The effects of Dioxin Poisoning

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Although not an obvious poison of choice, dioxins can be highly potent and cause many ill effects when an individual is exposed. It is because of the dioxins toxicity, that it is so extensively researched. This research is limited by boundries of ethics, and so when the opportunity to examine and monitor human a subject arises, it is used to full advantage. Examples of chronic exposure include Agent Orange in the Vietnam war and the Seveso disaster in 1976. Acute examples include two Austrian women who ingested TCDD and the case on which this assignment is based, presidential candidate Victor Yushchenko. The purpose of the following is to identify the toxicological evidence required to confirm that the poison is in fact dioxin and to consider the specificity of the toxicological responses for dioxin.

Dioxin is formed as an unintentional by-product of many industrial processes that involve chlorine, such as waste incineration, chemical and pesticide manufacturing, and pulp and paper bleaching. The main source in the environment comes from incinerators burning chlorinated wastes. (Mitrou, Dimitriadis & Raptis, 2000). Dioxins have never been manufactured for commercial use. Over the past few decades, industry and government have worked together to reduce industrial dioxin emissions to the environment. As a result, dioxin emissions, as monitored by the US Environmental Protection Agency (EPA), have plummeted by 92 percent since 1987. Dioxin Facts( 2005). The most toxic compound is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Figure 1.

 Structure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its metabolites 2,3,7-trichloro-8-hydroxydibenzo-p-dioxin (OH-TriCDD) and 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin (OH-TCDD)

Sorg, Zennegg, Schmid, Fedosyuk, Valikhnovsky, Gaide, Kniazevych & Saurat (2009).

Pure 2,3,7,8-TCDD is generally unavailable except for research purposes through scientific laboratory suppliers. (Dioxin Facts)

Although all dioxin congeners are thought to act in the same way, they are not all equally as toxic. Toxic Equivalency Factors (TEF), compare the relative toxicity of other congeners to that of TCDD. TCDD has a TEF value of 1. A congener with a TEF value of 0.5, is half as toxic as TCDD (Michigan Department of Community Health [MDCH], n.d.). TEF has only been assigned to dioxins, benzofurans, and coplanar polychlorinated biphenyls. The TEF method has been used to calculate body burdens of dioxins in humans. Induction of cancer in animals occurs at body burdens of 944 - 137 000 ng TCDD/kg body weight, while non-cancer effects in animals occur at body burdens of 10 - 12 500 ng/kg. DeVito, Birnbaum, Farland & Gasiewiez (1995).

A very small level of dioxin is present in all humans mostly from consuming meat and dairy products. Dioxins are fat soluble and bio accumulate up the food chain. They are also present in the air and soil.

(Dioxin Facts)

Toxic effects

Whether intentional or not, dioxin exposure produces some highly undesirable effects. The following is only a brief outline of the toxic effects after exposure to dioxins.

Chloracne - a severe form of acne that is more disfiguring than teenage acne and whose effects can last years after exposure - this was the only clinical effect established with certainty by Bertazzi, Bernucci, Brambilla, Consonni & Pesatori (1998). See fig 1.

Figure 1 - Photographs showing chloracne

(Derm Net)

Wasting syndrome - one of the most common symptoms seen in the animal species as a result of TCDD poisoning is body weight loss or reduced weight gain. This syndrome develops slowly and involves mostly the loss of fat and muscle tissue. On death, the body may weigh as little as 50 % its weight before poisoning. McConnely, Moore & Dalgald (1978).

Immune system - in all species studied by McConnely, Moore, Gupta, Rakes, Luster, Goldstein et al. (1980), as cited by Mitrou et al. (2001), TCDD and congeners produce a loss of lymphoid tissue. This is especially so in the thymus but also in the spleen and lymph nodes. This is due to necrosis of lymphocytes. ( Olson, Holscher & Neal [1980]).

Digestive System - mild to severe haemorrhaging and necrosis are caused by chlorinated aromatic hydro carbons which produce hyperplasic and hypertrophic lesions of the gastrointestinal mucosa. (Olsen et al. [1980]). Even at low doses, TCDD and related compounds produce hepatomeagaly in all species. This is caused by hyperplasia and hypertrophy of parenchymal cells. More specifically by proliferation of the smooth endoplasmic reticulum. McConnely et al. (1978).

Lipid metabolism - TCDD causes a reduction in the uptake of glucose in adipose tissue. This affects lipid metabolism and causes a drastic decline in the activity of lipoprotein lipase (LPL). The LPL enzyme controls the rate of lipolysis - lipogenesis and is key in the storage of triglycerides in adipose tissues. It is the reduction of LPL activity that is associated with TCDD induced wasting syndrome. Mitrou et al. (2001)

Lipids, mostly triglycerides, accumulate in other tissues, such as the liver, which become fatty. Poland & Knutson (1982).

Renal function - tests carried out by Anaizi and Cohen (1978) have shown that after exposure to TCDD, the transitional epithelial lining of the urinary tract proliferates to two to three times its normal thickness. This structural effect on renal tissue can be accompanied by a significant decrease in the glomerular filtration rate.

Reproductive system - in males rats, exposure to TCDD and its congeners cause decreased spermatogenesis and testicular weight as well as degeneration of the seminiferous tubules. In females, plasma progesterone and estrogen concentration were found to be decreased following exposure to TCDD. Kociba, Keeler, Park & Gehrich (1976).

Dioxin as a carcinogen - Dioxin is a known carcinogen. IARC, the International Agency for Research on Cancer, which is part of the World Health Organization, classified it as a known human carcinogen in 1997. However, this contradicts the findings of a review by Cole, Trichopoulos, Pastides, Starr, and Mandel (2003). The findings state that the evidence does not support the IARC's classification of TCDD as a Group 1 carcinogen. Instead, the evidence indicates that TCDD is not carcinogenic to human beings at low levels and that it may not be carcinogenic to them even at high levels.

Dioxin specific P450 induction - the induction of CY2S1 by TCDD is exceptional, because all previously well-characterized cases of the induction of cytochromes P450 by dioxin involve members of the CYP1 family. Rivera, Saarikoski & Hankinson (2001). This report also cites research by Kurose, Tohkin and Fukuhara (1999), which identifies another dioxin-inducible CYP2 family member.

Tests available for measuring dioxins in human blood

Bioassay tests - using genetically modified mammal cells, this test will provide an estimate of the total TEQ concentration but not provide a measure of individual dioxin congeners in a sample. This test may respond to other chemicals in the sample and so is only used for screening. The advantage of the bioassay test is that the cost is lower than other test methods. (MDCH)

High-resolution gas chromatography/mass spectroscopy (HR-GC/MS) - analysis is the best way to measure total dioxin TEQ concentration and individual congeners. If lipid analysis is also carried out on the sample of blood, then results of the test can be given as units of dioxin TEQ per unit of blood lipid. while the HR-GC/MS method is more specific, it is also much more costly than the bioassay test. (MDCH)

Until recently, no established treatment protocol existed for dioxin poisoning. Of the 17 PCDDs and PCDFs analysed in the Victor Yushchenko case, only TCDD levels were higher than those in the general population. This indicated acute intoxication with pure TCDD. (Sorg et al. [2009])Strategies employed by doctors in the Yuschenko case included continuous monitoring of the poison, its form, distribution and elimination and to search for medical molecular- based solutions for the organs that were affected by the toxin. HR-GC/MS was employed to identify and quantify TCDD and its possible metabolites in serum lipid and subcutaneous fat samples. Reference samples for hydroxylated dibenzo-p-dioxins were not commercially available, so C12-labelled 3,3',4,5'-tetrachloro-4-hydroxybiphenyl were used. The findings from previous studies by Patterson, Needham, Pirkle, Roberts, Bagby, Garrett, Andrews, Falk, Bernert, Sampson and Houk, on the existence of an equilibrium between serum and adipose tissue levels of TCDD, were confirmed.

Elimination and half-life

Research in this area is extensive but largely carried out on rodents and other animals, which has its disadvantages. Of the few human cases regarding acute TCDD intoxication, the patients' main route of elimination is in the faeces. This is true of the Yushchenko and the 1998 case of two women who ingested TCDD, one of whom had the highest levels of TCDD ever recorded. Geusau, Schmaldienst, Derfler, Papke and Abraham reported the woman's blood concentration levels as 144,000 pg/g lipid weight (as seen in fig.2) and a half life of 560 days, which is considerably shorter than the median values of 7-9 years reported for background and moderate exposure. This supports the inverse association of the half-life with tissue concentration as reported by Patterson et al.

All research and information considered, (HR-GC/MS) analysis would be the most effective way to identify any raised levels of dioxins and specify the congener/s. Knowledge from this analysis combined with other clinical evidence such as chloracne and confirmation of P450 induction would establish whether the individual was a victim of dioxin poisoning.

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