WikiJournal of Medicine/Dioxins and dioxin-like compounds: toxicity in humans and animals, sources, and behaviour in the environment
Jouko Tuomisto (2019), "Dioxins and dioxin-like compounds: toxicity in humans and animals, sources, and behaviour in the environment", WikiJournal of Medicine, 6 (1): 8, doi:10.15347/WJM/2019.008, ISSN 2002-4436, Wikidata Q83503827
PCDD/PCDFs are formed mostly as side products in burning processes, but PCBs were oils manufactured for many purposes. Because of toxicity and persistence, dioxin-like compounds have been regulated strictly since 1980s, and their levels in the environment and animals have decreased by an order of magnitude or more. Therefore the effects on wildlife have clearly decreased, and even populations at the top of the food web such as fish-eating birds or seals have recovered after serious effects on their reproductive capacity and developmental effects in their young especially in 1970s and 1980s. This does not exclude the possibility of some remaining effects.
In humans the intake is mostly from food of animal sources, but because our diet is much more diverse than that of such hallmark animals as white-tailed eagles or seals, the concentrations never increased to similar levels. However, during 1970s and 1980s effects were probably also seen in humans, including developmental effects in teeth, sexual organs, and the development of immune systems.
Both scientists and administrative bodies debate at the moment about the importance of remaining risks. This is very important, because the AH receptors seem to be physiologically important regulators of growth and development of organs, immunological development, food intake and hunger, and in addition regulate enzymes protecting us from many chemicals. Thus a certain level of activation is needed, although inappropriate stimulation of the receptor is harmful. This dualism emphasizes the importance of benefit versus risk analysis. As a whole, regulating the emissions to the environment is still highly important, but one should be very cautious in limiting consumption of important and otherwise healthy food items and e.g. breast feeding.Distinct toxic effects of high doses of dioxins in humans have been clearly demonstrated by frank poisonings and the highest occupational exposures. Hallmark effects have been skin lesions called chloracne, various developmental effects of children, and a slightly increased risk of total cancer rate. The highest dioxin levels have been ten thousand fold higher than those seen in the general population today.
Note: This review is based on original studies and scientific reviews, independently of existing Wikipedia articles, and as interpreted by author's 35 year experience in dioxin research. However, pieces of similar information can be found in Wikipedia articles Dioxins and dioxin-like compounds, 2,3,7,8-tetrachlorodibenzodioxin, Polychlorinated dibenzodioxins, Polychlorinated dibenzofurans, Polychlorinated biphenyl, and Persistent organic pollutant.
“Dioxins” is an imprecise term including structurally related groups of chemicals such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Certain polychlorinated biphenyls (dl-PCBs) and many other chemicals have dioxin-like properties. The term “dioxin-like” is used because these chemicals have a common mechanism of action, i.e. inappropriate stimulation of aryl hydrocarbon receptor (AH receptor, AHR, “dioxin receptor”).
Among compounds binding to the AH receptor, the higher the binding affinity, the higher will be the toxicity. High toxicity means that even low doses or low exposure levels are sufficient to produce toxic responses. Compounds with lower affinity for the AH receptor require higher doses to elicit similar toxic effects. Low-affinity compounds (e.g. some PCBs, usually at relatively high doses) can elicit toxic effects that are different from those of characteristic dioxin-like effects of chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Dioxins are a puzzling group of chemicals that have widely diverse effects in different cell-types, tissues and animal species. Many lay people consider them only dreaded environmental “superpoisons”. But they are also highly interesting tools for studying the mechanisms of intracellular receptors, gene expression, growth and development of organs, metabolism of chemicals in the body, carcinogenesis, food intake and hunger, as well as interactions of chemicals, microbes and immunological systems. The AH receptor, the mediator of dioxin toxicity seems to be an important physiological actor in the body, a ligand-activated transcription factor functionally similar but structurally unrelated to intracellular receptors such as steroid or thyroid receptors. This reminds us of the ultimate principle of Paracelsus: all things are poisons, only the dose makes that a thing is not a poison. AH receptors are necessary for many normal biological functions, and their physiological activation regulates our wellbeing, but their inappropriate activation leads to multiple forms of toxicity.
The best studied compound is the most toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The toxicity of other compounds is compared with this prototype. TCDD is assigned a toxicity equivalence factor (TEF) of 1. The potency and toxicokinetics of other compounds vary over orders of magnitude, and therefore each compound is assigned its own TEF that may range from 1 to 0.000 03 (or lower for fish, see below). The TEF for each compound forms the basis for defining toxic equivalency (TEQ) when assessing the toxicity of mixtures.
The metabolism and excretion of dioxins in mammals is generally very slow. Dioxins are also persistent and accumulate in the biosphere. Due to slow accumulation to animals and humans, delayed toxicity is the typical mode of harmful effects and the delay between exposure and effect complicates the assessment of risk from dioxins. Developmental adverse effects are seen at the lowest doses.
A few dramatic cases of accidental or deliberate acute poisoning are known. Two women were poisoned in Vienna, Austria, in 1998 by large doses of TCDD. In 2004 Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned with a huge dose of TCDD. A widely known dioxin accident took place in Seveso, Italy in 1976. These and similar high-dose incidents have delineated the acute effects on humans. As described in detail later in this article it is more difficult to ascertain, precisely, what are the human health effects of chronic low-dose exposures to dioxin-like compounds. This remains a contentious issue of importance to regulatory agencies as well as to the general public. For a short account of historical legacies of dioxins see Weber et al. Due to intensive research efforts dioxin toxicity is known and understood better than that of most environmental toxic agents. On the other hand, it is beguilingly complicated.
There are 75 possible congeners of polychlorinated dibenzo-p-dioxins (PCDD) and 135 possible congeners of polychlorinated dibenzofurans (PCDF). So-called lateral chlorine substitutions at the positions 2,3,7, and 8 (Fig. 1) allow the dioxins to bind to the AH receptor with high affinity. They also prevent enzymatic attacks on the molecule causing persistence both in human body and in the environment. Such compounds are particularly toxic and constitute the prototype for dioxin-like toxicity. TEF values have been assigned to 17 congeners (seven dibenzo-p-dioxins and ten dibenzofurans) having four to eight chlorine substitutions. Chlorines in excess of the four (2,3,7 and 8) decrease the potency, but the type of toxic effects remains mainly the same.
There are 209 PCB-compounds. Four non-ortho compounds that have no chlorine substitution in any o-position to the inter-ring C-C-bridge (2, 2’, 6 or 6’) have the greatest dioxin-like potency (Fig. 2). The toxicity of 3,3’,4,4’,5-penta-CB (PCB126) is comparable to those dioxins assigned the TEF value although high toxicity in humans has been challenged. Eight mono-ortho PCBs have very low activity. All other PCBs are devoid of noticeable dioxin-like effects. Only compounds that are able to assume a planar (flat) conformation can bind to the AH receptor. Non-ortho compounds rotate relatively freely along the C-C-bridge between the rings, but each o-chlorine causes a steric hindrance and makes it more difficult for the molecule to assume a planar conformation (Fig. 2).
Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, may share the toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data. Many other compounds bind to the AH receptor, e.g. polyaromatic hydrocarbons and polychlorinated azoxy-benzenes and naphthalenes.
Surprisingly, many natural compounds have very high affinity to AH receptors. These include e.g. indoles, flavones, benzoflavones, imidazoles and pyridines (for review, see Denison and Nagy; DeGroot et al.). They are usually metabolized rapidly, but due to continuous intake from food, especially vegetables, they may cause receptor activation at the same level as or higher than the present background concentrations of contaminant dioxins. Short-acting stimulations of the receptor may, however, be qualitatively different from the persistent stimulation of dioxins. Intriguingly many of these vegetables are considered very healthy.
Sources of different dioxin-like chemicals are different depending upon the chemical class. PCDD/F compounds are unwanted side products in burning processes or are impurities in the synthesis of PCBs, chlorophenol fungicides and phenoxy acid herbicides. Due to control measures, main sources are very different today than they were 30 or 40 years ago. The decrease in environmental levels was clearly demonstrated in sea bottom sediment core studies: the peak concentrations are in sediments layered in about 1980s. However, further reduction especially of air emissions is needed.
Any burning will produce PCDD/Fs if chlorine (particularly along with metal catalysts) is available, even burning wood and burning incense. Poorly controlled urban waste incineration was one of the most important sources in past. This can be technically solved by ensuring high incineration temperature (1,000 °C or higher), long burning time, and effective flue gas filtration. In modern good-quality incinerators PCDD/Fs are effectively removed. On the other hand, accidental dumpsite fires and backyard burning of waste are much more problematic and poorly controlled. In poor burning conditions the production of PCDD/Fs can be very high.
Many previous sources of PCDD/Fs are presently in reasonable control (e.g. decreased chlorine bleaching of pulp, syntheses of PCBs, chlorophenols and phenoxy acids etc.). Metal industries and local burning of solid fuels remain as sources. Emissions decreased between 1985 and 2004 by about 80 % in Europe (from 14 kg per year I-TEQ[a] to 2–4 kg), in the USA between 1987 and 2000 even more (from 14 kg to 1.4 kg) (Fig. 3). In the USA the top three current sources of dioxin emissions to air are forest fires, backyard burning of trash, and medical waste incinerators. The trend is not satisfactory in all countries, however. Electronic waste recycling in poorly-controlled conditions is a recent additional concern as a source of dioxin-like compounds. It should be noted that there are also natural sources of PCDD/Fs such as kaolinic clay and volcanic eruptions.
PCB compounds were in wide use from 1930s to 1980s for multiple purposes because they are technically excellent oils, resistant to pressure, chemically resistant, non-flammable, and do not conduct electricity. Although their production was discontinued in most countries in the 1980s, these compounds still linger in many products such as electrical transformers and plastic materials. Some of it ends up to the general environment. Only a minor portion of PCBs in mixtures are dioxin-like, depending on the matrix, for example non-ortho congeners are of the order of 0.1 % and mono-ortho congeners 10 % of the total amount of PCBs.
- I-TEQ (international TEQ for PCDD/Fs) was used before present TEQs were agreed under the auspices of the World Health Organization. The differences are minor. The TEQs used in this text are sometimes called WHO-TEQs.
Dioxins tend to accumulate in the environment, because they are persistent and not easily degraded by environmental microbes. Because dioxins are much more soluble in lipids than in water, they tend to accumulate in e.g. plankton (bioaccumulation). The concentration tends to magnify at each trophic level (biomagnification), which leads to high concentrations at the highest trophic levels, e.g. seals and predatory birds. Human concentrations are not nearly as high as in the most endangered wild species, because human diet is quite diverse. However, there have been concerns regarding the safety of wild and farmed fish in our diet (see below).
TCDD has been long known to be sensitive to photochemical dechlorination. If exposed to direct sunlight or UV-radiation, it will decompose in a matter of hours. Photocatalysis and other methods have also been tested in attempts to remove dioxins in soils and other environments. Because dioxins adsorb tightly to soil particles, and microbial degradation (mostly via dehalogenation) of dioxins is very slow, researchers have actively tried to search for mechanisms to increase degradation or to find especially active microbial species for the purposes of bioremediation. By and large, this has not been very successful. Also interactions with the microbiome in the intestines are poorly known.
|Dioxin literature is confusing to many readers, because units used may be less known and they are sometimes used in a confusing manner. Some dioxins are very potent and therefore the amounts of our concern are very small, usually measured as picograms or nanograms. Picogram is 0.000 000 000 001 g. Concentrations in animal or human tissues are usually expressed as pg/g lipid or ng/kg lipid. Some authors use non-standard expression ppt (parts per trillion). This is confusing and should be avoided, since trillion may mean 1012 or 1018 in different countries depending on the use of short scale or long scale system, resp.
To make it clear, weight units are g (gram), mg (milligram, 10-3 g), μg (microgram, 10-6 g), ng (nanogram, 10-9 g), pg (picogram, 10-12 g), fg (femtogram, 10-15 g).
Toxicokinetics: absorption, distribution and elimination
The main source of dioxins in animals and humans is food. Oral absorption of dioxins depends on the carrier. Dioxins in the fat of fish or meat are well absorbed, but those in e.g. soils poorly. Also dermal absorption depends on the carrier. After absorption they are distributed mostly to adipose tissue and to the liver. Liver sequestration increases at high dose levels due to induction of CYP1A2 binding dioxins.
Elimination of dioxins is slow, because they are not easily metabolized and urinary excretion is negligible. Elimination is mainly via faeces after slow metabolism in the liver, followed by biliary excretion into the gut. Variation between species is large, e.g. the half-life of TCDD in rats is about 3 weeks, in man about 7 years. Elimination half-lives of various congeners in people may vary tenfold (Table 1). There may be high individual variation. Very high concentrations seem to induce metabolizing enzymes and shorten the half-lives.
Table 1 | Elimination half-lives in humans of some PCDD/Fs.
Nursing mothers excrete dioxins in milk fat at approximately the same concentrations as their own level in body fat. This means that maternal dioxin levels decrease during the lactation period (even by 20%). Also placental PCDD/F concentrations are in the same range as in maternal body or breast milk (as pg/g fat) and placental transfer to the foetus occurs. Each delivery and lactation decreases the mother's body burden by 25–30%. In children elimination is faster than in adults, initially with a half-life of months rather than years, probably due to several factors, faster rate of faecal lipid excretion, and increased metabolism. Rapid growth and dilution decrease the concentrations as well, even if the body burden does not change to the same extent.
Mechanism of action: the Aryl Hydrocarbon Receptor
Most biological actions of dioxins, including their toxicity, are mediated by the AHR (Fig. 4). The AHR is an evolutionarily ancient receptor, an over 600-million-year old protein occurring in all vertebrates. Homologs of the AHR have also been discovered in invertebrates and insects. These primitive AHR-homologs do not bind dioxins or other external ligands. They seem to play important developmental roles in neuronal differentiation and regulation of feeding-related aggregation behaviour or in regulation of normal morphogenesis.
The AHR belongs to the family of basic Helix–Loop–Helix-PAS (bHLH/PAS) proteins, which have important roles in e.g. regulation of neural development, in generation and maintenance of circadian rhythms, in sensing cellular environment, and as transcriptional partners and co-activators. Although it is structurally different, the AHR acts as a transcription factor analogously to the nuclear receptors such as steroid receptors or thyroid receptors. The AHR is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner.
The AHR exists in the cytosol in a protein complex including several proteins (Fig. 5). These chaperones keep the AHR in a conformation able to bind a ligand but unable to enter the nucleus. After ligand binding, the protein complex enters into the nucleus. The AHR releases its chaperones and heterodimerizes with another bHLH/PAS protein, ARNT (AHR nuclear translocator). The AHR/ARNT dimer binds to DNA at the major groove of the DNA helix at specific sites, AHR response elements (also known as dioxin response elements, DREs, or xenobiotic response elements XREs).
In addition to this canonical pathway, some actions of dioxins and AHR are mediated via non-canonical pathways. These may be involved e.g. in interactions with other receptors, such as estrogen receptor, other transcription factors such as NFκB signalling complex, different kinases, and various epigenetic mechanisms. Interactions with the retinoid system are especially interesting, because some effects of dioxins are similar to symptoms of vitamin A deficiency (e.g. retarded growth, problems in reproduction) and some resemble the toxic effects of vitamin A (such as developmental malformations). It seems that dioxins are involved both in metabolic steps of retinoid activation and metabolism as well as in molecular interactions of retinoid receptors and AHR in the transactivation machinery. 
In response to activation by dioxins, the AHR signalling pathway modifies the expression levels of numerous genes. The best characterized of these at the molecular level is the induction of the gene for a Phase I cytochrome P-450 drug-metabolizing enzyme, CYP1A1.
Dioxin-activated AHR induces other Phase I and II enzymes that metabolize chemicals in the liver including CYP1A2, CYP1B1, CYP2S1, CYP2A5, ALDH3, GSTA1, UGT1A1, UGT1A6, UGT1A7 and NQO1. Probably this induction system evolved as a mechanism to enhance the elimination of foreign fat-soluble chemicals. In addition to xenobiotic-metabolizing enzymes, TCDD exposure modifies the expression of a large number of other genes. For example, in adult mouse or rat liver, hundreds of genes are affected. It is still unclear which genes are the most important for the toxic effects such as lethality, anorexia and wasting syndrome, and various hyperplastic and atrophic tissue changes.
The role of AH receptor predominantly as an inducer of metabolic enzymes to protect us from xenobiotics is rapidly changing. Mice lacking AHR (AHR knockout) have clearly demonstrated the necessity of AHR activation for normal physiology, and these animals are severely sick with e.g. cardiac hypertrophy, liver fibrosis, reproductive problems, and impaired immunology. AH receptors participate in many regulatory functions in the body (the reader is referred to recent reviews). An important area seems to be antibacterial and antiviral defence mechanisms and the regulation of innate immunity. AHR ligands are important at intestinal epithelial cells which serve as gatekeepers for their supply, and if AHR activation is too low, loss of important lymphoid cells and subsequent susceptibility to infections follow.
Dioxins and dioxin-like compounds vary in their potency and fate in the organisms. The toxicity of mixtures cannot be assessed by simply adding up the amounts or concentrations of all chemicals in the mixture. However, if the amount of a compound is standardized to the toxicologically equivalent amount of TCDD, chemicals with different potencies can be summed up and this equivalent quantity is very useful for regulatory and even some scientific purposes. Several versions of TEF have been used since 1984, proposed by Ontario Ministry of Environment, U.S. Environmental Protection Agency, and the Nordic Countries, respectively. International harmonization was undertaken by NATO/CCMS, and most recently the World Health Organization organized re-evaluations of TEF values in 1998, 2005 and 2013. Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, share many aspects of toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data. On interim basis the TEFs of respective chlorinated compounds has been recommended.
The toxicities can vary by a factor of 30,000, and TCDD is assigned a TEF of 1. Other chemicals are given TEF values of 1 to 0.000 03 (in fish down to <0.000 005) (Table 2). The amount of a given compound is multiplied by its TEF, resulting in the amount toxicologically equivalent to that of TCDD. These partial equivalent amounts are then added up to make the sum toxic equivalent (TEQ) of the mixture. This can be used as a proxy of the total dose of dioxin-like compounds. This is a consensus value based on several assumptions and not a strictly scientific fact. Therefore they should be regularly updated to reflect new and more accurate information. This is because there are a number of uncertainties regarding kinetics, additivity, species differences, and slopes of dose-response curves.
|Class||Congener||WHO-TEF 2005||WHO-TEF fish 1998||WHO-TEF birds 1998|
PCDD/F congeners usually seem to act additively, which justifies the use of TEFs. With less potent compounds, partial antagonism is possible. This may lead to overestimation of the total toxicity. In fact, some in vitro results indicate that there may be significant deviations in human sensitivity from the TEF values based mostly on rodent data.
If toxicity studies, such as on lethality, immunotoxicity and reproductive toxicity, are available, TEF values are based on them. If they are lacking, it may be necessary to base the values on in vitro information. Most studies are based on oral intake, so the values correlate best with oral toxicity. Internal TEF values based on concentrations in the body would be preferable, but there is not enough data to formulate them. Different endpoints of toxicity may lead to different TEF values; hence the values are always balanced compromises and show only the order of magnitude.
Slightly different TEF values have been assessed for fish and birds, in addition to those of humans and other mammals (Table 2).
Wildlife: exposures and toxic effects
Toxic effects in wildlife are difficult to sort out, because usually the exposures have been to mixtures of quite different chemicals such as PCDD/Fs, dioxin-like PCBs as well as simultaneous exposure to non-dioxin-like PCBs, DDT and other chlorinated insecticides such as aldrin, dieldrin, lindane and others. Effects of individual chemicals on animals have been studied in laboratory conditions, but ecological impact is more difficult to assess. Effects on wildlife and domestic animals have been reviewed, e.g.
Developmental and embryotoxicity are the most sensitive effects of dioxins. Trout and other salmonids are the most sensitive species of fish. Sensitivities among fish species vary up to 120-fold. Typical findings are excess mortality, oedema, haemorrhages, and craniofacial malformations. So-called blue sac disease of early embryos is associated with high concentrations of TCDD and other dioxin-like compounds. Adult fish are less susceptible showing wasting syndrome, fin necrosis, liver toxicity, and loss of weight at high doses, and impaired reproduction especially in females. Dioxins, along with overfishing, are considered a reason for the lake trout population crash in the Great Lakes in the U.S.A. and Canada in mid-twentieth century. Experimentally it is possible to pinpoint the results at a specific chemical, and the mechanisms of toxicity in fish have been studied in zebrafish, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden et al.).
A number of bird species have also been shown to be sensitive to embryonal toxicity and problems in reproduction. High concentrations of dioxins, PCBs and DDT in fish have threatened the populations of fish-eating birds, especially eagles and ospreys with incredible total PCB levels of up to 1,000 μg/g in fat, due to the position of these birds at the top of the food chain.
Marine mammals are also on top of the food chain, highest are polar bears. On the other hand, polar bears also metabolize polychlorinated compounds fairly effectively. PCB concentrations seem to be 2–5-fold higher than in seals, their main food source. In Canadian seals total PCB levels vary from 300 to 1,000 ng/g (wet weight in blubber), and TEQs are of the order of 0.5–0.6 pg/g. In the Baltic Sea, which is the most contaminated brackish water area in the world, total PCB levels in ringed seals are presently about 5,000 ng/g (in fat) and PCDD/F levels about 40 pg/g TEQ (in fat). The levels were 8-fold and 20-fold higher, resp., in 1970s, and at that time POPs are considered having been an important reason for their poor reproductive success. POPs are also implicated in bone deformities in seals and polar bears.
In addition to marine mammals, developmental effects were shown in bank voles living in an environment contaminated by chlorophenols and their dioxin impurities: they had third molars reduced in size. In laboratory rats, TCDD reduces dose-dependently the size of molars, most severely the third lower molars.
As in humans, the concentrations of dioxins (as well as DDT and its metabolites) in wildlife have clearly decreased over the years, e.g. in seals of the Baltic sea, in eggs of herring gulls of the Great Lakes, in eggs around contaminated harbour sites, and guillemot eggs of the Baltic sea, in white-tailed eagles in Scandinavia, as well as in salmon and Baltic herring in the Baltic sea. When the organochlorine levels have decreased, populations have recovered, e.g. white-tailed eagle and osprey. Brominated compounds have not decreased much so far, but they only contribute about 1 % of TEQs.
Concentrations in fish and in birds are dependent on the age of the animal. Correcting for this is necessary to reliably calculate time trends in trout. In Baltic herring, concentrations of both PCBs and PCDD/Fs increase several fold from age 1 year to age 8–15 years. In adult glaucous gulls, however, no age-correlation was found, suggesting that steady state levels are reached early in life. This implies relatively rapid elimination and a short half-life. In eagle nestlings, PCB concentrations decrease after hatching indicating that maternal load transferred to eggs is initially more important than the content of PCBs in their diet during the rapid growth.
Human intake and concentrations
Animal source food is the most important source of dioxins for humans. Fish is very important, and although meat and milk products have dominated in most countries, the concentrations in farming products have now declined due to active emission controls. In all foods the concentrations have decreased remarkably in the Western countries during the last 30 to 40 years, and the present daily intake is 1–2 pg/kg bw (TEQ). Human exposure from contaminated soil is very limited.
Dioxins accumulate during the whole lifetime, because their half-lives are very long (Fig. 6). PCDD/F concentrations in young people are 5–10 pg/g TEQ in fat, but 40–100 pg/g in older generations. Additionally, there is carry-over in older generations from earlier decades when the intake was 5 to 10 times higher than presently. For this reason concentrations (e.g. between population groups in epidemiological studies) cannot be compared without information on age and the year of sampling.
Dioxin concentrations (but not all PCBs) in humans have been decreasing for over 30 years, in line with decreasing environmental levels. The World Health Organization has organized dioxin follow-up measurements in breast milk since 1987. In more recent surveys also PCBs and some other persistent chlorinated compounds have been measured. Historical information is crucial, because effects on next generations are possible (see below), and if true in humans, the impact of high concentrations in 1970s would be seen during the 21st century.
Breast milk concentrations were very high in 1970s (Fig. 7), about 50 pg/g for PCDD/Fs and 50 pg/g for dl-PCBs (TEQ in fat). During the first systematic round of breast milk measurements in 1987, PCDD/F concentrations in many countries were between 30 and 40 pg/g TEQ in milk fat and during the last round in 2005–2010 between 5 and 10 pg/g in many European countries (generally below 10 pg/g), and low in many African countries, but still high in e.g. India, Egypt and the Netherlands (over 20 pg/g). Thus the concentrations have decreased by 80–90 % in many but not all countries.
Toxic effects in humans
Accidents, contamination episodes and occupational risks
A few dramatic accidental or deliberate cases of acute poisoning have taken place. Two women were poisoned in Vienna, Austria, in 1998 by huge doses of TCDD. Dioxin concentration in one of them was 144,000 pg/g in serum fat, the highest ever measured in humans. The dose must have been about 25 µg/kg. For comparison, contemporary concentrations in young people are 5–10 pg TEQ/g fat, and in older people 50 pg TEQ/g fat or more (Fig. 6), and daily intake is 1–2 pg TEQ/kg body weight. This victim survived despite the extraordinarily high levels of TCDD in her serum, but had severe chloracne lasting for years and weight loss. There were few other symptoms or laboratory findings: gastrointestinal symptoms and amenorrhea. Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned in 2004 with a large dose of TCDD; the concentration in fat was 108,000 pg/g. He suffered from severe gastrointestinal symptoms, indicating pancreatitis and hepatitis, and then developed severe chloracne, but survived. In both the Vienna poisoning and the Yushchenko poisoning the details of TCDD intake are unknown.
Perhaps the best known dioxin accident took place in Seveso, Italy in 1976. The town was contaminated by TCDD, after a tank containing 2,4,5-trichlorophenol released its contents to air. The highest levels (up to 56,000 pg/g in serum lipid) were found in children who ate local food and played outdoors. About 200 cases of chloracne occurred; other detectable human effects were few, although a number of animals such as rabbits died. Cancer studies have suggested a slightly increased number of hematopoietic and lymphatic tissue malignancies. In a cohort of women with measured individual TCDD levels a slightly increased risk of all cancers was found (1.8 fold risk vs. tenfold increase in TCDD concentration) as well as a non-significant increased risk of breast cancer.
Several developmental consequences were detected after the Seveso incident. Dental aberrations associated with TCDD levels were found 25 years after the accident in persons who had been less than five years old at the time of the accident. Lowered male/female sex ratios were found in the offspring of males exposed to high concentrations of TCDD. Decreased sperm quality was observed in young men exposed to TCDD in utero and during lactation or during infancy or prepuberty. Slightly increased risk of endometriosis as well as a dose-dependently increased time to pregnancy and infertility were found among the most heavily exposed women. However, in 30 years’ follow-up no association between TCDD exposure and adverse pregnancy outcomes were detected except for a non-significant decrease in birthweight. Some metabolic and endocrine effects were seen for a limited time period. Neonatal thyroid stimulating hormone levels were increased in newborns of mothers with high body burdens of TCDD.
There have also been several cases of food contamination. In Japan (Yusho incident, 1968) and in Taiwan (Yu-cheng incident, 1979) PCB oil used in heat exchangers leaked to rice bran oil. Consumption of contaminated oil caused over 2000 and about 2000 cases of poisoning, respectively. Most of the toxic effects have been attributed to PCDFs and dl-PCBs. The most dramatic health effects were caused by developmental toxicity during pregnancy. The average daily intake was calculated to have been 154,000 pg I-TEQ/kg in the Yusho incident, 100,000 fold higher than average background intake at present. The Yu-cheng incident was roughly similar, and the concentrations were still over 1300 pg I-TEQ/g fat about 15 years later. There were many skin problems such as hypersecretion of Meibomian glands in the eyes, swelling of eyelids, abnormal pigmentation of skin, hyperkeratosis and chloracne. Babies born to Yusho and Yu-cheng mothers were smaller than normal. They had dark brown pigmentation, gingival hyperplasia, and sometimes dentition at birth or other tooth deformities. Foetal deaths and miscarriages were common. Cancer studies initially gave inconsistent results in spite of the heavy exposure. Later, a combined analysis of both episodes indicated increased mortality from all causes, all cancers, lung cancer, and heart disease in men, and liver cancer in women.
Several feed and food contamination episodes with dioxin-like compounds have occurred also in Europe and elsewhere. A tank of recycled fats was contaminated with at least 160 kg PCB oil in 1999 in Belgium, and used for animal feed. Low fertility of chickens and deformed chicks were noted. About 1 g of dioxins and 2 g dl-PCBs (TEQ) were involved. This caused a major dioxin alarm, and European Union set very strict limits for dioxins in food and feed. Due to fairly rapid intervention, total dioxin concentrations in the population did not increase even in Belgium: 23.1 versus 22.9 pg TEQ/g fat. No health effects have been noted. Similar conclusions were drawn after a food contamination incident in Ireland: a short term exceedance of limit values is not likely to lead to health effects. The incidences show that careful food controls are necessary, but no individual health measures (e.g. abortions) are rational in case of short moderately increased intake, because human dioxin body burden (accumulated during the whole lifetime) is large compared with short-term additional exposures, and therefore levels increase very slowly.
Phenoxy acid herbicides (Agent Orange and others, contaminated by dioxins, especially TCDD) were used in large quantities during the Vietnam War. The veterans have been thoroughly studied, but variable levels complicate assessments. There is some evidence for increased cancer, diabetes, and hypertension in the most highly exposed groups. However, causal relationship has been difficult to prove, and e.g. in case of diabetes a reverse causality has been suggested, and dose-responses do not support causality. Effects on local population in Vietnam have been less scrutinized. Tooth enamel defects were found to be more common in dioxin-affected regions, as well as borderline impaired neurodevelopment and eating disorders. Both modelling and monitoring results suggest that although somewhat higher than normal, highly elevated exposures to TCDD are not common in local people occasionally exposed to spraying. However, there are remarkable differences in PCDD/F levels in breast milk in different locations, and hot spots exist.
Several industrial settings have caused high exposures to dioxins when synthesizing chlorophenols or phenoxy acid herbicides. Some of these main chemicals are carcinogenic which makes pinpointing the risk to a specific chemical problematic. Chloracne is a hallmark characteristic at the higher end of exposure levels. Occupational cancer studies have been pooled in a large international combined cohort, suggesting an increased risk of all cancers and of soft-tissue sarcoma. The difficulty in interpreting the effects is that exposure levels were not measured directly and appear to be highly variable, i.e. very high industrial levels and marginally increased levels in workers spraying phenoxy herbicides. The study was crucial for IARC evaluations, which have also been criticized. Especially the evidence on soft-tissue sarcoma is weak and based on very few cases, but a slight increase of all cancers is likely to be real considering recent new evidence on Yusho, Yu-cheng and Seveso accidents. An increase in lung cancer risk would be logical among smokers due to promotion. A recent meta-analysis concluded that there is an association between dioxins and increased all cancer incidence and mortality and non-Hodgkin's lymphoma mortality. The association was non-linear.
A review of high-exposure studies suggests that dioxin exposure is associated with increased mortality from cardiovascular disease and, especially, ischemic heart disease. High industrial male dioxin levels were associated with lowered male/female ratio of offspring agreeing with the Seveso results.
Risks connected with low exposures of general population
Tooth deformities have been considered a plausible developmental effect in a general population after a long breast-feeding with relatively high dioxin concentrations in breast milk (range 7.7–258) pg/g TEQ in fat. The effects were no longer seen when dioxin levels in milk decreased over the years. Cryptorchidism did not associate with placental levels of dioxins and PCBs, but adipose tissue levels at the time of operation may support an association. Sperm counts at age 18–19 years were inversely associated with dioxin levels at age 8–9 years in a cohort of Russian boys. The range of PCDD/F+PCB TEQ was 4.88–107 pg/g lipid, or relatively high for age due to local industrial emissions. Maternal levels of dioxins were 5 to 173 pg TEQ/g fat, but the levels in babies are not known. Several endpoints in male sexual development including those in the Russian Children study have been reviewed and the most sensitive endpoint was interpreted to be sperm count due to epididymal factors. It was hypothesized that the mechanism is associated with sperm DNA methylation in young adults.
Recently a number of cross-sectional studies have shown associations between type 2 diabetes and several POP compounds including dioxins (reviewed by Magliano et al.). Their significance remains uncertain, however, because ecological observational studies cannot prove causality, and prospective studies have been inconsistent. One of the problems is that similar results have been obtained with a large variety of chlorinated pesticides, non-dioxin-like PCBs, dl-PCBs, PCDDs and PCDFs. These compounds have different mechanisms of action, and the only common denominator is long half-life leading to unpredictable toxicokinetics. This suggests that the results may be confounded by diet and obesity which are by far the most important risk factors of type 2 diabetes. Well-planned controlled studies are clearly needed.
An international panel met in 1998, organized by the World Health Organization and International Programme on Chemical Safety, to give guidance for assessing tolerable daily intake (TDI) values. Critical body burdens were compared in humans and animals, and the respective estimated human intake was calculated. The most relevant effects were found to be sperm count, immune suppression, genital malformations, and neurobehavioural effects in offspring and endometriosis in adults. Thus the safety margins for different developmental effects were considered lowest. The TDI recommendation was 1-4 pg/kg TEQ, with an ultimate goal to reduce it to 1 pg/kg.
This recommendation was based on the intake of dioxins by women in fertile age subsequently delivering dioxins during pregnancy and breast feeding to the child. Dioxin concentration in breast milk fat is about the same as in mother's adipose tissue. Therefore a baby is exposed to higher daily amounts of dioxins during breastfeeding than at any later stage of life. Considering the amount of fat transported from mother to child during a long breast feeding period, this was considered the most vulnerable situation. Therefore the TDI does not directly guide intake in any other population group, including older children. It should be noted that the body burden of dioxins at steady state is about 5000 daily doses meaning that only long-term intake is important.
The Joint FAO/WHO Expert Committee on Food Additives (JECFA) derived in 2001 a provisional tolerable monthly intake (PTMI) of 70 pg TEQ/kg body weight. The Scientific Committee on Food (SCI) of the European Commission applied a tolerable weekly intake (TWI) of 14 pg TEQ/kg, which is very close to the JECFA PTMI. (Table 3) The U.S. Environmental Protection Agency (U.S. EPA) established an oral reference dose (RfD) of 0.7 pg/kg b.w. per day for TCDD. The differences are based on two factors, EPA assessment is based on human data and tenfold uncertainty factor, the others on animal data and a threefold safety factor. In view of different approaches European Food Safety Authority (EFSA) recommended a new comprehensive risk assessment, and recently EFSA Panel on Contaminants in the Food Chain (CONTAM) recommended a TWI of 2 pg TEQ/kg which is pending. (Table 3)
Table 3 | Tolerable intake estimates by different agencies in Europe and the United States.
|Agency||Tolerable dose||Tolerable dose expressed as TDI|
|WHO 2000||1-4 pg TEQ/kg|
|SCF 2001||14 pg TEQ/kg weekly||2 pg TEQ/kg|
|JECFA 2001||70 pg TEQ/kg monthly||2.3 pg TEQ/kg|
|USEPA 2012||0.7 pg TCDD/kg daily (reference dose)|
|EFSA CONTAM Panel 2018||2 pg TEQ/kg weekly||0.29 TEQ/kg|
The CONTAM panel of EFSA recommended a TWI of 2 pg/kg based heavily on the Russian Children Study. There is an uncertainty in that we do not know the sensitive time period, and if it is e.g. two first years of life associated with breast feeding, we do not know the concentrations that may have been higher than at 8–9 years. Modelling is limited by the lack of exact information on kinetics in small children. Decreasing sperm counts in many countries while the concentrations of dioxins have been decreasing, do not support a causal role of present dioxin intake. If multigenerational mechanisms are involved, it would be more important to evaluate the concentrations some decades back, and contemporary restrictions no longer help.
Setting strict arbitrary limits may fire back, and changes in diet, e.g. avoiding fish consumption could lead to harmful health effects. It is also a problem that potentially harmful intake may only concern certain age categories (esp. young women before their first pregnancy affecting the child), and otherwise fish consumption unquestionably means a health benefit.
Cancer risk from dioxin exposures has been hotly debated. IARC has deemed TCDD and 2,3,4,7,8-TCDF as carcinogenic to humans (class 1). However, the assessments are based on animal experiments and high accidental or occupational exposures. IARC only assesses the certainty of evidence regardless of the dose, and it remains unclear what is the risk for the general population. The high-exposure populations were exposed to 100–1000 or more times higher levels than the general population. Thus both animal studies and epidemiological studies refer to high doses and require extrapolation to low population levels. The assessment has been challenged in several papers on various grounds.
It may be concluded that dioxins are carcinogenic in animals and probably carcinogenic at high dose levels in humans. However, there is no good evidence that there would be any significant increase in cancer risk at the present levels detected in the general population. The WHO consultation group concluded that the potential cancer risk is taken care of, if TDI is determined on the basis of developmental effects.
A population risk in humans is unlikely on several grounds. Dioxins do not cause carcinogenic mutations of DNA. Therefore linear extrapolation is not likely to be valid, and safety margins can be applied as in other forms of toxicity. The important physiological role of the AH receptor means that an appropriate receptor activation is beneficial. Only inappropriate stimulation is harmful, which is the case with other receptors such as steroid and thyroid receptors.
Cancer interpretation based on case-control studies relying on exposure assessment by questionnaires after diagnosing cancer is problematic because of recall bias. Cohort studies have given equivocal results. A specific cancer that many studies associate with dioxins is soft tissue sarcoma. In a large case-control study with individual measured concentration data, no positive associations were found between soft-tissue sarcoma and TEQs or individual dioxins or PCBs. Rather there was a trend of decreasing risk at higher exposure groups suggesting a hormetic effect. Other side of the coin may even be that AH receptor agonists could be used in search for drugs in treating cancer. Recently a few among a large number of POPs analysed were found to correlate with breast cancer metastasis. In addition to chance effects there is a problem of causality: what is primary and what is secondary.
In conclusion the safety margins seem to be lowest for developmental effects. Sex ratio changes were seen at concentrations about 20 times the present levels, and for enamel defects in teeth and the sperm quality the margin may be slightly lower. These are in line with the assessment by the WHO panel.
The WHO panel based their assessment in the exposure of child-bearing women who excrete much of their body burden to the child during pregnancy and lactation. In other population groups the risks are low. The panel concluded that even if the safety margin concerning the child is fairly narrow, the benefits of breast feeding clearly exceed the risks. Similarly, the health benefits of fish consumption clearly exceed the risks of dioxins or other persistent organic compounds. In case of competing risks (e.g. cardiovascular disease) the application of precautionary principle may be dangerous. This means that while acknowledging the modest safety margins concerning food, it is more relevant to emphasize the importance of decreasing dioxin emissions to the environment and reducing environmental levels.
Effects in laboratory animals and their relevance in risk assessment
Effects of dioxins in animals can be broadly divided to clearly toxic effects (such as lethality, wasting syndrome, liver injury, developmental toxicity), and metabolic effects that often can be classified as adaptive responses (such as induction of enzymes metabolizing xenobiotic chemicals). Highly detailed descriptions on dioxin toxicity in animals can be found in several reviews.
The most conspicuous acute toxic effects in adult animals
Acute toxicity of dioxins differs highly among species (Table 4). Guinea pig is considered to be the most sensitive mammal; the LD50 of TCDD is about 1-2 µg/kg. Hamsters tolerate more than a thousand fold dose. The differences between and within species are sometimes based on different ligand binding affinities (e.g. C57BL/6 mice and ten times more resistant DBA2/2J mice), sometimes to the structure of the transactivation domain of the receptor (such as a thousand fold difference between Long-Evans and Han/Wistar/Kuo rats, and possibly between guinea pig and hamster). These differences have complicated risk assessment on the basis of animal studies.
It is typical that even after a high single dose the animals do not die immediately, but following a reduced feed intake and wasting (so called wasting syndrome) in two to three weeks. The syndrome is associated with decreased appetite and food intake, but the exact mechanism is not clear. A wasting-syndrome-like poisoning has never been seen in humans even after huge doses (see above). At very low doses there is a clear aversion response to novel foods which may not be related to the fatal wasting syndrome, but is rather an adaptive safety response preventing consumption of toxic food items.
Table 4 | Lethal dose in some animal species
|Species||LD50 (μg/kg body weight)|
Some changes in the transactivation domain of AH receptor influence drastically the wasting syndrome and lethality whereas biochemical effects such as CYP1A1 enzyme induction are unaffected as well as AHR binding. Therefore two types of dioxin effects have been proposed (Table 5). Type I responses include developmental effects, aversion to novel foods, and the typical induction of CYP1A1 and other oxidative enzymes which occur at the same dose levels regardless of the structure of the AHR. Type II responses with great variation between species and strains include several high-dose effects such as wasting syndrome, lethality, and liver toxicity. There is some evidence that tumour promotion might belong to type II responses.
Table 5 | Examples of toxic and adaptive responses to TCDD in very differently sensitive rat lines, the resistant Han/Wistar Kuopio and the sensitive Long-Evans strains (novel food aversion, resistant line A and sensitive line C developed from H/W and L-E strains).
|Response||H/W or line A||L-E or line C|
|The most sensitive toxic effects and adaptive responses (type I)|
|Enzyme induction||0.1-1 μg/kg||0.1-1 μg/kg|
|Aversion to novel foods||0.1-0.6 μg/kg||0.2-0.4 μg/kg|
|Developmental effects (teeth)||0.1-1 μg/kg (dam)||0.1-1 μg/kg (dam)|
|Robust toxic outcomes (type II)|
|Lethality||> 10,000 μg/kg||10 μg/kg|
|Severe anorexia and wasting syndrome||transient||to lethality|
|Tumour promotion||>100 μg/kg||>1 μg/kg|
|AH receptor binding||23 fmol/mg||20 fmol/mg|
Thus type I effects are relatively similar among species or strains (see also), but type II effects cannot be reliably predicted over species. It is of interest that many of the type I responses can be interpreted as defence mechanisms toward noxious chemicals via the AH receptor (induction of metabolism, aversion of toxic foods) and can therefore be considered adaptive and protective.
Dioxins cause various pleiotropic effects. There may be both proliferative responses and atrophic responses. Thymic atrophy and some immunological effects are consistent findings in multiple laboratory species. Liver toxicity is variable, it is typical in rabbits, but some effects are seen in other species, e.g. disturbances of porphyrin metabolism, oxidative damage, and fatty infiltration. There are also multiple high-dose effects on the nervous system, such as tryptophan metabolism or neuropathies. Generally speaking, adverse effects at low doses in adult animals are few.
Developmental effects have been found to be the most sensitive adverse effects of TCDD in several animal species. Transfer of dioxins through placenta varies by compound and animal species, and the amount transferred by lactation in rodents seems to be more than placental transfer. Comparison of single-dose studies to continuous daily intake studies resulting in a similar body burden is problematic, because distribution of dioxins during the peak concentration in the dam is different from long-term distribution.
Some of the effects are observed at exposure levels indicating relatively small safety margins to the human background exposure. The sensitive targets include developing male and female reproductive system, immune system, nervous system, and teeth and bone. Clear teratogenic effects such as cleft palate and hydronephrosis were detected early after relatively high doses in mice. Some developmental effects may be caused by indirect mechanisms, e.g. enzyme induction may lead to accelerated metabolism of thyroid hormones resulting in decreased hormone levels. Thyroid hormones are essential for normal development, notably the development of the nervous system. In many other cases the mechanisms seem to involve local growth factors, and the phenomenon cannot be described as endocrine disruption in strict sense.
Development of teeth and the skeleton are highly sensitive targets of dioxin toxicity in several vertebrate species. Teeth are useful indicators of developmental toxicity, because they do not undergo continuous remodelling after mineralization like bone, where remodelling may repair mineralization defects. Developmental defects of teeth can therefore be detected later in life, as in the case of the Seveso accident, when dental defects were observed 25 years after the accident.
In utero and lactational exposure to TCDD was shown to result in wide range of alterations in rats and mice at doses below 1 μg/kg to the dam. They included smaller molar size, delayed eruption, increased susceptibility to caries, altered mineral composition of enamel, increased fluctuating asymmetry of molars and complete arrest of development of the third molars. Sensitivity of tooth development to TCDD was also shown in rhesus monkeys, minks, rainbow trout and zebrafish. In tooth development (as well as in the development of several other organs), the target of toxicity seems to be the developing epithelium. Developmental defects are the consequence of impaired epithelial-mesenchymal signalling, and AHR, epidermal growth factor (EGF), transforming growth factor α (TGFα) and perhaps Jun kinases are involved in mediating the effects.
Cleft palate is the best-known skeletal effect of dioxins at relatively high maternal doses. In utero and lactational exposure to lower doses of TCDD was shown to affect long bones of rats, mice and rhesus monkeys by inducing altered bone geometry, decreased bone mineral density and biomechanical strength and retardation of bone matrix maturation. Further studies indicated that differentiation of bone marrow stem cells to bone forming osteoblasts and bone resorbing osteoclasts is disrupted by TCDD in AHR-dependent manner.
Several studies from different laboratories have indicated a variety of adverse effects on the male reproductive system after in utero or lactational exposure of rats to low doses of TCDD. These include reduction of cauda epididymal sperm counts, daily sperm production, weight of accessory sex organs as well as increased proportion of abnormal sperm and delayed puberty (reviewed by Bell et al.). There is remarkable variability among different studies, but the delay in developmental milestones for male reproductive endpoints seems to be the most consistent and sensitive finding. Also decreased male/female sex ratios were reported in the offspring of male mice exposed to TCDD for 12 weeks prior to mating. However, maternal exposure did not affect the sex ratio of rat offspring. The mechanism has been suggested to be reduced fertility of Y-bearing sperm.
Multigenerational and transgenerational effects
Understanding possible effects on next generations is essential for risk assessment, because dioxin concentrations in the environment and human intake have decreased, but effects initiated several decades ago might still linger with us. This was illustrated by the Seveso studies (see above). Epigenetically mediated multigenerational or transgenerational effects of TCDD have been found in rats and mice (reviewed by Viluksela and Pohjanvirta). Some of them were paternally mediated or resulted in adult onset disease states. Toxic effects are considered transgenerational if neither the parent nor the offspring is directly exposed (i.e. F3 generation is the first generation without direct exposure).
TCDD has been shown to cause typical epigenetic modifications (e.g. methylation, histone acetylation) in a number of studies. When these occur in gametes they may affect the future generations.
When pregnant rats were exposed to low doses of TCDD several endpoints of toxicity were found in F1-F3 (or F4) generations: primordial follicle loss, polycystic ovaries and early onset of puberty were observed in female F1 and F3 offspring, and histopathological alterations of testis and kidney abnormalities in male F1 and F3 offspring. These changes were associated with differentially methylated DNA regions in F3 generation sperm epigenome.
Relatively high doses of TCDD (10 μg/kg) in female mice indicated robust transgenerational changes in pregnancy outcomes and progesterone receptor density. In the offspring of exposed mice reduced fertility, increased incidence of premature birth and increased uterine sensitivity to inflammation were found in F1-F4 generations. Interestingly, infertility and increased incidence of premature birth was also found in unexposed female mice mated with males exposed to TCDD in utero. Premature birth was associated with reduced progesterone receptor expression and inflammation of placenta.
In male mice infertility and increased premature births in unexposed mating partners that persisted to F2 and F3 generations were associated with testicular inflammation and apoptosis of developing spermatocytes. The role of paternal exposure was also studied in male rat offspring (F1) exposed in utero and lactationally to low doses of TCDD and mated with unexposed females to obtain the F2 generation and further the F3 generation. The proportion of implantations per corpus luteum was significantly decreased in all three generations. Thus both maternal and paternal changes can lead to effects in offspring.
Small zebra fish have been extensively used to study the mechanisms of toxicity in fish in the laboratory, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden et al.). Apart from rats and mice, transgenerationally inherited dioxin-induced effects have also been studied in the zebrafish model. In zebrafish, TCDD-induced transgenerational and partly paternally-mediated effects include reproductive dysfunction, reduced fertility, skeletal malformations and lowered male/female sex ratio. These effects seem to be phenotypically very similar across these vertebrate classes.
Cancer in laboratory animals
Dioxins are clear multisite carcinogens in animal studies, but are not genotoxic as indicated both by mutagenicity assays and tumour promotion studies. Also the ability of TCDD to inhibit apoptosis and enhance proliferation supports a nongenotoxic mechanism of carcinogenicity.
Much of the cancer risk assessment has been based on an early rat study, demonstrating liver tumours in female rats at low doses (10 ng/kg/day TCDD for 2 years). Other studies have confirmed multisite carcinogenicity in several species, but the doses have usually been higher. Toxic hepatitis has also been found in animals with tumours.
Nongenotoxic or promoting mechanisms are favoured, especially inhibition of apoptosis of cancer precursor cells. When differently sensitive Long-Evans (Turku/AB) (L-E) and H/W (Kuopio) rat substrains were compared in a 3-month tumour promotion study, there was a difference in effective dose of almost two orders of magnitude, and in both strains tumour promotion was associated with signs of liver toxicity. Such findings suggest that carcinogenicity may be secondary to organ toxicity.
It has been speculated that induction of oxidative enzymes such as CYP1A1 would produce excessive reactive carcinogenic intermediates, and dioxins would thus indirectly increase cancer risk. Oxidation combined with subsequent conjugating reactions is, however, essentially a protective mechanism, and conjugation enzymes are induced simultaneously. Thus, while plausible, this mechanism would require disproportionate induction of oxidation over conjugation and be likely only at relatively high doses. In tumour promotion studies with two rat strains enzyme induction did not correlate with tumour promoting activity.
Interactions of dioxins with microbes and the immune system
Microbiomes related to the gut, skin and respiratory tract are in frontline of encountering xenobiotics. The microbiome of our intestinal system metabolizes many chemicals in our food, and on the other hand the chemicals may influence the microbes. There are complex interrelationships between chemicals, microbes and our immune systems. The host and microbiome together can even be seen as a “superorganism”. AH receptors and therefore dioxins are deeply involved in these interactions. Active research has started to meet the challenge of understanding these phenomena during the last few years, but obviously only the tip of the iceberg has been revealed as yet, and there is limited information about specific microorganisms, enzymes and genes involved.
The simplest part of these interactions is the effects of the microbiome on chemicals. Intestinal microbes can metabolize xenobiotics before they are absorbed into the body. This may increase or decrease physicochemical properties and toxicity. As to dioxins, not much is known; dehalogenation is possible, but obviously not very effective. On the other hand, several bacteria are able to metabolize polycyclic aromatic hydrocarbons also binding to AH receptors such as benzo(a)pyrene to carcinogenic metabolites prior to absorption.
As to the effect of dioxins on microbes, relatively high doses have been shown to cause remarkable changes in the overall population, and e.g. somewhat ambiguous changes in the Firmicutes vs. Bacteroides ratio in mice and increases in Lactobacillaceae and Desulfovibrionaceae have been noticed. These changes might be in part involved in the toxic effects, e.g. liver toxicity. AH receptors seem to sense microbial toxins and stimulate their neutralization by enzyme induction as well as regulating cytokine and chemokine production and leukocyte activation.
An interesting field in these interactions is the highly complex influence of chemicals via the AH receptors on the immune systems. This is mostly outside the scope of this review, and only dealt with briefly. Interested readers are encouraged to read the thorough recent review of Rothhammer and Quintana.
AHR activation seems to be crucial in maintaining intraepithelial lymphocytes in the intestines and skin as a first line of defence against microorganisms. By using several genetically modified mouse models it was shown that high constitutive activity of CYP1A1 depletes natural AHR ligands in the gut and this leads to similar deficiencies in immune defence mechanisms and increased susceptibility to infections as seen in AHR knockout animals. Interestingly this deficiency can be counteracted by increased supply of natural AHR ligands such as 6-formylindolo[3,2-b]carbazole (FICZ) many of which are present e.g. in vegetables. This implies that CYP enzymes act as feedback controls metabolizing more or less of the AHR ligand supply to keep the receptor activity at an optimal level. In fact AHR activity in intestinal epithelial cells, intraepithelial lymphocytes and innate lymphoid cells seems important for tissue homeostasis at the structural and functional level.
Respiratory system is the other important pathway for environmental noxious agents to the body, especially viral infections, and the AHR seems to be intrinsically involved in defence mechanisms. An interesting indole derivative is malassezin produced by pathogenic skin yeast Malassezia furfur. The question has been how AHR can mediate protective effects in some contexts and toxicity in others. This is partially an open question, but it may simply include the impact of time and dose. FICZ and other similar ligands are metabolized rapidly, and so their concentrations will never increase very high and persistent. Therefore their toxicity is not apparent.
Microglia are specialized macrophages in the central nervous system, and as such important for immune surveillance, debris removal and defence against microorganisms as well as for the development of immune functions and synapse maturation. AHR expression is upregulated in the CNS traumatic or autoimmune injury, and may control the inflammatory activities. Here AHR ligands produced by microbes may be important and deficits of AHR agonists have been reported in multiple conditions. Thus there may be option of therapeutic development of AHR ligands in autoimmune, neoplastic and degenerative diseases. Although the AHR signalling may be fundamental in neuronal development, overactivation seems harmful. Thus the current understanding is limited and active research is needed.
Dioxins are a group of related persistent, bioaccumulating environmental poisons that act via the AH receptor, an intracellular receptor which also serves to regulate multiple physiological functions. Hence a certain level of AH receptor activity is important in normal biology, but inappropriate activation leads to a number of deleterious effects.
The most sensitive adverse effects of dioxins are developmental consequences in different structures, from teeth and bones to sexual organs. This concerns specifically women in child-bearing age, because a child is exposed prenatally during pregnancy as well as postnatally via breast milk. The exposure is higher than in other population groups. The safety margins between the current environmental exposure levels and the levels required for sensitive adverse effects are presently about an order of magnitude, but the safe level was probably exceeded in the 1970s and 1980s. Transgenerational effects of these historical high exposures (causing milk dioxin levels of 50 to 100 pg TEQ per g fat, tenfold to contemporary levels) are of concern, but are so far poorly known.
Carcinogenicity has caused confusion, because it probably occurs at high industrial or accidental exposure levels, but dioxins are not genotoxic, and there is neither good evidence nor logical reason to assume that dioxins would cause cancer at levels below those causing developmental effects.
It is essential to understand dioxins as one risk factor among others rather than as a sole causative agent. This means that dose-responses should be appreciated in regulations as with any other chemical, and benefit-risk aspects should be carefully taken into account. Otherwise unwise remedy may turn out to be worse than the disease. It is risk management and political issue to decide how large safety margins are necessary.
In conclusion, strict environmental controls of dioxin emissions are still important and they should be the first priority. Limitations of important food items are problematic, and it is important to avoid measures that would increase competing risks. This danger is obvious when overregulating the levels in food. The benefits of e.g. breast feeding are estimated clearly greater than possible risks of contaminants, and the nutritional benefits of fish consumption also outweigh toxic effects, if any.
I appreciate the comments of several colleagues screening through the manuscript: Prof. Allan B. Okey, Toronto, Prof. Dieter Schrenk, Kaiserslautern, Prof. Robert Barouki, Paris, Prof. Xavier Coumoul, Paris, Prof. Raimo Pohjanvirta, Helsinki, Prof. Matti Viluksela, Kuopio, Dr. Jouni T. Tuomisto, Kuopio, and Dr. Hanna Miettinen, Kuopio. I also want to thank expert rewiewers Prof. Helmut Greim, Munich, Dr. Martin Rose, Manchester, and Prof. Helen Håkansson, Stockholm, for their constructive comments.
It is acknowledged that after writing a textbook chapter on the same topic, it was not possible to avoid some repetition of both style and details (Tuomisto and Viluksela). Otherwise there are no conflicts of interests. There was no funding for writing this article.
- Poland, A; Knutson, JC (1982). "2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity.". Annual review of pharmacology and toxicology 22: 517-54. doi:10.1146/annurev.pa.22.040182.002505. PMID 6282188.
- Pohjanvirta, R; Tuomisto, J (December 1994). "Short-term toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals: effects, mechanisms, and animal models.". Pharmacological reviews 46 (4): 483-549. PMID 7899475.
- Denison, MS; Nagy, SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals.". Annual review of pharmacology and toxicology 43: 309-34. doi:10.1146/annurev.pharmtox.43.100901.135828. PMID 12540743.
- Tuomisto, Jouko; Vartiainen, Terttu; Tuomisto, Jouni T. (2011). Synopsis on dioxins and PCBs (PDF) (Report). National Institute for Health and Welfare. ISSN 1798-0089.
- Denison, MS; Faber, SC (February 2017). "And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses.". Current opinion in toxicology 2: 124-131. doi:10.1016/j.cotox.2017.01.006. PMID 28845473.
- Rothhammer, V; Quintana, FJ (March 2019). "The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease.". Nature reviews. Immunology 19 (3): 184-197. doi:10.1038/s41577-019-0125-8. PMID 30718831.
- Barouki, Robert; Coumoul, Xavier; Fernandez-Salguero, Pedro M. (2007-03-30). "The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein". FEBS Letters 581 (19): 3608–3615. doi:10.1016/j.febslet.2007.03.046. ISSN 0014-5793. http://dx.doi.org/10.1016/j.febslet.2007.03.046.
- Weber, R; Tysklind, M; Gaus, C (March 2008). "Dioxin--contemporary and future challenges of historical legacies. Dedicated to Prof. Dr. Otto Hutzinger, the founder of the DIOXIN Conference Series.". Environmental science and pollution research international 15 (2): 96-100. PMID 18380226.
- Van den Berg, M; Birnbaum, LS; Denison, M; De Vito, M; Farland, W; Feeley, M; Fiedler, H; Hakansson, H et al. (October 2006). "The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds.". Toxicological sciences : an official journal of the Society of Toxicology 93 (2): 223-41. doi:10.1093/toxsci/kfl055. PMID 16829543.
- Larsson, M; van den Berg, M; Brenerová, P; van Duursen, MB; van Ede, KI; Lohr, C; Luecke-Johansson, S; Machala, M et al. (20 April 2015). "Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells.". Chemical research in toxicology 28 (4): 641-50. doi:10.1021/tx500434j. PMID 25654323.
- van den Berg, M; Denison, MS; Birnbaum, LS; Devito, MJ; Fiedler, H; Falandysz, J; Rose, M; Schrenk, D et al. (June 2013). "Polybrominated dibenzo-p-dioxins, dibenzofurans, and biphenyls: inclusion in the toxicity equivalency factor concept for dioxin-like compounds.". Toxicological sciences : an official journal of the Society of Toxicology 133 (2): 197-208. doi:10.1093/toxsci/kft070. PMID 23492812.
- DeGroot, Danica; He, Guochun; Fraccalvieri, Domenico; Bonati, Laura; Pandini, Allesandro; Denison, Michael S. (2011). "AHR Ligands: Promiscuity in Binding and Diversity in Response". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 63–79. ISBN 9781118140574.
- Connor, KT; Harris, MA; Edwards, MR; Budinsky, RA; Clark, GC; Chu, AC; Finley, BL; Rowlands, JC (July 2008). "AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo.". Journal of exposure science & environmental epidemiology 18 (4): 369-80. doi:10.1038/sj.jes.7500607. PMID 17912254.
- Gouedard, C.; Barouki, R.; Morel, Y. (2004-05-28). "Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism". Molecular and Cellular Biology 24 (12): 5209–5222. doi:10.1128/mcb.24.12.5209-5222.2004. ISSN 0270-7306. http://dx.doi.org/10.1128/mcb.24.12.5209-5222.2004.
- Mahiout, Selma; Lindén, Jere; Esteban, Javier; Sánchez-Pérez, Ismael; Sankari, Satu; Pettersson, Lars; Håkansson, Helen; Pohjanvirta, Raimo (2017-07). "Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats". Toxicology and Applied Pharmacology 326: 54–65. doi:10.1016/j.taap.2017.04.020. ISSN 0041-008X. http://dx.doi.org/10.1016/j.taap.2017.04.020.
- Kanan, Sofian; Samara, Fatin (January 2018). "Dioxins and furans: A review from chemical and environmental perspectives". Trends in Environmental Analytical Chemistry 17: 1–13. doi:10.1016/j.teac.2017.12.001.
- Assefa, Anteneh T.; Sobek, Anna; Sundqvist, Kristina L.; Cato, Ingemar; Jonsson, Per; Tysklind, Mats; Wiberg, Karin (2013-12-24). "Temporal Trends of PCDD/Fs in Baltic Sea Sediment Cores Covering the 20th Century". Environmental Science & Technology 48 (2): 947–953. doi:10.1021/es404599z. ISSN 0013-936X. http://dx.doi.org/10.1021/es404599z.
- Sobek, A; Sundqvist, KL; Assefa, AT; Wiberg, K (15 June 2015). "Baltic Sea sediment records: unlikely near-future declines in PCBs and HCB.". The Science of the total environment 518-519: 8-15. doi:10.1016/j.scitotenv.2015.02.093. PMID 25747358.
- Northcross, Amanda L.; Katharine Hammond, S.; Canuz, Eduardo; Smith, Kirk R. (2012-03). "Dioxin inhalation doses from wood combustion in indoor cookfires". Atmospheric Environment 49: 415–418. doi:10.1016/j.atmosenv.2011.11.054. ISSN 1352-2310. http://dx.doi.org/10.1016/j.atmosenv.2011.11.054.
- Hu, Ming-Tsan; Chen, Shen-Jen; Huang, Kuo-Lin; Lin, Yuan-Chung; Lee, Wen-Jhy; Chang-Chien, Guo-Ping; Tsai, Jen-Hsiung; Lee, Jia-Twu et al. (2009-08). "Characteritization of, and health risks from, polychlorinated dibenzo-p-dioxins/dibenzofurans from incense burned in a temple". Science of The Total Environment 407 (17): 4870–4875. doi:10.1016/j.scitotenv.2009.05.027. https://linkinghub.elsevier.com/retrieve/pii/S0048969709005026.
- Zhang, Mengmei; Buekens, Alfons; Li, Xiaodong (22 June 2017). "Open burning as a source of dioxins". Critical Reviews in Environmental Science and Technology 47 (8): 543–620. doi:10.1080/10643389.2017.1320154.
- Dopico, M; Gómez, A (September 2015). "Review of the current state and main sources of dioxins around the world.". Journal of the Air & Waste Management Association (1995) 65 (9): 1033-49. doi:10.1080/10962247.2015.1058869. PMID 26068294.
- Quass, U; Fermann, M; Bröker, G (March 2004). "The European dioxin air emission inventory project--final results.". Chemosphere 54 (9): 1319-27. doi:10.1016/S0045-6535(03)00251-0. PMID 14659425.
- "An Inventory Of Sources And Environmental Releases Of Dioxin-Like Compounds In The U.S. For The Years 1987, 1995, And 2000 (Final, Nov 2006)". cfpub.epa.gov. US EPA National Center for Environmental Assessment,Washington DC. Retrieved 2019-12-16.
- "Update to An Inventory of Sources and Environmental Releases of Dioxin-Like Compounds in the United States for the Years 1987, 1995, and 2000 (2013, External Review Draft)". cfpub.epa.gov. US EPA National Center for Environmental Assessment, Washington DC. Retrieved 2019-12-16.
- Momeniha, F; Faridi, S; Amini, H; Shamsipour, M; Naddafi, K; Yunesian, M; Niazi, S; Gohari, K et al. (2017). "Estimating national dioxins and furans emissions, major sources, intake doses, and temporal trends in Iran from 1990-2010.". Journal of environmental health science & engineering 15: 20. doi:10.1186/s40201-017-0283-1. PMID 29051819.
- Zhang, J; Jiang, Y; Zhou, J; Wu, B; Liang, Y; Peng, Z; Fang, D; Liu, B et al. (15 May 2010). "Elevated body burdens of PBDEs, dioxins, and PCBs on thyroid hormone homeostasis at an electronic waste recycling site in China.". Environmental science & technology 44 (10): 3956-62. doi:10.1021/es902883a. PMID 20408536.
- Hu, Jianfang; Xiao, Xiao; Peng, Ping'an; Huang, Weilin; Chen, Deyi; Cai, Ying (2013). "Spatial distribution of polychlorinated dibenzo-p-dioxins and dibenzo-furans (PCDDs/Fs) in dust, soil, sediment and health risk assessment from an intensive electronic waste recycling site in Southern China". Environmental Science: Processes & Impacts 15 (10): 1889. doi:10.1039/c3em00319a. PMID 23955158.
- Hoogenboom, Ron; Traag, Wim; Fernandes, Alwyn; Rose, Martin (April 2015). "European developments following incidents with dioxins and PCBs in the food and feed chain". Food Control 50: 670–683. doi:10.1016/j.foodcont.2014.10.010.
- Jin, LJ; Chen, BL (2017). "Natural origins, concentration levels, and formation mechanisms of organohalogens in the environment". Progr Chemistry 29: 1093-1114. doi:10.7536/PC170563. http://manu56.magtech.com.cn/progchem/EN/abstract/abstract11961.shtml.
- Rathna, R; Varjani, S; Nakkeeran, E (1 October 2018). "Recent developments and prospects of dioxins and furans remediation.". Journal of environmental management 223: 797-806. doi:10.1016/j.jenvman.2018.06.095. PMID 29986327.
- Kiviranta, H; Ovaskainen, ML; Vartiainen, T (September 2004). "Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland.". Environment international 30 (7): 923-32. doi:10.1016/j.envint.2004.03.002. PMID 15196840.
- Crosby, D.; Wong, A. (1977-03-25). "Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)". Science 195 (4284): 1337–1338. doi:10.1126/science.841331. ISSN 0036-8075. http://dx.doi.org/10.1126/science.841331.
- Isosaari, Pirjo; Tuhkanen, Tuula; Vartiainen, Terttu (2004-05). "Photodegradation of polychlorinated dibenzo-p-dioxins and dibenzofurans in soil with vegetable oil". Environmental Science and Pollution Research 11 (3): 181–185. doi:10.1007/bf02979673. ISSN 0944-1344. http://dx.doi.org/10.1007/bf02979673.
- Smidt, H; de Vos, WM (2004). "Anaerobic microbial dehalogenation.". Annual review of microbiology 58: 43-73. doi:10.1146/annurev.micro.58.030603.123600. PMID 15487929.
- Atashgahi, S; Shetty, SA; Smidt, H; de Vos, WM (2018). "Flux, Impact, and Fate of Halogenated Xenobiotic Compounds in the Gut.". Frontiers in physiology 9: 888. doi:10.3389/fphys.2018.00888. PMID 30042695.
- Liem, AK; Fürst, P; Rappe, C (April 2000). "Exposure of populations to dioxins and related compounds.". Food additives and contaminants 17 (4): 241-59. doi:10.1080/026520300283324. PMID 10912239.
- Fernández-González, R; Yebra-Pimentel, I; Martínez-Carballo, E; Simal-Gándara, J (2015). "A Critical Review about Human Exposure to Polychlorinated Dibenzo-p-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs) and Polychlorinated Biphenyls (PCBs) through Foods.". Critical reviews in food science and nutrition 55 (11): 1590-617. doi:10.1080/10408398.2012.710279. PMID 24279584.
- Warenik-Bany, M; Strucinski, P; Piskorska-Pliszczynska, J (NaN). "Dioxins and PCBs in game animals: Interspecies comparison and related consumer exposure.". Environment international 89-90: 21-9. doi:10.1016/j.envint.2016.01.007. PMID 26826359.
- La Merrill, Michele; Emond, Claude; Kim, Min Ji; Antignac, Jean-Philippe; Le Bizec, Bruno; Clément, Karine; Birnbaum, Linda S.; Barouki, Robert (2013-02). "Toxicological Function of Adipose Tissue: Focus on Persistent Organic Pollutants". Environmental Health Perspectives 121 (2): 162–169. doi:10.1289/ehp.1205485. ISSN 0091-6765. http://dx.doi.org/10.1289/ehp.1205485.
- van Birgelen, AP; van den Berg, M (April 2000). "Toxicokinetics.". Food additives and contaminants 17 (4): 267-73. doi:10.1080/026520300283342. PMID 10912241.
- Mitoma, C; Uchi, H; Tsukimori, K; Yamada, H; Akahane, M; Imamura, T; Utani, A; Furue, M (September 2015). "Yusho and its latest findings-A review in studies conducted by the Yusho Group.". Environment international 82: 41-8. doi:10.1016/j.envint.2015.05.004. PMID 26010306.
- Aylward, LL; Brunet, RC; Carrier, G; Hays, SM; Cushing, CA; Needham, LL; Patterson DG, Jr; Gerthoux, PM et al. (January 2005). "Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort.". Journal of exposure analysis and environmental epidemiology 15 (1): 51-65. doi:10.1038/sj.jea.7500370. PMID 15083163.
- Sorg, O; Zennegg, M; Schmid, P; Fedosyuk, R; Valikhnovskyi, R; Gaide, O; Kniazevych, V; Saurat, JH (3 October 2009). "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.". Lancet (London, England) 374 (9696): 1179-85. doi:10.1016/S0140-6736(09)60912-0. PMID 19660807.
- Milbrath, MO; Wenger, Y; Chang, CW; Emond, C; Garabrant, D; Gillespie, BW; Jolliet, O (March 2009). "Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding.". Environmental health perspectives 117 (3): 417-25. doi:10.1289/ehp.11781. PMID 19337517.
- Vartiainen, T; Jaakkola, JJ; Saarikoski, S; Tuomisto, J (February 1998). "Birth weight and sex of children and the correlation to the body burden of PCDDs/PCDFs and PCBs of the mother.". Environmental health perspectives 106 (2): 61-6. doi:10.1289/ehp.9810661. PMID 9432971.
- Virtanen, HE; Koskenniemi, JJ; Sundqvist, E; Main, KM; Kiviranta, H; Tuomisto, JT; Tuomisto, J; Viluksela, M et al. (June 2012). "Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta.". International journal of andrology 35 (3): 283-93. doi:10.1111/j.1365-2605.2011.01233.x. PMID 22150420.
- Feeley, M; Brouwer, A (April 2000). "Health risks to infants from exposure to PCBs, PCDDs and PCDFs.". Food additives and contaminants 17 (4): 325-33. doi:10.1080/026520300283397. PMID 10912246.
- Kreuzer, PE; Csanády, GA; Baur, C; Kessler, W; Päpke, O; Greim, H; Filser, JG (1997). "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.". Archives of toxicology 71 (6): 383-400. PMID 9195020.
- Kerger, BD; Leung, HW; Scott, P; Paustenbach, DJ; Needham, LL; Patterson DG, Jr; Gerthoux, PM; Mocarelli, P (October 2006). "Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children.". Environmental health perspectives 114 (10): 1596-602. doi:10.1289/ehp.8884. PMID 17035149.
- Leung, HW; Kerger, BD; Paustenbach, DJ; Ryan, JJ; Masuda, Y (September 2007). "Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients.". Toxicology and industrial health 23 (8): 493-501. doi:10.1177/0748233708089024. PMID 18669171.
- Kerger, BD; Leung, HW; Scott, PK; Paustenbach, DJ (April 2007). "Refinements on the age-dependent half-life model for estimating child body burdens of polychlorodibenzodioxins and dibenzofurans.". Chemosphere 67 (9): S272-8. doi:10.1016/j.chemosphere.2006.05.108. PMID 17207842.
- Lindén, J; Lensu, S; Tuomisto, J; Pohjanvirta, R (October 2010). "Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance.". Frontiers in neuroendocrinology 31 (4): 452-78. doi:10.1016/j.yfrne.2010.07.002. PMID 20624415.
- Hahn, Mark E.; Karchner, Sibel I. (2011). "Structural and Functional Diversification of AHRs during Metazoan Evolution". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 387–403. ISBN 9781118140574.
- Powell‐Coffman, Jo Anne; Qin, Hongtao (2011). "Invertebrate AHR Homologs: Ancestral Functions in Sensory Systems". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 405–411. ISBN 9781118140574.
- Tian, J; Feng, Y; Fu, H; Xie, HQ; Jiang, JX; Zhao, B (18 August 2015). "The Aryl Hydrocarbon Receptor: A Key Bridging Molecule of External and Internal Chemical Signals.". Environmental science & technology 49 (16): 9518-31. doi:10.1021/acs.est.5b00385. PMID 26079192.
- Bock, KW (1 April 2017). "Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options.". Biological chemistry 398 (4): 455-464. doi:10.1515/hsz-2016-0303. PMID 27805907.
- Brunnberg, Sara; Swedenborg, Elin; Gustafsson, Jan-Åke (2011-11-10). The AH Receptor in Biology and Toxicology. Hoboken, NJ, USA: John Wiley & Sons, Inc. pp. 127–141. ISBN 978-1-118-14057-4.
- Ko, Chia-I; Puga, Alvaro (2011-11-10). "Epigenetic mechanisms in AHR function". In Pohjanvirta, R (ed.). The AH Receptor in Biology and Toxicology. Hoboken, NJ, USA: John Wiley & Sons, Inc. pp. 157–178. ISBN 978-1-118-14057-4.
- Patrizi, B; Siciliani de Cumis, M (18 December 2018). "TCDD Toxicity Mediated by Epigenetic Mechanisms.". International journal of molecular sciences 19 (12). doi:10.3390/ijms19124101. PMID 30567322.
- Viluksela, M; Pohjanvirta, R (17 June 2019). "Multigenerational and Transgenerational Effects of Dioxins.". International journal of molecular sciences 20 (12). doi:10.3390/ijms20122947. PMID 31212893.
- Matsumura, Fumio (2011). "Nongenomic route of action of TCDD: Identity, characteristics, and toxicological significance". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 197–215. ISBN 9781118140574.
- Nilsson, Charlotte B.; Håkansson, Helen (2002-01). "The Retinoid Signaling System — A Target in Dioxin Toxicity". Critical Reviews in Toxicology 32 (3): 211–232. doi:10.1080/20024091064228. ISSN 1040-8444. http://dx.doi.org/10.1080/20024091064228.
- <Okey, AB; Franc, MA; Moffat, ID; Tijet, N; Boutros, PC; Korkalainen, M; Tuomisto, J; Pohjanvirta, R (1 September 2005). "Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor.". Toxicology and applied pharmacology 207 (2 Suppl): 43-51. doi:10.1016/j.taap.2004.12.028. PMID 15993909.
- Okey, AB (July 2007). "An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI.". Toxicological sciences : an official journal of the Society of Toxicology 98 (1): 5-38. doi:10.1093/toxsci/kfm096. PMID 17569696.
- Ma, Qiang (2011). "Overview of AHR Functional Domains and the Classical AHR Signaling Pathway: Induction of Drug Metabolizing Enzymes". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 33–45. ISBN 9781118140574.
- Tijet, N; Boutros, PC; Moffat, ID; Okey, AB; Tuomisto, J; Pohjanvirta, R (January 2006). "Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries.". Molecular pharmacology 69 (1): 140-53. doi:10.1124/mol.105.018705. PMID 16214954.
- Casado, FL; Singh, KP; Gasiewicz, TA (15 April 2010). "The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases.". Blood cells, molecules & diseases 44 (4): 199-206. doi:10.1016/j.bcmd.2010.01.005. PMID 20171126.
- Pohjanvirta, Raimo, ed. (2011). The AH Receptor in Biology and Toxicology. Wiley.
- Van Voorhis, M; Fechner, JH; Zhang, X; Mezrich, JD (27 April 2013). "The aryl hydrocarbon receptor: a novel target for immunomodulation in organ transplantation.". Transplantation 95 (8): 983-90. doi:10.1097/TP.0b013e31827a3d1d. PMID 23263608.
- Esser, C; Rannug, A (2015). "The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology.". Pharmacological reviews 67 (2): 259-79. doi:10.1124/pr.114.009001. PMID 25657351.
- Lahoti, TS; Boyer, JA; Kusnadi, A; Muku, GE; Murray, IA; Perdew, GH (November 2015). "Aryl Hydrocarbon Receptor Activation Synergistically Induces Lipopolysaccharide-Mediated Expression of Proinflammatory Chemokine (c-c motif) Ligand 20.". Toxicological sciences : an official journal of the Society of Toxicology 148 (1): 229-40. doi:10.1093/toxsci/kfv178. PMID 26259605.
- Sibilano, R; Pucillo, CE; Gri, G (January 2015). "Allergic responses and aryl hydrocarbon receptor novel pathway of mast cell activation.". Molecular immunology 63 (1): 69-73. doi:10.1016/j.molimm.2014.02.015. PMID 24656327.
- Kawajiri, K; Fujii-Kuriyama, Y (3 May 2017). "The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance.". Experimental animals 66 (2): 75-89. doi:10.1538/expanim.16-0092. PMID 27980293.
- Kolluri, SK; Jin, UH; Safe, S (July 2017). "Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target.". Archives of toxicology 91 (7): 2497-2513. doi:10.1007/s00204-017-1981-2. PMID 28508231.
- Moura-Alves, P; Faé, K; Houthuys, E; Dorhoi, A; Kreuchwig, A; Furkert, J; Barison, N; Diehl, A et al. (28 August 2014). "AhR sensing of bacterial pigments regulates antibacterial defence.". Nature 512 (7515): 387-92. doi:10.1038/nature13684. PMID 25119038.
- Boule, Lisbeth A.; Burke, Catherine G.; Jin, Guang-Bi; Lawrence, B. Paige (29 January 2018). "Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome". Scientific Reports 8 (1). doi:10.1038/s41598-018-20197-4.
- Schiering, C; Wincent, E; Metidji, A; Iseppon, A; Li, Y; Potocnik, AJ; Omenetti, S; Henderson, CJ et al. (9 February 2017). "Feedback control of AHR signalling regulates intestinal immunity.". Nature 542 (7640): 242-245. doi:10.1038/nature21080. PMID 28146477.
- Gutiérrez-Vázquez, C; Quintana, FJ (16 January 2018). "Regulation of the Immune Response by the Aryl Hydrocarbon Receptor.". Immunity 48 (1): 19-33. doi:10.1016/j.immuni.2017.12.012. PMID 29343438.
- Tuomisto, Jouko (2011). "The Toxic Equivalency Principle and its Application in Dioxin Risk Assessment". The AH Receptor in Biology and Toxicology. John Wiley & Sons, Ltd. pp. 317–330. ISBN 9781118140574.
- De Berg, Martin Vann; Peterson, Richard E.; Schrenk, Dieter (2000-04). "Human risk assessment and TEFs". Food Additives and Contaminants 17 (4): 347–358. doi:10.1080/026520300283414. ISSN 0265-203X. http://dx.doi.org/10.1080/026520300283414.
- Van den Berg, M; Birnbaum, L; Bosveld, AT; Brunström, B; Cook, P; Feeley, M; Giesy, JP; Hanberg, A et al. (December 1998). "Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife.". Environmental health perspectives 106 (12): 775-92. doi:10.1289/ehp.98106775. PMID 9831538.
- Viluksela, M; Stahl, BU; Birnbaum, LS; Schramm, KW; Kettrup, A; Rozman, KK (July 1998). "Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations.". Toxicology and applied pharmacology 151 (1): 57-69. doi:10.1006/taap.1998.8384. PMID 9705887.
- Safe, SH (August 1998). "Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach.". Environmental health perspectives 106 Suppl 4: 1051-8. doi:10.1289/ehp.98106s41051. PMID 9703492.
- Peters, AK; Leonards, PE; Zhao, B; Bergman, A; Denison, MS; Van den Berg, M (10 September 2006). "Determination of in vitro relative potency (REP) values for mono-ortho polychlorinated biphenyls after purification with active charcoal.". Toxicology letters 165 (3): 230-41. doi:10.1016/j.toxlet.2006.04.005. PMID 16750337.
- Howard, GJ; Schlezinger, JJ; Hahn, ME; Webster, TF (May 2010). "Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and competitive antagonists.". Environmental health perspectives 118 (5): 666-72. doi:10.1289/ehp.0901312. PMID 20435555.
- White, SS; Birnbaum, LS (October 2009). "An overview of the effects of dioxins and dioxin-like compounds on vertebrates, as documented in human and ecological epidemiology.". Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews 27 (4): 197-211. doi:10.1080/10590500903310047. PMID 19953395.
- Elonen, Gregory E.; Spehar, Robert L.; Holcombe, Gary W.; Johnson, Rodney D.; Fernandez, Joseph D.; Erickson, Russell J.; Tietge, Joseph E.; Cook, Philip M. (March 1998). "Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to seven freshwater fish species during early life-stage development". Environmental Toxicology and Chemistry 17 (3): 472–483. doi:10.1002/etc.5620170319.
- King-Heiden, TC; Mehta, V; Xiong, KM; Lanham, KA; Antkiewicz, DS; Ganser, A; Heideman, W; Peterson, RE (6 May 2012). "Reproductive and developmental toxicity of dioxin in fish.". Molecular and cellular endocrinology 354 (1-2): 121-38. doi:10.1016/j.mce.2011.09.027. PMID 21958697.
- Walker, Mary K.; Spitsbergen, Jan M.; Olson, James R.; Peterson, Richard E. (May 1991). "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Toxicity during Early Life Stage Development of Lake Trout ( )". Canadian Journal of Fisheries and Aquatic Sciences 48 (5): 875–883. doi:10.1139/f91-104.
- Vuorinen, P (2002-06). "PCDD, PCDF, PCB and thiamine in Baltic herring (Clupea harengus L.) and sprat [ Sprattus sprattus (L.) as a background to the M74 syndrome of Baltic salmon (Salmo salar L.)"]. ICES Journal of Marine Science 59 (3): 480–496. doi:10.1006/jmsc.2002.1200. ISSN 1054-3139. http://dx.doi.org/10.1006/jmsc.2002.1200.
- Helander, B; Bignert, A; Asplund, L (September 2008). "Using raptors as environmental sentinels: monitoring the white-tailed sea eagle Haliaeetus albicilla in Sweden.". Ambio 37 (6): 425-31. doi:10.1579/0044-7447(2008)37[425:uraesm]2.0.co;2. PMID 18833795.
- Braune, BM; Outridge, PM; Fisk, AT; Muir, DC; Helm, PA; Hobbs, K; Hoekstra, PF; Kuzyk, ZA et al. (1 December 2005). "Persistent organic pollutants and mercury in marine biota of the Canadian Arctic: an overview of spatial and temporal trends.". The Science of the total environment 351-352: 4-56. doi:10.1016/j.scitotenv.2004.10.034. PMID 16109439.
- Bjurlid, F; Roos, A; Ericson Jogsten, I; Hagberg, J (March 2018). "Temporal trends of PBDD/Fs, PCDD/Fs, PBDEs and PCBs in ringed seals from the Baltic Sea (Pusa hispida botnica) between 1974 and 2015.". The Science of the total environment 616-617: 1374-1383. doi:10.1016/j.scitotenv.2017.10.178. PMID 29066193.
- Olsson, Mats; Karlsson, Börje; Ahnland, Eva (September 1994). "Diseases and environmental contaminants in seals from the Baltic and the Swedish west coast". Science of The Total Environment 154 (2-3): 217–227. doi:10.1016/0048-9697(94)90089-2.
- Sonne, C; Dietz, R; Born, EW; Riget, FF; Kirkegaard, M; Hyldstrup, L; Letcher, RJ; Muir, DC (December 2004). "Is bone mineral composition disrupted by organochlorines in east Greenland polar bears (Ursus maritimus)?". Environmental health perspectives 112 (17): 1711-6. doi:10.1289/ehp.7293. PMID 15579418.
- Murtomaa, M; Tervaniemi, OM; Parviainen, J; Ruokojärvi, P; Tuukkanen, J; Viluksela, M (June 2007). "Dioxin exposure in contaminated sawmill area: the use of molar teeth and bone of bank vole (Clethrionomys glareolus) and field vole (Microtus agrestis) as biomarkers.". Chemosphere 68 (5): 951-7. doi:10.1016/j.chemosphere.2007.01.030. PMID 17335869.
- Kattainen, H; Tuukkanen, J; Simanainen, U; Tuomisto, JT; Kovero, O; Lukinmaa, PL; Alaluusua, S; Tuomisto, J et al. (1 August 2001). "In utero/lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats.". Toxicology and applied pharmacology 174 (3): 216-24. doi:10.1006/taap.2001.9216. PMID 11485382.
- Norstrom, RJ; Hebert, CE (August 2006). "Comprehensive re-analysis of archived herring gull eggs reconstructs historical temporal trends in chlorinated hydrocarbon contamination in Lake Ontario and Green Bay, Lake Michigan, 1971-1982.". Journal of environmental monitoring : JEM 8 (8): 835-47. doi:10.1039/b602378a. PMID 16896467.
- de Solla, Shane R.; Weseloh, D. V. Chip; Hughes, Kimberley D.; Moore, David J. (April 2016). "Forty-Year Decline of Organic Contaminants in Eggs of Herring Gulls ( ) from the Great Lakes, 1974 to 2013". Waterbirds 39 (sp1): 166–179. doi:10.1675/063.039.sp117.
- Hughes, K. D.; de Solla, S. R.; Weseloh, D. V. C.; Martin, P. A. (9 May 2016). "Long-term trends in legacy contaminants in aquatic wildlife in the Hamilton Harbour Area of Concern". Aquatic Ecosystem Health & Management 19 (2): 171–180. doi:10.1080/14634988.2016.1150113.
- Miller, A; Nyberg, E; Danielsson, S; Faxneld, S; Haglund, P; Bignert, A (September 2014). "Comparing temporal trends of organochlorines in guillemot eggs and Baltic herring: advantages and disadvantage for selecting sentinel species for environmental monitoring.". Marine environmental research 100: 38-47. doi:10.1016/j.marenvres.2014.02.007. PMID 24680644.
- Airaksinen, R; Hallikainen, A; Rantakokko, P; Ruokojärvi, P; Vuorinen, PJ; Parmanne, R; Verta, M; Mannio, J et al. (November 2014). "Time trends and congener profiles of PCDD/Fs, PCBs, and PBDEs in Baltic herring off the coast of Finland during 1978-2009.". Chemosphere 114: 165-71. doi:10.1016/j.chemosphere.2014.03.097. PMID 25113198.
- Miller, A; Hedman, JE; Nyberg, E; Haglund, P; Cousins, IT; Wiberg, K; Bignert, A (15 August 2013). "Temporal trends in dioxins (polychlorinated dibenzo-p-dioxin and dibenzofurans) and dioxin-like polychlorinated biphenyls in Baltic herring (Clupea harengus).". Marine pollution bulletin 73 (1): 220-30. doi:10.1016/j.marpolbul.2013.05.015. PMID 23806670.
- Vuorinen, Pekka J.; Roots, Ott; Keinänen, Marja (July 2017). "Review of organohalogen toxicants in fish from the Gulf of Finland". Journal of Marine Systems 171: 141–150. doi:10.1016/j.jmarsys.2016.12.002.
- Sulawa, Justine; Robert, Alexandre; Köppen, Ulrich; Hauff, Peter; Krone, Oliver (13 August 2009). "Recovery dynamics and viability of the white-tailed eagle (Haliaeetus albicilla) in Germany". Biodiversity and Conservation 19 (1): 97–112. doi:10.1007/s10531-009-9705-4.
- Rattner, BA; Lazarus, RS; Bean, TG; McGowan, PC; Callahan, CR; Erickson, RA; Hale, RC (15 October 2018). "Examination of contaminant exposure and reproduction of ospreys (Pandion haliaetus) nesting in Delaware Bay and River in 2015.". The Science of the total environment 639: 596-607. doi:10.1016/j.scitotenv.2018.05.068. PMID 29800853.
- Pagano, JJ; Garner, AJ; McGoldrick, DJ; Crimmins, BS; Hopke, PK; Milligan, MS; Holsen, TM (16 January 2018). "Age-Corrected Trends and Toxic Equivalence of PCDD/F and CP-PCBs in Lake Trout and Walleye from the Great Lakes: 2004-2014.". Environmental science & technology 52 (2): 712-721. doi:10.1021/acs.est.7b05568. PMID 29249152.
- Kiviranta, H; Vartiainen, T; Parmanne, R; Hallikainen, A; Koistinen, J (March 2003). "PCDD/Fs and PCBs in Baltic herring during the 1990s.". Chemosphere 50 (9): 1201-16. PMID 12547334.
- Bustnes, JO; Bakken, V; Skaare, JU; Erikstad, KE (September 2003). "Age and accumulation of persistent organochlorines: a study of Arctic-breeding glaucous gulls (Larus hyperboreus).". Environmental toxicology and chemistry 22 (9): 2173-9. PMID 12959547.
- Løseth, ME; Briels, N; Eulaers, I; Nygård, T; Malarvannan, G; Poma, G; Covaci, A; Herzke, D et al. (March 2019). "Plasma concentrations of organohalogenated contaminants in white-tailed eagle nestlings - The role of age and diet.". Environmental pollution (Barking, Essex : 1987) 246: 527-534. doi:10.1016/j.envpol.2018.12.028. PMID 30583161.
- EFSA Panel on Contaminants in the Food Chain (2018). "Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food". EFSA Journal 16: 5333. doi:10.2903/j.efsa.2018.5333. https://www.efsa.europa.eu/en/efsajournal/pub/5333.
- Demond, A; Franzblau, A; Garabrant, D; Jiang, X; Adriaens, P; Chen, Q; Gillespie, B; Hao, W et al. (7 February 2012). "Human exposure from dioxins in soil.". Environmental science & technology 46 (3): 1296-302. doi:10.1021/es2022363. PMID 22136605.
- Kiviranta, H; Tuomisto, JT; Tuomisto, J; Tukiainen, E; Vartiainen, T (August 2005). "Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in the general population in Finland.". Chemosphere 60 (7): 854-69. doi:10.1016/j.chemosphere.2005.01.064. PMID 15992592.
- Tuomisto, JT; Pekkanen, J; Kiviranta, H; Tukiainen, E; Vartiainen, T; Tuomisto, J (1 March 2004). "Soft-tissue sarcoma and dioxin: A case-control study.". International journal of cancer 108 (6): 893-900. doi:10.1002/ijc.11635. PMID 14712494.
- Tuomisto, J; Airaksinen, R; Kiviranta, H; Tukiainen, E; Pekkanen, J; Tuomisto, JT (2 November 2016). "A pharmacokinetic analysis and dietary information are necessary to confirm or reject the hypothesis on persistent organic pollutants causing type 2 diabetes.". Toxicology letters 261: 41-48. doi:10.1016/j.toxlet.2016.08.024. PMID 27575567.
- Consonni, D; Sindaco, R; Bertazzi, PA (September 2012). "Blood levels of dioxins, furans, dioxin-like PCBs, and TEQs in general populations: a review, 1989-2010.". Environment international 44: 151-62. doi:10.1016/j.envint.2012.01.004. PMID 22364893.
- van den Berg, M; Kypke, K; Kotz, A; Tritscher, A; Lee, SY; Magulova, K; Fiedler, H; Malisch, R (January 2017). "WHO/UNEP global surveys of PCDDs, PCDFs, PCBs and DDTs in human milk and benefit-risk evaluation of breastfeeding.". Archives of toxicology 91 (1): 83-96. doi:10.1007/s00204-016-1802-z. PMID 27438348.
- Norén, K; Meironyté, D (NaN). "Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20-30 years.". Chemosphere 40 (9-11): 1111-23. PMID 10739053.
- WHO. Levels of PCBs, PCDDs, and PCDFs in breast milk. World Health Organisation, Environmental Health Series 34 ; 1989.
- Geusau, A; Abraham, K; Geissler, K; Sator, MO; Stingl, G; Tschachler, E (August 2001). "Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects.". Environmental health perspectives 109 (8): 865-9. doi:10.1289/ehp.01109865. PMID 11564625.
- Saurat, JH; Kaya, G; Saxer-Sekulic, N; Pardo, B; Becker, M; Fontao, L; Mottu, F; Carraux, P et al. (January 2012). "The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko.". Toxicological sciences : an official journal of the Society of Toxicology 125 (1): 310-7. doi:10.1093/toxsci/kfr223. PMID 21998131.
- Mocarelli, P; Needham, LL; Marocchi, A; Patterson DG, Jr; Brambilla, P; Gerthoux, PM; Meazza, L; Carreri, V (April 1991). "Serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin and test results from selected residents of Seveso, Italy.". Journal of toxicology and environmental health 32 (4): 357-66. doi:10.1080/15287399109531490. PMID 1826746.
- Eskenazi, B; Warner, M; Brambilla, P; Signorini, S; Ames, J; Mocarelli, P (December 2018). "The Seveso accident: A look at 40 years of health research and beyond.". Environment international 121 (Pt 1): 71-84. doi:10.1016/j.envint.2018.08.051. PMID 30179766.
- Consonni, D; Pesatori, AC; Zocchetti, C; Sindaco, R; D'Oro, LC; Rubagotti, M; Bertazzi, PA (1 April 2008). "Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up.". American journal of epidemiology 167 (7): 847-58. doi:10.1093/aje/kwm371. PMID 18192277.
- Pesatori, AC; Consonni, D; Rubagotti, M; Grillo, P; Bertazzi, PA (15 September 2009). "Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up.". Environmental health : a global access science source 8: 39. doi:10.1186/1476-069X-8-39. PMID 19754930.
- Warner, M; Mocarelli, P; Samuels, S; Needham, L; Brambilla, P; Eskenazi, B (December 2011). "Dioxin exposure and cancer risk in the Seveso Women's Health Study.". Environmental health perspectives 119 (12): 1700-5. doi:10.1289/ehp.1103720. PMID 21810551.
- Alaluusua, S; Calderara, P; Gerthoux, PM; Lukinmaa, PL; Kovero, O; Needham, L; Patterson DG, Jr; Tuomisto, J et al. (September 2004). "Developmental dental aberrations after the dioxin accident in Seveso.". Environmental health perspectives 112 (13): 1313-8. doi:10.1289/ehp.6920. PMID 15345345.
- Mocarelli, P; Gerthoux, PM; Ferrari, E; Patterson DG, Jr; Kieszak, SM; Brambilla, P; Vincoli, N; Signorini, S et al. (27 May 2000). "Paternal concentrations of dioxin and sex ratio of offspring.". Lancet (London, England) 355 (9218): 1858-63. doi:10.1016/S0140-6736(00)02290-X. PMID 10866441.
- Mocarelli, P; Gerthoux, PM; Patterson DG, Jr; Milani, S; Limonta, G; Bertona, M; Signorini, S; Tramacere, P et al. (January 2008). "Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality.". Environmental health perspectives 116 (1): 70-7. doi:10.1289/ehp.10399. PMID 18197302.
- Mocarelli, P; Gerthoux, PM; Needham, LL; Patterson DG, Jr; Limonta, G; Falbo, R; Signorini, S; Bertona, M et al. (May 2011). "Perinatal exposure to low doses of dioxin can permanently impair human semen quality.". Environmental health perspectives 119 (5): 713-8. doi:10.1289/ehp.1002134. PMID 21262597.
- Eskenazi, B; Mocarelli, P; Warner, M; Samuels, S; Vercellini, P; Olive, D; Needham, LL; Patterson DG, Jr et al. (July 2002). "Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy.". Environmental health perspectives 110 (7): 629-34. doi:10.1289/ehp.02110629. PMID 12117638.
- Eskenazi, B; Warner, M; Marks, AR; Samuels, S; Needham, L; Brambilla, P; Mocarelli, P (March 2010). "Serum dioxin concentrations and time to pregnancy.". Epidemiology (Cambridge, Mass.) 21 (2): 224-31. doi:10.1097/EDE.0b013e3181cb8b95. PMID 20124903.
- Wesselink, A; Warner, M; Samuels, S; Parigi, A; Brambilla, P; Mocarelli, P; Eskenazi, B (February 2014). "Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso.". Environment international 63: 143-8. doi:10.1016/j.envint.2013.11.005. PMID 24291766.
- Sweeney, MH; Mocarelli, P (April 2000). "Human health effects after exposure to 2,3,7,8-TCDD.". Food additives and contaminants 17 (4): 303-16. doi:10.1080/026520300283379. PMID 10912244.
- Baccarelli, A; Giacomini, SM; Corbetta, C; Landi, MT; Bonzini, M; Consonni, D; Grillo, P; Patterson, DG et al. (29 July 2008). "Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin.". PLoS medicine 5 (7): e161. doi:10.1371/journal.pmed.0050161. PMID 18666825.
- Kashima, S; Yorifuji, T; Tsuda, T; Eboshida, A (May 2015). "Cancer and non-cancer excess mortality resulting from mixed exposure to polychlorinated biphenyls and polychlorinated dibenzofurans from contaminated rice oil: "Yusho".". International archives of occupational and environmental health 88 (4): 419-30. doi:10.1007/s00420-014-0966-1. PMID 25091711.
- Tsai, PC; Ko, YC; Huang, W; Liu, HS; Guo, YL (15 March 2007). "Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans.". The Science of the total environment 374 (2-3): 216-22. doi:10.1016/j.scitotenv.2006.12.024. PMID 17257654.
- Masuda, Y (February 1996). "Approach to risk assessment of chlorinated dioxins from Yusho PCB poisoning.". Chemosphere 32 (3): 583-94. PMID 8907236.
- Hsu, JF; Guo, YL; Yang, SY; Liao, PC (December 2005). "Congener profiles of PCBs and PCDD/Fs in Yucheng victims fifteen years after exposure to toxic rice-bran oils and their implications for epidemiologic studies.". Chemosphere 61 (9): 1231-43. doi:10.1016/j.chemosphere.2005.03.081. PMID 15893794.
- Onozuka, D; Yoshimura, T; Kaneko, S; Furue, M (1 January 2009). "Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a 40-year follow-up study of Yusho patients.". American journal of epidemiology 169 (1): 86-95. doi:10.1093/aje/kwn295. PMID 18974082.
- Li, MC; Chen, PC; Tsai, PC; Furue, M; Onozuka, D; Hagihara, A; Uchi, H; Yoshimura, T et al. (15 September 2015). "Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a meta-analysis of two highly exposed cohorts.". International journal of cancer 137 (6): 1427-32. doi:10.1002/ijc.29504. PMID 25754105.
- Malisch, R; Kotz, A (1 September 2014). "Dioxins and PCBs in feed and food--review from European perspective.". The Science of the total environment 491-492: 2-10. doi:10.1016/j.scitotenv.2014.03.022. PMID 24804623.
- Debacker, N; Sasse, A; van Wouwe, N; Goeyens, L; Sartor, F; van Oyen, H (April 2007). "PCDD/F levels in plasma of a belgian population before and after the 1999 belgian PCB/DIOXIN incident.". Chemosphere 67 (9): S217-23. doi:10.1016/j.chemosphere.2006.05.101. PMID 17208274.
- Tlustos, C.; Anderson, W.; Flynn, A.; Pratt, I. (2014-05-04). "Additional exposure of the Irish adult population to dioxins and PCBs from the diet as a consequence of the 2008 Irish dioxin food contamination incident". Food Additives & Contaminants: Part A 31 (5): 889–904. doi:10.1080/19440049.2014.893399. ISSN 1944-0049. http://www.tandfonline.com/doi/abs/10.1080/19440049.2014.893399.
- Michalek, JE; Pavuk, M (March 2008). "Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia.". Journal of occupational and environmental medicine 50 (3): 330-40. doi:10.1097/JOM.0b013e31815f889b. PMID 18332783.
- Cypel, YS; Kress, AM; Eber, SM; Schneiderman, AI; Davey, VJ (November 2016). "Herbicide Exposure, Vietnam Service, and Hypertension Risk in Army Chemical Corps Veterans.". Journal of occupational and environmental medicine 58 (11): 1127-1136. doi:10.1097/JOM.0000000000000876. PMID 27820763.
- Kerger, Brent D.; Scott, Paul K.; Pavuk, Marian; Gough, Michael; Paustenbach, Dennis J. (2012-06-21). "Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes". Critical Reviews in Toxicology 42 (8): 669–687. doi:10.3109/10408444.2012.694095. ISSN 1040-8444. http://dx.doi.org/10.3109/10408444.2012.694095.
- Steenland, K (2001-10-01). "Dioxin and diabetes mellitus: an analysis of the combined NIOSH and Ranch Hand data". Occupational and Environmental Medicine 58 (10): 641–648. doi:10.1136/oem.58.10.641. ISSN 1351-0711. http://dx.doi.org/10.1136/oem.58.10.641.
- Jaacks, Lindsay M.; Staimez, Lisa R. (2015-03). "Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: A systematic review". Environment International 76: 57–70. doi:10.1016/j.envint.2014.12.001. ISSN 0160-4120. http://dx.doi.org/10.1016/j.envint.2014.12.001.
- Young, Alvin (2019). "A Review of Public Health in Vietnam: 50 Years after Agent Orange was Sprayed". Health Education and Public Health 2 (2): 170-180. doi:10.31488 /heph.119. https://www.academia.edu/39168589/A_Review_of_Public_Health_in_Vietnam_50_Years_after_Agent_Orange_was_Sprayed.
- Pham, NT; Nishijo, M; Pham, TT; Tran, NN; Le, VQ; Tran, HA; Phan, HAV; Nishino, Y et al. (15 August 2019). "Perinatal dioxin exposure and neurodevelopment of 2-year-old Vietnamese children in the most contaminated area from Agent Orange in Vietnam.". The Science of the total environment 678: 217-226. doi:10.1016/j.scitotenv.2019.04.425. PMID 31075589.
- Tran, NN; Pham, TT; Ozawa, K; Nishijo, M; Nguyen, AT; Tran, TQ; Hoang, LV; Tran, AH et al. (2016). "Impacts of Perinatal Dioxin Exposure on Motor Coordination and Higher Cognitive Development in Vietnamese Preschool Children: A Five-Year Follow-Up.". PloS one 11 (1): e0147655. doi:10.1371/journal.pone.0147655. PMID 26824471.
- Nguyen, Anh Thi Nguyet; Nishijo, Muneko; Pham, Tai The; Tran, Nghi Ngoc; Tran, Anh Hai; Hoang, Luong Van; Boda, Hitomi; Morikawa, Yuko et al. (5 July 2018). "Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year-old Vietnamese children". BMC Pediatrics 18 (1): 213. doi:10.1186/s12887-018-1171-2. ISSN 1471-2431. https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1171-2.
- Armitage, JM; Ginevan, ME; Hewitt, A; Ross, JH; Watkins, DK; Solomon, KR (15 February 2015). "Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of Agent Orange in upland forests of Vietnam.". The Science of the total environment 506-507: 621-30. doi:10.1016/j.scitotenv.2014.11.026. PMID 25433383.
- Hue, NT; Nam, VD; Thuong, NV; Huyen, NT; Phuong, NT; Hung, NX; Tuan, NH; Son, LK et al. (1 September 2014). "Determination of PCDD/Fs in breast milk of women living in the vicinities of Da Nang Agent Orange hot spot (Vietnam) and estimation of the infant's daily intake.". The Science of the total environment 491-492: 212-8. doi:10.1016/j.scitotenv.2014.02.054. PMID 24613651.
- Flesch-Janys, D; Berger, J; Gurn, P; Manz, A; Nagel, S; Waltsgott, H; Dwyer, JH (1 December 1995). "Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany.". American journal of epidemiology 142 (11): 1165-75. doi:10.1093/oxfordjournals.aje.a117575. PMID 7485063.
- Ott, MG; Zober, A (September 1996). "Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident.". Occupational and environmental medicine 53 (9): 606-12. doi:10.1136/oem.53.9.606. PMID 8882118.
- Steenland, K; Piacitelli, L; Deddens, J; Fingerhut, M; Chang, LI (5 May 1999). "Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.". Journal of the National Cancer Institute 91 (9): 779-86. doi:10.1093/jnci/91.9.779. PMID 10328108.
- Boers, D; Portengen, L; Bueno-de-Mesquita, HB; Heederik, D; Vermeulen, R (January 2010). "Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers.". Occupational and environmental medicine 67 (1): 24-31. doi:10.1136/oem.2008.044222. PMID 19736176.
- "Pentachlorophenol and Some Related Compounds". IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 117. IARC. 2016. pp. 33–168. ISBN 978-92-832-0155-7.
- Tuomisto, J; Tuomisto, JT (5 May 2012). "Is the fear of dioxin cancer more harmful than dioxin?". Toxicology letters 210 (3): 338-44. doi:10.1016/j.toxlet.2012.02.007. PMID 22387160.
- Kogevinas, M; Becher, H; Benn, T; et al. (1997). "Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins". Am J Epidemiol 145: 1061-1075. doi:10.1093/oxfordjournals.aje.a009069. PMID 9199536.
- IARC Working Group on the Evaluation of Carcinogenic Risk to Humans (1997). Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. 69. International Agency for Research on Cancer. pp. 1–636.
- IARC Working Group on the Evaluation of Carcinogenic Risk to Humans (2012). 2,3,7,8-tetrachlorodibenzopara-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl. 100F. International Agency for Research on Cancer. pp. 339–378.
- Yamaguchi, N (1999-12). "Uncertainty in Risk Characterization of Weak Carcinogens". Annals of the New York Academy of Sciences 895 (1 UNCERTAINTY I): 338–347. doi:10.1111/j.1749-6632.1999.tb08094.x. ISSN 0077-8923. http://dx.doi.org/10.1111/j.1749-6632.1999.tb08094.x.
- Cole, P; Trichopoulos, D; Pastides, H; Starr, T; Mandel, JS (December 2003). "Dioxin and cancer: a critical review.". Regulatory toxicology and pharmacology : RTP 38 (3): 378-88. PMID 14623487.
- Boffetta, Paolo; Mundt, Kenneth A.; Adami, Hans-Olov; Cole, Philip; Mandel, Jack S. (2011-07). "TCDD and cancer: A critical review of epidemiologic studies". Critical Reviews in Toxicology 41 (7): 622–636. doi:10.3109/10408444.2011.560141. ISSN 1040-8444. http://dx.doi.org/10.3109/10408444.2011.560141.
- Xu, Jinming; Ye, Yao; Huang, Fang; Chen, Hanwen; Wu, Han; Huang, Jian; Hu, Jian; Xia, Dajing et al. (2016-11-29). "Association between dioxin and cancer incidence and mortality: a meta-analysis". Scientific Reports 6 (1). doi:10.1038/srep38012. ISSN 2045-2322. http://dx.doi.org/10.1038/srep38012.
- Humblet, O; Birnbaum, L; Rimm, E; Mittleman, MA; Hauser, R (November 2008). "Dioxins and cardiovascular disease mortality.". Environmental health perspectives 116 (11): 1443-8. doi:10.1289/ehp.11579. PMID 19057694.
- Ryan, JJ; Amirova, Z; Carrier, G (November 2002). "Sex ratios of children of Russian pesticide producers exposed to dioxin.". Environmental health perspectives 110 (11): A699-701. doi:10.1289/ehp.021100699. PMID 12417498.
- Alaluusua, S; Lukinmaa, PL; Vartiainen, T; Partanen, M; Torppa, J; Tuomisto, J (15 May 1996). "Polychlorinated dibenzo-p-dioxins and dibenzofurans via mother's milk may cause developmental defects in the child's teeth.". Environmental toxicology and pharmacology 1 (3): 193-7. PMID 21781681.
- Alaluusua, S; Lukinmaa, PL; Torppa, J; Tuomisto, J; Vartiainen, T (16 January 1999). "Developing teeth as biomarker of dioxin exposure.". Lancet (London, England) 353 (9148): 206. doi:10.1016/S0140-6736(05)77214-7. PMID 9923879.
- Koskenniemi, JJ; Virtanen, HE; Kiviranta, H; Damgaard, IN; Matomäki, J; Thorup, JM; Hurme, T; Skakkebaek, NE et al. (24 September 2015). "Association between levels of persistent organic pollutants in adipose tissue and cryptorchidism in early childhood: a case-control study.". Environmental health : a global access science source 14: 78. doi:10.1186/s12940-015-0065-0. PMID 26403566.
- Mínguez-Alarcón, L; Sergeyev, O; Burns, JS; Williams, PL; Lee, MM; Korrick, SA; Smigulina, L; Revich, B et al. (March 2017). "A Longitudinal Study of Peripubertal Serum Organochlorine Concentrations and Semen Parameters in Young Men: The Russian Children's Study.". Environmental health perspectives 125 (3): 460-466. doi:10.1289/EHP25. PMID 27713107.
- <Humblet, O; Williams, PL; Korrick, SA; Sergeyev, O; Emond, C; Birnbaum, LS; Burns, JS; Altshul, L et al. (15 July 2010). "Predictors of serum dioxin, furan, and PCB concentrations among women from Chapaevsk, Russia.". Environmental science & technology 44 (14): 5633-40. doi:10.1021/es100976j. PMID 20578718.
- Pilsner, JR; Parker, M; Sergeyev, O; Suvorov, A (April 2017). "Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility.". Reproductive toxicology (Elmsford, N.Y.) 69: 221-229. doi:10.1016/j.reprotox.2017.03.002. PMID 28286111.
- Pilsner, JR; Shershebnev, A; Medvedeva, YA; et al. (June 2018). "Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults.". Reproductive toxicology (Elmsford, N.Y.) 78: 40-49. doi:10.1016/j.reprotox.2018.03.007. PMID 29550351.
- Magliano, DJ; Loh, VH; Harding, JL; Botton, J; Shaw, JE (February 2014). "Persistent organic pollutants and diabetes: a review of the epidemiological evidence.". Diabetes & metabolism 40 (1): 1-14. doi:10.1016/j.diabet.2013.09.006. PMID 24262435.
- Tornevi, A; Sommar, J; Rantakokko, P; Åkesson, A; Donat-Vargas, C; Kiviranta, H; Rolandsson, O; Rylander, L et al. (July 2019). "Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples.". Environmental research 174: 35-45. doi:10.1016/j.envres.2019.04.017. PMID 31029940.
- Van Leeuwen, F.X.R.; Younes,, M.M., eds (April 2000). "Assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI). Geneva, Switzerland, 25-29 May 1998.". Food additives and contaminants 17 (4): 223-369. PMID 10960271.
- WHO temporary advisor group (April 2000). "Consultation on assessment of the health risk of dioxins; re-evaluation of the tolerable daily intake (TDI): executive summary.". Food additives and contaminants 17 (4): 223-40. doi:10.1080/713810655. PMID 10912238.
- "Opinion of the scientific committee on food on the risk assessment of dioxins and dioxin-like PCBs in food (S/CNTM/DIOXIN/20 final)" (PDF). hero.epa.gov. European Commission. 2001. Retrieved 2019-12-17.
- Rice, Glenn. "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments (External Review Draft)". cfpub.epa.gov. US EPA National Center for Environmental Assessment,Cincinnati Oh. Retrieved 2019-12-16.
- EFSA (European Food Safety Authority) (May 2015). "Scientific statement on the health‐based guidance values for dioxins and dioxin‐like PCBs". EFSA Journal 13 (5). doi:10.2903/j.efsa.2015.4124.
- Olsen, Sjúrđur Fróđi; Secher, Niels Jørgen (2002-10). "Low Consumption of Seafood in Early Pregnancy as a Risk Factor for Preterm Delivery: Prospective Cohort Study". Obstetrical & Gynecological Survey 57 (10): 651–652. doi:10.1097/00006254-200210000-00004. ISSN 0029-7828. http://dx.doi.org/10.1097/00006254-200210000-00004.
- Cohen, Joshua T.; Bellinger, David C.; Connor, William E.; Kris-Etherton, Penny M.; Lawrence, Robert S.; Savitz, David A.; Shaywitz, Bennett A.; Teutsch, Steven M. et al. (2005-11-01). "A Quantitative Risk–Benefit Analysis of Changes in Population Fish Consumption". American Journal of Preventive Medicine 29 (4): 325–334.e6. doi:10.1016/j.amepre.2005.07.003. ISSN 0749-3797. https://www.ajpmonline.org/article/S0749-3797(05)00253-9/abstract.
- Mozaffarian, Dariush; Rimm, Eric B. (2006-10-18). "Fish Intake, Contaminants, and Human Health". JAMA 296 (15): 1885. doi:10.1001/jama.296.15.1885. ISSN 0098-7484. http://dx.doi.org/10.1001/jama.296.15.1885.
- Starling, Phoebe; Charlton, Karen; McMahon, Anne; Lucas, Catherine (2015-03-18). "Fish Intake during Pregnancy and Foetal Neurodevelopment—A Systematic Review of the Evidence". Nutrients 7 (3): 2001–2014. doi:10.3390/nu7032001. ISSN 2072-6643. http://dx.doi.org/10.3390/nu7032001.
- Tuomisto, Jouni T.; Asikainen, Arja; Meriläinen, Päivi; Haapasaari, Päivi (2020-01-15). "Health effects of nutrients and environmental pollutants in Baltic herring and salmon: a quantitative benefit-risk assessment". BMC Public Health 20 (1): 64. doi:10.1186/s12889-019-8094-1. ISSN 1471-2458. PMID 31941472. PMC PMC6964011. https://doi.org/10.1186/s12889-019-8094-1.
- Schrenk, D; Chopra, M. "Dioxin activated AHR and cancer in laboratory animals". In Pohjanvirta, R (ed.). The AH receptor in biology and toxicology. Wiley. ISBN 9780470601822.
- Kogevinas, M (April 2000). "Studies of cancer in humans.". Food additives and contaminants 17 (4): 317-24. doi:10.1080/026520300283388. PMID 10912245.
- Kayajanian, Gary Michael (2002-01). "The J-Shaped Dioxin Dose Response Curve". Ecotoxicology and Environmental Safety 51 (1): 1–4. doi:10.1006/eesa.2001.2115. ISSN 0147-6513. http://dx.doi.org/10.1006/eesa.2001.2115.
- Tuomisto, J; Airaksinen, R; Pekkanen, J; Tukiainen, E; Kiviranta, H; Tuomisto, JT (15 March 2017). "Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies.". Toxicology letters 270: 8-11. doi:10.1016/j.toxlet.2017.02.011. PMID 28189645.
- Tuomisto, J; Pekkanen, J; Kiviranta, H; Tukiainen, E; Vartiainen, T; Viluksela, M; Tuomisto, JT (1 May 2006). "Dioxin cancer risk--example of hormesis?". Dose-response : a publication of International Hormesis Society 3 (3): 332-41. doi:10.2203/dose-response.003.03.004. PMID 18648613.
- Koual, Meriem; Cano-Sancho, German; Bats, Anne-Sophie; Tomkiewicz, Céline; Kaddouch-Amar, Yael; Douay-Hauser, Nathalie; Ngo, Charlotte; Bonsang, Hélène et al. (2019-11). "Associations between persistent organic pollutants and risk of breast cancer metastasis". Environment International 132: 105028. doi:10.1016/j.envint.2019.105028. ISSN 0160-4120. http://dx.doi.org/10.1016/j.envint.2019.105028.
- Tuomisto, JT; Tuomisto, J; Tainio, M; Niittynen, M; Verkasalo, P; Vartiainen, T; Kiviranta, H; Pekkanen, J (23 July 2004). "Risk-benefit analysis of eating farmed salmon.". Science (New York, N.Y.) 305 (5683): 476-7; author reply 476-7. doi:10.1126/science.305.5683.476. PMID 15273377.
- Birnbaum, LS; Tuomisto, J (April 2000). "Non-carcinogenic effects of TCDD in animals.". Food additives and contaminants 17 (4): 275-88. doi:10.1080/026520300283351. PMID 10912242.
- Tuomisto, J (1 September 2005). "Does mechanistic understanding help in risk assessment--the example of dioxins.". Toxicology and applied pharmacology 207 (2 Suppl): 2-10. doi:10.1016/j.taap.2005.01.053. PMID 15996698.
- Lensu, S; Tuomisto, JT; Tuomisto, J; Pohjanvirta, R (10 May 2011). "Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats.". Toxicology 283 (2-3): 140-50. doi:10.1016/j.tox.2011.03.007. PMID 21435369.
- Lensu, S; Tuomisto, JT; Tuomisto, J; Viluksela, M; Niittynen, M; Pohjanvirta, R (24 June 2011). "Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation.". Toxicology letters 203 (3): 252-7. doi:10.1016/j.toxlet.2011.03.025. PMID 21458548.
- Pohjanvirta, R; Wong, JM; Li, W; Harper, PA; Tuomisto, J; Okey, AB (July 1998). "Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain.". Molecular pharmacology 54 (1): 86-93. doi:10.1124/mol.54.1.86. PMID 9658193.
- Tuomisto, JT; Viluksela, M; Pohjanvirta, R; Tuomisto, J (15 February 1999). "The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines.". Toxicology and applied pharmacology 155 (1): 71-81. doi:10.1006/taap.1998.8564. PMID 10036220.
- Simanainen, U; Tuomisto, JT; Tuomisto, J; Viluksela, M (1 March 2003). "Dose-response analysis of short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in three differentially susceptible rat lines.". Toxicology and applied pharmacology 187 (2): 128-36. doi:10.1016/s0041-008x(02)00068-6. PMID 12649045.
- Viluksela, M; Bager, Y; Tuomisto, JT; Scheu, G; Unkila, M; Pohjanvirta, R; Flodström, S; Kosma, VM et al. (15 December 2000). "Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains.". Cancer research 60 (24): 6911-20. PMID 11156390.
- Miettinen, HM; Sorvari, R; Alaluusua, S; Murtomaa, M; Tuukkanen, J; Viluksela, M (June 2006). "The effect of perinatal TCDD exposure on caries susceptibility in rats.". Toxicological sciences : an official journal of the Society of Toxicology 91 (2): 568-75. doi:10.1093/toxsci/kfj158. PMID 16543294.
- Kransler, Kevin M.; McGarrigle, Barbara P.; Olson, James R. (2007-01). "Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig". Toxicology 229 (3): 214–225. doi:10.1016/j.tox.2006.10.019. ISSN 0300-483X. http://dx.doi.org/10.1016/j.tox.2006.10.019.
- Unkila, M; Pohjanvirta, R; Tuomisto, J (1999). "Dioxin-induced perturbations in tryptophan homeostasis in laboratory animals.". Advances in experimental medicine and biology 467: 433-42. doi:10.1007/978-1-4615-4709-9_55. PMID 10721086.
- Chen, CY; Hamm, JT; Hass, JR; Birnbaum, LS (1 June 2001). "Disposition of polychlorinated dibenzo-p-dioxins, dibenzofurans, and non-ortho polychlorinated biphenyls in pregnant long evans rats and the transfer to offspring.". Toxicology and applied pharmacology 173 (2): 65-88. doi:10.1006/taap.2001.9143. PMID 11384209.
- Li, X; Weber, LW; Rozman, KK (August 1995). "Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates.". Fundamental and applied toxicology : official journal of the Society of Toxicology 27 (1): 70-6. PMID 7589930.
- Bell, DR; Clode, S; Fan, MQ; Fernandes, A; Foster, PM; Jiang, T; Loizou, G; MacNicoll, A et al. (June 2010). "Interpretation of studies on the developmental reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring.". Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 48 (6): 1439-47. doi:10.1016/j.fct.2010.04.005. PMID 20388530.
- Birnbaum, LS (October 1995). "Developmental effects of dioxins.". Environmental health perspectives 103 Suppl 7: 89-94. doi:10.1289/ehp.95103s789. PMID 8593882.
- Yoshioka, W; Tohyama, C (31 January 2019). "Mechanisms of Developmental Toxicity of Dioxins and Related Compounds.". International journal of molecular sciences 20 (3). doi:10.3390/ijms20030617. PMID 30708991.
- Viluksela, M; Miettinen, HM; Korkalainen, M (2012). "Effects of dioxins on teeth and bone: The role of AHR". In Pohjanvirta, Raimo (ed.). The AH receptor in biology and toxicology. Wiley. pp. 285–297. ISBN 9780470601822.
- Miettinen, HM; Alaluusua, S; Tuomisto, J; Viluksela, M (1 October 2002). "Effect of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on rat molar development: the role of exposure time.". Toxicology and applied pharmacology 184 (1): 57-66. PMID 12392969.
- Keller, JM; Allen, DE; Davis, CR; Leamy, LJ (May 2007). "2,3,7,8-Tetrachlorodibenzo-p-dioxin affects fluctuating asymmetry of molar shape in mice, and an epistatic interaction of two genes for molar size.". Heredity 98 (5): 259-67. doi:10.1038/sj.hdy.6800928. PMID 17213866.
- Keller, JM; Huet-Hudson, YM; Leamy, LJ (May 2007). "Qualitative effects of dioxin on molars vary among inbred mouse strains.". Archives of oral biology 52 (5): 450-4. doi:10.1016/j.archoralbio.2006.10.017. PMID 17141729.
- Yasuda, I; Yasuda, M; Sumida, H; Tsusaki, H; Arima, A; Ihara, T; Kubota, S; Asaoka, K et al. (NaN). "In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects tooth development in rhesus monkeys.". Reproductive toxicology (Elmsford, N.Y.) 20 (1): 21-30. doi:10.1016/j.reprotox.2004.12.016. PMID 15808782.
- Render, JA; Bursian, SJ; Rosenstein, DS; Aulerich, RJ (February 2001). "Squamous epithelial proliferation in the jaws of mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB 126) or 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD).". Veterinary and human toxicology 43 (1): 22-6. PMID 11205072.
- Hornung, MW; Spitsbergen, JM; Peterson, RE (January 1999). "2,3,7,8-Tetrachlorodibenzo-p-dioxin alters cardiovascular and craniofacial development and function in sac fry of rainbow trout (Oncorhynchus mykiss).". Toxicological sciences : an official journal of the Society of Toxicology 47 (1): 40-51. doi:10.1093/toxsci/47.1.40. PMID 10048152.
- Planchart, A; Mattingly, CJ (15 March 2010). "2,3,7,8-Tetrachlorodibenzo-p-dioxin upregulates FoxQ1b in zebrafish jaw primordium.". Chemical research in toxicology 23 (3): 480-7. doi:10.1021/tx9003165. PMID 20055451.
- Partanen, AM; Alaluusua, S; Miettinen, PJ; Thesleff, I; Tuomisto, J; Pohjanvirta, R; Lukinmaa, PL (December 1998). "Epidermal growth factor receptor as a mediator of developmental toxicity of dioxin in mouse embryonic teeth.". Laboratory investigation; a journal of technical methods and pathology 78 (12): 1473-81. PMID 9881947.
- Abbott, BD; Buckalew, AR; DeVito, MJ; Ross, D; Bryant, PL; Schmid, JE (January 2003). "EGF and TGF-alpha expression influence the developmental toxicity of TCDD: dose response and AhR phenotype in EGF, TGF-alpha, and EGF + TGF-alpha knockout mice.". Toxicological sciences : an official journal of the Society of Toxicology 71 (1): 84-95. doi:10.1093/toxsci/71.1.84. PMID 12520078.
- Alaluusua, S; Lukinmaa, PL (December 2006). "Developmental dental toxicity of dioxin and related compounds--a review.". International dental journal 56 (6): 323-31. PMID 17243464.
- Diry, M; Tomkiewicz, C; Koehle, C; Coumoul, X; Bock, K Walter; Barouki, R; Transy, C (2006-04-17). "Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism". Oncogene 25 (40): 5570–5574. doi:10.1038/sj.onc.1209553. ISSN 0950-9232. http://dx.doi.org/10.1038/sj.onc.1209553.
- Miettinen, HM; Pulkkinen, P; Jämsä, T; Koistinen, J; Simanainen, U; Tuomisto, J; Tuukkanen, J; Viluksela, M (June 2005). "Effects of in utero and lactational TCDD exposure on bone development in differentially sensitive rat lines.". Toxicological sciences : an official journal of the Society of Toxicology 85 (2): 1003-12. doi:10.1093/toxsci/kfi136. PMID 15746008.
- Hermsen, SA; Larsson, S; Arima, A; Muneoka, A; Ihara, T; Sumida, H; Fukusato, T; Kubota, S et al. (20 November 2008). "In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys.". Toxicology 253 (1-3): 147-52. doi:10.1016/j.tox.2008.09.005. PMID 18835322.
- Nishimura, N; Nishimura, H; Ito, T; Miyata, C; Izumi, K; Fujimaki, H; Matsumura, F (1 May 2009). "Dioxin-induced up-regulation of the active form of vitamin D is the main cause for its inhibitory action on osteoblast activities, leading to developmental bone toxicity.". Toxicology and applied pharmacology 236 (3): 301-9. doi:10.1016/j.taap.2009.01.025. PMID 19367694.
- Finnilä, MA; Zioupos, P; Herlin, M; Miettinen, HM; Simanainen, U; Håkansson, H; Tuukkanen, J; Viluksela, M et al. (19 April 2010). "Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on bone material properties.". Journal of biomechanics 43 (6): 1097-103. doi:10.1016/j.jbiomech.2009.12.011. PMID 20132933.
- Korkalainen, M; Kallio, E; Olkku, A; Nelo, K; Ilvesaro, J; Tuukkanen, J; Mahonen, A; Viluksela, M (June 2009). "Dioxins interfere with differentiation of osteoblasts and osteoclasts.". Bone 44 (6): 1134-42. doi:10.1016/j.bone.2009.02.019. PMID 19264158.
- Ishihara, K; Warita, K; Tanida, T; Sugawara, T; Kitagawa, H; Hoshi, N (April 2007). "Does paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affect the sex ratio of offspring?". The Journal of veterinary medical science 69 (4): 347-52. doi:10.1292/jvms.69.347. PMID 17485921.
- Bell, DR; Clode, S; Fan, MQ; Fernandes, A; Foster, PM; Jiang, T; Loizou, G; MacNicoll, A et al. (September 2007). "Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. II: Chronic dosing causes developmental delay.". Toxicological sciences : an official journal of the Society of Toxicology 99 (1): 224-33. doi:10.1093/toxsci/kfm141. PMID 17545211.
- Manikkam, Mohan; Tracey, Rebecca; Guerrero-Bosagna, Carlos; Skinner, Michael K.; Shioda, Toshi (26 September 2012). "Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations". PLoS ONE 7 (9): e46249. doi:10.1371/journal.pone.0046249. PMID 23049995.
- Bruner-Tran, KL; Osteen, KG (April 2011). "Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations.". Reproductive toxicology (Elmsford, N.Y.) 31 (3): 344-50. doi:10.1016/j.reprotox.2010.10.003. PMID 20955784.
- Bruner-Tran, KL; Gnecco, J; Ding, T; Glore, DR; Pensabene, V; Osteen, KG (March 2017). "Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models.". Reproductive toxicology (Elmsford, N.Y.) 68: 59-71. doi:10.1016/j.reprotox.2016.07.007. PMID 27423904.
- Ding, T; McConaha, M; Boyd, KL; Osteen, KG; Bruner-Tran, KL (April 2011). "Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice.". Reproductive toxicology (Elmsford, N.Y.) 31 (3): 351-8. doi:10.1016/j.reprotox.2010.11.003. PMID 21093581.
- Bruner-Tran, KL; Ding, T; Yeoman, KB; Archibong, A; Arosh, JA; Osteen, KG (2014). "Developmental exposure of mice to dioxin promotes transgenerational testicular inflammation and an increased risk of preterm birth in unexposed mating partners.". PloS one 9 (8): e105084. doi:10.1371/journal.pone.0105084. PMID 25127480.
- Sanabria, M; Cucielo, MS; Guerra, MT; Dos Santos Borges, C; Banzato, TP; Perobelli, JE; Leite, GA; Anselmo-Franci, JA et al. (October 2016). "Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study.". Reproductive toxicology (Elmsford, N.Y.) 65: 29-38. doi:10.1016/j.reprotox.2016.06.019. PMID 27352640.
- Baker, TR; King-Heiden, TC; Peterson, RE; Heideman, W (December 2014). "Dioxin induction of transgenerational inheritance of disease in zebrafish.". Molecular and cellular endocrinology 398 (1-2): 36-41. doi:10.1016/j.mce.2014.08.011. PMID 25194296.
- Baker, TR; Peterson, RE; Heideman, W (April 2014). "Using zebrafish as a model system for studying the transgenerational effects of dioxin.". Toxicological sciences : an official journal of the Society of Toxicology 138 (2): 403-11. doi:10.1093/toxsci/kfu006. PMID 24470537.
- Meyer, DN; Baker, BB; Baker, TR (1 August 2018). "Ancestral TCDD Exposure Induces Multigenerational Histologic and Transcriptomic Alterations in Gonads of Male Zebrafish.". Toxicological sciences : an official journal of the Society of Toxicology 164 (2): 603-612. doi:10.1093/toxsci/kfy115. PMID 29788325.
- Kociba, RJ; Keyes, DG; Beyer, JE; Carreon, RM; Wade, CE; Dittenber, DA; Kalnins, RP; Frauson, LE et al. (November 1978). "Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats.". Toxicology and applied pharmacology 46 (2): 279-303. doi:10.1016/0041-008x(78)90075-3. PMID 734660.
- Dragan, YP; Schrenk, D (April 2000). "Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion.". Food additives and contaminants 17 (4): 289-302. doi:10.1080/026520300283360. PMID 10912243.
- Nebert, Daniel W.; Dalton, Timothy P.; Okey, Allan B.; Gonzalez, Frank J. (2004-03-17). "Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer". Journal of Biological Chemistry 279 (23): 23847–23850. doi:10.1074/jbc.r400004200. ISSN 0021-9258. http://dx.doi.org/10.1074/jbc.r400004200.
- Dietert, RR; Silbergeld, EK (April 2015). "Biomarkers for the 21st century: listening to the microbiome.". Toxicological sciences : an official journal of the Society of Toxicology 144 (2): 208-16. doi:10.1093/toxsci/kfv013. PMID 25795652.
- Sowada, J; Schmalenberger, A; Ebner, I; Luch, A; Tralau, T (April 2014). "Degradation of benzo[a]pyrene by bacterial isolates from human skin.". FEMS microbiology ecology 88 (1): 129-39. doi:10.1111/1574-6941.12276. PMID 24372170.
- Zhang, L; Nichols, RG; Correll, J; Murray, IA; Tanaka, N; Smith, PB; Hubbard, TD; Sebastian, A et al. (July 2015). "Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation.". Environmental health perspectives 123 (7): 679-88. doi:10.1289/ehp.1409055. PMID 25768209.
- Lefever, DE; Xu, J; Chen, Y; Huang, G; Tamas, N; Guo, TL (1 August 2016). "TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice.". Toxicology and applied pharmacology 304: 48-58. doi:10.1016/j.taap.2016.05.016. PMID 27221631.
- Hao, N; Whitelaw, ML (1 September 2013). "The emerging roles of AhR in physiology and immunity.". Biochemical pharmacology 86 (5): 561-70. doi:10.1016/j.bcp.2013.07.004. PMID 23856287.
- Li, Y; Innocentin, S; Withers, DR; Roberts, NA; Gallagher, AR; Grigorieva, EF; Wilhelm, C; Veldhoen, M (28 October 2011). "Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.". Cell 147 (3): 629-40. doi:10.1016/j.cell.2011.09.025. PMID 21999944.
- Guerrina, N; Traboulsi, H; Eidelman, DH; Baglole, CJ (5 December 2018). "The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health.". International journal of molecular sciences 19 (12). doi:10.3390/ijms19123882. PMID 30563036.
- Wille, G; Mayser, P; Thoma, W; Monsees, T; Baumgart, A; Schmitz, HJ; Schrenk, D; Polborn, K et al. (April 2001). "Malassezin--A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur.". Bioorganic & medicinal chemistry 9 (4): 955-60. PMID 11354679.
- Kobayashi, Y; Hirano, T; Omotehara, T; Hashimoto, R; Umemura, Y; Yuasa, H; Masuda, N; Kubota, N et al. (November 2015). "Immunohistochemical analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice.". The Journal of veterinary medical science 77 (11): 1355-61. doi:10.1292/jvms.15-0238. PMID 26096965.
- Kimura, E; Kubo, KI; Endo, T; Ling, W; Nakajima, K; Kakeyama, M; Tohyama, C (2017). "Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse.". PloS one 12 (8): e0183497. doi:10.1371/journal.pone.0183497. PMID 28820910.
- Tuomisto, J; Viluksela, M. "Dioxins II. human exposure and health risks". In D’Mello, J. P. F. (ed.). A handbook of environmental toxicology : human disorders and ecotoxicology. Wallingford, Oxfordshire, UK. ISBN 978-1-78639-467-5. OCLC 1085638074.