Evaluation of neural reflex activation as a potential mode of action for respiratory and cardiovascular effects of fine particulate matter.

OBJECTIVES: Mortality from respiratory and cardiovascular health conditions contributes largely to the total mortality that has been associated with exposure to PM2.5 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 PM2.5 occur through activation of neural reflexes. MATERIALS AND METHODS: We critically reviewed the experimental studies of PM2.5 (including ambient PM2.5, 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 PM2.5 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 PM2.5 exposure concentrations. RESULTS AND DISCUSSION: We found that the proposed MoA of neural reflex activation is biologically plausible for PM2.5-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 PM2.5 exposure levels. A role for the proposed MoA in PM2.5-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 PM2.5 could cause either respiratory or cardiovascular morbidities in humans, particularly at the ambient concentrations associated with total mortality in epidemiology studies.

Nickel in ambient particulate matter and respiratory or cardiovascular outcomes: A critical review.

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.

Evidence evaluated by European Food Safety Authority does not support lowering the temporary tolerable daily intake for bisphenol A.

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.

WITHDRAWN: Letter to editor: Evidence evaluated by EFSA does not support lowering the temporary tolerable daily intake for bisphenol A.

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Systematic review of the potential carcinogenicity of bisphenol A in humans.

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.

Systematic review of the association between long-term exposure to fine particulate matter and mortality.

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 PM2.5 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 PM2.5 concentrations and mortality from these studies is inadequate.

US EPA's TSCA risk assessment approach: a case study of asbestos in automotive brakes.

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.

Systematic review of the potential respiratory carcinogenicity of metallic nickel in humans.

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.

"Good Epidemiology Practice" Guidelines for Pesticide Exposure Assessment.

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.

A critical review of talc and ovarian cancer.

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.

A bounding quantitative cancer risk assessment for occupational exposures to asphalt emissions during road paving operations.

The International Agency for Research on Cancer recently classified straight-run bitumens and associated emissions during road paving as possibly carcinogenic to humans (Group 2B), owing to potential exposures to polycyclic aromatic hydrocarbons. We examine existing chemistry, exposure, epidemiology, and animal toxicity data to explore quantitative cancer risk implications for paving workers exposed to asphalt emissions from the data used in identifying this qualitative hazard. Epidemiology studies show no consistent cancer risk elevation. One skin-painting mouse study of paving asphalt emission condensate found a single tumor at only the highest tested dose, as did one rat inhalation study. These studies were used to develop an upper bound on possible carcinogenic potency of emissions that are inhaled or dermally deposited. Extending earlier work on roofing asphalt, we conducted time-to-tumor modeling using the dose-time-response shape for several dose levels of benzo[a]pyrene (B[a]P) in concurrent bioassay controls to infer presumed parallel dose-time-response curves for paving-asphalt-emission condensate. In addition, we developed a scientific rationale, based on general scaling considerations and on dermal uptake, for the chosen means to scale observed dermal cancer potencies in mice to apply to dermal exposures in humans. The results indicate that paving asphalt emissions have a reduced dermal cancer potency compared to roofing asphalt, consistent with the lower levels of the multi-ringed PAHs implicated in cancer risks. Based on existing occupational exposure studies, cancer risks to pavers from both dermal and inhalation exposure to asphalt emissions is within a range typically acceptable within regulatory frameworks.

Critique of the ACGIH 2016 derivation of toluene diisocyanate Threshold Limit Values.

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.

Critical review of long-term ozone exposure and asthma development.

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.

Short-term ozone exposure and asthma severity: Weight-of-evidence analysis.

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."

Comprehensive multipathway risk assessment of chemicals associated with recycled ("crumb") rubber in synthetic turf fields.

BACKGROUND: Thousands of synthetic turf fields in the US are regularly used by millions of individuals (particularly children and adolescents). Although many safety assessments have concluded that there are low or negligible risks related to exposure to chemicals found in the recycled rubber used to make these fields, concerns remain about the safety of this product. Existing studies of recycled rubber's potential health risks have limitations such as small sample sizes and limited evaluation of relevant exposure pathways and scenarios. OBJECTIVE: Conduct a comprehensive multipathway human health risk assessment (HHRA) of exposure to chemicals found in recycled rubber. METHODS: All available North American data on the chemical composition of recycled rubber, as well as air sampling data collected on or near synthetic turf fields, were identified via a literature search. Ingestion, dermal contact, and inhalation pathways were evaluated according to US Environmental Protection Agency (US EPA) guidance, and exposure scenarios for adults, adolescents, and children were considered. RESULTS: Estimated non-cancer hazards and cancer risks for all the evaluated scenarios were within US EPA guidelines. In addition, cancer risk levels for users of synthetic turf field were comparable to or lower than those associated with natural soil fields. CONCLUSIONS: This HHRA's results add to the growing body of literature that suggests recycled rubber infill in synthetic turf poses negligible risks to human health. This comprehensive assessment provides data that allow stakeholders to make informed decisions about installing and using these fields.

Dermal exposure to toluene diisocyanate and respiratory cancer risk.

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.

Evaluation of neural reflex activation as a mode of action for the acute respiratory effects of ozone.

Exposure to elevated levels of ozone has been associated with a variety of respiratory-related health endpoints in both epidemiology and controlled human exposure studies, including lung function decrements and airway inflammation. A mode of action (MoA) for these effects has not been established, but it has been proposed that they may occur through ozone-induced activation of neural reflexes. We critically reviewed experimental studies of ozone exposure and neural reflex activation and applied the International Programme on Chemical Safety (IPCS) mode-of-action/human relevance framework to evaluate the biological plausibility and human relevance of this proposed MoA. Based on the currently available experimental data, we found that the proposed MoA of neural reflex activation is biologically plausible for the endpoint of ozone-induced lung function decrements at high ozone exposures, but further studies are needed to fill important data gaps regarding the relevance of this MoA at lower exposures. A role for the proposed MoA in ozone-induced airway inflammation is less plausible, as the evidence is conflicting and is also of unclear relevance given the lack of studies conducted at lower exposures. The evidence suggests a different MoA for ozone-induced inflammation that may still be linked to the key events in the proposed MoA, such that neural reflex activation may have some degree of involvement in modulating ozone-induced neutrophil influx, even if it is not a direct role.

An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers.

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.

Evaluation of atherosclerosis as a potential mode of action for cardiovascular effects of particulate matter.

Epidemiology studies have consistently reported associations between PM2.5 exposure and cardiovascular (CV) morbidity and mortality, but the epidemiology evidence for associations between PM2.5 and subclinical measures of atherosclerosis is unclear. We critically reviewed the experimental studies of PM2.5 and effects associated with acceleration and exacerbation of atherosclerosis and evaluated whether they support a biologically plausible, human-relevant mode of action (MoA) for the associations between PM2.5 exposure and adverse CV outcomes reported in epidemiology studies. We focused on outcomes related to atherosclerotic plaque development, thrombosis, and coagulation, and we examined whether these outcomes were correlated with measures of oxidative stress and systemic or pulmonary inflammation, to evaluate whether these processes are likely to be key early events for atherogenic effects of PM. While the current experimental evidence indicates that the acceleration and exacerbation of atherosclerosis is a biologically plausible MoA in experimental animal models, we found that the human relevance of the key events in the proposed MoA is unclear and not well supported by the existing data. Further studies are needed to fill several important data gaps before the human relevance of this MoA can be established.