Integrated Risk Information System Research Articles

Occupational exposure, carcinogenic and non-carcinogenic risk assessment of formaldehyde in the pathology labs of hospitals in Iran

Formaldehyde, a known carcinogenic compound, is commonly used in various medical settings. The objective of this study was to assess the carcinogenic and non-carcinogenic risks associated with occupational exposure to formaldehyde. This study was conducted in the pathology labs of four hospitals in Tehran. Cancer and non-cancer risks were evaluated using the quantitative risk assessment method proposed by the United States environmental protection agency (USEPA), along with its provided database known as the integrated risk information system (IRIS). Respiratory symptoms were assessed using the American thoracic society (ATS) questionnaire. The results indicated that 91.23% of exposure levels in occupational groups exceed the NIOSH standard of 0.016 ppm. Regarding carcinogenic risk, 41.03% of all the studied subjects were in the definite carcinogenic risk range (LCR > 10−4), 23.08% were in the possible carcinogenic risk range (10−5 < LCR < 10−4), and 35.90% were in the negligible risk range (LCR < 10−6). The highest index of occupational carcinogenesis was observed in the group of lab technicians with a risk number of 3.7 × 10−4, followed by pathologists with a risk number of 1.7 × 10−4. Furthermore, 23.08% of the studied subjects were within the permitted health risk range (HQ < 1.0), while 76.92% were within the unhealthy risk range (HQ > 1.0). Overall, the findings revealed significantly higher carcinogenic and non-carcinogenic risks among lab technicians and pathologists. Therefore, it is imperative to implement control measures across various hospital departments to mitigate occupational formaldehyde exposure levels proactively. These findings can be valuable for policymakers in the health sector, aiding in the elimination or reduction of airborne formaldehyde exposure in work environments.

Effects of chemical composition of ambient PM2.5 measured in Seoul on potential health risks and generation of reactive oxygen species

This study assesses the health effects associated with the chemical species of ambient particulate matter (PM) with an aerodynamic diameter ≤2.5 μm (PM2.5) in Seoul, focusing on identifying key chemical constituents and their sources. We employed two approaches to estimate health risks: (1) evaluating carcinogenic and noncarcinogenic risks using IRIS (Integrated Risk Information System) data from the US EPA (Environmental Protection Agency), and (2) quantifying the generation of hydroxyl radicals (·OH) following exposure to PM2.5 in surrogate lung fluid (SLF). Our results show a significant impact on human health from certain elements (Cr, Ni, As, and Cd) and polycyclic aromatic hydrocarbons (PAHs) (DaeP, DahA, and BaP for carcinogenic risks; BaP and BeP for noncarcinogenic risks). Notably, Cr and BaP, which are influential in both risk assessment and ·OH generation, highlight their significant roles in human health impacts. However, other components (e.g., CPP, BaP, BghiP, BaA, CHR, PYR, FLT, Ca, Mg, and Cu), though contributors to ·OH generation, were not included in the EPA's health risk assessment, suggesting a need for a broader PM2.5 compositional analysis to more accurately determine exposure concentrations and assess inhalation risks. These components predominantly originate from anthropogenic sources, such as combustion, vehicles, and industrial activities, underscoring the significant health implications of the pollutants emitted from these sources. The study concluded that focusing solely on the mass reduction of PM2.5 may not suffice; a dual approach that reduces both mass concentration and chemical-specific health risks is imperative for effective public health protection.

Sensory irritation and use of the best available science in setting exposure limits: Issues raised by a scientific panel review of formaldehyde human research studies

As a high production volume chemical with recognized sensory irritation and widespread exposure, the human health risk potential of formaldehyde has been reviewed by many international regulatory agencies and scientific advisory bodies. A scientific panel, the Human Studies Review Board, under the auspices of the EPA's Toxic Substances Control Act (TSCA) program recently reviewed the sensory irritation studies included in the 2022 Draft Integrated Risk Information System (IRIS) Formaldehyde Hazard Assessment in the context of their use in a weight of evidence evaluation of acute inhalation health effects. This panel issued a series of recommendations on the use of these studies for the purposes of calculating exposure limits (e.g., study design preferences; uncertainty adjustment). Considering that these recommendations might reflect topic areas with varying degrees of scientific consensus, this commentary reflects on commonalities and distinctions amongst international formaldehyde exposure limits based on sensory irritation. Notably, each review panel charged with an assessment of the science recommended that no adjustment was needed to account for either exposure duration or human variability. These areas of scientific consensus should be considered as the best available science for the purposes of setting exposure limits in the anticipated TSCA Risk Evaluation on formaldehyde.

Визначення відповідності вітчизняної бази гігієнічних нормативів канцерогенних речовин в атмосферному повітрі населених місць вимогам ЄС

The purpose of this work was to assess the safety of domestic (hygienic) standards for carcinogenic substances in the atmospheric air of populated areas and determine the concentration level corresponding to the acceptable risk indicator. Materials and methods. Bibliosemantic, bibliographic and hygienic research methods were used in this research. The results were obtained based on the collection and analysis of data on chemical carcinogenic compounds dangerous to humans, based on materials from international Directives, domestic regulatory frameworks and the IARC database. To assess the danger of individual substances and hygienic regulatory levels, risk indicators were determined according to recommended methodological documents. Indicators of reference concentrations for carcinogenic substances standardized in Ukraine were taken from data of the integrated risk information system (IRIS) US EPA. Results and discussion: the studies conducted indicate the need to revise the hygienic standards for carcinogenic substances included in the domestic regulatory framework for the atmospheric air of populated areas. The current standards for the most part exceed the level of acceptable or acceptable risk of probable cancer development among the population and those employed in production. This issue can be resolved by using an accelerated methodology, which is based on the calculation of the dose-risk scale. Accepted hygienic standards for the indicator of carcinogenic risk should be considered as annual averages for the atmospheric air of populated areas, and the current average daily concentrations according to international recommendations should be aimed at preventing acute exposure to chemical carcinogens within 24 hours and manifest themselves over a period of about 14 days. Conclusion: sanitary (hygienic) standards for carcinogenic substances in the air, included in the domestic bases, overwhelmingly exceed the level of permissible (acceptable) risk of cancer development and do not ensure safety for the population and persons involved in production and require revision in accordance with the requirements of the EU countries and the USA. It is proposed to resolve this issue using an accelerated methodology, which is based on the calculation of the dose-risk relationship (scale).

Data-Driven Quantitative Structure-Activity Relationship Modeling for Human Carcinogenicity by Chronic Oral Exposure.

Traditional methodologies for assessing chemical toxicity are expensive and time-consuming. Computational modeling approaches have emerged as low-cost alternatives, especially those used to develop quantitative structure-activity relationship (QSAR) models. However, conventional QSAR models have limited training data, leading to low predictivity for new compounds. We developed a data-driven modeling approach for constructing carcinogenicity-related models and used these models to identify potential new human carcinogens. To this goal, we used a probe carcinogen dataset from the US Environmental Protection Agency's Integrated Risk Information System (IRIS) to identify relevant PubChem bioassays. Responses of 25 PubChem assays were significantly relevant to carcinogenicity. Eight assays inferred carcinogenicity predictivity and were selected for QSAR model training. Using 5 machine learning algorithms and 3 types of chemical fingerprints, 15 QSAR models were developed for each PubChem assay dataset. These models showed acceptable predictivity during 5-fold cross-validation (average CCR = 0.71). Using our QSAR models, we can correctly predict and rank 342 IRIS compounds' carcinogenic potentials (PPV = 0.72). The models predicted potential new carcinogens, which were validated by a literature search. This study portends an automated technique that can be applied to prioritize potential toxicants using validated QSAR models based on extensive training sets from public data resources.

EPA lawsuit targets Denka’s neoprene plant

The neoprene maker Denka Performance Elastomer is facing a lawsuit from the US government over chloroprene emissions from the company’s plant in LaPlace, Louisiana. In a complaint filed Feb. 28 , the Environmental Protection Agency (EPA) claims that people living near the facility “are being exposed to an unacceptably high risk of developing certain cancers because of Denka’s chloroprene emissions.” The agency, which has been monitoring the facility since 2016, wants the court to force the company to reduce emissions. Denka argues that the EPA’s risk assessment, conducted in 2010 by the agency’s Integrated Risk Information System, overpredicts the cancer risk from chloroprene by 130 times. The company plans to formally ask the EPA to incorporate a newer model into that assessment. Denka purchased the LaPlace facility from DuPont in late 2014. Since then, Denka says, it has spent over $35 million to upgrade its emission reduction systems, including installing

Industry sues EPA over ethylene oxide rule

A battle over the cancer risks of ethylene oxide air emissions from chemical plants has landed in court. The chemical maker Huntsman Petrochemical and two industry trade groups, the American Chemistry Council and the Louisiana Chemical Association, filed lawsuits Feb. 21 that challenge the US Environmental Protection Agency’s recent decision to maintain a 2020 regulation limiting ethylene oxide emissions from organic chemical manufacturing. That regulation relies on a controversial hazard assessment conducted by the EPA’s Integrated Risk Information System (IRIS) in 2016. The rule requires chemical manufacturers to reduce ethylene oxide emissions from equipment leaks, vents, and storage tanks to protect communities near industrial facilities. Industry wants the EPA to use a less protective risk assessment conducted by the Texas Commission on Environmental Quality (TCEQ). In December, the EPA rejected the TCEQ’s assessment . The EPA concluded that there is no scientific basis for changing its preference of using hazard

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest. This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM.

Lead exposure and antisocial behavior: A systematic review protocol.

Lead exposure remains highly prevalent worldwide despite decades of research highlighting its link to numerous adverse health outcomes. In addition to well-documented effects on cognition, there is growing evidence of an association with antisocial behavior, including aggression, conduct problems, and crime. An updated systematic review on this topic, incorporating study evaluation and a developmental perspective on the outcome, can advance the state of the science on lead and inform global policy interventions to reduce exposure. We aim to evaluate the link between lead exposure and antisocial behavior. This association will be investigated via a systematic review of human epidemiological and experimental nonhuman mammalian studies. The systematic review protocol presented in this publication is informed by recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER) and follows the study evaluation approach put forth by the U.S. EPA Integrated Risk Information System (IRIS) program. We will search the following electronic databases for relevant literature: PubMed, BIOSIS and Web of Science. Search results will be stored in EPA's Health and Environmental Research Online (HERO) database. Eligible human epidemiological studies will include those evaluating any population exposed to lead at any lifestage via ingestion or inhalation exposure and considering an outcome of antisocial behavior based on any of the following criteria: psychiatric diagnoses (e.g., oppositional defiant disorder (ODD), conduct disorder (CD), disruptive behavior disorders (DBD)); violation of social norms (e.g., delinquency, criminality); and aggression. Eligible experimental animal studies will include those evaluating nonhuman mammalian studies exposed to lead via ingestion, inhalation, or injection exposure during any lifestage. The following outcomes will be considered relevant: aggression; antisocial behavior; and altered fear, anxiety, and stress response. Screening will be conducted with assistance from an artificial intelligence application. Two independent reviewers for each data stream (human, animal) will screen studies with highest predicted relevance against pre-specified inclusion criteria at the title/abstract and full-text level. Study evaluation will be conducted using methods adapted from the U.S. EPA IRIS program. After data extraction, we will conduct a narrative review and quantitative meta-analysis on the human epidemiological studies as well as a narrative review of the experimental animal studies. We will evaluate the strength of each evidence stream separately and then will develop a summary evidence integration statement based on inference across evidence streams.

Health risk assessment of exposure to ambient formaldehyde in carpet manufacturing industries.

Formaldehyde is categorized as a definitive carcinogen by the International Agency for Research on Cancer. To the best of our knowledge, no study has assessed the health risks of occupational exposure of workers in carpet manufacturing plants to formaldehyde. Therefore, this study assesses the health risks of the occupational exposure to formaldehyde of 67 male workers in carpet manufacturing plants in Iran in 2022. Exposure to formaldehyde was quantitatively determined after collecting personal exposure samples from the workers' respiratory zone and spectrophotometric analysis based on method number 3500 of the National Institute of Occupational Safety and Health. In the next step, the carcinogenic and noncarcinogenic risks based on personal exposure to formaldehyde were evaluated. Sensitivity analyses were employed using the Monte Carlo simulation method. The mean inhalation exposure of workers to formaldehyde was 0.636 mg m-3. The inhalation cancer risk value based on the integrated risk information system for formaldehyde was 4.06×10-4 ± 3.17×10-5 (mean ± standard deviation), which exceeded the value reported by the US Environmental Protection Agency. An unacceptable carcinogenic risk level was found in 75.6% of workers. The highest mean inhalation cancer risk was 6.74×10-4 (i.e., 6.74 additional cases per 10,000 employees exposed) was found in sizing post employees. The hazard quotient of formaldehyde was 0.311±0.024. The formaldehyde concentration had a considerable effect on the health risk. The findings of this study provide valuable scientific information that supports the development of future policies to enhance the health status of employees in carpet manufacturing plants.

Data quality evaluation criteria for systematic review of epidemiology studies under the Toxic Substances Control Act (TSCA): refinement through practical application in risk evaluation

BACKGROUND AND AIM: The 2016 Frank R. Lautenberg Chemical Safety for the 21st Century Act and the 2017 Procedures for Chemical Risk Evaluation under the Amended Toxic Substances Control Act (TSCA) require the U.S. Environmental Protection Agency (EPA) to conduct risk evaluations using the best available science and weight of the scientific evidence. Therefore, EPA has developed systematic review methods including data quality evaluation criteria to evaluate scientific studies in specific disciplines including epidemiology. EPA has aimed to refine these criteria for practical application in risk evaluation of high-priority chemicals under TSCA. METHODS: EPA considered the pros and cons of multiple existing systematic review frameworks and guidance documents and drew upon these methodologies to develop data quality evaluation domains, metrics, and criteria for the systematic review of epidemiology studies under TSCA. EPA refined these domains, metrics, and criteria through practical application to add specificity to increase consistency among evaluators and to harmonize with the evaluation of animal toxicology studies under TSCA. RESULTS: EPA adopted aspects of methods including the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT) and EPA’s Integrated Risk Information System (IRIS) methods, but also aimed to be consistent with other disciplines and to address TSCA scientific standards. CONCLUSIONS: EPA has further refined data quality evaluation criteria for systematic review of epidemiology studies under TSCA in response to comments from peer reviewers, the public, the National Academies, and the TSCA Science Advisory Committee on Chemicals (SACC). Systematic review of epidemiology studies is a critical component of protecting human health under TSCA. DISCLAIMER: The views expressed in this presentation are solely those of the authors and do not represent the policies of EPA. Mention of trade names or commercial products should not be interpreted as an endorsement by EPA. KEY WORDS: Systematic Review, Data Quality Evaluation

Epidemiology Evidence for Health Effects of 150 per- and Polyfluoroalkyl Substances: A Systematic Evidence Map.

Background:Per- and polyfluoroalkyl substances (PFAS) comprise a large class of chemicals with widespread use and persistence in the environment and in humans; however, most of the epidemiology research has focused on a small subset.Objectives:The aim of this systematic evidence map (SEM) is to summarize the epidemiology evidence on approximately 150 lesser studied PFAS prioritized by the EPA for tiered toxicity testing, facilitating interpretation of those results as well as identification of priorities for risk assessment and data gaps for future research.Methods:The Populations, Exposure, Comparators, and Outcomes (PECO) criteria were intentionally broad to identify studies of any health effects in humans with information on associations with exposure to the identified PFAS. Systematic review methods were used to search for literature that was screened using machine-learning software and manual review. Studies meeting the PECO criteria underwent quantitative data extraction and evaluation for risk of bias and sensitivity using the Integrated Risk Information System approach.Results:193 epidemiology studies were identified, which included information on 15 of the PFAS of interest. The most commonly studied health effect categories were metabolic (), endocrine (), cardiovascular (30), female reproductive (), developmental (), immune (), nervous (), male reproductive (), cancer (), and urinary () effects. In study evaluation, 120 (62%) studies were considered High/Medium confidence for at least one outcome.Discussion:Most of the PFAS in this SEM have little to no epidemiology data available to inform evaluation of potential health effects. Although exposure to the 15 PFAS that had data was fairly low in most studies, these less-studied PFAS may be used as replacements for “legacy” PFAS, leading to potentially greater exposure. It is impractical to generate epidemiology evidence to fill the existing gaps for all potentially relevant PFAS. This SEM highlights some of the important research gaps that currently exist. https://doi.org/10.1289/EHP11185

Reference dose prediction by using CDK molecular descriptors: A non-experimental method

Reference dose (RfD) is an estimate of a daily dose that individual can be exposed chronically without obvious deleterious effects during a lifetime. In the area of toxicology, researchers always use the traditional approach by employing NOAEL/LOAEL or the benchmark dose (BMD) and other dose-response approaches to estimate RfD. These methods have, despite their typicalness, certain limitations. In this study, we present a novel method of the estimation of reference dose without experiments. The information of the organic chemicals is available from the Integrated Risk Information System (IRIS) of USEPA. Molecular descriptors for each molecular structure were calculated by an integrated platform, and the chemicals were classified into four categories based on molecular similarity: 128 contained benzene rings, 47 were heteroaromatics, 104 contained halogen substituents and 44 were halogenated aliphatic hydrocarbons. The predictive model of RfD was constructed by the multiple linear stepwise regression (MLR) method. Approximately 95% and 82% of the data points differ by less than 10-fold and 5-fold between the predicted values and the true values respectively. The non-experimental method improves the estimation efficiency and has a certain reference value to predict.

Cancer Risk and Diesel Exhaust Exposure Among Railroad Workers

Inhalation exposure to diesel exhaust in the railroad work environment causes significant and quantifiable cancer risks to many railroad workers. Diesel exhaust has been identified as a known human carcinogen by the International Agency for Research on Cancer (“IARC”) and as a potential carcinogen by the United States Environmental Protection Agency (“USEPA”), the California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (“OEHHA”), and the National Institute for Occupational Safety & Health (“NIOSH”). Peer-reviewed literature defines the ambient air concentrations of diesel exhaust for several railroad occupations as being above environmental background levels. This study uses diesel exhaust concentrations in the railroad work environment in conjunction with the USEPA’s Integrated Risk Information System (“IRIS”) risk assessment methodology to quantify the cancer risk posed to railroad workers due to occupational inhalation exposure to diesel exhaust. NIOSH Bulletin 68 (2017) states that there is “no known safe level” of exposure to carcinogens and recommends an evaluation of the USEPA’s IRIS guidance to evaluate quantitative risk assessment of human exposure to occupational carcinogens. This is the first study to utilize USEPA methodology to calculate the excess lung cancer risk caused by railroad workers’ cumulative exposure to diesel exhaust.

Formaldehyde causes leukemia, draft EPA review concludes

Formaldehyde is carcinogenic to humans, a draft risk assessment from the US Environmental Protection Agency concludes. The review, conducted by the agency’s Integrated Risk Information System (IRIS) program and released April 14, cites evidence that inhalation of formaldehyde causes nasopharyngeal cancer, sinonasal cancer, and myeloid leukemia in humans. Formaldehyde is used in making plywood, composite wood items, adhesives, and many other products. Consumers can be exposed to the chemical in tobacco smoke, construction materials, furniture, carpets, and other household products, the assessment says. The EPA was poised to release the draft formaldehyde review in early 2018, but it abruptly put the assessment on hold under the Donald J. Trump administration . The agency now plans to use the IRIS assessment to inform its upcoming formaldehyde risk evaluation under the Toxic Substances Control Act . The American Chemistry Council, which represents chemical manufacturers, has been pressuring the EPA to halt the

Comparison of Integrated Risk Information System and Navigation Guide approaches for study evaluation in systematic reviews of environmental epidemiology studies

BACKGROUND AND AIM: There are several approaches available for evaluating risk of bias in environmental epidemiology studies, but few case studies comparing them have been done. METHODS: The Integrated Risk Information System (IRIS) approach is a domain-based framework where each study is evaluated for risk of bias and study sensitivity. Eick et al. (2020) applied multiple approaches, including IRIS, to studies from a Navigation Guide (NG) systematic review of polybrominated diphenyl ethers (PBDEs) and neurodevelopment (Lam et al., 2017). In the current analysis, trained IRIS staff applied the IRIS approach, including PBDE exposure and cognitive testing-specific considerations, to the 10 studies of IQ and compared the results to those using the NG. This analysis was restricted to comparable domains: Exposure and Outcome Assessment, Confounding, Population/Selection, and Selective Reporting (and NG domains considered within the broader IRIS Exposure and Outcome domains). The IRIS and NG approaches have four rating levels that may not be strictly analogous but were interpreted as similar for identifying study deficiencies. RESULTS:We identified three studies with multiple “deficient” domain ratings (low confidence overall) using the IRIS approach. These studies also had multiple domains with “probably high risk of bias” in the NG systematic review. Among studies rated as high or medium confidence overall using the IRIS approach, there were differences in ratings between the approaches, but generally within the top two rating levels (IRIS good/adequate; NG low/probably low). CONCLUSIONS:The approaches identified the same studies as concerning for risk of bias. Among higher quality studies, some rating differences between tools may be attributed to different expertise/interpretations of evaluators. Additional comparisons would be elucidating, ideally with collaboration to ensure application of the approaches consistent with their intended use. Disclaimer: The views expressed in this abstract are those of the author and do not necessarily reflect the views or policies of the U.S. EPA. KEYWORDS: risk of bias, systematic review, environmental exposures, risk assessment

Evidence Synthesis and Integration Methods used in the US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS) Program *Abstract is associated with symposium proposal ID “66” (accepted status)

BACKGROUND AND AIM: US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS) assessments are an important source of toxicity information used by EPA, state and local health agencies, Tribes, other federal agencies, and international health organizations. METHODS: IRIS assessments, which include hazard identification and dose-response analyses, are conducted using systematic review methods for identifying evidence, evaluating individual studies, summarizing the relevant evidence (i.e., evidence synthesis), and arriving at summary conclusions regarding the overall body of evidence (i.e., evidence integration). The systematic review approaches used for IRIS assessments were developed through discussions within and outside EPA and informed by multiple reviews by the National Academy of Sciences (NAS). RESULTS:In brief, the strength of the evidence from the available human and animal health effect studies are summarized in parallel, but separately, using a structured evaluation of an adapted set of considerations first introduced by Sir Bradford Hill in 1965. Relevant mechanistic evidence that informs the biological plausibility and coherence within the available human or animal health effect studies is also considered. The terms associated with the different strength of evidence judgments for the human and animal evidence streams are robust, moderate, slight, indeterminate, and compelling evidence of no effect. CONCLUSIONS:These judgments are then combined to draw an overall judgment that incorporates inferences across evidence streams, such as the human relevance of findings in animals. The final output is an evidence integration narrative with terms reflecting the summary judgment of evidence demonstrates, evidence indicates (likely), evidence suggests, evidence inadequate, or strong evidence of no effect. The expert judgements made during evidence synthesis and integration are summarized in an evidence profile tables using structured web-forms housed within the EPA’s version of Health Assessment Workspace Collaborative (HAWC). *Abstract is associated with symposium proposal ID “66” (accepted status)

Comments from the perspective of pertinent committees of the US National Academies of Sciences

BACKGROUND AND AIM: This presentation will comment on the ISEE principles of evidence synthesis and evaluation in environmental health from the perspective of pertinent committees of the US National Academies of Sciences, Engineering, and Medicine (NASEM). METHODS: Over the last decade, beginning with the Review of the Environmental Protection Agency’s (EPA) Draft IRIS Assessment of Formaldehyde, multiple committees have addressed the role and conduct of systematic review within several distinct US regulatory frameworks, including those used under the Toxic Substances Control Act (TSCA) and the Integrated Risk Information System (IRIS). These committees have probed the details of how evidence is evaluated, synthesized, and integrated in these agency processes. RESULTS:One overarching finding is the lack of a set of harmonized approaches. Additionally, the EPA (and others) are challenged to develop approaches for systematic review for mechanistic and other toxicological research. CONCLUSIONS:Guidelines for principles of evidence evaluation and synthesis from ISEE could play a critical role as regulatory frameworks for using evidence continue to evolve; benchmarks are needed. KEYWORDS: principles, evidence synthesis, evaluation, environmental health

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

Background:Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.Objectives:We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.Methods:Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose–response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized.Results:We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose–response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose–response analysis.Conclusion:Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381