Dioxin poisoning
Environmental Chemicals

Author: Federica Mellone
Date: 26/01/2014



The chemical name for dioxin is 2,3,7,8- tetrachlorodibenzo para dioxin TCDD .

The name "dioxins" is often used for the family of structurally and chemically relatedpolychlorinated dibenzo para dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Certain dioxin-like polychlorinated biphenyls (PCBs) with similar toxic properties are also included under the term "dioxins". Some 419 types of dioxin-related compounds have been identified but only about 30 of these are considered to have significant toxicity, with TCDD being the most toxic. PCDD/Fs (polychlorinated dibenzo-p-dioxins)are Persistent Organic Pollutants (POPs), generated by incomplete combustion of carbonaceous and chlorinated compounds.

They have to be monitored at emission, from stationary sources like waste incinerator, because of their toxicity.
They are for instance products such as: inorganic impurities arisen during industrial combustion processes within foundries, used-oil combustion, bleaching of wood pulp, domestic heating and road traffic. The dioxin generation rate is determined by the weight loss of the solid sample. It is constant during time for temperatures ranging between 75 and 100°C and for generation flow rates greater than or equal to 50mLmin-1.

Dioxin formation from waste incineration.2007

Mechanism of action

TCDD and dioxin-like compounds act via a specific receptor present in all cells: the aryl hydrocarbon (AH) receptor.
This receptor is a transcription factor which is involved in expression of genes; in fact it has been shown that high doses of TCDD either increase or decrease the expression of several hundred genes in rats. Genes of enzymes activating the breakdown of foreign and often toxic compounds are classic examples of such genes. TCDD increases the enzymes breaking down, e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene.
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. 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.
AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as TCDD, the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.
Infact AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons (polychlorinated dibenzodioxins, dibenzofurans and biphenyls) and polycyclic aromatic hydrocarbons (3-methylcholanthrene, benzo(a)pyrene, benzanthracenes and benzoflavones).
Naturally occurring compounds that have been identified as ligands of AhR include derivatives of tryptophan such as indigo dye and indirubin, tetrapyrroles such as bilirubin, the arachidonic acid metabolites lipoxin A4 and prostaglandin G, modified low-density lipoprotein and several dietary carotinoids. One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.

AHR/ARNT. 2012

The Aryl-Hydrocarbon Receptor Protein Interaction Network (AHR-PIN) as Identified by Tandem Affinity Purification (TAP) and Mass Spectrometry.2013

Scientists have searched for the physiological functions of the AH receptor for years, and one obvious function is to increase the activity of enzymes breaking down foreign chemicals or normal chemicals of the body as needed. There may be other functions, however, related to growth of various organs or other regulatory functions. The AH receptor is phylogenetically highly conserved transcription factor with a history of at least 500 million years, and found in all vertebrates, and its ancient analogs are important regulatory proteins even in more primitive species.In fact, knock-out animals with no AH receptor are quite sick and develop poorly. All this implies that a certain level of AH receptor activation is physiological and necessary for the body.

TCDD is not mutagenic and not directly genotoxic.

Its main action in causing cancer 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. There are other explanations such as endocrine disruption or altered signal transduction. 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.

Cases of exposure

  • 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. A number of animals died, and high concentrations of TCDD, up to 56,000 pg/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.

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. Several other long-term effects have been suspected, but the evidence is not very strong.

  • In 2004, then-presidential candidate Viktor Yushchenko of Ukraine was poisoned with a large dose of TCDD. His blood TCDD concentration was measured 108,000 pg/g of fat, which is the second highest ever measured. This concentration implies a dose exceeding 2 mg, or 25 μg/kg of body weight. Also he suffered from chloracne for many years, but again after initial malaise, other symptoms or abnormal laboratory findings were few.
  • During the Vietnam War , between 1962 and 1971, the United States military sprayed nearly 20,000,000 US gallons (76,000,000 l) of chemical herbicides and defoliants in Vietnam. The studies underline that mothers who ate no or less meat than fish and mothers who consumed more freshwater fish than marine fish had lower levels of dioxins in their breast milk. However, the type of water and the eating habits of mothers contributed only partly to the increased dioxin levels in their breast milk; the length of residency was the most important risk factor associated with increased dioxin body burdens of mothers.

Maternal risk factors associated with increased dioxin concentrations in breast milk in a hot spot of dioxin contamination in Vietnam.2013

  • An area of Campania, known as the Triangle of death , is contaminated with TCDD due to years of illegal waste disposal by organized crime.

  • 25 million of euros have been allocated to introduce free health screenings for residents of high-pollution areas, such as Taranto , in Apulia, and the so-called Triangle of death in Campania. The industrial establishment Ilva and the Triangle of death are at the centre of several political controversies aroused by the seriousness of health issues.
    Infact 174 deaths have been traced back to the steelwork's emissions. The GIP's advisors believe that the exposure to the pollutants that have been released has caused and still cause degenerative processes that lead to diseases or death. About 3 million cubic metres of dioxin are released per hour by the main chimney of the Ilva factory, although this quantity is beneath the legal threshold ,the quantity released should be zero because even
    very small emissions increase the probability that a certain number of people may die.

Monitoring of PCDD/Fs and dioxin-like PCBs and seasonal variations in mussels from the Mar Grande and the Mar Piccolo of Taranto (Ionian Sea, Southern Italy).2014

Dioxin pathologies

Although formation of dioxins is local, environmental distribution is global. Dioxins are found throughout the world in the environment. The highest levels of these compounds are found in some soils, sediments and food, especially dairy products, meat, and fish. Due to its volatility, dioxin can move long distance in the atmosphere before deposition, contaminating the ground, water, animal feed and finally the human body . Once dioxins have entered the body, they endure a long time because of their chemical stability and their ability to be absorbed by fat tissue, where they are then stored in the body. Their half-life in the body is estimated to be seven to eleven year. Dioxin levels in the breast milk residing near hot spots of dioxin contamination areas remain much higher than in unsprayed areas, suggesting that fetuses and breast-fed infants may be exposed to high levels of dioxins.

A general model of dioxin contamination in breast milk: results from a study on 94 women from the Caserta and Naples areas in Italy.2013

The general negative effects on human health are represented by:

  • Dermal toxicity (chloracne)
  • Disturbances of productive functions
  • Neurological effects
  • Diseases of endocrine system
  • Immunotoxicity
  • Carcinogenicity.
  • Chloracne

Chloracne is an acne-like eruption of blackheads, cysts and pustules associated with over-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.
The condition was first described in German industrial workers in 1897 by von Bettman, and was initially believed to be caused by exposure to toxicchlorine (hence the name "chloracne"). It was only in the mid-1950s that chloracne was associated with aromatic hydrocarbons.The substances that may cause chloracne are now collectively known as chloracnegens.

  • Disturbances of productive functions: endometriosis and utero exposure

Abstract Adverse living and nutritional conditions in utero and in early infancy may influence the risk of diseases in adult life, because fetal growth seems determined by interactions between the environment and the fetal genome and these interactions may determine the risk of postnatal disease and the capacity to react to and cope with the postnatal environment. It has been proven that massive fetal exposure to toxic agents causes an increased incidence of negative outcomes in pregnant women; of particular interest is the association between in utero exposure to toxic agents and the occurrence of endometriosis. Dioxin has negative effects on the male reproductive system. It reduces spermatogenesis, leading to infertility.

  • Carcinogenicity

TCDD 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. Carcinogenicity is associated with tissue damage, and it is often viewed now 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.

Prevention and control of dioxin exposure 3

Prevention or reduction of human exposure is best done via source-directed measures, i.e. strict control of industrial processes to reduce formation of dioxins as much as possible. More than 90% of human exposure to dioxins is through the food supply, mainly meat and dairy products, fish and shellfish. Consequently, protecting the food supply is critical. One approach includes, as mentioned above, source-directed measures to reduce dioxin emissions. Secondary contamination of the food supply needs to be avoided throughout the food-chain. Good controls and practices during primary production, processing, distribution and sale are all essential to the production of safe food. Food contamination monitoring systems must be in place to ensure that tolerance levels are not exceeded. It is the role of national governments to monitor the safety of food supply and to take action to protect public health. When incidents of contamination are suspected, countries should have contingency plans to identify, detain and dispose of contaminated feed and food. The exposed population should be examined in terms of exposure (e.g. measuring the contaminants in blood or human milk) and effects (e.g. clinical surveillance to detect signs of ill health).

World Health organitation
National Institute of Environmental Health Sciences
Formation of PCDDs, PCDFs, and coplanar PCBs from incineration of various woods in the presence of chlorides. 2003
The Aryl-Hydrocarbon Receptor Protein Interaction Network (AHR-PIN) as Identified by Tandem Affinity Purification (TAP) and Mass Spectrometry.2013
A general model of dioxin contamination in breast milk: results from a study on 94 women from the Caserta and Naples areas in Italy.2013
Dioxin formation from waste incineration.
Monitoring of PCDD/Fs and dioxin-like PCBs and seasonal variations in mussels from the Mar Grande and the Mar Piccolo of Taranto (Ionian Sea, Southern Italy).2014
United States Environmental Protection Agency

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