2,3,7,8-Tetrachlorodibenzodioxin

Polychlorinated dibenzo-p-dioxin, chemical compound Dioxins and dioxin-like compounds September 2019 changed changed 477210210 2,3,7,8-tetrachlorodibenzo(b,e)(1,4)dioxine 200.svg skin-invert-image Dioxin-3D-Ball-and-Stick.png bg-transparent Dioxin-3D-vdW.png bg-transparent 2,3,7,8-Tetrachlorooxanthrene 2,3,7,8-Tetrachlorodibenzo[b,e][1,4]dioxineTetradioxinTetrachlorodibenzodioxinTetrachlorodibenzo-p-dioxin TCDD; TCDBD changed FDA DO80M48B6O correct chemspider correct EBI 28119 14865 correct kegg C07557 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 HGUFODBRKLSHSI-UHFFFAOYAA correct EBI 30327 correct chemspider 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 correct chemspider HGUFODBRKLSHSI-UHFFFAOYSA-N correct CAS 1746-01-6 15625 ClC1=C(Cl)C=C2OC(C=C(C(Cl)=C3)Cl)=C3OC2=C1 12 4 4 2 Colorless to white crystalline solid 1.8 g/cm3 305 0.2 μg/L10.1021/es00171a006 Shiu WY 53459209 Physical-chemical properties of chlorinated dibenzo-p-dioxins Environ Sci Technol 22 651–658 1988 1988EnST...22..651S 6 etal 6.8 1.5 × 10−9 mmHg MSDS 02 06 08 09 DANGER 225 304 315 336 361 373 401 410 201 202 210 233 240 241 242 243 260 264 271 273 280 301+310 303+361+353 304+340+312 308+313 331 332+313 362+364 370+378 391 403+233 403+235 405 501 4 1 0 201 μg/kg (oral, rat)120 μg/kg (intraperitoneal, mouse)https://www.t3db.ca/toxins/T3D0073 2,3,7,8-Tetrachlorodibenzo-p-dioxin (T3D0073) 5 September 2026 24 December 2014 T3DB Potent carcinogen and persistent organic pollutant. 164.2 none0594 N.D. Ca 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (sometimes shortened, though inaccurately, to simply dioxin) 10.15347/wjm/2019.008 free Dioxins and dioxin-like compounds: Toxicity in humans and animals, sources, and behaviour in the environment 2019 Tuomisto Jouko WikiJournal of Medicine 6 8 with the chemical formula C12H4Cl4O2. Pure TCDD is a colorless solid with no distinguishable odor at room temperature. It is usually formed as an unwanted product in burning processes of organic materials or as a side product in organic synthesis. 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, an herbicide used in the Vietnam War.Schecter A, Birnbaum L, Ryan JJ, Constable JD Dioxins: an overview Environ. Res. 101 3 419–28 2006 16445906 10.1016/j.envres.2005.12.003 2006ER....101..419S TCDD was released into the environment in the Seveso disaster.10.1080/026520300283379 M.H. Sweeney P. Mocarelli Human health effects after exposure to 2,3,7,8- TCDD Food Addit. Contam. 17 4 2000 303–316 10912244 11814994 It is a persistent organic pollutant. Biological activity in humans and animals TCDD and dioxin-like compounds act via a specific receptor present in all cells: the aryl hydrocarbon (AH) receptor.10.1080/026520300283333 L. Poellinger Mechanistic aspects—the dioxin (aryl hydrocarbon) receptor. Food Additives and Contaminants 17 4 2000 261–6 10912240 22295283 Mandal PK Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology J. Comp. Physiol. B 175 4 221–30 May 2005 15900503 10.1007/s00360-005-0483-3 20508397 10.1016/j.yfrne.2010.07.002 J. Lindén S. Lensu J. Tuomisto R. Pohjanvirta. Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. A review. Frontiers in Neuroendocrinology 31 4 2010 452–478 20624415 34036181 This receptor is a transcription factor which is involved in the expression of genes; it has been shown that high doses of TCDD either increase or decrease the expression of several hundred genes in rats.Tijet N, Boutros PC, Moffat ID 1913812 Hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries Molecular Pharmacology 69 1 2006 140–153 16214954 10.1124/mol.105.018705 etal These genes include the genes of enzymes responsible for the breakdown of foreign and often toxic compounds. Through the process of enzyme induction, TCDD increases the activation of enzymes responsible for breaking down carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene.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 10.1093/toxsci/kfm096 17569696 free These polycyclic hydrocarbons also activate the AH receptor, but less than TCDD and only temporarily. Even many natural compounds present in vegetables cause some activation of the AH receptor.Mandlekar S, Hong JL, Kong AN Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects Curr. Drug Metab. 7 6 661–75 August 2006 16918318 10.2174/138920006778017795DeGroot Danica He Guochun Fraccalvieri Domenico Bonati Laura Pandini Allesandro Denison Michael S. The AH Receptor in Biology and Toxicology 2011 John Wiley & Sons, Ltd 9781118140574 63–79 en AHR Ligands: Promiscuity in Binding and Diversity in Response 10.1002/9781118140574.ch4 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. The physiological function of the AH receptor has been the subject of continuous research.Rothhammer V Quintana FJ The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nature Reviews. Immunology March 2019 19 3 184–197 10.1038/s41577-019-0125-8 30718831 59603271 One obvious function is to increase the activity of enzymes breaking down foreign chemicals or normal chemicals of the body as needed. There seem to be many other functions, however, related to the development of various organs and the immune systems or other regulatory functions. The AH receptor is phylogenetically highly conserved, with a history of at least 600 million years, and is found in all vertebrates. Its ancient analogs are important regulatory proteins even in more primitive species. In fact, knock-out animals with no AH receptor are prone to illness and developmental problems. Taken together, this implies the necessity of a basal degree of AH receptor activation to achieve normal physiological function. Toxicity in humans In 2000, the Expert Group of the World Health Organization considered developmental toxicity as the most pertinent risk of dioxins to human beings.Consultation on assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI): Executive summary Food Additives & Contaminants 17 2000 223–240 10.1080/713810655 10912238 4 216644694 Because people are usually exposed simultaneously to several dioxin-like chemicals, a more detailed account is given at dioxins and dioxin-like compounds. Developmental effects In Vietnam and the United States, teratogenic or birth defects were observed in children of people who were exposed to Agent Orange or 2,4,5-T that contained TCDD as an impurity out of the production process. However, there has been some uncertainty on the causal link between Agent Orange/dioxin exposure. In 2006, a meta-analysis indicated large amount of heterogeneity between studies and emphasized a lack of consensus on the issue. 10.1093/ije/dyl038 16543362 Association between Agent Orange and birth defects: Systematic review and meta-analysis International Journal of Epidemiology 35 5 1220–1230 2006 Ngo Anh D Taylor Richard Roberts Christine L Nguyen Tuan V dmy-all free Stillbirths, cleft palate, and neural tube defects, with spina bifida were the most statistically significant defects. Later some tooth defects and borderline neurodevelopmental effects have been reported. After the Seveso accident, tooth development defects, changed sex ratio and decreased sperm quality have been noted. Various developmental effects have been clearly shown after high mixed exposures to dioxins and dioxin-like compounds, the most dramatic in Yusho and Yu-chen catastrophes, in Japan and Taiwan, respectively. Cancer It is largely agreed that TCDD is not directly mutagenic or genotoxic.10.1080/026520300283360 Y.P. Dragan D. Schrenk Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion Food Additives and Contaminants 17 4 2000 289–302 10912243 24500449 Its main action 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.M. Viluksela Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD resistant rat strains Cancer Res. 60 2000 24 6911–620 11156390 etal There are other explanations such as endocrine disruption or altered signal transduction.Knerr S, Schrenk D Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models Mol Nutr Food Res 50 10 897–907 October 2006 16977593 10.1002/mnfr.200600006 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.Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up Angela Cecilia Pesatori Dario Consonni Maurizia Rubagotti Paolo Grillo Pier Alberto Bertazzi Environmental Health 2009 8 39 10.1186/1476-069X-8-39 19754930 2754980 1 2009EnvHe...8...39P free TCDD was classified by the International Agency for Research on Cancer (IARC) as a carcinogen for humans (group 1).International Agency for Research on Cancer Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans IARC Lyon 1997 978-92-832-1269-0 http://monographs.iarc.fr/ENG/Monographs/vol69/index.php 69 Monographs on the Evaluation of Carcinogenic Risks to Humanshttps://www.ncbi.nlm.nih.gov/books/NBK304398/ 2,3,7,8-tetrachlorodibenzopara-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl IARC Working Group on the Evaluation of Carcinogenic Risk to Humans 2012 International Agency for Research on Cancer 100F 339–378 en In the occupational cohort studies available for the classification, the risk was weak and borderline detectable, even at very high exposures.Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins Am J Epidemiol 1997 145 12 1061–1075 10.1093/oxfordjournals.aje.a009069 9199536 free Therefore, the classification was, in essence, based on animal experiments and mechanistic considerations. This was criticized as a deviation from IARC's 1997 classification rules.Cole P, Trichopoulos D, Pastides H, Starr T, Mandel JS Dioxin and cancer: a critical review Regul. Toxicol. Pharmacol. 38 3 378–388 December 2003 14623487 10.1016/j.yrtph.2003.08.002 The main problem with IARC classification is that it only assesses qualitative hazard, i.e. carcinogenicity at any dose, and not the quantitative risk at different doses. According to a 2006 Molecular Nutrition & Food Research article, there were debates on whether TCDD was carcinogenic only at high doses which also cause toxic damage of tissues.Walker NJ, Wyde ME, Fischer LJ, Nyska A, Bucher JR 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 10 934–944 October 2006 16977594 1934421 10.1002/mnfr.200600031 A 2011 review concluded that, after 1997, further studies did not support an association between TCDD exposure and cancer risk.Boffetta P, Mundt KA, Adami HO, Cole P, Mandel JS TCDD and cancer: a critical review of epidemiologic studies Crit. Rev. Toxicol. 41 7 622–636 August 2011 21718216 3154583 10.3109/10408444.2011.560141 One of the problems is that in all occupational studies the subjects have been exposed to a large number of chemicals, not only TCDD. By 2011, it was reported that studies that include the update of Vietnam veteran studies from Operation Ranch Hand, had concluded that after 30 years the results did not provide evidence of disease.Buffler PA, Ginevan ME, Mandel JS, Watkins DK The Air Force health study: an epidemiologic retrospective Ann Epidemiol 21 9 673–687 September 2011 21441038 10.1016/j.annepidem.2011.02.001 On the other hand, the latest studies on Seveso population support TCDD carcinogenicity at high doses.Warner M Mocarelli P Samuels S Needham L Brambilla P Eskenazi B Dioxin exposure and cancer risk in the Seveso Women's Health Study. Environmental Health Perspectives December 2011 119 12 1700–1705 10.1289/ehp.1103720 21810551 3261987 2011EnvHP.119.1700W In 2004, an article in the International Journal of Cancer provided some direct epidemiological evidence that TCDD or other dioxins are not causing soft-tissue sarcoma at low doses, although this cancer has been considered typical for dioxins. There was in fact a trend of cancer to decrease.10.1002/ijc.11635 J.T. Tuomisto J. Pekkanen H. Kiviranta E. Tukiainen T. Vartiainen J. Tuomisto Soft-tissue sarcoma and dioxin: a case-control study Int. J. Cancer 108 6 2004 893–900 14712494 free This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk, according to a 2005 article in the journal Dose-Response.Tuomisto, J. Dioxin cancer risk –example of hormesis? Dose-Response 18648613 3 3 2005 332–341 2475943 10.2203/dose-response.003.03.004 etal Safety recommendations The Joint FAO/WHO Expert Committee on Food Additives (JECFA) derived in 2001 a provisional tolerable monthly intake (PTMI) of 70 pg TEQ/kg body weight. Malisch R, Kotz A 2014 Dioxins and PCBs in feed and food – review from European perspective. The Science of the Total Environment 491 2–10 10.1016/j.scitotenv.2014.03.022 24804623 2014ScTEn.491....2M The United States Environmental Protection Agency (EPA) established an oral reference dose (RfD) of 0.7 pg/kg b.w. per day for TCDDhttps://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=222203 https://web.archive.org/web/20100702143633/http://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=222203 dead 2 July 2010 EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments (External Review Draft) US EPA National Center for Environmental Assessment, Cincinnati Oh Rice Glenn cfpub.epa.gov en 2019-12-16 (see discussion on the differences in). According to the Aspen Institute, in 2011:The general environmental limit in most countries is 1,000 ppt TEq in soils and 100 ppt in sediment. Most industrialized countries have dioxin concentrations in soils of less than 12 ppt. The U.S. Agency for Toxic Substance and Disease Registry has determined that levels higher than 1,000 ppt TEq in soil require intervention, including research, surveillance, health studies, community and physician education, and exposure investigation. The EPA is considering reducing these limits to 72 ppt TEq. This change would significantly increase the potential volume of contaminated soil requiring treatment. Health Effects The Aspen Institute 23 September 2019 https://www.aspeninstitute.org/programs/agent-orange-in-vietnam-program/health-effects/ August 2011https://www.atsdr.cdc.gov/toxprofiles/tp104-c5.pdf Toxic Substances Portal Animal toxicology By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing TCDD.10.1146/annurev.pa.22.040182.002505 A. Poland J.C. Knutson 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity Annu. Rev. Pharmacol. Toxicol. 22 1982 517–554 6282188 1R. Pohjanvirta J. Tuomisto Short-term toxicity of 2,3,7,8-tetrachlorodibenzop-dioxin in laboratory animals: effects, mechanisms, and animal models Pharmacol. Rev. 46 1994 4 483–549 10.1016/S0031-6997(25)06814-0 7899475 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. 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. 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. 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. Developmental effects Developmental effects occur at very low doses in animals. They include frank teratogenicity such as cleft palate and hydronephrosis.10.1080/026520300283351 L.S. Birnbaum J. Tuomisto Non-carcinogenic effects of TCDD in animals Food Addit. Contam. 17 4 2000 275–288 10912242 45117354 Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents,10.1016/0041-008X(92)90103-Y T.A. Mably D.L. Bjerke R.W. Moore A. Gendron-Fitzpatrick R.E. Peterson 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 1992 118–126 1585364 1992ToxAP.114..118M 10.1006/taap.1997.8223 L.E. Gray J.S. Ostby W.R. Kelce 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 1997 11–20 9299592 1997ToxAP.146...11G https://zenodo.org/record/1229970 and the development of teeth in rats.10.1006/taap.2001.9216 H. Kattainen In utero/lactational 2,3,7,8- tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats Toxicol. Appl. Pharmacol. 174 3 2001 216–224 11485382 2001ToxAP.174..216K etal The latter is important in that tooth deformities were also seen after the Seveso accident10.1289/ehp.6920 S. Alaluusua Developmental dental aberrations after the dioxin accident in Seveso Environ. Health Perspect. 112 13 2004 1313–1318 15345345 1247522 2004EnvHP.112.1313A etal 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.10.1016/S0140-6736(05)77214-7 S. Alaluusua P.L. Lukinmaa J. Torppa J. Tuomisto T. Vartiainen Developing teeth as biomarker of dioxin exposure Lancet 353 1999 206 9923879 9148 31562457 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.10.1016/0041-008X(78)90075-3 R.J. Kociba Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8- tetrachlorodibenzo-p-dioxin in rats Toxicol. Appl. Pharmacol. 46 1978 2 279–303 734660 1978ToxAP..46..279K etal Dose-response of TCDD in causing cancer does not seem to be linear, 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 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.Schwarz M, Appel KE Carcinogenic risks of dioxin: mechanistic considerations Regul. Toxicol. Pharmacol. 43 1 19–34 October 2005 16054739 10.1016/j.yrtph.2005.05.008 Carcinogenicity is associated with tissue damage, and it is often viewed as secondary to tissue damage. 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.H. C. Pitot III Y. P. Dragan Chemical carcinogenesis C. D. Klaassen Casarett & Doull's Toxicology: the basic science of poisons https://archive.org/details/Casarett_Doulls_Toxicology_The_Basic_Science_of_Pns_6th_Edition McGraw-Hill New York 2001 978-0-07-134721-1 201–267 6th 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. 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. 10.1016/0140-6736(91)91898-5 1681353 Littorin M. Lynge E. Mathews J. D. Neuberger M. Osman J. Pearce N. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols The Lancet 338 8774 1027–1032 1991 23115128 It may also be formed along with other polychlorinated dibenzodioxins and dibenzofuranes in any burning of hydrocarbons where chlorine is present, especially if certain metal catalysts such as copper are also present. Harnly M. Stephens R. McLaughlin C. Marcotte J. Petreas M. Goldman L. 10.1021/es00003a015 Polychlorinated Dibenzo-p-dioxin and Dibenzofuran Contamination at Metal Recovery Facilities, Open Burn Sites, and a Railroad Car Incineration Facility Environmental Science & Technology 29 3 677–684 1995 22200276 1995EnST...29..677H Usually a mixture of dioxin-like compounds is produced, therefore a more thorough treatise is under dioxins and dioxin-like compounds. The greatest production occurs from waste incineration, metal production, and fossil-fuel and wood combustion.DHHS: Report on Carcinogens, Twelfth Edition (2011) (accessed 2013-08-01) Dioxin production can usually be reduced by increasing the combustion temperature. Total U.S. emissions of PCCD/Fs were reduced from ca. 14 kg TEq in 1987 to 1.4 kg TEq in 2000.Jouko Tuomisto &al.: Synopsis on Dioxins and PCBs https://web.archive.org/web/20110927215152/http://www.thl.fi/thl-client/pdfs/81322e2c-e9b6-4003-bb13-995dcd1b68cb 27 September 2011 (accessed 2013-08-01), p.40; using data from EPA's National Center for Environmental Assessment History TCDD was first synthesized in the laboratory in 19572008-12-14 ELFIS - Forst- und Holzwirtschaft http://www.bfafh.de/ELFIST/DDW?W=AUTOREN+INC+'sandermann'*&M=12&K=T1+02+40&R=Y&U=1 2024-11-20 https://web.archive.org/web/20081214214306/http://www.bfafh.de/ELFIST/DDW?W=AUTOREN+INC+'sandermann'*&M=12&K=T1+02+40&R=Y&U=1 14 December 2008 by Wilhelm Sandermann, and he also discovered the effects of the compound. Cases of exposure thumb|A photograph of Viktor Yushchenko after he was poisoned with TCDD. TCDD often causes disfiguring skin thickening and pitting. There have been numerous incidents where people have been exposed to high doses of TCDD. In 1953, a thermal runaway accident occurred at BASF during the chlorination of diphenyl oxide, as a result of which several workers developed severe chloracne. Similar cases had occurred 6 years earlier in the US and in 1952, 1954 and 1956 at the Boehringer Ingelheim company.64 1 https://www.ifz-muenchen.de/heftarchiv/2016_1.pdf#page=72 Vierteljahrshefte für Zeitgeschichte de Deutsche Wissenschaftler als Erfinder von "Agent Orange"? 69 German scientists as inventors of “Agent Orange”? 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. Many animals died, and high concentrations of TCDD, up to 56 ng/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.10.1080/15287399109531490 P. Mocarelli 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 1991 357–366 1826746 1991JTEHA..32..357M etal Long-term effects seem to include a slight excess of multiple myeloma and myeloid leukaemia, as well as some developmental effects such as disturbed development of teeth and excess of girls born to fathers who were exposed as children.10.1016/S0140-6736(00)02290-X P. Mocarelli Paternal concentrations of dioxin and sex ratio of offspring Lancet 355 9218 2000 1858–1863 10866441 etal 10281/16136 6353869 https://boa.unimib.it/bitstream/10281/16136/2/sex%20ratio%20lancet%202000.pdf free Several other long-term effects have been suspected, but the evidence is not very strong. In Times Beach, Missouri, several hundred people were poisoned by extremely high concentrations of TCDD by Russell Martin Bliss, who sprayed TCDD-contaminated waste oil on dusty roads to avoid large dust clouds. Bliss himself obtained the waste oil from NEPACCO, a company that produced defoliants and bactericides. No one was ever charged in relation to the incident, and the city of Times Beach was abandoned and disincorporated following an investigation by the CDC and EPA. This is marked as the single largest contamination of a civilian area by TCDD in United States history. In Vienna, two women were poisoned at their workplace in 1997, and the measured concentrations in one of them were the highest ever measured in a human being, 144 ng/g of fat. This is about 100,000 times the concentrations in most people and about 10,000 times the sum of all dioxin-like compounds in young people. They survived but suffered from difficult chloracne for several years. The poisoning likely happened in October 1997 but was not discovered until April 1998. At the institute where the women worked as secretaries, high concentrations of TCDD were found in one of the labs, suggesting that the compound had been produced there. The police investigation failed to find clear evidence of crime, and no one was ever prosecuted. Aside from malaise and amenorrhea there were few other symptoms or abnormal laboratory findings.10.1289/ehp.01109865 A. Geusau K. Abraham K. Geissler M.O. Sator G. Stingl E. Tschachler Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects Environ. Health Perspect. 109 8 2001 865–869 11564625 1240417 2001EnvHP.109..865G In 2004, presidential candidate Viktor Yushchenko of Ukraine was poisoned with a large dose of TCDD. His blood TCDD concentration was measured 108 ng/g of fat,O. Sorg M. Zennegg P. Schmid Fedosyuk R. R. Valikhnovskyi O. Gaide V. Kniazevych J.-H. Saurat 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites The Lancet 374 9696 2009 1179–1185 10.1016/S0140-6736(09)60912-0 19660807 24761553 which is the second highest ever measured. This concentration implies a dose exceeding 2 mg, or 25 μg/kg of body weight. He suffered from chloracne for many years, but after initial malaise, other symptoms or abnormal laboratory findings were few. An area of polluted land in Italy, known as the Triangle of Death, is contaminated with TCDD from years of illegal waste disposal by organized crime. 15384216 5 9 Italian "Triangle of death" linked to waste crisis Sep 2004 Lancet Oncol 525–527 10.1016/s1470-2045(04)01561-x Senior K Mazza A http://archivio.rassegna.it/2007/attualita/articoli/campania2.htm Il triangolo della morte rassegna.it March 2007 25 September 2014 15 February 2009 https://web.archive.org/web/20090215053207/http://archivio.rassegna.it/2007/attualita/articoli/campania2.htm deadhttp://www.repubblica.it/2004/h/sezioni/cronaca/acerra/lancet/lancet.html Discariche piene di rifiuti tossici quello è il triangolo della morte 31 August 2004 la Repubblica See also Toxic equivalency References External links U.S. National Library of Medicine: Hazardous Substances Databank – 2,3,7,8-Tetrachlorodibenzodioxin Dioxin synopsis Dioxins CDC – NIOSH Pocket Guide to Chemical Hazards Category:Chloroarenes Category:Dibenzodioxins Category:IARC Group 1 carcinogens Category:Blood agents