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2,3,7,8-Tetrachlorodibenzodioxin

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2,3,7,8-Tetrachlorodibenzodioxin
Names
IUPAC name
2,3,7,8-tetrachlorodibenzo[b,e][1,4]-dioxin [1]
Other names
Tetradioxin; Tetrachlorodibenzodioxin; Tetrachlorodibenzo-p-dioxin
Identifiers
3D model (JSmol)
Abbreviations TCDD; TCDBD
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.015.566 Edit this at Wikidata
KEGG
  • InChI=1S/C12H4Cl4O2/c13-5-1-9-10(2-6(5)14)18-12-4-8(16)7(15)3-11(12)17-9/h1-4H checkY
    Key: HGUFODBRKLSHSI-UHFFFAOYSA-N checkY
  • InChI=1/C12H4Cl4O2/c13-5-1-9-10(2-6(5)14)18-12-4-8(16)7(15)3-11(12)17-9/h1-4H
    Key: HGUFODBRKLSHSI-UHFFFAOYAA
  • Clc2cc1Oc3c(Oc1cc2Cl)cc(Cl)c(Cl)c3
Properties
C12H4Cl4O2
Molar mass 321.97 g/mol
Density 1.8 g cm−3
Melting point 305 °C (581 °F; 578 K)
0.2 µg/L at 25 °C[2]
log P 6.8
Vapor pressure 1.5 × 10−9 mmHg
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
4
1
0
Flash point 164.2 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (in short but inaccurately also called dioxin). It is the most potent compound (congener) of the series and became known as a contaminant in Agent Orange, a herbicide used in the Vietnam War,[3] as well as the Seveso disaster.[4] It is a persistent environmental contaminant usually present in a complex mixture of dioxin-like compounds.

Mechanism of action

TCDD and dioxin-like compounds act via a specific receptor present in all cells: the aryl hydrocarbon (AH) receptor.[5][6][7] This receptor is a transcription factor which is involved in expression of genes; in fact it has been shown that high doses of TCDD either increase or decrease the expression of several hundred genes in rats.[8] Genes of enzymes activating the breakdown of foreign and often toxic compounds are classic examples of such genes. TCDD increases the enzymes breaking down, e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene.[9]

These polycyclic hydrocarbons also activate the AH receptor, but less than TCDD and only temporarily.[9] Even many natural compounds present in vegetables cause some activation of the AH receptor.[10] This phenomenon can be viewed as adaptive and beneficial, because it protects the organism from toxic and carcinogenic substances. Excessive and persistent stimulation of AH receptor, however, leads to a multitude of adverse effects.[9]

Scientists have searched for the physiological functions of the AH receptor for years, and one obvious function is to increase the activity of enzymes breaking down foreign chemicals or normal chemicals of the body as needed. There may be other functions, however, related to growth of various organs or other regulatory functions. The AH receptor is phylogenetically highly conserved transcription factor with a history of at least 500 million years, and found in all vertebrates, and its ancient analogs are important regulatory proteins even in more primitive species.[7] In fact, knock-out animals with no AH receptor are quite sick and develop poorly.[7] All this implies that a certain level of AH receptor activation is physiological and necessary for the body.

TCDD is not mutagenic and not directly genotoxic.[11] Its main action in causing cancer is cancer promotion; it promotes the carcinogenicity initiated by other compounds. Very high doses may, in addition, cause cancer indirectly; one of the proposed mechanisms is oxidative stress and the subsequent oxygen damage to DNA.[12] There are other explanations such as endocrine disruption or altered signal transduction.[11][13] The endocrine disrupting activities seem to be dependent on life stage, being anti-estrogenic when estrogen is present (or in high concentration) in the body, and estrogenic in the absence of estrogen.[14]

Sources

TCDD has never been produced commercially except as a pure chemical for scientific research. It is, however, formed as a synthesis side product when producing certain chlorophenols or chlorophenoxy acid herbicides.[15] It may also be formed along with other polychlorinated dibenzodioxins and dibenzofuranes in any burning, especially if certain metal catalysts such as copper are present (see dioxins and dioxin-like compounds).[16]

Toxic effects

By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing 2,3,7,8-TCDD.[3][7][17][18] There is barely any organ without some effects by high doses of TCDD. In short-term toxicity studies in animals the typical effects are anorexia and wasting, and even after a huge dose animals die only 1 to 6 weeks after the TCDD administration.[18] Seemingly similar species are very differently sensitive to acute effects: lethal dose for a guinea pig is about 1 µg/kg, but to a hamster it is more than 1,000 µg/kg. A similar difference can be seen even between two different rat strains.[18] Various hyperplastic (overgrowth) or atrophic (wasting away) responses are seen in different organs, thymus atrophy is very typical in several animal species. TCDD also affects the balance of several hormones. In some species, but not in all, severe liver toxicity is seen.[7][18] Taking into account the low doses of dioxins in the present human population, only two types of toxic effects have been considered to cause a relevant risk to humans: developmental effects and cancer.[7]

Developmental effects

Developmental effects occur at very low doses in animals. They include frank teratogenicity such as cleft palate and hydronephrosis.[19] Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents,[19][20][21] and the development of teeth in rats.[22] The latter is important in that tooth deformities were also seen after the Seveso accident[23] and possibly after a long breast-feeding of babies in 1970s and 1980s when the dioxin concentrations in Europe were about ten times higher than at present.[24]

Cancer

Cancers can be induced in animals at many sites. At sufficiently high doses TCDD has caused cancer in all animals tested. The most sensitive is liver cancer in female rats, and this has long been a basis for risk assessment.[25] Dose-response of TCDD in causing cancer does not seem to be linear,[26] and there is a threshold below which it seems to cause no cancer. TCDD is not mutagenic or genotoxic, in other words, it is not able to initiate cancer, and the cancer risk is based on promotion[11] of cancer initiated by other compounds or on indirect effects such as disturbing defense mechanisms of the body e.g. by preventing apoptosis or programmed death of altered cells.[6][27] Carcinogenicity is associated with tissue damage, and it is often viewed now as secondary to tissue damage.[11]

TCDD may in some conditions potentiate the carcinogenic effects of other compounds. An example is benzo(a)pyrene that is metabolized in two steps, oxidation and conjugation. Oxidation produces epoxide carcinogens that are rapidly detoxified by conjugation, but some molecules may escape to the nucleus of the cell and bind to DNA causing a mutation, resulting cancer initiation. When TCDD increases the activity of oxidative enzymes more than conjugation enzymes, the epoxide intermediates may increase, increasing the possibility of cancer initiation. Thus a beneficial activation of detoxifying enzymes may lead to deleterious side effects.[28]

Cases of poisoning

Viktor Yushchenko with chloracne after his TCDD poisoning incident

There have been a number of accidents where people have been exposed to high doses of dioxin-like chemicals, but there are three historical cases of poisoning where the exposure has been to TCDD itself.

  • In 1976, thousands of inhabitants of Seveso, Italy were exposed to TCDD after an accidental release of several kilograms of TCDD from a pressure tank. A number of animals died, and high concentrations of TCDD, up to 56,000 pg/g of fat, were noted especially in children playing outside and eating local food. The acute effects were limited to about 200 cases of chloracne.[29] Long-term effects seem to include a slight excess of multiple myeloma and myeloid leukaemia,[14] as well as some developmental effects such as disturbed development of teeth[23] and excess of girls born to fathers who were exposed as children.[30] Several other long-term effects have been suspected, but the evidence is not very strong.[4]
  • In Vienna, two women were poisoned at their workplace in 1998, and the measured concentrations in one of them were the highest ever measured in a human being, 144,000 pg/g of fat. This is about one hundred thousandfold compared with TCDD concentrations in most people today, and about ten thousandfold compared with the sum of all dioxin-like compounds in young people today. She survived but suffered from difficult chloracne for several years. Aside from malaise and amenorrhea there were surprisingly few other symptoms or abnormal laboratory findings.[31]
  • In 2004, then-presidential candidate Viktor Yushchenko of Ukraine was poisoned with a large dose of TCDD. His blood TCDD concentration was measured 108,000 pg/g of fat,[32] which is the second highest ever measured. This concentration implies a dose exceeding 2 mg, or 25 μg/kg body weight. Also he suffered from chloracne for many years, but again after initial malaise, other symptoms or abnormal laboratory findings were few.[32]

Long-term effects in humans

The Expert Group of the World Health Organization considered developmental toxicity as the most pertinent risk of dioxins to human beings.[33] Because people are usually exposed simultaneously to a number of dioxin-like chemicals, more detailed account is given at dioxins and dioxin-like compounds.

Cancer in humans

TCDD was classified in 1997 by the International Agency for Research on Cancer as a carcinogen for humans (group 1).[34] In the occupational cohort studies available for the classification, the risk, even at very high exposures, was weak and borderline detectable.[15][27] Therefore human data were not deemed sufficient, and the classification was, in essence, based on animal experiments and mechanistic considerations.[34] This has been criticized as a deviation from IARC classification rules.[35] It is much debated, whether TCDD is carcinogenic only at high doses which also cause toxic damage of tissues.[11][12][26] Moreover, a recent review concludes that, after 1997, further studies do not support an association between TCDD exposure and cancer risk.[36] New studies include the update of Vietnam veteran studies from Ranch Hand operation, which concluded that after 30 years the results do not provide evidence of disease.[37]

There is also direct epidemiological evidence that TCDD is not carcinogenic at low doses, and in some studies cancer risk has even decreased.[38] This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk.[39]

See also

References

  1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "dioxin". doi:10.1351/goldbook.D01750
  2. ^ Shiu WY; et al. (1988). "Physical-chemical properties of chlorinated dibenzo-p-dioxins". Environ Sci Technol. 22: 651. doi:10.1021/es00171a006. {{cite journal}}: Explicit use of et al. in: |author= (help)
  3. ^ a b Schecter A, Birnbaum L, Ryan JJ, Constable JD (2006). "Dioxins: an overview". Environ. Res. 101 (3): 419–28. Bibcode:2006ER....101..419S. doi:10.1016/j.envres.2005.12.003. PMID 16445906.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b M.H. Sweeney, P. Mocarelli (2000). "Human health effects after exposure to 2,3,7,8- TCDD". Food Addit. Contam. 17 (4): 303–316. doi:10.1080/026520300283379. PMID 10912244.
  5. ^ L. Poellinger. Mechanistic aspects – the dioxin (aryl hydrocarbon) receptor (2000). "Mechanistic aspects—the dioxin (aryl hydrocarbon) receptor". Food Additives and Contaminants. 17 (4): 261–266. doi:10.1080/026520300283333. PMID 10912240.
  6. ^ a b P.K. Mandal. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. Journbal of Comparative Physiology B 2005:175:221-230.
  7. ^ a b c d e f J. Lindén, S. Lensu, J. Tuomisto, R. Pohjanvirta. (2010). "Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. A review". Frontiers in Neuroendocrinology. 31 (4): 452–478. doi:10.1016/j.yfrne.2010.07.002. PMID 20624415.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Tijet, N., Boutros, P. C., Moffat, I. D., et al. Aryl (2006). "Hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries". Molecular Pharmacology. 69 (1): 140–153. doi:10.1124/mol.105.018705. PMID 16214954.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b c Okey, A. B. (2007). "An aryl hydrocarbon receptor odyssey to the shores of toxicology: The Deichmann lecture, International congress of toxicology-XI". Toxicological Sciences. 98: 5–38.
  10. ^ S. Mandlekar, J. Hong, A.T. Kong. Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects. Current Drug metabolism. 2006:7:661-675.
  11. ^ a b c d e Y.P. Dragan, D. Schrenk (2000). "Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion". Food Additives and Contaminants. 17 (4): 289–302. doi:10.1080/026520300283360. PMID 10912243.
  12. ^ a b M. Viluksela; et al. (2000). "Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD resistant rat strains". Cancer Res. 60 (24): 6911–6920. PMID 11156390. {{cite journal}}: Explicit use of et al. in: |author= (help)
  13. ^ Knerr S, Schrenk D: Carcinogenicity of 2,3,7,8-tetrachlorodibenzo- p-dioxin in experimental models. Mol Nutr Food Res 2006, 50:897-907.
  14. ^ a b Angela Cecilia Pesatori, Dario Consonni, Maurizia Rubagotti, Paolo Grillo and Pier Alberto Bertazzi (2009). "Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up". Environmental Health. 8: 39. doi:10.1186/1476-069X-8-39. PMC 2754980. PMID 19754930.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  15. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/0140-6736(91)91898-5, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/0140-6736(91)91898-5 instead.
  16. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/es00003a015, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/es00003a015 instead.
  17. ^ A. Poland, J.C. Knutson (1982). "2,3,7,8-Tetrachlorodibenzo-P-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity". Annu. Rev. Pharmacol. Toxicol. 22: 517–554. doi:10.1146/annurev.pa.22.040182.002505. PMID 6282188.
  18. ^ a b c d R. Pohjanvirta, J. Tuomisto, (1994). "Short-term toxicity of 2,3,7,8-tetrachlorodibenzop-dioxin in laboratory animals: effects, mechanisms, and animal models". Pharmacol. Rev. 46 (4): 483–549. PMID 7899475.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  19. ^ a b L.S. Birnbaum, J. Tuomisto (2000). "Non-carcinogenic effects of TCDD in animals". Food Addit. Contam. 17 (4): 275–288. doi:10.1080/026520300283351. PMID 10912242.
  20. ^ T.A. Mably, D.L. Bjerke, R.W. Moore, A. Gendron-Fitzpatrick, R.E. Peterson (1992). "In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-pdioxin. 3. Effects on spermatogenesis and reproductive capability". Toxicol. Appl. Pharmacol. 114 (1): 118–126. doi:10.1016/0041-008X(92)90103-Y. PMID 1585364.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ L.E. Gray, J.S. Ostby, W.R. Kelce (1997). "A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long Evans Hooded rat offspring". Toxicol. Appl. Pharmacol. 146 (1): 11–20. doi:10.1006/taap.1997.8223. PMID 9299592.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ H. Kattainen; et al. (2001). "In utero/lactational 2,3,7,8- tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats". Toxicol. Appl. Pharmacol. 174 (3): 216–224. doi:10.1006/taap.2001.9216. PMID 11485382. {{cite journal}}: Explicit use of et al. in: |author= (help)
  23. ^ a b S. Alaluusua; et al. (2004). "Developmental dental aberrations after the dioxin accident in Seveso". Environ. Health Perspect. 112 (13): 1313–1318. doi:10.1289/ehp.6920. PMC 1247522. PMID 15345345. {{cite journal}}: Explicit use of et al. in: |author= (help)
  24. ^ S. Alaluusua, P.L. Lukinmaa, J. Torppa, J. Tuomisto, T. Vartiainen (1999). "Developing teeth as biomarker of dioxin exposure". Lancet. 353 (9148): 206. doi:10.1016/S0140-6736(05)77214-7. PMID 9923879.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ R.J. Kociba; et al. (1978). "Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8- tetrachlorodibenzo-p-dioxin in rats". Toxicol. Appl. Pharmacol. 46 (2): 279–303. doi:10.1016/0041-008X(78)90075-3. PMID 734660. {{cite journal}}: Explicit use of et al. in: |author= (help)
  26. ^ a b Nigel J. Walker, Michael E. Wyde, Lawrence J. Fischer, Abraham Nyska and John R. Bucher. Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats. Mol. Nutr. Food Res. 2006, 50, 934 – 944.
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  28. ^ H.C. Pitot III, Y.P. Dragan. Chemical carcinogenesis. In Casarett & Doull's Toxicology (ed. C.D. Klaassen), 6th ed., pp. 201-267, McGraw-Hill, New York 2001. ISBN 0-07-134721-6.
  29. ^ P. Mocarelli; et al. (1991). "Serum concentrations of 2,3,7,8- tetrachlorodibenzo-p-dioxin and test results from selected residents of Seveso, Italy". J. Toxicol. Environ. Health. 32 (4): 357–366. doi:10.1080/15287399109531490. PMID 1826746. {{cite journal}}: Explicit use of et al. in: |author= (help)
  30. ^ P. Mocarelli; et al. (2000). "Paternal concentrations of dioxin and sex ratio of offspring". Lancet. 355 (9218): 1858–1863. doi:10.1016/S0140-6736(00)02290-X. PMID 10866441. {{cite journal}}: Explicit use of et al. in: |author= (help)
  31. ^ A. Geusau, K. Abraham, K. Geissler, M.O. Sator, G. Stingl, E. Tschachler, (2001). "Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects". Environ. Health Perspect. 109 (8): 865–869. doi:10.1289/ehp.01109865. PMC 1240417. PMID 11564625.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  32. ^ a b Sorg, R.; Zennegg, M.; Schmid, P.; Fedosyuk, R; Valikhnovskyi, R.; Gaide, O.; Kniazevych, V.; Saurat, J.-H. (2009). "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites". The Lancet. 374 (9696): 1179–1185. doi:10.1016/S0140-6736(09)60912-0. PMID 19660807. {{cite journal}}: More than one of |first1= and |first= specified (help)
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  34. ^ a b International Agency for Research on Cancer (IARC). Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 69, Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans, 1997, Lyon, IARC
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  38. ^ J.T. Tuomisto, J. Pekkanen, H. Kiviranta, E. Tukiainen, T. Vartiainen, J. Tuomisto (2004). "Soft-tissue sarcoma and dioxin: a case-control study". Int. J. Cancer. 108 (6): 893–900. doi:10.1002/ijc.11635. PMID 14712494.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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