REFERENCE SET: FLUOROACETATE

1080

REFERENCE SET: FLUOROACETATE

Postby admin » Sat Jul 14, 2012 6:22 am

REFERENCE SET:

FLUOROACETATE


©1996-2012 PFPC


At least since the 1940s fluoroacetate is known as one of the most toxic substances anywhere (i.e. Thiemann, 1949; Saunders & Stacy, 1949; Hodge, 1949, etc.).

Compound 1080

Compound 1080 is sodium fluoroacetate. Since 1972 it has been illegal to spray Compound 1080 in the U.S., where it had been used widely as a rodent and coyote killer. However, it is still widely used in other countries such as New Zealand, or Australia where it is used to kill rabbits. In the US so-called live-stock-prevention (LSP) collars are also still in use.

For more info on Compound 1080, please see: http://poisonfluoride.com/phpbb2/viewtopic.php?t=479

Fluoroacetate

Fluoroacetate is also a metabolite of many other fluorinated pesticides and other organic fluoride compounds, such as those used in anesthetics (i.e. halothane, evoflurane, etc), or 5-fluorouracil, an agent given in cancer (chemo-therapy) treatment, etc.

Its use has been investigated and employed even in chemical warfare agents. It is the toxic breakdown product of organophosphates.

Fluoroacetate is formed in certain plants (i.e. Acacia georginae, Dichapetalum cymosum, Dichapetalum toxicarum, Gastrolobium grandiflorum, Oxylobium parviflorum, Palicourea margravii) after fluoride uptake from soil, water or air.

This has resulted in many serious cases of livestock poisoning and high stock losses (Oelrichs & McEwan, 1962).

Poisoning has also occurred in field workers exposed to fluoroacetate (Suh et al, 1970).

Fluoroacetate forms in cereals, water, plants, etc..

It is found in water after pollution of the atmosphere with fluorocarbons. As a result of the atmospheric degradation of hydrofluorocarbons and hydrochlorofluorocarbons, trifluoroacetate (TFA) will be formed. Through precipitation, fluoroacetate enters aquatic ecosystems.

Fluoroacetate - Thyroid & Liver


In the 1930s German scientists from Bayer and Knoll’s discovered that all organic fluoride compounds interfered with thyroid hormone function (i.e. Litzka 1936,1937; Kraft, 1937).

Inhibiting activities in the liver were established to be the main factor in anti-thyroid fluoride activity. It was known that the liver was the main organ for thyroid hormone conversion (T4 -> T3) (Litzka, 1937).

Regarding the toxicity of different fluoride compounds - it showed to be merely a matter of amplification. For example, while some organic fluoride compounds were effective with a 0.1ppm fluoride content, others were just as effective with as little as 0.001ppm of F- (Kraft, 1937).

More recent evidence firmly confirms these findings. For example, monofluorophosphate (MFP) and sodium fluoride, compounds commonly employed in fluoride toothpaste, have shown to have similar effects in liver cells (hepatocytes) as fluoroacetate (Shahed et al, 1979).

Further, PMSF (phenylmethylsulfonyl fluoride - a powerful serine protease inhibitor) and sodium fluoride have also shown identical effects in liver cells, and this was directly ascribed to the "F-" component (Bollen et al, 1988).

A vast amount of information is available on the potentiating powers of aluminumfluoride complexes.

The literature on other compounds such as PFOS/PFOA, PFDA, and their liver toxicity is extensive.

PMSF action is considered "analogous to that of diisopropylfluorophosphate" (DFP), a.o. the major ingredient in such pesticides as "Gliftor", which is thought to be toxic, again - because it is metabolized to fluoroacetate (Mead, 2001).

Compounds such as DFP inhibit an enzyme (prolyl endopeptidase) which inactivates thyroid-releasing-hormone (TRH). TRH is a byproduct of the hypothalamus and serves to stimulate the pituitary gland to produce thyroid stimulating hormone (TSH). TRH is produced by the hypothalamus when free thyroid hormone (FT3 and FT4) blood levels are low. -> feedback mechanism. DFP thus directly interferes with Free T3-mediated activities.

It is commonly thought that the toxicity of fluoroacetate is the result of its conversion into fluorocitrate which is a potent inhibitor of enzymes in the tricarboxylic-acid-cycle (i.e. Elliott & Kalnitsky, 1996).

However, much other relevant toxicity data exists showing other and unique fluoroacetate activities in different organs, including brain etc (i.e. Tecle & Casida, 1989; Twigg et al, 1986; Keller et al, 1996].

Many of these have nothing to do with any fluorocitrate formation or elevated citrate levels.

The elevated levels of citrate in blood do not become observable until 30 minutes after administration, and tend to reach their maximum at 4 hours after administration, similar as to the delayed bio-chemical effects observed in other cases of fluoride poisoning.

Adverse effects are observable much earlier than that and therefore possible sign that other mechanisms are at work, and that citrate elevations are perhaps a result of other such pre-existing mechanisms.

It has been shown that citrate levels are directly influenced by thyroid hormone (-> Free T3, see: Sochor et al, 1988; Maruo et al, 1992)

The literature suggests that this is due to reduction of adenosine triphosphate (ATP) levels.

From our extensive research into all kinds of fluoride compounds, both organic and inorganic, we know that toxicity is related to inhibition of activities related to Free T3, the biologically active thyroid hormone.

Paterson (1971) offered a most detailed investigation on interactions of fluoroacetate and thyroid hormones. Parkin et al (1977) found liver and thyroid disease in a rabbiter chronically exposed to fluoroacetate.

De-fluorination

Different enzymes are capable of defluorinating fluoroacetate, thus creating free fluoride ion.

Studies on rats have shown that "free" fluoride concentrations are higher in all tissues and plasma after fluoroacetate intake (Egekeze & Oehme, 1979).

Animal experiments have shown that this defluorination is due to an glutathione-dependent enzymic mechanism (Soiefer & Kostyniak, 1986; Mead et al, 1979; Twigg et al, 1986; Wang et al, 1986).

Glutathione is selenium dependent, and essential for thyroid hormone synthesis of T4 to T3. Inhibition of synthesis will lead to so-called biochemical-induced hypothyroidism.

Current medications given in hyperthyroidism such as PTU work by inhibiting this very same enzyme-mechanism, thus causing identical effects as is known as "selenium deficiency" (Veronikis et al, 1996). Of course fluoride is openly acknowledged in other countries such as China as being cause of selenium deficiency and resulting Kashin-Beck disease. Entire villages have been re-located as the result of fluoride contamination.

Glutathione has been shown to inhibit fluoroacetate toxicity.

Regarding the liver and fluoroacetate, it should be noted that the liver is the organ with the highest fluoroacetate-defluorination ability (Soiefer & Kostyniak, 1983).

Dogs are highly sensitive to fluoroacetate, and mass poisonings of dogs eating contaminated poultry have been documented (Egyed, 1979).

Toxicity is different according to route of precursor intake, i.e. inhalation or ingestion, and varies widely among species. It is further dependent on the individual's thyroid status.

Fluoroacetate crosses the brain barrier.

See also:
EPA Pesticide Fact Sheet
sodium fluoroacetate (1080) Chemical Profile 8/90

About the ADC

“ADC employees have been convicted in the past for illegally trading in 1080. In 1990, the U.S. Fish and Wildlife Service discovered illegal trade of LPCs and Compound 1080 to be common among those with access to them. There is a widespread belief by federal investigators that a black market for both still exists.”

Charlie's Story (Compound 1080 in soy formula)
http://home.att.net/~gtigerclaw/Charlie.html

References:

Arellano M, Malet-Martino M, Martino R, Gires P - "The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate" Br J Cancer 7(1):79-86 (1998)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Atzert SP - "A review of monofluoroacetate (Compound 1080) its properties, toxicology and use in predator and rodent control" Wildlife No. 146 (1971)

Berends AG, de Rooij CG, Boutonnet JC - “Toxicity of fluoroacetate to aquatic organisms” Environmental Toxicology and Chemistry 18 (5):1053 -1059 (1999)

Bobyleva V, Pazienza L, Muscatello U, Kneer N, Lardy H - "Short-term hypothermia activates hepatic mitochondrial sn-glycerol-3-phosphate dehydrogenase and thermogenic systems" Arch Biochem Biophys 380(2):367-72 (2000)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Bollen M, Stalmans W - "Fluorine compounds inhibit the conversion of active type-1 protein phosphatases into the ATPMg-dependent form" Biochem J 255(1):327-33 (1988)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Booth LH, Ogilvie SC, Wright GR, Eason CT - "Degradation of sodium monofluoroacetate (1080) and fluorocitrate in water." Bull Environ Contam Toxicol 62(1):34-9 (1999)

Bosakowski T, Levin AA - "Serum citrate as a peripheral indicator of fluoroacetate and fluorocitrate toxicity in rats and dogs." Toxicol Appl Pharmacol 85(3):428-36 (1986)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Buffa P, Peters RA - "Formation of citrate in vivo induced by fluoroacetate poisoning" Nature 163:194 (1949)

Chenoweth MB, Kandel A, Johnson LB, Bennett DR -"Factors influencing fluoroacetate poisoning.Practical treatment with glycerol monoacetate." Journal of Pharmacology and Experimental Therapeutics 102:31-49 (1951)

Deaciuc IV, Frecus G - "Effects Of Monofluoroacetate On The Concentration Of Some Metabolites In Resting And Stimulated Skeletal Muscle And In Liver Of The Rat In Vivo" Revue Roumaine de Biochimie 10(3):171-177 (1973)

De Wolf M, Lagrou A, Hilderson HJ, Dierick W - "Acid triacylglycerol lipase from bovine thyroid gland" Lipids 13(9):598-604 (1978)
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Egekeze JO, Oehme FW - "Inorganic and organic fluoride concentrations in tissues after the oral administration of sodium monofluoroacetate (Compound 1080) to rats" Toxicology 15(1):43-53 (1979) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Egyed MN - "Mass poisoning in dogs due to meat contaminated by sodium fluoroacetate or fluoroacetamide: Special reference to the differential diagnosis" Fluoride 12(2):76-84 (1979)

Elliott WB, Kalnitsky G - "Mechanism for Fluoroacetate Inhibition" Govt Reports Announcements & Index (GRA&I), Issue 02 (1996)

Feldwick, MG, Mead RJ, Kostyniak PJ - "Biochemical Effects of Fluoroacetate and Related Pesticides:The Potential of 4-Methylpyrazole as an Antidote" Proceedings of the science workshop on 1080. The Royal Society of New Zealand, Miscellaneous series 28:74-81 (1994) LINK

Fonnum F, Johnsen A, Hassel B - "Use of fluorocitrate and fluoroacetate in the study of brain metabolism" Glia 21(1):106-13 (1997) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Godoy HM, Del carmen Villarruel M - "Myocardial adenine nucleotides, hexose phosphates and inorganis phosphate, and the regulation of phosphofrucokinase activity during fluoroacetate poisoning in the rat" Biochem Pharmacol 23 (22):3179-89 (1974)

Goldman P -"The enzymatic cleavage of the carbon-fluorine bond in fluoroacetate" J Biol Chem 240:3434-8 (1965)

Hassel B, Bachelard H, Jones P, Fonnum F, Sonnewald U - "Trafficking of amino acids between neurons and glia in vivo. Effects of inhibition of glial metabolism by fluoroacetate" J Cereb Blood Flow Metab 17(11):1230-8 (1997) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Hodge HC, Sterner JH - "Tabulation Of Toxicity Classes" American Industrial Hygiene Association Quarterly, Vol. 10 pg. 93-96 (1949)

Hornfeldt CS, Larson AA - "Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord" Eur J Pharmacol 179(3):307-13 (1990) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Just WW, Gorgas K, Hartl FU, Heinemann P, Salzer M, Schimassek H - "Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver" Hepatology 9(4):570-81 (1989) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Keller DA, Roe DC, Lieder PH - "Fluoroacetate-mediated toxicity of fluorinated ethanes" Fundam Appl Toxicol 30(2):213-9 (1996) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Key BD, Howell RD, Criddle CS - "Fluorinated organics in the biosphere" Env Sci Tech 31(9):2445-2454 (1997)

King, DR, Oliver AJ, Mead RJ - "The adaption of some Western Australian mammals to food plants containing fluoroacetate" Australian Journal of Zoology 26: 699-712 (1978)

Kraft K -"Beiträge zur Biochemie des Fluors I.Über den Antagonismus zwischen Fluor und Thyroxin." Hoppe-Seglers
Z.Physiol. Chem 245:58 -65 (1937)

Krebs HC, Kemmerling W, Habermehl G - "Qualitative and quantitative determination of fluoroacetic acid in Arrabidea bilabiata and Palicourea marcgravii by 19F-NMR spectroscopy" Toxicon 32(8):909-13 (1994)

Liang CS - "Metabolic control of circulation. Effects of iodoacetate and fluoroacetate" Clin Invest 60(1):61-9 (1977)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Litzka G - "Die experimentellen Grundlagen der Behandlung des Morbus Basedow und der Hyperthyreose mittels Fluortyrosin" Med Wochenschr 63:1037-1040 (1937) (discusses the basis of the use of fluorides in anti-thyroid medication, documents activity on liver, inhibition of glycolysis, etc.)

Litzka G -"Erfolgskontrolle bei Behandlung der Schilddrüsenüberfunktion" Z. klin. Med.131:791-799 (1937)

Litzka G -"Die antithyreotoxische Wirkung des Fluortyrosins" Arch. exp. Pathol. u. Pharmakol. 183:436-458 (1936)

Litzka G -"Fluortyrosine" Klin Wochenschr. 15:1568-1569 (1936)

Maruo T, Katayama K, Barnea ER, Mochizuki M - "A role for thyroid hormone in the induction of ovulation and corpus luteum function Horm Res 37 Suppl 1:12-8 (1992)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Mead RJ - "Clinical Biochemistry - Projects " , Honours Projects 2002, Biological Sciences Divison of Science and Engineering, Murdoch University (2001) http://wwwscience.murdoch.edu.au/honours/biology.html

Mead RJ, Segal W - "Fluoroacetic acid biosynthesis: A proposed mechanism" Austral J Biol Sci 25(2):327-333 (1972)

Mead RJ, Oliver AJ, King DR - "Metabolism and defluorination of fluoroacetate in the brush-tailed possum (Trichosurus vulpecula)" Aust J Biol Sci 32(1):15-26 (1979) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Oelrichs PB, McEwan T - "The toxic principle of Acacia georginae" Queensland J Agr Sci 19:1-16 (1962)

Parkin PJ, McGiven AR, Bailey RR - "Chronic sodium monofluoroacetate (compound 1080) intoxication in a rabbiter" N. Z. Med J 85(581): 93-96 (1977)

Parkin PJ, McGiven AR, Bailey RR - "Chronic sodium monofluoroacetate (compound 1080) intoxication in a rabbiter": N. Z. Med J 85(581): 93-96 (1977)

* "A 59-year-old rabbiter with repeated exposure to SMFA (sodium monofluoracetate) presented with renal, hepatic, neurologic, and thyroid dysfunction.....Liver abnormalities were demonstrated by enzyme tests and histological examination of the biopsy specimen...”

Paterson RA - "Metabolic control of rat heart glycolysis after acute ischaemia. Fluoracetate treatment and thyroid interactions" J Mol Cell Cardiol 2(3):193-210 (1971)

Peters RA, Spencer H, Bidstrup PL - "Subacute fluoroacetate poisoning" J Occup Med 23 (2):112-113 (1981)

Saunders BC, Stacey GJ - "Toxic Fluorine Compounds Containing The C-F Link. Part IV. (a) 2-Fluoroethyl Fluoroacetate And Allied Compounds. (b) 2:2'-Difluorodiethyl Ethylene Dithioglycol Ether" Journal of the Chemical Society 916-919 (1949)

Shahed AB, Miller AR, Allmann DW - "Influence of sodium fluoride and disodium monofluorophosphate on glucose metabolism in rat hepatocytes." Biochem Biophys Commun 91 (2):583-591 (1979)

Schomburg L, Bauer K - "Thyroid hormones rapidly and stringently regulate the messenger RNA levels of the thyrotropin-releasing hormone (TRH) receptor and the TRH-degrading ectoenzyme" Endocrinology 136(8):3480-5 (1995)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Shinoda K, Mitsumori K, Uneyama C, Uehara M - "Induction and inhibition of testicular germ cell apoptosis by fluoroacetate in rats" Arch Toxicol 74(1):33-9 (2000) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Siviter RJ, Cockle SM - "Peptides related to thyrotrophin-releasing hormone are degraded in seminal plasma by an enzyme similar to prolyl endopeptidase" J Endocrinol 144(1):61-6(1995)
http://www.ncbi.nlm.nih.gov/entrez/quer ... 6&db=m&Dop t=r

Sochor M, Ball MR, Baquer NZ - "Effect of thyroid hormones on the levels of metabolic intermediates in diabetic rat liver" Biochem Int 16(1):15-23 (1988)
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Soiefer AI, Kostyniak PJ - “The enzymatic defluorination of fluoroacetate in mouse liver cytosol: the separation of defluorination activity from several glutathione S-transferases of mouse liver” Arch Biochem Biophys 225(2):928-35(1983)

* “The liberation of free fluoride ion from fluoroacetate (FAc) proceeds as an enzyme-catalyzed dehalogenation reaction in the soluble fractions of several organs of the CFW Swiss mouse. Liver contained the highest FAc defluorinating activity...”

Stewart GG, Abbs ET, Roberts DJ - "Biochemical Effects Of Fluoroacetate Administration In Rat Brain, Heart And Blood" Biochemical Pharmacology 19 (6):1861-1866 (1969)

Stier A, Kunz HW, Walli AK, Schimassek H - "Effects on growth and metabolism of rat liver by halothane and its metabolite trifluoroacetate" Biochem Pharmacol 21(16):2181-92 (1972)

Suh D, Kim, Hong D, Hong S - "Acute intoxication due to agricultural chemicals" Taehan Naekwa Hakkoe Chapci 13(3): 197-206 (1970)

Sullivan JL, Smith FA, Wilkenfeld RM, Garman RH, Kostyniak PJ - "Monofluoroacetate and trifluoroethanol as testicular poisons in the rat" Toxicol Appl Pharmacol 45(1):291-292 (1978)

Swanson RA, Graham SH - "Fluorocitrate and fluoroacetate effects on astrocyte metabolismin vitro" Brain Res 664(1-2):94-100 (1994) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Taylor WM, D'Costa M, Angel A, Halperin ML - "Insulin-like effects of fluoroacetate on lipolysis and lipogenesis in adipose tissue" Can J Biochem 55(9):982-7 (1977)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Tecle B, Casida JE - "Enzymatic defluorination and metabolism of fluoroacetate, fluoroacetamide, fluoroethanol, and (-)-erythro-fluorocitrate in rats and mice examined by 19F and 13C NMR" Chem Res Toxicol 2(6):429-35 (1989) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Thiemann HA - "New Insecticides and Rodenticides and Their Health Aspects" American Industrial Hygiene Association Quarterly 10(1):10-15 (1949)

Twigg LE, Mead RJ, King DR - "Metabolism of fluoroacetate in the skink (Tiliqua rugosa) and the rat (Rattus norvegicus)" Aust J Biol Sci 39(1):1-15 (1986) http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Veronikis IE, Braverman LE, Alex S, Fang SL, Norvell B, Emerson CH - "Comparison of the Effects of Propylthiouracil and Selenium Deficiency on T3 Production in the Rat" Endocrinology 137(6): 2580-2585 (1996)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Wang SL, Rice SA, Serra MT, Gross B - "Purification and identification of rat hepatic cytosolic enzymes responsible for defluorination of methoxyflurane and fluoroacetate" Drug Metab Dispos 14(4):392-8 (1986)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Winninger C, Lestienne P, Dimicoli JL, Bieth JG - "NMR and enzymatic investigation of the interaction between elastase and sodium trifluoroacetate." Biochim Biophys Acta 526(1):227-34 (1978)

Zhou JL, Kauffman FC, Ballow CH, Thurman RG - "Inhibition of mixed-function oxidation in perfused rat liver by fluoroacetate treatment" Biochem Pharmacol 33(2):319-23 (1984)
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

SOURCE:
http://bruha.com/science/html/fluoroacetate.html
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