Protocol for Developing the Fluoride Human Health Toxicity Assessment.

Abstract

Note: The US EPA has a new dedicated website on Fluoride in Drinking Water at
https://www.epa.gov/sdwa/fluoride-drinking-water

EXCERPTS FROM EPA’S NEW 186 PAGE REPORT:

Executive Summary

The U.S. Environmental Protection Agency (EPA) is committed to ensuring clean and safe drinking water for all Americans with the goal of protecting human health, including children’s health. The EPA Office of Water (OW) is developing a new Fluoride Human Health Toxicity Assessment (toxicity assessment herein) that will review the available scientific information on the health risks of fluoride exposure and determine the amount of fluoride that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects (i.e., toxicity value).

This Protocol for the Fluoride Human Health Toxicity Assessment (protocol herein) is the second step necessary for developing the toxicity assessment (Figure 1). The first planning step was the Preliminary Assessment Plan and Literature Survey for the Fluoride Human Health Toxicity Assessment (assessment plan herein) (U.S. EPA, 2026) that was released in January 2026. The protocol is an expanded version of the assessment plan. The protocol includes all of the content of the assessment plan (revised and updated to reflect feedback from the public) and additionally describes the methods that will be used to develop the toxicity assessment. The protocol is a methods document, not a toxicity assessment; it does not present the levels of fluoride exposure associated with harmful health effects. Determining these levels is part of the forthcoming draft toxicity assessment that will be developed according to the methods outlined in this protocol. The draft toxicity assessment will be released for public comment.

Toxicity assessments focus on determining the levels of exposure associated with potential harmful health effects of a contaminant to derive toxicity values that will protect against these harmful effects. Therefore, the Fluoride Human Health Toxicity Assessment will not consider beneficial effects of fluoride such as dental cavity prevention. Once final, the toxicity assessment can inform future steps under the Safe Drinking Water Act (SDWA). Although the EPA does not make recommendations about adding fluoride to drinking water, the final toxicity assessment could be used by the Centers for Disease Control and Prevention (CDC) to inform recommendations about the addition of fluoride to drinking water (United States Executive Office of the President Donald Trump, 2025).

Background. The EPA last evaluated the potential harmful health effects associated with fluoride exposure in 2010 (U.S. EPA, 2010a). In the EPA OW’s 2010 assessment, the EPA determined that severe dental fluorosis, characterized by abnormal tooth enamel development in children, was the most sensitive harmful human health effect (i.e., occurring at the lowest fluoride exposure levels), and therefore, the toxicity value for fluoride derived in that assessment was based on this harmful health effect. In the fourth iteration of the EPA’s process for reviewing existing drinking water regulations (Six-Year Review 4) (U.S. EPA, 2023a), the EPA concluded that the National Primary Drinking Water Regulation for fluoride was not a candidate for revision due to the need to evaluate emerging research on the association between fluoride exposure and neurodevelopment and cognition in children, which was under review by the National Toxicology Program (NTP) at that time. In its Six-Year Review 4 report, the EPA committed to considering the NTP (2024) report on fluoride exposure and neurodevelopment and cognition, when final, to inform development of an updated Fluoride Human Health Toxicity Assessment. The report by NTP was finalized in 2024 (NTP, 2024).

Following through on this commitment, the EPA is developing an updated Fluoride Human Health Toxicity Assessment, the objective of which is to determine the fluoride level that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects (known as a toxicity value—specifically, noncancer reference dose or RfD).

Protocol Objective. The objective of this protocol is to describe the approaches and the peer-reviewed human health risk assessment methodology that will be used to develop the toxicity assessment. The protocol outlines the scope of the toxicity assessment, including how key science issues related to fluoride exposure and health effects evaluations will be addressed. It includes some elements (Sections 2 to 4) that were previously described in the assessment plan and have been revised in response to public comment. The protocol also describes the systematic review methods and fluoride-specific considerations that will be used to identify and evaluate evidence and derive a toxicity value for fluoride. The methods described in the protocol include how the EPA will: 1) prioritize the most informative studies, using a combination of automated prioritization processes and manual screening; 2) evaluate fluoride-specific studies to identify the best available science; and 3) identify studies that will be most useful for dose-response analysis and toxicity value derivation.

Consideration of Public Comments. The EPA publicly released the assessment plan (U.S. EPA, 2026), which describes the information that will be included in the Fluoride Human Health Toxicity Assessment, for a 30-day public comment period. The EPA reviewed all public input received (approximately 1,000 comments), considered all comments, and incorporated relevant feedback into protocol development. A summary of the public comments that the EPA received on the assessment plan and the agency’s responses, including descriptions of how public comments informed protocol development, are provided in Appendix A.

Toxicity Assessment Scope. The protocol outlines the scoping and problem formulation for the Fluoride Human Health Toxicity Assessment that were described in the assessment plan, which have been revised for clarity in response to public comments. The scoping and problem formulation steps are intended to ensure the development of a focused, fit-for-purpose toxicity assessment. To help define scope, the EPA critically reviewed existing fluoride health effects assessments published by national and international agencies to evaluate their scientific conclusions about the types of harmful health effects associated with fluoride exposure. From this review, two well-established harmful health effects in children—dental fluorosis (i.e., abnormal tooth enamel development) and neurodevelopmental effects (i.e., abnormal brain development)—were identified as the most sensitive (i.e., occurring at the lowest exposure levels) harmful health effects associated with fluoride exposure (EFSA Scientific Committee, 2025; Health Canada, 2024; NTP, 2024; U.S. EPA, 2010b). The EPA has accepted these conclusions and will not repeat previous work to re-establish these hazards. However, this acceptance of hazard does not imply that the harmful effects occur at all doses or exposure levels. The EPA’s future Fluoride Human Health Toxicity Assessment will independently evaluate the health effects data and develop a dose-response analysis (i.e., an analysis of how harmful health effects (response) change with increasing dose or exposure). The dose-response analysis will determine the doses or exposure levels at which harmful effects occur. Many human studies on fluoride are available; therefore, the EPA’s toxicity assessment will focus only on human data.

The toxicity assessment will focus on systematically identifying the best available human studies on dental fluorosis and neurodevelopmental effects of fluoride exposure to derive a toxicity value. For toxicity value derivation, estimates of fluoride exposure reported in human studies (e.g., in drinking water, urine) need to be converted into values that represent a person’s daily fluoride intake to account for fluoride exposure from all potential sources, not just from drinking water. To determine daily fluoride intake, the EPA will ensure that fluoride exposure from sources other than drinking water is accounted for when examining toxicity values based on the concentration of fluoride in drinking water. Additionally, information on how fluoride moves through and is eliminated from the body will be incorporated into the toxicity value derivation process.

Literature Survey Results. As reported in the assessment plan, the EPA conducted a comprehensive, initial literature survey by conducting an initial search of the available published literature for studies on fluoride and reviewing the search results. Preliminary results of the survey were reported in the assessment plan, and full results are reported in this protocol. A total of 268,093 studies were identified. Machine learning-based artificial intelligence and other automated tools, in combination with manual review by scientific experts, were used to efficiently review the literature search results and identify studies most likely to be relevant to the toxicity assessment. Quality control checks were performed to ensure that the automated screening tools captured relevant studies. The studies prioritized through these methods then underwent further manual review by experts. The EPA identified 671 human studies examining fluoride exposure and dental fluorosis or adverse neurodevelopmental effects (e.g., cognition, behavior, and sensory/motor effects). The results of the preliminary literature survey are available for review via an interactive online application that allows users to search for, sort, and track the studies through each step of the survey. As outlined in this protocol, an updated literature search will be performed during toxicity assessment development to ensure that relevant studies published since the initial literature search can be incorporated into the toxicity assessment (Section 4.3).

Toxicity Assessment Methods. The protocol describes methods for conducting the steps of the future Fluoride Human Health Toxicity Assessment, including literature searching and screening; evaluation of studies and extraction of key information from them; dose-response analysis; and toxicity value derivation. The methods described in the protocol are consistent with agency guidance and peer-reviewed agency systematic review and human health risk assessment methodologies (U.S. EPA, 2022b, 2014a, b, 2012, 2011b, 2005, 2002b, 1998, 1996a, 1991). These methods identify the best available science in accordance with sound and objective scientific practices (SDWA 1412(b)(3)(A)(i) (U.S. EPA, 2019d)). The EPA’s systematic review methods ensure that agency assessments are transparent, reproducible, and uphold scientific integrity. They promote the use of the best available, unbiased, peer-reviewed studies. The methods are consistent with Gold Standard Science as defined in (United States Executive Office of the President Donald Trump, 2025).

Approaches specific to the Fluoride Human Health Toxicity Assessment are described throughout the protocol, including planned methods to address the key science issues described in Section 2.4. The objective of the toxicity assessment and specific steps the EPA will follow to accomplish the objective are outlined in Section 3. The literature search, prioritization, and screening methods (Section 4) are customized to the challenges involved in managing the large fluoride health effects database and the toxicity assessment scope. The refined evaluation plan (Section 5) describes how reviewers will identify the studies most likely to be relevant for dose-response analysis based on considerations specific to the future Fluoride Human Health Toxicity Assessment. For study evaluation of epidemiology studies (Section 6.2), fluoride- and outcome-specific criteria are provided to supplement the generic study evaluation considerations that are relevant to all exposures and outcomes. These criteria include explicit descriptions of how different exposure metrics (e.g., drinking water, biomarkers) are interpreted during study evaluation (relevant to key science issues on validity of exposure measures and completeness of exposure characterization). Fluoride-specific pharmacokinetic models and approaches for evaluating them are provided in Section 6.3 (relevant to key science issue on understanding pharmacokinetics of fluoride in the body). The approach to data extraction is described in Section 7. Lastly, Section 8 describes methods for dose-response analysis, including selection of studies and analytical methods, with fluoride-specific considerations throughout (relevant to key science issue of dental fluorosis adversity).

Next Steps. The EPA will develop a draft toxicity assessment according to the methods described in this protocol. The toxicity assessment will summarize the harmful health effects associated with fluoride exposure during pregnancy and childhood and will determine the amount of fluoride that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects (the RfD). The draft toxicity assessment will be released for external peer review and public comment (Figure 1). The EPA will consider the external peer review and public comments, revise the draft toxicity assessment as appropriate, and then publish a final toxicity assessment.

Figure 1. Steps in the Development of the Final Fluoride Human Health Toxicity Assessment

1. Introduction

The U.S. Environmental Protection Agency (EPA) Office of Water (OW) is developing an updated fluoride human health toxicity assessment (toxicity assessment herein) based on a systematic review of studies on harmful health effects associated with fluoride exposure (U.S. EPA, 2025b). The purpose of the toxicity assessment is to derive a final toxicity value for oral fluoride exposure, called a reference dose (RfD). An RfD is an estimate of the amount of a chemical (in this case, fluoride) that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects.

The first planning step in developing the toxicity assessment was publishing the Preliminary Assessment Plan and Literature Survey for the Fluoride Human Health Toxicity Assessment (assessment plan herein) (U.S. EPA, 2026) in January 2026 for a 30-day public comment period. The assessment plan described the EPA’s preliminary plan for developing the toxicity assessment, including the justification for conducting the toxicity assessment (background); intended scope or focus of the toxicity assessment (problem formulation); areas of scientific complexity (key science issues); toxicity assessment objectives (specific aims); the criteria that the EPA used to identify relevant data during the preliminary literature survey (literature search and screening); and results of the preliminary literature survey.

This Protocol for the Fluoride Human Health Toxicity Assessment (protocol herein) is an expanded version of the assessment plan and further describes how the toxicity assessment will be conducted. The protocol includes an overview of the assessment plan content (including revisions made in response to public comments) and additionally describes the methods for conducting the systematic review and dose-response analysis for the toxicity assessment. In developing the protocol, the EPA reviewed and considered all public comments received on the assessment plan during the 30-day public comment period (Appendix A).

Section Overview: The EPA is developing a fit-for-purpose toxicity assessment for fluoride. The toxicity assessment will determine the levels of fluoride exposure associated with harmful human health effects and will derive a toxicity value called an oral RfD. An RfD is an estimate of the amount of fluoride that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects. The oral RfD for fluoride may be used to inform future decisions about potential revisions to the existing fluoride drinking water standard under the Safe Drinking Water Act.

This document is the protocol, which is a roadmap for how the toxicity assessment will be conducted. The protocol includes the scope of the Fluoride Human Health Toxicity Assessment, which focuses on two harmful health effects in children related to fluoride exposure: dental fluorosis (which causes weakened tooth enamel and reduced tooth health) and effects on brain
development (such as lower IQ). The agency will use a rigorous, transparent, systematic process to identify and evaluate human studies that assess the relationship between fluoride exposure and dental fluorosis or brain development. This process allows the EPA to select the best available data to establish an oral RfD for fluoride.

The U.S. Environmental Protection Agency (EPA) Office of Water (OW) is developing an updated fluoride human health toxicity assessment (toxicity assessment herein) based on a systematic review of studies on harmful health effects associated with fluoride exposure (U.S. EPA, 2025b). The purpose of the toxicity assessment is to derive a final toxicity value for oral fluoride exposure, called a reference dose (RfD). An RfD is an estimate of the amount of a chemical (in this case, fluoride) that a person can ingest daily over a lifetime and be unlikely to experience harmful health effects.

The first planning step in developing the toxicity assessment was publishing the Preliminary Assessment Plan and Literature Survey for the Fluoride Human Health Toxicity Assessment (assessment plan herein) (U.S. EPA, 2026) in January 2026 for a 30-day public comment period. The assessment plan described the EPA’s preliminary plan for developing the toxicity assessment, including the justification for conducting the toxicity assessment (background); intended scope or focus of the toxicity assessment (problem formulation); areas of scientific complexity (key science issues); toxicity assessment objectives (specific aims); the criteria that the EPA used to identify relevant data during the preliminary literature survey (literature search and screening); and results of the preliminary literature survey.

This Protocol for the Fluoride Human Health Toxicity Assessment (protocol herein) is an expanded version of the assessment plan and further describes how the toxicity assessment will be conducted. The protocol includes an overview of the assessment plan content (including revisions made in response to public comments) and additionally describes the methods for conducting the systematic review and dose-response analysis for the toxicity assessment. In developing the protocol, the EPA reviewed and considered all public comments received on the assessment plan during the 30-day public comment period (Appendix A).

Acknowledgments

This document was prepared by the Drinking Water Science and Engineering Division (DWSED), Office of Ground Water and Drinking Water (OGWDW), Office of Water (OW) of the U.S. Environmental Protection Agency (EPA). The DWSED/OGWDW/OW authors of this protocol document include Laura Dishaw (protocol lead) and Carlye Austin (protocol co-lead), Elizabeth Radke (lead of the Fluoride Human Health Toxicity Assessment), Thomas Bateson (co-lead of the Fluoride Human Health Toxicity Assessment), Todd Zurlinden (co-lead of the Fluoride Human Health Toxicity Assessment), Michael Dzierlenga (lead for the response to public comments on the assessment plan), Krista Christensen (no longer at the EPA), Paige Bommarito, Rachel Shaffer, Czarina Cooper, Lindsey Foote, Brittany Jacobs, Alexandra Lee, Casey Lindberg, Kelsey Miller, Hongyu Ru, Marie Russell, Paul Schlosser, Avanti Shirke, Anthony Su, J. Michael Wright, and Erin Yost. The agency appreciates the important contributions from EPA scientists in the Office of Applied Science and Environmental Solutions (OASES), including Chris Brinkerhoff, Sarah Gallagher, Rebecca Nachman, and Deborah Segal. The agency is also thankful for the valuable management oversight and review provided by Colleen Flaherty, Susan Euling, and Terra Haxton.
The systematic literature search and screening included in this document was prepared in collaboration with ICF under the EPA Contract 68HERC23D0003. ICF contributors included Samantha Snow, Meredith Clemons, Sorina Eftim, Alexander Lindahl, Wren Tracy, and Janielle Vidal.

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