2,3,7,8-Tetrachlorodibenzodioxin

2,3,7,8-Tetrachlorodibenzodioxin
Identifiers
Abbreviations TCDD; TCDBD
CAS number 1746-01-6 Y
PubChem 15625
ChemSpider 14865 Y
KEGG C07557 Y
ChEBI CHEBI:28119 Y
ChEMBL CHEMBL30327 Y
Jmol-3D images Image 1
Properties
Molecular formula C12H4Cl4O2
Molar mass 321.97 g/mol
Density 1.8 g cm−3
Melting point

305 °C, 578 K, 581 °F

Solubility in water 0.2 µg/L at 25 °C[2]
log P 6.8
Vapor pressure 1.5 × 10−9 mmHg
Hazards
NFPA 704
1
4
0
Flash point 164.2 °C
 Y (verify) (what is: Y/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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.

Contents

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]

Also these polycyclic hydrocarbons 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. 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).

Toxic effects in animal studies

By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing 2,3,7,8-TCDD.[3][7][15][16] 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.[16] 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.[16] 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][16] 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.[17] Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents,[17][18][19] and the development of teeth in rats.[20] The latter is important in that tooth deformities were also seen after the Seveso accident[21] 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.[22]

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.[23] Dose-response of TCDD in causing cancer does not seem to be linear,[24] 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][25] 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.[26]

Cases of poisoning

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

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.[31] 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).[32] In the occupational cohort studies available for the classification, the risk, even at very high exposures, was weak and borderline detectable.[25] Therefore human data were not deemed sufficient, and the classification was, in essence, based on animal experiments and mechanistic considerations.[32] This has been criticized as a deviation from IARC classification rules.[33] It is much debated, whether TCDD is carcinogenic only at high doses which also cause toxic damage of tissues.[11][12][24] Moreover, a recent review concludes that, after 1997, further studies do not support an association between TCDD exposure and cancer risk.[34] 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.[35]

There is also direct epidemiological evidence that TCDD is not carcinogenic at low doses, and in some studies cancer risk has even decreased.[36] This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk.[37]

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: 651. doi:10.1021/es00171a006. 
  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. 
  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. 
  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. 
  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. 
  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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2754980. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1247522. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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.
  25. ^ a b M. Schwarz, K.E. Appel. Carcinogenic risks of dioxin: Mechanistic considerations. Regulatory Toxicology and Pharmacology. 2005:43:19-34-
  26. ^ 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.
  27. ^ 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. 
  28. ^ 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. 
  29. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1240417. 
  30. ^ a b 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): 1179–1185. doi:10.1016/S0140-6736(09)60912-0. PMID 19660807. 
  31. ^ "Consultation on assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI): Executive summary". Food Additives & Contaminants 17: 223–240. 2000. doi:10.1080/713810655. 
  32. ^ 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
  33. ^ P. Cole et al. Dioxin and cancer: A critical review. Regulatory Toxicology and Pharmacology 2003:38:378-388.
  34. ^ P. Boffetta, K.A. Mundt, H-O. Adami, P. Cole, J.S. Mandel. TCDD and cancer: A critical review of epidemiological studies. Critical Reviews in Toxicology 2011:41:622-636.
  35. ^ P.A. Buffler, M.E. Ginevan, J.S. Mandel, D.K. Watkins. The Air Force health study: An epidemiologic retsrospective. Annals of Epidemiology 2011:21:673-687.
  36. ^ 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. 
  37. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2475943. 

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