Dioxins and
dioxin-like compounds (DLC) are by-products of various industrial processes, and are commonly regarded as highly toxic
compoundCompound may refer to:* Chemical compounds, combinations of two or more elements* Compound , a cluster of buildings having a shared purpose, usually inside a fence or wall...
s that are environmental pollutants and
persistent organic pollutantthumb|right|275px|State parties to the Stockholm Convention on Persistent Organic PollutantsPersistent organic pollutants are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes...
s (POPs). They include:
- Polychlorinated dibenzo-p-dioxins (PCDDs), or simply, but inaccurately, dioxins. Technically PCDDs are derivatives of dibenzo-p-dioxin
Dibenzo-p-dioxin or dibenzo-1,4-dioxin is an organic heterocyclic compound in which two benzene rings are connected by a 1,4-dioxin ring. Its molecular formula is C12H8O2...
. There are 75 PCDDs, and seven of them are specifically toxic.
- Polychlorinated dibenzofurans
Polychlorinated dibenzofurans are a group of halogenated organic compounds which are toxic environmental pollutants. They are known teratogens, mutagens, and suspected human carcinogens. PCDFs tend to co-occur with polychlorinated dibenzodioxins...
(PCDFs), or simply furans. Technically PCDFs are derivatives of dibenzofuranDibenzofuran, is a heterocyclic organic compound with the chemical structure shown at right. It is an aromatic compound that has two benzene rings fused to one furan ring in the middle. All of the numbered carbon atoms have a hydrogen atom bonded to each of them...
. There are 135 congeners (derivatives differing only in the number and location of chlorine atoms). Whilst they strictly speaking are not dioxins, ten of them have "dioxin-like" properties.
- Polychlorinated biphenyl
Polychlorinated biphenyls are a class of organic compounds with 2 to 10 chlorine atoms attached to biphenyl, which is a molecule composed of two benzene rings. The chemical formula for PCBs is C12H10-xClx...
s (PCBs), which also are not dioxins, but twelve of them have "dioxin-like" properties. Under certain conditions PCBs may form more toxic dibenzofurans through partial oxidation.
- Finally, dioxin may refer to dioxin proper, the basic chemical unit of the more complex dioxins. This simple compound is not persistent and has no PCDD-like toxicity.
Because dioxins refer to such a broad class of compounds that vary widely in toxicity, the concept of toxic equivalence (TEQ) has been developed to facilitate risk assessment and regulatory control.
Toxic equivalence factorToxic equivalence factor 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....
s (TEFs) exist for seven
congenerCongener 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...
s of dioxins, ten
furanFuran is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....
s and twelve PCBs. The reference
congenerCongener 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...
is the most toxic dioxin
2,3,7,8-tetrachlorodibenzo-p-dioxin2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
(TCDD) which per definition has a TEF of one.
In reference to their importance as environmental toxicants the term dioxins is used almost exclusively to refer to the sum of compounds (as TEQ) from the above groups which demonstrate the same specific toxic
mode of actionHistorically, pesticides have often been classified according to their chemical groups and this is useful for understanding the properties of a given compound. However, it is the Mode of Action group which possibly represents the most useful pesticide classification for biologists...
associated with
TCDD2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
. These include 17 PCDD/Fs and 12 PCBs. Incidents of contamination with PCBs are also often reported as dioxin contamination incidents since it is this toxic characteristic which is of most public and regulatory concern.
Mechanism of toxicity
The toxic effects of dioxins are measured in fractional equivalencies of TCDD (
2,3,7,8-tetrachlorodibenzo-p-dioxin2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
), the most toxic and best studied member of its class (see
TCDD2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
for more detailed description of the mechanism). The toxicity is mediated through the interaction with a specific intracellular protein, the
aryl hydrocarbon (AH) receptorThe 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...
, a transcriptional enhancer, affecting a number of other regulatory proteins. This receptor is a
transcription factorIn 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
expressionGene 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 many
geneA 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. TCDD binding to the AH receptor induces the cytochrome P450 1A class of
enzymeEnzymes 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 which function to break down toxic compounds, e.g., carcinogenic polycyclic hydrocarbons such as benzo
(a)pyrene.
While the affinity of dioxins and related industrial toxicants to this receptor may not fully explain all their toxic effects including immunotoxicity, endocrine effects and
tumor promotionTumor promotion is a process in which existing tumors are stimulated to grow. It is the second phase in tumor development. Tumor promoters are not able to cause tumors to form.-External links:* entry in the public domain NCI Dictionary of Cancer Terms...
, toxic responses appear to be typically dose-dependent within certain concentration ranges. A multiphasic
dose-response relationshipThe dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
has also been reported, leading to uncertainty and debate about the true role of dioxins in cancer rates.
The endocrine disrupting activity of dioxins is thought to occur as a down-stream function of AH receptor activation, with thyroid status in particular being a sensitive marker of exposure. It is important to note that TCDD, along with the other PCDDs, PCDFs and dioxin-like coplanar PCBs are not direct agonists or antagonists of hormones, and are not active in assays which directly screen for these activities such as ER-CALUX and AR-CALUX. These compounds have also not been shown to have any direct mutagenic or
genotoxicIn 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....
activity. Their main action in causing cancer is cancer promotion. A mixture of PCBs such as Aroclor may contain PCB compounds which are known
estrogen agonistsEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
, but on the other hand are not classified as dioxin-like in terms of toxicity. Mutagenic effects have been established for some lower chlorinated chemicals such as 3-chlorodibenzofuran, which is neither persistent nor an AH receptor agonist.
Toxicity in animals
The symptoms reported to be associated with dioxin toxicity in animal studies are incredibly wide ranging, both in the scope of the biological systems affected and in the range of dosage needed to bring these about. Acute effects of single high dose dioxin exposure include wasting syndrome, and typically a delayed death of the animal in 1 to 6 weeks. By far most toxicity studies have been performed using
2,3,7,8-tetrachlorodibenzo-p-dioxin2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
.
The of TCDD varies wildly between species and even strains of the same species, with the most notable disparity being between the seemingly similar species of
hamsterHamsters are rodents belonging to the subfamily Cricetinae. The subfamily contains about 25 species, classified in six or seven genera....
and
guinea pigThe 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...
. The oral for guinea pigs is as low as 0.5 to 2 μg/Kg body weight, whereas the oral for hamsters can be as high as 1 to 5 mg/Kg body weight. Even between different mouse or rat strains there may be tenfold to thousandfold differences in acute toxicity. Many pathological findings are seen in the
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
,
thymusThe 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....
and other organs.
Some chronic and sub-chronic exposures can be harmful at much lower levels, especially at particular developmental stages including foetal, neonatal and pubescent stages. Well established developmental effects are cleft palate,
hydronephrosisHydronephrosis 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...
, disturbances in
tooth developmentTooth development or odontogenesis is the complex process by which teeth form from embryonic cells, grow, and erupt into the mouth. Although many diverse species have teeth, non-human tooth development is largely the same as in humans...
and sexual development as well as endocrine effects.
Human toxicity
Dioxins have been considered highly toxic and able to cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.
This is based on animal studies. Unequivocal evidence of the toxic effects on dioxins on human beings have been shown by surprisingly few studies. The best proven is
chloracneChloracne 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...
. Even in poisonings with huge doses of
TCDD2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
, the only persistent effects after the initial
malaiseMalaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
have been
chloracneChloracne 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...
and amenorrhea. In occupational settings many symptoms have been seen, but exposures have always been to a multitude of chemicals including chlorophenols, chlorophenoxy acid herbicides, and
solventA solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
s. Therefore proof of dioxins as causative factors has been difficult. The suspected effects in adults are liver damage, and alterations in
hemeA heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
metabolism, serum
lipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
levels,
thyroidThe thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
functions, as well as diabetes and
immunological effectsImmunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
.
In line with animal studies, developmental effects may be much more important than effects in adults. These include disturbances of
toothTeeth are small, calcified, whitish structures found in the jaws of many vertebrates that are used to break down food. Some animals, particularly carnivores, also use teeth for hunting or for defensive purposes. The roots of teeth are embedded in the Mandible bone or the Maxillary bone and are...
development, and of sexual development. An example of the variation in responses is clearly seen in a study following the
Seveso 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...
indicating that
spermThe term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
count and motility were affected in different ways in exposed males, depending on whether they were exposed before, during or after puberty.
Carcinogenicity
Dioxins are well established
carcinogensCarcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
in animal studies, although the precise mechanistic role is not clear. Dioxins are not mutagenic or
genotoxicIn 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....
. The
United States Environmental Protection AgencyThe U.S. Environmental Protection Agency is an agency of the federal government of the United States charged with protecting human health and the environment, by writing and enforcing regulations based on laws passed by Congress...
has categorised dioxin, and the mixture of substances associated with sources of dioxin toxicity as a "likely human carcinogen". The
International Agency for Research on CancerThe International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....
has classified TCDD as a human carcinogen (class 1) on the basis of clear animal carcinogenicity and limited human data, but was not able to classify other dioxins. It is thought that the presence of dioxin can accelerate the formation of tumours and adversely affect the normal mechanisms for inhibiting tumour growth, without actually instigating the carcinogenic event.
As with all toxic endpoints of dioxin, a clear dose-response relationship is very difficult to establish. After accidental or high occupational exposures there is evidence on human carcinogenicity. There is much controversy especially on cancer risk at low population levels of dioxins. Among fishermen with high dioxin concentrations in their bodies, cancer deaths were decreased rather than increased. Some researchers have also proposed that dioxin induces cancer progression through a very different mitochondrial pathway.
Risk assessment
The uncertainty and variability in the dose-response relationship of dioxins in terms of their toxicity, as well as the ability of dioxins to bioaccumulate mean that the
tolerable daily intakeTolerable daily intake refers to the daily amount of a chemical that has been assessed safe for human being on long-term basis . Originally acceptable daily intake was introduced in 1961 to define the daily intake of a food additive which, during the entire lifetime, appears to be without...
(TDI) of dioxin has been set very low, 1-4 pg/Kg body weight per day, i.e. 0.000 000 000 07 to 0.000 000 000 28 g per 70-kg person per day, to allow for this uncertainty and ensure public safety in all instances. Specifically, the TDI has been assessed based on the safety of children born to mothers exposed all their lifetime prior to pregnancy to such a daily intake of dioxins. It is likely that the TDI for other population groups could be somewhat higher. The most important cause for differences in different assessments is carcinogenicity. If the dose-response of TCDD in causing cancer is linear, it might be a true risk. If the dose-response is of a threshold-type or J-shape, there is little or no risk at the present concentrations. Understanding the mechanisms of toxicity better is hoped to increase the reliability of risk assessment.
Human intake and levels
Most intake of dioxin-like chemicals is from food of animal origin: meat, dairy products or fish predominate depending on the country. The daily intake of dioxins and dioxin-like PCBs as TEQ is of the order of 100 pg/day, i.e. 1-2 pg/kg/day. In many countries both the absolute and relative significance of dairy products and meat have decreased due to strict emission controls, and brought about the decrease of total intake. E.g. in the United Kingdom the total intake of PCDD/F in 1982 was 239 pg/day and in 2001 only 21 pg/day (WHO-TEQ). Since the half-lives are very long (for e.g. TCDD 7–8 years), the body burden will increase almost over the whole lifetime. Therefore the concentrations may increase five- to tenfold from age 20 to age 60. For the same reason, short term higher intake such as after food contamination incidents, is not crucial unless it is extremely high or lasts for several months or years.
The highest body burdens were found in Western Europe in the 1970s and early 1980s, and the trends have been similar in the U.S. The most useful measure of time trends is concentration in breast milk measured over decades. In many countries the concentrations have decreased to about one tenth of those in 1970s, and the total TEQ concentrations are now of the order of 10-30 pg/g fat (please note the units, pg/g is the same as ng/kg, or the non-standard expression ppt used sometimes in America). The decrease is due to strict emission controls and also to the control of concentrations in food. In the U.S. young adult female population (age group 20-39), the concentration was 9.7 pg/g lipid in 2001-2002 (geometric mean).
Certain professions such as subsistence fishermen in some areas are exposed to exceptionally high amounts of dioxins and related substances. This along with high industrial exposures may be the most valuable source of information on the health risks of dioxins.
Common uses
According to the Agency of Toxic Substances & Disease Registry:
- Dioxins are not intentionally produced and have no known use. They are the by-product
A by-product is a secondary product derived from a manufacturing process or chemical reaction. It is not the primary product or service being produced.A by-product can be useful and marketable or it can be considered waste....
s of various industrial processes (i.e., bleaching paper pulp, and chemical and pesticide manufacture) and combustionCombustion or burning is the sequence of exothermic chemical reactions between a fuel and an oxidant accompanied by the production of heat and conversion of chemical species. The release of heat can result in the production of light in the form of either glowing or a flame...
activities (i.e., burning household trash, forest fires, and waste incineration). The defoliant Agent OrangeAgent 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...
, used during the Vietnam WarThe Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...
, contained dioxins. Dioxins are found at low levels throughout the world in air, soilSoil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...
, waterWater is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, sedimentSediment is naturally occurring material that is broken down by processes of weathering and erosion, and is subsequently transported by the action of fluids such as wind, water, or ice, and/or by the force of gravity acting on the particle itself....
, and in foods such as meats, dairy, fish, and shellfish. The highest levels of dioxins are usually found in soil, sediment, and in the fatty tissues of animals. Much lower levels are found in air and water.
- CDDs are not manufactured commercially in the United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
except on a small scale for use in chemical and toxicological research. They are unique among the large number of organochlorine compounds of environmental interest in that they were never produced intentionally as desired commercial products.
Dioxins belong to the persistent organic chemicals ("dirty dozen") the production and use of which was banned by the
Stockholm ConventionStockholm Convention on Persistent Organic Pollutants is an international environmental treaty, signed in 2001 and effective from May 2004, that aims to eliminate or restrict the production and use of persistent organic pollutants .- History :...
in 2001.
Environmental sources
PCB-compounds, always containing low concentrations dioxin-like PCBs and PCDFs, were synthesized at large amounts for various technical purposes (see Polychlorinated biphenyls). They have entered the environment through accidents such as fires or leaks from transformers or heat exchangers, or from PCB-containing products in waste landfills or during incineration. Because PCBs are somewhat volatile, they have also been transported long distances by air leading to global distribution including the Arctic.
PCDD/F-compounds were never synthesized for any purpose, except for small quantities for scientific research. Small amounts of PCDD/Fs are formed whenever carbon, oxygen and chlorine are available at suitable temperatures. This is augmented by metal catalysts such as copper. The optimal temperatures are 400 to 700 °C. This means that formation is highest when organic material is burned at poor burning conditions. The most important sources of PCDD/Fs have been incineration of mixed municipal or hospital waste at too low temperatures as well as metal smelting and refining. Chlorine bleaching of pulp has been an important source of PCDD/Fs to waterways. PCDD/Fs are also formed as synthesis side products of several chemicals, especially PCBs, chlorophenols, chlorophenoxy acid herbicides and
hexachloropheneHexachlorophene, also known as Nabac, is a disinfectant. The compound occurs as a white to light-tan crystalline powder, which either is odorless or produces a slightly phenolic odor. In medicine, hexachlorophene is very useful as a topical anti-infective, anti-bacterial agent, often used in soaps...
. A poorly appreciated but important production of dioxins is “backyard barrel burning” of waste.
When the problems were realized, both industries and municipal authorities have worked to decrease the emissions. In waste incineration this is based on basically two improvements, increase of burning temperatures to over 1000 °C at a long enough residence time for burning gases, and flue gas cleaning and filtering techniques. This has been very important in Europe, because most of municipal mixed waste is incinerated. Then dioxins spread around the incinerator, and the fallout on pastures caused accumulation in farm animals, and high concentrations in dairy and meat products. Therefore European Union set in 2000 very strict exhaust limit values for dioxins, 0.1 ng/Nm³ (TEQ in exhaust gases).
Both in Europe and in U.S.A. the emissions have decreased dramatically since the 1980s, by even 90 %. This has also led to decreases in human body burdens, which is neatly demonstrated by the decrease of dioxin concentrations in breast milk.
Unfortunately the private small-scale burning (“backyard barrel burning”) has not decreased effectively, and in the U.S. it is now the most important source of dioxins. Total annual emissions decreased from 14 kg in 1987 to 1.4 kg in 2000. However, backyard barrel burning decreased only modestly from 0.6 kg to 0.5 kg, resulting in over one third of all dioxins coming in the year 2000 from backyard burning alone.
Low concentrations of dioxins have been found in some soils without any anthropogenic contamination. A puzzling case of milk contamination was detected in Germany. The reason was found out to be kaolin added to animal feed. Dioxins have been repeatedly detected in clays from Europe and USA since 1996. Contamination of clay is assumed to be the result of ancient forest fires or similar natural reasons, and enrichment during clay sedimentation.
Environmental persistence and bioaccumulation
All groups of dioxin-like compounds are persistent in the environment. Neither soil microbes nor animals are able to break down effectively the PCDD/Fs with lateral chlorines (positions 2,3,7, and 8). This causes very slow elimination. Ultraviolet light is able to slowly break down these compounds. Lipophilicity (tendency to seek for fat-like environments) and very poor water solubility make these compounds move from water environment to living organisms having lipid cell structures. This is called
bioaccumulationBioaccumulation refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. Bioaccumulation occurs when an organism absorbs a toxic substance at a rate greater than that at which the substance is lost...
. Increase in chlorination increases both stability and lipophilicity. The compounds with the very highest chlorine numbers (e.g. octachlorodibenzo-p-dioxin) are, however, so poorly soluble that this hinders their bioaccumulation. Bioaccumulation is followed by
biomagnificationBiomagnification, also known as bioamplification or biological magnification, is the increase in concentration of a substance that occurs in a food chain as a consequence of:* Persistence...
. Lipid soluble compounds are first accumulated to microscopic organisms such as phytoplankton (plankton of plant character, e.g. algae). Phytoplankton is consumed by animal plankton, this by invertebrates such as insects, these by small fish, and further by large fish and seals. At every stage or
trophic levelThe trophic level of an organism is the position it occupies in a food chain. The word trophic derives from the Greek τροφή referring to food or feeding. A food chain represents a succession of organisms that eat another organism and are, in turn, eaten themselves. The number of steps an organism...
the concentration is higher, because the persistent chemicals are not “burned off” when the higher organism uses the fat of the prey organism to produce energy.
Due to bioaccumulation and biomagnification the species at the top of the trophic pyramid are most vulnerable to dioxin-like compounds. In Europe the
white-tailed eagleThe White-tailed Eagle , also known as the Sea Eagle, Erne , or White-tailed Sea-eagle, is a large bird of prey in the family Accipitridae which includes other raptors such as hawks, kites, and harriers...
and some species of seals have been close to extinct due to poisoning of persistent organic pollutants. Likewise in America the populations of
bald eagleThe Bald Eagle is a bird of prey found in North America. It is the national bird and symbol of the United States of America. This sea eagle has two known sub-species and forms a species pair with the White-tailed Eagle...
declined because of POPs causing thinning of eggs and other reproductive problems. Usually the failure has been attributed mostly to
DDTDDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....
, but dioxins are also a possible cause of reproductive effects. Both in America and in Europe many waterfowl have high concentrations of dioxins, but usually not high enough to disturb their reproductive success Due to supplementary winter feeding and other measures also the white-tailed eagle is recovering (see
White-tailed eagleThe White-tailed Eagle , also known as the Sea Eagle, Erne , or White-tailed Sea-eagle, is a large bird of prey in the family Accipitridae which includes other raptors such as hawks, kites, and harriers...
). Also ringed seals in the Baltic Sea are recovering.
Human being is also at the top of the trophic pyramid, but due to a multitude of food sources as compared with seals and eagles feeding almost exclusively on fish, human concentrations are much less, 10-100 pg/g, compared with 9000 to 340,000 pg/g (TEQ in lipid) in eagles.
Because of different physicochemical properties, not all congeners of dioxin-like compounds find their routes to human beings equally well. Measured as TEQs, the dominant congeners in human tissues are 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 1,2,3,6,7,8-HxCDD and 2,3,4,7,8-PeCDF. This is very different from most sources where hepta- and octa-congeners may predominate. The WHO panel re-evaluating the TEF values in 2005 expressed their concern that emissions should not be uncritically measured as TEQs, because all congeners are not equally important. They stated that “when a human risk assessment is to be done from abiotic matrices, factors such as fate, transport, and bioavailability from each matrix be specifically considered”.
All POPs are poorly water soluble, especially dioxins. Therefore ground water contamination has not been a problem even in cases of severe contamination due to the main chemicals such as chlorophenols. In surface waters dioxins are bound to organic and inorganic particles.
Fate of dioxins in human body
The same features causing persistence of dioxins in the environment, also cause very slow elimination in humans and animals. Because of low water solubility, kidneys are not able to secrete them in urine as such. They should be metabolised to more water-soluble metabolites, but also metabolism especially in humans is extremely slow. This results in biological half-lives of several years for all dioxins. That of TCDD is estimated to be 7 to 8 years, and for other PCDD/Fs from 1.4 to 13 years, PCDFs on average slightly shorter than PCDDs.
Dioxins are absorbed well from the digestive tract, if they are dissolved in fats or oils (e.g. in fish or meat). On the other hand, dioxins tend to adsorb tightly to soil particles, and absorption may be quite low: 13.8 % of the given dose of TEQs in contaminated soil was absorbed.
In mammalian organisms dioxins are found mostly in fat. Concentrations in fat seem to be relatively similar, be it serum fat, adipose tissue fat or milk fat. This gives the possibility to measure body burden of dioxins by analysing breast milk. Initially, however, at least in laboratory animals, after a single dose high concentrations are found in the liver, but in a few days adipose tissue will predominate. In rat liver, however, high doses cause induction of CYP1A2 enzyme, and this binds dioxins. Thus depending on the dose, the ratio of fat and liver tissue concentrations may vary considerably in rodents.
Sources of human exposure
The most important source of human exposure is fatty food of animal origin (see Human intake, above). There is quite a lot of variation between different countries as to the most important items. In U.S. and Central Europe milk and dairy products and meat have been by far the most important sources. In some countries, notably in Finland and to some extent in Sweden, fish is important due to contaminated Baltic fish and very low intake from any other sources. In most countries a significant decrease of dioxin intake has occurred due to stricter controls during the last 20 years.
Historically occupational exposure to dioxins has been a major problem. Dioxins are formed as important toxic side products in the production of PCBs, chlorophenols, chlorophenoxy acid herbicides, and other chlorinated organic chemicals. This caused very high exposures to workers in poorly controlled hygienic conditions. Many workers had
chloracneChloracne 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...
. In a
NIOSHNational Institute of Occupational Health , also known as Statens arbeidsmiljøinstitutt or STAMI is a government body organised by the Norwegian Ministry of Labour and Social Inclusion. The institute deals with a range of health areas, with staff with competence in medicine, physiology, chemistry,...
study in the U.S., the average concentration of TCDD in exposed persons was 233 ng/kg (in serum lipid) while it was 7 ng/kg in unexposed workers, even though the exposure had been 15-37 years earlier. This indicates a huge previous exposure, in fact the exact back-calculation is debated, and the concentrations may have been even several times higher than originally estimated.
Handling and spraying of chlorophenoxy acid herbicides may also cause quite high exposures, as clearly demonstrated by the users of
agent orangeAgent 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...
in
Vietnam WarThe Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...
. The highest concentrations were detected in nonflying enlisted personnel (e.g. filling the tanks of planes), although the variation was huge, 0 to 618 ng/kg TCDD (mean 23.6 ng/kg). Other occupational exposures (working at paper and pulp mills, steel mills and incinerators) have been remarkably lower.
Accidental exposures have been huge in some cases. The highest concentrations in people after the
Seveso accidentThe 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...
were 56,000 ng/kg, and the highest exposure ever recorded was found in Austria in 1998, 144,000 ng/kg (see
TCDD2,3,7,8-Tetrachlorodibenzo-p-dioxin is a polychlorinated dibenzo-p-dioxin . It is the most potent compound 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...
). This is equivalent to a dose of 20 to 30 μg/kg TCDD, a dose that would be lethal to guinea pigs and some rat strains.
Exposure from contaminated soil is possible, if children eat dirt or if dioxins are blown up in dust. This was clearly demonstrated in Missouri, when waste oils were used as dust suppressant in horse arenas. Many horses and other animals were killed due to poisoning. Dioxins are neither volatile nor water soluble, and therefore exposure of human beings depends on direct eating of soil or production of dust which carries the chemical. Contamination of ground water or breathing vapour of the chemical are not likely to cause a significant exposure. Currently, in the United States, there are 126 Superfund sites (with a completed exposure pathway) contaminated with dioxins.
TEF values
All dioxin-like compounds share a common mechanism of action via the aryl hydrocarbon receptor (AHR), but their potencies are very different. This means that similar effects are caused by all of them, but much larger doses of some of them are needed than of TCDD. Binding to the AHR as well as persistence in the environment and in the organism depends on the presence of so called "lateral chlorines", in case of dioxins and furans, chlorine substitutes in positions 2,3,7, and 8. Each additional chlorine decreases the potency, but qualitatively the effects remain similar. Therefore a simple sum of different dioxin congeners is not a meaningful measure of toxicity. To compare the toxicities of various congeners and to render it possible to make a toxicologically meaningful sum of a mixture, a toxicity equivalency (TEQ) concept was created.
Each congener has been given a toxicity equivalence factor (TEF). This indicates its relative toxicity as compared with TCDD. Most TEFs have been extracted from
in vivo toxicity data on animals, but if these are missing (e.g. in case of some PCBs), less reliable
in vitro data have been used. After multiplying the actual amount or concentration of a congener by its TEF, the product is the virtual amount or concentration of TCDD having effects of the same magnitude as the compound in question. This multiplication is done for all compounds in a mixture, and these "equivalents of TCDD" can then simply be added, resulting in TEQ, the amount or concentration of TCDD toxicologically equivalent to the mixture.
The TEQ conversion makes it possible to use all studies on the best studied TCDD to assess the toxicity of a mixture. This resembles the common measure of all alcoholic drinks: beer, wine and whiskey can be added together as absolute alcohol, and this sum gives the toxicologically meaningful measure of the total impact.
The TEQ only applies to dioxin-like effects mediated by the AHR. Some toxic effects (especially of PCBs) may be independent of the AHR, and those are not taken into account by using TEQs.
TEFs are also approximations with certain amount of scientific judgement rather than scientific facts. Therefore they may be re-evaluated from time to time. There have been several TEF versions since the 1980s. The most recent re-assessment was by an expert group of the World Health organization in 2005.
WHO Toxic Equivalence Factors (WHO-TEF) for the
dioxin-like congeners of concern
generated with :de:Wikipedia:Helferlein/VBA-Macro for EXCEL tableconversion V1.7<\hiddentext>>
| Polychlorinated dioxins |
|
2,3,7,8-TCDD
| 1 |
1,2,3,7,8-PeCDD
| 1 |
1,2,3,4,7,8-HxCDD
| 0.1 |
1,2,3,6,7,8-HxCDD
| 0.1 |
1,2,3,7,8,9-HxCDD
| 0.1 |
1,2,3,4,6,7,8-HpCDD
| 0.01 |
| OCDD Octachlorodibenzodioxin is a lesser known polychlorinated dibenzodioxin . It is a teratogen, mutagen, and a possible carcinogen....
| 0.0003 |
Polychlorinated dibenzofurans
| |
2,3,7,8-TCDF
| 0.1 |
1,2,3,7,8-PeCDF
| 0.03 |
2,3,4,7,8-PeCDF
| 0.3 |
1,2,3,4,7,8-HxCDF
| 0.1 |
1,2,3,6,7,8-HxCDF
| 0.1 |
1,2,3,7,8,9-HxCDF
| 0.1 |
2,3,4,6,7,8-HxCDF
| 0.1 |
1,2,3,4,6,7,8-HpCDF
| 0.01 |
1,2,3,4,7,8,9-HpCDF
| 0.01 |
OCDF
| 0.0003 |
Non-ortho-substituted PCBs
| |
3,3',4,4'-TCB (PCB77)
| 0.0001 |
3,4,4',5-TCB (PCB81)
| 0.0003 |
3,3',4,4',5-PeCB (PCB126)
| 0.1 |
3,3',4,4',5,5'-HxCB (PCB169)
| 0.03 |
Mono-ortho-substituted PCBs
| |
2,3,3',4,4'-PeCB (PCB105)
| 0.00003 |
2,3,4,4',5-PeCB (PCB114)
| 0.00003 |
2,3',4,4',5-PeCB (PCB118)
| 0.00003 |
2',3,4,4',5-PeCB (PCB123)
| 0.00003 |
2,3,3',4,4',5-HxCB (PCB156)
| 0.00003 |
2,3,3',4,4',5'-HxCB (PCB157)
| 0.00003 |
2,3',4,4',5,5'-HxCB (PCB167)
| 0.00003 |
2,3,3',4,4',5,5'-HpCB (PCB189)
| 0.00003 |
(T = tetra, Pe = penta, Hx = hexa, Hp = hepta, O = octa)
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