How the NRC reviewed the work by Zhao et al. (1998)

Comments on the 2006 NAS/NRC report

How the NRC reviewed the work by Zhao et al. (1998)

Postby pfpcnews » Fri Jul 21, 2006 7:56 am

Comments on the NAS Report: Fluoride in Drinking Water: A Scientific Review of EPA's Standards

Today we will start a series of postings addressing the shortcomings of the 2006 NRC Review. Our first posting is a critique concerning the NRC's review of the important study by Zhao et al. from 1998.

NOTE: This is a plain text version of the article. For the original and hyper-linked version of this article, please see:

How the NRC reviewed the work by Zhao et al. (1998)

© 2006 PFPC

On March 22, 2006, the National Research Council (NRC) released its long-awaited review of the EPA’s standards for fluoride in drinking water (NRC, 2006). It included a chapter on the effects of fluoride on the endocrine system, citing for the first time some of the studies which have been published showing the effects of fluoride on thyroid hormone metabolism. Included in the review was a study conducted by Zhao and colleagues (1998) entitled “Long-term Effects of Various Iodine and Fluorine Doses on the Thyroid and Fluorosis in Mice”.

On Oct. 29, 2003 the PFPC had submitted the study to the NRC for inclusion in the Review.

Earlier in the same year (2003), the CDC’s Agency for Toxic Substances and Disease Registry (ATSDR) had published its updated Toxicological Profile for fluorine, hydrogen fluoride, and fluorides. The Zhao study was also reviewed by the ATSDR, but - like earlier major reviews on the subject of fluoride effects on thyroid function (i.e. Demole, 1970; Buergi, 1984), the ATSDR chose to state the exact opposite to what was actually reported in the original study.

The ATSDR stated that Zhao et al. “did not find any alterations in serum T3 or T4 levels in mice exposed to 3.2 mg/kg/day as sodium fluoride in drinking water for 100 or 150 days.” (ATSDR 2003, Page 109).

This statement is and was entirely false, as one can easily verify by looking at a table comparing the values or reading the entire study by Zhao et al.. Very significant alterations were reported.

How did the NRC review this study?

Well, the NRC didn’t deny any effects as the ATSDR did, but it only reported half the facts and distorted the actual findings.

(The relevant sections in the NRC Review can be found here (Page 227, text) and here (Page 452, Table E-1).

Let’s examine the NRC statements a bit closer.

Text Portion

The NRC states:

Zhao et al.(1998), using male Kumin mice, found that both iodine- deficient and iodine-excess conditions produced goiters, but, under iodine-deficient conditions, the goiter incidence at 100 days increased with increased intake of fluoride.

FACT: (What the NRC didn’t state)

1) While this statement is correct, there is much more. Zhao et al. further showed that under iodine-excess conditions, increasing fluoride intake at all levels reduced the goiters found in iodine-excess conditions. (This is exactly the reason why fluorides were used as an anti-thyroid medication for numerous decades in Europe and elsewhere. It was originally used to treat people who suffered from Basedow’s Disease -> goiter and hyperthyroidism caused by excessive iodine consumption).


At 100 days, the high fluoride groups had elevated serum T4 at all concentrations of iodine intake and elevated T3 in iodine-deficient animals.

FACT: (What the NRC didn’t state)

2) This is only a small part of the findings. The NRC failed to state the levels found in iodine-normal conditions which show a dose-dependent increase of T4 caused by fluoride, but also a dose-dependent decrease of T3 (the biologically active thyroid hormone). See: Table.

NOTE: This, of course, shows the effects of fluoride as a TSH analogue. (TSH stimulates the thyroid gland’s T4 secretion into circulation, while at the same time regulates its conversion into T3 in all peripheral tissue.)

This occurs via amplitude-dependent activation of G proteins. TSH regulates via G-protein-regulated pathways.

For over 40 years, fluoride has been used extensively in laboratory investigations as a TSH analogue (=> clone, mimic). Substances which mimic hormones are called endocrine disruptors. [SEE: TSH]

This is not mentioned at all in the NRC report. In fact, it is stated that fluoride acts ‘probably not in the sense of mimicking a normal hormone’.

3) The NRC further failed to state that thyroid hormone levels changed greatly after 150 days as opposed to 100 days (i.e. T4 reduced to half). Why was such an important aspect neglected and not, at least, mentioned? See: Table.


High fluoride intake significantly inhibited the radioiodine uptake in the low- and normal-iodine groups.

FACT: (What the NRC didn’t state)

4) Zhao states:

“Under the ID conditions fluoride in normal and excessive level increased thyroid radioiodine uptake after 100 days, but as the treatment with the same fluoride dose reached 150 days, the uptake was inhibited. Under the IN and IE conditions, excessive fluorine tended to show reducing effect on the radioiodine uptake. Thus, it seemed that the effect of fluorine on radioiodine uptake varied with the changes in fluorine concentration and exposure
time as well as with these of iodine." (See also: Table 4 in Zhao paper)

Table E-1

In Table E-1 of the NRC Review the following info is given:


For iodine-excess groups, thyroid weight relative to body weight decreased significantly with increasing fluoride intake.

FACT: (What the NRC didn’t state)

5) The NRC here makes no mention of the time periods involved, nor the fact that thyroid weight increased in ID groups with increasing fluorine intake.

Zhao et al. state:

At 100 days in ID groups the absolute thyroid weight increased with fluorine intake (P<0.01;Tab.3), but no difference in relative thyroid weight was found, since the body weight of mice increased simultaneously (Tab.2). However, under IE conditions at 100 days the relative thyroid weight decreased with increasing fluorine intake (P<0.05;Tab.3). After 150 days the absolute and relative thyroid weight was significantly increased in ID and IE groups irrespective of
fluorine intake (not shown). (SEE: #1 above)


For iodine-deficient groups, goiter incidence at 100 days was 18%, 44 %, and 66% for low-, normal-, and high-fluoride groups, respectively; at 150 days, goiter incidence was 81-100%.

FACT: (What the NRC didn’t state)

6) See 1, above.


Fluoride excess groups at 100 days had elevated T4 with all concentrations of iodine intake and elevated T3 for iodine deficient animals.

FACT: (What the NRC didn’t state)

7) See #2 and #3, above.


Fluoride excess significantly inhibited radioiodine uptake in iodine deficient and iodine normal groups.

FACT: (What the NRC didn’t state)

8) See #4, above.


Incisor fluorosis occurred only in the fluoride excess groups; severity was greater in the iodine-deficient animals.

FACT: (What the NRC didn’t state)

9) While the NRC made no mention of the interaction of thyroid hormones and dental fluorosis at all in its text section, instead stating that the matter “has not been studied” (Pg. 236) the table by Zhao et al. shows the obvious relationship, which, by the way, the authors had also found in earlier investigations (Zhao et al. 1988; 1992).

Zhao et al. write:

“The results of this experiment showed that iodine deficiency increased the incisor fluorosis incidence and severity of injuries caused by excessive fluoride. At the same time, both ID and IE could increase the fluoride content in the limb bones. Since, under FD (fluoride-deficient) conditions, significant differences in bone fluoride content under different iodine conditions were observed, these apparently indicate that iodine intake does influence the dental and skeletal fluorosis.

It is further interesting that the NRC Review in its chapter on tooth effects (Chapter 4) makes no mention at all of the findings by Zhao et al..


Bone fluoride in fluoride-excess animals was greater in iodine-deficient (means, 2,260-2,880 ppm ash) or iodine-excess animals (means, 2,140-2,380 ppm ash) than in iodine-normal animals
(means, 1,832-2,100 ppm ash).

FACT: (What the NRC didn’t state)

10) Again, the NRC Review makes no mention of this at all in its text portion (Chapter 8), nor in the chapter discussing fluoride effects on bone (Chapter 5), although the data shows a direct relationship. The table supplied by Zhao et al (Table 6) also shows that, under fluoride-normal and iodine-normal conditions, much more fluoride was deposited after 150 days than in either iodine-deficient or iodine-excessive conditions. Under iodine-normal and fluoride-excessive conditions, less fluoride was deposited in bone after 150 days than after 100 days.

A word about the fluoride concentrations used:

Zhao et al. used concentrations of 0.0 ppm F- in water
(fluoride-deficient), 0.6 ppm (fluoride-normal) and 30 ppm (fluoride- excessive).

To put these figures in perspective:

A concentration of 30 ppm is not excessive for rodents.

It is a well-established fact that rats require approx. 10 times more fluoride to produce similar fluoride plasma levels as are observed in
humans. The reason is that the metabolism of rats is 10 times faster than in humans [Rat thyroids secrete T4 at a rate 10 times faster than humans (Capen, 2003)]. Because of this, concentrations of 100 ppm fluoride in water are routinely used by dental researchers investigating dental fluorosis in rats. (see Smith et al, 1993, for a discussion; also Guy & Taves, 1973; Paes & Dapas, 1982; Singer & Ophaug, 1982; etc.)

Was the research by Zhao et al. reviewed correctly by the NRC?


Iodine deficiency disorders and dental fluorosis currently affect more than a third of the world’s population. Surely it is time to evaluate this matter properly?

“Globally, 2.2 billion people (38% of the world's population) live in areas with iodine deficiency and risk its complications. Iodine deficiency was once considered a minor problem, causing goiter, an unsightly but seemingly benign cosmetic blemish. However, it is now known that the effects on the developing brain are much more deadly, and constitute a threat to the social and economic development of many countries. At least 90% of IDD consequences remain hidden.” (ICCIDD, 2006)



Agency for Toxic Substances and Disease Registry (ATSDR). 2003. Toxicological Profile for fluorine, hydrogen fluoride, and fluorides. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Capen CC. Thyroid disease in animals. American Thyroid Assciation. 2003 ... _Capen.pdf

Borke JL, Whitford GM. Chronic fluoride ingestion decreases 45Ca
uptake by rat kidney membranes. J Nutr 1999;129(6):1209-13
(1 micromol /L = 0.019 ppm)

Furlani TA, Whitford GM, Granjeiro JM, Buzalaf MAR. Effect storage time on detectable fluoride in rat nails. Rev. Fac. Odontol Bauru 2001; 9(3/4):113-22

Guy WS, Taves DR. Relation between F in drinking water and human plasma. J Den Res 1973;52:238

ICCIDD Literature 2001 (accessed 2006)

National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C

Paez D, Dapas O. Biochemistry of fluorosis X:Comparative study of the fluoride in biological fluids. Fluoride 1982;15:87-96

Singer L, Ophaug R. Ionic and nonionic fluoride in plasma (or serum). Crit Rev Clin Lab Sci. 1982;18(2):111-40

Smith CE, Nanci A, Denbesten PK. Effects of chronic fluoride exposure on
morphometric parameters defining the stages of amelogenesis and ameloblast modulation in rat incisors. Anat Rec. 1993;237(2):243-58

Zhao W, Zhu H, Yu Z, Aoki K, Misumi J, Zhang X. Long-term Effects of Various Iodine and Fluorine Doses on the Thyroid and Fluorosis in Mice.
Endocr Regul 1998;32(2):63-70

Zhao WY, Zhu HM, Gao YZ, Qin L, Chen CY, Xu DQ. A preliminary study of the interaction of iodide and fluoride in experimental iodide-goiter and fluorosis. Chinese Preventive Medicine 1988; 22:146-148

Zhao WY, Zhu HM, Gao YZ, Qin L, Chen CY, Xu DQ. The study of iodine and fluorine combined action on experimental goiter and fluorosis. J Chinese Endemic Diseases, Prevention and Treatment 1992;(7):16-18
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