FLUORIDE ACTION NETWORK PESTICIDE PROJECT

Sulfuryl Fluoride. Comments submitted to US EPA from Ellen Connett on the Proposed Pesticide Temporary Tolerances that appeared in the September 5, 2001, Federal Register.

Email Submission to: opp-docket@epa.gov

Date: September 29, 2001

Submission from:

Ellen Connett, 82 Judson Street, Canton NY 13617

Re: COMMENTS ON docket control number OPP-301166

Federal Register: September 5, 2001 (Volume 66, Number 172) [Page 46415-46425]

[OPP-301166; FRL-6799-6]

Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

________________________________________________________________

The comment period on this important Proposed Rule was insufficient.

ADVERSE EFFECTS ON BRAIN. The Proposed Rule cites several animal studies for adverse effects on the brain from exposure to Sulfuryl fluoride. (It would have been helpful to the public if EPA put into context the uniqueness or otherwise of pesticidal substances approved for human consumption that adversely affect the brain.)

For example, the following results are cited:

1. In a 2-generation reproduction inhalation study in rats, vacuolation of the white matter in the brain… were observed in the parental animals.

2. In 2-week inhalation studies in rats, dogs and rabbits, different target organs were affected… In rabbits, the primary target organ was the brain, in which malacia (necrosis) and vacuolation were observed in the cerebrum.

3. In subchronic (90-day) inhalation studies in rats, dogs, rabbits and mice, the brain was the major target organ. Malacia and/or vacuolation were observed in the white matter of the brain in all four species. The portions of the brain most often affected were the caudate-putamen nucleus in the basal ganglia, the white fiber tracts in the internal and external capsules, and the globus pallidus of the cerebrum.

4. In chronic (1-2 year) inhalation studies in rats, dogs and mice, target organs were the same as in the 90-day studies… Other treatment-related effects in rats included effects in the brain (vacuolation of the cerebrum and thalamus/hypothalamus)…

5. In chronic (1-2 year) inhalation studies in rats, dogs and mice, target organs were the same as in the 90-day studies…. In dogs and mice, increased mortalities, malacia and/or vacuolation in the white matter in the brain

6. In a 2-generation reproduction inhalation study in rats, vacuolation of the white matter in the brain…

7. In a 90-day study (rat)… Vacuolation of the white matter in the cerebrum was also observed at 300 ppm in this study.

In 1998 the results of a long-term, low-dose rat study were published. One rat group was exposed to sodium fluoride (NaF); the other to a fluoroaluminum complex (AlF3); both in double-distilled deionized water (ddw). A third group received only the ddw water. Both the fluoride exposed groups

“exhibited a bimodal distribution of vascular B-amyloid in both hemispheres of the lateral posterior thalamus, it was either absent or present in high levels of both treated groups.”

B-amyloid deposits on the brain are found in patients with Alzheimer’s disease.

The authors speculate that fluoride enables aluminum to cross the blood-brain barrier. They stated:

“Both the AlF3 and NaF groups had increased brain Al levels relative to the controls. The Al level in the NaF group was double that of controls and the Al level in the AlF3 group was even greater. The Al detected in the controls and NaF groups is most likely due to the presence of this element in the rat chow. Reported estimates of the Al content in Purina Rodent Laboratory Chow range from 150 ppm to 8300 ppm Al. These data indicate that normal rat chow provides the Al availability for all animals, including the controls.”

The authors speculate that in the NaF exposed rats, the fluoride enabled the aluminum in the rat chow to move into the brain. According to the authors,

“While the small amount of AlF3 in the drinking water of rats required for neurotoxic effects is surprising, perhaps even more surprising are the neurotoxic results of NaF at the dose given in the present study (2.1 ppm)… F has diverse actions on a variety of cellular and physiological functions including the inhibition of a variety of enzymes, a corrosive action in acid mediums, hypocalcemia, phyperkalemia, and perhaps cerebral impairment… In summary, chronic administration of AlF3 and NaF in the drinking water of rats resulted in distinct morphological alterations in the brains, including effects on neurons and cerebrovasculature.”

The authors also noted:

“Histological evidence of glomerular distortions and other signs of kidney disorders were found in animals in both the AlF3 and NaF groups.” (ref: Varner JA et al. 1998)

Alzheimer’s disease is an obvious severe condition that society is deeply concerned about. The human experiment that EPA is attempting to approve in allowing very high levels of inorganic fluoride for human consumption is distinctly unwise until the consequences of the results of the Varner et al. study are addressed. Until then, all unnecessary exposure to inorganic fluoride must be defined as unsafe to human health, scientifically unwise, and unethical. Of particular importance are the consequences of the Varner et al. study to children. EPA noted in its Sulfuryl fluoride RED document of 1992:

“Very young children may be more susceptible than adults to sulfuryl fluoride neurotoxicity because the developing brain may be more vulnerable to chemical injury (p 15).”

I urge the EPA to invoke the precautionary principle and revoke this EUP.

PROPOSED RULE: The temporary tolerances will expire April 1, 2006. This will allow approximately 18 months after the end of the EUP, for all the treated commodities to clear commerce…. The tolerance expression will clarify that the tolerance for fluoride residues in or on raisins covers residues from application of both cryolite to grapes, expected to be the major source of fluoride residues of fluoride from post-harvest treatment with sulfuryl fluoride.

COMMENT: Economic impacts of this EUP on California export markets has neither been assessed or discussed.

This EUP effectively will affect every one who eats walnuts and raisins in the US; as well as a considerable export market. California produces 99 percent of the walnuts grown in the US and 38 percent of the world’s production. Over 40 percent of the California crop is currently exported (ref: http://www.sarep.ucdavis.edu/BIFS/bifs01/annual.htm#walnut). Raisin consumption accounts for over one-half of the dried fruit consumed in the US (ref: http://cherokee.agecon.clemson.edu/otlk332.htm).

The proposed very high tolerance levels for inorganic fluoride in and on raisins (30 ppm) and walnuts (12 ppm) could result in adverse economic impacts for the US export market to Europe and Japan. Note in the the FR, July 6, 2000 [OPP-301008; FRL-6590-1] that the European Community established a tolerance of 1 ppm for fluoride residues in Wine that effectively changed the course of the use of cryolite on grapes grown for the export wine market:

“…for the 2000 crop year, nearly all major California wineries with export markets have advised their growers that they will not accept grapes which have been treated with cryolite or any other product which would affect the level of fluorides in wine. The European Community recently established strict tolerance levels of 1 ppm with respect to fluoride residues. There is a direct correlation between even limited use of cryolite on wine grapes which can result in fluoride levels in wine above 3 ppm.”

PROPOSED RULE: The fluoride tolerance for raisins must also account for naturally occurring levels of fluoride in raisins. Residues of fluoride from use of sulfuryl fluoride on raisins are expected to be at most trace levels with most raisins having non-detectable (1.1 ppm) residue levels.

COMMENT: Lack of transparency as to why the Fluoride tolerances are so high for raisins.

1.1 ppm is high for human consumption of inorganic fluoride; the adjective “non-detectable” is misleading. The EPA was negligent for not providing clear information to the public for the reason(s) why fluoride residues on raisins from the use of Sulfuryl fluoride are “to be at most” 1.1 ppm and why a 30 ppm tolerance is being requested. EPA’s Dennis McNeilly informed me this summer that the current tolerance for fluoride from the use of cryolite in and on raisins is 7 ppm, the same as for grapes (albeit that the Federal Register of August 7, 1997 [PF-750; FRL-5727-3] lists no approved tolerance for raisins; see Comment No. 6 below). The public has been offered no information for the basis of the four-fold increase of inorganic fluoride in and on raisins. Because of this the public have been denied the right to submit relevant comments. This EUP has been issued prematurely because (1) EPA did not provide a clear explanation for this exponential tolerance increase; and (2) EPA noted that the “fluoride tolerance for raisins must also account for naturally occuring levels of fluoride in raisins.” However, EPA did not inform the public in the Proposed Rule what the “naturally occurring levels” of fluoride in raisins are. By not doing so, the public has been doubly disadvantaged in submitting relevant comments to the high tolerance of 30 ppm in raisins that EPA has proposed.

PROPOSED RULE: Sulfuryl fluoride is a fumigant that is being proposed as a methyl bromide alternative for the post-harvest control of pests in stored walnuts and raisins. In the future, it is likely that other commodities may be proposed for post-harvest, stored commodity fumigation using this fumigant.

COMMENT: EPA’s RED on Sulfuryl Fluoride states that Dietary Exposure, Environmental Fate, and Ecological Effects Risk Assessment were never examined because Sulfuryl fluoride was not registered for food use. To consider it “likely” that fluoride tolerances for other food commodities will be proposed is premature and a cause of serious concern without this relevant information.

PROPOSED RULE: EPA determines that the tolerance is “safe” – to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.” This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to “ensure that there is a reasonable certainty that no harm will result to infants and children… The only significant exposure pathway for inorganic fluoride is via the diet (food + drinking water).

COMMENT: EPA did not consider all the routes of current exposure to fluoride (“The only significant exposure pathway for inorganic fluoride is via the diet (food + drinking water.”) especially to children. The proposed fluoride tolerances for raisins (30 ppm) and walnuts (12 ppm) are too high; and are NOT safe.

Since fluoridation of US drinking water began in 1945 our exposure to other sources of fluoride has increased substantially. These include:

1. Processing food and beverages with fluoridated water. According to ATSDR, “Cooking food in fluoridated water results in increased dietary fluoride levels.” (ref: ATSDR. 1993.)

2. Children in North America are already being over-exposed to fluoride according to the information in the Table below which was published in a Canadian government 1999 report (ref: Canada Report 1999, p 55):

Table 16: Recommended and actual fluoride intake estimates (Lewis and Limeback, 1996)
Age group: Recommended Fluoride intake Actual Fluoride Intake
— (microgram/kg bw/day) —
Up to 6 months 3-71(99) 14-93 (formula-fed)0.5-2.6 (breast-fed)
7 months to 4 years 56-81(105) 87-160*45-96**
5 to 11 years 32-45(58) 49-79*26-44**
12 to 19 years 24-33 33-45*17-21**
20 years and over 32-41 47-58*32-36**
( ): Upper value to prevent moderate fluorosis
* Estimate of actual intake based on consumption of fluoridated water
** Estimate of actual intake based on consumption of non-fluoridated water


3. Mother to Infant Exposure:

a. Placenta: Fluoride crosses the placenta and is transferred from mother to foetus (p 20. re: Canada Report 1993).

b. Breast Milk: Natural levels of fluoride in human milk are estimated at approximately 0.01 ppm which are approximately a hundred times less than baby formula reconstituted with fluoridated water. (ref: CJ Spak et al. 1983)

c. Fluoridated Water. Fluoride levels in breast milk are significantly higher for women consuming fluoridated water compared to women consuming non-fluoridated water. According to the 1993 Canada Report:

“The mean concentration of inorganic fluoride in breast milk obtained from 32 women consuming drinking water containing < 0.16 ppm (mg/L) fluoride was 4.4 ng/g; the concentration in breast milk obtained from 112 women consuming water containing 1 ppm (mg/L) fluoride was 9.8 ng/g (page 19. ref: Canada Report 1993).”

See Table directly below for percentage of fluoridated drinking water for each state.

4. Air pollution from fluoride emitting industries. According to the latest TRI (1999) Hydrogen Fluoride (CAS No. 7664-39-3) alone ranked 6th for Air Emissions of Toxic Chemicals released in the U.S. Also included in the fourth column of the Table below is the “Percent of Public Water Supply Population Using Fluoridated Water (p xx; ref: CDC 1993).”

TRI RankHF Air Releases in 1999 State Pounds HF released HF Rank to Air in State TRI % of fluoridated public drinking water
1 OH 6,648,502 3 87.9
2 NC 5,053,418 3 78.5
3 PA 4,638,649 3 50.9
4 GA 4,359,289 4 92.1
5 WV 4,288,093 3 82.1
6 IN 4,186,760 6 98.6
7 AL 3,983,259 5 82.6
8 TX 3,677,457 7 64.0
9 FL 2,988,867 6 58.3
10 IL 2,504,137 6 95.2
11 MI 2,412,653 6 88.5
12 MO 2,370,885 4 71.4
13 KY 2,149,358 6 100
14 SC 2,100,535 5 90.0
15 TN 1,893,633 9 92.0
16 WA 1,819,099 6 53.2
17 VA 1,670,413 6 72.1
18 NY 1,638,044 3 69.7
19 MD 1,570,837 4 85.8
20 IA 1,250,170 7 91.4
21 WI 1,228,618 7 93.0
22 NE 1,178,771 2 62.1
23 OK 1,142,949 3 58.0
24 AR 920,097 7 58.7
25 CO 747,419 1 81.7
26 KS 741,885 9 58.4
27 AZ 700,278 2 49.9
28 ND 644,032 2 96.4
29 MS 614,385 9 48.4
30 LA 559,476 13 55.7
31 UT 485,174 3 3.1
32 NV 413,300 2 2.1
33 MT 387,815 6 25.9
34 NJ 257,023 11 16.2
35 NM 230,793 2 66.2
36 NH 192,460 6 24.0
37 OR 170,038 13 24.8
38 MA 158,232 8 57.0
39 DE 156,129 6 67.4
40 WY 146,208 4 35.7
41 MN 139,747 17 93.4
42 ID 130,955 10 130,955
43 SD 85,010 5 100
44 AK 46,285 5 61.2
45 CA 9,823 47 15.7*
46 VT 2,775 7 57.4
47 RI 2,476 14 100
48 ME 2,381 34 55.8
49 CT 1,019 52 85.9
50 PR 539 49 na
51 HI 32 20 13.0
* In 1996 California passed a statewide mandatory fluoridation Bill.


5. Dental products.
According to a 1993 Canadian report: “Dental products that contain fluoride, such as toothpaste, have been identified as significant sources of inorganic fluoride for children and adolescents (p 42, ref: Canada Report 1993.)”According to a 1999 Canadian report, “A recent paper analyzed reports to the American Association of Poison Control Centres (Shulman et al, 1997) of suspected over-ingestion of fluoride from home-use dental products. Children under the age of 6 years accounted for 80% of the reports. Although the outcomes were not serious, many required medical treatment. Fluoridated toothpastes and mouthrinses can result in levels of ingestion that may be toxic. For example, 50 g of 1,000 ppm of toothpaste could result in toxicity in a child of 10 kg body weight. Consequently, products containing fluoride should be kept out of reach of children to prevent these potentially serious levels of ingestion (p 35. ref: Canada Report 1999).”

6. Pesticide residues. One example is of the current and proposed tolerances for cryolite. As reported in the Federal Register of August 7, 1997 [PF-750; FRL-5727-3] notice for tolerances from the The Cryolite Task Force.

Commodity Tolerance: Current Tolerance: Proposed in 1997
Cabbage 7 ppm 45 ppm
Citrus Fruits 7 ppm 95 ppm
Collards 7 ppm 35 ppm
Eggplant 7 ppm 30 ppm
Lettuce 7 ppm
Lettuce, head 180 ppm
Lettuce, leaf 40 ppm
Peaches 7 ppm 10 ppm
Raisins none 55 ppm
Tomatoes 7 ppm 30 ppm
Tomato paste none 45 ppm


7. PROPOSED RULE:
EPA notes that anticipated fluoride exposure resulting from post-harvest use of sulfuryl fluoride on walnuts and raisins is negligible in comparison to fluoride levels permitted under the Safe Drinking Water Act. The Agency’s Office of Water has set a MCLG of 4.0 ppm for fluoride. The Office of Pesticides Programs has used this number as the exposure level in drinking water. This concentration is a level that provides no known or anticipated adverse health effects.

COMMENT: In 1994, Freni, a FDA researcher, published results from a study that found an association to high fluoride concentrations in drinking water (3 ppm) with decreased birth rates. I am not aware of any peer-reviewed published report that refutes Freni on this. Freni raised the question “whether public health concerns and toxicologic research should not shift their focus from the isolated intake from fluoridated water to the potential toxicity of the total fluoride intake.” (Ref: Freni SC. 1994. Exposure to high fluoride concentrations in drinking water is associated with decreased birth rates. Journal of Toxicology and Environmental Health, 42:109-12.)

Population subsets unusually susceptible to fluoride’s toxic effects. According to ATSDR 1993, pp 112-113 (ref: ATSDR 1993).

“Existing data indicate that subsets of the population may be unusually susceptible to the toxic effects of fluoride and its compounds. These populations include the elderly, people with deficiencies of calcium, magnesium, and/or vitamin C, and people with cardiovascular and kidney problems. Because fluoride is excreted through the kidney, people with renal insufficiency would have impaired renal clearance of fluoride. Fluoride retention on a low-protein, low-calcium, and low-phosphorous diet was 65% in patients with chronic renal failure, compared with 20% in normal subjects. Serum creatinine levels were weekly correlated (r=).35-o.59) with serum fluoride levels… Impaired renal clearance of fluoride has also been found in people with diabetes mellitus and cardiac insufficiency. People over the age of 50 often have decreased renal fluoride clearance. This may be because of the decreased rate of accumulation of fluoride in bones or decreased renal function. This decreased clearance of fluoride may indicate that elderly people are more susceptible to fluoride toxicity.

“Poor nutrition increases the incidence and severity of dental fluorosis and skeletal fluorosis. Comparison of dietary adequacy, water fluoride levels, and the incidence of skeletal fluorosis in several villages in India suggested that vitamin C deficiency played a major role in the disease. Calcium intake met minimum standards, although the source was grains and vegetables, rather than milk, and bioavailability was not determined. Because of the role of calcium in bone formation, calcium deficiency would be expected to increase susceptibility to effects of fluoride… Inadequate dietary levels of magnesium may affect the toxic effects of fluoride….”

Some people with cardiovascular problems may be at increased risk of fluoride toxicity. Fluoride inhibits glycolysis by inhibiting enolase. It also inhibits energy metabolism through the tricarboxylic acid cycle by blocking the entry of pyruvate and fatty acids and by inhibiting succinic dehydrogenase.”There is evidence that daily doses of 34 mg fluoride (0.48 mg/kg/day) increases the risk of nonvertebral fractures in women with postmenopausal osteoporosis. Postmenopausal women and elderly men in fluoridated communities may also be at increased risk of fractures.”

Fluoride is an Endocrine Disruptor. As reported in the Federal Register of August 7, 1997 [PF-750; FRL-5727-3] notice for tolerances from the The Cryolite Task Force: “Endocrine effects have not been recognized as toxicological endpoints for fluoride by any worldwide regulatory authority.” However, in scientific circles worldwide fluoride is known as G-protein activators (ref: G-Protein 1-10; -a few of many examples). Fluoride mimics the action of many water-soluble hormones by interacting with G proteins to transmit hormonal messages across cell membranes. Because of this Fluoride is an endocrine disruptor and children are particularly vulnerable because of their developing hormonal systems. EPA is negligent if it does not review the substantial body of scientific literature on fluoride and G-proteins. EPA has the ability and expertise to do this. It is incumbent upon EPA to be perceived to be responsive to the science of an issue. EPA should be responsive that in the Proposed Rule the following impacts on the thyroid gland from animal studies are noted:

a. In mice, follicular cell hypertrophy was noted in the thyroid gland.

b. In dogs and mice, increased mortalities, malacia and/or vacuolation in the white matter in the brain, histopathology in the lungs, and follicular cell hypertrophy in the thyroid gland were observed.

Earlier menstruation in community with fluoridated water.

In 1945, Newburg NY was the first city to be fluoridated in the US. Ten years after fluoridation began researchers noted that girls began menstruation five months earlier compared to girls in the control city of unfluoridated Kingston NY. The researchers at the time commented that this was not significant; however, several scientists that I have contacted said this finding was significant. (Schlesinger, ER et al (1956). Newburgh-Kingston caries-fluorine study X111. Pediatric findings after ten years. Journal of the American Dental Association. V 52.)

Regression analysis of cancer incidence rates and water fluoride in the U.S.A. based on IACR/ IARC (WHO) data (1978-1992). International Agency for Research on Cancer. Takahashi K, Akiniwa K, Narita K. J Epidemiol 2001 Jul;11(4):170-9.

“Age-specific and age-standardized rates (ASR) of registered cancers for nine communities in the U.S.A. (21.8 million inhabitants, mainly white) were obtained from IARC data (1978-82, 1983-87, 1988-92). The percentage of people supplied with “optimally” fluoridated drinking water (FD) obtained from the Fluoridation Census 1985, U.S.A. were used for regression analysis of incidence rates of cancers at thirty six sites (ICD-WHO, 1957). About two-thirds of sites of the body (ICD) were associated positively with FD, but negative associations were noted for lip cancer, melanoma of the skin, and cancers of the prostate and thyroid gland. In digestive organs the stomach showed only limited and small intestine no significant link. However, cancers of the oral cavity and pharynx, colon and rectum, hepato-biliary and urinary organs were positively associated with FD. This was also the case for bone cancers in male, in line with results of rat experiments. Brain tumors and T-cell system Hodgkin’s disease, Non-Hodgkin lymphoma, multiple myeloma, melanoma of the skin and monocytic leukaemia were also correlated with FD. Of the 36 sites, 23 were positively significant (63.9%), 9 not significant (25.0%) and 4 negatively significant (11.1%). This may indicate a complexity of mechanisms of action of fluoride in the body, especially in view of the coexisting positive and negative correlations with the fluoridation index. The likelihood of fluoride acting as a genetic cause of cancer requires consideration.”

PROPOSED RULE: Dietary exposure to fluoride from drinking water is estimated to average 0.057 mg/kg/day

COMMENT. It is important for EPA to use the range of exposure 0.023 to 0.094 mg/kg/day, instead of the average (0.057 mg/kg/day) to insure that heavily exposed individuals do not disappear from concern.

References:

ATSDR 1993. Toxicological profile for fluorides, hydrogen fluoride, and fluorine. Report No. TP-91/17)

Canada Report 1993. Priority Substances List Assessment Report. Inorganic Fluorides, Government of Canada, Environment Canada, Health Canada, Canadian Environmental Protection Act. ISBN 0-662-21070-9 Cat. No. En40-215/32E-

Canada Report 1999. BENEFITS AND RISKS OF WATER FLUORIDATION. An Update of the 1996 Federal-Provincial Sub-committee Report. Prepared under contract for: Public Health Branch, Ontario Ministry of Health First Nations and Inuit Health Branch, Health Canada. Submitted by: Dr David Locker Community Dental Health Services Research Unit, Faculty of Dentistry, University of Toronto November 15, 1999.) Report can be downloaded from: http://www.gov.on.ca/MOH/english/pub/ministry/fluoridation/fluor.pdf

CDC 1993. Chart 1, p xx. Fluoridation Census 1992. Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Oral Health, Atlanta, Georgia 30333.

CJ Spak et al (1983). Fluoride in human milk. Acta Paediatrica Scandinavica; V 72, No 5; pp 699-701. September.

Luke J (2001). Fuoride deposition in the aged human pinal gland. Caries Research V35. pp 125-128.

Varner JA et al. (1998). Chronic administration of aluminum-fluoride and sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Research, 784:284-298.)

G-Protein

1. Chen CJ (1988). Effects of fluoride on parathyroid hormone secretion and intracellular second messengers in bovine parathyroid cells. J Bone Miner Res 1 Jun;3(3):279-88G-Protein

2. Tezelman S (1994). Desensitization of adenylate cyclase in Chinese hamster ovary cells transfected with human thyroid-stimulating hormone receptor. Endocrinology Mar;134(3):1561-9G-Protein

3. Okajima F et al (1989). P2-purinergic agonists activate phospholipase C in a guanine nucleotide- and Ca2+-dependent manner in FRTL-5 thyroid cell membranes. FEBS Lett Aug 14;253(1-2):132-6G-Protein

4. Thrane EV et al (2001). Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK. Toxicol Sci May;61(1):83-91G-Protein

5. Jaumot M et al (2001). Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene Jul 5;20(30):3949-58G-Protein

6. Emamghoreishi M et al (2000). Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder. Biol Psychiatry Oct 1;48(7):665-73G-Protein

6-a. Sayeski PP et al (2000). The role of Ca2+ mobilization and heterotrimeric G protein activation in mediating tyrosine phosphorylation signaling patterns in vascular smooth muscle cells. Mol Cell Biochem Sep;212(1-2):91-8G Protein

7. Hattori Y (2000). Predominant contribution of the G protein-mediated mechanism to NaF-induced vascular contractions in diabetic rats: association with an increased level of G(qalpha) expression. J Pharmacol Exp Ther Feb;292(2):761-8G-Protein

8. Graff I et al (1987). Carbachol and sodium fluoride, but not TSH, stimulate the generation of inositol phosphates in the dog thyroid. FEBS Lett Jan 5;210(2):204-10G Protein

9. Anna A and Patocka J (1999). Pharmacological and toxicological effects of aluminofluoride complexes. Fluoride, V 32, No. 4. pgs 230-242.)G-Protein