Optimizing Chemicals Management in the United States and Canada through the Essential-Use Approach.

Chemicals have improved the functionality and convenience of industrial and consumer products, but sometimes at the expense of human or ecological health. Existing regulatory systems have proven to be inadequate for assessing and managing the tens of thousands of chemicals in commerce. A different approach is urgently needed to minimize ongoing production, use, and exposures to hazardous chemicals. The premise of the essential-use approach is that chemicals of concern should be used only in cases in which their function in specific products is necessary for health, safety, or the functioning of society and when feasible alternatives are unavailable. To optimize the essential-use approach for broader implementation in the United States and Canada, we recommend that governments and businesses (1) identify chemicals of concern for essentiality assessments based on a broad range of hazard traits, going beyond toxicity; (2) expedite decision-making by avoiding unnecessary assessments and strategically asking up to three questions to determine whether the use of the chemical in the product is essential; (3) apply the essential-use approach as early as possible in the process of developing and assessing chemicals; and (4) engage diverse experts in identifying chemical uses and functions, assessing alternatives, and making essentiality determinations and share such information broadly. If optimized and expanded into regulatory systems in the United States and Canada, other policymaking bodies, and businesses, the essential-use approach can improve chemicals management and shift the market toward safer chemistries that benefit human and ecological health.

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern.

Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs' role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency's current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.

Effective communications strategies to increase the impact of environmental health research.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are the subject of a growing body of research with the potential to positively impact public and ecological health. However, to effect positive change, findings must be communicated beyond the scientific community. OBJECTIVE: We sought to (a) evaluate the relationships between communications strategy, media attention, and scholarly citations of PFAS research and (b) offer guidance for researchers and communications professionals who would like to publicize future work and increase its impact. METHODS: We analyzed 273 peer-reviewed epidemiological studies on PFAS human health impacts with publication years 2018-2020, as collected by a pre-existing database. We investigated whether a press release was issued, open-access status, abstract and press release readability, timing of publication and press release distribution, journal impact factor, study type and sample size, statistical significance of finding(s), number of scholarly citations, and the Altmetric Attention Score (a measure of media attention). DISCUSSION: Of papers reporting a statistically significant association with health harm, those with a press release received 20 times more media attention (as assessed by Altmetric scores) than those that did not. However, only 6.2% of all papers and 7.8% of significant papers issued one. Among papers with a press release, media attention was positively correlated with better abstract and press release readability and speed in issuing the press release. Scholarly citations were positively correlated with media attention, presence of a press release, and open-access status. CONCLUSION: Most papers with significant findings on PFAS are published without a press release and receive little or no media attention. This reduces the likelihood that important research is reaching the public and decisionmakers who can translate science into action. Issuing a press release and receiving media attention also appear to increase scholarly citations. We provide recommendations for authors to increase the reach and impact of future papers.

Impacts of food contact chemicals on human health: a consensus statement.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Exploring the endocrine activity of air pollutants associated with unconventional oil and gas extraction.

BACKGROUND: In the last decade unconventional oil and gas (UOG) extraction has rapidly proliferated throughout the United States (US) and the world. This occurred largely because of the development of directional drilling and hydraulic fracturing which allows access to fossil fuels from geologic formations that were previously not cost effective to pursue. This process is known to use greater than 1,000 chemicals such as solvents, surfactants, detergents, and biocides. In addition, a complex mixture of chemicals, including heavy metals, naturally-occurring radioactive chemicals, and organic compounds are released from the formations and can enter air and water. Compounds associated with UOG activity have been linked to adverse reproductive and developmental outcomes in humans and laboratory animal models, which is possibly due to the presence of endocrine active chemicals. METHODS: Using systematic methods, electronic searches of PubMed and Web of Science were conducted to identify studies that measured chemicals in air near sites of UOG activity. Records were screened by title and abstract, relevant articles then underwent full text review, and data were extracted from the studies. A list of chemicals detected near UOG sites was generated. Then, the potential endocrine activity of the most frequently detected chemicals was explored via searches of literature from PubMed. RESULTS: Evaluation of 48 studies that sampled air near sites of UOG activity identified 106 chemicals detected in two or more studies. Ethane, benzene and n-pentane were the top three most frequently detected. Twenty-one chemicals have been shown to have endocrine activity including estrogenic and androgenic activity and the ability to alter steroidogenesis. Literature also suggested that some of the air pollutants may affect reproduction, development, and neurophysiological function, all endpoints which can be modulated by hormones. These chemicals included aromatics (i.e., benzene, toluene, ethylbenzene, and xylene), several polycyclic aromatic hydrocarbons, and mercury. CONCLUSION: These results provide a basis for prioritizing future primary studies regarding the endocrine disrupting properties of UOG air pollutants, including exposure research in wildlife and humans. Further, we recommend systematic reviews of the health impacts of exposure to specific chemicals, and comprehensive environmental sampling of a broader array of chemicals.

New Look at BTEX: Are Ambient Levels a Problem?

Benzene, toluene, ethylbenzene, and xylene (BTEX) are retrieved during fossil fuel extraction and used as solvents in consumer and industrial products, as gasoline additives, and as intermediates in the synthesis of organic compounds for many consumer products. Emissions from the combustion of gasoline and diesel fuels are the largest contributors to atmospheric BTEX concentrations. However, levels indoors (where people spend greater than 83% of their time) can be many times greater than outdoors. In this review we identified epidemiological studies assessing the noncancer health impacts of ambient level BTEX exposure (i.e., nonoccupational) and discussed how the health conditions may be hormonally mediated. Health effects significantly associated with ambient level exposure included sperm abnormalities, reduced fetal growth, cardiovascular disease, respiratory dysfunction, asthma, sensitization to common antigens, and more. Several hormones including estrogens, androgens, glucocorticoids, insulin, and serotonin may be involved in these health outcomes. This analysis suggests that all four chemicals may have endocrine disrupting properties at exposure levels below reference concentrations (i.e., safe levels) issued by the U.S. Environmental Protection Agency. These data should be considered when evaluating the use of BTEX in consumer and industrial products and indicates a need to change how chemicals present at low concentrations are assessed and regulated.

Public Health Risks of PFAS-Related Immunotoxicity Are Real.

PURPOSE OF REVIEW: The discovery of per- and polyfluoroalkyl substances (PFAS) in the environment and humans worldwide has ignited scientific research, government inquiry, and public concern over numerous adverse health effects associated with PFAS exposure. In this review, we discuss the use of PFAS immunotoxicity data in regulatory and clinical decision-making contexts and question whether recent efforts adequately account for PFAS immunotoxicity in public health decision-making. RECENT FINDINGS: Government and academic reviews confirm the strongest human evidence for PFAS immunotoxicity is reduced antibody production in response to vaccinations, particularly for tetanus and diphtheria. However, recent events, such as the economic analysis supporting the proposed national primary drinking water regulations and clinical monitoring recommendations, indicate a failure to adequately incorporate these data into regulatory and clinical decisions. To be more protective of public health, we recommend using all relevant immunotoxicity data to inform current and future PFAS-related chemical risk assessment and regulation. Biological measures of immune system effects, such as reduced antibody levels in response to vaccination, should be used as valid and informative markers of health outcomes and risks associated with PFAS exposure. Routine toxicity testing should be expanded to include immunotoxicity evaluations in adult and developing organisms. In addition, clinical recommendations for PFAS-exposed individuals and communities should be revisited and strengthened to provide guidance on incorporating immune system monitoring and other actions that can be taken to protect against adverse health outcomes.

The PFAS-Tox Database: A systematic evidence map of health studies on 29 per- and polyfluoroalkyl substances.

BACKGROUND: PFAS (per-and polyfluoroalkyl substances) are a large class of synthetic chemicals widely used in consumer products and industrial processes. The scientific literature on PFAS has increased dramatically in the last decade. Many stakeholders, including regulators, scientists, non-governmental organizations, and concerned individuals could benefit from an efficient way to access the health and toxicological literature related to PFAS. OBJECTIVE: To create a systematic evidence map of the available peer-reviewed health or toxicological research for 29 PFAS. METHODS: A protocol for conducting this systematic evidence map was initially published on Zenodo (Pelch et al. 2019c), then peer reviewed and published in Environment International (Pelch et al. 2019d). PubMed database was searched through January 25, 2021. Studies were screened for inclusion and exclusion according to the Populations, Exposures, Comparators, and Outcomes (PECO) statement. Inclusion criteria were intentionally broad and included any human, animal, and/or in vitro study that investigated exposure to one of the 29 PFAS of interest and a human health or toxicological effect. Selected study details were extracted from included studies as described in the protocol. Study appraisal was not conducted. The included studies and extracted meta-data are freely available in the online, interactive systematic evidence map at https://pfastoxdatabase.org. RESULTS: Over 15,000 studies were retrieved from the PubMed literature searches. After manual screening, 1,067 studies were identified and included as investigating the health or toxicological effect of one or more PFAS of interest. There were 505 human, 385 animal, and 220 in vitro studies. Summary tables of the extracted data and overall observations are included in this report. CONCLUSIONS: The PFAS-Tox Database is a useful tool for searching, filtering, and identifying peer reviewed research on the health and toxicological effects of the included PFAS. In this summary of the evidence map we provide examples of data gaps and clusters revealed by the database, with the goal of helping direct future research efforts, facilitate systematic reviews (e.g. on immune effects, mixtures of PFAS, or effects of short chain PFAS), inform regulatory risk assessments, and improve opportunities for cross-disciplinary coordination. We also discuss how this tool supports scientists, regulatory agencies, and other individuals by increasing awareness and access to current evidence regarding the health effects associated with PFAS exposure.

Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers.

BACKGROUND: To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides. OBJECTIVES: This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and in vitro models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health. DISCUSSION: Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285.

Improving the quality of toxicology and environmental health systematic reviews: What journal editors can do.

Systematic reviews are fast increasing in prevalence in the toxicology and environmental health literature. However, how well these complex research projects are being conducted and reported is unclear. Since editors have an essential role in ensuring the scientific quality of manuscripts being published in their journals, a workshop was convened where editors, systematic review practitioners, and research quality control experts could discuss what editors can do to ensure the systematic reviews they publish are of sufficient scientific quality. Interventions were explored along four themes: setting standards; reviewing protocols; optimizing editorial workflows; and measuring the effectiveness of editorial interventions. In total, 58 editorial interventions were proposed. Of these, 26 were shortlisted for being potentially effective, and 5 were prioritized as short-term actions that editors could relatively easily take to improve the quality of published systematic reviews. Recent progress in improving systematic reviews is summarized, and outstanding challenges to further progress are highlighted.

Scientific Basis for Managing PFAS as a Chemical Class.

This commentary presents a scientific basis for managing as one chemical class the thousands of chemicals known as PFAS (per- and polyfluoroalkyl substances). The class includes perfluoroalkyl acids, perfluoroalkylether acids, and their precursors; fluoropolymers and perfluoropolyethers; and other PFAS. The basis for the class approach is presented in relation to their physicochemical, environmental, and toxicological properties. Specifically, the high persistence, accumulation potential, and/or hazards (known and potential) of PFAS studied to date warrant treating all PFAS as a single class. Examples are provided of how some PFAS are being regulated and how some businesses are avoiding all PFAS in their products and purchasing decisions. We conclude with options for how governments and industry can apply the class-based approach, emphasizing the importance of eliminating non-essential uses of PFAS, and further developing safer alternatives and methods to remove existing PFAS from the environment.

Recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER).

BACKGROUND: There are several standards that offer explicit guidance on good practice in systematic reviews (SRs) for the medical sciences; however, no similarly comprehensive set of recommendations has been published for SRs that focus on human health risks posed by exposure to environmental challenges, chemical or otherwise. OBJECTIVES: To develop an expert, cross-sector consensus view on a key set of recommended practices for the planning and conduct of SRs in the environmental health sciences. METHODS: A draft set of recommendations was derived from two existing standards for SRs in biomedicine and developed in a consensus process, which engaged international participation from government, industry, non-government organisations, and academia. The consensus process consisted of a workshop, follow-up webinars, email discussion and bilateral phone calls. RESULTS: The Conduct of Systematic Reviews in Toxicology and Environmental Health Research (COSTER) recommendations cover 70 SR practices across eight performance domains. Detailed explanations for specific recommendations are made for those identified by the authors as either being novel to SR in general, specific to the environmental health SR context, or potentially controversial to environmental health SR stakeholders. DISCUSSION: COSTER provides a set of recommendations that should facilitate the production of credible, high-value SRs of environmental health evidence, and advance discussion of a number of controversial aspects of conduct of EH SRs. Key recommendations include the management of conflicts of interest, handling of grey literature, and protocol registration and publication. A process for advancing from COSTER's recommendations to developing a formal standard for EH SRs is also indicated.

Predictors of methamphetamine injection in out-of-treatment IDUs.

From 2004-2006, 439 injection drug users were recruited in Denver, Colorado, to participate in a study of drug use and HCV risk. Over two-thirds were male, more than half were white, and 28% were methamphetamine injectors. The Risk Behavior Assessment, which assesses demographics, drug use, and HIV risk behaviors, was used. Variables were assessed for association with methamphetamine (MA) injection. A logistic regression model was built using forward stepwise method to determine independent associations between variables of interest and MA injection. The study's limitations are noted, and implications are described.

Environmental Chemicals and Autism: A Scoping Review of the Human and Animal Research.

BACKGROUND: Estimates of autism prevalence have increased dramatically over the past two decades. Evidence suggests environmental factors may contribute to the etiology of the disorder. OBJECTIVES: This scoping review aimed to identify and categorize primary research and reviews on the association between prenatal and early postnatal exposure to environmental chemicals and the development of autism in epidemiological studies and rodent models of autism. METHODS: PubMed was searched through 8 February 2018. Included studies assessed exposure to environmental chemicals prior to 2 months of age in humans or 14 d in rodents. Rodent studies were considered relevant if they included at least one measurement of reciprocal social communicative behavior or repetitive and stereotyped behavior. Study details are presented in interactive displays using Tableau Public. RESULTS: The search returned 21,603 unique studies, of which 54 epidemiological studies, 46 experimental rodent studies, and 50 reviews were deemed relevant, covering 152 chemical exposures. The most frequently studied exposures in humans were particulate matter ([Formula: see text]), mercury ([Formula: see text]), nonspecific air pollution ([Formula: see text]), and lead ([Formula: see text]). In rodent studies, the most frequently studied exposures were chlorpyrifos ([Formula: see text]), mercury ([Formula: see text]), and lead ([Formula: see text]). DISCUSSION: Although research is growing rapidly, wide variability exists in study design and conduct, exposures investigated, and outcomes assessed. Conclusions focus on recommendations to guide development of best practices in epidemiology and toxicology, including greater harmonization across these fields of research to more quickly and efficiently identify chemicals of concern. In particular, we recommend chlorpyrifos, lead, and polychlorinated biphenyls (PCBs) be systematically reviewed in order to assess their relationship with the development of autism. There is a pressing need to move forward quickly and efficiently to understand environmental influences on autism in order to answer current regulatory questions and inform treatment and prevention efforts. https://doi.org/10.1289/EHP4386.

PFAS health effects database: Protocol for a systematic evidence map.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) confer waterproof, greaseproof, and non-stick properties when added to consumer products. They are also used for industrial purposes including in aqueous film forming foams for firefighting. PFAS are ubiquitous in the environment, are widely detected in human biomonitoring studies, and are of growing regulatory concern across federal, state, and local governments. Regulators, scientists, and citizens need to stay informed on the growing health and toxicology literature related to PFAS. OBJECTIVES: The goal of this systematic evidence map is to identify and organize the available health and toxicology related literature on a set of 29 PFAS of emerging and growing concern. SEARCH AND STUDY ELIGIBILITY: We will search the electronic database PubMed for health or toxicological studies on 29 PFAS of emerging concern. Eligible studies must contain primary research investigating the link between one or more of the PFAS of interest and a health effect, toxicological, or biological mechanistic endpoint. STUDY APPRAISAL AND SYNTHESIS METHODS: Title and abstract screening and full text review will require a single reviewer for inclusion to the next level and two independent reviewers for exclusion. Study quality will not be conducted for this evidence mapping. Study characteristics will be extracted and coded from the included studies and checked for accuracy by a second reviewer. The extracted and coded information will be visualized in a publicly available, interactive database hosted on Tableau Public. Results of the evidence mapping will be published in a narrative summary.

Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) has increased in prevalence in the past decade. Studies attempting to identify a specific genetic component have not been able to account for much of the heritability of ADHD, indicating there may be gene-environment interactions underlying the disorder, including early exposure to environmental chemicals. Based on several relevant studies, we chose to examine bisphenol A (BPA) as a possible contributor to ADHD in humans. BPA is a widespread environmental chemical that has been shown to disrupt neurodevelopment in rodents and humans. OBJECTIVES: Using the Office of Health Assessment and Translation (OHAT) framework, a systematic review and meta-analysis was designed to determine the relationship between early life exposure to BPA and hyperactivity, a key diagnostic criterion of ADHD. DATA SOURCES: Searches of PubMed, Web of Science, and Toxline were completed for all literature to January 1, 2017. STUDY ELIGIBILITY CRITERIA: For inclusion, the studies had to publish original data, be in the English language, include a measure of BPA exposure, and assess if BPA exposure affected hyperactive behaviors in mice, rats or humans. Exposure to BPA had to occur at <3 months of age for humans, up to postnatal day 35 for rats and up to postnatal day 40 for mice. Exposure could occur either gestationally (via maternal exposure) or directly to the offspring. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were evaluated using the OHAT risk of bias tool. The effects in humans were assessed qualitatively. For rodents exposed to 20 µg/kg/day BPA, we evaluated the study findings in a random effects meta-analytical model. RESULTS: A review of the literature identified 29 rodent and 3 human studies. A random effects meta-analysis showed significantly increased hyperactivity in male rodents. In humans, early BPA exposure was associated with hyperactivity in boys and girls. LIMITATIONS, CONCLUSIONS, AND IMPLICATIONS OF KEY FINDINGS: We concluded that early life BPA exposure is a presumed human hazard for the development of hyperactivity. Possible limitations of this systematic review include deficiencies in author reporting, exclusion of some literature based on language, and insufficient similarity between human studies. SRs that result in hazard-based conclusions are the first step in assessing and mitigating risks. Given the widespread exposure of BPA and increasing diagnoses of ADHD, we recommend immediate actions to complete such risk analyses and take next steps for the protection of human health. In the meantime, precautionary measures should be taken to reduce exposure in pregnant women, infants and children. The present analysis also discusses potential mechanisms by which BPA affects hyperactivity, and the most effective avenues for future research. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not available.

Melamine, beyond the kidney: A ubiquitous endocrine disruptor and neurotoxicant?

Melamine is commonly used in a variety of consumer products such as furniture, dining ware, and food utensils. The chemical infamously gained worldwide attention by its illegal addition to a variety of foodstuffs in order to falsify protein content, which led to serious, sometimes fatal, health impacts in children and pets. This resulted in a large amount of published primary studies and reviews of the impacts of melamine exposure on kidney function. However, a growing body of literature suggests that melamine may have impacts beyond renal dysfunction. We conducted a scoping review of this literature which yielded more than 40 studies with human, animal, and in vitro findings. Neurological impacts, reproductive function, and anthropometric outcomes were identified as possible candidates for systematic review based on evidence stream and replication of endpoints. The results of this analysis provide a basis for prioritizing future research on health impacts associated with melamine exposure.