient ozone concentrations in six metropolitan areas in Texas from 2001 to 2013. Using generalized linear regression models, we estimated the effect of daily 8-hour maximum ozone concentrations on asthma HAs for all ages combined, and for those aged 5-14, 15-64, and 65+years. We fit penalized regression splines to evaluate the shape of the C-R curves., Results: Using a log-linear model, estimated risk per 10ppb increase in average daily 8-hour maximum ozone concentrations was highest for children (relative risk [RR]=1.047, 95% confidence interval [CI]: 1.025-1.069), lower for younger adults (RR=1.018, 95% CI: 1.005-1.032), and null for older adults (RR=1.002, 95% CI: 0.981-1.023). However, penalized spline models demonstrated significant nonlinear C-R relationships for all ages combined, children, and younger adults, indicating the existence of thresholds. We did not observe an increased risk of asthma HAs until average daily 8-hour maximum ozone concentrations exceeded approximately 40ppb., Conclusion: Ozone and asthma HAs are significantly associated with each other; susceptibility to ozone is age-dependent, with children at highest risk. C-R relationships between average daily 8-hour maximum ozone concentrations and asthma HAs are significantly curvilinear for all ages combined, children, and younger adults. These nonlinear relationships, as well as the lack of relationship between average daily 8-hour maximum and peak ozone concentrations, have important implications for assessing risks to human health in regulatory settings., (Copyright © 2017. Published by Elsevier Ltd.)

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

Bisphenol A (BPA) is a high production volume chemical that is used in plastics and epoxy coatings. In 2015, California's Office of Environmental Health Hazard Assessment (OEHHA) added BPA to the Proposition 65 list of chemicals "known to cause reproductive toxicity" based on its Developmental and Reproductive Toxicant Identification Committee's (DART-IC) conclusion that BPA has been shown to cause female reproductive toxicity. A critical factor in determining compliance with Proposition 65 is a Maximum Allowable Dose Level (MADL), which is the exposure level at which a chemical would have no observable reproductive effect even if a person were exposed to 1000 times that level. We performed a comprehensive review of the literature, including the studies reviewed by DART-IC, and derived an oral MADL. Of all the studies we identified, Delclos et al. (2014) is of sufficient quality, has the lowest no observed effect level (NOEL), and results in the most conservative MADL of 157 μg/d. This is generally supported by other studies, including those that were considered by DART-IC. Also, the oral MADL provides a similar margin of safety as OEHHA's dermal MADL and other regulatory guidelines. Taken together, the scientific data support an oral MADL of 157 μg/d., (Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.)