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Showing posts with label Ваксини. Show all posts
Showing posts with label Ваксини. Show all posts
2019/02/15
http://www.fluorideresearch.org/…/FJ2016_v49_n4Pt1_p379-400…
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
379 Developmental neurotoxicity of fluoride: a quantitative risk analysis 379
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
DEVELOPMENTAL NEUROTOXICITY OF FLUORIDE: A
QUANTITATIVE RISK ANALYSIS TOWARDS
ESTABLISHING A SAFE DAILY DOSE OF
FLUORIDE FOR CHILDREN
J William Hirzy,a,* Paul Connett,a Quanyong Xiang,b Bruce J Spittle,c David C Kennedyd
Binghamton, NY, and San Diego, CA, USA; Nanjing, Peoples Republic of China;
and Dunedin, New Zealand;
ABSTRACT: Background: A recent 2015 study from New Zealand indicated water
fluoridation did not have an effect on children’s IQs. A 2012 meta-analysis showed
that children with higher fluoride exposure have lower IQs than similar children with
lower exposures. Levels of the fluoride ion (F) in blood and urine in children have
been linked quantitatively to a significantly lower IQ. The United States
Environmental Protection Agency (USEPA) is in the process of developing a healthbased drinking water standard for fluoride. Objectives: (i) To assess the findings of
the recent IQ study on water fluoridation and (ii) to estimate a daily dose of fluoride
that might protect children from lowered IQ and be relevant to the pending USEPA
standard setting process. Method: We compared the estimated exposed and control
doses received in the recent water fluoridation study, and compared the estimated
differences in those exposures to our findings regarding an adverse effect level. We
used two methods, both with uncertainty factors, to estimate a protective fluoride
dose: the traditional Lowest Observed Adverse Effect Level/No Observed Adverse
Effect Level (LOAEL/NOAEL) and the benchmark dose (BMD) methods. We used 3 mg
F/L in drinking water as an “adverse effect concentration,” along with the reported
fluoride intakes from food, in the LOAEL/NOAEL method. We used the doseresponse relationship in one of the studies cited in the meta-analysis for the BMD
analysis. Arsenic, iodine, and lead levels were accounted for in studies we used.
Results and conclusions: Exposure differences between the control and exposed
populations in the 2015 water fluoridation study appear to be too small to detect an
effect on IQ. BMD analysis shows the possible safe dose to protect against a 5 point
IQ loss is about 0.045 mg F/day. The safe dose estimated with the LOAEL/NOAEL
method is about 0.047 mg F/day. For 90th percentile children’s body mass at 8–13 yr,
these RfDs can be expressed as 0.0010 mg F/kg-day.
Key Words: Developmental neurotoxicity; Fluoride; IQ; Quantitative risk analysis.
INTRODUCTION
Interest in the developmental neurotoxicity of fluoride has grown significantly
since the 2006 report of the National Research Council Committee (NRC) on
Fluoride Toxicity that recommended the United States Environmental Protection
Agency (USEPA) set a new drinking water standard.1
A large body of evidence, over 300 animal and human studies, indicates that the
fluoride ion is neurotoxic. This includes over 40 studies published in China, Iran,
India, and Mexico2
that found an association between lowered IQ and exposure to
fluoride.3 A meta-analysis by Choi et al. found that, in 26 out of 27 studies,
children in a high F-exposed community had a lowered mean IQ compared to
aAmerican Environmental Health Studies Project (AEHSP), 104 Walnut Street, Binghamton, NY
13905, USA; bDepartment of Non-communicable Chronic Disease Control, Jiangsu Province
Center for Disease Control and Prevention, 172 Jiangsu Road, Nanjing, Peoples Republic of
China; c727 Brighton Road, Ocean View, Dunedin 9035, New Zealand; dPreventive Dental
Health Association, 1068 Alexandria Drive, San Diego, CA 92107, USA: *For correspondence:
J William Hirzy, 506 E Street, N.E., Washington, DC 20002, USA. E-mail: jwhirzy@gmail.com
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
380 Developmental neurotoxicity of fluoride: a quantitative risk analysis 380
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
children in a low F-exposed community.4
In contrast, Broadbent et al. found no
significant difference in IQ between children living in an artificially fluoridated
community and those in a non-fluoridated community in New Zealand.5
In this
paper, we explain the substantial limitations of this latter paper. Osmunson et al.
also analyzed that paper in greater detail, showing it to be incapable of detecting
IQ loss from fluoride.6
We used data from Choi et al.4 and a set of the best IQ studies from China by
Xiang et al.7-11 which accounted for many important confounding variables, to
estimate a safe reference dose for fluoride using the two standard risk analysis
techniques used by the USEPA to protect children in the USA from lowered IQ.
Based on our calculations, a protective daily dose should be no higher than 0.05
mg/day, or 0.0010 mg/kg-day for children aged 8 to 13 yr. We based our risk
analysis primarily on information from China, because scientists in that nation
have been by far the most active in generating information on fluoride and
children’s IQ. We are unaware of any similar studies having been done in the
USA.
The 2015 study by Broadbent et al.5 found no statistically significant difference
in intelligence between groups of children in fluoridated or non-fluoridated
communities in New Zealand. A key limitation of this study is that the difference
in fluoride intake between the fluoridated and non-fluoridated communities was
small, thereby diminishing the power of the study to detect an effect of fluoride on
IQ. The study classified exposure groups in three ways: residence in areas
receiving fluoridated drinking water at 0.85 mg/L or areas with fluoride levels
between 0.0 and 0.3 mg/L; whether or not 0.5 mg fluoride tablets were ingested
daily; and whether fluoridated toothpaste was used always, sometimes or never.
The numbers of children who lived in areas with fluoridated water (891), those
who lived in areas with non-fluoridated water (99), those taking fluoride
supplements (139), those that did not take supplements or were unclassified (853),
and those who always/sometimes/never used fluoridated tooth paste (634/240/22)
did not provide a well-defined low exposure group on which to base an assessment
of fluoride’s effect on IQ. In an October 2014 publication, Broadbent et al.12
provided additional, albeit very limited additional exposure information, on the
study,5
which although published online in January 2015 was accepted in
December 2013. Menkes et al.13 addressed these issues, among others, in a
comprehensive commentary on Broadbent et al.5
They concluded that the study,
“…appears to have overstated available evidence.” Likewise, Osmunson et al.
reached a similar conclusion.6
We provide a detailed analysis and discussion of the small difference between
the exposed and control cohorts in Broadbent et al.5,12 that explains our
concurrence with Menkes et al. and Osmunson et al. We also present a comparison
of the results of applying dose-response BMD analyses to our estimates of high
and low fluoride exposures from Broadbent et al.5,12 and from our plausible
exposure estimates for children in the USA
Prominent examples of the growing body of literature indicating that fluoride is
a developmental neurotoxicant in humans include studies by Malin and Till,14
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
381 Developmental neurotoxicity of fluoride: a quantitative risk analysis 381
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
Wang SX et al.,15 Zhang et al.,16 the meta-analysis by Choi et al.,4 and the set of
studies by Xiang et al.7-11
Malin and Till14 reported an association between the prevalence of artificial
water fluoridation and the prevalence of attention deficit-hyperactivity disorder
(ADHD) in the United States. They determined ADHD and water fluoridation
prevalence, state by state, from children’s health surveys conducted by the Centers
for Disease Control and Prevention (CDC) and water fluoridation data, and also
from CDC sources. They showed that, after correcting for household income, the
incidence of ADHD in the years 2003, 2007, and 2011, measured at the state level,
increased as the percentage of each state’s population drinking fluoridated water
increased, as measured in 1992. The authors discussed their statistical analytical
methods that were able to predict that a 1% increase of water fluoridation
incidence over that of 1992 was associated with about 67,000 extra diagnoses of
ADHD in 2003, about 97,000 extra diagnoses in 2007, and about 131,000 in 2011.
They discussed the limitations of their work, and offered plausible mechanisms by
which artificial water fluoridation might cause or contribute to ADHD.
Wang et al.15 showed a statistically significant negative relationship between
urinary fluoride levels and IQ among children. They examined both fluoride and
arsenic as covariates, and showed, through determination of urinary fluoride and
arsenic levels, that fluoride was most likely the source of the effect. They reported
a statistically significant IQ difference of 4.3 IQ points between high (n=106,
5.1±2.0 mg F/L) and control (n=110, 1.5±1.6 mg F/L) urinary fluoride groups.
Zhang et al.16 found a significant negative relationship between both urinary
and serum fluoride levels and IQ in children. Further, they showed that a subset of
the study cohort with the val/val(158) allele of the catechol-O-methyltransferase
(COMT) gene was more susceptible to a fluoride-induced reduction of IQ than
were the rest of the cohort, who had the two alternate genotype alleles (met/met
and val/met) of that gene. This gene codes for the major enzyme involved in the
metabolic degradation of dopamine, which is recognized as having an important
role in cognition. The two median and inter-quartile ranges of fluoride levels in
drinking water were: high 1.46 (range 1.23–1.57); and control 0.60 (range 0.58–
0.68) mg F/L. Differences between the high exposure and control exposure groups
for water fluoride, serum fluoride, and urine fluoride level were statistically
significant. Both serum fluoride, and urine fluoride were significantly related to
water fluoride levels, and both were also significantly related to lowered IQ. For
the high urinary fluoride level group, the IQ point difference from controls was –
2.42 per mg F/L (95% C.I. –4.59–0.24, p<0.05).
The Choi et al. study identified 39 studies that investigated drinking water
fluoride levels and neurodevelopmental outcomes in children.4
Only 27 of these
met selection criteria for their meta-analysis. Choi et al. concluded that, “Children
who lived in areas with high fluoride exposure had lower IQ scores than those who
lived in low-exposure or control areas,” and presented reasons why the conclusion
is valid: remarkable consistency; relatively large effect; studies were independent
of each other by different researchers and in widely differing areas; and although
confounders such as co-exposures to iodine, lead, and arsenic were not considered
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
382 Developmental neurotoxicity of fluoride: a quantitative risk analysis 382
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
in some of the studies, they were considered in others. Ten studies from Choi et
al.4
had mean high-fluoride drinking water levels of less than 3 mg/L, which is
lower than the current health-based drinking water standard in the United States,17
The average IQ loss among these eight studies was 7.4 points. As described below,
the quality of the Choi et al. study and its findings prompted us to examine ways to
use and build on it and the Xiang et al. series to try estimating where a safe dose, if
any, lay.
One of the studies included in the Choi et al.4 meta-analysis was by Xiang et al.7
The Xiang et al. research group, alone among those cited by Choi et al.,4 published
a set of studies, referred to above, from which the total fluoride doses could be
estimated, permitting a dose-response analysis. This was the key to being able to
use the benchmark dose method, described below, while recognizing the
limitations imposed by the relatively small number of children studied. This set of
studies also included data on co-exposures to lead,7 arsenic,9 and iodine,10 as well
as other potential confounding factors which were accounted for, and we used this
set in our work for these reasons.
The studies by Xiang et al. were conducted on 512 children in the high-fluoride
Wamiao village (n=222) and the low-fluoride Xinhuai village (n=290). The
studies, in which individual exposure and effects measurements were collected on
all the children, investigated fluoride exposures, rates and severity of dental
fluorosis, impacts on thyroid function, and performance on IQ tests. Xiang and
coworkers found a statistically significant negative relationship between urinary,7
serum,8
and drinking water7
fluoride levels and IQ. We combined exposure data
from Xiang et al.7
with additional such data from Xiang et al.,11 in which water
intake rates and fluoride intakes from food for the two villages were provided, to
derive total fluoride exposures for the two village cohorts (Table 1).
Table 1. Water fluoride (F) concentrations (mg F/L) and doses (mg F/day), total fluoride
doses from both water and food (mg F/day), and IQ’s, in the low-fluoride village of
Xinhuai (F) and the high-fluoride village of Wamiao (A-E).
(Values are mean±SD)
Group No. of
samples
Water F
concentration
(mg/L)
Water F dose
(mg/day)
Total F
dose*
(mg/day)
IQ
F 290 0.36±0.15 0.45±0.19 0.87±0.19 100.41±13.21
A 9 0.75±0.14 0.93±0.17 1.54±0.17 99.56±14.13
B 42 1.53±0.27 1.90±0.34 2.51±0.33 95.21±12.22†
C 111 2.46±0.30 3.05±0.37 3.66±0.37 92.19±12.98‡
D 52 3.28±0.25 4.07±0.31 4.68±0.31 89.88±11.98‡
E 8 4.16±0.22 5.16±0.27 5.77±0.27 78.38±12.68‡
*Total fluoride dose (mg F/day): for group F the low-fluoride village of Xinhuai = water
fluoride dose + 0.42 mg/day from food; for groups A-E from the high-fluoride Wamiao
village = water fluoride dose + 0.61 mg/day from food; the food fluoride doses are from
Xiang et al.11 The SDs for the mean food fluoride intakes were not reported by group.
Compared to group F: †
p<0.05; ‡
p< 0.01.
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
383 Developmental neurotoxicity of fluoride: a quantitative risk analysis 383
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
In the Xiang et al. study,7 on drinking water fluoride levels and IQ in which the
dose-response relationship was observed, the confounding factors of family
income, parental education levels, and urine iodine levels were taken into account.
The results also showed a dose-response relationship between the percent of
children with an IQ less than 80 and fluoride levels in drinking water in the highfluoride village (Figure 1, produced with the fluoride exposures shown in Table 1.)
.
Measurements by Xiang et al. of co-exposure to arsenic,10 the urinary iodine
levels,7
and the blood-lead levels9
in the two villages indicated that the decrement
in IQ seen in the high-fluoride children was unlikely to have been due to arsenic,
iodine deficiency, or lead. The high-fluoride village had lower mean arsenic levels
than the low-fluoride village (Table 2).
IQ
(mean±95% CI,
IQ points)
120
110
100
90
80
70
60
Figure 1. IQ (IQ points) and water fluoride concentrations (mg F/L) in Wamiao village,
stratified into 5 groups according to the drinking water fluoride level. The letter designations,
A-E, correspond to the groups listed in Table 1. The values for the IQ and drinking water
fluoride concentration are from Table 8 in Xiang et al.7
0 1 2 3 4 5
Water fluoride (mean±SD, mg F/L) in groups A-E in Wamiao village
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
384 Developmental neurotoxicity of fluoride: a quantitative risk analysis 384
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
While studies by Xiang et al.,7,8 Wang SX et al.,15 Ding et al.,18 and Zhang et
al.,16 link lower IQs in children to individualized metrics of fluoride exposure (i.e.,
urine and serum fluoride), it is not possible at this time to translate directly the
dose-responses seen in these studies into safe daily doses and thus into a protective
drinking water standard. We describe in the section on method the techniques we
used for that purpose.
USEPA is in the process of developing a new Maximum Contaminant Level
Goal (MCLG) for fluoride as recommended by the NRC Committee on Fluoride
Toxicity in Drinking Water.17,19-21 The MCLG is a non-enforceable health-based
drinking water goal, and serves as a basis for the development of the enforceable
federal standard, the Maximum Contaminant Level (MCL). The current MCLG is
4 mg F/L, which was established to protect against crippling skeletal fluorosis.17
In order to establish a new MCLG, USEPA must anticipate the adverse effect of
fluoride that occurs at the lowest daily dose and then set the MCLG at a level to
protect against that effect for everyone, including sensitive sub-populations, with
an adequate margin of safety.22
Detailed studies on the economic impact of IQ loss that include sensitivity
analyses, and percentile exposures to methylmercury, lead, and endocrine
disrupting chemicals have been published by Trasande et al.,23 Attina and
Trasande,24 and Bellanger et al.,25 respectively. Based on these studies and our
estimated safe levels of exposure to fluoride, we can conclude now only that it is
highly probable that some economic loss to US society can be attributed to current
fluoride exposures. In a future paper we intend to use methodologies employed by
Table 2. Levels of arsenic, iodine, and lead in the children of Wamiao and Xinhuai villages
Element Parameters Wamiao
village
Xinhuai
village
p
n 17 20
Arsenic*
(µg/L) Mean±SD 0.24±0.26 16.40±19.11 0.001
Range 0–0.50 0–48.50
n 46 40
Iodine†
(µg/L)
Mean±SD 280.7±87.2 301.0±92.9 >0.3
Range 131.3–497.1 148.5±460.9
n 71 67
Lead‡
(µg/L)
Mean±SD 22.0±13.7 23.6±14.2 >0.48
Range 1.36–55.0 1.36–61.1
*Level in drinking water, from Xiang et al10; †
level in urine, from Xiang et al7
; ‡
level in
blood, from Xiang et al.9
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
385 Developmental neurotoxicity of fluoride: a quantitative risk analysis 385
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
these researchers to elucidate the disease and economic burden across the U.S.
population.
OBJECTIVES
Our objectives were (i) to address the Broadbent et al. studies5,12 in more detail
and (ii) to estimate a daily dose of fluoride with an adequate margin of safety that
would be consistent with the mandate facing USEPA in setting a new MCLG that
might prevent reduced IQ in children, including in sensitive subpopulations.
METHOD
General: We used two data sets and two risk analysis methods in our risk work.
The first data set included the group of ten studies in Choi et al.4
that found IQ
decrements among children drinking water with 3 mg/L or less fluoride, along
with rates of water and food fluoride intakes from Xiang et al.11 These were used
to estimate a Lowest Observed Adverse Effect Level (LOAEL) for IQ loss. The
second data set included IQ measurements corresponding to specific drinking
water fluoride levels from Xiang et al.7
along with the water and fluoride in food
intake rates cited above.
The two risk analysis methods were the LOAEL/NOAEL and the benchmark
dose (BMD) methods, both of which are used by USEPA and both of which
include uncertainty factors (UFs) as described in the sections on the LOAEL/
NOAEL and BMD methods. These risk analysis methods depend upon first
estimating from the available data either the highest dose that does not result in an
observed adverse effect, NOAEL, or in the case of the BMD method, a dose that
would result in a specified level of adverse effect. UFs aim to provide an adequate
margin of safety to protect against the adverse effect. They are applied to estimate
the NOAEL (in the LOAEL/NOAEL method) and to account for, e.g., interindividual variability, in utero toxicity, and the severity of the effect, inter alia. As
used by USEPA, generally no more than three UFs are applied in any analysis, and
they are set at 1, 3, or 10, representing no need for adjustment, one-half, or one
order of magnitude, respectively. The daily dose estimated by these methods is
known as the Reference Dose (RfD), which is a dose, within one order of
magnitude, that can be experienced throughout life without adverse effect. It is
normally expressed as mg/kg of body weight per day, mg/kg-day.
We chose instead to express RfD values in units of mg/day, as well as mg/kgday, for the following reasons. Our analysis was based on data from studies that
measured daily intakes of fluoride, reported in mg/day, by children generally aged
8–13 yr, most of whom were Chinese. Given the published evidence for in utero
toxicity, it is not possible to know at what developmental stage(s) the observed
adverse effect was manifested in these children. This makes estimating an RfD in
mg/kg-day problematic. Given these considerations, we elected to express the RfD
values in mg/day that might protect over the entire period from conception through
adolescence. Furthermore, we were able to make direct comparison of our results
with the estimated daily fluoride intakes of US children in mg/day that are
presented in Table 7-1 by USEPA.21
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
386 Developmental neurotoxicity of fluoride: a quantitative risk analysis 386
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
LOAEL/NOAEL method: To avoid over estimating risk, we considered a 3.0 mg/
L drinking water fluoride level from Choi et al.4
as a Lowest Observed Adverse
Effect Concentration, even though at least three other lower concentrations (0.88
mg/L, Lin et al.;26 1.53 mg/L, Xiang et al.;7 and 1.40 mg/L, Zhang et al.;16 the
latter two with p<0.05 and p<0.01, respectively, from controls) have been
associated with loss of IQ. We considered the combined water (1.24 L/day) and
food intake rates from Xiang et al.11 (0.50 mg F/day, mean of the high-fluoride and
low-fluoride villages), to be the LOAEL. We used these values because all the
work of Xiang et al. was with the same cohort of 512 children, aged 8–13 years,
and most of the studies reported by Choi et al.4 were on children of the same or a
similar age range and in the same country. (Two of the 10 Choi et al.4 studies with
high-fluoride levels of less than 3 mg/L were from Iran.) We applied three UFs to
the LOAEL: one each to estimate the NOAEL, UF 3; to account for interindividual variability, UF 10; and for the in utero toxicity, UF 3. We chose these
UF values because the well-documented effect of neurotoxicity of fluoride does
not seem to require higher uncertainty adjustments for LOAEL to NOAEL and for
in utero toxicity. However, the relatively small number of individuals, primarily
Chinese children, on whom we base our work, does merit an uncertainty
adjustment of a full order of magnitude for inter-individual variability.
Benchmark dose method: This method uses a computer program to fit doseresponse data and to determine a dose that results in a specified adverse effect
level, known as the Benchmark Response (BMR) or the Point of Departure, POD.
The program also yields the lower 95th confidence limit on the BMD referred to as
the Benchmark Dose Lower-confidence Limit (BMDL). From this BMDL we
estimated an RfD for the specified BMR by applying UFs as described above for
inter-individual variability and in utero toxicity. We used exposure data from
Xiang et al.7,11 to calculate the total fluoride doses for the 6 water fluoride
exposure groups from the high-fluoride Wamiao (groups A-E) and the lowfluoride Xinhuai (group F) shown in Table 1.
We used these calculated dose-response data with the USEPA’s Benchmark Dose
Software,27 setting the BMR at loss of 5 IQ points (Figure 2). We chose that
response level because it approximates the first statistically significant IQ
decrement range observed in Xiang.7
We also ran the program and using a
BMR’s of a 1 IQ point loss and of 1 standard deviation from the mean IQ of the
control village, Xinhuai. The latter is recommended in the USEPA guidance28 for
comparison purposes. Among the available BMD models, the linear model
showed the best fit with the dose-response data.
The results of the RfD calculations using the LOAEL/NOAEL and Benchmark
dose methods are shown in Table 3.
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
387 Developmental neurotoxicity of fluoride: a quantitative risk analysis 387
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
We also did BMD analyses of Xiang et al.7 data restricted to the single, high
fluoride village, Wamiao, which has a wide range of water fluoride levels, as well
as for data from both villages. We found dose-response curves and BMD results to
be very similar from these two BMD analyses, providing evidence that there are
no unmeasured or inadequately controlled sources of confounding between the
two villages.
In the high fluoride village of Wamiao a dose-response relationship exists
between drinking water fluoride levels and percent of <80 IQ children. There were
34 of 222 children (15.3%) in that category. In the low fluoride village of Xinhuai
19 of 290 (6.5%) children were in that category7 (Figure 3).
0 1 2 3 4 5 6
Total fluoride dose (mg F/day) in Wamiao (A-E) and Xinhuai (F) villages
110
105
100
95
90
85
80
75
70
65
Figure 2. Benchmark dose analysis of IQ and total daily fluoride dose in Wamiao (A-E) and
Xinhuai (F) villages. The letter designations, A-F, correspond to the groups listed in Table 1.
The Benchmark Response (BMR) was set at a loss of 5 IQ points. IQ = –3.0675 × total fluoride
dose + 103.17
Table 3. Lowest Observed Adverse Effect Levels (LOAELs) and reference doses (RfDs) in
mg F/day using the Lowest Observed Adverse Effect Level/ No Observed Adverse Effect
Level (LOAEL/NOAEL) and the Benchmark Dose Level (BMDL) methods
RfD method LOAEL (mg F/day) RfD (mg F/day)
LOAEL/NOAEL 4.22* 0.047||
BMDL5
† 1.35 0.045**
BMDL1
‡ 0.27 0.0090**
BMDL1SD
§ 3.58 0.12**
*Calculation of LOAEL with a Lowest Adverse Effect Concentration in drinking water of 3.0
mg F/L: Fluoride from water: Daily water intake 1.24 L/day × Concentration of fluoride in
water 3 mg F/L=3.72 mg F/day; F from food: 0.50 mg F/day; Total F intake from water and
food=4.22 mg F/day; †
BMDL5 for 5 IQ point loss; ‡
BMDL1 for 1 IQ point loss; §
BMDL1SD for
13.21 IQ point loss (1 standard deviation from the control mean IQ); ||Uncertainty factor (UF)
usage with LOAEL/NOAEL RfD method: LOAEL to NOAEL: UF=3; inter-individual variability:
UF=10; in utero toxicity: UF=3; **Uncertainty factor (UF) usage with BMDL RfD method:
inter-individual variability: UF=10; in utero toxicity: UF=3.
IQ (mean±95% CI, IQ points)
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
388 Developmental neurotoxicity of fluoride: a quantitative risk analysis 388
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
We also did BMD analyses of the Xiang et al.7
data, restricted to the single,
high-fluoride village, Wamiao, which has a wide range of water fluoride levels, as
well as for data from both villages. We found the dose-response curves and BMD
results to be very similar from these two BMD analyses, providing evidence that
there are no unmeasured or inadequately controlled sources of confounding
between the two villages.
In the high-fluoride village of Wamiao, a dose-response relationship exists
between the drinking water fluoride levels and the percent of <80 IQ children,
with 34 of 222 children (15.32%) being in that category (Figure 3). In the lowfluoride village of Xinhuai, 19 of 290 (6.55%) children were in that category.7
.
RESULTS
Table 2 gives our estimates of fluoride RfDs based on the LOAEL/NOAEL and
BMD methodologies, with footnote explanation of details. The RfDs range from
0.12 to 0.0090 mg/day for BMDLs set at IQ point losses of 1 S.D. (from Xiang et
al.7 and 1, respectively. The RfD based on LOAEL/NOAEL calculations is 0.047
mg/day.
RESULTS
Table 3 gives our estimates of fluoride RfDs based on the LOAEL/NOAEL and
BMD methodologies, with a footnote explanation of the details. The RfDs range
from 0.12 to 0.0090 mg/day for the BMDLs set at IQ point losses of 1 SD (from
Xiang et al.7
) and 1, respectively. The RfD based on the LOAEL/NOAEL
calculations is 0.047 mg/day.
0 1 2 3 4 5
Water fluoride (mean±SD, mg F/L) in groups A-E in Wamiao village
40
30
20
10
0
Prevalence
of IQ<80
(%)
Figure 3. The percentage of persons with an IQ<80 and the drinking water fluoride levels, in
groups A-E in Wamiao village. The letter designations, A-E, correspond to the groups listed
in Table 1. The values for the prevalence of IQ<80 and the drinking water fluoride
concentration are from Table 8 in Xiang et al.7
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
389 Developmental neurotoxicity of fluoride: a quantitative risk analysis 389
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
Table 4 shows results of our BMD analysis for IQ effect, with our interpretation
of the difference between the high- and low-fluoride exposure groups, from the
Broadbent et al.5,12 data discussed in the introduction. That BMD analysis used
the curve generated for Figure 2.
We show in Table 5 the results of our BMD analysis, using the same curve, of
plausible high and low fluoride exposures among children in the USA.
Regarding total fluoride exposure Broadbent et al.12 state, “We did conduct an
analysis in which total fluoride intake was estimated, but we did not include that in
the current study5
because it was focused on claims about community water
fluoridation. No significant differences in IQ by estimated total fluoride intake
prior to age 5 years were observed; those with high total fluoride intake had
slightly higher IQs than those with low total fluoride intake.”
Table 4. Benchmark dose method (BMD) analysis of the estimates of fluoride (F) intake in
the low and high F exposure groups from Broadbent et al.5,12
Low F
exposure
group
(dose in mg
F/day)
High F
exposure
group
(dose in mg
F/day)
High F
exposure group
/Low F
exposure group
ratio
Difference
between low
and high F
exposure
groups
Total F Intake 1.19 1.41 1.2 0.22 mg F/day
IQ points 99.52 98.84 0.67 IQ points
Table 5. Benchmark dose method (BMD) analysis of the estimates of fluoride (F) intake in
hypothetical low and high F exposure groups of US children
Low F
exposure
group
(dose in mg
F/day)
High F
exposure
group
(dose in mg
F/day)
High F
exposure group
/Low F
exposure group
ratio
Difference
between low
and high F
exposure
groups
Total F Intake 0.50 2.0 4.0 1.5 mg F/day
IQ points 101.63 97.03 4.6 IQ points
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
390 Developmental neurotoxicity of fluoride: a quantitative risk analysis 390
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
The key question regarding whether the Broadbent et al.5 study had the power to
detect a difference in IQ resolves itself into whether there was any significant
difference in total fluoride exposure among the “high” and “low” exposure groups.
We provide information below that indicates there were no such differences in
exposure.
The use of fluoride supplements by children in the unfluoridated area is the most
important variable, followed closely by use of fluoridated toothpaste. Broadbent et
al.12 addressed the issue of the use of fluoride supplements among the 99 subjects
who did not reside in a fluoridated community in the Broadbent et al.5 publication;
they also noted that the aim of this latter study5 was to examine the effect of
community water fluoridation (CWF), and not to study whether total fluoride
exposure affected IQ.
In the light of the reasonable inference that the effect of a water soluble toxic
agent delivered orally is essentially independent on whether it comes from a
solution of the toxicant or in tablet form followed by drinking water to dissolve the
tablet, it is unfortunate that, if no difference in IQ as a function of total fluoride
exposure was observed, this fact was not reported in the original peer-reviewed
paper, along with a statistical analysis.
Since the question of whether a difference in IQ could have been detected in the
Broadbent et al.5 study is so critical, and since, unfortunately, Broadbent et al.
provided no total fluoride data in that study, we estimated the total fluoride
exposure for the children in the CWF and non-CWF areas. We based these
estimates in part on information provided in Broadbent et al.5,12
The Broadbent et al.5
study classified the exposure groups in three ways:
residence in areas receiving fluoride via drinking water at 0.85 mg F/L or areas
with fluoride levels between 0.0 and 0.3 mg F/L; whether or not 0.5 mg
fluoride tablets were ingested; and whether fluoridated toothpaste was used
always, sometimes, or never. In Broadbent et al.,12 they reported that of the 99
subjects taking supplements who did not live in CWF areas, 22 used 0.5 mg
fluoride tablets daily and 31 less than daily, leaving 46 who did not use
supplements. We assumed the 31 children took tablets twice a week, for an
average daily dose of 1.0 mg F/7 days = 0.14 mg F/day. We accordingly used
these supplement data as follows:
22/99 × 0.5 mg F/day = 0.11 mg F/day; 31/99 × 0.14 mg F/day = 0.044 mg F/
day. Total average daily dose of fluoride supplementation among the 99 who never
lived in a CWF area is therefore 0.11 + 0.044 = 0.15 mg F/day. Based on the
information in Broadbent et al.,12 we estimated that about 35 of the 891 who lived
in CWF areas took daily supplements and 38 took them “now and again,” we
calculated as above the total average supplement dose in CWF areas at about 0.03
mg F/day.
For fluoride exposures from drinking water, toothpaste, food, and beverages, we
assumed that New Zealand children of the age under study would be similar to US
children of the same age in body mass and drinking water, solid food, beverage
consumption, and toothpaste use technique. Guha-Chowdhury et al.29 surveyed
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
391 Developmental neurotoxicity of fluoride: a quantitative risk analysis 391
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
the total fluoride intake for a population of New Zealand children who lived in
fluoridated areas (n=32) and non-fluoridated areas (n=34). Because of differences
in drinking water fluoride levels reported in that study and by Broadbent et al.,5
we
limit our use of the Guha-Chowdhury et al.29 data to fluoride ingestion via
toothpaste use in our estimation based on both Broadbent et al. studies.5,12 No
significant difference in mean fluoride intake from toothpaste between the
populations was reported (0.32 mg F/day and 0.34 mg F/day). In Broadbent et al.,5
of the 896 children for whom responses to the toothpaste use question were
reported, only 22 reported no use of fluoridated toothpaste; for 96 children
toothpaste use data are lacking.
Based on USEPA data in Table 7–1,21 New Zealand children in CWF and nonCWF areas would receive about 0.25 mg F/day from solid food sources (Table 6).
Further, assuming that New Zealand children would have mean drinking water
intakes that are about the same as US children, they would ingest 417 mL/day of
drinking water based on Table 3–521(Table 7).
Table 6. Representative values for fluoride intakes (mg F/day) used in the calculation of the
relative source contribution for drinking water. Based on Table 7–121
Age
group
(yr)
Drinking
water
intake*
(mg F/day)
Food
intake from
solid foods
(mg F/day)
Beverage
intake
(mg F/day)
Toothpaste
intake
(mg F/day)
Soil intake
(mg F/day)
Total
intake
(mg F/day)
Relative
source
contribution
for drinking
water
(%)
0.5–<1 0.84 0.25† – 0.07 0.02 1.19 71
1–<4 0.63 0.16 0.36 0.34 0.04 1.53 41
4–<7 0.82 0.35 0.54 0.22 0.04 1.97 42
7–<11 0.86 0.41 0.60 0.18 0.04 2.09 41
11–<14 1.23 0.47 0.38 0.20 0.04 2.32 53
>14 1.74 0.38 0.59 0.10‡ 0.02 2.83 61
*Consumers only; 90th percentile intake except for >1 yr. The >14 yr value is based on the
Office of Water (OW), United States Environmental Protection Agency, policy of 2L/day.
†Includes foods, fluoride in powdered formula, and fruit juices; no allocation for other
beverages.
‡Assumed to be 50% of the value for the 11–14 -year-old age group.
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
392 Developmental neurotoxicity of fluoride: a quantitative risk analysis 392
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
For our assessment we assumed that the fluoride level in the non-CWF area,
with fluoride levels between 0.0 and 0.3 mg/L, was the average of the range, viz.,
0.15 mg F/L. Thus in the CWF and non-CWF areas, respectively, fluoride intakes
from drinking water would be 0.35 mg F/day (0.417 L water/day × 0.85 mg F/L)
and 0.06 mg F/day (0.417 L water/day × 0.15 mg F/L). Whether New Zealand
children would also receive fluoride via beverages would depend on whether
beverages were produced with fluoridated water or were fruit juices containing
fluoride residues. In the US, where that is the case, fluoride intake from beverages
adds approximately 0.4 mg/day to the intake.21 We assumed that both the CWF
and non-CWF children would ingest that same amount of fluoride from beverages,
no matter what the fluoride content of the beverages was. So we assumed the same
fluoride intake from beverages for these children as for the US children of 0.4 mg
Table 7. Fluoride intake from the consumption of municipal water (direct and indirect*) at
the average fluoride concentration of 0.87 mg F/L as determined by monitoring records
for 2002 through 2006. Based on Table 3–521
adapted from USEPA, 2004, Table 5.1. A130
Group
(age in yr)
Water consumption (mL/day)† Fluoride intake (mg F/day)†
Mean 90% CI Upper
bound
Mean 90% CI Upper
bound
Infants<0.5 296 329 0.26 0.29
0.5–0.9 360 392 0.31 0.34
1–3 311 324 0.27 0.28
4–6 406 426 0.35 0.37
7–10 453 485 0.39 0.42
11–14 594 642 0.52 0.56
15–19 761 823 0.66 0.72
20+ 1,098 1,127 0.96 0.98
Total population 926 949 0.81 0.83
*Indirect consumption refers to intake through beverages and foods that include fluoridated
drinking water as an ingredient.
†Based on an average fluoride concentration of 0.87 mg F/L.
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
393 Developmental neurotoxicity of fluoride: a quantitative risk analysis 393
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
F/day. The estimated total fluoride intakes in the CWF and non-CWF areas for the
New Zealand children are shown in Table 8.
Assuming these estimates are reasonable, the difference between these groups,
which Broadbent in his newsletter statement12 characterizes as “high” and “low,”
are significantly smaller (less than 0.2 mg F/day) than the differences in the studies
cited in Choi et al.4
(range from the 13 studies in which mean values were clearly
indicated: 0.54–3.66 mg F/day, mean: 2.00 mg F/day) and reported in the several
Xiang et al. publications.7,9-11 Our benchmark dose analysis of the data from
Xiang et al.7,10,11 showed a threshold 1 IQ point loss attributable to a daily dose of
0.27 mg F/day.
Regarding the controls used in Broadbent et al.,5 in the On Tap newsletter
statement Broadbent et al.12 report that, “We controlled for a similar set of
confounders to those controlled by Meier et al. (2012) in their study of cannabis
exposure and IQ.” Meier et al.31 reported controlling for years of education,
cannabis use in the past 24 hr or past week, persistent substance dependency
(tobacco, hard-drugs, or alcohol), age of onset or cessation of cannabis use, and
schizophrenia. Neither Broadbent et al.5
nor Meier et al.31 reported control for coexposure to iodine, arsenic, or lead.
Revisiting the key question on the usefulness of the two Broadbent studies,5,12
the latter of which12 provided no statistics: were there any significant differences
in exposures? It is unlikely that a less than 0.2 mg F/day difference in exposure
would lead to a detectable difference in IQ. That no significant difference in IQs
was reported in Broadbent et al.,5 nor demonstrated in the subsequent notice in the
National Fluoridation Information Service newsletter, Broadbent et al.,12 is not
surprising.
DISCUSSION
Table 5 indicates that the effect of fluoride on IQ is quite large, with a predicted
mean 5 IQ point loss when going from a dose of 0.5 mg F/day to 2.0 mg F/day,
Table 8. Estimated total fluoride intakes in community water fluoridation (CWF) and
non-CWF areas in New Zealand
Fluoride source Estimated fluoride intake in
CWF residence area
(mg F/day)
Estimated fluoride intake in
non-CWF residence area
(mg F/day)
Drinking water 0.35 0.06
Food 0.25 0.25
Toothpaste 0.33 0.33
Beverages 0.40 0.40
Supplements 0.03 0.15
Total 1.36 1.19
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
394 Developmental neurotoxicity of fluoride: a quantitative risk analysis 394
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
which is an exposure range one might expect when comparing individuals in the
USA with a low total intake to those with a higher total intake. However, when
comparing a fluoridated area of the USA to an unfluoridated area it would be hard
to discern a mean IQ difference, because of the multiple sources of fluoride intake
besides drinking water. These sources greatly reduce the contrast in total fluoride
intake between fluoridated and unfluoridated areas, as shown with the Broadbent
et al.5,12 publications. A very high hurdle is thus created to gaining useful
information in the USA, as it was in New Zealand, via a large, long-range
longitudinal epidemiological study of fluoride and IQ.
In any event, as Table 5 indicates, based on the dose-response seen in the Xiang
et al. study,7 the implication for US children appears to be that children whose
fluoride exposures are held to a minimum, e.g., 0.5 mg F/day or less, may have as
much as a 4 or 5 point IQ advantage, or more, over children whose exposures are
greater than 2 mg F/day, all other factors affecting IQ being equal.
USEPA’s fluoride assessment documents20,21 are targeted at protecting 95.5
percent of children from severe dental fluorosis while providing a fluoride dose
deemed adequate give some protection against dental caries. Given the
publications by the USEPA and USDHHS,32 it appears likely that those agencies
will adhere to recommending that fluoride levels in drinking water be maintained
at or about 0.7 mg/L. At that level the 90th percentile of water intake in the NRC,
Table B-4,1
delivers about 0.8 mg F/day (1.1 L water/day × 0.7 mg F/L = 0.77 mg
F/day) (Table 9).
Table 9. Estimated average daily water ingestion (mL/day) from community sources during
1994–1995, by people who consume water from community sources. Based on Table B-41 from
EPA 200033
Population Mean
(mL/day)
50th percentile
(mL/day)
90th percentile
(mL/day)
95th percentile
(mL/day)
99th percentile
(mL/day)
All consumers 1000 785 2,069 2,600 4,273
<0.5 yr 529 543 943 1,064 1,366
0.5–0.9 yr 502 465 950 1,122 1,529
1–3 yr 351 267 719 952 1,387
4–6 yr 454 363 940 1,213 1,985
7–10 yr 485 377 995 1,241 1,999
11–14 yr 641 473 1,415 1,742 2,564
15–19 yr 817 603 1,669 2,159 3,863
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
395 Developmental neurotoxicity of fluoride: a quantitative risk analysis 395
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
While our work does not touch on the question of whether such a level in
drinking water offers dental health benefits, it indicates that an intake rate greater
than 0.047 mg F/day poses a significant risk of lowering IQ of exposed children.
Thus, our work bears on USEPA’s response to the NRC1
recommendation to
conduct a risk assessment toward establishing a new MCLG for fluoride to protect
all children, including sensitive subpopulations, with an adequate margin of safety.
Table 7–1 from USEPA21 shows the total fluoride intakes from all sources of
exposure by age grouping in mg/day (Table 6). Based on that Table and other data
from USEPA20 and the NRC, Table B-41 (Tables 6, 7, and 9), the current average
mean fluoride exposures for US children range from about 0.80 mg F/day to about
1.65 mg F/day. These doses are 17 to 35 times higher than our higher estimated
RfD of 0.047 mg F/day. At the 90th percentile of water intake, the total fluoride
doses for US children are 25 to 60 times higher than our higher RfD. These data
imply that at present the risk of IQ loss among children in the US is high.
While the sources of fluoride cited in Table 7–1 USEPA21 (Table 6) exceed the
fluoride levels that we estimate would be protective for all children, a natural
source of fluoride does not. Fluoride levels found in human breast milk are
approximately 0.004 mg/L, Ekstrand,34 which result in daily doses of ca. 0.002–
0.004 mg F/day USEPA.35 These doses are well below our estimated RfD,
including the value we obtained by BMD analysis using a 1 point IQ loss BMR.
This confers some degree of biological plausibility to our work to the extent that
we are not over estimating the risk associated with fluoride exposure. While the
breast provides protection from the mother’s serum fluoride levels,34 the placenta
does not. Fluoride readily crosses the placenta and, in general, the average cord
blood concentrations are approximately 60% of the maternal serum
concentrations.36 Evidence that fluoride affects neural development in utero has
been shown in a number of human studies. For example, He37 found that pre-natal
fluoride toxicity occurs in humans, manifested in an alteration in the density of
neurons and in the number of undifferentiated neurons observed in therapeutically
aborted fetuses. Yu et al.38 found reduced synthesis of neurotransmitters and a
decrease in the density and function of their receptors in brains of aborted fetuses
in an endemic fluorosis area of China compared to similar fetuses in a nonendemic fluorosis area. Dong et al.39 found differences in the amino acid and
monoamine neurotransmitter content in brains of aborted fetuses from an endemic
fluorosis area of China compared with those from a non-fluorosis area. Both bone
and brain tissues of these fetuses showed statistically significantly higher fluoride
levels from the fluorosis area than from the control area. Du et al.40 reported in
detail on the adverse changes in neuron development found in brain tissue from
fetuses from endemic fluorosis areas of China (fluoride levels 0.28±0.14 µg/g)
compared to similar tissues from non-endemic areas (fluoride level 0.19±0.06 µg/
g) (p<0.05). Mullenix et al.41 showed that pregnant rats dosed with fluoride at a
level that produced serum fluoride levels equivalent to those observed in humans
who consumed drinking water at the current MCLG concentration of 4 mg F/L
gave birth to pups displaying lifelong neurological impairment. Finally, Choi et
al.42 discussed the fact that, “…systemic exposure should not be so high as to
Research report
Fluoride 49(4 Pt 1):379-400
October-December 2016
396 Developmental neurotoxicity of fluoride: a quantitative risk analysis 396
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
impair children’s neurodevelopment especially during the highly vulnerable
windows of brain development in utero and during infancy…” In this regard, the
fluoride intake levels that the mothers of the subject children from the Choi et al.
studies,4,42 and the Xiang et al. studies7,11 experienced may have played a part in
the reported IQ losses. For this reason the RfD values we derived may have at least
some value for the protection of the fetuses carried by pregnant women as well as
for the children in infancy that they subsequently deliver.
We relied on data from the meta-analysis4 that employed well-documented
selection criteria for the subject studies used in the analysis, and that provided
“evidence supporting a statistically significant association between the risk factor”
(fluoride exposure) and lowered IQ among higher fluoride exposed children. In so
doing, we conformed to the recommendation of Bellinger43 regarding use of metaanalyses in assessments like ours. The Choi et al. meta-analysis4 found an average
decrement of about 7 IQ points in the higher fluoride exposed groups, and the ten
studies from it on which we based our use of 3 mg F/L as the adverse effect
concentration showed an average decrement of 8 points. Based on our RfD
findings, it is reasonable to suspect that some children in the USA have
experienced IQ loss from pre- and post-natal fluoride exposures.
We calculated the RfD values for the two extreme drinking water fluoride
exposures in publications cited by Choi et al.4
and Wang SX et al.15 and showed a
statistically significant IQ loss in children at a mean drinking water fluoride level
of 8.3 mg/L. Using the same LOAEL/NOAEL methodology and the same water
and food intake assumptions as above, we derived a RfD of 0.12 mg/day. Lin et
al.26 showed a statistically significant IQ loss in an area with low iodine intakes
with a fluoride water level of 0.88 mg/L, leading to an RfD of 0.018 mg/day. This
study is significant because the Safe Drinking Water Act22 stipulates that the
whole population, including sensitive subgroups, must be protected by the MCLG
for fluoride. In the 2007–2008 National Health and Nutritional Examination
Survey, Caldwell et al.44 found that about 5% of children aged 6–11 yr had a
urinary iodine concentration of <50 µg/L. Urinary iodine levels of 20–49 µg/L
indicate moderate iodine deficiency and levels <20 µg/L show severe deficiency.45
Thousands of US children fall into this sensitive subgroup of iodine deficiency.
Since USEPA20 apparently intends to protect 99.5 percent of US children from
severe dental fluorosis with a new MCLG, it is not unreasonable to expect that
USEPA will take iodine insufficiency into account as a risk factor for IQ loss from
fluoride as well.
In a population of 320 million, the population level impact of an average 5 IQ
point loss, beyond purely dollars of income loss, is a reduction of about 4 million
people with IQ>130 and an increase of almost as many people with IQ<70.46
LIMITATIONS
In general, our RfD work is based on a limited amount of quantitative data, most
of which is from Chinese studies, most of which were of ecological design.
Unfortunately, we were unable to find any data on human intellectual performance
as a function of fluoride exposures in the USA. Nor were there studies, other than
those by the Xiang et al. research group, which provided any useful dose-response
Research report
Fluoride 49(4 Pt 1):379-400
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397 Developmental neurotoxicity of fluoride: a quantitative risk analysis 397
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
information. While there is growing interest in the USA in this area of research,
there are significant impediments to such work as mentioned above.
In estimating RfD values, we used mean water consumption rates, except as
noted, and mean IQ measurements that were derived from different testing
methods, recognizing the limitations of these uses and those inherent in ecological
studies generally. The data we used for the food component in estimating total
fluoride intakes were also mean values from one study that were not accompanied
by standard deviations. They were, however, somewhat higher than the values for
children’s food fluoride exposures in the USA. This indicates that we used a
conservatively high fluoride dose to estimate the adverse effect level from those
studies.
Inasmuch as the timing effect of fluoride exposure on neurodevelopment is not
precisely known, these age-variable mean consumption rates may introduce some
error. Further, it may be that the fluoride exposures that the pregnant mother
experiences may, at least partially, influence the outcome for the child.
In our estimates of exposures in the Broadbent publications, our estimates for the
use of dental products and supplements are based on averaging the available data
on populations, and not on measurements of individual children’s experiences.
The RfDs we estimated were derived from data on primarily Chinese children of
similar age and body mass to children in the USA, for whom these safe levels are
intended. Finally, use of mean measured IQ levels cannot speak to the experience
of individual children for a variety of reasons, and Choi et al.4 point out this
limitation. While Choi et al.4,42 urge caution in using their results to determine an
exposure limit, we feel we have been cautious, and that simply ignoring the
available dose-response information amid the substantial body of evidence of
developmental neurotoxicity could result in policies that are insufficiently
protective of public health. Finally, based on the available data, which do not
provide sufficient information to assess at what stage the adverse effects of
fluoride on neural development occur, one cannot be certain that there is any safe
daily dose of fluoride that would prevent developmental neurotoxicity.
Limitations inherent to both the BMD and LOAEL/NOAEL methods, including
the quantity and quality of underlying research and the number and values selected
for UFs, apply to our use of those methods for determining RfDs. Clearly, it would
have been useful to have a more robust data set on which to base our risk analysis,
but waiting for more such data that are unlikely to be developed in the near future
did not seem reasonable to us.
CONCLUSIONS
The information now available supports a reasonable conclusion that exposure
of the developing brain to fluoride should be minimized, and that economic losses
associated with lower IQ’s may be quite large. While Choi et al.42 also caution
against systemic exposures to “high levels” of fluoride, the requirement of the Safe
Drinking Water Act to protect all children, including those with special
sensitivities and those in utero, against developmental neurotoxicity makes it
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Fluoride 49(4 Pt 1):379-400
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398 Developmental neurotoxicity of fluoride: a quantitative risk analysis 398
towards establishing a safe daily dose of fluoride for children
Hirzy, Connett, Xiang, Spittle, Kennedy
imperative to be conservative in defining the term “high level.” We believe our
analysis provides some insight on this definition.
Because it is not clear what stage(s) of development is/are sensitive to fluoride
toxicity, well-funded research into this effect should be a priority. If sufficient
exposure information were to be gathered, it would be useful in identifying where
and among whom the greatest risk for IQ loss exists. The work of Zhang et al.16
and the iodine data reported in NHANES44 are germane to this point. Meanwhile,
based on the current information, implementation of protective standards and
policies seems warranted and should not be postponed while more research is
done. The amount of consistently observed adverse effects on neurological
development reported by multiple research groups world-wide, which culminated
in the addition of fluoride by Grandjean and Landrigan47 to their list of known
developmental neurotoxicants, and the imminent publication of a health based
fluoride drinking water standard in the USA makes addressing extant data
mandatory sooner rather than later.
ACKNOWLEDGMENTS, COMPETING INTERESTS STATEMENT,
AND AUTHORS’ CONTRIBUTIONS
This work was not supported by any outside funding source. Two authors have
received small stipends from the American Environmental Health Sciences Project
(AEHSP), a not-for-profit organization that works on public health issues arising
from exposures to toxics, such as hazardous waste combustion products,
fluoridation chemicals, and other dental products. Thanks are due to Chris Neurath
for his work on the Benchmark Dose graphs, and to Michael Connett for his
maintenance of the scientific literature data base on fluoride for the AEHSP.
The authors declare that they have no competing interests.
JWH did the quantitative risk analysis, wrote the methods section, most of the
discussion and conclusions, and some of the introduction. PC conceived the idea
for the paper, critiqued drafts, and wrote a major part of the introduction. BJS
prepared the graphic material and also critiqued the paper as a whole. DCK
provided suggestions for many of the references. QYX made suggestions on
proper use of his research results in this paper.
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dx.doi:10.1016/j.ntt.2014.11.001
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399 Developmental neurotoxicity of fluoride: a quantitative risk analysis 399
towards establishing a safe daily dose of fluoride for children
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