Dioxins and dioxin like compounds

Mechanism of toxicity

The toxic effects of dioxins are measured in fractional equivalencies of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the most toxic and best studied member of its class (see TCDD for more detailed description of the mechanism). The toxicity is mediated through the interaction with a specific intracellular protein, the aryl hydrocarbon (AH) receptor, a transcriptional enhancer, affecting a number of other regulatory proteins. This receptor is a transcription factor which is involved in expression of many genes. TCDD binding to the AH receptor induces the cytochrome P450 1A class of enzymes which function to break down toxic compounds, e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene (but making many of them more toxic in the process).

While the affinity of dioxins and related industrial toxicants to this receptor may not fully explain all their toxic effects including immunotoxicity, endocrine effects and tumor 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 dioxins in cancer rates.

The endocrine disrupting activity of dioxins is thought to occur as a down-stream function of AH receptor activation, with thyroid status in particular being a sensitive marker of exposure. It is important to note that TCDD, along with the other PCDDs, PCDFs and dioxin-like coplanar PCBs are not direct agonists or antagonists of hormones, and are not active in assays which directly screen for these activities such as ER-CALUX and AR-CALUX. These compounds have also not been shown to have any direct mutagenic or 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 on the other hand are not classified as dioxin-like in terms of toxicity. Mutagenic effects have been established for some lower chlorinated chemicals such as 3-chlorodibenzofuran, which is neither persistent nor an AH receptor agonist.

Toxicity in animals

The symptoms reported to be associated with dioxin toxicity in animal studies are incredibly wide ranging, both in the scope of the biological systems affected and in the range of dosage needed to bring these about. Acute effects of single high dose dioxin exposure include wasting syndrome, and typically a delayed death of the animal in 1 to 6 weeks. By far most toxicity studies have been performed using 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The LD₅₀ 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 LD₅₀ for guinea pigs is as low as 0.5 to 2 μg/kg body weight, whereas the oral LD₅₀ 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 chronic and sub-chronic exposures can be harmful at much lower levels, especially at particular developmental stages including foetal, neonatal and pubescent stages. Well established developmental effects are cleft palate, hydronephrosis, disturbances in tooth development and sexual development as well as endocrine effects.

Human toxicity

Dioxins have been considered highly toxic and able to cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer. This is based on animal studies. The best proven is chloracne. Even in poisonings with huge doses of TCDD, the only persistent effects after the initial malaise have been chloracne and amenorrhea. In occupational settings many symptoms have been seen, but exposures have always been to a multitude of chemicals including chlorophenols, chlorophenoxy acid herbicides, and solvents. Therefore, proof of dioxins as causative factors has been difficult. 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.

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.

Intrauterine exposure to dioxins and dioxin-like compounds as an environmental toxin in pregnancy has subtle effects on the child later in life that include changes in liver function, thyroid hormone levels, white blood cell levels, and decreased performance in tests of learning and intelligence.

Exposure to dioxins can happen in a number of ways, most often as by-products of industrial waste. However, dioxins can result from natural processes including volcanic eruptions and forest fires, and manufacturing processes such as smelting, chlorine bleaching of paper pulp, and the creation of some herbicides and pesticides. Even at levels 100X lower than those associated with its cancer causing effects, the presence of dioxin can cause immune system damage, severe reproductive and developmental problems, and interference with regulatory hormones.

The Endometriosis Research Center (ERC) has testified before the California State Legislature concerning Assembly Bill 2820 [Cardoza, D-Merced] that, "feminine hygiene products (i.e. tampons) do indeed test positive for Dioxin. Dioxin, in turn, is a well-documented catalyst for Endometriosis - and the effects of Dioxin are cumulative; able to be measured as much as 20 or 30 years after exposure." The ERC also references an independent study that found, in an assessment of four brands of tampons and four brands of baby diapers, dioxins "were present at detectable concentrations in all samples." The presence of this toxin in tampons may be linked to endometriosis because dioxins last a long time in the body; they are chemically stable and can be absorbed by fat tissue, where they are then stored in the body. Their half-life in the body is estimated to be 7 to 11 years.

Carcinogenicity

Dioxins are well established carcinogens in animal studies, although the precise mechanistic role is not clear. Dioxins are not mutagenic or genotoxic. 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, but was not able to classify other dioxins. It is thought that the presence of dioxin can accelerate the formation of tumours and adversely affect the normal mechanisms for inhibiting tumour growth, without actually instigating the carcinogenic event.

As with all toxic endpoints of dioxin, a clear dose-response relationship is very difficult to establish. After accidental or high occupational exposures there is evidence on human carcinogenicity. There is much controversy especially on cancer risk at low population levels of dioxins. Among fishermen with high dioxin concentrations in their bodies, cancer deaths were decreased rather than increased. Some researchers have also proposed that dioxin induces cancer progression through a very different mitochondrial pathway.

Risk assessment

The uncertainty and variability in the dose-response relationship of dioxins in terms of their toxicity, as well as the ability of dioxins to bioaccumulate mean that the tolerable daily intake (TDI) of dioxin has been set very low, 1-4 pg/kg body weight per day, i.e. 7x10⁻¹¹ to 2.8x10⁻¹⁰g per 70-kg person per day, to allow for this uncertainty and ensure public safety in all instances. Specifically, the TDI has been assessed based on the safety of children born to mothers exposed all their lifetime prior to pregnancy to such a daily intake of dioxins. It is likely that the TDI for other population groups could be somewhat higher. The most important cause for differences in different assessments is carcinogenicity. If the dose-response of TCDD in causing cancer is linear, it might be a true risk. If the dose-response is of a threshold-type or J-shape, there is little or no risk at the present concentrations. Understanding the mechanisms of toxicity better is hoped to increase the reliability of risk assessment.

Controversy

Greenpeace and some other environmental groups have called for the chlorine industry to be phased out. However, chlorine industry supporters say that "banning chlorine would mean that millions of people in the third world would die from want of disinfected water". (Although critics point out the existence of alternative water disinfection methods.)

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.

In 2008, Chile experienced a pork crisis caused by high dioxin concentrations in their pork exports. The contamination was found to be due to zinc oxide used in pork feed, and caused reputational and financial losses for the country, as well as leading to the introduction of new food safety regulations.

Human intake and levels

Most intake of dioxin-like chemicals is from food of animal origin: meat, dairy products, or fish predominate, depending on the country. The daily intake of dioxins and dioxin-like PCBs as TEQ is of the order of 100 pg/day, i.e. 1-2 pg/kg/day. In many countries both the absolute and relative significance of dairy products and meat have decreased due to strict emission controls, and brought about the decrease of total intake. E.g. in the United Kingdom the total intake of PCDD/F in 1982 was 239 pg/day and in 2001 only 21 pg/day (WHO-TEQ). Since the half-lives are very long (for e.g. TCDD 7–8 years), the body burden will increase almost over the whole lifetime. Therefore, the concentrations may increase five- to tenfold from age 20 to age 60. For the same reason, short term higher intake such as after food contamination incidents, is not crucial unless it is extremely high or lasts for several months or years.

The highest body burdens were found in Western Europe in the 1970s and early 1980s, and the trends have been similar in the U.S. The most useful measure of time trends is concentration in breast milk measured over decades. In many countries the concentrations have decreased to about one tenth of those in the 1970s, and the total TEQ concentrations are now of the order of 10-30 pg/g fat (please note the units, pg/g is the same as ng/kg, or the non-standard expression ppt used sometimes in America). The decrease is due to strict emission controls and also to the control of concentrations in food. In the U.S. young adult female population (age group 20-39), the concentration was 9.7 pg/g lipid in 2001-2002 (geometric mean).

Certain professions such as subsistence fishermen in some areas are exposed to exceptionally high amounts of dioxins and related substances. This along with high industrial exposures may be the most valuable source of information on the health risks of dioxins.

Uses

Dioxins have no common uses. They are manufactured on a small scale for chemical and toxicological research, but mostly exist as by-products of industrial processes such as bleaching paper pulp, pesticide manufacture, and combustion processes such as waste incineration. The defoliant Agent Orange contained dioxins. The production and use of dioxins was banned by the Stockholm Convention in 2001.

TEF values

All dioxin-like compounds share a common mechanism of action via the aryl hydrocarbon receptor (AHR), but their potencies are very different. This means that similar effects are caused by all of them, but much larger doses of some of them are needed than of TCDD. Binding to the AHR as well as persistence in the environment and in the organism depends on the presence of so-called "lateral chlorines", in case of dioxins and furans, chlorine substitutes in positions 2,3,7, and 8. Each additional non-lateral chlorine decreases the potency, but qualitatively the effects remain similar. Therefore, a simple sum of different dioxin congeners is not a meaningful measure of toxicity. To compare the toxicities of various congeners and to render it possible to make a toxicologically meaningful sum of a mixture, a toxicity equivalency (TEQ) concept was created.

Each congener has been given a toxicity equivalence factor (TEF). This indicates its relative toxicity as compared with TCDD. Most TEFs have been extracted from in vivo toxicity data on animals, but if these are missing (e.g. in case of some PCBs), less reliable in vitro data have been used. After multiplying the actual amount or concentration of a congener by its TEF, the product is the virtual amount or concentration of TCDD having effects of the same magnitude as the compound in question. This multiplication is done for all compounds in a mixture, and these "equivalents of TCDD" can then simply be added, resulting in TEQ, the amount or concentration of TCDD toxicologically equivalent to the mixture.

The TEQ conversion makes it possible to use all studies on the best studied TCDD to assess the toxicity of a mixture. This resembles the common measure of all alcoholic drinks: beer, wine and whiskey can be added together as absolute alcohol, and this sum gives the toxicologically meaningful measure of the total impact.

The TEQ only applies to dioxin-like effects mediated by the AHR. Some toxic effects (especially of PCBs) may be independent of the AHR, and those are not taken into account by using TEQs.

TEFs are also approximations with certain amount of scientific judgement rather than scientific facts. Therefore, they may be re-evaluated from time to time. There have been several TEF versions since the 1980s. The most recent re-assessment was by an expert group of the World Health organization in 2005.

WHO Toxic Equivalence Factors (WHO-TEF) for the dioxin-like congeners of concern

(T = tetra, Pe = penta, Hx = hexa, Hp = hepta, O = octa)

Dioxin screening

There are two main methods for screening of dioxins and dioxin-like compounds: