2,3,7,8-Tetrachlorodibenzodioxin
Encyclopedia
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (in short but inaccurately also called dioxin). It is the most potent compound (congener
) of the series and became known as a contaminant in Agent Orange
, a herbicide used in the Vietnam War, as well as the Seveso disaster
. It is a persistent environmental contaminant usually present in a complex mixture of dioxin-like compounds.
. This receptor is a transcription factor
which is involved in expression
of gene
s; 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 enzyme
s 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.
Also these polycyclic hydrocarbons 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.
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.
s or chlorophenoxy acid herbicides. It may also be formed along with other polychlorinated dibenzodioxins and dibenzofuranes in any burning, especially if certain metal catalysts such as copper are present (see dioxins and dioxin-like compounds
).
and wasting, and even after a huge dose animals die only 1 to 6 weeks after the TCDD administration. Seemingly similar species are very differently sensitive 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. 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. 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 effect
s and cancer
.
. Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents, and the development of teeth in rats. The latter is important in that tooth deformities were also seen after the Seveso accident and possibly after a long breast-feeding of babies in 1970s and 1980s when the dioxin concentrations in Europe were about ten times higher than at present.
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 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.
), but there are three historical cases of poisoning where the exposure has been to TCDD itself.
.
as a carcinogen
for humans (group 1). In the occupational cohort studies available for the classification, the risk, even at very high exposures, was weak and borderline detectable. Therefore human data were not deemed sufficient, and the classification was, in essence, based on animal experiments and mechanistic considerations. This has been criticized as a deviation from IARC classification rules. It is much debated, whether TCDD is carcinogenic only at high doses which also cause toxic damage of tissues. Moreover, a recent review concludes that, after 1997, further studies do not support an association between TCDD exposure and cancer risk. New studies include the update of Vietnam veteran studies from Ranch Hand operation, which concluded that after 30 years the results do not provide evidence of disease.
There is also direct epidemiological evidence that TCDD is not carcinogenic at low doses, and in some studies cancer risk has even decreased. This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk.
Congener
Congener has several different meanings depending on the field in which it is used. Colloquially, it is used to mean a person or thing like another, in character or action.-Biology:In biology, congeners are organisms within the same genus...
) of the series and became known as a contaminant in Agent Orange
Agent Orange
Agent Orange is the code name for one of the herbicides and defoliants used by the U.S. military as part of its herbicidal warfare program, Operation Ranch Hand, during the Vietnam War from 1961 to 1971. Vietnam estimates 400,000 people were killed or maimed, and 500,000 children born with birth...
, a herbicide used in the Vietnam War, as well as the Seveso disaster
Seveso disaster
The Seveso disaster was an industrial accident that occurred around 12:37 pm July 10, 1976, in a small chemical manufacturing plant approximately north of Milan in the Lombardy region in Italy...
. It is a persistent environmental contaminant usually present in a complex mixture of dioxin-like compounds.
Dioxins and dioxin-like compounds
Dioxins and dioxin-like compounds are by-products of various industrial processes, and are commonly regarded as highly toxic compounds that are environmental pollutants and persistent organic pollutants . They include:...
Mechanism of action
TCDD and dioxin-like compounds act via a specific receptor present in all cells: the aryl hydrocarbon (AH) receptorAryl hydrocarbon receptor
The Aryl hydrocarbon receptor is a member of the family of basic-helix-loop-helix transcription factors. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones...
. This receptor is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
which is involved in expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s; 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 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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.
Also these polycyclic hydrocarbons 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.
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
Genotoxic
In genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation....
. 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
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
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.
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 chlorophenolChlorophenol
A chlorophenol is any organochloride of phenol that contains one or more covalently bonded chlorine atoms. Chlorophenols are produced by electrophilic halogenation of phenol with chlorine. Most chlorophenols have a number of different isomers...
s or chlorophenoxy acid herbicides. It may also be formed along with other polychlorinated dibenzodioxins and dibenzofuranes in any burning, especially if certain metal catalysts such as copper are present (see dioxins and dioxin-like compounds
Dioxins and dioxin-like compounds
Dioxins and dioxin-like compounds are by-products of various industrial processes, and are commonly regarded as highly toxic compounds that are environmental pollutants and persistent organic pollutants . They include:...
).
Toxic effects in animal studies
By far most information on toxicity of dioxin-like chemicals is based on animal studies utilizing 2,3,7,8-TCDD. There is barely any organ without some effects by high doses of TCDD. In short-term toxicity studies in animals the typical effects are anorexiaAnorexia (symptom)
Anorexia is the decreased sensation of appetite...
and wasting, and even after a huge dose animals die only 1 to 6 weeks after the TCDD administration. Seemingly similar species are very differently sensitive to acute effects: lethal dose for a guinea pig
Guinea pig
The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
is about 1 µg/kg, but to a hamster
Hamster
Hamsters are rodents belonging to the subfamily Cricetinae. The subfamily contains about 25 species, classified in six or seven genera....
it is more than 1,000 µg/kg. A similar difference can be seen even between two different rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
strains. Various hyperplastic (overgrowth) or atrophic (wasting away) responses are seen in different organs, thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
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. 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 effect
Developmental toxicity
Developmental toxicity is any structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behaviour, and which is caused by environmental insult...
s and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Developmental effects
Developmental effects occur at very low doses in animals. They include frank teratogenicity such as cleft palate and hydronephrosisHydronephrosis
Hydronephrosis is distension and dilation of the renal pelvis calyces, usually caused by obstruction of the free flow of urine from the kidney, leading to progressive atrophy of the kidney...
. Development of some organs may be even more sensitive: very low doses perturb the development of sexual organs in rodents, and the development of teeth in rats. The latter is important in that tooth deformities were also seen after the Seveso accident and possibly after a long breast-feeding of babies in 1970s and 1980s when the dioxin concentrations in Europe were about ten times higher than at present.
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. Dose-response of TCDD in causing cancer does not seem to be linear, 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 of cancer initiated by other compounds or on indirect effects such as disturbing defense mechanisms of the body e.g. by preventing apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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 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.
Cases of poisoning
There have been a number of accidents where people have been exposed to high doses of dioxin-like chemicals (see Dioxins and dioxin-like compoundsDioxins and dioxin-like compounds
Dioxins and dioxin-like compounds are by-products of various industrial processes, and are commonly regarded as highly toxic compounds that are environmental pollutants and persistent organic pollutants . They include:...
), but there are three historical cases of poisoning where the exposure has been to TCDD itself.
- In 1976, thousands of inhabitants of SevesoSevesoSeveso is a town and comune in the Province of Monza and Brianza, in the Region of Lombardy. The economy of the town has traditionally been based around the furniture industry....
, Italy were exposed to TCDD after an accidental releaseSeveso disasterThe Seveso disaster was an industrial accident that occurred around 12:37 pm July 10, 1976, in a small chemical manufacturing plant approximately north of Milan in the Lombardy region in Italy...
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 chloracneChloracneChloracne 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...
. Long-term effects seem to include a slight excess of multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
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 ViennaViennaVienna is the capital and largest city of the Republic of Austria and one of the nine states of Austria. Vienna is Austria's primary city, with a population of about 1.723 million , and is by far the largest city in Austria, as well as its cultural, economic, and political centre...
, two women were poisoned at their workplace in 1998, and the measured concentrations in one of them were the highest ever measured in a human being, 144,000 pg/g of fat. This is about hundred thousandfold compared with TCDD concentrations in most people today, and about ten thousandfold compared with the sum of all dioxin-like compounds in young people today. She survived but suffered from difficult chloracne for several years. Aside from malaise and amenorrhea there were surprisingly few other symptoms or abnormal laboratory findings.
- In 2004, then-presidential candidate Victor Yushchenko of UkraineUkraineUkraine is a country in Eastern Europe. It has an area of 603,628 km², making it the second largest contiguous country on the European continent, after Russia...
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 body weight. Also he suffered from chloracne for many years, but again after initial malaise, other symptoms or abnormal laboratory findings were few.
Long-term effects in humans
The Expert Group of the World Health Organization considered developmental toxicity as the most pertinent risk of dioxins to human beings. Because people are usually exposed simultaneously to a number of dioxin-like chemicals, more detailed account is given at dioxins and dioxin-like compoundsDioxins and dioxin-like compounds
Dioxins and dioxin-like compounds are by-products of various industrial processes, and are commonly regarded as highly toxic compounds that are environmental pollutants and persistent organic pollutants . They include:...
.
Cancer in humans
TCDD was classified in 1997 by the International Agency for Research on CancerInternational Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....
as a carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
for humans (group 1). In the occupational cohort studies available for the classification, the risk, even at very high exposures, was weak and borderline detectable. Therefore human data were not deemed sufficient, and the classification was, in essence, based on animal experiments and mechanistic considerations. This has been criticized as a deviation from IARC classification rules. It is much debated, whether TCDD is carcinogenic only at high doses which also cause toxic damage of tissues. Moreover, a recent review concludes that, after 1997, further studies do not support an association between TCDD exposure and cancer risk. New studies include the update of Vietnam veteran studies from Ranch Hand operation, which concluded that after 30 years the results do not provide evidence of disease.
There is also direct epidemiological evidence that TCDD is not carcinogenic at low doses, and in some studies cancer risk has even decreased. This is called a J-shape dose-response, low doses decrease the risk, and only higher doses increase the risk.
See also
- Dioxins and dioxin-like compoundsDioxins and dioxin-like compoundsDioxins and dioxin-like compounds are by-products of various industrial processes, and are commonly regarded as highly toxic compounds that are environmental pollutants and persistent organic pollutants . They include:...
- Polychlorinated dibenzodioxins
- Seveso disasterSeveso disasterThe Seveso disaster was an industrial accident that occurred around 12:37 pm July 10, 1976, in a small chemical manufacturing plant approximately north of Milan in the Lombardy region in Italy...
- List of IARC Group 1 carcinogens
- ChloracneChloracneChloracne 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...