FLUORIDE ACTION NETWORK

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NOTE from FAN.

February, 28 2002

The ATSDR (Agency for Toxic Substances and Disease Registry) published its second draft Toxicological Profile for Fluorides in September 2001. Public comments on the draft report were due by February 22, 2002. The following are the comments submitted by Ellen and Paul Connett to ATSDR. The Connetts submitted their comments on February 26 after having received an extension from ATSDR.

ATSDR was mandated by Congress in 1987 to prepare toxicological profiles for hazardous substances at Superfund sites (on the National Priorities List) "that pose the most significant potential threat to human health, as determined by ATSDR and EPA." Currently there are 275 hazardous substances in this category. In 1987, 150 hazardous substances were identified, and fluoride was included in that list. The first Toxiciological Profile for Fluoride was published in 1993.


Ellen and Paul Connett
82 Judson Street, Canton NY 13617
Tel: 315-379-9200. Fax: 315-379-0448. E-mail: wastenot@northnet.org

Comments submitted to:
Dr. Ganga Choudhary
Division of Toxicology, Agency for Toxic Substances and Disease Registry,
Mailstop E-29, 1600 Clifton Road, NE,
Atlanta, Georgia 30333

Re: Docket Control Number ATSDR-173

February 26, 2002

Comments on Draft Toxicological Profile on Fluorides

 

Introduction.

We are probably wasting our time submitting these comments, however we hold out a very fragile hope that one agency of the USPHS can analyze the fluoride toxicity issue with integrity, i.e. independently of the well-known policy of the USPHS[US Public Health Service] to promote water fluoridation at all costs.

Both of us in our work (Ellen Connett is editor of Waste Not which covers many toxics isues and Dr. Paul Connett teaches Environmental Chemistry and Toxicology at St. Lawrence University) have relied heavily on the fact-filled Toxicological Profiles provided by the ATSDR. We seriously hope that this fine body of resource material is not compromised by political pressures emanating from the USPHS policy of aggressively promoting water fluoridation, a practice which has been rejected by most of the civilized world. The USPHS has been promoting fluoridation ever since 1950, when it first endorsed water fluoridation, before one single trial had been completed and before anything but a very rudimentary analysis of potential health problems had been completed. They weren't being scientific then and they are not being scientific now.

Our comments will be largely confined to the issue of fluoride, which will include discussion of the toxicity of sodium fluoride, hexafluorosilicic acid and its sodium salt; sulfuryl fluoride and organofluorine compounds. While the latter two compounds may appear to go beyond the remit of the ATSDR report they do not, because sulfuryl fluoride, used as a fumigant rapidly hydrolyzes to free fluoride ion, and the toxicological discussions by the USEPA on this substance are nearly all based upon fluoride residues. Moreover, a number of the organofluorine compounds are also metabolized to free fluoride ion either in the body or in the environment. Our comments will also address the issue of fluoridation, a practice which regrettably the authors of the ATSDR report appear to endorse via their frequent quotation of biased DHSS statements misrepresenting both its efficacy and safety.

Our comments will be handled in 19 sections, with each section having its own set of references. These 19 sections are:

1. Hexafluorosilicic acid.
2. Accumulation of fluoride in the pineal gland.
3. Fluoride and G-proteins.
4. Fluoride and the thyroid gland.
5. Fluoride and the brain. Lowering of IQ.
6. Fluoride and fertility.
7. Fluoride and Osteosarcoma.
8. Fluoride and Bone fractures.
9. Fluoride and Osteoarthritis.
10. Dental fluorosis.
11. Dental decay.
12. Fluoride exposure in poor communities.
13. Margin of safety.
14. The Hodge mistake.
15. Imprecise use of language.
16. Political influence.
17. Inorganic fluoride pesticides and the Brain.
18. Organofluorine pesticides and the Brain.
19. Conclusion: Future research.

TABLES:

Table 1: Some Fluorinated School Drinking Water Systems
Table 2. Fluoride Residue Tolerances from the use of Cryolite
Table 3. Brain effects from Organofluorine and fluoride pesticides
Table 4. Fluoride Tolerances proposed by Dow on February 15, 2002
Table 5. Bone effects from Organofluorine and fluoride pesticides
Table 6. Liver effects from Organofluorine and fluoride pesticides
Table 7. Thyroid effects from Organofluorine and fluoride pesticides
Table 8. Reproductive effects from Organofluorine and fluoride pesticides
Table 9. Air pollution from fluoride emitting industries


1. Hexafluorosilicic acid.

The agent used to fluoridate over 90% of the fluoridated water supplies in the US is hexafluorosilicic acid (or its sodium salt). However, the review concentrates only on the agent which is used to fluoridate just 9% of the water fluoridated in the US, namely sodium fluoride (CDC). This reflects the fact that nearly all the toxicological studies performed for "fluoride" have used sodium fluoride. Whether this is a reasonable thing to do under the circumstances is open to question. The US EPA (http://www.fluoridealert.org/EPA-Masters.jpg) has acknowledged that they do not have any toxicological data for hexafluorosilicic acid.

Urbansky and Schock's (2000) claim that the 23% solution of hexafluorosilicic acid (obtained from the scrubbing systems of the phosphate fertilizer industry) becomes essentially identical to a solution of sodium fluoride when it is diluted at the public water works, has been challenged by Masters and Coplan (http://www.dartmouth.edu/~rmasters/). They point to a Ph.D. thesis produced in Germany in the 1970's, which showed that under physiological conditions two fluoride ions remain on the silicon and that this solution behaved differently in biological systems (http://www.fluoridealert.org/westendorf.pdf). A further controversial area not discussed in the ATSDR report is the fact that this fluoridating agent is not pharmaceutical grade and is known to be contaminated with toxic metals like lead and arsenic as well as trace amounts of radioactive isotopes. At the very least these topics should have been discussed, with the possible outcome of recommending future research in this area.

Pertaining to the use of hexafluorosilicic acid, and its sodium salt, as fluoridating agents, there are two published studies by Masters and Coplan (1999, 2000) of considerable importance. Masters and Coplan found a significant increase in children's blood lead in both Massachusetts and New York associated with the use of these silicofluorides to fluoridate water but not with the use of sodium fluoride. Knowing that very low levels of lead are associated with behavioral and developmental problems in young children, including hyperactivity and a lowering of IQs, this is a very serious finding. It was a serious omission not to have cited or discussed these studies.

On page 60 the ATSDR authors refer to hydrofluosilicic acid (same as hexafluorosilicic acid) as follows: "Fluoride is often added to the water in the form of hydrofluosilicic acid, so exposure to this chemical is included in some epidemiological studies." This statement is far too vague. The studies need to be referenced and discussed.

  1. Masters, R.D. and Coplan, M. (1999).Water treatment with silicofluorides and lead toxicity. Intern. J. Environmental Studies. 56: 435-9.
  2. Masters, R.D. et al. (2000). Association of Silicofluoride Treated Water with Elevated Blood Lead. Neurotoxicology. 21:6, 1091-1099.
  3. Urbansky, E.T. and M.R. Schock (2000) Can fluoridation affect lead(II) in potable water? Hexafluorosilicate and fluoride equilibria in aqueous solution. Intern. J. Environmental Studies

2. Accumulation of fluoride in the pineal gland.

The pineal gland is a small endocrine gland located between the two hemispheres of the brain. Its main function involves the production of the hormone melatonin in four enzymatically controlled steps from the naturally occurring amino acid tryptophan. Melatonin has many important regulating roles in the body. When researcher Jennifer Luke discovered that the pineal gland is not protected by the blood brain barrier, had a high diffusion rate of blood (second only to the kidney) and it was also a calcifying tissue (i.e. it lays down the same crystals of calcium hydroxy apatite as are produced in the teeth and the bones), she hypothesized that this small tissue would be a magnet for fluoride.

When 11 corpses were analyzed she found that the levels of fluoride in the crystals in the pineal glands were extremely high (a mean of about 9000 ppm). This research was part of Luke's Ph.D. thesis and was published in 2001 in the journal Caries Research. The second half of Luke's thesis examined the effect of fluoride on the production of melatonin in Mongolian gerbils. She showed that the levels of a melatonin metabolite excreted in the urine was significantly lowered in high fluoride treated animals, and the animals showed signs of reaching puberty earlier than controls.

In our view, the Caries Research article should have been included in the ATSDR review since it pertains directly to the question of whether fluoride is an endocrine disrupter, and its impact on children, namely, the age of onset of puberty. For the record it was published before the ATSDR profile was released (September, 2001) and before the most recent study cited in the profile (DHHS, 2001b, August 17, 2001). Luke also noted that a finding in the health study in the Nerwburgh-Kingston fluoridation trial, which was not thought significant at the time, was the fact that on average the girls in Newburgh started menstruating 5 months earlier than the non-fluoridted Kingston girls ( Schlessinger et al, 1956).

We will gladly forward a copy of Luke's thesis if the ATSDR authors wish to investigate her animal work directly.

  1. Luke, J. (1997). The Effect of Fluoride on the Physiology of the Pineal Gland. Ph.D. Thesis. University of Surrey, Guilford.
  2. Luke, J. (2001). Fluoride Deposition in the Aged Human Pineal Gland.Caries Res. 35:125-128.
  3. Schlesinger, E.R., et al (1956). Newburgh-Kingston Caries-Fluorine Study XIII. Pediatric Findings After ten Years. Journal of the American Dental Association, 52

3. Fluoride and G-proteins.

It is now well established in the biochemical literature that fluoride in the presence of trace amounts of aluminum is capable of switching on the G-protein signaling mechanism used for the transmission of signals which arrive at the outside of cells and result in changed activity inside the cell. It would appear that AlF4- can sit in the pocket on the G-protein that is normally occupied by the third phosphate of GTP. Normally the G-protein is in the "off" position when GDP occupies the site; and in the "on" position when GTP occupies the site. However, when the site is occupied by GDP and AlF4-, it looks to the G-protein as if GTP is present, and is thus switched "on." The GDP (off) - GTP (on) switch is normally triggered when a messenger arrives at the receptor on the outside of the membrane. With AlF4- present the G-protein is switched on without the messenger. It is thus activated without a hormonal signal. The activated G-protein in turn activates the enzyme (adenyl cyclase) which converts ATP to cyclic AMP, which in turn excites a cascade mechanism resulting in changes inside the cell.

As this G-protein signal is a key step in the mechanism of action of many water soluble hormones, a number of neurotransmitters and growth factors, this topic should have been covered in the sections on mechanism of action; endocrine disruption; neurological effects and developmental effects. Thus omitting any discussion of this topic was serious on several fronts. If one goes to the PubMed web and enters fluoride and G-proteins one gets about 800 hits. An important review of this issue and a good starting point for many of these references is provided by Strunecka and Patocka (1999).

A recent report adds some urgency to this issue. Pommerenk and Schafran (2002) have reported in the American Water Works Association journal that when fluoride is added to the water treatment process early, and not as the terminal step, it can cause a tenfold increase in aluminum concentration in the water supply.

  1. Pommerenk, P. and G.C. Schafran (2002) Effects of pre fluoridation on removal of particles and organic matter. American Water Works Association Journal . 94, No.2
  2. Strunecka, A. and Patocka, J. (1999). Pharmacological and toxicological effects of aluminofluoride complexes. Fluoride, 32, 230-242.

4. Fluoride and the thyroid gland

While some reference was made to fluoride's impact on thyroid hormone levels, the issue was covered very briefly and the authors failed to mention the fact that in the past sodium fluoride tablets have been given to patients to relieve the symptoms of hyperthyroidism (Bachinskii, 1985, Galletti and Joyet, 1958). Independent observers have argued that if fluoride can lower the activity of the thyroid gland of someone suffering from an overactive thyroid gland, it might also reduce the activity of a normal thyroid gland and thus produce the symptoms of hypothyroidism, or it might further exacerbate the problems with those with existing hypothyroidism. Of particular concern in this respect is the fact that millions of people in the US are suffering from hypothyroidism. According to the DHHS (1991) the range of doses adults receive who live in optimally fluoridated areas is 1.6 to 6.6 mg/day (Table 23). This range overlaps the range of doses used in the Galletti and Joyet (1958) treatment regime for hyperthyroidism (2.3 — 4.5 mg per day).

This issue should have been discussed in the section on endocrine disruption and the section on neural development, as the thyroid gland is intimately involved in early brain development.

  1. Bachinskii PP, et al. (1985) Action of the body fluorine of healthy persons and thyroidopathy patients on the function of hypophyseal-thyroid system. Probl Endokrinol (Mosk) 31(6):25-9.
  2. Jooste PL, et al. (1999). Endemic goitre in the absence of iodine deficiency in schoolchildren of the Northern Cape Province of South Africa. Eur J Clin Nutr 53(1):8-12.
  3. Galletti, P. & Joyet, G. (1958). Effect of Fluorine on Thyroidal Iodine Metabolism in Hyperthyroidism. Journal of Clinical Endocrinology; 18:1102-1110 http://www.fluoridealert.org/galletti.htm
  4. Lin, F.F. et al (1991). The relationship of a low-iodine and high-fluoride environment to subclinical cretinism in Xinjiang. Iodine Deficiency Disorder Newsletter 7 (also listed in the brain section).
  5. Yang Y. et al. (1994). [Effects of high iodine and high fluorine on children's intelligence and the metabolism of iodine and fluorine]. Zhonghua Liu Xing Bing Xue Za Zhi. 15(5):296-298.
  6. Zhao, W. (1998). Long-term Effects of Various Iodine and Fluorine Doses on the Thyroid and Fluorosis in Mice. Endocr Regul 32(2):63-70.

5 .Fluoride and the brain. Lowering of IQ.

While the authors referred to several papers on the lowering of IQ in China, there were several others that dealt with fluoride's impact on the brain that they missed. I have listed these below. The ATSDR authors did not discuss that it is possibly a combination of low iodide (a known factor in mental retardation) and moderate exposure to fluoride which may be particularly deleterious for neural development. While it is true that the incidence of iodide deficiency in the US has been largely counteracted with the use of iodized salt, the possibility that some pregnant women in the US may have such a shortage should not be ignored. According to the CDC, iodide deficiency has actually increased in recent years. (See http://www.cdc.gov/od/oc/media/pressrel/ad981001.htm). I have also included some other studies on the brain omitted by the ATSDR authors.

While the authors cited the work of Lu et al (2000), it would have been helpful if they had followed up on some of the Chinese literature cited by these authors, even though the papers may be difficult to locate and /or translate. One that was not difficult to locate was the paper by Zhao et al (1996) where the authors found an approximate 5-10 point IQ deficit in children from a community with water containing 4 ppm natural fluoride compared to one containing 1 ppm. Since we fluoridate at 1 ppm, and the EPA's MCL is 4 ppm, this paper should be considered relevant. Considering the seriousness of this outcome, the margin of safety (see discussion in section 12 below), especially in a situation where one cannot control the dose, is ridiculously small.

It should also be noted that some schools in the US add 4.5 ppm of fluoride to their drinking water systems. For example, seventy-five (75) schools in Indiana fluoridate their drinking water systems at 4.5 ppm; sixty-one (61) schools (or communities) in North Carolina fluoridate their drinking water systems at 4.5 ppm; and sixty-four (64) schools in Kentucky fluoridate their drinking water systems at 4.0 ppm (US DHHS, 1993). We have included the names of these schools in Table 1 (below).

While the ATSDR authors cited the work of Varner et al (1998) we felt that they gave this important paper too little attention. What was remarkable about this work is how low the concentrations were that were given to the rats which caused brain damage. Both AlF3 and NaF given to the animals for one year at the level of 1 ppm fluoride (the same level used in public drinking water) caused both kidney and brain damage, an accumulation of aluminum into the brain and the formation of amyloid plagues which are associated with Alzheimer's disease. Apparently, this is the third time that Isaacson and his co-workers have found effects on the brain at these remarkably low levels. Moreover, as a result of this work aluminum fluoride was recently nominated by the Environmental Protection Agency and National Institute of Environmental Health Sciences for testing by the National Toxicology Program. According to the EPA and NIEHS, aluminum fluoride is a "drinking water contaminant" with "known neurotoxicity" and a "high health research priority." If fluoride is added to water which contains aluminum, then aluminum fluoride complexes will form (BNA, 2000, see http://www.fluoridealert.org/alum-fluoride.htm). Aluminum sulfate is frequently used as a flocculating agent in public water treatment plants. We have also just discovered from an article that appeared in the American Water Works Association newsletter that if fluoride is added too early in the water treatment process it can increase the aluminum concentration in the delivered water by a factor of 10 (see section 3 above).

Elsewhere, the authors acknowledge that problems like skeletal fluorosis are seen in India at levels of fluoride in the drinking water which are not so very much higher than those found in the US, and yet we appear not to have similar incidences of skeletal fluorosis. While it is possible that the early stages of skeletal fluorosis are not being detected in the US (see below), it is also a possibility, again as the authors acknowledge, that fluoride's toxicity is exacerbated by poor nutrition. The US is not without poor nutrition in certain communities and it would be well to take seriously the impact of fluoride in combination with, or in the absence of, other key trace elements, pollutants and nutrients. Both Isaacson's work and the Chinese work provide some very important pointers here and they should be taken very seriously. If the ATSDR authors think there are weaknesses in these studies then at the very least they should be recommending follow up work which takes these weaknesses into account.

  1. Calderon, J, et al (2000). Influence of Fluoride Exposure on Reaction Time and Visuospatial Organization in Children. Epidemiology 11(4): S153.
  2. Isaacson, R.L. et al (1997). Toxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia. Neuroprotective Agents. Ann NY Acad Sci. 825: 152-66.
  3. Li, Y. et al (1994). Effect of an excessive fluoride intake on mental work capacity of children and a preliminary study of its mechanism. Hua His I Ko Ta Hsueh Hsueh Pao, 25: 251-4 (cited in Lu, 2000).
  4. Lin, F.F. et al (1991). The relationship of a low-iodine and high-fluoride environment to subclinical cretinism in Xinjiang. Iodine Deficiency Disorder Newsletter 7.
  5. Pang, Y. et al (1994). Protective effect of magnesium and selenium on the damage caused to brain cells by fluoride. Chinese Journal of Epidemiology, 13: 329-330 ( cited in Lu, 2000).
  6. Ren, D.L. et al ( 1989).An investigation of intelligence development of children aged 8-14 years in high fluoride and low iodine areas. Chinese Journal of Endemic Diseases. 4: 251-4 (cited in Lu, 2000).
  7. US DHHS (1993). Fluoridation Census 1992. Published by the U.S. Department of Health & Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Oral Health, Atlanta, Georgia 30333.
  8. Varner, J.A. et al (1998). Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Research, 784, 284-298.
  9. Yang W. et al (1998). The protective effect of a SOD inducer on the brain changes of chronic fluorosis. Chinese J. Epidemiology, 17: 101-4.
  10. Yang Y. et al. (1994). Effects of high iodine and high fluorine on children's intelligence and the metabolism of iodine and fluorine. Zhonghua Liu Xing Bing Xue Za Zhi. 15(5):296-298.
  11. Yu, Y. et al. (1996). Changes in neurotransmitters and their receptors in human foetal brain from and endemic fluorosis area. Chung Hua Liu Hsing Ping Hsueh Tsa Chih; 15: 257-9 (cited in Lu, 2000).
  12. Zhao, L.B. et al (1996). Effect of high-fluoride water supply on children's intelligence. Fluoride, 29, 190-192.

6. Fluoride and fertility.

On page 92 the ATSDR authors provide a critique of the methodology used by Freni in his 1994 study which found lowered fertility in counties which have fluoride levels at 3 ppm or higher. We would like to ask if this critique has been published elsewhere and whether Freni has responded to this criticism. The authors also write that "other studies have not found a similar correlation" but they do not provide any references to these other studies, could they please do so?

7. Fluoride and osteosarcoma.

We were disappointed that the ATSDR authors did not use a more holistic approach to this serious issue. We have the following:

a) The observations by Caffey(1955) quoted by the NAS in their 1977 report, to the effect that the Newburg-Kingston study (Schlessinger at al, 1956) showed a greater incidence of cortical bone defects in the fluoridated community compared to the non-fluoridated one.

b) This led the NAS authors to recommend that researchers should check to see if there is an increase in oestosarcomas in fluoridated communities. Note the authors single out studies on MALES under 30 for special attention.

"There was an observation in the Kingston-Newburgh (Ast et al, 1956) study that was considered spurious and has never been followed up. There was a 13.5% incidence of cortical defects in bone in the fluoridated community but only 7.5% in the non-fluoridated community... Caffey (1955) noted that the age, sex, and anatomical distribution of these bone defects are `strikingly' similar to that of osteogenic sarcoma. While progression of cortical defects to malignancies has not been observed clinically, it would be important to have direct evidence that osteogenic sarcoma rates in males under 30 have not increased with fluoridation"

c) Then we have the NTP finding in 1990 (discussed by the ATSDR authors) of a dose-related increase in osteosarcoma in MALE rats but not female ones.

d) Then we have the SEER findings (discussed by the ATSDR authors) of a greater increase in osteosarcomas in young MALES in fluoridated areas.

e) Then we have the findings by Cohn in NJ that in three counties in NJ there was nearly a seven fold incidence of osetosarcoma in young MALES in fluoridated towns compared to non-fluoridated ones. This study was not cited by the ATSDR authors.

1. Then, of course we have other studies which did not find this relationship. That is not unusual in the case of relatively rare cancers.

We see too many red flags here. It is not enough in our view a) to dilute the NTP animal finding by stressing that the osteosarcomas were found in the male rats but not the females, since this was precisely the pattern that was expected in 1977, and also observed in at least two epidemiological studies and b) to dismiss the findings in the SEER report by pointing to the length of exposure. This is a very cavalier approach to a very serious possibility and smacks of an agency which is trying to defend a position (water fluoridation is safe in the case of the DHHS), rather than a meticulous follow up on every detail of this issue. We expect the ATSDR to do better and not simply parrot the DHHS. If, indeed, there is the slightest chance that a few children may succumb to osteosarcoma as a result of early exposure to fluoride, should we be putting the benefits of a very marginal reduction in tooth decay (see below) above this life threatening risk?

At the very least we would have expected the ATSDR to discuss the biological plausibility of fluoride causing osteosarcoma. After all we know that a) fluoride concentrates in the bone b) the bone is rapidly growing in teenagers c) fluoride interferes with hydrogen bonds, which are critical to DNA structure, replication and function d) fluoride interferes in vitro with many enzymes, including enzymes involved with DNA repair mechanisms, which have magnesium as a cofactor e) fluoride has been shown to be mutagenic in some studies and f) there is considerable controversy about the way certain cancers were downgraded in the NTP study. The initial finding of this study was of "clear evidence of carcinogenicity" a finding which was later downgraded to "equivocal evidence" (Marcus, 1990). EPA Professional Headquarters Union has requested that Congress establish an independent review of this study's results (Hirzy 2000, see http://www.fluoridealert.org/testimony.htm).

  1. Cohn, P.D. (1992). An Epidemiologic Report on Drinking Water and Fluoridation. New Jersey Department of Health, Trenton, NJ.
  2. Hirzy, J.W. (1999). Why the EPA's Headquarters Union of Scientists Opposes Fluoridation. Press release from National Treasury Employees Union, May 1, 1999. (for text see http://www.fluoridealert.org/hp-epa.htm )
  3. Marcus, W. (1990). Memorandum from Dr. William Marcus,to Alan B. Hais, Acting Director Criteria & Standards Division ODW, US EPA, DATED MAY 1, 1990, and subsequent memos. These can be viewed on the web at
  4. National Academy of Sciences (1977). Drinking Water and Health. National Academy Press, Washington, DC., pp. 388-389.
  5. NTP. National Toxicology Program [NTP] (1990). Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3f1 Mice. Technical report Series No. 393. NIH Publ. No 91-2848. National Institute of Environmental Health Sciences, Research Triangle Park, N.C. The results of this study are summarized in the Department of Health and Human Services report (DHHS,1991).
  6. Schlesinger, E.R., et al (1956). Newburgh-Kingston Caries-Fluorine Study XIII. Pediatric Findings After ten Years. Journal of the American Dental Association, 52

8. Fluoride and bone fractures.

The ATSDR authors do a fairly good job reviewing the literature on the possible relationship between fluoride exposure and hip fracture.

They do a particularly good job dealing with the evidence that high doses of sodium fluoride administered over a short period of time (34 mg/day for 2-4 years) can increase bone mineral density in osteoporosis patients but at the same time make the bones more subject to breakage via torsional stress. That such treatments have led to an increase in hip fractures, not a decrease, as hoped and anticipated, provides a highly significant data point. This is recognized by the ATSDR authors and clearly raises the question that if relatively high doses over a short period makes bones more brittle to fracture, what about lower doses over much longer periods of time, say 6 mg per day over 70 years.

Their further discussion of the several investigations into a possible association between living in fluoridated communities (fluoride exposure range from 1.6 —6.6 mg per day according to DHHS, 1991) and hip fracture in the elderly was fair and balanced. As they point out many of these studies (as many of the studies which compare dental decay rates) are limited because they are ecological in nature with no data on individual exposure. It was unfortunate therefore that they missed out two studies, which I feel are most important in helping to resolve this matter. For the record, both of these studies were published in 2001, BEFORE the ATSDR draft was released (September 2001) and both published BEFORE the latest study referenced in the ATSDR study (DHHS, 2001 b, which was published on August 17, 2001).

Li et al (2001) looked at hip fracture rates in elderly residents in six Chinese villages with different levels of fluoride in their well water. They determined a relative risk ratio for each of six villages taking the level of hip fractures in the village with 1 ppm as their control. While they found little difference in the hip fracture rates in the villages less than 1 ppm, they found that the rates almost doubled when the levels of fluoride went above 1.5 ppm and tripled when they went over 4.5 ppm. This apparent dose response adds a great deal of weight to this ecological study, and indicates a very small margin of safety for this serious end point.

Alarcon-Herrera et al (2001) in a study conducted in Mexico found a linear correlation between the severity of dental fluorosis in both children and adults and the incidence of bone fracture. I think this paper is exceptionally important not only for this particular finding but also in providing an elegant way of using a biomarker for fluoride exposure in children. It has been known since Dean’s studies in the 1930’s (see also Heller et al ,1997) that there is a strong linear correlation between the level of fluoride in drinking water and the severity of dental fluorosis in children. This biomarker could be used to investigate other childhood concerns possibly related to fluoride exposure, such as IQ deficits; hyperactivity ; earlier onset of puberty, and thyroid function. This needs to be addressed by the ATSDR authors in their biomarker section.

  1. Alarcon-Herrera , M.T. ,et al (2001). Well water fluoride, dental fluorosis, and bone fractures in the Guadaina Valley of Mexiico. Fluoride , 34(2) 138-48.
  2. Li, Y., C. Liang, et al. (1999). Effect of Long-Term Exposure to Fluoride in Drinking Water on Risks of Bone Fractures. J Bone Miner Res.16(5):932-9.

9. Fluoride and osteoarthritis.

While not many cases of skeletal fluorosis have been documented in the US (possibly because few doctors are trained to recognize the disease) much of the discussion has been focussed on the stage of the disease which produces crippling effects. It was on this end point, for example, that the US EPA set its MCL for fluoride at 4 ppm. However, there are several stages of this disease and the early stages are less obvious to the untrained observer. What is particularly disturbing is that the earliest clinical symptoms of the disease are identical to the early symptoms of oestoarthritis and other forms of arthritis. With over 40 million Americans suffering from various forms of arthritis, the possibility that fluoride may be causing osteoarthritis or exacerbating it, becomes a very important question. This is especially so since the cause of osteoarthritis has not been identified; it is usually explained as being part of the aging process. We have to ask whether part of this "aging process" is the steady accumulation of fluoride in our bones.

The fluoride bone levels (ashed) associated with the pre-clinical phase of skeletal fluorosis are in the range 3,500-5,500 ppm (Table 23, DHHS, 1991). It would be nice to know how close we are getting to these levels with lifetime exposure to fluoride from many sources. Unfortunately, despite its heavy promotion of water fluoridation and the millions of dollars spent on dental research, the US PHS has never sought fit to do the most elementary thing of preparing a comprehensive data base on fluoride bone levels in the US as a function of age, sex, race, location, fluoridation status, disease status, diet or anything else. Hopefully, even at this late stage the ATSDR could recommend that this data be collected so that at some point in the future this issue could be put on a scientific, as opposed to polemical, basis.

10. Dental fluorosis.

In the preface to "Fluoridation Census 1992" (US DHHS, 1993) it states:

"Adjusted fluoridation is the conscious maintenance of the optimal fluoride concentration in the water
supply for reducing dental caries and minimizing the risk of dental fluorosis (p iv)." (Our emphasis)

The ATSDR authors acknowledge that the percentage of children in the US who suffer from dental fluorosis (mottling of the tooth enamel), has increased considerably since the fluoridation program was commenced in 1945. However, their reference to this is dated (DHHS, 1991). A larger and more comprehensive analysis was carried out by Heller et al (1997). They found that in optimally fluoridated communities (0.7 — 1.2 ppm F) the percentage of children with dental fluorosis on at least two teeth was 29.9%. The original goal of those who launched fluoridation (e.g. H. Trendley Dean) was to hold dental fluorosis in it mildest form to 10% of the population. Not only have we seen a threefold increase, but the dental fluorosis being observed is not all in its mildest form. In some communities in the US dental fluorosis has been found to impact up to 80% of the children (Williams, 1990; Lalumandier, 1995 and Morgan, 1998). The recent York Review commissioned by the UK government, and not cited by the ATSDR authors, estimated that fluorosis impacts (on an average basis worldwide) 48% of the population when the water is fluoridated at the optimal level.

It is not acceptable, in our view, to dismiss this outcome as merely a "cosmetic" effect. This is a clear case of "linguistic detoxification" or rather simply parroting a political maneuver to protect the fluoridation program at all costs. Paraphrasing what one commentator said about this, it is like describing the blue line that appears on the gum in some cases of lead poisoning as a merely a "cosmetic effect". For a scientist, both the blue line on the gum in the case of lead poisoning and the white or colored specks on the tooth enamel in the case of fluoride exposure, is the first visible sign that the toxic substance in question has had its first visible toxic effect on the body. It should raise the question of possible invisible effects.

It should also raise the question of the mechanism by which fluoride achieves this end point. This was briefly touched on by the ATSDR authors but it needs more elaboration. They could have quoted Pam DenBesten’s 1997 paper which provides some evidence that dental fluorosis is caused by the inhibition of an enzyme (a protease) which removes the last little bit of protein from between the calcium hydroxy apatite prisms before they fuse to form the smooth enamel surface. It is the failure to remove this protein which causes the gaps in the enamel surface. The important question to ask from the toxicological point of view is: if fluoride is able to poison this enzyme in the growing tooth what other enzymes in the body can it poison? For example, what enzymes in the growing bone may it poison? What enzymes in the pineal gland may it poison? The work of Jennifer Luke, discussed above, bears on the latter question. In addition to the dental fluorosis discussion, this issue needs more examination in the section on mechanism of action.

  1. DenBesten, P (1999). Biological mechanism of dental fluorosis relevant to the use of fluoride supplements. Community Dent. Oral Epidemiol., 27, 41-7.
  2. Heller KE et al (1997). Dental Caries and Dental Fluorosis at Varying Water Fluoride Concentrations. J of Pub Health Dent, 57;No. 3, 136-143.
  3. Lalumandier JA et al (1995). The prevalence and risk factors of fluorosis among patients in a pediatric dental practice. Pediatric Dentistry - 17:1, 19-25.
  4. Luke, J. (1997). The Effect of Fluoride on the Physiology of the Pineal Gland. Ph.D. Thesis. University of Surrey, Guildord.
  5. Luke, J. (2001). Fluoride Deposition in the Aged Human Pineal Gland. Caries Res. 35:125-128.
  6. Morgan L et al (1998). Investigation of the possible associations between fluorosis, fluoride exposure, and childhood behavior problems. Pediatric Dentistry - 20:4, 244-252.
  7. US DHHS (1993). Fluoridation Census 1992. Published by the U.S. Department of Health & Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Oral Health, Atlanta, Georgia 30333.
  8. Williams JE et al (1990). Community Water Fluoride Levels, Preschool Dietary Patterns, and The Occurrence of Fluoride Enamel Opacities. J of Pub Health Dent; 50:276-81.

11. Dental decay.

The ATSDR authors rely heavily on the DHHS, which is a heavy promoter of water fluoridation, for most of their comments on the efficacy of water fluoridation, without considering the objectivity of this agency in this matter. For example on page 12 they cite the DHHS (1991) report as follows: "The PHS report stated that fluoride in the drinking water substantially reduces tooth decay". However, the word "substantially" is hardly supported by the largest survey that they cite (Brunelle and Carlos, 1990). We examine the details below.

On page 26 of the DHHS (1991) review they state: "In 1986 and 1987 the National Institute of Dental research (NIDR) conducted a National Survey of Oral Health to determine the prevalence of oral disease in 39,000 U.S. children 5 to 17 years of age (Brunelle and Carlos, 1990) and to compare the results with those of similar studies conducted in 1979 and 1980. Children who resided continuously in fluoridated areas had 18 per cent lower DMFS than did those who resided in non-fluoridated areas, where fluoride was also widely available from sources other than community water supplies".

However, what they fail to point out is:

a) Dr. John Yiamouyiannis looked at this same data set used by Brunelle and Carlos (obtained under the Freedom of Information Act) and found no statistical difference between the DMFT (as opposed to DMFS. DMFT is a count of decayed, missing and filled teeth and DMFS is an account of decayed, missing and filled surfaces, a more stringent measure than DMFT because there are on average 5 surfaces to each tooth) for the children living in fluoridated and non-fluoridated communities.

b) Brunelle and Carlos do not establish that this 18% difference is statistically significant.

c) The 18% figure may sound large (but not as large as the 60% frequently claimed by promoters of fluoridation) but when one examines the table in which the data is laid out (Table 6) we find that the 18% is a result of the mathematical vagaries of comparing two small numbers. The average DMFS for the children living in the fluoridated communities was 2.69 and those living in non-fluoridated communities was 3.29. This is a difference of 0.6, and indeed, 0.6 is 18% of 3.29, but more to the point, is the fact that 0.6 is six tenths of one tooth surface out of 128 tooth surfaces in a child’s mouth, i.e. less than 0.5% of the child’s tooth surfaces!

So the "substantial" reduction in tooth decay cited by the ATSDR is actually based on a non-statistical finding of a saving of less than 1 % of the tooth surfaces in a child’s mouth. That, unfortunately, is what one finds when one reads the actual literature rather than the "spin" put on it by the agencies (and the authors Brunelle and Carlos in this case) that promote this practice. Hopefully, the ATSDR authors will now read the Brunelle and Carlos paper and the Yiamouyiannis papers for themselves and determine if they can honestly parrot the nonsense of a "substantial" reduction in tooth decay caused by water fluoridation.

They should also review the York Review’s findings on this matter. Based upon their worldwide review (based on longitudinal studies only) of the studies of dental decay and fluoridation (none of which they were able to give an A grading for quality), they calculated an average reduction of 15% in DMFT in favor of fluoridated communities. They also found a worldwide average of 48% incidence of dental fluorosis (see above).

The ATSDR authors should also study an analysis carried out by Dr. David Locker for the Ontario government. He concluded that:

"The magnitude of [fluoridation's] effect is not large in absolute terms, is often not statistically significant and may not be of clinical significance."

"Canadian studies do not provide systematic evidence that water fluoridation is effective in reducing decay in contemporary child populations. The few studies of communities where fluoridation has been withdrawn do not suggest significant increases in dental caries as a result. More research is needed to document the benefits of fluoridation to adult and elderly populations in terms of reductions in coronal and root decay. Research is also needed to document improvements in the oral health-related quality of life that accrue to populations exposed to fluoridated water in order to enhance the credibility of this public health initiative."

"Although it was initially thought that the main mode of action of fluoride was through its incorporation into enamel, thereby reducing the solubility of the enamel, this pre-eruptive effect is likely to be minor."

On page 16, the ATSDR authors state that "communities that no longer fluoridate their water have experienced an increase in caries (DHHS 2000)". Even if that was the case in the past it is certainly not true today. Recent published studies from Cuba (Kunzel and Fischer, 2000), former East Germany (Kunzel and Fischer 1997, Kunzel et al, 2000) Finland (Seppa et al, 2000) and Canada (Maupome et al, 2001) where researchers have followed tooth decay rates after fluoridation was halted have not found an increase, but actually a continuing decrease in tooth decay.

Data collected by WHO (and published online) also indicate that the same decline in tooth decay, which is ascribed to water fluoridation in the US, has been happening in many other non-fluoridated industrial countries. In fact the dental decay rates among children in largely unfluoridated Europe are just as good if not better than fluoridated children in the US. The lack of substantial difference in tooth decay rates in fluoridated and non-fluoridated communities, and the continued decline in dental caries even after the maximal calculated benefit of fluoridation would have occurred, has prompted a number of researchers (e.g. Disendorf, 1986; Colquhoun, 1997 and DeLeifde, 1998) to offer alternative explanations for the improved dental status that has occurred in recent decades.

On an interesting historical note, one of the early trials (1945-55) which helped to launch fluoridation took place in Newburgh, NY, with Kingston, NY as the control community. After 10 years of this trial it looked as if there was a large decrease in dental caries in the fluoridated community compared to the non-fluoridated community. However, when children were re-examined in these two cities in 1995 (50 years after the trial began) there was practically no difference in the dental decay in the two communities. If anything, the teeth in still unfluoridated Kingston were slightly better than still fluoridated Newburgh (Kumar and Green, 1998).

The largest survey of tooth decay ever carried out was by Teotia and Teotia in India. Over a 30 year period they have examined the teeth of over 400,000 children and have found that dental decay increases with fluoride concentration in the water and decreases with calcium concentration.

In the light of all the evidence that the benefits of water fluoridation are minimal at best, one is forced to ask, and hopefully the authors of the ATSDR will ask themselves, if these slender benefits could possibly justify any or all of the risks that we have discussed above.

There is one more point that needs to be made on fluoride and dental decay and that pertains to its supposed mechanism of action. The ATSDR authors on pages 133-134 were able to include a lengthy quotation from the CDC’s August 17, 2001 MMWR report. In this quote they include a shattering concession made by the CDC:

" In the earliest days of fluoride research, investigators hypothesized that fluoride affects enamel and inhibits dental caries only when incorporated into developing enamel (i.e., preeruptively, before the tooth erupts in the mouth)…(However) Laboratory and epidemiologic research that has led to the better understanding of how fluoride prevents dental caries indicates that fluoride’s predominant effect is posteruptive and topical…fluoride works primarily after teeth have erupted…"

Unfortunately, the CDC has not drawn the logical conclusion from this statement. We urge the authors of the ATSDR to attempt to do so. They should try this series of statements for their logical consistency:

a) If the benefits of fluoride can be achieved topically

b) If communities worldwide have demonstrated that they have been able to achieve the same or better dental decay rates without putting fluoride in the water,

c) If dental decay rates today don’t go up when fluoride is removed from the water, and

d) If all the risks, whether they be large or small, proved or unproved, associated with fluoride and discussed by the authors of the ATSDR report, arise from systemic exposure to fluoride, why on earth would anyone advocate putting this stuff into our drinking water?

Equipped with this logic why would any government be so convinced about this policy, that it would be prepared to use police powers to override dissent (majority, minority or individual) and thereby remove one of the tenets of modern medicine: the patient’s right to informed consent on the medication that he or she takes?

This is what the associate editor of the British Medical Journal , Dr. Douglas Carnall, wrote after the publication of the York Review:

"The systematic review published this week (p 855) shows that much of the evidence for fluoridation was derived from low quality studies, that its benefits may have been overstated, and that the risk to benefit ratio for the development of the commonest side effect (dental fluorosis, or mottling of the teeth) is rather high…

Professionals who propose compulsory preventive measures for a whole population have a different weight of responsibility on their shoulders than those who respond to the requests of individuals for help. Previously neutral on the issue, I am now persuaded by the arguments that those who wish to take fluoride (like me) had better get it from toothpaste rather than the water supply."

And, this is what Professor Trevor Sheldon, who chaired the advisory board for the York review had to say, in a statement released in the House of Lords:

In my capacity of chair of the Advisory Group for the systematic review on the effects of water fluoridation recently conducted by the NHS Centre for Reviews and Dissemination the University of York and as its founding director, I am concerned that the results of the review have been widely misrepresented.  The review was exceptional in this field in that it was conducted by an independent group to the highest international scientific standards and a summary has been published in the British Medical Journal. It is particularly worrying then that statements which mislead the public about the review's findings have been made in press releases and briefings by the British Dental Association, the British Medical Association, the National Alliance for Equity in Dental Health and the British Fluoridation Society. I should like to correct some of these errors.  

1    Whilst there is evidence that water fluoridation is effective at reducing caries, the quality of the studies was generally moderate and the size of the estimated benefit, only of the order of 15%, is far from "massive".  

2    The review found water fluoridation to be significantly associated with high levels of dental fluorosis which was not characterised as "just a cosmetic issue".  

   The review did not show water fluoridation to be safe. The quality of the research was too poor to establish with confidence whether or not there are potentially important adverse effects in addition to the high levels of fluorosis. The report recommended that more research was needed.  

4    There was little evidence to show that water fluoridation has reduced social inequalities in dental health.  

   The review could come to no conclusion as to the cost-effectiveness of water fluoridation or whether there are different effects between natural or artificial fluoridation.  

6    Probably because of the rigour with which this review was conducted, these findings are more cautious and less conclusive than in most previous reviews.  

   The review team was surprised that in spite of the large number of studies carried out over several decades there is a dearth of reliable evidence with which to inform policy. Until high quality studies are undertaken providing more definite evidence, there will continue to be legitimate scientific controversy over the likely effects and costs of water fluoridation.  

(Signed) T.A. Sheldon,

Professor Trevor Sheldon, MSc, MSc, DSc, FMedSci

 

1. Brunelle, J.A. and Carlos, J.P. (1990). J. Dent. Res 69, (Special edition), 723-727.
2. Colquhoun, J (1997) "Why I changed my mind on Fluoridation. Perspectives in Biology and Medicine, 41, 29-44.
http://www.fluoride-journal.com/98-31-2/312103.htm
3. DHHS (1991). Review of Fluoride: Benefits and Risks, Report of the Ad Hoc Committee on Fluoride of the Committee to Coordinate Environmental Health and Related Programs. Department of Health and Human Services, USA.
4. De Liefde, B. (1998). The Decline of Caries in New Zealand Over the past 40 Years. New Zealand Dental Journal, 94, 109-113.
5. Diesendorf, M.(1986). The Mystery of Declining Tooth Decay. Nature, 322, 125-129.
6. Hileman, B. (1989). New Studies Cast Doubt on Fluoridation Benefits. Chemical and Engineering News, 67 (19) 1-60, May 8, 1989. http://www.fluoridealert.org/NIDR.htm
7. Kumar, JV and Green, E.L. (1998). Recommendations for Fluoride Use in Children. NY State Dental Journal, February, 41-48.
8. Kunzel, W. and T. Fischer (1997). Rise and fall of caries prevalence in German towns with different F concentrations in drinking water. Caries Res 31(3): 166-73.
9. Kunzel, W. and T. Fischer (2000). Caries prevalence after cessation of water fluoridation in La Salud, Cuba. Caries Res 34(1): 20-5.
10. Kunzel, W., Fischer, T., Lorenz R., Bruhmann, S. (2000). Decline in caries prevalence after the cessation of water fluoridation in former East Germany. Community Dent. Oral Epidemiol. 28(5): 382-389.
11. Locker, D. (1999). Benefits and Risks of Water Fluoridation. An Update of the 1996 Federal-Provincial Sub-committee Report. Prepared for Ontario Ministry of Health and Long Term Care.
12. Maupome, G. et al. (2001). Patterns of dental caries following the cessation of water fluoridation. Community Dent Oral Epidemiol 29(1): 37-47.
13. Seppa, L., Karkkaimen, S. and Hausen, H. (2000) Caries trends 1992-98 in two low-fluoride Finnish towns formerly with and without fluoride. Caries Res 34(6): 462-8.
14. Sheldon, T. Statement in the House of Lords. http://www.fluoridealert,org/sheldon.htm.
15. Teotia, S.P.S. and M, Teotia (1994). Dental caries: a disorder of high fluoride and low dietary calcium interactions (30 years of personal research). Fluoride. 27 (2) 59-66.
16. The York Review. McDonagh, M. et al. (2000). A Systematic Review of Public Water Fluoridation. NHS Center for Reviews and Dissemination, University of York, September 2000. http://www.fluoridealert.org/york.htm A summary of the Review appeared in the British Medical Journal.
17. Yiamouyiannis, J.A. (1990). Water Fluoridation and Tooth decay: Results from the 1986-87 National Survey of U.S. Schoolchildren. Fluoride, 23, 55-67. http://www.fluoridealert.org/DMFTs.htm
18. WHO (Online). WHO Oral Health Country/Area Profile Programme. Department of Noncommunicable Diseases Surveillance/Oral Health. WHO Collaborating Centre, Malmö University, Sweden. http://www.whocollab.od.mah.se/euro.html


12. Fluoride exposure in poor communities.

One of the sad ironies of the current aggressive promotion of the fluoridation by the Surgeon General and other arms of the US PHS is their targeting of poor communities to receive the bounties of this measure in the name of equity.

While it is true that there is a strong correlation between poverty and tooth decay, the York Review found no evidence that fluoridation actually achieved the goal of leveling the playing field. According to the chairman of the advisory committee for this study, Professor Trevor Sheldon (see full statement above): "There was little evidence to show that water fluoridation has reduced social inequalities in dental health."  

Moreover, even though most inner cities in the US are fluoridated the rate of tooth decay in lower income families there is still very high. In fact, the Boston Globe (Kong, Nov 11, 1999) bemoaned the fact that Boston had a dental health crisis, even though this city has been fluoridated since the 1970s.

This is probably due to a number of factors: 1) many people on Medicaid get very poor preventive dental care 2) people in lower income brackets usually have a less nutritious diet and 3) a prevalent form of dental disease "baby bottle tooth decay", caused by babies being exposed to long periods to baby bottles filled with cows’ milk or sugared water, is frequently found in low income communities. Fluoridation has been found to be ineffective at preventing baby bottle tooth decay, otherwise known as early childhood caries (Jones, 2000 - see http://www.fluoridealert.org/BBTD.htm).

The relevance of this section to the ATSDR report is to draw attention to this mistaken, albeit well intended, targeting. Because it is precisely in the lower income families in the US where one would expect to find poor nutrition and we have seen from studies in India, that it is poor nutrition which exacerbates fluoride’s toxic effects. This might take the form of low protein diets; shortage of vitamin C and other vitamins and a shortage of minerals like calcium, magnesium, selenium and iodide.

  1. Kong, D. (1999). City to launch battle against dental 'crisis.' Boston Globe November 11. http://www.fluoridealert.org/f-boston.htm

 

13. Margin of Safety.

If one was approaching fluoride as a new drug being put on the market, one would want to have some answers to some very basic questions. Firstly, what is the therapeutic dose? What is the dose in mg per day a child or adult would need to fight tooth decay? Secondly, what is the toxic dose for a range of end points? From this we could calculate the margin of safety for the most sensitive endpoint. Further, since this particular drug occurs naturally and is also available in many commercial products and in our diet, we would want to know the total dose we get from all sources. When we get these answers we would be in a position to say how far short, or how far in excess, of the therapeutic dose our current exposure leaves us. We would also know how far short, or how far in excess, we are for the most sensitive toxic end point; i.e., just how far we are into the safety margin .

I would hope that the ATSDR authors would go through this exercise and make the results very clear to the public. I think we can probably assume that such calculations would show that average exposure to fluorine and hydrogen fluoride is below the most sensitive toxic end point . However, the calculations on fluoride are disturbing. There is no margin of safety for dental fluorosis (one in three children are impacted today in areas which have 0.7 — 1.2 ppm in the water). There is a margin less than 2 for increased hip fracture (Li et al, 2001) and a margin of 3 for lowered fertility (Freni, 1994). A margin of 4 for lowered IQ (Zhao, 1996) and a margin of between 2-5 for a possible lowering of the activity of the thyroid gland (Galletti and Joyet, 1958).

There is also a margin of only 4 between the so called optimal level in drinking water (1 ppm) and the US EPA’s maximum contaminant level (MCL) of 4 ppm.

Compounding this margin of safety concern is the fact that once fluoride is put in the water it is impossible to control the dose each individual receives. This is because some people (e.g. manual laborers, athletes and diabetics) drink more water than others, and because, we receive fluoride from sources other than the water supply. Other sources of fluoride include food and beverages processed with fluoridated water; fluoridated dental products, and pesticide residues on food.

As one doctor has aptly stated, "No physician in his right senses would prescribe for a person he has never met, whose medical history he does not know, a substance which is intended to create bodily change, with the advice: 'Take as much as you like, but you will take it for the rest of your life because some children suffer from tooth decay. ' It is a preposterous notion."

Promoters of fluoridation manage to duck the "margin of safety" question by referring to fluoride as a nutrient, the implication being that we have a large margin of safety. However, we were glad to see that the ATSDR authors acknowledged that the evidence for fluoride being an essential nutrient is not very strong (page 60). We further argue that there is another line of evidence that fluoride is not needed for the growth of healthy teeth or healthy bones by virtue of the fact that the level of fluoride in mothers’ milk is very low, about 0.01 ppm i.e., 100 times lower than the level added to artificially fluoridate drinking water (IOM, 1997, page 292 for references).

We would argue that since all life emerged from the sea which has a concentration of fluoride over 1 ppm, nature is telling us something by virtue of the fact that it has essentially excluded fluoride from the baby’s first food supply.

The fact that incoming fluoride is either excreted through the kidney or sequestered in the bone, also tells us that nature didn’t want fluoride coming too close to the workings of our soft tissues. Biology and chemistry gives us several answers as to why this is so. Firstly, Emsley showed in 1981 that the fluoride ion forms a strong hydrogen bond with the amide function which is the in the backbone of proteins and particularly important at their active sites, and could well explain fluoride’s ability to inhibit many enzymes. Hydrogen bonds are also critical for the functioning of nucleic acids and could explain fluoride’s mutagenic properties. Secondly, fluoride forms complex ions with many ions like magneisum and calcium which play key roles in biology, and also toxic metals like lead, beryllium and aluminum. It is possible that these complexes might carry fluoride to places it would otherwise have difficulty reaching, e.g. crossing the blood brain barrier and reaching the brain. Or conversely, it might mean that fluoride helps to ferry these toxic metals to places where they might not easily have entered, and the Varner paper (1998), gives possible disturbing evidence of that. We also have the puzzling role that the silicon fluorides might have in facilitating the uptake of lead into children’s blood (Masters and Coplan, 1999, 2000) and the more clearly defined role in the case of aluminum fluoride complexes switching on G-protein signaling mechanisms (Strunecka and Patocka, 1999).

  1. Emsley, J. et al (1981). An Unexpectedly Strong Hydrogen Bond: Ab Initio Calculations and Spectroscopic Studies of Amide-Fluoride Systems. Journal of the American Chemical Society, 103, 24-28.
  2. IOM (Institute of Medicine,1997). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. National Academy Press.
  3. Masters, R.D. and Coplan, M. (1999).Water treatment with silicofluorides and lead toxicity. Intern. J. Environmental Studies. 56: 435-39.
  4. Masters, R.D. et al. (2000). Association of Silicofluoride Treated Water with Elevated Blood Lead. Neurotoxicology. 21:6, 1091-1099.
  5. Strunecka, A. and Patocka, J. (1999). Pharmacological and toxicological effects of aluminofluoride complexes. Fluoride, 32, 230-242.
  6. Varner, J.A. et al (1998). Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Research, 784, 284-298.

 

14. The Hodge mistake.

In at least two places (page 20 and 81) the ATSDR authors make an unreferenced statement to the fact that the dose needed to reach crippling skeletal fluorosis is 20-80 mg of fluoride for 10 years or more. In actual fact this number is based on an old "mistake" by Harold Hodge, which he later corrected. When Hodge was calculating this dose he incorrectly converted Kaj Roholm’s figures from mg per kilogram bodyweight per day to mg per day by multiplying by the bodyweight in pounds not kilograms. A citizen activist (Ms. Darlene Sherrell) has energetically pursued this issue for many years and has managed to "correct" most of the publications where this mistake has occurred.

For the record, Hodge first published a correction to his old mistake in 1979 in a paper delivered at an AAAS symposium where he stated:

"Crippling fluorosis as an occupational disease follows exposures estimated at 10 to over 25 mg of fluoride daily during periods of 10-20 years." 

The National Research Council first used this correction in 1993, when they wrote:

"Crippling skeletal fluorosis might occur in people who have ingested 10-20 mg of fluoride per day for 10-20 years."

Unfortunately, many authorities have repeated Hodge’s mistake by repeating his earlier number from older reviews.

  1. Hodge, H. (1979). The Safety of Fluoride Tablets or Drops, Continuing Evaluation of the Use of Fluorides. AAAS Symposium, Boulder, CO, Westview Press, 1979.
  2. National Research Council (1993). Health Effects of Ingested Fluoride. National Academy Press, Washington DC. page 59.

 

15. The use of imprecise language.

If the purpose of those who write about fluoride and fluoridation is not deliberately propagandistic it is necessary that they be very precise in their descriptions of the doses when referring to end points of concern. To put this into context it is the position of those who promote fluoridation like the ADA and the US PHS to dismiss all adverse findings pertaining to fluoride or fluoridation as being irrelevant because the methodology was poor; the work was not peer reviewed; the study was done on animals and not humans and the doses were very high and not in the range expected from exposure to fluoridated water and other sources in daily life.

For those who wish to treat the issue scientifically and objectively it is important that they use the words pertaining to dose and effects very precisely and not resort to vague terms like "high" , "large", "substantial". This is critically important because of the very narrow margin of safety between the therapeutic dose for fluoride and the dose which can lead to a toxic end point, discussed above (see section 12) as well as the exaggerated claims made for the benefit of water fluoridation.

Here are some examples from the ATSDR report. Our emphasis is in italics.

On page 8. "Skeletal fluorosis can be caused by eating, drinking or breathing large amounts of fluorides."

"Reproductive effects…have been seen in laboratory animals at high doses."

On page 12, "Fluoride in the drinking water substantially reduces tooth decay"

On page 16, "Readers should keep in mind that adverse health effects generally occur at high exposure levels".

On page 16, "fluoridation (at approximately 1 ppm) results in a notable reduction in coronal and root surface caries in children and adults"

16. Political influence.

As a professor of chemistry who teaches environmental chemistry and toxicology, and as an editor of a newsletter (Waste Not) which deals with many toxic issues, we have both come to rely fairly heavily on the Toxicological profiles developed by ATSDR as important reference and teaching tools. It would be tragic in our view if the value of these profiles is tainted by political pressures or anything other than an unbiased review of the literature. It comes as a shock to find that this latest review of fluoride contains a number of statements, assertions and insertions (compared with the previous addition) which smacks of a requirement to toe the line on the US PHS agenda to promote the safety and efficacy of water fluoridation at all costs. Below we have listed several examples of where the authors appear, maybe unwittingly, to be serving a political agenda as opposed to a strictly scientific one.

a) Many citizens and scientists like ourselves have cited a paragraph from the previous ATSDR toxicological profile on fluorides on susceptible populations. That paragraph was as follows:

" 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".

In the latest profile, this paragraph is unchanged except for the addition of one sentence which reads:

"However, these effects would not be expected at typical exposure levels (1 ppm fluoride)".

It is difficult to escape the conclusion that this sentence has been inserted by someone in order to further the aim of promoting water fluoridation.

Since the margin of safety for toxic outcomes or other outcomes of concern (e.g. dental fluorosis, hip fracture, early or pre-clinical symptoms of skeletal fluorosis, infertility, accumulation in the pineal gland, the possible lowering of IQs and the lowering of the activity of the thyroid gland) is so close to the therapeutic dose for fighting tooth decay (within a factor of 4), this additional sentence is extremely misleading. The issue is about what factors increase susceptibility. If the margin of safety is two and your renal clearance goes down by 50% you have a problem.

On page 143 the ATSDR authors cite studies which support the statement that "Poor nutrition increases the incidence and severity of dental fluorosis." Clearly, they are talking about susceptibility increases at or close to 1ppm.

On page 94, the ATSDR authors make the point that "The available human data suggest that fluoride has the potential to be developmentally toxic at doses associated with moderate to severe fluorosis."

The very fact that communities in India suffer severe cases of skeletal fluorosis at natural levels of fluoride which overlap those that occur in some places in the United States, clearly indicates that nutritional deficiencies such as calcium and vitamin C can have a serious effect even at moderate exposures of fluoride.

b) One of the aspects of propaganda is to repeat a statement again and again, usually without factual evidence being provided. The authors of the ATSDR toxicological profile tell us that adding fluoride to water reduces tooth decay, on pages 7 (twice), 8, 9, 12, 15, 16, 18 (twice), 20, 81 and 133. Why is it necessary to tell us this 12 times? Moreover, in no case was sufficient documentation offered to substantiate the claims of a large benefit. Nor was any information offered to indicate that this practice is highly controversial and has been rejected by most industrialized countries.

c) Another promotional technique of those advocating fluoridation is to dismiss the damage caused to the tooth enamel by fluoride (dental fluorosis) as not a "health effect" or even the first visible sign of fluoride’s toxicity but as merely a "cosmetic" effect of no health significance. The ATSDR authors fall for this ploy several times. They tell us that dental fluorosis is a "cosmetic" effect on page 10, 17, 20, 138, and 161.

  1. Inorganic fluoride pesticides and the brain.

EPA has set tolerances for fluoride residues from the use of the pesticide Cryolite (sodium aluminum fluoride ) for a variety of commodities. (The highest level is 22 ppm for processed potato waste which is fed to cows.— see Table 2 for tolerance levels). Many of these tolerances will be increased due to current proposals for the use of sulfuryl fluoride as a fumigant on post-harvest and stored food commodities. EPA has stated that fluroide is the toxicological endpoint of concern for both cryolite and sulfuryl fluoride. Both convert to the fluoride anion in the body.

While the tolerance for fluoride residues on grapes is 7 ppm, we do not know if there is a tolerance for fluoride levels in wine. In 1996 Ostrom (1) published the results of an analysis of fluoride in California wine. The levels were as high as 12 ppm/liter for Zinfandel and French Colombard. This research was performed at California State University, Fresno. The report is accessible at: http://cati.csufresno.edu/verc/rese/96/960601/index.html

On September 5, 2001 (2) the Federal Register published EPA's risk assessment on fluoride in preparation to set food tolerances for an increased number of new food uses for Sulfuryl fluoride. Up to this time sulfuryl fluoride was used only as a structural fumigant, never on food, and thus several critical studies have not been performed. The public was given one month to submit comments on Dow's proposal and EPA's risk assessment. EPA's risk assessment cited the following studies of inorganic fluoride's effect on the brain:

1. In a 2-generation reproduction inhalation study in rats, vacuolation of the white matter in the brain was 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. (In dogs and rabbits, clinical signs of neurotoxicity [including tremors, tetany, incoordination, convulsions and/or hind limb paralysis] were also observed.)

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 two exposures on consecutive days for 6 hours/day at 300 ppm vacuolation of the white matter in the cerebrum of the rat was observed.

EPA's risk assessment of September 5, 2001, clearly demonstrates that the brain was the primary target organ in rats, dogs, mice, and rabbits in several of these studies. ATSDR paid little attention to the effect of fluoride on the brain. ATSDR made no comment on the stunning speculation made by the authors of a study published in 1998: fluoride enables aluminum to cross the blood-brain barrier (3, Varner et al.). This was a serious ommision.

From the results of the animal studies in EPA’s risk assessment it is clear that the white matter of the brain is under attack. According to Christopher Filley, author of The Behavioral Neurology of White Matter (Oxford University Press, 2001):

"…the assumption that the singular phenomena of human behavior predominantly require the activities of the cortical gray matter is one of the most pervasive in all of neuroscience. Whereas there is an impressive body of evidence in support of this belief, it is worth recalling that the cerebral cortex consists of only the outermost 3 millimeters of the brain. Moreover, a wealth of clinical experience suggests that disorders affecting structures below the cortex, many of which are white matter tracts, reliably and significantly alter mental functions. Thus, the notion that mental life is exclusively represented in the cortical gray matter should be considered an oversimplification.

"A wide range of syndromes involving both cognitive decline and emotional dysfunction has been linked with structural involvement of the brain white matter. Clinical observations of patients with white matter disorders generate the essential data to support this claim. Much additional information has been gathered with the help of magnetic resonance imaging (MRI), a powerful neuroimaging technique that has provided unprecedented views of the white matter and permitted correlations with neurobehavioral syndromes. These syndromes may equal or surpass in clinical importance the various deficits in motor and sensory function of white matter lesions well known from classical neurology. Whereas caution is still appropriate in assessing the neurobehavioural importance of white matter changes, it is no longer possible to ignore them. (p 3-4)…

"Early clinical features of cerebral white matter involvement typically include confusion, inattention, memory dysfunction, and personality change… Measures of attention, cognitive speed, memory retrieval, visuopatial skills, and executive function are likely to be most sensitive to subtle white matter dysfunction. In contrast to disorders primarily involving the cortex, higher cerebral functions such as language, praxis, and perception are uncommonly affected; the usual preservation of language is an important point because affected individuals may display normal language and thus appear cognitively intact, when in fact they have significant deficits in other neurobehavioral domains (p 249)."


The majority of Filley’s book examines the ‘Disorders of White Matter,’ which are wide-ranging and include Multiple Sclerosis, HIV dementia, Lupus, Migraine, Hydrocephalus, to name a few. [It appears plausible that when certain people complain of headaches after drinking wine, which as noted above can contain up to 12 ppm fluoride/liter, that the cause is fluoride.]

We urge ATSDR to examine the animal studies that show explicit injury to the white matter of the brain. The studies in Table 3 (below) clearly demonstrate that fluoride and organofluorine pesticides affect the brain. In this context it might be well for the ATSDR authors to revisit in more detail the work of Dr. Phylllis Mullenix on fluoride’s impact on rat behavior and its uptake into the brain, which they handled only very briefly.

On February 7, 2002 (4) EPA approved the first tolerances for residues of fluoride (in and on raisins at 30 ppm; and in and on walnuts at 12 ppm). EPA noted that the levels for raisins accounted for the fluoride residues from the use of cryolite (which were 7 ppm). This approval marked the first time fluoride tolerances were approved for walnuts.

On February 15, 2002, the Federal Register (5) published a petition by Dow for more fluoride tolerances on 40 raw and processed food commodities from the use of sulfuryl fluoride. The highest was for processed wheat germ at 98 ppm - see Table 4 (below).

For the inorganic fluoride pesticides Sodium fluoroacetate (Compound 1080) and Fluoroacetamide (Compound 1081) EPA noted that the brain and the heart are the organs most prominently affected. <http://www.epa.gov/oppfead1/safety/healthcare/handbook/Chap17.pdf>

EPA allows the use of Sodium fluoride as a pesticide under the umbrella of "Inerts," specifically a List 4-B inert. The USDA’s National Organics Standards approved the use of EPA’s List 4 Inerts in organic food production, and Sodium fluoride is included. Vani and Pratap (6) published a study using Sodium fluoride. They state that fluoride accumulates in the brain (for abstract, see Table 3). Sodium fluoride is also used as a wood preservative.

1. Ostrom GS (1996). Cryolite on grapes/Fluoride in wines - A guide for growers and vintners to determine optimum cryolite applications on grapevines. CATI Publication #960601. California Agricultural Technology Institute. http://cati.csufresno.edu/verc/rese/96/960601/index.html
2. Federal Register. September 5, 2001. Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances. [OPP-301166; FRL-6799-6] http://www.epa.gov/fedrgstr/EPA-PEST/2001/September/Day-05/p22283.htm
3. Varner, JA et al (1998). Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Research, 784, 284-298.
4. Federal Register. February 5, 2002. Fluoride; Temporary Pesticide Tolerances. Final Rule. [OPP-301166A; FRL-6823-4] http://www.epa.gov/fedrgstr/EPA-PEST/2002/February/Day-07/p2983.htm
5. Federal Register. February 15, 2002. [PF-1068; FRL-6822-2] http://www.epa.gov/fedrgstr/EPA-PEST/2002/February/Day-15/p3661.htm
6. Vani ML and Reddy KP (2000). Effects of fluoride accumulation on some enzymes of brain and gastrocemius muscle of mice. Fluoride. Vol. 33 No. 1:17-26 http://www.fluoride-journal.com/00-33-1/331-17.pdf

18. Organofluorine pesticides and the Brain.

Tables 3, 5, 6, 7, 8 list some of the studies on organofluorine pesticides effects on bone, brain, liver, thyroid, and reproductive systems. The correlation between fluoride and organofluorine pesticides is, as yet, unclear. But the similarities for adverse effects are too common to ignore.

The studies on brain effects listed in Table 3 demonstrate that organofluorine pesticides should be generating more concern among public health officials in light of the Varner et al. Study (ref 3 above) and EPA’s risk assessment of September 7, 2001 (ref 2 above). In Table 3 references are given for the impact of fluoride from fluorocarbons, which, not too long ago, the scientific community told the public were inert. CFC’s are damaging our ozone layer. Perfluorinated compounds (PFOS) were used willy-nilly because they were considered inert. Only recently was it found that PFOS have been accumulating in the tissues of humans and wildlife globally. According to EPA:

"PFOS accumulates to a high degree in humans and animals. It has an estimated half-life of 4 years in humans. It thus appears to combine Persistence, Bioaccumulation, and Toxicity properties to an extraordinary degree." http://www.chemicalindustryarchives.org/dirtysecrets/scotchgard/pdfs/226-0629.pdf#page=2

It may turn out that exposure to fluoride, its many compounds, and organofluorine pesticides is damaging our brains, with our youth and senior citizens the most vulnerable. While we realize the political nature of this element and its compounds; its value to industry, energy, and our military; we remain hopeful that someone in government will be able to analyse fluoride in an objective and scientific manner.

One of the most striking effects listed in Table 3 are the animal studies on the organofluorine pesticide Chlorfenapyr.

In a subchronic oral toxicity study, Spongiform Encephalopathy was noted in the brain and myelin of the spinal cord of both males and females receiving the 320 ppm treatment level. The RfD Committee also recommended that a special developmental neurotoxicity study be conducted based upon the effects of spongyform myelopathy and/or vacuolation seen in the brain and spinal cord of rats and mice.

The CAS name for Chlorfenapyr is 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitril. Its CAS No. is 122453-73-0.

The combination of fluoride and bromide creates a particularly toxic substance. What is worrisome is that Chlorfenapyr residues are permitted on food. Bromethalin, an acutely toxic rodenticide, is another example.

We did a database search of the EPA Office of Pesticide Programs at http://www.epa.gov/pesticides/search.htm for spongiform and spongyform. The only substance cited was Chlorfenapyr. Mad Cow Disease is also called Bovine Spongiform Encephalopathy (BSE) which is a chronic, degenerative disorder affecting the central nervous system of cattle. There are 19 tolerances for residues of chlorfenapyr in the US: for residues under the cateogries: Cotton, Milk, Cattle, Hog, Sheep, Horse, and Goat. We urge the ATSDR to investigate this issue specifically. Perhaps a starting point would be an investigation of the workers and residents in the area surrounding the production site of Chlorfenapyr: Eastman Chemical Company in Kingsport TN 37660 .

19. Conclusion and Future Research.

The ATSDR document has a great deal of factual information on the toxicology of fluorine, hydrogen fluoride and fluorides which will be of great value to citizens and scientists alike.

There have been some major omissions from the literature: these include Masters and Coplan’s work on the association between the use of silcofluorides for fluoridating water supplies and blood levels in children’s blood; Luke’s work on the pineal gland; Li et al’s work on hip fracture in China; and Alarcon-Herrera et al’s work correlating the severity of dental fluorosis with bone fractures in a region in Mexico; the impact of aluminum fluoride on G-protein signaling mechanisms, which are important for many water soluble hormones and should have been discussed under the heading of mechanism of action,endocrine disruption, neural development, and children’s special sensitivity; the impact of fluoride on the thyroid gland; Heller et al’s survey of dental fluorosis and the five recent studies which have been done which show that dental decay has not increased in communities where fluoridation has been halted.

We feel a more holistic, rather than dismissive, discussion should have been made on the issue of a possible relationship between fluoride exposure and osteosarcoma; the thyroid gland and fertility. Special consideration should be given to a possible mechanism of action for these end points.

We feel it is important that the "taint" of political influence be removed from this report. The task of the authors is to give us a clear idea of the potential health problems from being exposed to fluoride from all sources. Citizens need to know what our current daily dose is and how close that is to various end points of concern. It is not their task to forward the political agenda of the DHSS to increase the number of communities who add fluoride to their water supplies. It is certainly not their task to continue to exaggerate the benefits of water fluoridation, or to downplay the risks of adding fluoride to the drinking water at a level 100 times the level found in mothers’ milk.

Language should be chosen carefully when it implies some kind of quantification. Vague terms like "large" or "substantial" should be quantified.

In discussing future research, we hope that the authors of this ATSDR report will call for a comprehensive analysis of the level of fluoride in the bones of the American people; a careful calculation of the total exposure children are getting to fluoride today from all sources including industrial air pollution and fluorinated drugs; the use of dental fluorosis as a biomarker for fluoride exposure in studies pertaining to children such as bone fractures, lowering of IQs, onset of puberty , osteosarcoma, melatonin levels and thyroid hormone levels; a closer examination of the Chinese studies which have looked at fluoride’s impact on the brain and the thyroid system, especially in the situation where the exposure to fluoride is coupled with low iodide levels in the diet; research aimed at investigating whether the high incidence of osteoarthritis and hypothyroidism in the US has fluoride exposure as a causal component; a repeat of Luke’s work on the pineal gland; further investigation of a possible relationship between the use of hexafluorosilicic acid to fluoridate water and children’s blood lead levels; more work on the excitation of G-proteins by aluminum fluoride complexes; and a comprehensive look at the toxicology of aluminum fluoride, hexafluorosilicic acid and its sodium salt; sulfuryl fluoride and organofluorine compounds with a particular attention to the possible production of free fluoride ion in any tissues, especially the brain.

Hydrogen fluoride. Examination of the TRI reports would idicate a very large emission of HF into the environment from a number of industrial sources and power stations (albeit, not all sources are reported in TRI). We recommend that an assessment be made of the total emissions of hydrogen fluoride in the US and its contributiom to TOTAL EXPOSURE to the daily dose. Of particular concern is that some evidence indicates that the health dangers posed via inhalation are significantly greater than via ingestion (Presentation by Phyllis Mullenix at the Annual Conference of the American College of Toxicology. Washington DC. November 6, 2002). Historically a number of health conditions were triggered due to air pollution of sulfur oxides and particulate. The time is long overdue to examine the question as to how much of these health concerns have been caused by HF on the one hand, and fluoride on the particulates on the other. See Table 9 (below) for a state-by-state breakdown of HF emissions as reported by TRI.

Finally, we would urge the ATSDR authors to ask for more studies on the effect of halting fluoridation to see if the recent results of lowering dental decay as observed in Cuba, Finland, Germany and Canada can be reproduced in the US.

_______________________________________________________________

 

Tables 1 - 9 below

 


Table 1: Some Fluorinated School Drinking Water Systems.

Table 2. Fluoride Residue Tolerances from the use of Cryolite
Table 3. Brain Effects from Organofluorine pesticides
Table 4. Fluoride Tolerances proposed by Dow on February 15, 2002.
Table 5. Bone Effects from Organofluorine pesticides
Table 6. Liver Effects from Organofluorine pesticides
Table 7. Thyroid Effects from Organofluorine pesticides
Table 8. Reproductive
Effects from Organofluorine pesticides
Table 9. Air pollution from fluoride emitting industries

 

Table 1.
Some fluorinated School Drinking Water Systems.
Ref: “Fluoridation Census 1992,” Volume 1. September 1993. U.S. Department of Health & Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Oral Health, Atlanta, Georgia 30333

* May be community drinking water systems and not school drinking water systems.

School Population Served School drinking water systems fluoridated at: Fluoridation Start Date
Bartholomew County, INDIANA
Cross Cliff Elem

186 4.5 ppm 1977
Carroll County, INDIANA
Carroll Elem

1225 4.5 ppm na
Delaware County, INDIANA
Daleville Elem
Cowan Elem
Desoto Elem
Harrison Elem
Perry Elem
Wes-Del Middle

355
333
151
216
239
230
4.5 ppm 1977
1977
1978
1978
1976
1980
Elkhart County, INDIANA
Concord Ox-Bow Elem
Concord South Elem
Harley-Hoblen Elem
Jefferson Elem
Jimtown Elem
New Paris Elem
Union Elem

468
486
342
457
1068
434
233
4.5 ppm na
1978
1976
1978
1978
1992
1979
Hamilton County, INDIANA
Cumberland Road Elem
Durbin Elem
Fall Creek Elem

519
239
388
4.5 ppm
1980
1980
1979
Hancock County, INDIANA
Eden Elem
Maxwell Middle

378
203
4.5 ppm 1976
1976
Henry County, INDIANA
Blue River Elem
Westwood Elem

450
262
4.5 ppm 1977
1976
Jasper County, INDIANA
Wheatfield Elem

472 4.5 ppm 1980
Kosciusko County, INDIANA
Atwood Elem
Leesburg School

174
619
4.5 ppm 1985
1985
La Grange County, INDIANA
Honeyville Elem

116 4.5 ppm 1977
Lake County, INDIANA
John Wood Elem
MacArthur Elem
Winfield Elem
Wood, John Elem

458
606
586
388
4.5 ppm 1978
1977
1974
1978
La Porte County, INDIANA
Coolspring Elem
Critchfield, FW Elem
Galana Elem
Hudson Lake Elem
Indian Trail Elem
Kingsbury Elem
Springfield Elem

401
494
231
163
436
293
362
4.5 ppm 1979
1978
1990
1990
1992
1978
1979
Madison County, INDIANA
College Corner Elem
Cunningham Elem
East Elem
Jackson Elem
Killbuck Elem
Leach Elem
North Madison Elem

369
248
820
165
373
295
254
4.5 ppm 1977
1977
na
1981
1977
1981
1979
Marshall County, INDIANA
Monterry Elem

106 4.5 ppm 1991
Miami County, INDIANA
North Miami Elem

709 4.5 ppm 1980
Morgan County, INDIANA
Eminence Elem
Green Twp Elem
North Madison Elem

409
289
254
4.5 ppm 1979
1979
1979
Newton County, INDIANA
Lake Village Elem
Lincoln Elem

296
466
4.5 ppm 1974
1976
Noble County, INDIANA
Rome City Elem/Middle

488 4.5 ppm 1978
Porter County, INDIANA
Boone Grove School
Brummitt Elem
Jackson Elem
Liberty Elem
Liberty Middle
Morgan Twp School
Pine Elem
Union Center Elem
Union Middle
Washington Twp Sch

918
447
437
469
479
439
322
404
243
592
4.5 ppm 1978
1979
1979
1979
1979
1980
1979
1980
1980
1977
Pulaski County, INDIANA
West Central Elem

564 4.5 ppm 1982
St. Joseph County, INDIANA
Eggleston Elem
Greene Elem & Middle
Laville Elem
Warren Elem

550
457
1508
457
4.5 ppm 1977
1979
1977
1977
Starke County, INDIANA
Oregon-Davis School

771 4.5 ppm na
Steuben County, INDIANA
Pleasant Lake Elem

195 4.5 ppm 1969
Tippecanoe County, INDIANA
Dayton Elem
Hershey Elem

302
721
4.5 ppm 1974
na
Warren County, INDIANA
Pine Village Elem

147 4.5 ppm 1973
White County, INDIANA
Eastlawn School

183 4.5 ppm na
Alleghany County, N.C.
Glade Creek *
Piney Creek *

182
246
4.5 ppm 1973
1973
Ashe County, N.C.
Fleetwood *
Riverview *

214
251
4.5 ppm 1973
1973
Avery County, N.C.
Riverside Elem

233 4.5 ppm 1974
Davie County
Pinebrook *

560 4.5 ppm 1972
Duplin County, N.C.
East Duplin *
Grady B F *
Wallace *

639
440
875
4.5 ppm 1975
1975
1975
Haywood County, N.C.
Fines Creek *

68 4.5 ppm 1973
Hoke County, N.C.
West Hoke *

490 4.5 ppm 1974
Jackson County, N.C.
Fairview Elem
Smokey Mt Elem

802
402
4.5 ppm 1981
1981
Mitchell County, N.C.
Buladean *
Tipton Hill *

131
102
4.5 ppm 1974
1975
Moore County, N.C.
Cameron *
Sandhills Farmlife *

395
314
4.5 ppm 1974
1974
Pender County, N.C.
Topsail Middle
Topsail Primary

360
281
4.5 ppm 1977
1977
Person County, N.C.
Bethel Hill Elem.
Helena Elem
Oak Lane Elem
Woodland Elem

250
608
307
305
4.5 ppm 1980
1981
1981
1980
Polk County, N.C.
Sunnyview *

162 4.5 ppm 1975
Sampson County, N.C.
Clement *
Halls Piney Grove *
Hargrove *
Hobbton *
Midway *
Union Elem

395
252
448
429
455
602
4.5 ppm 1972
1970
1970
1979
1976
1972
Stokes County, N.C.
Francisco Elem
Germanton Elem
Pine Hall Elem
Reynolds, Nancy
Sandy Ridge Elem

154
270
201
172
260
4.5 ppm 1977
1977
1977
1977
1977
Surry County, N.C.
Beulah *
Copeland *
Low Gap *
Mountain Park *
Shoals Elem
Westfield *
White Plains *

333
306
106
160
181
214
396
4.5 ppm 1972
1975
1982
1972
1972
1972
1972
Transylvania County, N.C.
Rosman Elem

352 4.5 ppm 1980
Vance County, N.C.
Carver *
New Hope Elem

330
330
4.5 ppm 1977
1977
Watauga County, N.C.
Bethel Elem
Mabel *
Valle Crucis *

181
300
370
4.5 ppm 1973
1973
1973
Wilkes County, N.C.
Boomer-Ferguson *
Mt Pleasant *
Ronda-Clingman *
Traphill *

181
1021
355
252
4.5 ppm 1975
1974
1974
1975
Yadkin County, N.C.
Courtney *
Fall Creek *
Forbush *
West Yadkin *
359
292
200
541
4.5 ppm 1972
1972
1972
1972
Yancey County, N.C.
Bald Creek *
Bee Log *
Clearmont *
Micaville *
South Toe *

199
63
140
200
150
4.5 ppm 1974
1974
1974
1974
1974
Bell County, KENTUCKY
Cubbage Elem
Frakes Elem

182
271
4.0 ppm 1979
1982
Breckinridge County, KENTUCKY
Milner Elem

120 4.0 ppm na
Bullitt County, KENTUCKY
Nicholas Elem

380 4.0 ppm 1976
Breathitt County, KENTUCKY
Rousseau Elem
Turner Elem

200
200
4.0 ppm 1975
1975
Carlisle County, KENTUCKY
Carlisle *

894 4.0 ppm 1979
Carter County, KENTUCKY
Carter Elem

272 4.0 ppm 1977
Casey County, KENTUCKY
Douglas Elem
Garrett Elem

250
250
4.0 ppm 1977
1977
Clay County, KENTUCKY
Big Creek Elem
Hacker Elem
Red Bird Elem

500
410
350
4.0 ppm 1975
1975
na
Elliott County, KENTUCKY
Isonville Elem

232 4.0 ppm 1976
Floyd County, KENTUCKY
Melvin Elem
Osborne Elem

335
365
4.0 ppm 1975
1975
Graves County, KENTUCKY
Cuba Elem

350 4.0 ppm 1975
Harlan County, KENTUCKY
Black Mt. Elem
Cranks Elem
Holmes Mill Elem
Rosspoint Elem
Verda Elem
Wallins Elem

225
70
137
200
370
590
4.0 ppm 1973
1980
1973
1975
1973
1973
Knott County, KENTUCKY
Beaver Creek Elem
Beckham Combs Elem
Caney Creek Elem
Carr Creek Elem
Cordia Elem/High
Emmalena Elem
Hindman Elem
Jones Fork Elem

475
250
200
720
280
362
650
250
4.0 ppm 1974
1973
na
1973
na
1973
1973
1973
Lawrence County, KENTUCKY
Blaine Elem

427 4.0 ppm 1977
Leslie County, KENTUCKY
Beech Fork Elem
Big Creek Elem
Hayes Lewis Elem

200
212
400
4.0 ppm na
na
1973
Letcher County, KENTUCKY
Arlie Boggs Elem
Beckham Bates Elem
Campbells Br. Elem
Cowan Elem
Hemphill Elem
Kingdom Come *
Letcher School
300
310
200
460
230
225
925
4.0 ppm 1973
na
1973
1973
1973
1973
1973
Lewis County, KENTUCKY
Laurel Elem

158 4.0 ppm 1977
Magoffin County, KENTUCKY
J. T. Arnette Elem

280 4.0 ppm 1974
Morgan County, KENTUCKY
Crockett Elem
Ezel Elem
Wrigley Elem

292
370
232
4.0 ppm 1977
1976
1973
Perry County, KENTUCKY
Big Creek Elem
Buckhorn Elem
Leatherwood Elem
Lost Creek School
Robinson Elem
Viper Elem
Willard Elem

190
400
400
200
360
440
559
4.0 ppm 1975
1973
1980
1973
1974
1973
na
Pike County, KENTUCKY
Brushy Elem
Jackson Rowe Elem
Majestic School
Phelps Elem/High
Sycamore Elem

176
412
325
380
275
4.0 ppm 1976
1973
1974
1974
1976
Wayne County, KENTUCKY
Big Sinking Elem
Powersburg Elem
Rocky Branch Elem

130
180
120
4.0 ppm 1975
1975
1975
Whitley County, KENTUCKY
Nevisdale *
Poplar Creek Elem

175
300
4.0 ppm 1975
1975
* these may be community drinking water systems and not school drinking water systems.

 

*************************************************************

TABLE 2

Fluoride Residue Tolerances from the use of Cryolite

On-line as of January 5, 2002 - http://www.epa.gov/pesticides/food/viewtols.htm

Chemical Name Crop PPM CFR
Cryolite APRICOT 7 180.145
Cryolite BEET, WITHOUT TOPS 7.0 180.145
Cryolite BLACKBERRY 7 180.145
Cryolite BLUEBERRY (HUCKLEBERRY) 7.0 180.145
Cryolite BOYSENBERRY 7 180.145
Cryolite BROCCOLI 7.0 180.145
Cryolite BRUSSELS SPROUT 7.0 180.145
Cryolite CABBAGE 7.0 180.145
Cryolite CAULIFLOWER 7.0 180.145
Cryolite COLLARDS 7.0 180.145
Cryolite CRANBERRY 7.0 180.145
Cryolite CUCUMBER 7.0 180.145
Cryolite DEWBERRY 7 180.145
Cryolite EGGPLANT 7.0 180.145
Cryolite FRUIT, CITRUS, GROUP 7.0 180.145
Cryolite GRAPE 7.0 180.145
Cryolite KALE 7 180.145
Cryolite KIWIFRUIT 15.0 180.145
Cryolite KOHLRABI 7.0 180.145
Cryolite LETTUCE 7.0 180.145
Cryolite LOGANBERRY 7 180.145
Cryolite MELON 7.0 180.145
Cryolite NECTARINE 7 180.145
Cryolite PEACH 7.0 180.145
Cryolite PEPPER 7.0 180.145
Cryolite PLUM, PRUNE, FRESH 7.0 180.145
Cryolite POTATO 2.0 180.145
Cryolite POTATO, WASTE, PROCESSED, (WET & DRY) 22.0 180.145
Cryolite PUMPKIN 7.0 180.145
Cryolite RADISHE, WITHOUT TOPS 7.0 180.145
Cryolite RASPBERRY 7.0 180.145
Cryolite RUTABAGA, WITHOUT TOPS 7.0 180.145
Cryolite SQUASH 7.0 180.145
Cryolite SQUASH, SUMMER 7.0 180.145
Cryolite STRAWBERRY 7.0 180.145
Cryolite TOMATO 7.0 180.145
Cryolite TURNIP, WITH TOPS 7.0 180.145
Cryolite YOUNGBERRY 7 180.145

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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TABLE 3

BRAIN effects from Organofluorine and fluoride pesticides
(Five in this list are not pesticides)

Note: This is not an exhaustive list. When time allows we will be adding more information to this Table.

Acifluorfen, sodium

The toxicity database is adequate for selecting toxicity endpoints for risk assessments, although a developmental neurotoxicity study is required because of neurotoxicity which occurred in a developmental rat study (dilated lateral ventricles of the brain)... A developmental toxicity study in rats found qualitative evidence of increased susceptibility of offspring because developmental toxicity (increased resorptions, reduced fetal weights, slightly dilated lateral ventricles of the brain, hemorrhage in the eyeball, slight dilation of the renal pelvis, hemorrhage in peritoneal cavity and subcutaneous spaces, and changes in ossification) was accompanied by minimal maternal toxicity (excess salivation and piloerection)... the Hazard Identification Assessment Review Committee recommended that a developmental neurotoxicity study in rats be conducted based on neurotoxicity observed in a developmental toxicity study in rats (increased incidence of dilated lateral ventricles of the fetal brain, MRID 00122743). In addition, no neurotoxicity studies are available for acifluorfen or for structurally related compounds which might provide an understanding on the effects of acifluorfen on the developing nervous system.

Ref: EPA, Sodium Acifluorfen. HED Chapter for the Reregistration Eligibility Decision. April 27, 2001. http://www.epa.gov/oppsrrd1/reregistration/acifluorfen/newrisk.pdf

Bromethalin
Pub Med Abstract abstracts:
Spongy change (edema--characterized by the formation of vacuoles in extracellular spaces and myelin lamellae), hypertrophied fibrous astrocytes, and hypertrophied oligodendrocytes were observed in the white matter of the cerebrum, cerebellum, brain stem, spinal cord, and optic nerve of all bromethalin-dosed cats. Spongy change occasionally extended into contiguous cerebellar Purkinje cell layer and cerebral cortical gray matter. The severity of lesions varied among cats but was most pronounced in cat No. 5 (480 hours after dosing).

Ref: Vet Pathol 1992 Mar;29(2):139-44
Neuropathologic findings of bromethalin toxicosis in the cat. Dorman DC, Zachary JF, Buck WB.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1632057&dopt=Abstract

Bromethalin
Dogs given a single oral dose of bromethalin at 6.25 mg/kg developed a toxic syndrome characterized by hyperexcitability, tremors, seizures, depression, and death within 15-63 hours after bromethalin administration. Gross lesions included mild cerebral edema (2/5) and mild pulmonary congestion (2/5). Histologic lesions included diffuse white matter spongiosis (5/5), mild microgliosis (3/5), optic nerve vacuolization (3/5), mild thickening of Bowman's capsule (2/5), and occasional splenic megakaryocytes (2/5). Ultramicroscopic examination of midbrain stem revealed occasional swollen axons, intramyelinic vacuolization, and myelin splitting at the intraperiod line. Bromethalin was detected in kidney, liver, fat, and brain tissues, using gas chromatography with electron capture detection. Photodegradation of extracted bromethalin may limit accurate quantification of tissue residues.

Ref: J Vet Diagn Invest 1990 Apr;2(2):123-8
Diagnosis of bromethalin toxicosis in the dog.
Dorman DC, Simon J, Harlin KA, Buck WB. Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801. PMID: 2094433 http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2094433&dopt=Abstract

Bromethalin
Bromethalin is a new rodenticide for the control of commensal rodents. Doses in excess of the LD50 (2 mg/kg in rats) will cause death within 8-12 hr and it is preceded by one to three episodes of clonic convulsions with death usually due to respiratory arrest. Multiple low doses or sublethal intoxication yields hind leg weakness and loss of tactile sensation in rodents. Histopathology of the brain and spinal cord of these animals revealed a spongy degeneration of the white matter which was shown upon ultramicroscopic examination to be intramyelenic edema. No inflammation or cellular destruction of neuronal tissue was noted. LD50 values ranged from 1.8 mg/kg in the cat to approximately 13 mg/kg in rabbits. The only apparent nonsusceptible species was the guinea pig which could tolerate doses in excess of 1000 mg/kg without effect. Identification of the desmethyl metabolite was demonstrated in the blood and liver of treated animals by comparison of chromatographic retention times to that of a reference standard, but direct mass spectral identification was unsuccessful in part due to the low dose which could be administered. Therefore, the metabolism of bromethalin was studied by indirect means. Animals were pretreated with three inducers of microsomal drug metabolism: phenobarbital, 3-methylcholanthrene (3MC), and Aroclor 1254 (Aroclor) and one inhibitor, SKF-525A. Pretreated mice or rats were given an LD50 dose of bromethalin or the desmethyl analog and the percentage of surviving animals was determined. (ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3229590

Fundam Appl Toxicol 1988 Nov;11(4):664-72 The toxicity and mechanism of action of bromethalin: a new single-feeding rodenticide. van Lier RB, Cherry LD. Toxicology Division, Lilly Research Laboratories, Greenfield, Indiana 46140. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3229590&dopt=Abstract

Chlorfenapyr

ii. Subchronic Oral Toxicity in Mice... Spongiform encephalopathy was noted in the brain and myelin of the spinal cord of both males and females receiving the 320 ppm treatment level. The LEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0 mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy in  20% of the test animals at this treatment level. The NOEL is 7.1 mg/kg/day (40 ppm)... The RfD Committee also recommended that a special developmental neurotoxicity study be conducted based upon the effects of a spongyform myelopathy and/or vacuolation seen in the brain and spinal cord of treated rats and mice. They concluded that the registrant should also conduct a mechanistic study to determine the cause/relationship of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain lesions (vacuolation) and/or scabbing of the skin in a 1 year neurotoxicity study in rats and a chronic/carcinogenicity study in mice) Acceptable MOE = 1000 (includes FQPA Factor)

Ref: US EPA, Feb 12, 1998: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr. http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf

Note: In a search of EPA's OPP database <http://www.epa.gov/pesticides/search.htm> for "spongiform encephalopathy" - "spongyform myelopathy" - "spongyform" - , the only substance cited was Chlorfenapyr. Mad Cow Disease is also called Bovine spongiform encephalopathy (BSE) which is a chronic, degenerative disorder affecting the central nervous system of cattle. Human Man Cow Disease is CDF... In the US the 19 tolerances for residues of chlorfenapyr are: Cotton, Milk, Cattle, Hog, Sheep, Horse, and Goat. For more accessible information on Chlorfenapyr see: http://www.fluoridealert.org/pesticides/CHLORFENAPYR-PAGE.htm

Ethane, 1,1-dichloro-1-fluoro- (CAS No. 1717-00-6) - (Not a pesticide)

A Neurobehavioral and Neuropathological Effects Study in Rats: The only effect noted was a significant reduction in brain weight in females exposed to the highest concentration (rats were dosed at 15,000 ppm for 16 weeks and 2 days and observed for effects until week 21 of the study).

Ref: Federal Register. December 9, 1997. 40 CFR Part 721 [OPPTS-50629; FRL-5752-9] RIN 2070-AB27

Fipronil

The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day). The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day) based on: Decreased auditory startle response; reduced swimming direction scores, group mean angle measurements, and water ``Y'' maze times trails; and decreased absolute-brain weights. The NOEL for developmental neurotoxicity is 10 ppm (0.90 mg/kg/day).

Federal Register. July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.
Ref: http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
or: http://www.epa.gov/fedrgstr/EPA-PEST/1998/July/Day-17/p18987.htm

Fluazinam

90-Day oral toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolation of the cerebral white matter (equivocal)...
Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes
Special study: 4-Week dietary (Range-finding) mice NOAEL = not identified (Males; <555 mg/kg/day; Females: <658 mg/ kg/day) LOAEL = Males: 555 mg/kg/day; Females: 658 mg/kg/day based on vacuolation of white matter in brain, increased liver weights, histopathology in liver...
Eight special mechanistic studies
to assess the CNS white matter vacuolation: White matter vacuolation in the CNS of mice, rats, and dogs was found to be due to Impurity-5.

Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Sept.7.2001.htm
or: http://www.epa.gov/fedrgstr/EPA-PEST/2001/September/Day-07/p22525.htm

Flufenacet

NOEL = 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] LOEL = 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in females] based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T3, T4 and ALT values in both sexes, and increased incidence of microscopic lesions in the brain [axonal degeneration], eye [vacuolization of the ciliary body epithelium], kidney [hyperplasia of the epithelial cells], spinal cord [axonal degeneration], sciatic nerve [axonal degeneration] and liver [hepatocytomegaly].
Ref: EPA Pesticide Fact Sheet, April 1998 http://www.epa.gov/opprd001/factsheets/flufenacet.pdf

Flufenacet

A rat subchronic neurotoxicity study with a NOEL of 120 ppm (7.3 mg/kg/day in males and 8.4 mg/kg/day in females) and a LOEL of 600 (38.1 mg/kg/day in males and 42.6 mg/kg/day in females) based on microscopic lesions in the cerebellum/medulla and spinal cords....

A 1-year dog chronic feeding study with a NOEL was 40 ppm (1.29 mg/kg/day in males and 1.14 mg/kg/day in females) and a LOEL of 800 ppm (27.75 mg/kg/day in males and 26.82 mg/kg/day in females) based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve and liver.

A 55-day dog study with subcutaneous administration of thiadone flufenacet metabolite supports the hypothesis that limitations in glutathione interdependent pathways and antioxidant stress result in metabolic lesions in the brain and heart following flufenacet exposure.

Ref: Federal Register, September 23, 1998. Flufenacet; Time-Limited Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Flufenacet.FR.Sept.23.1998.htm

Fluorouracil - (pharmaceutical)

Absorption, Distribution & Excretion : Fluorouracil is distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues. Despite its limited lipid solubility, the drug readily crosses the blood-brain barrier and distributes into CSF and brain tissue... [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993).

Available at: http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
From: Website search for "Fluorouracil" at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Fluoride

Non-Human Toxicity Excerpts : /ACUTE POISONING/ IF SUFFICIENT FLUORIDE IS ABSORBED ... FLUORIDE ION INCREASES CAPILLARY PERMEABILITY AND ALSO PRODUCES A COAGULATION DEFECT. THESE ACTIONS LEAD TO HEMORRHAGIC GASTROENTERITIS & HEMORRHAGES, CONGESTION, & EDEMA IN VARIOUS ORGANS INCL THE BRAIN. CLINICAL MANIFESTATIONS ... INCLUDE EXCITABILITY, MUSCLE TREMORS, WEAKNESS, URINATION, DEFECATION, SALIVATION, EMESIS, SUDDEN COLLAPSE, CLONIC CONVULSIONS, COMA, & DEATH DUE TO RESP & CARDIAC FAILURE. CYANOSIS & EARLY RIGOR MORTIS ... . /FLUORIDE/

Ref: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 1014

Ref: Website search for "Ammonium silicofluoride" (CAS No. 16919-19-0) at:
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Fluorocarbons - (Not a pesticide)
(See Ref. 1 below for specific substances)

There is a significant accumulation of propellant in the brain, liver and lung compared to blood levels, signifying a tissue distribution of propellant similar to that of chloroform.

Ref: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203

Website ref: Hazardous Substances Data Bank: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Fluorocarbons

Fluorocarbon propellants: Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication. Prolonged exposure or daily use may result in damage to several organ systems. Clinical problems include cardiac arrhythmias, bone marrow depression, cerebral degeneration, and damage to liver, kidney, & peripheral nerves. Death occasionally has been attributed to inhalant abuse, probably via the mechanism of cardiac arrhythmias, especially accompanying exercise or upper airway obstruction.

Ref: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 575] http://www.fluoridealert.org/pesticides/Dichlorodifluorometh.TOXNET.htm

Halothane - (Anesthetic)

Non-Human Toxicity Excerpts : Rats exposed prenatally by administered to the dams of 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week and postnatally up to 60 days after birth to the same concentration had later impairments in learning ability. Reduced learning ability was correlated with persistent synaptic malformation in the cerebral cortex. Other changes in the neurons noted in young adult rats exposed to 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week for 8 weeks included destruction of the rough-surfaced endoplasmic reticulum, dilatation of the Golgi complex and focal cytoplasmic vacuolation. Offspring of rats exposed to 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week throughout pregnancy had ultrastructural changes in the liver within 24 hr of birth. These changes included myelin figures and large areas of focal cytoplasmic degradation in many hepatocytes; accumulation of lipids within hepatocytes and leucocytic infiltration were noted in many cases. Focal necrosis was observed in more than 50% of tissue samples.

Ref: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V11 288

Note: Halothane is one of many synonyms for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE CASRN: 151-67-7 at: Information from search for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE on the
Hazardous Substances Data Bank: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Indoxycarb or Indoxacarb

Non-neoplastic changes were noted in the brain of both sexes and in the heart of males only of mice that died or were sacrificed in extremis. Neuronal necrosis was reported in two high-dose males and two females and in one female at 100 ppm. Both high-dose males were sacrificed in extremis, one while receiving the 150 ppm diet (day 133) and the other while receiving the 125 ppm diet (test day 302). The two affected females died or were killed in extremis (day 83 and 108, respectively) while receiving 200 ppm. Residual vacuolation of the piriform cortex was observed in 2 female high-dose mice that survived to the 18-month scheduled sacrifice.

Ref: CA EPA, Summary of Toxicology data. http://www.cdpr.ca.gov/docs/toxsums/pdfs/5331.pdf

Oxyfluorfen

Absolute and relative thymus weights were decreased in mid-dose males (-14%/-10%)and high-dose males (-32%/- 18%)...Vacuolation of the adrenal cortex was present in high-dose females. Thymic atrophy occurred in high-dose males and females.... Fine vacuolation of adrenal glands (slight)and cortical atrophy of the thymus (slight) were increased in high-dose males... Absolute and/or relative organ weights in the high-dose groups that showed statistically significant changes relative to control weights (thyroid gland in both sexes and kidney in females at 12 months and brain, pituitary, and spleen in females sacrificed at 24 months) had no microscopic correlates and are not considered toxicologically significant.

Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

Quinoxyfen

XDE-795: One Year Chronic Dietary Toxicity Study in Beagle Dogs'... XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Beagle dogs (4/sex/dose) at 0, 5, 20 or 200 mg/kg/day for 1year. NOEL = 20 mg/kg (A male at 200 mg/kg was killed moribund, due to a severe weight decrease (2 kg), decreased hemoglobin and RBC counts. Both sexes had significantly decreased body weights and food consumption at 200 mg/kg.... Statistically significantly increased relative organ weights were observed in both sexes at 200 mg/kg (brain, kidney, pituitary).

Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

Sodium fluoroacetate (Compound 1080) and Fluoroacetamide (Compound 1081)

Sodium fluoroacetate and fluoroacetamide are readily absorbed by the gut, but only to a limited extent across skin. The toxic mechanism is distinct from that of fluoride salts. Three molecules of fluoroacetate or fluoroacetamide are combined in the liver to form a molecule of fluorocitrate, which poisons critical enzymes of the tricarboxylic acid (Krebs) cycle, blocking cellular respiration. The heart, brain, and kidneys are the organs most prominently affected... Crimidine and sodium fluoroacetate are no longer registered for use as pesticides.

Ref: US EPA http://www.epa.gov/oppfead1/safety/healthcare/handbook/Chap17.pdf

Sodium fluoride

Summary: This study reports accumulation of fluoride and altered activities of some enzymes involved in free-radical metabolism and membrane function in whole brain and gastrocnemius muscle of female mice treated with NaF (20mg/kg/body weight) for 14 days. The body weight and somatic index were decreased, whereas fluoride levels were significantly increased (p<0.01) in both brain and gastrocnemius muscle. The enzymes SOD, GST, and catalase decreased significantly (p<0.01) in contrast to XOD activity, which moderately increased. SDH, LDH, AlAT, AAT, and CPK activities and membrane-bound enzymes, viz Na + -K + , Mg ++ and Ca ++ ATPase and AChE were decreased significantly (p<0.01) in both brain and gastrocnemius muscle. The effect of fluoride on enzymes of muscle was comparatively larger, which corroborates the greater accumulation of fluoride in muscle than brain. This study therefore shows that both brain and muscle are affected by fluoride with inhibition of some enzymes associated with free-radical metabolism, energy production and transfer, membrane transport, and synaptic transmission, but with an enhanced activity of XOD.

Ref: Fluoride (2000). Vol. 33 No. 1:17-26. EFFECTS OF FLUORIDE ACCUMULATION ON SOME ENZYMES OF BRAIN AND GASTROCNEMIUS MUSCLE OF MICE, by M Lakshmi Vani and K Pratap Reddy- http://www.fluoride-journal.com/00-33-1/331-17.pdf

Sulfuryl fluoride

Vikane, sulfuryl fluoride, Lot No. TWP 830919-408, 99.8%, was administered to New Zealand White rabbits via inhalation for 6 hours/day, 5 days/week for 13 weeks at 0, 30, 100 or 300 ppm. Seven animals per sex per group. NOEL = 30 ppm; [cerebral vacuolation in regions of internal and external capsules, putamen, and globus pallidus of one female: and nasal tissue inflammation in one male]. At 300 ppm, common brain findings were vacuolation to severe malacia of cerebrum (both sexes, in the above regions), and gliosis and/or hypertrophy of vascular endothelial cells in some females in the same regions.

Ref: CA EPA, Summry of Toxicolgy Data, August 1, 1986 http://www.cdpr.ca.gov/docs/toxsums/pdfs/618.pdf

Sulfuryl fluoride

In rabbits, the primary target organ was the brain, in which malacia (necrosis) and vacuolation were observed in the cerebrum...
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...
In chronic (1-2 year) inhalation studies in rats, dogs and mice, target organs were the same as in the 90-day studies. In rats, severe kidney damage caused renal failure and mortalities in many animals. Additional gross and histopathological lesions in numerous organs and tissues were considered to be secondary to the primary effect on the kidneys. Other treatment-related effects in rats included effects in the brain (vacuolation of the cerebrum and thalamus/hypothalamus) and respiratory tract (reactive hyperplasia and inflammation of the respiratory epithelium of the nasal turbinates, lung congestion, aggregates of alveolar macrophages). 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...
In a 2-generation reproduction inhalation study in rats, vacuolation of the white matter in the brain, pathology in the lungs (pale, gray foci; increased alveolar macrophages) and decreased body weights were observed in the parental animals...
[Humans]: Short-term inhalation exposure to high concentrations has caused respiratory irritation, pulmonary edema, nausea, abdominal pain, central nervous system depression, and numbness in the extremities.

Ref: Federal Register. September 5, 2001. Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.
http://www.fluoridealert.org/pesticides/Sulfuryl.Flu.FR.Sept.5.2001.htm

Trifluorothymidine - (Pharmaceutical. Not a pesticide)

Abstract: Metabolism of trifluorothymidine (TFT) and its transport across the blood-brain barrier (BBB) has been measured quantitatively in rats by fluorine-19 nuclear magnetic resonance spectroscopy ((19)F NMR). It is demonstrated that TFT crosses the BBB in micromolar quantities and is metabolized in brain tissue primarily to its free base trifluoromethyluracil (TFMU) by the enzyme thymidine phosphorylase (TP). It is further proposed that the rate of TFMU production can be used as a measure of cerebral TP. The glycols of both TFMU, and to a lesser degree TFT, are generated via an oxidative route. In contrast, the major pathway for hepatic metabolism of this compound is through reduction of the nitrogen base moiety and generation of 5-6-dihydro species followed by ring degradation. Thus, in addition to TFMU as well as the dihydroxy (glycol)-, and the dihydro-species of both TFT and TFMU, alpha-trifluoromethyl-beta-ureidopropionic acid (F(3)MUPA) and alpha-trifluoromethyl-beta-alanine (F(3)MBA) were detected in liver extracts. The total metabolite levels in liver were 2-5 times higher than in the brain. Low levels of fluoride ion were detected in all the extracts from brain and liver, as well as blood and urine. This study characterizes TFT as a potential chemotherapeutic agent for use against brain tumors. Copyright 1999 John Wiley & Sons, Ltd. PMID: 10516619

Ref: NMR Biomed 1999 Oct;12(6):373-80.
Quantitative 19F NMR study of trifluorothymidine metabolism in rat brain.
Pouremad R, Bahk KD, Shen YJ, Knop RH, Wyrwicz AM
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10516619&form=6&db=m&Dopt=b

Reference 1.

Specific fluorocarbons cited in the Hazardous Substances Data Bank:
(search at: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB )
BROMOCHLORODIFLUOROMETHANE (Freon 12B1) -353-59-3
1-BROMO-2-FLUOROETHANE -762-49-2
BROMOTRIFLUOROMETHANE (Freon 13B1) -75-63-8
1-CHLORO-1,1-DIFLUOROETHANE (Freon 142; Freon 142B) -75-68-3\
CHLORODIFLUOROMETHANE (Freon 22) -75-45-6
1-CHLORO-2-FLUOROETHANE -762-50-5
CHLOROPENTAFLUOROETHANE -76-15-3
CHLOROTETRAFLUOROETHANE (HCFC 124a) -63938-10-3
2-CHLORO-1,1,1,2-TETRAFLUOROETHANE (Freon 124); 2837-89-0
DIBROMODIFLUOROMETHANE (Freon 12B2) 75-61-6
1,2-DIBROMOTETRAFLUOROETHANE (Freon 114B2) -124-73-2
1,2-DICHLORO-1,1-DIFLUOROETHANE -1649-08-7
DICHLOROFLUOROMETHANE (Freon 21) -75-43-4
1,2-DICHLORO-1,1,2-TRIFLUOROETHANE 354-23-4
DICHLORO-1,1,2-TRIFLUOROETHANE 90454-18-5
1,2-DICHLORO-1,1,2,2-TETRAFLUOROETHANE (Propellant 114) -76-14-2
DICHLOROTRIFLUOROETHANE (HFC 123a) -34077-87-7
2,2-DICHLORO-1,1,1-TRIFLUOROETHANE (Freon 123) -306-83-2
1,1-DICHLORO-1,2,2-TRIFLUOROETHANE - 812-04-4
1,1-DICHLORO-1,2,2,2-TETRAFLUOROETHANE (Frigen 114A) -374-07-2
DICHLORODIFLUOROMETHANE (Freon 12)( 75-71-8
1,1-DICHLORO-1-FLUOROETHANE (Freon 141) -1717-00-6
1,2-DIFLUOROETHANE -624-72-6
HCFC-124a -354-25-6
PENTAFLUOROETHANE -354-33-6
1,1,2,2-TETRACHLORO-1,2-DIFLUOROETHANE (Freon 112) -76-12-0
1,1,1,2-TETRACHLORO-2,2-DIFLUOROETHANE (CFC-112a) -76-11-9
1,1,1,2-TETRAFLUOROETHANE -811-97-2
TRICHLOROFLUOROMETHANE (Freon 11) -75-69-4
1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE (Freon 113) -76-13-1
TRIFLUOROMETHANE ( Freon 23) -75-46-7

 

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Table 4


Fluoride Tolerances proposed by Dow on February 15, 2002.
Ref: Federal Register, Feb 15, 2002. [PF-1068; FRL-6822-2]

http://www.epa.gov/fedrgstr/EPA-PEST/2002/February/Day-15/p3661.htm

In or On Raw Commodity: Inorganic
Fluoride tolerances
Sulfuryl fluoride tolerances
Almond 10 0.2
Barley, grain 10 0.01
Beechnut 30 6
Brazil (nut) 30 6
Butternut 30 6
Cashew 30 6
Chestnut 30 6
Chinquapin 30 6
Corn, field, grain 7 0.04
Corn, pop, grain 7 0.04
Date 5 0.03
Fig 5 0.05
Filbert 30 6
Fruit, dried 5 0.05
Grape, raisin 5 0.01
Hickory (nut) 30 6
Macadamia (nut) 30 6
Millet, grain 25 0.05
Oat, grain 17 0.01
Pecan 23 6
Pistachio 18 0.5
Plum, prune 5 0.01
Rice, grain 10 0.04
Rice, wild, grain 25 0.05
Sorghum, grain 25 0.05
Triticale, grain 25 0.05
Walnut 30 6
Wheat, grain 25 0.04
     
Tolerances: On the processed products
Corn, field, flour 26 0.01
Corn, field, grits 10 0.01
Corn, field, meal 28 0.01
Corn, field, refined oil 3 9
Rice, bran 31 0.01
Rice, brown 14 0.01
Rice, hulls 35 0.08
Rice, polished rice 18 0.01
Wheat, bran 40 0.01
Wheat, flour 10 0.03
Wheat, germ 98 0.01
Wheat milled by products 35 0.01
Wheat, shorts 38 0.01

 

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TABLE 5

BONE effects from Organofluorine and fluoride pesticides
(All but two in this list are organofluorine or fluoride pesticides)

Note: This is not an exhaustive list. When time allows we will be adding more information to this Table.

Acifluorfen, sodium

A developmental toxicity study in rats found qualitative evidence of increased susceptibility of offspring because developmental toxicity (increased resorptions, reduced fetal weights, slightly dilated lateral ventricles of the brain, hemorrhage in the eyeball, slight dilation of the renal pelvis, hemorrhage in peritoneal cavity and subcutaneous spaces, and changes in ossification) was accompanied by minimal maternal toxicity (excess salivation and piloerection)...

Ref: EPA, Sodium Acifluorfen. HED Chapter for the Reregistration Eligibility Decision. April 27, 2001. http://www.epa.gov/oppsrrd1/reregistration/acifluorfen/newrisk.pdf

Carfentrazone-ethyl

Developmental toxicity study - rat... Examination of fetuses for alterations of external, visceral, and skeletal development revealed significantly increased litter incidences of wavy and thickened ribs in the 1,250 mg/kg/day treatment group. The developmental LOAEL is 1,250 mg/kg/day (based upon a significant increase in the litter incidences of wavy and thickened ribs); the developmental NOAEL is 600 mg/kg/day.

Ref: Federal Register. August 1, 2001. Carfentrazone-ethyl; Pesticide Tolerances for Emergency Exemptions. Final Rule. http://www.fluoridealert.org/pesticides/Carfentrazone-e.FR.Aug1.01.htm

1-Chloro-1,1-difluoroethane

Damske et al. (1978) exposed 20 pregnant CRL:COBS CD (SD) BR rats to 0, 3259, or 9420 ppm HCFC-142b (0, 13,460, or 38,905 mg/cu.m, respectively) for 6 hours/day on gestation days 6-15. Dams were sacrificed on day 20, and the fetuses were weighed, sexed, and examined for external malformations... Some skeletal variations described by the study authors were classified as "commonly encountered" or "unusual skeletal variations", but no further information is given. Reduced ossification was described for several areas, including the interparietal and supraoccipital bones of the skull and the hyoid bone.."

Ref: US EPA IRIS, CASRN 75-68-3 . http://www.fluoridealert.org/pesticides/1-Chloro-1.1-difluoroe.IRIS.htm

Clodinafop-propargyl

In a developmental toxicity study in rats, the highest dose level of 160 mg/kg resulted in reduced body weight gain of the dams and signs of retarded fetal body weight and incomplete ossification of vertebrae and sternebrae... The EPA's Hazard Identification Assessment Review Committee (HIARC) concluded that based on an increase in bilateral distension and torsion of the ureters and delayed ossification in the fetuses, the developmental LOAEL was 40 mg/kg/day and the NOAEL was 5 mg/kg/day.

Ref: Federal Register. Arpil 26, 2000. [PF-938; FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm

Cyfluthrin

Rat developmental studies via inhalation: In the second study, the dams were exposed to analytical concentrations of 0, 0.09, 0.25, 0.59 or 4.2 mg/m3 of the test material. The dams were sacrificed on day 20 and their pups removed by caesarian section. The maternal NOEL was 1.1 mg/ m3 and the maternal LOEL was 4.7 mg/m3 (reduced motility, dyspnea, piloerection, ungroomed coats and eye irritation. The developmental NOEL was 0.59 mg/m3 and the developmental LOEL was 1.1 mg/m3 (increases in the incidence of runts and skeletal anomalies in the sternum (1.1 mg/m3 and above); increases in post-implantation losses and decreases in pup weights (4.7 mg/m3 and above) and increased incidences of late embryonic deaths, in skeletal anomalies in the extremities, pelvis and skull and in microphthalmia (23.7 mg/m3).

Ref: Federal Register, November 26, 1997. Cyfluthrin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/Cyfluthrin.FR.Nov.26.1997.htm

Diflubenzuron

At all dose levels, histopathological examinations indicated dose related increases of hemosiderosis and congestion of the spleen, hemosiderosis and chronic hepatitis of the liver, and mild erythroid hyperplasia of the bone marrow... Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological examinations indicated non-neoplastic treatment-related effects in the spleen, liver, bone marrow and adrenal gland. A treatment-related increased incidence of uncommon sarcomas of the spleen was observed in the male rats in this study. These sarcomas included fibrosarcomas, hemangiosarcomas and osteosarcomas, many of which metastasized to other sites. The combined incidence of these sarcomas in male rats was 0/49, 1/50, 3/50 and 38/50 at dose levels of 0, 2, 6 and 18 mg/kg/day respectively. In female rats, 1 fibrosarcoma was observed at 6 mg/kg/day and 1 osteosarcoma at 18 mg/kg/day. No additional uncommon sarcomas of the spleen were observed in the female rats in this study. A marginally increased incidence of pheochromocytomas was also observed in the adrenal gland of male and female rats at 18 mg/kg/day. For male rats, the incidence was 13/49, 14/48, 15/48 and 26/49 and for female rats was 2/50, 3/50, 1/50 and 6/50 at dose levels of 0, 2, 6 and 18 mg/kg/day respectively. Decreased incidence of mononuclear cell leukemia and of malignant lymphomas were also noted in the treated male and female rats in this study. (National Toxicology Program (NTP) Report No. 351; July, 1989)..."

Ref: US EPA RED. August 1997. http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf

Diflufenzopyr

In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female Sprague Dawley rats at dose levels of 0, 100, 300, or 1000 mg/kg/day from days 6 through 15 of gestation... Developmental effects, characterized as significantly lower fetal body weights in males( 5%) and skeletal variations, exhibited as incompletely ossified and unossified sternal centra and reduced fetal ossification sites for caudal vertebrae, were observed at 1000 mg/kg/day. The developmental LOAEL is 1000 mg/kg/day, based on decreased fetal body weights and skeletal variations. The developmental NOAEL is 300 mg/kg/day...
In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female New Zealand White rabbits at dose levels of 0, 30, 100, or 300 mg/kg/day from days 6 through 19 of gestation... Developmental effects, characterized as significant increases in the incidence of supernumerary thoracic rib pair ossification sites occurred at the 300 mg/kg/day dose."

Ref: US EPA Pesticide Fact Sheet. January 28, 1999. http://www.fluoridealert.org/pesticides/Diflufenzopr.EPAFacts.Jan99.pdf

Epoxiconazole

A developmental study was conducted via oral gavage in rats resulted in dosages of 0, 5, 15, and 45 mg/kg/day HDT with a developmental toxicity NOAEL of 5 mg/kg/day and a maternal toxicity of 5 mg/kg/day based on the following:.. d. A significant number of fetuses with skeletal variations (especially rudimentary cervical and/or accessory 14th rib(s)) in the high dose group tested were observed. However, no malformations were observed in any pups in this study. iii. In a second developmental study in rats via dermal exposure for 6 hours/day on intact skin with dosages of 0, 100, 400, and 1,000 mg/kg/day (HDT) with a development toxicity NOAEL of 400 mg/kg/day and a maternal toxicity of 400 mg/kg/day based on increased placental weights and a slight increase in the number of fetuses with skeletal variations was observed at the highest dose tested."

Ref: Federal Register. September 22, 2000. [PF-961; FRL-6737-8].
http://www.fluoridealert.org/pesticides/Epoxiconazole.FR.Sept.2000.htm

Ethalfluralin

Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for 1-year. The NOAEL was 4 mg/kg/day. The LOAEL was 20 mg/kg/ day, based on increased urinary bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and increased erythroid series of the bone marrow. Elevated alkaline phosphatase levels were found at the two higher doses and siderosis of the liver at the high dose.

Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9] http://www.fluoridealert.org/pesticides/Ethalfluralin.FR.Nov14.2001.htm

Ethylene fluorohydrin

REPRODUCTIVE HAZARDS: An increase in sternebral ossification defects, hydronephrosis, runting (pup weight less than 2.7 g), variant rib ossifications, extra vertebral ossification centers, cardiac septal defects, and intrauterine growth retardation were noted in rats.

Ref: TOXNET profile from Hazardous Substances Data Base. http://www.fluoridealert.org/pesticides/Ethylene.fluorohydri.TOXNET.htm

Fipronil

The Developmental Toxicity LOEL was 2.5 mg/kg/day and the NOEL was 1.0 mg/ kg/day based on the slight increase in fetal and litter incidence of reduced ossification of several bones... (hyoid, 5th/6th sternebrae, 1st thoracic vertebral body, pubic bone, and one or two metatarsi)...

Federal Register. July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.
Ref: http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm

Fluazinam

Prenatal developmental toxicity -rats. LOAEL = 250 mg/kg/day based on decreased fetal body weights and placental weights, increased facial/cleft palates, diaphragmatic hernia, and delayed ossification in several bone types, greenish amniotic fluid and possible increased late resorptions and postimplantation loss...
Prenatal developmental toxicity -rabbits. LOAEL = 12 mg/kg/day based on an increase in total litter resorptions and possible fetal skeletal abnormalities.

Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fluazinam.FR.Sept.7.2001.htm

Flucarbazone-sodium

Prenatal development: LOAEL = 500 mg/kg/ day based on decreased fetal weight and increased incidence of delayed fetal ossification...

Ref: Federal Register. September 29, 2000. Flucarbazone-sodium; Time-Limited Pesticide Tolerances. Final Rule. http://www.fluoridealert.org/pesticides/Flucarbazone_Na.FR.Sept2000.htm

Fluorocarbon propellants -
(not used as pesticide; though in the past some were used as propellants for pesticides)

Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication. Prolonged exposure or daily use may result in damage to several organ systems. Clinical problems include cardiac arrhythmias, bone marrow depression, cerebral degeneration, and damage to liver, kidney, & peripheral nerves. Death occasionally has been attributed to inhalant abuse, probably via the mechanism of cardiac arrhythmias, especially accompanying exercise or upper airway obstruction.

Ref: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 575] http://www.fluoridealert.org/pesticides/Dichlorodifluorometh.TOXNET.htm

Fluorouracil - (pharmaceutical)

Potential Adverse Effects on Fetus: Exposure in first trimester: skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus... the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased.

TOXNET profile from Hazardous Substances Data Base. http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Fluroxypyr

The developmental NOAEL is 250 mg/kg/day, the LOEL is 500 mg/kg/day based on reduced ossification... The developmental toxicity NOAEL is 300 mg/kg/day, and the LOEL is 600 mg/ kg/day, based on an increase in two ossification variations incompletely ossified cervical vertebral transverse processes and pubes.

Ref: Federal Register. September 30, 1998. Fluroxypyr; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fluroxypyr.FR.Sept.30.1998.htm

Flurprimidol

A rat teratology study using doses of 0, 2.5, 10, 45 or 200 mg/kg/day of flurprimidol had a maternal toxicity NOEL of 10 mg/kg/day and a LEL of 45 mg/kg/day based on decreased body weight gain and food consumption. The developmental NOEL was 10 mg/kg/day and the LEL was 45 mg/kg/day based on decreased fetal weight, increased incidence of hydronephrosis, hydroureter and numerous developmental skeletal anomalies.

Ref: US EPA Pesticide Fact Sheet. February 22, 1989.
http://www.fluoridealert.org/pesticides/Flurprimidol.EPA.Facts.1989.htm

Flutolanil

A rabbit developmental study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL of 25 mg/kg/day based on histopathological finds in the liver and a developmental NOEL of 25 mg/kg/day and a developmental LOEL of 125 mg/kg/day based on increased skeletal variations... Reproductive and developmental toxicity... A rat developmental study with a maternal NOEL of 25 mg/kg/day and with a maternal LOEL of 125 mg/kg/day based on decreased body weight gain initially and a developmental NOEL of 25 mg/kg/day and a developmental LOEL of 125 mg/kg/day based on decreased fetal body weight, delayed development [mainly delays in ossification in the skull, vertebrae, sternebrae, and appendages], and an increase in the incidence of extra ribs. A rabbit developmental study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL of 25 mg/kg/day based on histopathological finds in the liver and a developmental NOEL of 25 mg/kg/day and a developmental LOEL of 125 mg/kg/day based on increased skeletal variations.

Ref: Federal Register. June 23, 1998. [PF-813; FRL-5795-1]
http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm

Fomesafen

Acute toxicity. EPA has selected the developmental NOEL of 7.5 mg/kg/day from the oral rat developmental toxicity study for the acute dietary endpoint; at the lowest observed effect level (LOEL) of 50 mg/ kg/day, fetuses had delayed or partial ossification and extra ribs.

Ref: Federal Register. July 9, 1997. [OPP-300512; FRL-5729-5] RIN 2070-AB78
http://www.fluoridealert.org/pesticides/Fomesafen.FR.July.9.1997.htm

Haloxyfop-methyl

Oral doses of 7.5 mg/kg/day of haloxyfop-methyl given to rats from days 6 to 15 of pregnancy caused delayed bone formation in the offspring (U.S. Environmental Protection Agency. 1994. Integrated Risk Information System (IRIS) through TOXNET. U.S. EPA. Washington, DC. ).

Ref: http://www.fluoridealert.org/pesticides/Haloxyfop.ALL.Extoxnet.1994.htm

Indoxacarb

Prenatal developmental in nonrodents--rabbitts. Developmental NOAEL = 500 mg/kg/ day LOAEL = 1,000 mg/kg/day based on decr. fetal body weights and reduced ossification of the sternebrae.

Ref: Federal Register. September 29, 2000. Indoxacarb; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Indoxacarb.FR.Sept.2000.htm

Isoxaflutole

Developmental toxicity, observed at 100 and 500 mg/kg/day, were manifested as increased incidences of fetuses/litters with various anomalies: growth retardations (decreased fetal body weight; increased incidence of delayed ossification of sternebrae, metacarpals and metatarsals). In addition, an increased incidence of vertebral and rib anomalies and high incidence of subcutaneous edema were observed at 500 mg/kg/day. The incidences of these anomalies were higher than the concurrent control values and in some cases exceeded the range for historical controls... Developmental toxicity, observed at 5 mg/kg/day consisted of increased incidence of 27th pre-sacral vertebrae. Additional findings noted at 20 and 100 mg/kg/day were manifested as increased number of postimplantation loss and late resorptions, as well as growth retardations in the form of generalized reduction in skeletal ossification, and increased incidence of 13 pairs of ribs.

Ref: Federal Register, September 23, 1998. Isoxaflutole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Isoxaflutole.FR.Sept23.1998.htm

Lactofen

Developmental toxicity-- Rats. Pregnant rats were administered oral doses of 0, 15, 50 and 150 mg/kg/day Lactofen Technical on days 6- 19 of gestation. Maternal toxicity (death, abortion and reduced body weight gain) was observed at 150 mg/kg/day. Developmental toxicity (reduced fetal weight, slightly reduced ossification, bent ribs and bent limb bones) was also observed at 150 mg/kg/day. The NOEL for this study was 50 mg/kg/day."

Ref: Federal Register, February 25, 1998. [PF-789; FRL-5767-5]
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Sulfentrazone

Developmental Study in rats. Developmental LOAEL = 25 mg/kg/day based on decreased fetal weight and retarded skeletal development as evidenced by an increased number of litters with any variation and by decreased numbers of caudal vertebral and metacarpal ossification sites.

In the dermal developmental study in rats, the maternal (systemic) NOAEL was 250 mg/kg/day and a LOAEL was not determined. The developmental (fetal) NOAEL was 100 mg/kg/day, based on decreased fetal weight and increased fetal variations (hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, incompletely ossified ischia or pubes, and reduced numbers of thoracic vertebral and rib ossification sites) at the LOAEL of 250 mg/kg/day.

Ref: Federal Register. August 1, 2001. Sulfentrazone; Pesticide Tolerances for Emergency Exemptions. Final Rule. http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Aug1.2001.htm

Trifloxystrobin

Subchronic toxicity. In subchronic studies, several mortality related changes were reported for the top dose in dogs (500 mg/kg) and rats (800 mg/kg). At these dose levels, excessive toxicity has resulted in body weight loss and mortality with the associated and non-specific changes in several organs (such as atrophy in the thymus, pancreas, bone marrow, lymph node, and spleen) which are not considered specific target organs for the test compound... In the rabbit teratology study, body weight loss and dramatically reduced food consumption were observed in the dam at 250 mg/ kg. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the increase in skeletal anomaly of fused sternebrae-3 and sternebrae-4 at the top dose level of 500 mg/kg. This finding is regarded as a marginal effect on skeletal development that could have resulted from the 40-65% lower food intake during treatment at this dose level. The developmental NOAEL was 250 mg/kg.

Ref Federal Register. November 14, 2001. [PF-1048; FRL-6806-6] http://www.fluoridealert.org/pesticides/Trifloxystrobin.FR.Nov14.01.htm

Triflusulfuron methyl

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).

Ref: Federal Register. August 8, 2001. [PF-1036; FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm

 

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TABLE 6

LIVER effects from Organofluorine and fluoride pesticides
(All but 4 in this list are Organofluorine or Fluoride pesticides.)

Note: This is not an exhaustive list. When time allows we will be adding more information to this Table.

Acifluorfen, sodium

4. Carcinogenicity. Acifluorfen has been classified as a Group B2 (probable human carcinogen) chemical by the OPP Cancer Peer Review Committee (CPRC), based on an increased number of liver tumors in both sexes of mice and a high incidence of uncommonly occurring stomach papillomas in male mice. The Committee recommended using the Q1* approach for quantification of human risk. The Q1* is 0.11 (mg/kg/day)-1.

Ref: Federal Register. July 25, 1997. Sodium Salt of Acifluorfen; Pesticide Tolerances for Emergency Exemptions. Final Rule. http://www.epa.gov/fedrgstr/EPA-PEST/1997/July/Day-25/p19668.htm

Clodinafop-propargyl

Dietary treatment of rats with concentrations over 2 years resulted in initial inappetence in males and reduced body weight development in both sexes treated at 750 ppm. The main target organ of toxicity was the liver. Changes in plasma protein and lipid levels, strongly enhanced serum activities of liver enzymes, increased liver weights, and severe liver necroses were observed at dietary doses of 300 and 750 ppm in males and at 750 ppm in females. The degenerative lesions provide strong evidence that these dose levels exceeded a maximum tolerated dose (MTD). Top dose group males showed a higher incidence of prostate adenoma, while prostate hyperplasia was reduced. However, the total incidence of proliferative changes in the prostate remained unchanged indicating a progression from prostate hyperplasia to adenoma. Females treated at the same high dose had higher incidences of ovary tubular adenoma. The slightly enhanced incidences of these lesions are likely a consequence of the severe disturbance of the general metabolic balance due to excessive liver toxicity. In fact, male rats fed 750 ppm exhibited a marked increase in peroxisomal oxidation, and an increase in cytochrome P450 4A1/ A3 and 4A2 in their livers. Further, a decrease in cytochrome P450 isoenzymes including CYP 2A, CYP 3A, and male-specific CYP 2C11 was observed. The total oxidation rate of testosterone, aromatase (CYP 19A1) activity plasma estradiol concentration and plasma-- dihydrotestosterone are altered at this level of treatment. Clodinafop- propargyl is a potent peroxisome proliferator in the rat liver and this peroxisomal prolifering activity manifests itself by altering Cytochrome P450-dependent monooxygenses which are involved in steroid hormone homeostasis. The NOAEL of 10 ppm was equivalent to a mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in females. The EPA HIARC concluded that based on hepatocellular hypertrophy and kidney findings, the NOAEL was 1 ppm (0.031 in males and 0.034 in females. Carcinogenicity. The EPA HIARC recommended, based on the increased incidence of prostate and ovarian tumors in rats and hepatocellular tumors in mice, that the Cancer Assessment Review Committee review clodinafop-propargyl... The scientific evidence available amply demonstrates that exposure to substances that produce tumors by a peroxisome proliferator mode of action does not represent a risk of tumor development in man. Novartis, therefore, has concluded that clodinafop-propargyl is not a carcinogen of relevance to humans.

Ref: Federal Register. April 26, 2000. [PF-938; FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm

Cyhalofop-butyl

5. Subchronic and chronic toxicity, and oncogenicity. Cyhalofop- butyl caused increases in liver and kidney weights, microscopic hepatocellular hypertrophy, renal tubular microscopic effects, and distended gallbladders when given at sufficiently high dose levels to the appropriate species for 13 weeks. Similar increases in liver and kidney weights, hepatocellular hypertrophy, and renal effects were also observed in chronic toxicity studies in rodents. In addition, mice had liver inflammation (microgranulomas). Chronic toxicity in dogs was limited to decreased body weight and the occurrence of concretions in the gallbladder. Using the Guidelines for Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992), it is proposed that cyhalofop and cyhalofop-butyl be classified as Group E for carcinogenicity (no evidence of carcinogenicity) based on the results of carcinogenicity studies in two species. Dow AgroSciences LLC believes that there was no evidence of carcinogenicity in an 18-mouse feeding study and a 24-month rat feeding study at all dosages tested.

Ref: Federal Register. April 25, 2001. [PF-1009; FRL-6774-7]
http://www.fluoridealert.org/pesticides/Cyhalofop-butyl.FR.Apr.2001.htm

Diclosulam

Based on oral feeding studies, the primary target organs are the liver and kidney. In a subchronic rat feeding study, the primary target organ is the liver including increased relative organ weight, hepatocellular hypertrophy, and slight multifocal necrosis. Decreased body weight and kidney lesions were also noted. Liver effects were also noted in a subchronic dog study and included increased relative liver weight, centrilobular hepatocellular changes, and hepatocellular necrosis accompanied by elevated ALP, AST, and ALT.

Ref: Federal Register. March 8, 2000. Diclosulam; Pesticide Tolerance. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/2000/March/Day-08/p5635.htm

Diflubenzuron

At all dose levels, histopathological examinations indicated dose related increases of hemosiderosis and congestion of the spleen, hemosiderosis and chronic hepatitis of the liver, and mild erythroid hyperplasia of the bone marrow... Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological examinations indicated non-neoplastic treatment-related effects in the spleen, liver, bone marrow and adrenal gland... (National Toxicology Program (NTP) Report No. 351; July, 1989)..."

Ref: US EPA RED. August 1997. http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf

Ethalfllluralin

Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for 1-year. The NOAEL was 4 mg/kg/day. The LOAEL was 20 mg/kg/ day, based on increased urinary bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and increased erythroid series of the bone marrow. Elevated alkaline phosphatase levels were found at the two higher doses and siderosis of the liver at the high dose.

Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9] http://www.fluoridealert.org/pesticides/Ethalfluralin.FR.Nov14.2001.htm

Fluthiacet-methy

A chronic reference dose (RfD) (0.001 mg/kg/day) was identified for fluthiacet-methyl, based on non-neoplastic liver findings (increase in absolute and relative liver weights, fatty changes, chronic inflammation, karyomegaly, single cell necrosis and ceroid/lipofuscin pigmentation).

Ref. Federal Register. December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-21/p31497.htm

Fluazinam

Carcinogenicity mice NOAEL = Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day [[Page 46732]] LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females. Clear evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females.
90-Day oral toxicity rats NOAEL: Males = 3.8 mg/kg/day; Females = 4.3 mg/kg/day [[Page 46731]] LOAEL Males = 38 mg/kg/day; Females = 44 mg/kg/day based on increased liver weights and liver histopathology in males, and increased lung and uterus weights in females.
90-Day oral toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolation of the cerebral white matter (equivocal).
Prenatal developmental toxicity Maternal NOAEL = 4 mg/kg/day rabbits LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology...
Reproduction and fertility effects Parental/Systemic NOAEL = 1.9 mg/ rats kg/day LOAEL = 9.7 mg/kg/day based on liver pathology in F1 males...
Combined chronictoxicity/ NOAEL = Males: 0.38 mg/kg/day; carcinogenicity rats Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors) in male rats, but not in females.

Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females,
Special studies: 4-Week dietary (Range-finding) rats NOAEL = Males: 5.1 mg/kg/day; Females: 5.3 mg/kg/day LOAEL = Males: 26.4 mg/kg/day; Females: 25.9 mg/kg/day based on decreased body weight gain and food consumption, increased serum phospholipids, increased total cholesterol, increased relative liver weights, and liver histopathology.
4-Week dietary (Range-finding) mice NOAEL = not identified (Males; <555 mg/kg/day; Females: <658 mg/ kg/day) LOAEL = Males: 555 mg/kg/day; Females: 658 mg/kg/day based on vacuolation of white matter in brain, increased liver weights, histopathology in liver.
90-Day dietary (Special liver study) rats NOAEL = not determined (Males: <37.6 mg/kg/day, Females: <44.7 mg/kg/day) LOAEL = Males: 37.6 mg/kg/day, Females: 44.7 mg/kg/day based on increased relative liver weights and liver histopathology...
iii. Cancer. Since fluazinam has been classified as Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential, an exposure assessment was not performed.

Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/2001/September/Day-07/p22525.htm

Fludioxonil

The kidney and liver have been identified as target organs in subchronic and chronic toxicity studies... In a 90-day subchronic dietary toxicity study in rats, the NOEL was 10 ppm based on liver toxicity.
Ref: Federal Register. Februry 5, 1997. [PF-695; FRL-5584-1]
http://www.epa.gov/docs/fedrgstr/EPA-PEST/1997/February/Day-05/p2711.htm

4. Carcinogenicity. Fludioxonil has been classified as a Group D not classifiable as to human carcinogenicity, chemical by the Cancer Peer Review Committee. The Group D classification was based on the statistically significant increase in liver tumors in female rats for combined adenoma/carcinoma only, the lack of tumorigenic response in male rats or in either sex of the mouse, and the need for additional mutagenicity studies.
Ref: Federal Register. June 30, 1999. Fludioxonil; Pesticide Tolerance for Emergency Exemption. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.June.1999.htm

Flufenacet

Chronic feeding studies in dog and rat showed structural or functional alterations in liver, kidney, haematology, spleen, and thyroid. Flufenacet induces neuropathogical changes in the brain and spinal cord (axonal swelling) in rat and dog. The overall evaluation of the observed changes demonstrates that these effects occur only after repeated and prolonged exposure to high dose levels of flufenacet, which saturate metabolic pathways, and exceed the animal capacity to rapidly metabolise and excrete it. The liver was considered the primary target organ, with increases in organ weight, cell size and number, and/or associated changes in liver function tests.


Ref: European Commission, Health & Consumer Protection Directorate-General, Scientific Committee on Plants, October 17, 2001. SCP/FLUFEN/002-Final. http://europa.eu.int/comm/food/fs/sc/scp/out112_ppp_en.pdf

Fluorocarbons - (not a pesticide)
(See Ref. 1 below for specific substances)

There is a significant accumulation of propellant in the brain, liver and lung compared to blood levels, signifying a tissue distribution of propellant similar to that of chloroform.

Ref: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203

Website ref: Hazardous Substances Data Bank: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Flutolanil

A rabbit developmental study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL of 25 mg/kg/day based on histopathological finds in the liver... A rabbit developmental study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL of 25 mg/kg/day based on histopathological finds in the liver and a developmental NOEL of 25 mg/kg/day and a developmental LOEL of 125 mg/kg/day based on increased skeletal variations.

Ref: Federal Register. June 23, 1998. [PF-813; FRL-5795-1]
http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm

Fomesafen

PubMed Abstract: Administration of herbicide fomesafen and of fomesafen combined with one dose of iron to 44 mice during 3 to 14 months caused hyperplastic and preneoplastic changes in the liver tissue which had been described in experimental carcinogenesis* small groups of altered hepatocytes storing glycogen or lipids and foci of small basophilic liver cells occurred as early as after 3 months. Altered hepatocytes were found more frequently in mice getting fomesafen and iron. Later nodular hyperplasia of liver cells developed with nodes 3-20 mm in diameter which mostly consisted of altered hepatocytes with plenty of glycogen. After 12 and 14 month-lasting administration of fomesafen and fomesafen with iron, the hepatocellular carcinoma was proved in 5 mice. In 4 mice, the preneoplastic changes in liver tissue were accompanied by micronodular hyperplasia of liver cells which did not participate on the development of big nodes and hepatocellular carcinoma. PMID: 9624829, UI: 98287925 Ref: Cesk Patol 1998 Apr;34(2):67-71 [Morphologic findings in liver tissue in mice after long-term administration of the herbicide fomesafan]. [Article in Czech] Chlumska A, Fakan F, Krijt J. http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=9624829&form=6&db=m&Dopt=b

Halothane - (Fluorinated anethestic)

Non-Human Toxicity Excerpts : Rats exposed prenatally by administered to the dams of 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week and postnatally up to 60 days after birth to the same concentration had later impairments in learning ability. Reduced learning ability was correlated with persistent synaptic malformation in the cerebral cortex. Other changes in the neurons noted in young adult rats exposed to 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week for 8 weeks included destruction of the rough-surfaced endoplasmic reticulum, dilatation of the Golgi complex and focal cytoplasmic vacuolation. Offspring of rats exposed to 80 mg/cu m (10 ppm) halothane for 8 hr/day on 5 days a week throughout pregnancy had ultrastructural changes in the liver within 24 hr of birth. These changes included myelin figures and large areas of focal cytoplasmic degradation in many hepatocytes; accumulation of lipids within hepatocytes and leucocytic infiltration were noted in many cases. Focal necrosis was observed in more than 50% of tissue samples.

Ref: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V11 288

Oxyfluorfen

Microscopic changes observed at 12 months included binucleate hepatocytes (6/10), central lobular hepatocyte hypertrophy (7/10), and enlarged hepatocyte nuclei (6/10) in high dose females compared to 0/5 for controls. Similar changes were not seen at the terminal sacrifice, despite the fact that the animals received higher doses during the last 12 months of the study. Therefore the findings at 12 months may be an adaptive effect... The microscopic liver and kidney lesions were generally classified slight in mid-dose animals and slight to moderate in high-dose animals... The only treatment-related histopathological lesion in the liver was slight to moderate bile pigmented hepatocytes in both sexes after 104 weeks (n.s.) and hepatocellular vacuolization was seen in high-dose females.

Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

Sodium fluoride

Absorption, Distribution & Excretion : RATS GIVEN (18)FLUORIDE ION AS A RADIOTRACER BY CONTINUOUS IV INFUSION OF SODIUM FLUORIDE FOR 3 HR SHOWED AT SUBLETHAL DOSE RATES, BLOOD FLUORIDE CONCN NEARS STEADY STATE PROPORTIONAL TO FLUORIDE INFUSION RATE. BLOOD, KIDNEY, & LUNG HAD HIGHEST CONCN @ DOSES UP TO 3 MG FLUORIDE/KG/HR, BUT @ 6 MG/KG/HR THE FLUORIDE OF THE LIVER, SPLEEN & HOLLOW ORGANS INCR SHARPLY. AMT ABOVE THIS WAS NOT WELL PROCESSED BY EXCRETORY MECHANISM. RATS INFUSED 3 HR WITH 6 MG FLUORIDE/KG/HR: DURING INFUSION FLUORIDE CONCN OF BONE & OTHER TISSUES WAS HIGH, BONE THE HIGHEST. OF SOFT TISSUES, LUNG HAD THE HIGHEST, BRAIN, TESTES, & FAT PADS THE LEAST CONCN. DURING DEPLETION PHASE, TISSUE FLUORIDE CONCN DECR, BONE FLUORIDE REMAINED CONSTANT, & SUBSTANTIAL AMOUNT REMAINED IN THE LUNG. /Sodium Fluoride/

Ref: KNAUS RM ET AL; TOX APPL PHARM 38 (2): 335-43 (1976)

Website ref: Sodium Fluoride, Ammonium fluroide, Carbonyl difluroride (353-50-4) at: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Sulfuryl fluoride

In a developmental toxicity inhalation study in rats, no developmental toxicity was observed in the pups. Although no maternal toxicity was observed in this study at the highest dose tested (225 ppm), significant maternal toxicity (decreased body weight, body weight gain and food consumption; increased water consumption and kidney weights; and gross pathological changes in the kidneys and liver) was observed in a previously conducted range-finding study at a slightly higher dose level (300 ppm)...

Ref: Federal Register. September 5, 2001. Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.
http://www.fluoridealert.org/pesticides/Sulfuryl.Flu.FR.Sept.5.2001.htm

Thiazopyr

A 1 year feeding study in dogs at 0, 0.8, 7.8, 86.0 with males, and 0.8, 8.8, and 78.0 with females with a NOEL of 0.8 mg/kg/day. The Loel was based on hepatocellular hypertrophy and hyperplasia. A 10% increase in prothrombin time and several and several changes in blood chemistry: increased SGOT, SGPT, GGT and ALK levels and decreased cholesterol, albumin and total protein and calcium were observed in high- dose dogs. There were increases in absolute weights, liver and body weight and liver to brain weight, heptotoxicity characterized by enlargement and/or discoloration in some high dose animals and by hepatocellular hypertrophy/hyperplasia in the 0.8 and 7.8 mg/kg/day dogs. The NOEL was based on hepatocellular hypertrophy and hyperplasia.

A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.

90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyrid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.

A developmental toxicity study in rats at 0, 10, 100 and 250 mg/kg/day with a maternal toxicity NOEL of 100 mg/kg/day. The effect were increased liver weight, increased slivation, significantly decreased body weight gain and decreased food consumption. The developmental NOEL was also 100 mg/kg/day. The effects at the high dose were increased incidence of unossified sternebrae and 7th cervical rib variation.

Ref: US EPA Pesticide Fact Sheet. February 20, 1997. http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Trifloxystrobin

4. Subchronic toxicity. In subchronic studies, several mortality related changes were reported for the top dose in dogs (500 mg/kg) and rats (800 mg/kg). At these dose levels, excessive toxicity has resulted in body weight loss and mortality with the associated and non-specific changes in several organs (such as atrophy in the thymus, pancreas, bone marrow, lymph node, and spleen) which are not considered specific target organs for the test compound. In the dog, specific effects were limited to hepatocellular hypertrophy at 150 mg/kg and hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target organ effects in the rat were noted as hepatocellular hypertrophy (200 mg/kg) and the related liver weight increase (50 mg/kg). In the mouse, target organ effects included single cell necrosis (300 mg/kg) and hypertrophy (1,050 mg/ kg) in the liver and extramedullary hematopoiesis (300 mg/ kg) and hemosiderosis in the spleen (1,050 mg/kg). In general, definitive target organ toxicity, mostly in the liver, was seen at high feeding levels of over 100 mg/kg for an extended treatment period. At the lowest observed adverse effect level (LOAEL), no serious toxicity was observed other than mostly non-specific effects including a reduction in body weight and food consumption or liver hypertrophy. 5. Chronic toxicity. The liver appears to be the major primary target organ based on the chronic studies conducted in mice, rats, and dogs. It was identified as a target organ in both the mouse and the dog studies with trifloxystrobin. However, no liver effect was seen in the chronic rat study which produced the lowest NOAEL of 2.5 mg/kg based on reduced body weight gain and food consumption seen at higher dose levels.

Ref: Federal Register. November 14, 2001. [PF-1048; FRL-6806-6]
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2001_register&docid=01-28199-filed

Trifluorothymidine - (Not a pesticide)

Abstract: Metabolism of trifluorothymidine (TFT) and its transport across the blood-brain barrier (BBB) has been measured quantitatively in rats by fluorine-19 nuclear magnetic resonance spectroscopy ((19)F NMR). It is demonstrated that TFT crosses the BBB in micromolar quantities and is metabolized in brain tissue primarily to its free base trifluoromethyluracil (TFMU) by the enzyme thymidine phosphorylase (TP). It is further proposed that the rate of TFMU production can be used as a measure of cerebral TP. The glycols of both TFMU, and to a lesser degree TFT, are generated via an oxidative route. In contrast, the major pathway for hepatic metabolism of this compound is through reduction of the nitrogen base moiety and generation of 5-6-dihydro species followed by ring degradation. Thus, in addition to TFMU as well as the dihydroxy (glycol)-, and the dihydro-species of both TFT and TFMU, alpha-trifluoromethyl-beta-ureidopropionic acid (F(3)MUPA) and alpha-trifluoromethyl-beta-alanine (F(3)MBA) were detected in liver extracts. The total metabolite levels in liver were 2-5 times higher than in the brain. Low levels of fluoride ion were detected in all the extracts from brain and liver, as well as blood and urine. This study characterizes TFT as a potential chemotherapeutic agent for use against brain tumors. Copyright 1999 John Wiley & Sons, Ltd. PMID: 10516619

Ref: NMR Biomed 1999 Oct;12(6):373-80.
Quantitative 19F NMR study of trifluorothymidine metabolism in rat brain. Pouremad R, Bahk KD, Shen YJ, Knop RH, Wyrwicz AM.

PubMed: http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10516619&form=6&db=m&Dopt=b

Triflusulfuron methyl

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).

Ref: Federal Register. August 8, 2001. [PF-1036; FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm

Vinyl fluoride - (Not a pesticide)

Carcinogenicity: Vinyl fluoride (VF) is reasonably anticipated to be a human carcinogen based on evidence of tumor induction at multiple organ sites in rats and mice. Inhalation exposure of rats to vinyl fluoride resulted in increased incidences of hepatic hemangiosarcomas, hepatocellular adenomas or carcinomas, and Zymbal gland carcinomas; inhalation exposure of mice to VF resulted in increased incidences of hepatic hemangiosarcomas, bronchiolar-alveolar adenomas or adenocarcinomas, hepatocellular adenomas, mammary gland adenocarcinomas, and Harderian gland adenomas (Bogdanffy et al. 1995; IARC 1995). The tumor response to VF in laboratory animals is similar to the responses to vinyl chloride, a known human carcinogen (NTP 1998; IARC 1987), and to vinyl bromide, a probable human carcinogen (IARC 1986). A unique feature of vinyl chloride carcinogenicity is the induction of rare hepatic hemangiosarcomas in rats and mice and the causal association in epidemiological studies between vinyl chloride exposure and excess risk of hemangiosarcoma of the liver (NTP 1998). The fact that VF, vinyl chloride, and vinyl bromide induce rare hemangiosarcomas of the liver in experimental animals and induce the formation of similar DNA adducts suggests a possible common mechanism of carcinogenicity for these vinyl halides.

Ref: Draft report on carcinogens. Background document for Vinyl fluoride.
http://www.fluoridealert.org/VF.pdf

 

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TABLE 7

THYROID effects from Organofluorine and fluoride pesticides

All in this list are Organofluorine pesticides, except for Sulfuryl fluoride, which is an inorganic fluoride pesticide.

Note: This is not an exhaustive list. When time allows we will be adding more information to this Table.

Fipronil

Fipronil has been classified as a Group C (Possible Human) Carcinogen based on an increase in thyroid follicular cell tumors in both sexes of the rat. The increase is statistically significant by both pair-wise and trend analyses. The RfD methodology was selected for quantification because the thyroid tumors appeared to be related to a disruption in the thyroid-pituitary status and there was no apparent concern for mutagenicity or available information from structurally related analogs.
An acceptable chronic rat feeding study identified the following effects: seizures, including seizures resulting in death, decreased body weight gain, decreased food consumption and food conversion efficiency, decreased hematology measures, alterations in clinical chemistry (cholesterol, calcium, and protein), alterations in thyroid hormones, alterations in urine chemistry, changes on gross necropsy, increase in liver and thyroid weights, and progressive senile nephropathy (kidney effects). The NOEL for systemic toxicity was 0.5 ppm. The LOEL of 1.5 ppm was based on an increase in incidence of clinical signs and alterations in clinical chemistry and thyroid parameters. Based on this study, the RfD Committee recommended that the RfD be established using the NOEL and an uncertainty factor of 100 to account for the interspecies extrapolation and intraspecies variability. The RfD was set at 0.0002 mg/kg/day...
The LOEL for parental (systemic) toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for females) based on effects on the thyroid, liver, and pituitary gland...
Subchronic Toxicity (Rat): NOEL = 5 ppm for males (0.33 mg/kg/day) and females (0.37 mg/kg/day. LOEL 30 ppm for males (1.93 mg/kg/day) and females (2.28 mg/kg/day) based on alterations in serum protein values and increased weight of the liver and thyroid...
Combined Chronic Toxicity/Carcinogenicity (Rat): NOEL = 0.5 ppm for males (0.019 mg/kg/day) and females (0.025 mg/kg/day). LOEL 1.5 ppm for males (0.059 mg/kg/day) and females (0.078 mg/kg/day) based on an increased incidence of clinical signs and alterations in clinical chemistry and thyroid parameters. The study demonstrated that fipronil is carcinogenic to rats at doses of 300 ppm in males (12.68 mg/kg/day) and females (16.75 mg/kg/day)...
Multigeneration Reproduction Study (Rat): NOEL for parental (systemic) toxicity was 3 ppm (0.25 mg/kg/day for males and 0.27 mg/kg/day for females). LOEL for parental (systemic) toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for females) based on systemic signs including increase in the absolute and relative weights of the thyroid glands and liver in males and females of the F0 and F1 generations; decrease in the absolute weight of the pituitary gland in females in the F1 parental animals; and increase incidence of follicular epithelial hypertrophy of the thyroid glands in females of the F1 generation.

Ref: US EPA Pesticide Fact Sheet. May 1996.
http://www.fluoridealert.org/pesticides/Fipronil.EPA.Facts.May.1996.htm

Fluazinam

Combined chronictoxicity/ NOAEL = Males: 0.38 mg/kg/day; carcinogenicity rats Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors) in male rats, but not in females...
Cancer (oral, dermal, inhalation). Increases in thyroid gland follicular cell tumors in male rats; increases in hepatocellular (liver) tumors in male mice.\2\
iii. Cancer. Since fluazinam has been classified as Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential, an exposure assessment was not performed.

Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Sept.7.2001.htm

Flucarbazone-sodium

28-Day oral toxicity in nonrodents (dogs). NOAEL = 164 mg/kg/ day in males and 171 mg/kg/day in females LOAEL = 1,614 mg/kg/ day in males and 1,319 mg/kg/day in females based on decreased body weight gain, decreased food consumption, decreased T4 levels and increased thyroxine-binding capacity, induction of microsomal enzymes, increased liver weight and liver histopathology in both sexes.
90-Day oral toxicity in nonrodents (dogs). NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females with the occurrence of slight, adaptive induction of hepatic microsomal enzymes LOAEL = 162 mg/kg/ day in males and 170 mg/kg/day in females based on decreased T4 levels, increased thyroxine-binding capacity, induction of microsomal enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver in both sexes.
One year dog feeding LOAEL = 183 mg/kg/day based on decreased body weight gain, decreased thyroxine, increased N- demethylase, and increased liver weight.

Ref: Federal Register. September 29, 2000. Flucarbazone-sodium; Time-Limited Pesticide Tolerances. Final Rule. http://www.fluoridealert.org/pesticides/Flucarbazone_Na.FR.Sept2000.htm

Flufenacet

A 84-day rat feeding study with a No Observed Effect Level (NOEL) less than 100 ppm (6.0 mg/kg/day) for males and a NOEL of 100 ppm (7.2 mg/kg/day) for females and with a Lowest Observed Effect Level (LOEL) of 100 ppm (6.8 mg/kg/day) for males based on suppression of thyroxine (T4) level and a LOEL of 400 ppm (28.8 mg/kg/day) for females based on hematology and clinical chemistry findings.

Ref: Federal Register. September 23, 1998. Flufenacet; Time-Limited Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Flufenacet.FR.Sept.23.1998.htm

Isoxaflutole

A 24-month chronic feeding/oncogenicity study in rats administered at levels of 0.5, 2, 20 or 500 mg/kg bwt/day) with an overall NOEL of 2.0 mg/kg/day based on non-neoplastic changes in the cornea, sciatic nerve, thigh muscle, thyroid and liver observed at 20 mg/kg/day. An increased incidence of hepatocellular adenomas and carcinomas was observed at 500 mg/kg bwt/day for males and females. In addition, most of the 500 mg/kg/day males with liver tumors also had follicular cell adenomas in the thyroid.
3. Common mechanism of action. No other pesticides have been identified which inhibit 4-HPPDase. The thyroid and liver tumors observed with isoxaflutole in the rodent studies are most likely indirectly related to a significant induction of the hepatic microsomal enzymes PROD, BROD, and UDPGT. While hepatic microsomal enzyme induction in rodents is likely to be produced by many other pesticides, there is no data to indicate that these effects would be cumulative with any other pesticide. Considering the rapid elimination of isoxaflutole in the animal metabolism study, the effects associated with isoxaflutole are unlikely to be cumulative with any other compound. Further, considering the known sensitivity of the rat to the development of thyroid lesions in response to an imbalance of thyroid hormones and rodents to the development of liver tumors in response to the induction of microsomal enzymes, occurrence of these tumors via these mechanisms in rodent studies have little if any practical relevance for human cancer or risk assessment. Epidemiological studies support the position that neither thyroid tumors observed in rats due to an imbalance of thyroid hormones or liver tumors observed in rodents exposed to inducers of microsomal enzyme activity are likely to occur in humans. Therefore, only the potential risks associated with exposure to isoxaflutole are considered for this assessment.
F. Estrogenic Effects No evidence of estrogenic or androgenic effects were noted in any study. No adverse effects on mating or fertility indices and gestation, live birth, or weaning indices were noted in the 2-generation rat reproduction study. An imbalance of thyroid hormones related to the induction of UDPGT was noted in rats. However, considering species differences in the half-life of thyroid hormones in rodent versus primates (12 to 24 hours in rat compared to 5 to 9 days in humans) and differences in the responsiveness of thyroid cells to TSH, thyroid hormone levels in humans are unlikely to be affected by the extremely low levels of isoxaflutole residues that might be present in food. Therefore, Rhone-Poulenc believes that isoxaflutole is not likely to cause any endocrine effects in most species including humans.

Ref: Federal Register. February 26, 1997. [PF-701; FRL-5585-2]
http://www.fluoridealert.org/pesticides/Isoxaflutole.FR.Feb.26.1997.htm

Oxyfluorfen

Absolute and relative thymus weights were decreased in mid-dose males (-14%/-10%)and high-dose males (-32%/- 18%)...Vacuolation of the adrenal cortex was present in high-dose females. Thymic atrophy occurred in high-dose males and females.... Fine vacuolation of adrenal glands (slight)and cortical atrophy of the thymus (slight) were increased in high-dose males... Absolute and/or relative organ weights in the high-dose groups that showed statistically significant changes relative to control weights (thyroid gland in both sexes and kidney in females at 12 months and brain, pituitary, and spleen in females sacrificed at 24 months) had no microscopic correlates and are not considered toxicologically significant.

Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

Sulfuryl fluoride

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.

Ref: Federal Register. September 5, 2001. Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.
http://www.fluoridealert.org/pesticides/Sulfuryl.Flu.FR.Sept.5.2001.htm

Thiazopyr

A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.

90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyrid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.

Ref: US EPA Pesticide Fact Sheet. February 20, 1997. http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

 

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TABLE 8

REPRODUCTIVE effects from Organofluorine and fluoride pesticides
All but three in this list are Organofluorine pesticides

Note: This is not an exhaustive list. When time allows we will be adding more information to this Table.

Clodinafop-propargyl

Dietary treatment of rats with concentrations over 2 years resulted in initial inappetence in males and reduced body weight development in both sexes treated at 750 ppm. The main target organ of toxicity was the liver. Changes in plasma protein and lipid levels, strongly enhanced serum activities of liver enzymes, increased liver weights, and severe liver necroses were observed at dietary doses of 300 and 750 ppm in males and at 750 ppm in females. The degenerative lesions provide strong evidence that these dose levels exceeded a maximum tolerated dose (MTD). Top dose group males showed a higher incidence of prostate adenoma, while prostate hyperplasia was reduced. However, the total incidence of proliferative changes in the prostate remained unchanged indicating a progression from prostate hyperplasia to adenoma. Females treated at the same high dose had higher incidences of ovary tubular adenoma. The slightly enhanced incidences of these lesions are likely a consequence of the severe disturbance of the general metabolic balance due to excessive liver toxicity. In fact, male rats fed 750 ppm exhibited a marked increase in peroxisomal oxidation, and an increase in cytochrome P450 4A1/ A3 and 4A2 in their livers. Further, a decrease in cytochrome P450 isoenzymes including CYP 2A, CYP 3A, and male-specific CYP 2C11 was observed. The total oxidation rate of testosterone, aromatase (CYP 19A1) activity plasma estradiol concentration and plasma-- dihydrotestosterone are altered at this level of treatment. Clodinafop- propargyl is a potent peroxisome proliferator in the rat liver and this peroxisomal prolifering activity manifests itself by altering Cytochrome P450-dependent monooxygenses which are involved in steroid hormone homeostasis. The NOAEL of 10 ppm was equivalent to a mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in females. The EPA HIARC concluded that based on hepatocellular hypertrophy and kidney findings, the NOAEL was 1 ppm (0.031 in males and 0.034 in females...
8. Endocrine disruption. No special studies investigating potential estrogenic or endocrine effects of clodinafop-propargyl have been conducted. However, the standard battery of required studies has been completed. These studies include an evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure. Although prostate adenomas and ovarian adenomas were observed to be statistically increased in rats at the highest feeding level with clodinafop-propargyl, this feeding level clearly exceeded the MTD and the livers in these rats were severely compromised. These findings in the endocrine organs were considered to be secondary to the severe liver effects.

Ref: Federal Register. April 26, 2000. [PF-938; FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm

Dichlorofluoromethane (CFC-21)

NOTE: EPA"List 2 Inert" - used as a propellant for pesticides.

CFC-21 has produced "pre-implantation" loss in pregnant rats exposed at 10,000 ppm. After exposure for 6 hr daily, on days 6 to 15 of gestation, 15 or 25 pregnant females had no viable fetuses or implantation sites on the uterine wall. Pregnancy outcome and fetal development in the other 10 rats were unaffected.

Ref: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 434
Website: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Dichlorofluoromethan.TOXNET.htm

Ethane, 1,1-dichloro-1-fluoro- (CAS No. 1717-00-6) - (Not a Pesticide)

Toxicity results: Rat Inhalation Carcinogenicity Study: The only significant effects noted were a statistically significant increased incidence of benign testicular interstitial cell tumors in male rats in the mid and high dose ranges (5,000 ppm and 15,000-20,000 ppm). The high dose was \1/3\ of the 4-hour LC<INF>50</INF>.

Ref: Federal Register. December 9, 1997. 40 CFR Part 721 [OPPTS-50629; FRL-5752-9] RIN 2070-AB27

Ethalfluralin

EPA's Office of Pesticide Program's Carcinogenicity Peer Review Committee concluded that ethalfluralin should be classified as Group C, a possible human carcinogen, based on increased mammary gland fibroadenomas and adenomas/fibroadenomas combined in female rats. The tumor incidences were statistically significant at both the mid and high dose, and exceeded of the upper range of historical controls. Based on a low dose extrapolation, the Q1* of 8.9 x 10-2 (mg/kg/day)-1 has been calculated.

Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9] http://www.fluoridealert.org/pesticides/Ethalfluralin.FR.Nov14.2001.htm

Ethylene fluorohydrin

REPRODUCTIVE HAZARDS. An increase in sternebral ossification defects, hydronephrosis, runting (pup weight less than 2.7 g), variant rib ossifications, extra vertebral ossification centers, cardiac septal defects, and intrauterine growth retardation were noted in rats.

Ref: TOXNET profile from Hazardous Substances Data Base. http://www.fluoridealert.org/pesticides/Ethylene.fluorohydri.TOXNET.htm

Fluazinam

5. Chronic toxicity. Fluazinam was not carcinogenic in rats. A NOAEL of 10 ppm (0.43 mg/kg/day) of fluazinam was established based on the following effects at 1,000 and/or 100 ppm: lower food consumption and efficiency of food utilization, slight anemia, elevated cholesterol, increased liver weights, an increased number of macroscopic liver and testes lesions and an increased incidence of microscopically observed lung, liver, pancreas, lymph node and testes lesions. An additional study was conducted to further define the NOAEL for long-term effects in the rat. In the second study, a NOAEL of 50 ppm (2.2 mg/kg/day) was established based on liver and testes effects.

Ref: Federal Register. December 6, 2000. [PF-983; FRL-6573-7]
http://www.fluoridealert.org/pesticides/Fluazinam.FR.December.2000.htm

Fluthiacet-methyl

Carcinogenicity in rats. NOAEL males = 2.1 mg/kg/day LOAEL in males = 130 mg/kg/day NOAEL in females = 2.5 mg/kg/day LOAEL in females = 154 mg/kg/day. In males there were decreased body weight, liver toxicity, pancreatic toxicity and microcytic anemia. In females there were liver toxicity, uterine toxicity and slight microcytic anemia. In males only at 130 and 219 mg/kg/day there was respectively, an increase in the trend toward pancreatic exocrine adenomas and pancreatic islet cell adenomas.

Ref: Federal Register. December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-21/p31497.htm

Fluoride

PubMed Abstract: OBJECTIVE: The present study focuses on serum testosterone concentrations in patients with skeletal fluorosis, in order to assess the hormonal status in fluoride toxicity. METHODS: Serum testosterones were compared for patients afflicted with skeletal fluorosis (n = 30) and healthy males consuming water containing less than 1 ppm fluoride (Control 1, n = 26) and a second category of controls (Control 2, n = 16): individuals living in the same house as the patients and consuming same water as patients but not exhibiting clinical manifestations of skeletal fluorosis. RESULTS: Circulating serum testosterones in skeletal fluorosis patients were significantly lower than those of Control 1 at p < 0.01. Testosterone concentrations of Control 2 were also lower than those of Control 1 at p < 0.05 but were higher than those of the patient group. CONCLUSIONS: Decreased testosterone concentrations in skeletal fluorosis patients and in males drinking the same water as the patients but with no clinical manifestations of the disease compared with those of normal, healthy males living in areas nonendemic for fluorosis suggest that fluoride toxicity may cause adverse effects in the reproductive system of males living in fluorosis endemic areas.

Ref: J Toxicol Clin Toxicol 1996;34(2):183-9
Circulating testosterone levels in skeletal fluorosis patients.
Susheela AK, Jethanandani P
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8618252&dopt=Abstract PMID: 8618252, UI: 96186260

Fluoroacetamide

REPRODUCTIVE HAZARD: Fluoroacetamide has caused testicular degeneration in rats... In mice, oral administration of fluoroacetamide resulted in a prolonged pregnancy and the young suffered from cyanosis, respiratory distress, reduced growth, and decreased survival.

Ref: TOXNET profile from Hazardous Substances Data Bank.
http://www.fluoridealert.org/pesticides/Fluoroacetic.Acid.TOXNET.htm

Haloxyfop-ethoxyethyl

Reproductive Effects: In rats, oral doses of 10 and 50 mg/kg/day of haloxyfop-ethoxyethyl from days 6 to 16 of pregnancy reduced the number of live offspring per litter and caused vaginal bleeding in the mother (5). Teratogenic Effects: Oral doses of 50 mg/kg/day of haloxyfop-ethoxyethyl in rats between days 6 and 16 of pregnancy caused developmental abnormalities in the offspring's urogenital system and death to the fetus (5). Oral doses of 7.5 mg/kg/day of haloxyfop-methyl given to rats from days 6 to 15 of pregnancy caused delayed bone formation in the offspring (6).

Ref: EXTOXNET Pesticide Information Profile
http://pmep.cce.cornell.edu/profiles/extoxnet/haloxyfop-methylparathion/haloxyfop-ext.html

Hexafluoroacetone - (Not a pesticide)

Non-Human Toxicity Excerpts : Testicular atrophy was induced in rats by dermal application of hexafluoroacetone (HFA) at 39 or 130 mg/kg/day for 14 days, but not at a dosage of 13 mg/kg/day. Affected germ cells were mostly spermatids and to a lesser extent spermatocytes; spermatogonia were unaffected. Late spermatids were retained in Sertoli cells and showed degenerative changes. Sertoli cells exhibited cytoplasmic vacuolation, distended endoplasmic reticulum and a marked increase ln lipid droplets. Leydig cells exhibited a slight increase in lipid droplets, fewer mitochondria and diminution and segregation of the agranular endoplasmic reticulum from mitochondria. A correlation between ultrastructural and biochemical changes in HFA induced testicular atrophy was presented.

Ref: Lee KP, Gullies PJ; Exp Mol Pathol 40 (1): 29-37 (1994)

Hydramethylnon

Hydramethylnon is a male reproductive toxicant which appears to specifically target the germinal cells and/or tissues in the testes... The reproductive NOEL was 25 ppm (1.66 mg/kg/day for males) and the lowest observed effect level (LOEL) was 50 ppm (3.32 mg/kg/day for males), based upon histopathological findings in the testes and the epididymides. Also, at 75 ppm (5.05 mg/kg/day in males), reproductive performance of the males was decreased with longer precoital intervals, lower pregnancy rates, reduced gestation weight gain for females and smaller litters... The evidence of male infertility and testicular atrophy at 90 mg/kg/day in the dominant lethal assay is consistent with similar findings observed in the chronic rat study, the 18-month mouse feeding study, the 2-generation reproduction study, and the 91-day oral gavage study in dogs.

Ref: Federal Register. August 14, 1998. [PF-824; FRL-6023-2]
http://www.fluoridealert.org/pesticides/Hydramethylnon.FR.Aug.14.98.htm

Lambda-Cyhalothrin

A carcinogenicity study in mice fed dose levels of 0, 20, 100, or 500 ppm (0, 3, 15, or 75 mg/kg/day) in the diet for 2 years. A systemic NOEL was established at 100 ppm and systemic LOEL at 500 ppm based on decreased body weight gain in males throughout the study at 500 ppm. The Agency has determined that the chemical was not tested at a sufficiently high dose level for carcinogenicity testing in female mice. In addition, due to an equivocal finding for mammary tumors in females (1/52, 0/52, 7/52, 6/52), the Agency classified the chemical as a Group D carcinogen.

Ref: Federal Register. March 27, 1995. Lambda-Cyhalothrin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/Lambda-Cyhal.FR.Mar.27.1995.htm

Sodium fluoride

Absorption, Distribution & Excretion : RATS GIVEN (18)FLUORIDE ION AS A RADIOTRACER BY CONTINUOUS IV INFUSION OF SODIUM FLUORIDE FOR 3 HR SHOWED AT SUBLETHAL DOSE RATES, BLOOD FLUORIDE CONCN NEARS STEADY STATE PROPORTIONAL TO FLUORIDE INFUSION RATE. BLOOD, KIDNEY, & LUNG HAD HIGHEST CONCN @ DOSES UP TO 3 MG FLUORIDE/KG/HR, BUT @ 6 MG/KG/HR THE FLUORIDE OF THE LIVER, SPLEEN & HOLLOW ORGANS INCR SHARPLY. AMT ABOVE THIS WAS NOT WELL PROCESSED BY EXCRETORY MECHANISM. RATS INFUSED 3 HR WITH 6 MG FLUORIDE/KG/HR: DURING INFUSION FLUORIDE CONCN OF BONE & OTHER TISSUES WAS HIGH, BONE THE HIGHEST. OF SOFT TISSUES, LUNG HAD THE HIGHEST, BRAIN, TESTES, & FAT PADS THE LEAST CONCN. DURING DEPLETION PHASE, TISSUE FLUORIDE CONCN DECR, BONE FLUORIDE REMAINED CONSTANT, & SUBSTANTIAL AMOUNT REMAINED IN THE LUNG. /Sodium Fluoride/

Ref: KNAUS RM ET AL; TOX APPL PHARM 38 (2): 335-43 (1976)

Website ref: Sodium Fluoride, Ammonium fluroide, Carbonyl difluroride (353-50-4) at:
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Sodium fluoride

PubMed Abstract: A single microdose (50 micrograms/50 microL) injection of sodium fluoride (NaF) into the vasa deferentia of adult male albino rats (Rattus norvegicus) caused arrest of spermatogenesis and absence of spermatozoa in the lumina of the seminiferous tubules of the testes, which consequently led to a decline in the sperm count in the caudae epididymides. Scanning electron microscopy of cauda and vas deferens sperm revealed deflagellation and tail abnormalities. This is probably related to the alterations in the internal milieu of these organs which rendered the spermatozoa immotile and consequently caused fertility impairment in the experimental animals. Thus microdoses of sodium fluoride were found to affect reproductive function and fertility rate. PMID: 1839778, UI: 92240073

Ref: Reprod Toxicol 1991;5(6):505-12
Microdose vasal injection of sodium fluoride in the rat.
Chinoy NJ, Rao MV, Narayana MV, Neelakanta E

Sodium fluoride

PubMed Abstract: The effects of sodium fluoride (NaF) ingestion in two doses (10 and 20 mg/kg body weight) for 30 days on histology and histocytometry of reproductive organs of the adult male mouse were investigated. In order to study reversibility, treatment was withdrawn for one and two months. The testes, epididymides, vas deferens, prostate, and seminal vesicle were utilized for the study by standard hematoxylin-eosin staining and an ocular eye piece and micrometer scale. NaF treatment caused severe disorganization and denudation of germinal epithelial cells of seminiferous tubules with absence of sperm in the lumina. The Leydig cell and nucleus diameters were not affected. The caput epididymis showed fewer changes than the cauda. However, epithelial cell nuclear pyknosis and absence of luminal sperm were observed. A reduction in epithelial cell height, nuclear pyknosis, denudation of cells, and absence of sperm occurred in the cauda epididymis. The vas deferens epithelium showed nuclear pyknosis, clumped stereocilia, and cell debris but no sperm in the lumen and an increase in the lamina propria. The prostate and seminal vesicles were not affected by treatment. Withdrawal of treatment caused marked recovery in the histoarchitecture of these organs. The effects of NaF treatment are therefore transient and reversible.

Ref: Reprod Toxicol 1989;3(4):261-7
Effects of fluoride on the histoarchitecture of reproductive organs of the male mouse.
Chinoy NJ, Sequeira E

Sodium fluoride

PubMed Abstract: OBJECTIVE--To address the role of fluoride in causing defects to spermatids and epididymal spermatozoa. METHODS--Male rabbits were treated with 10 mg NaF/kg body weight daily for 18 months and maintained under identical laboratory conditions along with the control rabbits not given NaF. Testis and epididymis (caput) were investigated for ultrastructural details of spermatids and spermatozoa. RESULTS--A wide variety of structural defects were observed in the flagellum, the acrosome, and the nucleus of the spermatids and epididymal spermatozoa of fluoride-treated rabbits. Abnormalities included absence of outer microtubules, complete absence of axonemes, structural and numeric aberrations of outer dense fibers, breakdown of the fibrous sheath, and structural defects in the mitochondria of the middle piece of the flagellum. Detachment and peeling off of the acrosome from the flat surfaces of the nucleus were also observed. CONCLUSION--The abnormalities observed render the sperm nonfunctional and ineffective, and thus there is a possible role of fluoride in causing infertility.

Ref: Int J Fertil Menopausal Stud 1994 May-Jun;39(3):164-71
Ultrastructural studies of spermiogenesis in rabbit exposed to chronic fluoride toxicity.
Kumar A, Susheela AK
PMID: 7920753, UI: 95004768

Sodium fluoride

PubMed Abstract: Effects of sodium fluoride (NaF) on washed, ejaculated human spermatozoa at doses of 25, 50, and 250 mM were investigated in vitro at intervals of 5, 10, and 20 min. Sodium fluoride (NaF) did not affect the extracellular pH of sperm, except that a slight acidification was caused by the 250 mM dose only. The treatment caused a significant enhancement in acid phosphatase (ACPase) and hyaluronidase activities after 5 and 10 min. However, the decrease in the lysosomal enzyme activity after 20 min treatment could have been due to the gradual increase in fluoride accumulation by spermatozoa leading to membrane damage. Silver nitrate staining of sperm revealed elongated heads, deflagellation, and loss of the acrosome together with coiling of the tail. Sperm glutathione levels also showed a time-dependent decrease with complete depletion after 20 min indicating rapid glutathione oxidation in detoxification of the NaF. The altered lysosomal enzyme activity and glutathione levels together with morphologic anomalies resulted in a significant decline in sperm motility with an effective dose of 250 mM.

Ref: Reprod Toxicol 1994 Mar-Apr;8(2):155-9
In vitro fluoride toxicity in human spermatozoa.
Chinoy NJ, Narayana MV
PMID: 8032126, UI: 94305257

Sulfentrazone

Chronic dietary (all populations) NOAEL= 14.0 mg/kg/day. 2-Generation Reproduction in Rats. LOAEL = 33/44 mg/kg/day in males and females, respectively, based on: (1) Decreased maternal body weight and/or body weight gain during gestation in both P and F1 generations, (2) reduced premating body weight gains in the second generation (F1 adults), (3) increased duration of gestation in both F1 and F2 dams, (4) reduced prenatal viability (fetal and litter), (5) reduced litter size, (6) increased number of stillborn pups, (7) reduced pup and litter postnatal survival, and (8) decreased pup body weights throughout gestation. In males, effects included decreased fertility in F1 generation and/or atrophy of the germinal epithelium of the testes, oligospermia and intratubular degeneration of the seminal product in the epididymis.

Ref: Federal Register. August 1, 2001. Sulfentrazone; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Aug1.2001.htm

Trichlorofluoromethane

/was/ tested by inhalation on Sprague-Dawley rats and Swiss mice. The animals were exposed for 4 hr a day, 5 days a week; rats were exposed for 104 weeks, and mice were exposed for 78 weeks. Animals were observed until spontaneous death. Trichlorofluoromethane exposure to rats caused no carcinogenic effects. Trichlorofluoromethane exposure to mice caused increased numbers of total tumors in females which was dose related, mammary tumors in females at 5000 ppm, lung adenomas and leukemias in females, both dose related.

Ref: Maltoni C et al; Annals of the New York Academy of Sciences 534: 261-82 (1988)
Website: TOXNET profile from Hazardous Substances Data Base. http://www.fluoridealert.org/pesticides/Trichlorofluorometha.TOXNET.htm

Triflusulfuron methyl

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).

Ref: Federal Register. August 8, 2001. [PF-1036; FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm

Vinyl fluoride - (Not a pesticide)

Carcinogenicity: Vinyl fluoride (VF) is reasonably anticipated to be a human carcinogen based on evidence of tumor induction at multiple organ sites in rats and mice. Inhalation exposure of rats to vinyl fluoride resulted in increased incidences of hepatic hemangiosarcomas, hepatocellular adenomas or carcinomas, and Zymbal gland carcinomas; inhalation exposure of mice to VF resulted in increased incidences of hepatic hemangiosarcomas, bronchiolar-alveolar adenomas or adenocarcinomas, hepatocellular adenomas, mammary gland adenocarcinomas, and Harderian gland adenomas (Bogdanffy et al. 1995; IARC 1995). The tumor response to VF in laboratory animals is similar to the responses to vinyl chloride, a known human carcinogen (NTP 1998; IARC 1987), and to vinyl bromide, a probable human carcinogen (IARC 1986). A unique feature of vinyl chloride carcinogenicity is the induction of rare hepatic hemangiosarcomas in rats and mice and the causal association in epidemiological studies between vinyl chloride exposure and excess risk of hemangiosarcoma of the liver (NTP 1998). The fact that VF, vinyl chloride, and vinyl bromide induce rare hemangiosarcomas of the liver in experimental animals and induce the formation of similar DNA adducts suggests a possible common mechanism of carcinogenicity for these vinyl halides.

Ref: Draft report on carcinogens. Background document for Vinyl fluoride.
http://www.fluoridealert.org/VF.pdf

 

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TABLE 9

Air pollution from fluoride emitting industries.

According to the 1999 Toxics Release Inventory (TRI) Hydrogen Fluoride (HF) (CAS No. 7664-39-3) ranked 6th for Air Emissions of Toxic Chemicals released in the U.S.

The fourth column of this Table is the "Percent of Public Water Supply Population Using Fluoridated Water (p xx)" by state.
Ref: Fluoridation Census 1992. Published in 1993 by the U.S. Department of Health & Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Oral Health, Atlanta, Georgia 30333.

TRI Rank

HF 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 48.3
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.

 

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Letter sent with submission:

February 26, 2002

Dr. Ganga Choudhary
Division of Toxicology, Agency for Toxic Substances and Disease Registry,
Mailstop E-29, 1600 Clifton Road, NE,
Atlanta, Georgia 30333

Re: Docket Control Number ATSDR-173

Comments on Draft Toxicological Profile on Fluorides

Dear Dr. Choudhary

Thank you for approving our request to extend the deadline for the submission of our comments on the draft Toxicological Profile for Fluorides. Our comments on the draft profile are attached. They are also available online at: http://www.fluoridealert.org/pesticides/Fluorides.Comments.ATSDR.02.htm

ATSDR offers an invaluable service by providing interested parties with hard copies of the Toxicological Profiles and the opportunity to comment. We would like to offer four recommendations that would improve the process:

1. That ATSDR hold a public meeting with the authors of the Tox Profiles to allow the public an opportunity to hear the response from the authors on the comments submitted on the draft documents.

2. That new Tox Profiles also be accessible on the web to allow commentators and others the ability to search the documents.

3. That all public comments submitted to ATSDR on the Tox Profiles be made available online.

4. The specific purpose of the Toxicological Profile is to "provide information on the hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List." It would be helpful if ATSDR would identify the location of these facilities in future profiles and provide an abbreviated history on the source and estimated quantify of the hazardous substances.

Sincerely,

Ellen and Paul Connett.