<unk>  toxicity is based on inappropriate activation of a physiologically important receptor, and therefore dose-response must be carefully considered. Inappropriate stimulation of many receptors leads to toxic outcomes, e.g. overdose of vitamin A leads to inappropriate activation of retinoid receptors resulting in e.g. malformations, and overdoses of corticosteroids or sex hormones lead to a multitude of adverse effects. Therefore it is important to separate the effects of low doses causing activation of the receptor around the physiological range from the effects of high toxic doses. This is all the more important because of large differences in exposures even among human beings. Western populations today are exposed to<unk> s at doses leading to concentrations of 5 to 100 picograms/g (as TEQ in body fat), and the highest concentrations in accidental or deliberate poisonings have been 10,000 to 144,000 pg/g leading to dramatic but not lethal outcomes. The most relevant toxic outcomes of<unk> s both in humans and animals are cancer and the developmental effects of offspring. Both have been documented at high doses, most accurately in animal experiments. As to developmental effects there is an agreement that the present<unk>  levels in many populations are not very far from those causing some effects, but there is not yet consensus on the safe level. As to cancer, there is a disagreement on how to extrapolate the risk from high toxic doses to the present low exposures. While the affinity of<unk> s and related industrial toxicants to the Ah receptor may not fully explain all their toxic effects including immunotoxicity, endocrine effects and tumor promotion, toxic responses appear to be typically dose-dependent within certain concentration ranges. A multiphasic dose–response relationship has also been reported, leading to uncertainty and debate about the true role of<unk> s in cancer rates. The endocrine disrupting activity of<unk> s 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<unk> -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<unk>  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<unk>  which are known estrogen agonists but are not classified as<unk> -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<unk>  toxicity in animal studies are incredibly wide-ranging, both in the scope of the biological systems affected and in the range of dosage needed to bring these about. Acute effects of single high dose<unk>  exposure include reduced feed intake and wasting syndrome, and typically a delayed death of the animal in 1 to 6 weeks. By far most toxicity studies have been performed using 2,3,7,8-tetrachlorodibenzo-p-dioxin. The of TCDD varies wildly between species and even strains of the same species, with the most notable disparity being between the seemingly similar species of hamster and guinea pig. The oral for guinea pigs is as low as 0.5 to 2 μg/kg body weight, whereas the oral for hamsters can be as high as 1 to 5 mg/kg body weight. Even between different mouse or rat strains there may be tenfold to thousandfold differences in acute toxicity. Many pathological findings are seen in the liver, thymus, and other organs. Some effects such as thymic atrophy are common in many species, but e.g. liver toxicity is typical in rabbits. Low doses. Very few signs of toxicity are seen in adult animals after low doses, but developmental effects may occur at low<unk>  levels, including foetal, neonatal, and possibly pubescent stages. Well established developmental effects are cleft palate, hydronephrosis, disturbances in tooth development and sexual development, and endocrine effects. Surprisingly, enzyme induction, several developmental effects and aversion to novel foods occur at similar dose levels in animals that respond differently to acute high-dose toxicity. Therefore it has been suggested that<unk>  effects be divided to type I effects (enzyme induction etc.) and type II effects (lethality, liver damage, anorexia, and tumour promotion). The reason may be different requirements of the transactivation domain structure of the AH receptor for different genes. Some of these low-dose effects can in fact be interpreted as protective rather than toxic (enzyme induction, aversion to novel foods). Human toxicity High doses. Toxicity of<unk> s at high doses has been well documented after accidents, deliberate poisonings, food contamination episodes, and high industrial exposures. 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. Also in this case the most prominent symptom was chloracne after initial stomach pain indicating hepatitis and pancreatitis. These episodes show that a human being is not as sensitive as the most sensitive animals, since the doses must have been up to 25 μg/kg. Two serious food contamination accidents were caused by PCB oils used in heat exchangers. The PCB oil leaked to rice bran oil consumed by thousands of people in Japan (Yusho disease 1968) and Taiwan (Yu-cheng disease 1979). The toxic effects have been attributed to<unk> -like PCBs and PCDFs. Their daily intake was up to 100,000 times higher than average intake presently. There were many skin problems, chloracne, swelling of eyelids, and hypersecretion of Meibomian glands in the eyes. Babies born to Yusho and Yu-cheng mothers were smaller than normal, they had dark pigmentation and sometimes teeth at birth and tooth deformities. Foetal deaths and miscarriages were common. Perhaps the best known<unk>  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. In line with animal studies, developmental effects may be much more important than effects in adults. These include disturbances of tooth development, 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<unk> s 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. Low exposures. Effects after low exposures such as from food have been difficult to prove. Levels of<unk> s in contemporary population are 5 to 20 pg/g (TEQ in fat) and 50 to 100 pg in older people or at least 1000 times lower than those in poisonings (see above). Tooth deformities have been considered plausible after long breast-feeding, when the<unk>  concentrations were high in 1970s and 1980s. When the concentrations decreased during 1990s and 2000s, the effects were no longer seen. According to a study in Russia, sperm counts in 18-19 year old young men were lower when<unk>  levels were higher at the age of 8 to 9 years. This was in industrial environments causing relatively high exposures to boys as well as their mothers. The contamination panel of the European Food Safety Agency (EFSA) recommended decreasing tolerable weekly intake (TWI) levels based on the Russian children study. 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. TWI levels are not applied for breast feeding, because benefits of breast milk are judged to be far more important than the remote risks of<unk> s. A general conclusion may be that safety margins are not very great concerning developmental effects, but toxic effects are not<unk> ly at the present population levels of<unk> s. A number of cross-sectional studies have shown associations between type 2 diabetes and several POP<unk>  including<unk> s. Such observational studies cannot prove causality, i.e. there may be an association
Dioxins and dioxin-like compounds
Polychlorinated naphthalene
Polychlorinated dibenzodioxins
Organobromine compound
Organochlorine compound
Polycyclic aromatic hydrocarbon
Loline alkaloid
Polychlorinated dibenzofurans