Toxicology 2,3,7,8-Tetrachlorodibenzodioxin

1 toxicology

1.1 cancer
1.2 mechanism of action
1.3 teratogenic effects
1.4 epidemiology

toxicology

the expert group of world health organization considered developmental toxicity pertinent risk of dioxins human beings. because people exposed simultaneously number of dioxin-like chemicals, more detailed account given @ dioxins , dioxin-like compounds.

cancer

tcdd classified in 1997 international agency research on cancer carcinogen humans (group 1). in occupational cohort studies available classification, risk, @ high exposures, weak , borderline detectable. therefore, human data not deemed sufficient, , classification was, in essence, based on animal experiments , mechanistic considerations. has been criticized deviation iarc classification rules. debated whether tcdd carcinogenic @ high doses cause toxic damage of tissues. moreover, recent review concludes that, after 1997, further studies not support association between tcdd exposure , cancer risk. new studies include update of vietnam veteran studies ranch hand operation, concluded after 30 years results not provide evidence of disease.

there direct epidemiological evidence tcdd not carcinogenic @ low doses, , in studies cancer risk has decreased. called j-shape dose-response, low doses decrease risk, , higher doses increase risk.

mechanism of action

tcdd , dioxin-like compounds act via specific receptor present in cells: aryl hydrocarbon (ah) receptor. receptor transcription factor involved in expression of genes; in fact has been shown high doses of tcdd either increase or decrease expression of several hundred genes in rats. genes of enzymes activating breakdown of foreign , toxic compounds classic examples of such genes. tcdd increases enzymes breaking down, e.g., carcinogenic polycyclic hydrocarbons such benzo(a)pyrene.

these polycyclic hydrocarbons activate ah receptor, less tcdd , temporarily. many natural compounds present in vegetables cause activation of ah receptor. phenomenon can viewed adaptive , beneficial, because protects organism toxic , carcinogenic substances. excessive , persistent stimulation of ah receptor, however, leads multitude of adverse effects.

the physiological function of ah receptor has been subject of continuous research. 1 obvious function increase activity of enzymes breaking down foreign chemicals or normal chemicals of body needed. there may other functions, however, related growth of various organs or other regulatory functions. ah receptor phylogenetically highly conserved transcription factor history of @ least 500 million years, , found in vertebrates, , ancient analogs important regulatory proteins in more primitive species. in fact, knock-out animals no ah receptor prone illness , developmental problems. taken together, implies necessity of basal degree of ah receptor activation achieve normal physiological function.

while mutagenic , genotoxic effects of tcdd disputed , confirmed foster development of cancer. main action in causing cancer cancer promotion; promotes carcinogenicity initiated other compounds. high doses may, in addition, cause cancer indirectly; 1 of proposed mechanisms oxidative stress , subsequent oxygen damage dna. there other explanations such endocrine disruption or altered signal transduction. endocrine disrupting activities seem dependent on life stage, being anti-estrogenic when estrogen present (or in high concentration) in body, , estrogenic in absence of estrogen.

teratogenic effects

in vietnam , united states, teratogenic or birth defects observed in children of persons exposed agent orange or 2,4,5-t contained tcdd impurity out of production process. scientific data supporting causal link between agent orange/dioxin exposure , birth defects controversial , weak, in part due poor methodology. in 2006 anh duc ngo , colleagues, of university of texas health science center in austin, published meta-analysis exposed large amount of heterogeneity/(different findings) between studies, finding consistent lack of consensus on issue. despite this, statistical analysis of studies examined resulted in data increase in birth defects/relative risk(rr) exposure agent orange/dioxin appears on order of 3 in vietnamese funded studies 1.29 in rest of world. casual relationship near threshold of statistical significance in still-births, cleft palate, , neural tube defects, spina bifida being statistically significant defect. large discrepancy in rr between vietnamese studies , in rest of world have been suggested due bias in vietnamese studies.

epidemiology

the world health organization recommends monthly limit of 70 picograms per kilogram of body weight, or 0.07 ppt (parts per trillion) in blood.

the general environmental limit in countries 1,000 ppt teq (toxic equivalent) in soils , 100 ppt in sediment. industrialized countries have dioxin concentrations in soils of less 12 ppt.
the u.s. agency toxic substance , disease registry has determined levels higher 1,000 ppt teq in soil require intervention, including research, surveillance, health studies, community , physician education, , exposure investigation.
the u.s. environmental protection agency considering reducing these limits 72 ppt teq. change increase potential volume of contaminated soil requiring treatment.




^ consultation on assessment of health risk of dioxins: re-evaluation of tolerable daily intake (tdi): executive summary . food additives & contaminants. 17 (4): 223–240. 2000. doi:10.1080/713810655. pmid 10912238. 
^ international agency research on cancer (1997). polychlorinated dibenzo-para-dioxins , polychlorinated dibenzofurans. monographs on evaluation of carcinogenic risks humans. 69. lyon: iarc. isbn 92-832-1269-x. 
^ cite error: named reference xl invoked never defined (see page).
^ cite error: named reference schwarz invoked never defined (see page).
^ cole p, trichopoulos d, pastides h, starr t, mandel js (december 2003). dioxin , cancer: critical review . regul. toxicol. pharmacol. 38 (3): 378–88. doi:10.1016/j.yrtph.2003.08.002. pmid 14623487. 
^ y.p. dragan; d. schrenk (2000). animal studies addressing carcinogenicity of tcdd (or related compounds) emphasis on tumour promotion . food additives , contaminants. 17 (4): 289–302. doi:10.1080/026520300283360. pmid 10912243. 
^ m. viluksela; et al. (2000). liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (tcdd) in tcdd-sensitive , tcdd resistant rat strains . cancer res. 60 (24): 6911–20. pmid 11156390. 
^ walker nj, wyde me, fischer lj, nyska a, bucher jr (october 2006). comparison of chronic toxicity , 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. 
^ boffetta p, mundt ka, adami ho, cole p, mandel js (august 2011). tcdd , cancer: critical review of epidemiologic studies . crit. rev. toxicol. 41 (7): 622–36. doi:10.3109/10408444.2011.560141. pmc 3154583 . pmid 21718216. 
^ buffler pa, ginevan me, mandel js, watkins dk (september 2011). air force health study: epidemiologic retrospective . ann epidemiol. 21 (9): 673–87. doi:10.1016/j.annepidem.2011.02.001. pmid 21441038. 
^ j.t. tuomisto; j. pekkanen; h. kiviranta; e. tukiainen; t. vartiainen; j. tuomisto (2004). soft-tissue sarcoma , dioxin: case-control study . int. j. cancer. 108 (6): 893–900. doi:10.1002/ijc.11635. pmid 14712494. 
^ tuomisto, j.; et al. (2005). dioxin cancer risk –example of hormesis? . dose-response : publication of international hormesis society. 3 (3): 332–341. doi:10.2203/dose-response.003.03.004. pmc 2475943 . pmid 18648613. 
^ l. poellinger (2000). mechanistic aspects—the dioxin (aryl hydrocarbon) receptor . food additives , contaminants. 17 (4): 261–6. doi:10.1080/026520300283333. pmid 10912240. 
^ mandal pk (may 2005). dioxin: review of environmental effects , 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. 
^ j. lindén; s. lensu; j. tuomisto; r. pohjanvirta. (2010). dioxins, aryl hydrocarbon receptor , central regulation of energy balance. review . frontiers in neuroendocrinology. 31 (4): 452–478. doi:10.1016/j.yfrne.2010.07.002. pmid 20624415. 
^ tijet n, boutros pc, moffat id, et al. (2006). hydrocarbon receptor regulates distinct dioxin-dependent , dioxin-independent gene batteries . molecular pharmacology. 69 (1): 140–153. doi:10.1124/mol.105.018705. pmid 16214954. 
^ okey ab (july 2007). aryl hydrocarbon receptor odyssey shores of toxicology: deichmann lecture, international congress of toxicology-xi . toxicol. sci. 98 (1): 5–38. doi:10.1093/toxsci/kfm096. pmid 17569696. 
^ mandlekar s, hong jl, kong (august 2006). modulation of metabolic enzymes dietary phytochemicals: review of mechanisms underlying beneficial versus unfavorable effects . curr. drug metab. 7 (6): 661–75. doi:10.2174/138920006778017795. pmid 16918318. 
^ giri, a. k. (nov 1986). mutagenic , genotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, review . mutat res. 168 (3): 241–8. doi:10.1016/0165-1110(86)90022-9. pmid 3540643. 
^ 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. 
^ angela cecilia pesatori; dario consonni; maurizia rubagotti; paolo grillo; pier alberto bertazzi (2009). cancer incidence in population exposed dioxin after seveso accident : twenty years of follow-up . environmental health. 8 (1): 39. doi:10.1186/1476-069x-8-39. pmc 2754980 . pmid 19754930. 
^ king, jesse, birth defects caused agent orange . embryo project encyclopedia (2012-11-08). http://embryo.asu.edu/handle/10776/4202. issn 1940-5030
^ association between agent orange , birth defects: systematic review , meta-analysis, int. j. epidemiol. (october 2006) 35 (5): 1220-1230. doi: 10.1093/ije/dyl038 first published online: march 16, 2006
^ toxic substances portal (pdf). 
^ health effects - aspen institute . aspen institute. retrieved 2017-02-20.