Polychlorinated dibenzodioxins

and substituent numbering scheme of the parent compound dibenzo-1,4-dioxin The structure of dibenzo-1,4-dioxin consists of two benzene rings joined by two oxygen bridges. This makes the compound an aromatic diether. The name dioxin formally refers to the central dioxygenated ring, which is stabilized by the two flanking benzene rings. In PCDDs, chlorine atoms are attached to this structure at any of eight different places on the molecule, at positions 1–4 and 6–9. There are 75 different PCDD congeners (that is, related dioxin compounds). The toxicity of PCDDs depends on the number and positions of the chlorine atoms. Congeners that have chlorine in the 2, 3, 7, and 8 positions have been found to be significantly toxic. In fact, 7 congeners have chlorine atoms in the relevant positions which were considered toxic by the World Health Organization toxic equivalent (WHO-TEQ) scheme. ==Historical perspective==

Low concentrations of dioxins existed in nature prior to industrialization as a result of natural combustion and geological processes. Dioxins were first unintentionally produced as by-products from 1848 onwards as Leblanc process plants started operating in Germany. Later, dioxins were found in Times Beach, Missouri and Love Canal, New York and Seveso, Italy. More recently, dioxins have been in the news with the poisoning of President Viktor Yushchenko of Ukraine in 2004, the Naples Mozzarella Crisis, the 2008 Irish pork crisis, and the German feed incident of 2010. ==Sources of dioxins==

The United States Environmental Protection Agency inventory of sources of dioxin-like compounds is possibly the most comprehensive review of the sources and releases of dioxins, but other countries now have substantial research as well. , Cumbria, UK Occupational exposure is an issue for some in the chemical industries, historically for those making chlorophenols or chlorophenoxy acid herbicides or in the application of chemicals, notably herbicides. In many developed nations there are now emissions regulations which have dramatically decreased the emissions Incinerator emissions of dioxins have been reduced by over 90% as a result of new emissions control requirements. Incineration in developed countries is now a very minor contributor to dioxin emissions. Dioxins are also generated in reactions that do not involve burning — such as chlorine bleaching fibers for paper or textiles, and in the manufacture of chlorinated phenols, particularly when reaction temperature is not well controlled. Compounds involved include the wood preservative pentachlorophenol, and also herbicides such as 2,4-dichlorophenoxyacetic acid (or 2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Higher levels of chlorination require higher reaction temperatures and greater dioxin production. Dioxins may also be formed during the photochemical breakdown of the common antimicrobial compound triclosan. ==Sources of human intake==

increases the child's body burden. Dioxin exposure can also occur from contact with Pentachlorophenol (Penta) treated lumber as Pentachlorophenol often contains dioxins as a contaminant. Children's daily intakes during breast feeding are often many times above the intakes of adults based on body weight. This is why the WHO consultation group assessed the tolerable intake so as to prevent a woman from accumulating harmful body burdens before her first pregnancy. Breast fed children usually still have higher dioxin body burdens than non breast fed children. The WHO still recommends breast feeding for its other benefits. In many countries dioxins in breast milk have decreased by even 90% during the two last decades. Dioxins are present in cigarette smoke. Dioxin in cigarette smoke was noted as "understudied" by the US EPA in its "Re-Evaluating Dioxin" (1995). In that same document, the US EPA acknowledged that dioxin in cigarettes is "anthropogenic" (man-made, "not likely in nature"). ==Metabolism==

Dioxins are absorbed primarily through dietary intake of fat, as this is where they accumulate in animals and humans. In humans, the highly chlorinated dioxins are stored in fatty tissues and are neither readily metabolized nor excreted. The estimated elimination half-life for highly chlorinated dioxins (4–8 chlorine atoms) in humans ranges from 4.9 to 13.1 years. The persistence of a particular dioxin congener in an animal is thought to be a consequence of its structure. Dioxins with no lateral (2, 3, 7, and 8) chlorines, which thus contain hydrogen atoms on adjacent pairs of carbons, can more readily be oxidized by cytochromes P450. The oxidized dioxins can then be more readily excreted rather than stored for a long time. ==Toxicity==

of 2,3,7,8-tetrachlorodibenzodioxin 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) is considered the most toxic of the congeners (for the mechanism of action, see 2,3,7,8-Tetrachlorodibenzodioxin and Aryl hydrocarbon receptor). Other dioxin congeners including PCDFs and PCBs with dioxin-like toxicity, are given a toxicity rating from 0 to 1, where TCDD = 1 (see Dioxins and dioxin-like compounds). This toxicity rating is called the Toxic Equivalence Factor concept, or TEF. TEFs are consensus values and, because of the strong species dependence for toxicity, are listed separately for mammals, fish, and birds. TEFs for mammalian species are generally applicable to human risk calculations. The TEFs have been developed from detailed assessment of literature data to facilitate both risk assessment and regulatory control. Dioxins and other persistent organic pollutants (POPs) are subject to the Stockholm Convention. The treaty obliges signatories to take measures to eliminate where possible, and minimize where not possible to eliminate, all sources of dioxin. ==Health effects in humans==

on the ear and neck of a herbicide production worker Dioxins build up primarily in fatty tissues over time (bioaccumulation), so even small exposures may eventually reach dangerous levels. In 1994, the US EPA reported that dioxins are a probable carcinogen, but noted that non-cancer effects (reproduction and sexual development, immune system) may pose a greater threat to human health. TCDD, the most toxic of the dibenzodioxins, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC). TCDD has a half-life of approximately 8 years in humans, although at high concentrations, the elimination rate is enhanced by metabolism. The health effects of dioxins are mediated by their action on a cellular receptor, the aryl hydrocarbon receptor (AhR). Exposure to high levels of dioxins in humans causes a severe form of persistent acne, known as chloracne. High occupational or accidental levels of exposures to dioxins have been shown by epidemiological studies to lead to an increased risk of tumors at all sites. Other effects in humans (at high dose levels) may include: • Developmental abnormalities in the enamel of children's teeth. • Central and peripheral nervous system pathology • Thyroid disorders • Damage to the immune systems • Endometriosis • Diabetes Recent studies have shown that high exposure to dioxins changes the ratio of male to female births among a population such that more females are born than males. Dioxins accumulate in food chains in a fashion similar to other chlorinated compounds (bioaccumulation). This means that even small concentrations in contaminated water can be concentrated up a food chain to dangerous levels because of the long biological half life and low water solubility of dioxins. ==Toxic effects in animals==

While it has been difficult to establish specific health effects in humans due to the lack of controlled dose experiments, studies in animals have shown that dioxin causes a wide variety of toxic effects. In particular, TCDD has been shown to be teratogenic, mutagenic, carcinogenic, immunotoxic, and hepatotoxic. Furthermore, alterations in multiple endocrine and growth factor systems have been reported. The most sensitive effects, observed in multiple species, appear to be developmental, including effects on the developing immune, nervous, and reproductive systems. The most sensitive effects are caused at body burdens relatively close to those reported in humans. Among the animals for which TCDD toxicity has been studied, there is strong evidence for the following effects: • Birth defects (teratogenicity) :In rodents, including rats, mice, hamsters and guinea pigs, birds, and fish. • Cancer (including neoplasms in the mammalian lung, oral/nasal cavities, thyroid and adrenal glands, and liver, squamous cell carcinoma, and various animal hepatocarcinomas) :In rodents and fish. • Hepatotoxicity (liver toxicity) :In rodents, and fish. • Endocrine disruption :In rodents • Immunosuppression :In rodents and fish. The LD50 of dioxin also varies wildly between species with the most notable disparity being between the ostensibly similar species of hamster and guinea pig. The oral LD50 for guinea pigs is as low as 0.5 to 2 μg/kg body weight, whereas the oral LD50 for hamsters can be as high as 1 to 5 mg/kg body weight, a difference of as much as thousandfold or more, and even among rat strains there may be thousandfold differences. ==Agent Orange==

spraying Agent Orange over Vietnamese agricultural land Agent Orange was the code name for one of the herbicides and defoliants the U.S. military used as part of its herbicidal warfare program, Operation Ranch Hand, during the Vietnam War from 1961 to 1971. It was a mixture of 2,4,5-T and 2,4-D. The 2,4,5-T used was contaminated with 2,3,7,8-tetrachlorodibenzodioxin (TCDD), an extremely toxic dioxin compound. During the Vietnam war, between 1962 and 1971, the United States military sprayed of chemical herbicides and defoliants in Vietnam, eastern Laos and parts of Cambodia, as part of Operation Ranch Hand. By 1971, 12% of the total area of South Vietnam had been sprayed with defoliating chemicals, which were often applied at rates that were 13 times as high as the legal USDA limit. In South Vietnam alone, an estimated 10 million hectares of agricultural land were ultimately destroyed. In some areas, TCDD concentrations in soil and water were hundreds of times greater than the levels considered safe by the U.S. Environmental Protection Agency. According to Vietnamese Ministry of Foreign Affairs, 4.8 million Vietnamese people were exposed to Agent Orange, resulting in 400,000 people being killed or maimed, and 500,000 children born with birth defects. The Red Cross of Vietnam estimates that up to 1 million people are disabled or have health problems due to Agent Orange contamination. The United States government has challenged these figures as being unreliable and unrealistically high. ==Dioxin exposure incidents==

• In 1949, in a Monsanto herbicide production plant for 2,4,5-T in Nitro, West Virginia, 240 people were affected when a relief valve opened. • In 1963, a dioxin cloud escaped after an explosion in a Philips-Duphar plant (now Solvay Group) near Amsterdam. • Neratovice chloralkali plant, air view Between 1965 and 1968 production of 2,4,5-trichlorophenol in Spolana Neratovice plant in Czechoslovakia seriously poisoned about 60 workers with dioxins; after 3 years of investigation of the health problems of workers, Spolana stopped manufacture of 2,4,5-T (most of which was supplied to the US military in Vietnam). Several buildings of the Spolana chemical plant were heavily contaminated by dioxins. Unknown amounts of dioxins were flushed into the Elbe and Mulde rivers during the 2002 European flood, contaminating soil. Analysis of eggs and ducks found dioxin levels 15 times higher than the EU limit and a high concentration of dioxin-like PCBs in the village of Libiš. In 2004, the state health authority published a study which analysed the level of toxic substances in human blood near Spolana. According to the study, dioxin levels in Neratovice, Libiš and Tišice were about twice the level of the control group in Benešov. The quantity of dioxins near Spolana is significantly higher than the background levels in other countries. According to the US EPA, even a background level can pose a risk of cancer from 1:10000 to 1:1000, about 100 times higher than normal. The consumption of local fish, eggs, poultry, and some produce was prohibited because of post-flood contamination. • Also during 1965 through 1968, Dr. Albert M. Kligman was contracted by the Dow Chemical Company to perform threshold tests for TCDD on inmates at Holmesburg Prison in Philadelphia after Dow studies revealed adverse effects on workers at Dow's Midland, Michigan, plant were likely due to TCDD. A subsequent test by Dow in rabbit ear models when exposed to 4–8μg usually caused a severe response. The human studies carried out in Holmesburg failed to follow Dow's original protocol and lacked proper informed consent by the participants. As a result of poor study design and subsequent destruction of records, the tests were virtually worthless even though ten inmates were exposed to 7,500μg of TCDD. • In 1976, large amounts of dioxins were released in an industrial accident at Seveso, Italy, although no immediate human fatalities or birth defects occurred. • In 1978, dioxins were some of the contaminants that forced the evacuation of the Love Canal neighborhood of Niagara Falls, New York. • From 1982 through to 1985, Times Beach, Missouri, was bought out and evacuated under order of the United States Environmental Protection Agency due to high levels of dioxins in the soil caused by applications of contaminated oil meant to control dust on the town's dirt roads. The town eventually disincorporated. • In the spring of 1990, a chemical plant Khimprom in Ufa, Russia released phenol into the water tributaries. An investigation revealed previously classified disposal of dioxin in manufacturing 2,4,5-Trichlorophenoxyacetic acid. The accident affected 670,000 people. Dioxin was found in tap water. It was assumed that it resulted from chlorophenol produced by a reaction with chlorine in water purification. • Explosions resulting from the terrorist attacks on the US on 11 September 2001, released massive amounts of dust into the air. The air was measured for dioxins from 23 September 2001, to 21 November 2001, and reported to be "likely the highest ambient concentration that have ever been reported [in history]." The United States Environmental Protection Agency report dated October 2002 and released in December 2002 titled "Exposure and Human Health Evaluation of Airborne Pollution from the World Trade Center Disaster" authored by the EPA Office of Research and Development in Washington states that dioxin levels recorded at a monitoring station on Park Row near City Hall Park in New York between 12 and 29 October 2001, averaged 5.6 parts per trillion, or nearly six times the highest dioxin level ever recorded in the U.S. Dioxin levels in the rubble of the World Trade Centers were much higher with concentrations ranging from 10 to 170 parts per trillion. The report did no measuring of the toxicity of indoor air. • In a 2001 case study, • with chloracne after his TCDD poisoning incident In 2004, in a notable individual case of dioxin poisoning, Ukrainian politician Viktor Yushchenko was exposed to the second-largest measured dose of dioxins, according to the reports of the physicians responsible for diagnosing him. This is the first known case of a single high dose of TCDD dioxin poisoning, and was diagnosed only after a toxicologist recognized the symptoms of chloracne while viewing television news coverage of his condition. In another case, parents claimed dioxin from pollution caused the death of their 8-year-old daughter; the trial took place in the summer of 2007, and a jury wholly rejected the family's claims, as no scientific connection could be proven between DuPont and the family's tragic loss. DuPont's DeLisle plant is one of three titanium dioxide facilities (including Edgemoor, Delaware, and New Johnsonville, Tennessee) that are the largest producers of dioxin in the country, according to the US EPA's Toxic Release Inventory. DuPont maintains its operations are safe and environmentally responsible. • In 2007, thousands of tonnes of foul-smelling refuse were piled up in Naples, Italy and its surrounding villages, defacing entire neighbourhoods. Authorities discovered that polychlorinated dibenzodioxins levels in buffalo milk used by 29 mozzarella makers exceeded permitted limits; after further investigation they impounded milk from 66 farms. Authorities suspected the source of the contamination was from waste illegally disposed of on land grazed by buffalo. Prosecutors in Naples placed 109 people under investigation on suspicion of fraud and food poisoning. Sales of Mozzarella cheese fell by 50% in Italy. • In December 2008 in Ireland dioxin levels in pork were disclosed to have been between 80 and 200 times the legal limit. All Irish pork products were withdrawn from sale both nationally and internationally. In this case the dioxin toxicity was found to be mostly due to dioxin-like polychlorinated dibenzofurans and polychlorinated biphenyls, and the contribution from actual polychlorinated dibenzodioxins was relatively low. It is thought that the incident resulted from the contamination of fuel oil used in a drying burner at a single feed processor, with PCBs. The resulting combustion produced a highly toxic mixture of PCBs, dioxins and furans, which was included in the feed produced and subsequently fed to a large number of pigs. • According to data in 2009, in 2005 the production of dioxin by the steel industry ILVA in Taranto (Italy) accounted for 90.3 per cent of the overall Italian emissions, and 8.8 per cent of the European emissions. • German dioxin incident: In January 2011 about 4700 German farms were banned from making deliveries after self-checking of an animal feed producer had shown levels of dioxin above maximum levels. This incident appeared to involve PCDDs and not PCBs. ==Dioxin testing==

The analyses used to determine these compounds' relative toxicity share common elements that differ from methods used for more traditional analytical determinations. The preferred methods for dioxins and related analyses use high resolution gas chromatography/mass spectrometry (HRGC/HRMS). Concentrations are determined by measuring the ratio of the analyte to the appropriate isotopically labeled internal standard. Also novel bio-assays like DR CALUX are nowadays used in identification of dioxins and dioxin-like compounds. The advantage in respect to HRGC/HRMS is that it is able to scan many samples at lower costs. Also it is able to detect all compounds that interact with the Ah-receptor which is responsible for carcinogenic effects. ==See also==