2,3,7,8-Tetrachlorodibenzodioxin

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Contents

2,3,7,8-Tetrachlorodibenzodioxin
2,3,7,8-tetrachlorodibenzo(b,e)(1,4)dioxine 200.svg
Dioxin-3D-Ball-and-Stick.png
Dioxin-3D-vdW.png
Names
Preferred IUPAC name
2,3,7,8-Tetrachlorooxanthrene
Other names
2,3,7,8-Tetrachlorodibenzo[b,e][1,4]dioxine
Tetradioxin
Tetrachlorodibenzodioxin
Tetrachlorodibenzo-p-dioxin
Identifiers
3D model (JSmol)
AbbreviationsTCDD; TCDBD
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.015.566 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • 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 Yes check.svgY
    Key: HGUFODBRKLSHSI-UHFFFAOYSA-N Yes check.svgY
  • 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
  • ClC1=C(Cl)C=C2OC(C=C(C(Cl)=C3)Cl)=C3OC2=C1
Properties
C12H4Cl4O2
Molar mass 321.96 g·mol−1
AppearanceColorless to white crystalline solid [1]
Density 1.8 g/cm3
Melting point 305 °C (581 °F; 578 K)
0.2 μg/L [2]
log P 6.8
Vapor pressure 1.5 × 10−9 mmHg
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Potent carcinogen and persistent organic pollutant. [1]
GHS labelling:
GHS-pictogram-flamme.svg GHS-pictogram-skull.svg GHS-pictogram-silhouette.svg GHS-pictogram-pollu.svg
Danger
H225, H304, H315, H336, H361, H373, H401, H410
P201, P202, P210, P233, P240, P241, P242, P243, P260, P264, P271, P273, P280, P301+P310, P303+P361+P353, P304+P340+P312, P308+P313, P331, P332+P313, P362+P364, P370+P378, P391, P403+P233, P403+P235, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 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 (327.6 °F; 437.3 K)
NIOSH (US health exposure limits):
PEL (Permissible)
none [1]
REL (Recommended)
Ca [1]
IDLH (Immediate danger)
N.D. [1]
Safety data sheet (SDS) MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (sometimes shortened, though inaccurately, to simply 'dioxin') [3] 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. [4] TCDD was released into the environment in the Seveso disaster. [5] 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. [6] [7] [8] 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. [9] Genes of enzymes activating the breakdown of foreign and often toxic compounds are classic examples of such genes (enzyme induction). TCDD increases the enzymes breaking down, e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene. [10]

These polycyclic hydrocarbons also activate the AH receptor, but less than TCDD and only temporarily. [10] Even many natural compounds present in vegetables cause some activation of the AH receptor. [11] [12] 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. [10]

The physiological function of the AH receptor has been the subject of continuous research. [13] 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. [13] 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. [8] In fact, knock-out animals with no AH receptor are prone to illness and developmental problems. [8] 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. [14] 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. [15] 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. [3] After the Seveso accident, tooth development defects, changed sex ratio and decreased sperm quality have been noted. [3] 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. [3]

Cancer

It is largely agreed that TCDD is not directly mutagenic or genotoxic. [16] 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. [17] There are other explanations such as endocrine disruption or altered signal transduction. [16] [18] 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. [19]

TCDD was classified by the International Agency for Research on Cancer (IARC) as a carcinogen for humans (group 1). [20] [21] In the occupational cohort studies available for the classification, the risk was weak and borderline detectable, even at very high exposures. [22] [23] [3] Therefore, the classification was, in essence, based on animal experiments and mechanistic considerations. [20] This was criticized as a deviation from IARC's 1997 classification rules. [24] 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. [3] 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. [16] [17] [25] A 2011 review concluded that, after 1997, further studies did not support an association between TCDD exposure and cancer risk. [26] 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. [27] On the other hand, the latest studies on Seveso population support TCDD carcinogenicity at high doses. [19] [28]

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. [29] 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 . [30]

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. [31] The United States Environmental Protection Agency (EPA) established an oral reference dose (RfD) of 0.7 pg/kg b.w. per day for TCDD [32] (see discussion on the differences in [3] ).

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. [33] [34]

Animal toxicology

By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing TCDD. [4] [8] [35] [36] 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. [36] 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. [36] 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. [8] [36] 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. [3] [8]

Developmental effects

Developmental effects occur at very low doses in animals. They include frank teratogenicity such as cleft palate and hydronephrosis. [37] Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents, [37] [38] [39] and the development of teeth in rats. [40] The latter is important in that tooth deformities were also seen after the Seveso accident [41] 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. [42]

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. [43] Dose-response of TCDD in causing cancer does not seem to be linear, [25] 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 [16] 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. [23] [7] Carcinogenicity is associated with tissue damage, and it is often viewed now as secondary to tissue damage. [16]

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. [44]

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. [45] 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. [46] Usually a mixture of dioxin-like compounds is produced, [3] 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. [47] 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. [48]

History

TCDD was first synthesized in the laboratory in 1957 [49] by Wilhelm Sandermann, and he also discovered the effects of the compound.

Cases of exposure

A photograph of Viktor Yushchenko after he was poisoned by TCDD. TCDD often causes disfiguring facial swelling Viktor Yuschenko.jpg
A photograph of Viktor Yushchenko after he was poisoned by TCDD. TCDD often causes disfiguring facial swelling

There have been numerous incidents where people have been exposed to high doses of TCDD.

See also

Related Research Articles

Polychlorinated dibenzodioxins (PCDDs), or simply dioxins, are a group of long-lived polyhalogenated organic compounds that are primarily anthropogenic, and contribute toxic, persistent organic pollution in the environment.

<span class="mw-page-title-main">Seveso disaster</span> Toxic chemical leak in Italy in 1976

The Seveso disaster was an industrial accident that occurred around 12:37 pm on 10 July 1976, in a small chemical manufacturing plant approximately 20 kilometres (12 mi) north of Milan in the Lombardy region of Italy. It resulted in the highest known exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in residential populations, which gave rise to numerous scientific studies and standardized industrial safety regulations, including the European Union's Seveso III Directive. This accident was ranked eighth in a list of the worst man-made environmental disasters by Time magazine in 2010.

<span class="mw-page-title-main">Chloracne</span> Medical condition

Chloracne is an acneiform eruption of blackheads, cysts, and pustules associated with exposure to certain halogenated aromatic compounds, such as chlorinated dioxins and dibenzofurans. The lesions are most frequently found on the cheeks, behind the ears, in the armpits and groin region.

Benzo(<i>a</i>)pyrene Carcinogenic compound found in smoke and soot

Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites, more commonly known as BPDE, react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

<span class="mw-page-title-main">Persistent organic pollutant</span> Organic compounds that are resistant to environmental degradation

Persistent organic pollutants (POPs) are organic compounds that are resistant to degradation through chemical, biological, and photolytic processes. They are toxic and adversely affect human health and the environment around the world. Because they can be transported by wind and water, most POPs generated in one country can and do affect people and wildlife far from where they are used and released.

<span class="mw-page-title-main">2,4,5-Trichlorophenoxyacetic acid</span> Chemical compound

2,4,5-Trichlorophenoxyacetic acid, a synthetic auxin, is a chlorophenoxy acetic acid herbicide used to defoliate broad-leafed plants. It was developed in the late 1940s, synthesized by reaction of 2,4,5-Trichlorophenol and chloroacetic acid. It was widely used in the agricultural industry until being phased out, starting in the late 1970s due to toxicity concerns. Agent Orange, a defoliant used by the British in the Malayan Emergency and the U.S. in the Vietnam War, was equal parts 2,4,5-T and 2,4-D. 2,4,5-T itself is toxic with a NOAEL of 3 mg/kg/day and a LOAEL of 10 mg/kg/day. Agent Pink contained 100% 2,4,5-T. Additionally, the manufacturing process for 2,4,5-T contaminates this chemical with trace amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is a carcinogenic persistent organic pollutant with long-term effects on the environment. With proper temperature control during production of 2,4,5-T, TCDD levels can be held to about .005 ppm. Before the TCDD risk was well understood, early production facilities lacked proper temperature controls and individual batches tested later were found to have as much as 60 ppm of TCDD.

<span class="mw-page-title-main">Agent Pink</span>

Agent Pink is the code name for a powerful herbicide and defoliant used by the U.S. military in its herbicidal warfare program during the Vietnam War. The name comes from the pink stripe painted on the barrels to identify the contents. Largely inspired by the British use of herbicides and defoliants during the Malayan Emergency, it was one of the rainbow herbicides that included the more infamous Agent Orange. Agent Pink was only used during the early "testing" stages of the spraying program before 1964.

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The aryl hydrocarbon receptor is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originally thought to function primarily as a sensor of xenobiotic chemicals and also as the regulator of enzymes such as cytochrome P450s that metabolize these chemicals. The most notable of these xenobiotic chemicals are aromatic (aryl) hydrocarbons from which the receptor derives its name.

<span class="mw-page-title-main">Azinphos-methyl</span> Chemical compound

Azinphos-methyl (Guthion) is a broad spectrum organophosphate insecticide manufactured by Bayer CropScience, Gowan Co., and Makhteshim Agan. Like other pesticides in this class, it owes its insecticidal properties to the fact that it is an acetylcholinesterase inhibitor. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act, and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

The aryl-hydrocarbon receptor repressor also known as AHRR is a human gene.

<span class="mw-page-title-main">Polychlorinated dibenzofurans</span> Family of organic compounds

Polychlorinated dibenzofurans (PCDFs) are a family of organic compounds with one or several of the hydrogens in the dibenzofuran structure replaced by chlorines. For example, 2,3,7,8-tetrachlorodibenzofuran (TCDF) has chlorine atoms substituted for each of the hydrogens on the number 2, 3, 7, and 8 carbons. Polychlorinated dibenzofurans with chlorines at least in positions 2,3,7 and 8 are much more toxic than the parent compound dibenzofurane, with properties and chemical structures similar to polychlorinated dibenzodioxins. These groups together are often inaccurately called dioxins. They are known developmental toxicants, and suspected human carcinogens. PCDFs tend to co-occur with polychlorinated dibenzodioxins (PCDDs). PCDFs can be formed by pyrolysis or incineration at temperatures below 1200 °C of chlorine containing products, such as PVC, PCBs, and other organochlorides, or of non-chlorine containing products in the presence of chlorine donors. Dibenzofurans are known persistent organic pollutants (POP), classified among the dirty dozen in the Stockholm Convention on Persistent Organic Pollutants.

<span class="mw-page-title-main">2008 Irish pork crisis</span> International recall of Irish pork

The Irish pork crisis of 2008 was a dioxin contamination incident in Ireland that led to an international recall of pork products from Ireland produced between September and early December of that year. It was disclosed in early December 2008 that contaminated animal feed supplied by one Irish manufacturer to thirty-seven beef farms and nine pig farms across Republic of Ireland, and eight beef farms and one dairy farm in Northern Ireland, had caused the contamination of pork with between 80 and 200 times the EU's recommended limit for dioxins and dioxin-like PCBs i.e. 0.2 ng/g TEQ fat. The Food Safety Authority of Ireland moved on 6 December to recall from the market all Irish pork products dating from 1 September 2008 to that date. The contaminated feed that was supplied to forty-five beef farms across the island was judged to have caused no significant public health risk, accordingly no recall of beef was ordered. Also affected was a dairy farm in Northern Ireland; some milk supplies were withdrawn from circulation. Processors refused to resume slaughter of pigs until they received financial compensation.

<span class="mw-page-title-main">Dioxins and dioxin-like compounds</span> Class of chemical compounds

Dioxins and dioxin-like compounds (DLCs) are a group of chemical compounds that are persistent organic pollutants (POPs) in the environment. They are mostly by-products of burning or various industrial processes or, in the case of dioxin-like PCBs and PBBs, unwanted minor components of intentionally produced mixtures.

Chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs) are a group of compounds comprising polycyclic aromatic hydrocarbons with two or more aromatic rings and one or more chlorine atoms attached to the ring system. Cl-PAHs can be divided into two groups: chloro-substituted PAHs, which have one or more hydrogen atoms substituted by a chlorine atom, and chloro-added Cl-PAHs, which have two or more chlorine atoms added to the molecule. They are products of incomplete combustion of organic materials. They have many congeners, and the occurrences and toxicities of the congeners differ. Cl-PAHs are hydrophobic compounds and their persistence within ecosystems is due to their low water solubility. They are structurally similar to other halogenated hydrocarbons such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Cl-PAHs in the environment are strongly susceptible to the effects of gas/particle partitioning, seasonal sources, and climatic conditions.

Toxic equivalency factor (TEF) expresses the toxicity of dioxins, furans and PCBs in terms of the most toxic form of dioxin, 2,3,7,8-TCDD. The toxicity of the individual congeners may vary by orders of magnitude.

Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level.

Benzo(<i>c</i>)fluorene Chemical compound

Benzo[c]fluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzo[c]fluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen. Other names for benzo[c]fluorene are 7H-benzo[c]fluorene, 3,4-benzofluorene, and NSC 89264.

Heptachlorodibenzo-<i>p</i>-dioxin Chemical compound

1,2,3,4,6,7,8-Heptachlorodibenzo-para-dioxin (often referred to as 1,2,3,4,6,7,8-HpCDD) is a polychlorinated derivative of dibenzo-p-dioxin and can therefore be categorized as polychlorinated dibenzo-p-dioxin (PCDD), a subclass of dioxins which includes 75 congeners. HpCDD is the dibenzo-p-dioxin which is chlorinated at positions 1, 2, 3, 4, 6, 7, and 8. It is a polycyclic heterocyclic organic compound, since HpCDD contains multiple cyclic structures (two benzene rings connected by a 1,4-dioxin ring) in which two different elements (carbon and oxygen) are members of its rings. HpCDD has molecular formula C12HCl7O2 and is an off-white powder, which is insoluble in water.

Tommaso A. Dragani is an Italian genetic epidemiologist whose research is focused on understanding the genetic control of complex phenotypes.

Ilya Borisovich Tsyrlov is a Russian-American biochemist, molecular toxicologist and virologist. He is known for his studies and research on enzymology, drug metabolism, environmental toxicology, bioinformatics, virology, and cancer. Tsyrlov has authored 4 monographs, and co-authored over 280 publications on microsomal, purified and recombinant monooxygenases, and mechanisms of CYP induction by xenobiotics.

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