Dioxin toxicity is based on inappropriate activation of a physiologically important receptor, and therefore dose-response must be carefully considered. The endocrine disrupting activity of dioxins is thought to occur as a down-stream function of AH receptor activation, with thyroid status in particular being a sensitive marker of exposure. TCDD, along with the other PCDDs, PCDFs and dioxin-like coplanar PCBs are not direct agonists or antagonists of hormones, and are not active in assays which directly screen for these activities such as ER-CALUX and AR-CALUX. These compounds have also not been shown to have any direct
mutagenic or
genotoxic activity. Their main action in causing cancer is cancer promotion. A mixture of PCBs such as
Aroclor may contain PCB compounds which are known
estrogen agonists but are not classified as dioxin-like in terms of toxicity. Mutagenic effects have been established for some lower chlorinated chemicals such as 3-chlorodibenzofuran, which is neither persistent nor an AH receptor agonist.
Toxicity in animals High doses. The symptoms reported to be associated with dioxin toxicity in animal studies are incredibly wide-ranging, both in the scope of the biological systems affected and in the range of dosage needed to bring these about. Well established developmental effects are
cleft palate,
hydronephrosis, disturbances in
tooth development and
sexual development, and
endocrine effects. Three women in Vienna, Austria, were poisoned with large doses of TCDD in 1998. The highest concentration of TCDD in fat tissue was 144,000 pg/g, the highest ever reported in human beings. The main feature was
chloracne, a serious skin disease. The victim survived, and other symptoms were modest after initial
gastrointestinal symptoms and
amenorrhea. Another acute incident was the deliberate poisoning of
Victor Yushchenko, then presidential candidate of Ukraine, in 2004. TCDD concentration in fat was 108,000 pg/g. In this case, the most prominent symptoms were
chloracne,
hepatitis and
pancreatitis. The deliberate poisoning case shows that a human being is not as sensitive as other animals, since Yushchenko survived a dose estimated at around 25 μg/kg. Two serious food contamination accidents were caused by PCB oils used in heat exchangers. Perhaps the best known dioxin accident occurred in Seveso, Italy, in 1976. A tank of
chlorophenols released its contents to air including many kilograms of TCDD, and contaminated much of the city. The highest TCDD levels were found in children, up to 56,000 pg/g fat. Acute effects were limited to chloracne, although many animals such as rabbits died after eating contaminated grass. Dental aberrations were found after 25 years in persons exposed as children, and a slightly increased cancer risk was confirmed 35 years later. and of sexual development. An example of the variation in responses is clearly seen in a study following the
Seveso disaster indicating that
sperm count and motility were affected in different ways in exposed males, depending on whether they were exposed before, during or after puberty. In occupational settings many symptoms have been seen, but exposures have always been to a multitude of chemicals including
chlorophenols,
chlorophenoxy acid herbicides, and
solvents. Therefore, definitive proof of dioxins as causative factors has been difficult to obtain. By far the best proven effect is chloracne. The suspected effects in adults are liver damage, and alterations in
heme metabolism, serum
lipid levels,
thyroid functions, as well as
diabetes and
immunological effects. or at least 1000 times lower than those in poisonings (see above). Tooth deformities have been considered plausible after long breast-feeding, when the dioxin concentrations were high in 1970s and 1980s. When the concentrations decreased during 1990s and 2000s, the effects were no longer seen. This was in industrial environments causing relatively high exposures to boys as well as their mothers. This recommendation can be challenged, because it does not properly consider competing risks following from lost benefits of important and healthy food items such as certain fish. A general conclusion may be that safety margins are not very great concerning developmental effects, but toxic effects are not likely at the present population levels of dioxins. A number of
cross-sectional studies have shown associations between
type 2 diabetes and several POP compounds including dioxins. Such observational studies cannot prove causality, i.e. there may be an association which does not prove that one is the cause of the other. The main problem is that similar associations can be found with many quite different POPs, which have only long
half-lives and tendency to accumulate in lipids in common. This suggests that they may all be related to diet and obesity which are by far the most common causes of type 2 diabetes. is insignificant compared with daily dioxin intake from food. The
United States Environmental Protection Agency has categorised dioxin, and the mixture of substances associated with sources of dioxin toxicity as a "likely human carcinogen". The
International Agency for Research on Cancer has classified TCDD as a human carcinogen (class 1) on the basis of clear animal carcinogenicity and limited human data, and subsequently also 2,3,4,7,8-PCDF and PCB 126 as class 1 carcinogens. The mechanism is thought to be mainly promotion, i.e. dioxins can accelerate the formation of tumours caused by other factors, and adversely affect the normal mechanisms for inhibiting tumour growth. As with many toxic endpoints of dioxin, a clear dose–response relationship is difficult to establish. After accidental or high occupational exposures there is evidence on human carcinogenicity. Increases in cancer have been modest, in fact reaching statistical significance has been difficult even after high accidental or occupational exposures like in Yusho and Yucheng poisonings, Seveso accident, and combined occupational cohorts. All this means that in case of important beneficial food items and breast feeding a thorough benefit/risk analysis is needed before setting limits, in order to avoid increased other risks or lost benefits.
Risk assessment The uncertainty and variability in the dose–response relationship of dioxins in terms of their toxicity, as well as the ability of dioxins to
bioaccumulate, have led WHO experts to recommending very low
tolerable daily intake (TDI) of dioxin, 1-4 pg/kg body weight per day, i.e. 7×10−11 to 2.8×10−10g per 70-kg person per day, to allow for this uncertainty and ensure public safety in all instances. Recently also developmental effects have been reassessed by the Contamination Panel of the
European Food Safety Agency (EFSA). They propose decreasing the
tolerable weekly intake (TWI) from 14 pg/kg to 2 pg/kg. This resembles the common measure of all alcoholic drinks: beer, wine and whiskey can be added together as absolute alcohol, and this sum gives the toxicologically meaningful measure of the total impact. The TEQ only applies to dioxin-like effects mediated by the AHR. Some toxic effects (especially of PCBs) may be independent of the AHR, and those are not taken into account by using TEQs. TEFs are also approximations with certain amount of scientific judgement rather than scientific facts. Therefore, they may be re-evaluated from time to time. There have been several TEF versions since the 1980s. The most recent re-assessment was by an expert group of the World Health organization in 2005. and
substituent numbering scheme of the parent compound
dibenzo-p-dioxin :(T = tetra, Pe = penta, Hx = hexa, Hp = hepta, O = octa) File:2,3,7,8-substituted PCDD.svg|The 2,3,7,8-substituted PCDDs
Sharon Beder and others have argued that the dioxin controversy has been very political and that large companies have tried to play down the seriousness of the problems of dioxin. The companies involved have often said that the campaign against dioxin is based on "fear and emotion" and not on science. ==Human intake and levels==