Talk:Dioxins and dioxin-like compounds

Links

Replaced link with one that seemed more credible. --Mkcas (talk) 23:09, 16 June 2010 (UTC)

Dioxins/Polychlorinated dibenzo-p-dioxins/PCBs etc

I think the entire area related to dioxin as a toxin, the chemical compounds called dioxins and related compounds such as PCBs, needs a major overhaul to properly join up and clarify the relationships between these compounds, their toxicity and their environmental importance. At present there is unnecessary duplication between articles, and confusing contradictions.

It is a very complex area, so it may take some time to get things right.

I would suggest that this article dioxins and dioxin-like compounds should act as a hub for the associated information on the individual toxic compounds, toxic equivalency factors, contamination incidents and so on. Most of these compounds have no relevance outside of their role as toxins and I feel this is the most natural way for the issue to be arranged. I would suggest that dioxin is redirected to this article, and the article on PCDDs is linked from this location, with appropriate disambiguation notices.

Arthurbagwaste (talk) 13:26, 8 September 2010 (UTC)

I have tried to fix the text in such a manner that it would include the most pertinent points of mixtures of dioxin-like chemicals. It would be possible to include the material specific for polychlorinated dibenzodioxins either under TCDD or under polychlorinated dibenzodioxins, but not both, to avoid redundance. Most of information available is in fact on TCDD, and this has then been extrapolated to the whole group. There exists relatively scarce information specifically on other congeners. PCBs clearly require their own chapter, but others (such as PCDFs) only a short summary with reference to dioxins and dioxin-like compounds.Viinamakelainen (talk) 21:37, 20 January 2011 (UTC)

You have done an excellent job IMO. This is an excellent concise summary of the issues, with most of the inaccuracies which dog the other articles on this topic, thankfully absent. I would say with a little tweaking, and addition of some diagrams, this article could easily serve as the hub page for Dioxin - ie searches for "dioxin/s" should go directly here, rather than the rather redundant DAB, with links to articles on PCDDs, PCDFs, PCBs etc for more detailed chemical information. I'd say the information on exposure incidents, which currently lives uneasily at polychlorinated dibenzodioxins could also be incorporated. Many of the incidents do not involve an PCDDs at all but involve contamination with PCBs, which is widely reported and understood as a source of "dioxin".

Arthurbagwaste (talk) 11:27, 1 February 2011 (UTC)

Mechanism of action

Unfortunately I have to say that the new chapter on mechanisms on Feb 4, 2011 was quite outdated. AH receptor ("dioxin receptor") is now quite clearly defined, and there is fairly good knowledge on what it does and what it does not do. The most recent review is that of Linden et al 2010 which can be found in the reference list. There is up-to-date information on the mechanism of action under 2,3,7,8-tetrachlorodibenzodioxin. Toxicity and carcinogenicity are NOT linear as shown by practically all occupational health studies and by a case-control study on soft tissue sarcoma (Tuomisto et al, 2004, also in the reference list), as well as in animal studies (Nigel J. Walker, Michael E. Wyde, Lawrence J. Fischer, Abraham Nyska and John R. Bucher: Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats, Mol. Nutr. Food Res. 2006, 50, 934 – 944, and Viluksela et al 2000, in the reference list of 2,3,7,8-TCDD). And the risk in fishermen is NOT INCREASED but DECREASED (Turunen et al, 2008, also in the reference list). Therefore I have undone the chapter. Maybe a short chapter on the mechanism of action would be useful here, but in fact all mechanistic studies are based on TCDD, so a thorough treatise belongs under 2,3,7,8-tetrachlorodibenzodioxin.Viinamakelainen (talk) 10:54, 4 February 2011 (UTC)

There was no mentioning of a dioxin receptor. The AH-receptor is indeed the receptor responsible for some of the effects (there is no dioxin-receptor per se, the dioxin receptor is the Ah-receptor!). The Ah-receptor has a well developed section in wikipedia and is indeed responsible for some of the toxic effects of dioxins and related substances. Viinamakelainen did not understand the article Turunen et al, 2008, correctly. The risk is still increased but not at higher concentrations where the risk decreases relative to lower concentration. I am reinstating my expansion "Mechanism of action", and kindly ask other user to support my intitial expansion.Osterluzei (talk) 12:58, 5 February 2011 (UTC)

Also, there is a mechanism of toxicity we discuss not the actions. This is a section relating to the toxicology of "dioxins" and related substances. We are not talking about a drug substance. If we want to talk about all the effects dioxin and related substances have, we get nowhere. Also, since I initiated this discussion and there was no mentioning of any mechanism before, with the exeption of some of the cited articles, why not leave my section intact and add yours? The article I cited is excellent and was the starting point for many articles to come. In science, we can refer to older work and build on them. This approach is reasonable. You just followed my foot trail and whipe mine out. Also Viinamakelainen tries to explain that dioxin is actually good for us? This statement is so far and dangerously from the truth. There is no indication that high dioxin exposure lead to a decreased risk. Just because of a single Finnish study, we must now believe that dioxins are good for us? Osterluzei (talk) 13:19, 5 February 2011 (UTC)

I cleaned up the section "Mechanism of toxicity" in such a way that there is no double talk and all the contributions are honored. The result is a compact paragraph. I ask contributors to adapt the "live and let live" tactic. With the kindest regards. ML Osterluzei (talk) 13:54, 5 February 2011 (UTC)

My main point was that most of mechanistic studies have been performed on 2,3,7,8-TCDD, and therefore it is more logical that the mechanism of action is there in detail. I have every reason to respect the article of Lennart Dencker whom I know well, but it was simply a quarter of a century ago, and much water has poured in the Rhein after that. The non-linear response to TCDD is not based on a couple of papers, but many, and the view has been generally accepted by EPA (though grudgingly) and by NIEHS in America, and WHO and EFSA experts. So there is no reason to go back to the ideas of 1970s and early 1980s. We have to be very careful with the dose question. AH receptor is a physiological receptor important to life as ailing knock-out animals have shown, so it is necessary, and a certain level of AH receptor activation is necessary. Also steroids are necessary, but high doses cause lots of trouble, it is as simple as that. I'll return to the issue after I have finished some urgent other tasks.Viinamakelainen (talk) 18:24, 6 February 2011 (UTC)

Viinamakelainen, you are absolutely right with your comments and reviews of the toxicity of dioxin and related substances, and I do take back some of my comments, which have not been fully correct. I have therefore crafted this section in such a way that your statements remain valid and to the point. Directly mutagenic or carcinogenic effects of TCDD and congeners are indeed not established and your remarks are supported by a number of papers and US EPA findings. There are however Japanese studies that found similar substances (in this case monochlorinated dibenzofurans) are mutagenic. But strictly speaking these are not PCDFs.Osterluzei (talk) 00:54, 13 February 2011 (UTC)

This section needs a bit of expansion and clarification to get it right, I have made some minor amendments thus far. The carcinogenicity of TCDD is strongly linked to its interaction with other chemicals such as PAHs, and endogenous hormones, rather than an inherent character of the molecule itself, which is mostly stable, unreactive and inert in a biological sense, apart from being the highest affinity ligand of the AH receptor. Modern thinking is now that TCDD deranges an organism's ability to cope with other chemical,immunological and environmental challenges, and this is the key to understanding its toxic mechanism. I will get my hands on some refs, and hopefully propose a rewrite based on this. Arthurbagwaste (talk) 15:15, 23 February 2011 (UTC)

I am sorry Arthurbagwaste but your explanations with regard to the toxicity of TCDD are rather unclear. I believe Viinamakelainen has done a great job introducing this section and expand it with me. What you mean by "deranges an organism's ability to cope with other chemical and ...challenges". As you write, the molecule does not have to be reactive itself to interfer with biochemical processes esp. if it is a xenobiotic attaching to a particular receptor. The relative stability of these compounds with regard to enzymatic degradation is obvious if you look at their biological half-life, and current research really points at a direct interaction with regulatory proteins and receptors. Please do not change anything in that section before checking with Viinamakelainen first, as he is guarding this page a bit. There are still many questions to be answered about the toxic effects of dioxins, PCB's and PCDF's but please only introduce material from peer reviewed journals and discuss it here first. The issue here is that dioxins and related xenobiotics do attach to this aryl-hydrocarbon receptor but also are endocrine disrupters (q.v.) and this link, I will add right now. This term seems common and applicable for environmental scientists. Maybe our dialog should also be about how these toxins are assayed. We have functional biological assays reporter gene (CALUX) test, immuno test kits, cell-based technologies and the traditional GC-MS methods to quantify the analyte(s). Thank you. Osterluzei (talk) 03:31, 4 March 2011 (UTC)

What you mention is a common failing in many discussions on dioxins. The PCBs which are known to have primary endocrine disrupting activity (ie activity in endocrine focused gene reporter assays such as ER-CALUX and AR-CALUX) are the non-coplanar, ortho-substituted compounds, which are precisely NON-dioxin like, do not activate the AhR and do not have a TEQ value. Conflating the two mechanisms of action is the source of significant confusion in many accounts of dioxin toxicity by non-specialists. That is not to say dioxins do not have an effect on the endocrine system in affected organisma. Dioxin-like compounds have a single mode of action; constitutive activation of the AhR which appears to result in downstream disregulation of cellular processes - increased epoxide formation from PAHs, inflammatory responses, neutrophil migration also including serum thyroid hormone concentration, calcium homeostasis and so on. As I mentioned earlier I am in the process of compiling a detailed and well referenced description of these issues, which I hope will clarify things. I would suggest that your edit regarding PCBs acting as endocrine disrupters is in fact a little misleading in the context of a discussion about "dioxin-like" toxicity.

Arthurbagwaste (talk) 14:25, 4 March 2011 (UTC)

Just to add I am also very happy that people are finally taking an interest in sorting this topic out on wikipedia, as it has been very poorly covered up to now. I also apologise as some of my earlier updates were undertaken a little hastily and may have seemed rather arrogant. I am happy to work to a consensus with all interested parties. Dioxin is a fascinating and incredibly complex toxin, I hope that we can form some useful insights and present a good summary of this topic. Arthurbagwaste (talk) 14:47, 4 March 2011 (UTC)

Here is an early draft of the text I propose, which I hope we can work into a consensus article.

The toxic effects of dioxins are measured in fractional equivalencies of TCDD (2,3,7,8-tetrachlorodibenzodioxin), the most toxic member of its class. 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. Binding of a range of compounds, normally lipophilic xenobiotics, to this receptor serves to induce the upregulation of the cytochrome p450 1A enzyme system, which then catalyses the break down of these compounds to water-soluble metabolites which can be more easily eliminated from the body. (Dennison) Dioxins are particular in that, although they are the most potent activators of this receptor, they do no function as substrates of the cytochrome enzymes produced. This constitutive state of activation is thought to form the basis of the myriad of toxic outcomes which can be linked to dioxin exposure. No other direct interaction of dioxins with any other receptor has yet been reported. Effects which have been linked to dioxin exposure in humans and animals include inflammatory disorders, tumour promotion, bone and tooth malformation, thyroid hormone disruption, increased mortality from influenza infection as well as other more subtle changes in biochemistry which have no obvious clinical symptoms. Dioxin toxicity has a number of interesting features. The first of these is the striking difference between the lethality LD50 of TCDD in different species, most notably in guinea pigs, where the oral LD50 is 0.5-2.0 μg/kg and hamsters where the oral LD50 is 1160-5000 mg/kg (a difference of as much as 10,000,000-fold) http://ces.iisc.ernet.in/energy/HC270799/HDL/ENV/enven/vol336.htm. The second important aspect is the difference between acute, high level, short-term exposure and chronic, low-level, long term exposure, particularly at important stages of development. This is most ably illustrated by the case of Victor Yushchenko, who was apparently administered a very large dose of around 2 g of pure TCDD, and apparently has suffered only limited, short-term effects, e.g.chloracne, contrasted with reports from the Seveso incident in Italy where exposure to relatively small quantities of dioxin have led to long term reproductive harm in those exposed around the onset of puberty. These aspects make assessing the risk of dioxin exposure a very difficult and complex task. Arthurbagwaste (talk) 15:30, 4 March 2011 (UTC)

Arthurbagwaste. Thank you so much for your input. I totally understand your remarks with regard to the effect of PCB's, and they are indeed not dioxin-like, not even chemically speaking. You might very well know more about dioxins than I do, but the substances we discuss here on wikipedia are in the section of "dioxin and dioxin-like substances". For environmental scientists, PCB's are counted among the dioxins despite their chemical and biological differences because they only share some of the acute and chronic toxic effects. I am mentioning these two mechanisms *next to each other* because we adher to the discussion of the Dioxins and dioxin-like compounds (section) in the title. There was once this decision made to put the (PCDDs), the (PCDFs), and the polychlorinated biphenyls (PCBs) in one group. These compounds are often analyzed with GC-MS in special protocols, and are often added together even though not all of them have the same biological activity. Yes, the PCB's do not activate AhR and do not have a TEQ value but are endocrine disruptors (these are of course two different mechanisms). But don't accuse me of conflating these two mechanisms. Again, I only stated that PCB's are endocrine disruptors and PCB's are in this section, counted among the dioxin and dioxin-like substances. I thought introducing the link "endocrine disruptor" was worth wile because it is correct (what the subtle differences are of those effects within the group is discussed in the section PCB's) The PCB's are indeed endocrine disruptors (see section PCB's) and are grouped together with other xenobiotics based on their chemical and biological and environmental similarities. We know that the coplanar and mono-ortho-(PCBs) have no direct dioxin-like effects with regard to the Ah-receptor but this subtle discussion is already exercised in those respective entries for PCB's. I would not change anything in that section, and you should apply your valuable expansions in the respective entries of the individual dioxin-like substances. The section should be left as it is; the cytochrome P450 1A upregulation is already very well described by Viinamakelainen. And the cases of acute poisonings do not belong into the mechanism or mode of action section, I believe. Thanks. Osterluzei (talk) 19:56, 6 March 2011 (UTC)

To clarify further, PCBs are divided into (at least) 2 groups. Ortho-substituted and non-ortho-substituted (coplanar) PCBs. For toxicological purposes these are completely distinct. the latter group includes PCBs 77, 126, 169 etc, which are "dioxin-like". Their only measureable toxicity is activation of the Ahr and dioxin-like toxic effects. These compounds are not "endocrine disruptors", that is a feature associated with the former group (PCBs 44, 52, 153 etc.) So if we are to confine discussion within this section to "dioxin-like" chemicals, then mention of a toxic characteristic that is not associated with any dioxin-like chemicals seems at odds with that. I also draw attention to the mention of 3-chlorodibenzofuran as "dioxin-like" is also inaccurate. These comments may be interesting, but I can't help feeling they distract from providing a concise discussion of dioxins and other chemicals which have the same effect.

We need to clarify whether the term "dioxin-like" is used in the context of this article to refer to the chemistry of the compounds of interest, or their biological effect. I can see no need for an article to do the former, and considerable need for the latter.Arthurbagwaste (talk) 11:25, 7 March 2011 (UTC)

We are pretty much following what has been presented in the title and the first paragraph of dioxin and dioxin-like substances, and I did that accordingly when I introduced a separate paragraph on the mechanism of toxicity which was further clarified and corrected by Viinamakelainen. And indeed among the dioxins are also counted those substances, which are chemically and biologically not dioxins themselves. I therefore do not see any problems with discussing those substances as they are mentioned in the title. I agree, it is a priori confusing to include such substances that are not dioxins, but it is done that way in practice. Again, if one wants to discuss those chemicals separately than one should do that in the respective entries. And if we want to change the title to "mode of action" that is fine too. I am not trying to be pedantic with the titles but essentially, your recommendations would lead to a total break up of the entries under "dioxins and dioxin-like-substances". I would find that regrettable because environmental scientists tend to discuss these three main groups PCDD's, PCDF's and PCB's together, and the TEF's remain valid also for the PCB's, right?. If changes should be made, I believe Viinamakelainen should have such oversight. Thanks. Osterluzei (talk) 16:56, 8 March 2011 (UTC)

Quite the opposite to what I am proposing Osterluzei. I think that all the chemicals which possess dioxin like toxicity should be grouped together, whether chemically dioxin-like or not. We know that many of the major "dioxin" exposure incidents involve no "dioxin" chemicals at all, often only PCBs are involved. It is right that dioxin toxicity is discussed in a single article, which refers to all the possible sources of dioxin-like toxicity and their effects - splitting articles based on individual chemical classes is what has led to the current confusing and unfit-for-purpose state of affairs on wikipedia with regards this topic. For example the Belgian incident is currently referred to in polychlorinated dibenzodioxins even though it is known that this contamination involved only PCBs and no PCDDs. These inaccuracies occur far too frequently under the current organisation, which is why I hope that this article "dioxins and dioxin-like chemicals" can become a more suitable hub for the topic of dioxin as a biological and environmental toxin. It's a tricky subject, with a lot of overlapping and conflicting terminology between disciplines, which is leading to poor quality, lowest common denominator articles as people from each discipline (chemistry, environmental science, toxicology, medicine, biochemistry etc.) argue from their own position. A coherent, consensus driven approach is needed, and it is this that I am calling for.

I would say that the individual entries for each chemical class; PCBs, PCDDs, PCDFs etc., should contain only relevant chemical information, but any discussion of dioxin-like toxicity, exposure, contamination incidents should link back to a hub article dealing with all these issues under a single coherent article. To me, this article is most suitable to serve as this.

Also with regard to PCBs it is correct to say PCBs are dioxin-like and also endocrine disrupting and neurotoxic as a group, but I think it needs to be made perfectly clear that when it comes to individual PCB chemicals that they are either "dioxin-like" or "endocrine disrupting and neurotoxic", these are actually mutually exclusive properties. e.g. PCB-126 has a TEF of 0.1, but it has no neurotoxic or endocrine-disrupting activity, whereas PCB-52 has no TEF and does not interact in any way with the AhR etc. but is highly neurotoxic and estrogenic through an entirely different pathway. It is related to the structure of the chemicals themselves. non-ortho substituted PCBs are co-planar; flat like dioxin and furan molecules, whereas when they are substituted in the ortho- position they cannot adopt this conformation, and the two phenyl groups lie at an angle to one another. This means that in biochemical and toxicological terms, they are completely different species.

Arthurbagwaste (talk) 09:22, 9 March 2011 (UTC)

This is interesting and important discussion which comes back my previous proposal that the mechanism of actions should be concentrated mainly in the article 2,3,7,8-tetrachlorodibenzodioxin, because it has been best studied. At least 90% of all mechanistic studies on dioxins have been performed using TCDD, among in vivo studies even more. Non-dioxin-like PCB effects are then something else, and should be dealt with in the article on PCBs. Unfortunately I am a bit busy with other things but would like to return to this issue soon. By the way there is some more discussion in my talk page.Viinamakelainen (talk) 20:38, 12 March 2011 (UTC)

I am very much pleased with the outcome of our discussion on the mechanism of toxicity of dioxin and dioxin-like substances. Most of the input has been very constructive, and I want to thank everybody involved for their supportive role to craft this paragraph. Once again, it shows that cooperation and constructive criticism is the best approach to arrive at a well-differentiated text that addresses the rather complex topic of toxicity of these environmental pollutants, which interestingly enough, also develop in the natural environment affected by forest fires for example. I particularly like the introduction of the different biological (CALUX) assays and the resulting differentiation of those "dioxins", which show no endocrine activity, as compared to the existing chemical testing methods that are able to detect this group of compounds independently of their distinct biological activities. This then facilitates the correlation of chemical detection with existing bioassays, which are now frequently used to screen agricultural products and environmental samples. Please, I encourage other interested readers to expand this paragraph as new research will shed more light on this highly relevant topic. (Osterluzei (talk) 22:37, 10 May 2011 (UTC))

Partner article published

A partner article to this Wikipedia page has been published at:

• Tuomisto, J (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.

Similar to the parallel publication system used by Gene in their Gene Wiki Reviews (see Category:Wikipedia articles with corresponding academic peer reviewed articles). T.Shafee(Evo&Evo)^talk 05:18, 16 December 2019 (UTC)