The National Toxicology Program
Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects (“Review”)
• The NTP Reviews
• Fluoride Action Network’s submissions
• Documents, News Articles, and Videos
• The Peer-Reviewers
The 2 Draft NTP Reviews
This first National Toxicology Program (NTP) Review was initiated in response to a nomination from the Fluoride Action Network (FAN). The NTP began the Review in 2016 and produced its first draft in 2019. This draft was sent to the National Academies of Sciences, Engineering and Medicine (NASEM) for peer-review. In response, the NASEM recommended that NTP make several changes.
The conclusion of NTP’s first 2019 draft Review, page 2, was:
NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a consistent pattern of findings in human studies across several different populations showing that higher fluoride exposure is associated with decreased IQ or other cognitive impairments in children. However, the consistency is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water).
On September 16, 2020, NTP sent their second draft review to NASEM, incorporating the changes they requested. The members of the NASEM committee to peer-review the Review are available here.
The conclusion of NTP’s 2020 second draft Review, page 2, was:
NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a moderate level of evidence that shows a consistent and robust pattern of findings in human studies across several different populations demonstrating that higher fluoride exposure (e.g., >1.5 mg/L in drinking water) is associated with lower IQ and other cognitive effects in children. Limited and weaker evidence is considered to provide an inadequate level of evidence that fluoride is associated with cognitive effects in adults.
What is a “presumed” rating?
The NTP used the OHAT* method for rating fluoride’s hazard. The five ratings are: Known, Presumed, Suspected, Not classifiable, or Not identified to be a hazard to humans.
The NTP rating of “presumed” is the highest confidence rating without doing a controlled human experiment, which would be illegal.
Comparison of NTP monographs for other chemicals found only the chemical warfare agent Sarin to receive the confidence rating “known hazard” and that was because there were controlled human experiments.
* OHAT is the abbreviation for Office of Health Assessment and Translation, which is within the Division of the National Toxicology Program at the National Institute of Environmental Health Sciences.
Fluoride Action Network’s submissions
The Director of FAN, Paul Connett, PhD, noted in his comments submitted to NASEM,
Chris Neurath, research director for FAN submitted substantive comments to both NASEM and the NTP on the 2020 Review (see all his submissions at the bottom).
Chris identifies with specificity the downgrading of evidence in the Review in his full submission with tables and figures. It will shock those who have read the literature to learn that the NTP Review excluded the Bashash 20171 study.
Downgraded evidence in the 2020 Review:
• Excluded the largest effect in the strongest study: Bashash 2017.
• Excluded strongest low-dose studies from dose-response meta-analysis.
• Unnecessary division of studies lowers power in dose-response meta-analyses.
• Simplistic exposure assessment underestimates hazard at doses relevant to US.
• NTP’s simplistic dose-response meta-analysis methods underestimated effects at low doses because they used the mean exposure while most studies had individual-level exposures that ranged well below the mean.
• Improperly downgraded the animal evidence to “inadequate” despite the NTP 2016 review of the animal evidence concluding it was “low to moderate”.
• The NTP monograph deviated from the OHAT guidelines in its section “Generalizability to the U.S. Population”.
• Meta-analyses have inadequate documentation.
Connett noted in his comments,
Chris Neurath identified the following strengths and weaknesses of the 2020 Review:
• The revised and updated review has identified substantially more higher quality studies with the number going from 18 to 29.
• Of the 29 higher quality studies, 27 found statistically significant adverse effects, which is a very high degree of consistency.
• The NTP has addressed recommendations of both NASEM and FAN to improve the clarity and validity of quality scoring methods.
• The addition of meta-analyses also improves clarity of the evidence.
• The conclusion of “presumed developmental neurotoxity” has thus grown substantially stronger and is solidly supported by the body of evidence.
• Our written submission has detailed discussion of weaknesses.
• By far the greatest weakness is the ad hoc section titled “Generalizability to the US Population”. This is, in effect, a risk assessment requiring a valid exposure assessment and dose-response assessment, but NTP has done neither. The NTP’s methods led to an underestimate of the confidence that fluoride causes harm at exposures below 1.5 mg/L.
• The NTP made the fundamental error of equating drinking water concentration with internal dose.
• The NTP’s exposure assessment consisted of a single one-sentence footnote referenced to a CDC database that is restricted and not available to the public.
• There was no proper dose-response assessment. The only planned dose-response assessment was a dose-response meta-analysis, yet it was not carried out for the 10 highest quality studies with individual-level exposure data. These 10 highest quality studies were also those finding affects at the lowest doses. The failure to conduct a dose-response meta-analysis on the strongest studies at low doses leads to a severe underestimate of the confidence of adverse effects at low doses.
• For the dose-response meta-analysis of group-level studies, NTP improperly used just the mean doses to define doses, even though many studies had a wide range of exposures in each exposure group, including exposures that fell below the cut-off level 1.5 mg/L.
• We are conducting a dose-response meta-analysis with the 10 individual-level studies and will supply it to the NAS.
• When proper dose-response assessments are made with the 29 higher quality studies, we found remarkable consistency of adverse effects. 18 studies were at exposures below 1.5 mg/L and 17 of those found adverse effects.
• Therefore, the evidence below 1.5 mg/L is as strong and consistent as that above 1.5 mg/L.
• Finally, a fundamental goal of the OHAT systematic review method is to ensure consistency of NTP evaluations across different chemicals.
Chris concluded this list with,
• When comparing the fluoride monograph to those for other chemicals we find a dramatic double standard, with fluoride needing to pass a far higher bar to reach a conclusion of presumed hazard than other chemicals.
• We believe the NASEM committee and NTP must take a larger perspective and ensure fluoride is treated in the same way as any other chemical being evaluated by NTP.
Documents on NTP’s Review
Documents and Submissions
The Peer-Reviewers of the NTP Review:
David A. Savitz (chair) is professor of epidemiology and Associate Dean for Research at the Brown University School of Public Health, with joint appointments in obstetrics and gynecology and pediatrics at the Alpert Medical School. He was also vice president of research at the university from 2013-2017. His epidemiological research has addressed a wide array of important public health issues, including environmental hazards in the workplace and community, reproductive health outcomes, and environmental influences on cancer. He has worked extensively on health effects of nonionizing radiation, pesticides, drinking water treatment byproducts, and perfluorinated compounds. Before joining Brown University, Dr. Savitz held appointments as the Charles W. Bluhdorn Professor of Community and Preventive Medicine at Mount Sinai School of Medicine and a professor at the University of North Carolina School of Public Health. He was president of the Society for Epidemiologic Research and the Society for Pediatric and Perinatal Epidemiologic Research and was a North American Regional Councilor for the International Epidemiological Association. Dr. Savitz was elected to the National Academy of Medicine in 2007. Dr. Savitz received his MS in preventive medicine from the Ohio State University and his PhD in epidemiology from the University of Pittsburgh Graduate School of Public Health.
Germaine M. Buck Louis is dean of the College of Health and Human Services at George Mason University. Her research has addressed a mixture of environmental exposures, including endocrine disruptors, stress, diet, and physical activity in relation to a spectrum of reproductive outcomes in men and women. She was an early pioneer in the application of the exposome research paradigm for understanding environmental influences on human fecundity and fertility impairments. Before joining the university, Dr. Louis was the director for the Division of Intramural Population Health Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, where she led population health scientists in designing research aimed at enhancing the health and well-being of fetuses, pregnant women, children, and young adults. She has served the National Academies, Pan American Health Organization, U.S. Environmental Protection Agency, and World Health Organization in various roles. She is a former president of the Society of Pediatric and Perinatal Epidemiologic Research and of the Society for Epidemiologic Research and has served on the boards for the American College of Epidemiology and the International Society for Environmental Epidemiology. Dr. Louis received her PhD in epidemiology from the State University of New York at Buffalo.
Kevin Crofton is principal and consultant at R3 Fellows, LLC. Previously, he worked for more than 30 years as a developmental neurotoxicologist at the Environmental Protection Agency in the National Center for Computational Toxicology in the Office of Research and Development where he served as Deputy Director. Dr. Crofton also served as an adjunct associate professor at North Carolina State University and University of North Carolina. His research interests include developmental neurotoxicity with an emphasis on understanding the consequences of endocrine disruption on neurodevelopment. He received the U.S. Environmental Protection Agency’s Distinguished Career Service Award. He served as a councilor for the International Neurotoxicology Association and the President for the Neurotoxicology Section at the Society for Toxicology. Dr. Crofton received an MS in toxicology from Miami University and his PhD in toxicology from the University of North Carolina at Chapel Hill.
Akhgar Ghassabian is an investigator and assistant professor in Departments of Pediatrics, Population Health, and Environmental Medicine at the New York University (NYU) School of Medicine. Her research interests focus on identifying environmental exposures that contribute to the etiology of developmental disabilities in childhood. Before joining NYU, Dr. Ghassabian was the intramural research training award fellow at the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health. During her doctoral and postdoctoral training, Dr. Ghassabian was involved in birth cohort studies in Europe and in the United States. She was a collaborator on European epidemiological consortia examining the effect of nutrition and air pollution on children’s neurodevelopment. Dr. Ghassabian was the recipient of the Rubicon Award from the Netherlands Organization for Scientific Research in 2014 and the Robin/Guze Young Investigator Award from the American Psychopathological Association in 2019. She obtained her MD from Tehran University of Medical Sciences and a PhD in epidemiology at Erasmus University Rotterdam, the Netherlands.
Judith B. Klotz is an affiliate faculty member in the Department of Occupational and Environmental Health at the Dornsife School of Public Health, Drexel University, and an adjunct associate professor in the Department of Epidemiology at the Rutgers School of Public Health. She is member of the Health Effects Committee of the New Jersey Drinking Water Quality Institute and of the Public Health standing committee of the Science Advisory Board, both advisory groups of the New Jersey Department of Environmental Protection. Dr. Klotz has served on several National Academies Committees, including the Subcommittee on Fluoride in Drinking Water and the Committee on the Review of the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens. She received her MS in genetics from the University of Michigan and her DrPH in environmental health sciences from Columbia University.
Juleen Lam is an assistant professor in the Department of Health Sciences at the California State University, East Bay. She is also an affiliate researcher in the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of California at San Francisco, School of Medicine. Her research interests are in environmental epidemiology, evaluation of population exposures to environmental contaminants, assessment and communication of environmentalrisks, and reproductive and developmental health. She specializes in analysis of environmental health data and development and application of risk assessment methods. Of particular note, Dr. Lam has been involved in the development of systematic review methods for environmental health data and has been a pivotal role in implementing, publishing, and disseminating these approaches in academic and government settings. She is a member of the US Environmental Protection Agency Board of Scientific Counselors Chemical Safety for Sustainability Subcommittee. She is currently serving on the National Academies Committee to Review DOD’s Approach to Deriving an Occupational Exposure Limit for TCE. She received her MS in environmental engineering management from George Washington University and her MHS in biostatistics and PhD in environmental health policy from the Johns Hopkins University Bloomberg School of Public Health.
Pamela J. Lein is a professor of neurotoxicology in the Department of Molecular Biosciences at the University of California, Davis, School of Veterinary Medicine. Her research interests are in how environmental stressors interact with genetic susceptibilities to influence the risk and severity of neurodevelopmental disorders and neurodegeneration. Because altered patterns of connectivity are associated with neurological deficits, her research focuses on investigating how environmental contaminants, chemical convulsants, and inflammation perturb neuronal connectivity as determined using biochemical, morphogenic, and electrophysiological end points. Her group is also developing biomarkers of organophosphate neurotoxicity and testing novel therapeutic approaches for protecting against the neurodegenerative effects associated with neurotoxic proconvulsants. Dr. Lein was a member of the National Academies Committee to Review Report on Long-Term Health Effects on Army Test Subjects. She received her MS in environmental health from East Tennessee State University and her PhD in pharmacology and toxicology from the State University of New York at Buffalo.
Michael L. Pennell is associate professor in the Division of Biostatistics in the College of Public Health at The Ohio State University. His research interests are in nonparametric Bayes, first hitting time models for survival analysis; design and analysis of Group Randomized Trials; joint modeling outcomes of different scales; statistical methods in toxicological risk assessment; and statistical applications in biomedical research, including cancer control, pathology, and veterinary medicine. Dr. Pennell has served as an ad hoc member of US Environmental Protection Agency (EPA) Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel, the EPA Science Advisory Board on trichloroethylene and Libby Amphibole Asbestos, and the Chemical Safety Advisory Subcommittee for 1-bromopropane. He currently serves on the National Academies Committee to Evaluate the IRIS Protocol for Inorganic Arsenic. He received his MS and PhD in biostatistics from the University of North Carolina at Chapel Hill.
Craig Steinmaus is an associate adjunct professor of epidemiology at the University of California Berkeley (UCB). He is also a public health medical officer III at the California Environmental Protection Agency (CalEPA) and is the UCB director of the Arsenic Health Effects Research Group. He is a board-certified physician with over 12 years of patient-care experience. His epidemiologic research has involved studies of drinking water contaminants with a focus on early-life exposure and other factors conferring susceptibility. He also teaches graduate courses on epidemiology, causal inference, and systematic review at UCB and at the University of California San Francisco. Dr. Steinmaus has served on several study sections of the National Institutes of Health and Centers for Disease Control and Prevention and is currently a full member of the Cancer, Heart, and Sleep Epidemiology, A study section. His work at the CalEPA Water Toxicology section has involved systematic reviews and risk assessments of drinking water agents, including nitrate, arsenic, copper, perchlorate, fluoride, chromium, and trihalomethanes. He received his MD at the University of California, Davis School of Medicine, and his MPH in environmental health sciences from the University of California, Berkeley.
Charles V. Vorhees is a professor at the University of Cincinnati’s College of Medicine. He is co-director of the Animal Behavior Core and program director of the Teratology Training Program. He is on the graduate faculty of the Graduate Programs in Neuroscience and Molecular and Developmental Biology. His research interests focus on brain development behavior. He was a founding member of the Neurobehavioral Teratology Society in 1977 and was elected president in 1984-85 and 2012-13. Dr. Vorhees has served on multiple scientific advisory committees for the US Food and Drug Administration, US Environmental Protection Agency, and National Institutes of Health. He was on the National Academies Subcommittee on Reproductive and Developmental Toxicants. Dr. Vorhees obtained his MA and PhD in neurobiology from Vanderbilt University.
Kimberly Yolton is a Professor at Cincinnati Children’s Hospital Medical Center (CCHMC) and the University of Cincinnati College of Medicine, and Director of Research in the Department of General and Community Pediatrics. She is a developmental psychologist and epidemiologist with over 25 years of experience studying the impact of prenatal and early life exposures on neurobehavior from infancy through childhood and directs the longitudinal Health Outcomes and Measures of the Environment (HOME) Study. She was formerly the director of a follow-up clinic serving high-risk infants and young children and has extensive experience with infants and children who were prenatally exposed to substances of abuse, who were born prematurely or at low birth weight, or who come from disadvantaged home environments. She was involved in the initial development of the NICU Network Neurobehavioral Scale (NNNS), a specialized neurobehavioral assessment tool used with healthy and high-risk newborns, and conducts frequent trainings on the proper administration, scoring, and interpretation of the instrument for research and clinical purposes. She has been affiliated with the NIH-funded Neonatal Research Network for over 25 years at two different sites, as an examiner, Gold Standard reviewer for intelligence testing, follow-up principal investigator, and steering committee member. She frequently collaborates with investigators regarding neurobehavioral assessment and staff training strategies to acquire the most appropriate outcome measures with the highest standards of reliability and validity. She earned her PhD in child development and developmental psychology from The Ohio State University and completed a 3-year NRSA fellowship in Pediatric Environmental Health at CCHMC.