Fluoride Developmental Neurotoxicity:

Dose-Response Analyses of Recent High Quality Studies

Chris Neuratha, Paul Connettb, Michael Connettc, Bill Hirzyb
a American Environmental Health Studies Project, b Fluoride Action Network, c Waters Kraus & Paul

Recent health assessments by NTP or NAS

with conclusions of "presumed" hazard in
High quality studies identified in NTP review*
Risk of Bias scores, exposure levels, effect directions
humans
500
# of animal studies
450 # of human studies
Did selection of study participants result
400 in appropriate comparison groups?
Number of qualifying studies

Did the study design or analysis account

350 for important confounding and modifying
variables?
300

overlapping study sample

Were outcome data complete with respect
to attrition or exclusion from analysis?

as Zhou 2019
250
Can we be confident in the
exposure characterization?
200
Can we be confident in the
outcome assessment?
150
Were all measured
100 outcomes reported?

Were there any other potential

50 threats to internal validity?

0
fluoride PFOA BDE-47 air pollution i i iiii– i i ii
Chemical Of 27 high quality studies 25 found statistically significant adverse effects ( ),
2 found no effect ( ), and none found beneficial effect ( )
= exposures below 0.7 mg/L water F or equivalent (11 studies)
American Environmental Health Studies Project
= exposures below 1.5 mg/L water F or equivalent (4 studies)
i = exposures above 1.5 mg/L water F or equivalent (10 studies)

Predicted IQ points lost by various risk factors, USA

Dose-response analysis summaries Notes
ENVIRONMENTAL CHEMICAL EXPOSURES:
Fluoride
1.) Exposures measured as urine F
Lead Study Effect Magnitude β BMDL
Organophosphate pesticides
Methylmercury
concentrations are considered
SOCIOECONOMIC, NUTRITIONAL, PSYCHOSOCIAL FACTORS:
Xiang 2003 –5.7 IQ / 1 mg/L water F 0.27 mg/d equivalent to drinking water F
Iron deficiency
Nonorganic failure to thrive
Xiang 2003 +10% IQ<80 / 1 mg/L water F concentrations.
NEURODEVELOPMENTAL DISORDERS: Zhang 2015b –9.7 IQ / 1 mg/L urine F 0.16 mg/L
Postnatal traumatic brain…
ADHD Cui 2018 –12.3 IQ / 1 mg/L urine F 0.00 mg/L 2.) Community water fluoridation
Pediatric bipolar disorder
ASDs Bashash 2017 –6.3 IQ / 1 mg/L urine F 0.10 mg/L concentration is typically 0.7 – 1.0
Duchenne muscular…
MEDICAL CONDITIONS:
Bashash 2018 +5.7 pts / 1 mg/L urine F mg/L.
Brain tumors
Acute lymphocytic leukemia
Green 2019 –4.5 IQ / 1 mg/L urine F 0.12 mg/L 3.) For studies with multiple
Type 1 diabetes Till 2020 –8.8 IQ / 1 mg/L water F 0.06 mg/L subpopulations, outcomes or
Preterm birth
Congenital heart disease
exposure measures, the most
0 1 2 3 4 5 6 average –7.9 IQ / 1 mg/L 0.09 mg/L
IQ points lost per year, millions sensitive significant association was
chosen, consistent with standard risk
assessment practice.
Examples of studies suitable for dose-response analyses 4.) Benchmark Dose analyses
Dose-response curves and BMD analyses based on data or figures in each paper (BMD) used response (BMR) of –1
IQ point as adverse effect.
Xiang 2003 Xiang 2003 Zhang 2015b Cui 2018
genotype DRD2_SNP T/T
5.) No intra-species Uncertainty
115 genotype COMT_SNP combined
BMD analysis BMD analysis Factor (UF) applied to BMDLs.
Percent of children with IQ < 80

using PROAST using PROAST

Expon. m3- model
Mean IQ of children

Hill m5- model

110
6.) BMDLs for Xiang 2003 from Hirzy
Mean IQ

2016; for Bashash 2017, Green

IQ 2019 from Grandjean 2019; for
105
Zhang 2015b, Cui 2018, Till 2020 by
Neurath using PROAST BMD
100 BMD
BMD
BMD software or linear dose-response
Water F concentration, mg/L 0 1 2 3 method of Grandjean 2019.
Water F concentration, mg/L
(stratified in 5 levels, Wamiao Village) (stratified in 5 levels, Wamiao Village) Child Urine F (mg/L) Child Urine F (mg/L)
References
*Adapted from NTP draft monograph data:
Bashash 2017 Bashash 2018 Green 2019 Till 2020 https://hawcproject.org/assessment/405/
105
https://hawcproject.org/summary/visual/524/
GCI score age 4 y
β = -6.3 (-10.8,-1.7) Hirzy 2016
Child's IQ at age 4 yrs

100
per 1.0 mg/L https://www.fluorideresearch.org/494Pt1/files/FJ
Loss
of 6 IQ
points
2016_v49_n4Pt1_p379-400_pq.pdf
95

Grandjean 2019
90 https://doi.org/10.1186/s12940-019-0551-x
Range of
fluoride
85 levels in
women in boys formula-fed infants PROAST BMD software:
the USA β = 5.68 pts per 1.0 mg/L β = -4.5 (-8.4,-0.6) β = -19.6 (-28.3,-6.7) https://proastweb.rivm.nl/
80
P = 0.0054 per 1.0 mg/L per 1.0 mg/d
0.0 0.5 1.0 1.5 2.0 2.5 additional information:
Maternal urine fluoride (mg/L) http://fluoridealert.org/studies/neurath-
powerpoint-developmental-neurotoxicity/

ver. 10, Nov. 5, 2020