Dioxins and dioxin-like compounds: toxicity in humans and animals, sources, and behaviour in the environment

Dioxins and dioxin-like compounds comprise a group of chemicals including polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), as well as certain dioxin-like polychlorinated biphenyls (dlPCB), and potentially others. They act via a common mechanism, stimulation of aryl hydrocarbon receptor (AH receptor, AHR), a vital transcription factor in cells. There are very high differences in potency among these compounds, i.e. in the ability to stimulate the receptor. This leads to ten thousand-fold or higher differences in doses causing similar toxic effects. Most of these compounds are eliminated very slowly in the environment, animals, or humans, which makes them persistent. They are much more soluble in fat than in water, and therefore they tend to accumulate in lipid or fatty tissues, and concentrate along the food web (bioaccumulation and biomagnification). 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. 1 National Institute for Health and Welfare, Kuopio, Finland *Author correspondence: j.tuomisto@dnainternet.net ORCID: 0000-0003-1710-0377 Licensed under: CC-BY Received 05-08-2019; accepted 12-12-2019 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. WikiJournal of Medicine, 2019, 6(1):8 doi: 10.15347/wjm/2019.008 Review Article 2 of 26 | WikiJournal of Medicine General introduction “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 2,3,7,8tetrachlorodibenzo-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.