NRC – Recommendations
I went through the NRC, Fluoride in Drinking Water book and extracted only the recommendations. They can view them in a short 9 page summary.
http://health.groups.yahoo.com/group/FluoridePoisoning/message/9339

Each section has recommendations for more research, proving that the uncertainties of fluoride are not an illusion. What is more disturbing is that less than 5 of all the studies used silicofluorides, the chemical used in most water fluoridation.

NRC recommendations

FLUORIDE IN DRINKING WATER
A SCIENTIFIC REVIEW OF EPA’S STANDARDS

Committee on Fluoride in Drinking Water

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

Summary

RESEARCH NEEDS

As noted above, gaps in the information on fluoride prevented the committee from

making some judgments about the safety or the risks of fluoride at concentrations of 2 to 4 mg/L.

The following research will be useful for filling those gaps and guiding revisions to the MCLG

and SMCL for fluoride.

• Exposure assessment

— Improved assessment of exposure to fluoride from all sources is needed for a

variety of populations (e.g., different socioeconomic conditions). To the extent possible,

exposures should be characterized for individuals rather than communities, and epidemiologic

studies should group individuals by exposure level rather than by source of exposure, location of

residence, or fluoride concentration in drinking water. Intakes or exposures should be

characterized with and without normalization for body weight. Fluoride should be included in

nationwide biomonitoring surveys and nutritional studies; in particular, analysis of fluoride in

blood and urine samples taken in these surveys would be valuable.

• Pharmacokinetic studies

— The concentrations of fluoride in human bone as a function of exposure

concentration, exposure duration, age, sex, and health status should be studied. Such studies

would be greatly aided by noninvasive means of measuring bone fluoride. Information is

particularly needed on fluoride plasma and bone concentrations in people with small-to-moderate

changes in renal function as well as in those with serious renal deficiency.

— Improved and readily available pharmacokinetic models should be developed.

Additional cross-species pharmacokinetic comparisons would help to validate such models.

• Studies of enamel fluorosis

— Additional studies, including longitudinal studies, should be done in U.S.

communities with water fluoride concentrations greater than 1 mg/L. These studies should focus

on moderate and severe enamel fluorosis in relation to caries and in relation to psychological,

behavioral, and social effects among affected children, their parents, and affected children after

they become adults.

— Methods should be developed and validated to objectively assess enamel fluorosis.

Consideration should be given to distinguishing between staining or mottling of the anterior teeth

and of the posterior teeth so that aesthetic consequences can be more easily assessed.

— More research is needed on the relation between fluoride exposure and dentin

fluorosis and delayed tooth eruption patterns.

10 FLUORIDE IN DRINKING WATER: A SCIENTIFIC REVIEW OF EPA’S STANDARDS

• Bone studies

— A systematic study of clinical stage II and stage III skeletal fluorosis should be

conducted to clarify the relationship between fluoride ingestion, fluoride concentration in bone,

and clinical symptoms.

— More studies of communities with drinking water containing fluoride at 2 mg/L or

more are needed to assess potential bone fracture risk at these higher concentrations.

Quantitative measures of fracture, such as radiologic assessment of vertebral body collapse,

should be used instead of self-reported fractures or hospital records. Moreover, if possible, bone

fluoride concentrations should be measured in long-term residents.

• Other health effects

— Carefully conducted studies of exposure to fluoride and emerging health

parameters of interest (e.g., endocrine effects and brain function) should be performed in

populations in the United States exposed to various concentrations of fluoride. It is important

that exposures be appropriately documented.

2

Measures of Exposure to Fluoride in the United States

RECOMMENDATIONS

• Fluoride should be included in nationwide biomonitoring surveys and nutritional studies

(e.g., CDC’s National Health and Nutrition Examination Survey and affiliated studies). In

particular, analysis of fluoride in blood and urine samples taken in these surveys would be

valuable.

• National data on fluoridation (e.g., CDC 1993) should be updated on a regular basis.

• Probabilistic analysis should be performed for the uncertainty in estimates of individual

and group exposures and for population distributions of exposure (e.g., variability with respect to

long-term water consumption). This would permit estimation of the number of people exposed

at various concentrations, identification of population subgroups at unusual risk for high

exposures, identification or confirmation of those fluoride sources with the greatest impact on

individual or population exposures, and identification or characterization of fluoride sources that

are significant contributors to total exposure for certain population subgroups.

• To assist in estimating individual fluoride exposure from ingestion, manufacturers and

producers should provide information on the fluoride content of commercial foods and

beverages.

• To permit better characterization of current exposures from airborne fluorides, ambient

concentrations of airborne hydrogen fluoride and particulates should be reported on national and

regional scales, especially for areas of known air pollution or known sources of airborne

72 FLUORIDE IN DRINKING WATER: A SCIENTIFIC REVIEW OF EPA’S STANDARDS

fluorides. Additional information on fluoride concentrations in soils in residential and

recreational areas near industrial fluoride sources also should be obtained.

• Additional studies on the relationship between individual fluoride exposures and

measurements of fluoride in tissues (especially bone and nails) and bodily fluids (especially

serum and urine) should be conducted. Such studies should determine both absolute intakes

(mg/day) and body-weight normalized intakes (mg/kg/day).

• Assumptions about the influence of environmental factors, particularly temperature, on

water consumption should be reevaluated in light of current lifestyle practices (e.g., greater

availability of air conditioning, participation in indoor sports).

• Better characterization of exposure to fluoride is needed in epidemiology studies

investigating potential effects. Important exposure aspects of such studies would include the

following:

– collecting data on general dietary status and dietary factors that could influence

exposure or effects, such as calcium, iodine, and aluminum intakes

– characterizing and grouping individuals by estimated (total) exposure, rather

than by source of exposure, location of residence, fluoride concentration in drinking

water, or other surrogates

– reporting intakes or exposures with and without normalization for body weight

(e.g., mg/day and mg/kg/day)

– addressing uncertainties associated with exposure, including uncertainties in

measurements of fluoride concentrations in bodily fluids and tissues

– reporting data in terms of individual correlations between intake and effect,

differences in subgroups, and differences in percentages of individuals showing an effect

and not just differences in group or population means.

• Further analysis should be done of the concentrations of fluoride and various fluoride

species or complexes (especially fluorosilicates and aluminofluorides) present in tap water, using

a range of water samples (e.g., of different hardness and mineral content). Research also should

include characterizing any changes in speciation that occur when tap water is used for various

purposes—for example, to make acidic beverages.

• The possibility of biological effects of SiF6

2-, as opposed to free fluoride ion, should be

examined.

• The biological effects of aluminofluoride complexes should be researched further,

including the conditions (exposure conditions and physiological conditions) under which the

complexes can be expected to occur and to have biological effects.

3

Pharmacokinetics of Fluoride

RESEARCH RECOMMENDATIONS

• Additional research is needed on fluoride concentrations in human bone as a function of

magnitude and duration of exposure, age, gender, and health status. Such studies would be

greatly aided by noninvasive means of measuring bone fluoride. As discussed in other chapters

of this report, some soft tissue effects may be associated with fluoride exposure. Most

measurements of fluoride in soft tissues are based on short-term exposures and some atypically

high values have been reported. Thus, more studies are needed on fluoride concentrations in soft

tissues (e.g., brain, thyroid, kidney) following chronic exposure.

• Research is needed on fluoride plasma and bone concentrations in people with small to

moderate changes in renal function as well as patients with serious renal deficiency. Other

potentially sensitive populations should be evaluated, including the elderly, postmenopausal

women, and people with altered acid-base balance.

• Improved and readily available pharmacokinetic models should be developed.

• Additional studies comparing pharmacokinetics across species are needed.

• More work is needed on the potential for release of fluoride by the metabolism of

organofluorines.

4

Effects of Fluoride on Teeth

RECOMMENDATIONS

• Additional studies, including longitudinal studies, of the prevalence and severity of

enamel fluorosis should be done in U.S. communities with fluoride concentrations higher than 1

mg/L. These studies should focus on moderate and severe enamel fluorosis in relation to caries

and in relation to psychological, behavioral, and social effects among affected children, their

parents, and affected children after they become adults.

• Methods should be developed and validated to objectively assess enamel fluorosis.

Consideration should be given to distinguishing between staining or mottling of the anterior teeth

and of the posterior teeth so that aesthetic consequences can be more easily assessed.

• More research is needed on the relation between fluoride exposure and dentin fluorosis

and delayed tooth eruption patterns.

5

Musculoskeletal Effects

RECOMMENDATIONS

• A more complete analysis of communities consuming water with fluoride at 2 and 4

mg/L is necessary to assess the potential for fracture risk at those concentrations. These studies

should use a quantitative measure of fracture such as radiological assessment of vertebral body

collapse rather than self-reported fractures or hospital records. Moreover, if possible, bone

fluoride concentrations should be measured in long-term residents.

MUSCULOSKELETAL EFFECTS 147

• The effects of fluoride exposure in bone cells in vivo depend on the local

concentrations surrounding the cells. More data are needed on concentration gradients during

active remodeling. A series of experiments aimed at quantifying the graded exposure of bone

and marrow cells to fluoride released by osteoclastic activity would go a long way in estimating

the skeletal effects of this agent.

• A systematic study of stage II and stage III skeletal fluorosis should be conducted to

clarify the relationship of fluoride ingestion, fluoride concentration in bone, and clinical

symptoms. Such a study might be particularly valuable in populations in which predicted bone

concentrations are high enough to suggest a risk of stage II skeletal fluorosis (e.g., areas with

water concentrations of fluoride above 2 mg/L).

• More research is needed on bone concentrations of fluoride in people with altered renal

function, as well as other potentially sensitive populations (e.g., the elderly, post-menopausal

women, people with altered acid-balance), to better understand the risks of musculoskeletal

effects in these populations.

6

Reproductive and Developmental Effects of Fluoride

RECOMMENDATIONS

• Studies in occupational settings are often useful in identifying target organs that might

be susceptible to disruption and in need of further evaluation at the lower concentrations of

exposure experienced by the general population. Therefore, carefully controlled studies of

occupational exposure to fluoride and reproductive parameters are needed to further evaluate the

possible association between fluoride and alterations in reproductive hormones reported by

Ortiz-Perez et al. (2003).

• Freni (1994) found an association between high fluoride concentrations (3 mg/L or

more) in drinking water and decreased total fertility rate. The overall study approach used by

Freni has merit and could yield valuable new information if more attention is given to controlling

for reproductive variables at the individual and group levels. Because that study had design

limitations, additional research is needed to substantiate whether an association exists.

• A reanalysis of data on Down’s syndrome and fluoride by Takahashi (1998) suggested a

possible association in children born to young mothers. A case-control study of the incidence of

Down’s syndrome in young women and fluoride exposure would be useful for addressing that

issue. However, it may be particularly difficult to study the incidence of Down’s syndrome

today given increased fetal genetic testing and concerns with confidentiality

7

Neurotoxicity and Neurobehavioral Effects

RECOMMENDATIONS

On the basis of information largely derived from histological, chemical, and molecular

studies, it is apparent that fluorides have the ability to interfere with the functions of the brain

and the body by direct and indirect means. To determine the possible adverse effects of fluoride,

additional data from both the experimental and the clinical sciences are needed.

• The possibility has been raised by the studies conducted in China that fluoride can

lower intellectual abilities. Thus, studies of populations exposed to different concentrations of

fluoride in drinking water should include measurements of reasoning ability, problem solving,

IQ, and short- and long-term memory. Care should be taken to ensure that proper testing

methods are used, that all sources of exposure to fluoride are assessed, and that comparison

populations have similar cultures and socioeconomic status.

• Studies of populations exposed to different concentrations of fluoride should be

undertaken to evaluate neurochemical changes that may be associated with dementia.

Consideration should be given to assessing effects from chronic exposure, effects that might be

delayed or occur late-in-life, and individual susceptibility (see Chapter 2 and 3 for discussion of

subpopulations that might be more susceptible to the effects of fluoride from exposure and

physiologic standpoints, respectively).

• Additional animal studies designed to evaluate reasoning are needed. These studies

must be carefully designed to measure cognitive skills beyond rote learning or the acquisition of

simple associations, and test environmentally relevant doses of fluoride.

• At the present time, questions about the effects of the many histological, biochemical,

and molecular changes caused by fluorides cannot be related to specific alterations in behavior or

to known diseases. Additional studies of the relationship of the changes in the brain as they

affect the hormonal and neuropeptide status of the body are needed. Such relationships should

be studied in greater detail and under different environmental conditions.

• Most of the studies dealing with neural and behavioral responses have tested NaF. It is

important to determine whether other forms of fluoride (e.g., silicofluorides) produce the same

effects in animal models.

8

Effects on the Endocrine System

RECOMMENDATIONS

• Further effort is necessary to characterize the direct and indirect mechanisms of

fluoride’s action on the endocrine system and the factors that determine the response, if any, in a

given individual. Such studies would address the following:

— the in vivo effects of fluoride on second messenger function

— the in vivo effects of fluoride on various enzymes

— the integration of the endocrine system (both internally and with other systems

such as the neurological system)

— identification of those factors, endogenous (e.g., age, sex, genetic factors, or

preexisting disease) or exogenous (e.g., dietary calcium or iodine concentrations, malnutrition),

associated with increased likelihood of effects of fluoride exposures in individuals

— consideration of the impact of multiple contaminants (e.g., fluoride and

perchlorate) that affect the same endocrine system or mechanism

— examination of effects at several time points in the same individuals to identify

any transient, reversible, or adaptive responses to fluoride exposure.

• Better characterization of exposure to fluoride is needed in epidemiology studies

investigating potential endocrine effects of fluoride. Important exposure aspects of such studies

would include the following:

— collecting data on general dietary status and dietary factors that could influence the

response, such as calcium, iodine, selenium, and aluminum intakes

224 FLUORIDE IN DRINKING WATER: A SCIENTIFIC REVIEW OF EPA’S STANDARDS

— characterizing and grouping individuals by estimated (total) exposure, rather than

by source of exposure, location of residence, fluoride concentration in drinking water, or other

surrogates

— reporting intakes or exposures with and without normalization for body weight

(e.g., mg/day and mg/kg/day), to reduce some of the uncertainty associated with comparisons of

separate studies

— addressing uncertainties associated with exposure and response, including

uncertainties in measurements of fluoride concentrations in bodily fluids and tissues and

uncertainties in responses (e.g., hormone concentrations)

— reporting data in terms of individual correlations between intake and effect,

differences in subgroups, and differences in percentages of individuals showing an effect and not

just differences in group or population means.

— examining a range of exposures, with normal or control groups having very low

fluoride exposures (below those associated with 1 mg/L in drinking water for humans).

• The effects of fluoride on various aspects of endocrine function should be examined

further, particularly with respect to a possible role in the development of several diseases or

mental states in the United States. Major areas for investigation include the following:

— thyroid disease (especially in light of decreasing iodine intake by the U.S.

population);

— nutritional (calcium-deficiency) rickets;

— calcium metabolism (including measurements of both calcitonin and PTH);

— pineal function (including, but not limited to, melatonin production); and development of glucose intolerance and diabetes.

9

Effects on the Gastrointestinal, Renal,

Hepatic, and Immune Systems

RECOMMENDATIONS

Gastric Effects

• Studies are needed to evaluate gastric responses to fluoride from natural sources at

concentrations up to 4 mg/L and from artificial sources. Data on both types of exposures would

help to distinguish between the effects of water fluoridation chemicals and natural fluoride.

Consideration should be given to identifying groups that might be more susceptible to the gastric

effects of fluoride.

• The influence of fluoride and other minerals, such as calcium and magnesium, present

in water sources containing natural concentrations of fluoride up to 4 mg/L on gastric responses

should be carefully measured.

Renal and Hepatic Effects

• Rigorous epidemiologic studies should be carried out in North America to determine

whether fluoride in drinking water at 4 mg/L is associated with an increased incidence of kidney

stones. There is a particular need to study patients with renal impairments.

• Additional studies should be carried out to determine the incidence, prevalence, and

severity of renal osteodystrophy in patients with renal impairments in areas where there is

fluoride at up to 4 mg/L in the drinking water.

• The effect of low doses of fluoride on kidney and liver enzyme functions in humans

needs to be carefully documented in communities exposed to different concentrations of fluoride

in drinking water.

Immune Response

• Epidemiologic studies should be carried out to determine whether there is a higher

prevalence of hypersensitivity reactions in areas where there is elevated fluoride in the drinking

water. If evidence is found, hypersensitive subjects could then be selected to test, by means of

Effects on the Gastrointestinal, Renal, Hepatic, and Immune Systems 259

double-blinded randomized clinical trials, which fluoride chemicals can cause hypersensitivity.

In addition, studies could be conducted to determine what percentage of immunocompromised

subjects have adverse reactions when exposed to fluoride in the range of 1-4 mg/L in drinking

water.

• More research is needed on the immunotoxic effects of fluoride in animals and humans

to determine if fluoride accumulation can influence immune function.

• It is paramount that careful biochemical studies be conducted to determine what

fluoride concentrations occur in the bone and surrounding interstitial fluids from exposure to

fluoride in drinking water at up to 4 mg/L, because bone marrow is the source of the progenitors

that produce the immune system cells.

10

Genotoxicity and Carcinogenicity

RECOMMENDATIONS

Carcinogenicity

• The results of the Douglass et al. multicenter osteosarcoma study (expected in the

summer of 2006) could add important data to the current body of literature on fluoride risks for

osteosarcoma because the study includes bone fluoride concentrations for cases and controls.

When this study is published, it should be considered in context with the existing body of evidence

to help determine what follow-up studies are needed.

• Further research on a possible effect of fluoride on bladder cancer risk should be conducted.

Since bladder cancer is relatively common (compared with osteosarcoma), both cohort

and case-control designs would be feasible to address this question. For example, valuable data

might be yielded by analyses of cancer outcomes among the cohorts followed for other health

outcomes, such as fractures (see Chapter 5).

Genotoxicity

• The positive in vivo genotoxicity studies described in the chapter were conducted in India

and China, where fluoride concentrations in drinking water are often higher than those in the

United States. Further, each had a dearth of information on the selection of subjects and was

based on small numbers of participants. Therefore, in vivo human genotoxicity studies in U.S.

populations or other populations with nutritional and sociodemographic variables similar to those

in the United States should be conducted. Documentation of subject enrollment with different

fluoride concentrations would be useful to addressing the potential genotoxic hazards of fluoridated

water in this country.

11

Drinking Water Standards for Fluoride

FINDINGS AND RECOMMENDATIONS

Maximum-Contaminant-Level Goal

In light of the collective evidence on various health end points and total exposure to

fluoride, the committee concludes that EPA’s MCLG of 4 mg/L should be lowered. Lowering

the MCLG will prevent children from developing severe enamel fluorosis and will reduce the

lifetime accumulation of fluoride into bone that the majority of the committee concluded is likely

to put individuals at increased risk of bone fracture and possibly skeletal fluorosis, which are

particular concerns for subpopulations that are prone to accumulating fluoride in their bone.

Recommendation: To develop an MCLG that is protective of severe enamel fluorosis,

clinical stage II skeletal fluorosis, and bone fractures, EPA should update the risk assessment of

fluoride to include new data on health risks and better estimates of total exposure (relative

source contribution) in individuals and to use current approaches to quantifying risk,

considering susceptible subpopulations, and characterizing uncertainties and variability.

Secondary Maximum Contaminant Level

The prevalence of severe enamel fluorosis is very low (near zero) at fluoride

concentrations below 2 mg/L. However, from a cosmetic standpoint, the SMCL does not

completely prevent the occurrence of moderate enamel fluorosis. EPA has indicated that the

SMCL was intended to reduce the severity and occurrence of the condition to 15% or less of the

exposed population. The available data indicates that fewer than 15% of children would

experience moderate enamel fluorosis of aesthetic concern (discoloration of the front teeth).

However, the degree to which moderate enamel fluorosis might go beyond a cosmetic effect to

create an adverse psychological effect or an adverse effect on social functioning is not known.

Recommendations: Additional studies, including longitudinal studies, of the prevalence

and severity of enamel fluorosis should be done in U.S. communities with fluoride concentrations

greater than 1 mg/L. These studies should focus on moderate and severe enamel fluorosis in

relation to caries and in relation to psychological, behavioral, and social effects among affected

children, among their parents, and among affected children after they become adults.

To better define the aesthetics of enamel fluorosis, methods should be developed and

validated to objectively assess enamel fluorosis. Staining and mottling of the anterior teeth

should be distinguished from staining of the posterior teeth so that aesthetic consequences can

be more easily assessed.