2,3,7,8-Tetrachlorodibenzodioxin

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
Abbreviations TCDD; TCDBD
1746-01-6 Yes
ChEBI CHEBI:28119 Yes
ChEMBL ChEMBL30327 Yes
ChemSpider 14865 Yes
Jmol-3D images Image
KEGG C07557 Yes
PubChem 15625
UNII DO80M48B6O 
Properties
C
12H
4Cl
4O
2
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
Main hazards carcinogen, teratogen[3]
EU classification T+
R-phrases R26/27/28 R45
S-phrases S36/37 S62
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
4
0
Flash point 164.2 °C (327.6 °F; 437.3 K)
US health exposure limits (NIOSH):
none[3]
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
Infobox references

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (sometimes shortened, though inaccurately, to simply "dioxin") with the chemical formula C
12H
4Cl
4O
2. TCDD is a colorless solid with no distinguishable odor at room temperature. It is usually formed as a side product in organic synthesis and burning of organic materials.

TCDD is the most potent compound (congener) of its series (polychlorinated dibenzodioxins, known as PCDDs or simply dioxins) and became known as a contaminant in Agent Orange, a herbicide used in the Vietnam War.[4] TCDD was released into the environment in the Seveso disaster.[5] It is a persistent environmental contaminant usually present in a complex mixture of dioxin-like compounds, and is a carcinogen.[6]

Health effects

The Expert Group of the World Health Organization considered developmental toxicity as the most pertinent risk of dioxins to human beings.[7] Because people are usually exposed simultaneously to a number of dioxin-like chemicals, a more detailed account is given at dioxins and dioxin-like compounds.

Cancer

TCDD was classified in 1997 by the International Agency for Research on Cancer as a carcinogen for humans (group 1).[6] In the occupational cohort studies available for the classification, the risk, even at very high exposures, was weak and borderline detectable.[8][9] Therefore human data were not deemed sufficient, and the classification was, in essence, based on animal experiments and mechanistic considerations.[6] This has been criticized as a deviation from IARC classification rules.[10] It is much debated, whether TCDD is carcinogenic only at high doses which also cause toxic damage of tissues.[11][12][13] Moreover, a recent review concludes that, after 1997, further studies do not support an association between TCDD exposure and cancer risk.[14] 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.[15]

There is also direct epidemiological evidence that TCDD is not carcinogenic at low doses, and in some studies cancer risk has even decreased.[16] This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk.[17]

Mechanism of action

TCDD and dioxin-like compounds act via a specific receptor present in all cells: the aryl hydrocarbon (AH) receptor.[18][19][20] 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.[21] 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.[22]

These polycyclic hydrocarbons also activate the AH receptor, but less than TCDD and only temporarily.[22] Even many natural compounds present in vegetables cause some activation of the AH receptor.[23] 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.[22]

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.[20] In fact, knock-out animals with no AH receptor are quite sick and develop poorly.[20] All this implies that a certain level of AH receptor activation is physiological and necessary for the body.

While the mutagenic and genotoxic effects of TCDD are sometimes disputed[11] and sometimes confirmed[24] it does foster the development of cancer. 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][25] 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.[26]

Teratogenic effects

In Vietnam and the USA teratogenic or birth defects were observed on children of persons that were exposed to Agent Orange or 2,4,5-T that contained TCDD as an impurity out of the production process. A meta-analysis of 22 studies from 1966 to 2002 was published 2006 in the International Journal of Epidemiology and concluded that "Parental exposure to Agent Orange appears to be associated with an increased risk of birth defects."[27]

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.[8] 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).[28]

The greatest production occurs from waste incineration, metal production, and fossil-fuel and wood combustion.[29] Total US emissions of PCCD/Fs were reduced from ca. 14 kg TEq in 1987 to 1.4 kg TEq in 2000.[30]

Other animals

By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing TCDD.[4][20][31][32] Almost all organs are affected 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.[32] Seemingly similar species have varying sensitivities 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.[32] 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.[20][32] 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.[20]

Developmental effects

Developmental effects occur at very low doses in animals. They include frank teratogenicity such as cleft palate and hydronephrosis.[33] Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents,[33][34][35] and the development of teeth in rats.[36] The latter is important in that tooth deformities were also seen after the Seveso accident[37] and possibly after a long breast-feeding of babies in the 1970s and 1980s when the dioxin concentrations in Europe were about ten times higher than at present.[38]

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.[39] Dose-response of TCDD in causing cancer does not seem to be linear,[13] 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.[9][19] 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 in 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.[40]

Cases of exposure

Viktor Yushchenko with chloracne after his TCDD poisoning incident

There have been a number of incidents where people have been exposed to high doses of TCDD or with a combination of TCDD and other dioxin-like chemicals, including:

See also

References

  1. ↑ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "dioxin".
  2. ↑ Shiu WY et al. (1988). "Physical-chemical properties of chlorinated dibenzo-p-dioxins". Environ Sci Technol 22 (6): 651–658. Bibcode:1988EnST...22..651S. doi:10.1021/es00171a006.
  3. ↑ 3.0 3.1 "NIOSH Pocket Guide to Chemical Hazards #0594". National Institute for Occupational Safety and Health (NIOSH).
  4. ↑ 4.0 4.1 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.
  5. ↑ 5.0 5.1 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.
  6. ↑ 6.0 6.1 6.2 International Agency for Research on Cancer (1997). Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans. Monographs on the Evaluation of Carcinogenic Risks to Humans 69. Lyon: IARC. ISBN 92-832-1269-X.
  7. ↑ "Consultation on assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI): Executive summary". Food Additives & Contaminants 17 (4): 223–240. 2000. doi:10.1080/713810655. PMID 10912238.
  8. ↑ 8.0 8.1 Saracci, R.; Kogevinas, M.; Winkelmann, R.; Bertazzi, P. A.; Bueno De Mesquita, B. H.; Coggon, D.; Green, L. M.; Kauppinen, T.; l'Abbé, K. A.; Littorin, M.; Lynge, E.; Mathews, J. D.; Neuberger, M.; Osman, J.; Pearce, N. (1991). "Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols". The Lancet 338 (8774): 1027. doi:10.1016/0140-6736(91)91898-5.
  9. ↑ 9.0 9.1 Schwarz M, Appel KE (October 2005). "Carcinogenic risks of dioxin: mechanistic considerations". Regul. Toxicol. Pharmacol. 43 (1): 19–34. doi:10.1016/j.yrtph.2005.05.008. PMID 16054739.
  10. ↑ Cole P, Trichopoulos D, Pastides H, Starr T, Mandel JS (December 2003). "Dioxin and cancer: a critical review". Regul. Toxicol. Pharmacol. 38 (3): 378–88. doi:10.1016/j.yrtph.2003.08.002. PMID 14623487.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 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. ↑ 12.0 12.1 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): 6911–20. PMID 11156390.
  13. ↑ 13.0 13.1 Walker NJ, Wyde ME, Fischer LJ, Nyska A, Bucher JR (October 2006). "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 50 (10): 934–44. doi:10.1002/mnfr.200600031. PMC 1934421. PMID 16977594.
  14. ↑ Boffetta P, Mundt KA, Adami HO, Cole P, Mandel JS (August 2011). "TCDD and cancer: a critical review of epidemiologic studies". Crit. Rev. Toxicol. 41 (7): 622–36. doi:10.3109/10408444.2011.560141. PMC 3154583. PMID 21718216.
  15. ↑ Buffler PA, Ginevan ME, Mandel JS, Watkins DK (September 2011). "The Air Force health study: an epidemiologic retrospective". Ann Epidemiol 21 (9): 673–87. doi:10.1016/j.annepidem.2011.02.001. PMID 21441038.
  16. ↑ 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.
  17. ↑ Tuomisto, J. et al. (2005). "Dioxin cancer risk –example of hormesis?". Dose-response : a publication of International Hormesis Society 3 (3): 332–341. doi:10.2203/dose-response.003.03.004. PMC 2475943. PMID 18648613.
  18. ↑ L. Poellinger. Mechanistic aspects – the dioxin (aryl hydrocarbon) receptor (2000). "Mechanistic aspects—the dioxin (aryl hydrocarbon) receptor.". Food Additives and Contaminants 17 (4): 261–6. doi:10.1080/026520300283333. PMID 10912240.
  19. ↑ 19.0 19.1 Mandal PK (May 2005). "Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology". J. Comp. Physiol. B, Biochem. Syst. Environ. Physiol. 175 (4): 221–30. doi:10.1007/s00360-005-0483-3. PMID 15900503.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 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.
  21. ↑ Tijet, N., Boutros, P. C., Moffat, I. D. Aryl et al. (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.
  22. ↑ 22.0 22.1 22.2 Okey AB (July 2007). "An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI". Toxicol. Sci. 98 (1): 5–38. doi:10.1093/toxsci/kfm096. PMID 17569696.
  23. ↑ Mandlekar S, Hong JL, Kong AN (August 2006). "Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects". Curr. Drug Metab. 7 (6): 661–75. doi:10.2174/138920006778017795. PMID 16918318.
  24. ↑ "Mutagenic and genotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a review.". Mutat Res 168 (3): 241–8. Nov 1986. doi:10.1016/0165-1110(86)90022-9. PMID 3540643.
  25. ↑ Knerr S, Schrenk D (October 2006). "Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models". Mol Nutr Food Res 50 (10): 897–907. doi:10.1002/mnfr.200600006. PMID 16977593.
  26. ↑ 26.0 26.1 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 (1): 39. doi:10.1186/1476-069X-8-39. PMC 2754980. PMID 19754930.
  27. ↑ Ngo A. D., Taylor R., Roberts C. L., Nguyen T. V. (October 2006). "Association between Agent Orange and birth defects: systematic review and meta-analysis". International Journal of Epidemiology 35 (5): 1220–1230. doi:10.1093/ije/dyl038. PMID 16543362.
  28. ↑ Harnly, M.; Stephens, R.; McLaughlin, C.; Marcotte, J.; Petreas, M.; Goldman, L. (1995). "Polychlorinated Dibenzo-p-dioxin and Dibenzofuran Contamination at Metal Recovery Facilities, Open Burn Sites, and a Railroad Car Incineration Facility". Environmental Science & Technology 29 (3): 677. doi:10.1021/es00003a015.
  29. ↑ DHHS: Report on Carcinogens, Twelfth Edition (2011) (accessed 2013-08-01)
  30. ↑ Jouko Tuomisto &al.: Synopsis on Dioxins and PCBs (accessed 2013-08-01), p.40; using data from EPA's National Center for Environmental Assessment
  31. ↑ 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 (1): 517–554. doi:10.1146/annurev.pa.22.040182.002505. PMID 6282188.
  32. ↑ 32.0 32.1 32.2 32.3 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.
  33. ↑ 33.0 33.1 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 37.0 37.1 S. Alaluusua et al. (2004). "Developmental dental aberrations after the dioxin accident in Seveso". Environ. Health Perspect. 112 (13): 1313–8. doi:10.1289/ehp.6920. PMC 1247522. PMID 15345345.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ Pitot III, H.C.; Dragan, Y.P. (2001). "Chemical carcinogenesis". In Klaassen, C.D. Casarett & Doull's Toxicology: the basic science of poisons (6th ed.). New York: McGraw-Hill. pp. 201–267. ISBN 0-07-134721-6.
  41. ↑ 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.
  42. ↑ P. Mocarelli et al. (2000). "Paternal concentrations of dioxin and sex ratio of offspring". Lancet 355 (9218): 1858–63. doi:10.1016/S0140-6736(00)02290-X. PMID 10866441.
  43. ↑ 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): 865–9. doi:10.1289/ehp.01109865. PMC 1240417. PMID 11564625.
  44. ↑ 44.0 44.1 Sorg, O.; 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): 1179–85. doi:10.1016/S0140-6736(09)60912-0. PMID 19660807.
  45. ↑ "Italian "Triangle of death" linked to waste crisis.". Lancet Oncol 5 (9): 525–7. Sep 2004. doi:10.1016/s1470-2045(04)01561-x. PMID 15384216.
  46. ↑ "Il triangolo della morte". rassegna.it. March 2007. Retrieved 2008-09-26.
  47. ↑ "Discariche piene di rifiuti tossici quello è il triangolo della morte". la Repubblica. 2004-08-31. Retrieved 2008-09-26.

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