Recently Yee et al. published a commentary in the Annals,1 focusing on a meta-analysis of 74 human observational studies by Taylor et al. published in JAMA Pediatrics,2 which found an inverse association between fluoride exposure and children’s intelligence quotient (IQ). Although many of the authors’ critiques are directly addressed in Taylor et al. and in their previous commentary,3 the group would like to take this opportunity to respond.

[This corrects the article DOI: 10.1371/journal.pone.0296699.].

Importance:Previous meta-analyses suggest that fluoride exposure is adversely associated with children's IQ scores. An individual's total fluoride exposure comes primarily from fluoride in drinking water, food, and beverages. Objective:To perform a systematic review and meta-analysis of epidemiological studies investigating children's IQ scores and prenatal or postnatal fluoride exposure. Data Sources:BIOSIS, Embase, PsycInfo, PubMed, Scopus, Web of Science, CNKI, and Wanfang, searched through October 2023. Study Selection:Studies reporting children's IQ scores, fluoride exposure, and effect sizes. Data Extraction and Synthesis:Data were extracted into the Health Assessment Workplace Collaborative system. Study quality was evaluated using the OHAT risk-of-bias tool. Pooled standardized mean differences (SMDs) and regression coefficients were estimated with random-effects models. Main Outcomes and Measures:Children's IQ scores. Results:Of 74 studies included (64 cross-sectional and 10 cohort studies), most were conducted in China (n = 45); other locations included Canada (n = 3), Denmark (n = 1), India (n = 12), Iran (n = 4), Mexico (n = 4), New Zealand (n = 1), Pakistan (n = 2), Spain (n = 1), and Taiwan (n = 1). Fifty-two studies were rated high risk of bias and 22 were rated low risk of bias. Sixty-four studies reported inverse associations between fluoride exposure measures and children's IQ. Analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure (47 high risk of bias, 12 low risk of bias; n = 20 932 children) showed an inverse association between fluoride exposure and IQ (pooled SMD, -0.45; 95% CI, -0.57 to -0.33; P < .001). In 31 studies reporting fluoride measured in drinking water, a dose-response association was found between exposed and reference groups (SMD, -0.15; 95% CI, -0.20 to -0.11; P < .001), and associations remained inverse when exposed groups were restricted to less than 4 mg/L and less than 2 mg/L; however, the association was null at less than 1.5 mg/L. In analyses restricted to low risk-of-bias studies, the association remained inverse when exposure was restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in drinking water. In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, -0.15; 95% CI, -0.23 to -0.07; P < .001). Associations remained inverse when exposed groups were restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine; the associations held in analyses restricted to the low risk-of-bias studies. Analysis of 13 studies with individual-level measures found an IQ score decrease of 1.63 points (95% CI, -2.33 to -0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among low risk-of-bias studies, there was an IQ score decrease of 1.14 points (95% CI, -1.68 to -0.61; P < .001). Associations remained inverse when stratified by risk of bias, sex, age, outcome assessment type, country, exposure timing, and exposure matrix. Conclusions and Relevance:This systematic review and meta-analysis found inverse associations and a dose-response association between fluoride measurements in urine and drinking water and children's IQ across the large multicountry epidemiological literature. There were limited data and uncertainty in the dose-response association between fluoride exposure and children's IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L. These findings may inform future comprehensive public health risk-benefit assessments of fluoride exposures.

Environmental exposures significantly influence cancer risk, but their mutational impact remains unclear. We perform whole-exome sequencing of hepatocellular carcinomas (HCCs) from B6C3F1/N mice that arise spontaneously with age (2 years old) or following chronic exposure to one of ten potential human carcinogens that operate through genotoxic or non-genotoxic mechanisms. HCCs from mice exposed to drinking water disinfection byproducts, such as bromochloroacetic acid (BCA) and bromodichloroacetic acid (BDCA), show dose-dependent increases in mutational burden, distinct mutational signatures (BCA-mSBS12 and BDCA-mSBS25), and enrichment of the aTn→aCn mutational motif. In contrast, HCCs from other exposures, as well as from spontaneous tumors, show comparable mutational burdens, mutational signatures, and enrichment of the nCg→nTg mutational motif. These findings suggest that many environmental carcinogens promote tumorigenesis by amplifying endogenous mutagenic processes rather than initiating distinct mutational events. Our results highlight the utility of rodent models for investigating environmental carcinogenesis and provide insights relevant to human cancer risk assessment.

ImportancePrevious meta-analyses suggest that fluoride exposure is adversely associated with children’s IQ scores. An individual’s total fluoride exposure comes primarily from fluoride in drinking water, food, and beverages.ObjectiveTo perform a systematic review and meta-analysis of epidemiological studies investigating children’s IQ scores and prenatal or postnatal fluoride exposure.Data SourcesBIOSIS, Embase, PsycInfo, PubMed, Scopus, Web of Science, CNKI, and Wanfang, searched through October 2023.Study SelectionStudies reporting children’s IQ scores, fluoride exposure, and effect sizes.Data Extraction and SynthesisData were extracted into the Health Assessment Workplace Collaborative system. Study quality was evaluated using the OHAT risk-of-bias tool. Pooled standardized mean differences (SMDs) and regression coefficients were estimated with random-effects models.Main Outcomes and MeasuresChildren’s IQ scores.ResultsOf 74 studies included (64 cross-sectional and 10 cohort studies), most were conducted in China (n = 45); other locations included Canada (n = 3), Denmark (n = 1), India (n = 12), Iran (n = 4), Mexico (n = 4), New Zealand (n = 1), Pakistan (n = 2), Spain (n = 1), and Taiwan (n = 1). Fifty-two studies were rated high risk of bias and 22 were rated low risk of bias. Sixty-four studies reported inverse associations between fluoride exposure measures and children’s IQ. Analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure (47 high risk of bias, 12 low risk of bias; n = 20 932 children) showed an inverse association between fluoride exposure and IQ (pooled SMD, −0.45; 95% CI, −0.57 to −0.33; P < .001). In 31 studies reporting fluoride measured in drinking water, a dose-response association was found between exposed and reference groups (SMD, −0.15; 95% CI, −0.20 to −0.11; P < .001), and associations remained inverse when exposed groups were restricted to less than 4 mg/L and less than 2 mg/L; however, the association was null at less than 1.5 mg/L. In analyses restricted to low risk-of-bias studies, the association remained inverse when exposure was restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in drinking water. In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, −0.15; 95% CI, −0.23 to −0.07; P < .001). Associations remained inverse when exposed groups were restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine; the associations held in analyses restricted to the low risk-of-bias studies. Analysis of 13 studies with individual-level measures found an IQ score decrease of 1.63 points (95% CI, −2.33 to −0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among low risk-of-bias studies, there was an IQ score decrease of 1.14 points (95% CI, –1.68 to –0.61; P < .001). Associations remained inverse when stratified by risk of bias, sex, age, outcome assessment type, country, exposure timing, and exposure matrix.Conclusions and RelevanceThis systematic review and meta-analysis found inverse associations and a dose-response association between fluoride measurements in urine and drinking water and children’s IQ across the large multicountry epidemiological literature. There were limited data and uncertainty in the dose-response association between fluoride exposure and children’s IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L. These findings may inform future comprehensive public health risk-benefit assessments of fluoride exposures.

We recently completed a comprehensive systematic review of the literature on fluoride exposure and neurodevelopment and cognition, resulting in two publications. The 2024 National Toxicology Program Monograph concluded-with moderate confidence-that higher fluoride exposure is associated with lower IQ in children. The 2025 meta‑analysis, published in JAMA Pediatrics, quantitatively synthesized over 70 epidemiological studies and likewise reported an inverse association between fluoride exposure and children's IQ. This inverse association persisted when analyses were restricted to the best evidence, the high‑quality studies, and was consistent across subgroups defined by sex, age, country, outcome assessment method, timing of exposure, and exposure matrix (e.g., urine or drinking water). Notably, among the high‑quality evidence, inverse associations were still observed at fluoride exposure levels below 1.5 mg/L, based on both urinary and drinking‑water measurements. These publications have received considerable public and media attention, prompted healthy scientific discourse, and have been cited by public health decision‑makers. Many scientific comments were carefully considered and resolved during development and peer review, which contributed to the rigor of the final documents. However, some recurrent critiques continue to be raised. This viewpoint provides a high‑level summary of these key critiques and corresponding responses to help the public, media, and the scientific community better understand the strength and implications of the scientific evidence on fluoride exposures and neurodevelopment and cognition.

Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent with apical end point BMDs, opening the door to using molecular BMDs to derive human health-based guidance values for chemical exposure. Metabolomics measures the responses of small-molecule endogenous metabolites to chemical exposure, complementing transcriptomics by characterizing downstream molecular phenotypes that are more closely associated with apical end points. The aim of this study was to apply BMD modeling to in vivo metabolomics data, to compare metabolic BMDs to both transcriptional and apical end point BMDs. This builds upon our previous application of transcriptomics and BMD modeling to a 5-day rat study of triphenyl phosphate (TPhP), applying metabolomics to the same archived tissues. Specifically, liver from rats exposed to five doses of TPhP was investigated using liquid chromatography-mass spectrometry and 1H nuclear magnetic resonance spectroscopy-based metabolomics. Following the application of BMDExpress2 software, 2903 endogenous metabolic features yielded viable dose-response models, confirming a perturbation to the liver metabolome. Metabolic BMD estimates were similarly sensitive to transcriptional BMDs, and more sensitive than both clinical chemistry and apical end point BMDs. Pathway analysis of the multiomics data sets revealed a major effect of TPhP exposure on cholesterol (and downstream) pathways, consistent with clinical chemistry measurements. Additionally, the transcriptomics data indicated that TPhP activated xenobiotic metabolism pathways, which was confirmed by using the underexploited capability of metabolomics to detect xenobiotic-related compounds. Eleven biotransformation products of TPhP were discovered, and their levels were highly correlated with multiple xenobiotic metabolism genes. This work provides a case study showing how metabolomics and transcriptomics can estimate mechanistically anchored points-of-departure. Furthermore, the study demonstrates how metabolomics can also discover biotransformation products, which could be of value within a regulatory setting, for example, as an enhancement of OECD Test Guideline 417 (toxicokinetics).

The cancer hazard associated with lifetime exposure to radiofrequency radiation (RFR) was examined in Sprague Dawley (SD) rats at the Ramazzini Institute (RI), Italy. There were increased incidences of gliomas and cardiac schwannomas. The translational relevance of these rare rat tumors for human disease is poorly understood. We examined the genetic alterations in RFR-derived rat tumors through molecular characterization of important cancer genes relevant for human gliomagenesis. A targeted next-generation sequencing (NGS) panel was designed for rats based on the top 23 orthologous human glioma-related genes. Single-nucleotide variants (SNVs) and small insertion and deletions (indels) were characterized in the rat gliomas and cardiac schwannomas. Translational relevance of these genetic alterations in rat tumors to human disease was determined through comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) database. These data suggest that rat gliomas resulting from life-time exposure to RFR histologically resemble low grade human gliomas but surprisingly no mutations were detected in rat gliomas that had homology to the human IDH1 p.R132 or IDH2 p.R172 suggesting that rat gliomas are primarily wild-type for IDH hotspot mutations implicated in human gliomas. The rat gliomas appear to share some genetic alterations with IDH1 wildtype human gliomas and rat cardiac schwannomas also harbor mutations in some of the queried cancer genes. These data demonstrate that targeted NGS panels based on tumor specific orthologous human cancer driver genes are an important tool to examine the translational relevance of rodent tumors resulting from chronic/life-time rodent bioassays.

Throughput needs, costs of time and resources, and concerns about the use of animals in hazard and safety assessment studies are fueling a growing interest in adopting new approach methodologies for use in product development and risk assessment. However, current efforts to define "next-generation risk assessment" vary considerably across commercial and regulatory sectors, and an a priori definition of the biological scope of data needed to assess hazards is generally lacking. We propose that the absence of clearly defined questions that can be answered during hazard assessment is the primary barrier to the generation of a paradigm flexible enough to be used across varying product development and approval decision contexts. Herein, we propose a biological questions-based approach (BQBA) for hazard and safety assessment to facilitate fit-for-purpose method selection and more efficient evidence-based decision-making. The key pillars of this novel approach are bioavailability, bioactivity, adversity, and susceptibility. This BQBA is compared with current hazard approaches and is applied in scenarios of varying pathobiological understanding and/or regulatory testing requirements. To further define the paradigm and key questions that allow better prediction and characterization of human health hazard, a multidisciplinary collaboration among stakeholder groups should be initiated.

BACKGROUND:The Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA) was a collaborative research effort to better link academic research with governmental guideline studies. This review explores the secondary goal of CLARITY-BPA: to identify endpoints or technologies from CLARITY-BPA and prior/concurrent literature from these laboratories that may enhance the capacity of rodent toxicity studies to detect endocrine disrupting chemicals (EDCs).METHODS:A systematic literature search was conducted with search terms for BPA and the CLARITY-BPA participants. Relevant studies employed a laboratory rodent model and reported results on 1 of the 10 organs/organ systems evaluated in CLARITY-BPA (brain and behavior, cardiac, immune, mammary gland, ovary, penile function, prostate gland and urethra, testis and epididymis, thyroid hormone and metabolism, and uterus). Study design and findings were summarized, and a risk-of-bias assessment was conducted.RESULTS:Several endpoints and methods were identified as potentially helpful to detect effects of EDCs. For example, molecular and quantitative morphological approaches were sensitive in detecting alterations in early postnatal development of the brain, ovary, and mammary glands. Hormone challenge studies mimicking human aging reported increased susceptibility of the prostate to disease following developmental BPA exposure. Statistical analyses for nonmonotonic dose responses, and computational approaches assessing multiple treatment-related outcomes concurrently in linked hormone-sensitive organ systems, reported effects at low BPA doses.CONCLUSIONS:This review provided an opportunity to evaluate the unique insights provided by nontraditional assessments in CLARITY-BPA to identify technologies and endpoints to enhance detection of EDCs in future studies.

Objectives: The objective of the study is to present the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) conceptual approach to the assessment of certainty of evidence from modeling studies (i.e., certainty associated with model outputs). Study Design and Setting: Expert consultations and an international multidisciplinary workshop informed development of a conceptual approach to assessing the certainty of evidence from models within the context of systematic reviews, health technology assessments, and health care decisions. The discussions also clarified selected concepts and terminology used in the GRADE approach and by the modeling community. Feedback from experts in a broad range of modeling and health care disciplines addressed the content validity of the approach. Results: Workshop participants agreed that the domains determining the certainty of evidence previously identified in the GRADE approach (risk of bias, indirectness, inconsistency, imprecision, reporting bias, magnitude of an effect, dose-response relation, and the direction of residual confounding) also apply when assessing the certainty of evidence from models. The assessment depends on the nature of model inputs and the model itself and on whether one is evaluating evidence from a single model or multiple models. We propose a framework for selecting the best available evidence from models: 1) developing de novo, a model specific to the situation of interest, 2) identifying an existing model, the outputs of which provide the highest certainty evidence for the situation of interest, either "off-the-shelf'' or after adaptation, and 3) using outputs from multiple models. We also present a summary of preferred terminology to facilitate communication among modeling and health care disciplines. Conclusion: This conceptual GRADE approach provides a framework for using evidence from models in health decision-making and the assessment of certainty of evidence from a model or models. The GRADE Working Group and the modeling community are currently developing the detailed methods and related guidance for assessing specific domains determining the certainty of evidence from models across health care-related disciplines (e.g., therapeutic decision-making, toxicology, environmental health, and health economics). (C) 2020 Published by Elsevier Inc.

The cancer hazard associated with exposure to cell phone radiofrequency radiation (RFR) was examined using lifetime exposure in Sprague-Dawley (SD) rats at the Ramazzini Institute (RI), Italy. There were increased incidences of gliomas in the brain and schwannomas in the heart. In order to understand the translational relevance of these rat tumors for human disease, we examined the top 23 orthologous cancer genes mutated in human gliomas using a custom built a next-generation sequencing gene panel for rats based on Illumina’s TruSeq Custom Amplicon Technology. SD rat tissues (gliomas =15; cardiac schwannomas=9, interim (1 year) sacrificed non-tumor brain tissues from RFR exposed rats =30, control brain and heart control tissues from lifetime exposure=10 each, and age-matched control brain tissues from interim sacrificed rats=10) from the RI-RFR cancer bioassay were examined in this study. The deepSNV R-package with various filtering criteria and the read depth of >1000x were used to identify single-nucleotide variants (SNVs) in the rat gliomas and schwannomas. At 5% allelic frequency, there were an average of 43 SNVs per rat glioma and point mutations were detected in 9 genes (Arid1a, Cic, Tert promoter, Tp53, Atrx, Nf1, Pdgfra, Pi3kr1, and Setd2) in at least 3 or more rat gliomas based on population frequency. Five genes (Nf1, Tert promoter, Setd2, Arid1a, and Pdgfra) harbored SNVs in interim sacrificed brain tissues that were also present in RFR-exposed gliomas from lifetime exposure. Interestingly, no mutations were detected in hotspot regions of Idh1, Idh2, Egfr or Braf. In contrast to most human gliomas which harbor mutations in IDH1 and IDH2 genes, the rat gliomas seem to be Idh1 wild type with mutations in the other glioma-related genes. Primary cardiac tumors are extremely rare in humans. With this targeted NGS panel (at allelic frequency of 2.5%), there were an average of 146 SNVs per rat cardiac schwannoma and unique point mutations were detected in Cic, Egfr, Arid1a, Nf1, Setd2, Cdkn2a, Erbb2, Atrx, Pdgfra, and Notch1 in 3 or more cardiac schwannomas. A subset of the SNVs (Arid1a, Tp53, and Nf1) in rat gliomas was confirmed in human gliomas in the COSMIC database supporting the translational relevance of the rat gliomas for human disease. In addition, several SNVs from rat gliomas and cardiac schwannomas were found in various human cancers including carcinomas, hematopoietic neoplasms, melanomas and neuroendocrine tumors. In conclusion, the rat gliomas appear to share genetic alterations with a subtype of IDH1 wildtype human gliomas and rat primary cardiac schwannomas also harbor mutations in some of the queried cancer genes. Citation Format: Ramesh C. Kovi, Andrea Vornoli, Ashley Brooks, Thai Vu T. Ton, Miaofei Xu, Eva Tibaldi, Federica Gnudi, Jian-Liang Li, Robert C. Sills, John R. Bucher, Fiorella Belpoggi, Arun R. Pandiri. Genetic profiling of rat gliomas and cardiac schwannomas from cell phone radiofrequency radiation exposure using a targeted next-generation sequencing gene panel [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-084.

A 5-day in vivo rat model was evaluated as an approach to estimate chemical exposures that may pose minimal risk by comparing benchmark dose (BMD) values for transcriptional changes in the liver and kidney to BMD values for toxicological endpoints from traditional toxicity studies. Eighteen chemicals, most having been tested by the National Toxicology Program in 2-year bioassays, were evaluated. Some of these chemicals are potent hepatotoxicants (eg, DE71, PFOA, and furan) in rodents, some exhibit toxicity but have minimal hepatic effects (eg, acrylamide and alpha,beta-thujone), and some exhibit little overt toxicity (eg, ginseng and milk thistle extract) based on traditional toxicological evaluations. Male Sprague Dawley rats were exposed once daily for 5 consecutive days by oral gavage to 8-10 dose levels for each chemical. Liver and kidney were collected 24 h after the final exposure and total RNA was assayed using high-throughput transcriptomics (HTT) with the rat S1500(+) platform. HTT data were analyzed using BMD Express 2 to determine transcriptional gene set BMD values. BMDS was used to determine BMD values for histopathological effects from chronic or subchronic toxicity studies. For many of the chemicals, the lowest transcriptional BMDs from the 5-day assays were within a factor of 5 of the lowest histopathological BMDs from the toxicity studies. These data suggest that using HTT in a 5-day in vivo rat model provides reasonable estimates of BMD values for traditional apical endpoints. This approach may be useful to prioritize chemicals for further testing while providing actionable data in a timely and cost-effective manner.

The National Toxicology Program tested two common radiofrequency radiation (RFR) modulations emitted by cellular telephones in a 2-year rodent cancer bioassay that included interim assessments of additional animals for genotoxicity endpoints. Male and female Hsd:Sprague Dawley SD rats and B6C3F1/N mice were exposed from Gestation day 5 or Postnatal day 35, respectively, to code division multiple access (CDMA) or global system for mobile modulations over 18 hr/day, at 10-min intervals, in reverberation chambers at specific absorption rates of 1.5, 3, or 6 W/kg (rats, 900 MHz) or 2.5, 5, or 10 W/kg (mice, 1,900 MHz). After 19 (rats) or 14 (mice) weeks of exposure, animals were examined for evidence of RFR-associated genotoxicity using two different measures. Using the alkaline (pH > 13) comet assay, DNA damage was assessed in cells from three brain regions, liver cells, and peripheral blood leukocytes; using the micronucleus assay, chromosomal damage was assessed in immature and mature peripheral blood erythrocytes. Results of the comet assay showed significant increases in DNA damage in the frontal cortex of male mice (both modulations), leukocytes of female mice (CDMA only), and hippocampus of male rats (CDMA only). Increases in DNA damage judged to be equivocal were observed in several other tissues of rats and mice. No significant increases in micronucleated red blood cells were observed in rats or mice. In conclusion, these results suggest that exposure to RFR is associated with an increase in DNA damage. Environ. Mol. Mutagen. 61:276–290, 2020. © 2019 Wiley Periodicals, Inc.

Since 2009, the Tox21 project has screened similar to 8500 chemicals in more than 70 high-throughput assays, generating upward of 100 million data points, with all data publicly available through partner websites at the United States Environmental Protection Agency (EPA), National Center for Advancing Translational Sciences (NCATS), and National Toxicology Program (NTP). Underpinning this public effort is the largest compound library ever constructed specifically for improving understanding of the chemical basis of toxicity across research and regulatory domains. Each Tox21 federal partner brought specialized resources and capabilities to the partnership, including three approximately equal-sized compound libraries. All Tox21 data generated to date have resulted from a confluence of ideas, technologies, and expertise used to design, screen, and analyze the Tox21 10K library. The different programmatic objectives of the partners led to three distinct, overlapping compound libraries that, when combined, not only covered a diversity of chemical structures, use-categories, and properties but also incorporated many types of compound replicates. The history of development of the Tox21 "10K" chemical library and data workflows implemented to ensure quality chemical annotations and allow for various reproducibility assessments are described. Cheminformatics profiling demonstrates how the three partner libraries complement one another to expand the reach of each individual library, as reflected in coverage of regulatory lists, predicted toxicity end points, and physicochemical properties. ToxPrint chemotypes (CTs) and enrichment approaches further demonstrate how the combined partner libraries amplify structure-activity patterns that would otherwise not be detected. Finally, CT enrichments are used to probe global patterns of activity in combined ToxCast and Tox21 activity data sets relative to test-set size and chemical versus biological end point diversity, illustrating the power of CT approaches to discern patterns in chemical-activity data sets. These results support a central premise of the Tox21 program: A collaborative merging of programmatically distinct compound libraries would yield greater rewards than could be achieved separately.

BACKGROUND:Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge. OBJECTIVES:Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied. METHODS:We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment. DISCUSSION:Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro, in silico, and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745.