Talk:WikiJournal Preprints/Dioxins and dioxin-like compounds

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Article information

Author: Jouko Tuomisto[a][i]ORCID iD.svg 

Tuomisto, J. 





Plagiarism check[edit]

Artículo bueno.svg Pass. Report from WMF copyvios tool: Some false positives flagged due to unformatted references mathcing wording of published articles (not regarded as plagiarism). T.Shafee(Evo﹠Evo)talk 11:48, 18 August 2019 (UTC)

Peer review 1[edit]

Review by Martin Rose , University of Manchester
This review was submitted on , and refers to this previous version of the article


The article is well written and was a pleasure to read. It is comprehensive, well written and the style is factual and un-emotive. I have very few specific comments that the author may choose to incorporate or ignore as he wishes.

1. It would be good to include a comment on mixed halogenated dioxins where PBDD/Fs are mentioned - there are many more congeners when mixed halogenated congeners are considered.

2. The comment: 'there have been concerns regarding the safety of wild fish in our diet (see below)' should be adjusted; there are also concerns about farmed fish. The most important factors for fish are the lipid content and their position in the food chain, i.e whether or not they are predatory species.

3. In the section on TEFs, it may be worth mentioning that all organisations involved with establishing these values recommend that they should be regularly updated, say every 5 years, to reflect new information, but in practice this does not happen.

4. The dioxins in food incident in Belgium is well covered, but there is no mention of the Irish incident which was of a lower scale but nevertheless important, and about a decade later, which can show how a subsequent incident was managed on the basis of lessons learned.

Response

1 Mixed halogenated congeners were added under Chemistry

2. Farmed fish were added under Environmental fate

3. A need to update TEF values was added under Toxicity equivalents

4. A sentence on the Irish incident and a reference was added under Accidents, contamination episodes and occupational risks

Spontaneous review[edit]

Review by Sachin T. Jose , GS Medical College and Hospital, India
This review was submitted on , and refers to this previous version of the article


After receiving a mail from the coordinator thought of putting a comment here similar to the above, since it is my first edit here would go slow, I assume there is lacuna in here management is missing.

Peer review 2[edit]

Review by Helmut Greim , Technical University of Munich
This review was submitted on , and refers to this previous version of the article


This is a comprehensive review on dioxins and related compounds. Since it covers chemistry, sources, environmental fate, toxicokinetics, animal and human toxicology etc some passages would benefit from more details and if the rational of the conclusions would be more elaborated. Moreover, many of the important conclusions e.g. on diabetes, cardiovascular and heart diseases are either hidden in the text or insufficiently justified. The manuscript would benefit if the chapter Conclusion addresses all effects under discussion and the extent of justification.

In addition, the following information may be considered:

Photocatalysis

TCDD is essentially non-volatile and becomes strongly adsorbed to surfaces. For example, TCDD on jungle foliage has a half-life of 2–4 hours (Crosby and Wong, 1977; Wong and Crosby, 1978 Crosby DG, Wong AS. 1977. Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Science 195:1337-8 Wong AS and Crosby DG. 1978. Decontamination of2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by photochemical action. New York, NY: SP Medical & Scientific Books.

Diabetes

Kerger et al., (2012) has evaluated the Ranch Hand findings and discussed the association between TCDD exposure and diabetes. Multiple factors associated with clinical onset and severity of diabetes were correlated to increased serum lipid TCDD concentrations due to mobilization of adipose tissue lipid stores related to weight loss. Controlling for the impact of large serum TCDD increases from major weight loss among Ranch Hand veterans led to the disappearance of the statistically significant association between diabetes and TCDD.

Kerger BD, Scott PK, Pavuk M, Gough M, Paustenbach DJ. 2012. Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. Crit Rev Toxicol 42:669-87 Lindsay MJ, Staimez LR (2015) Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia – A systematic review. Environ International 76, 57-70

Wasting syndrome

Studies of humans with very high acute doses of TCDD in poisoning incidents and industrial accidents like Seveso have shown no evidence of the characteristic multi-organ failure, thyroid perturbations, and loss of muscle and fat as observed in ‘wasting syndrome’ in test animals (Sorg et al., 2009; Saurat et al., 2012).

Sorg O, Zennegg M, Schmid P et al. 2009. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 374:1179-85 Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, et al. 2012. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci 125:310-7

Additional points

Sources, paragraph 2 indicates that any burning will produce PCDD/Fs and describes the major environmental sources, whereas indoor sources are not addressed. I am sure that the author has a lot of information on emissions from candles, incense and others.

Toxicokinetics, last sentence: the faster elimination in children is partially explained by rapid growth and dilution. The sentence should be modified because the rapid growth and by that the increased fat compartment contribute to a lower TCDD fat concentration, which has nothing to do with elimination.

Toxic effects in humans, paragraph 6: last sentence: “because human dioxin levels increase very slowly.” Although this is correct, the reason is that due to the relative large body burden smaller short-term additional exposures result in small increases of the existing lipid concentrations.

Risks connected with lower exposures: A short description how the TDI values have been derived should be added. Last paragraph indicates that pregnant women and breast-feeding excretes much of the body burden to the child. Please explain why.

The most conspicuous acute toxic effects, paragraph 2: Type 2 responses include developmental effects, aversion to novel food etc. The latter needs explanation.

Response

General. Thoroughness is a challenging issue when writing a review with wide scope, because readability and many details are difficult to combine. I certainly agree that many chapters could give more information, but to keep the length reasonable I hope that the text gives a general touch on the issue and that more information can be found in the numerous references. Many suggestions by the reviewer have hopefully improved the text also in this sense, and the comments of an experienced toxicologist are highly appreciated.

Photocatalysis. A sentence on rapid photocatalysis was added under Environmental fate

Diabetes. The text was clarified and the references given by the reviewer double-checked (they were in fact there) under Accidents, contamination episodes and occupational risks

Wasting syndrome. A sentence on wasting syndrome was added under Laboratory studies and their relevance in risk assessment

Indoor sources. A comment with references was added on burning and incense under Sources

Toxicokinetics. Elimination and growth dilution were clearly separated in the text (very good comment) under Toxicokinetics: absorption, distribution and elimination

Toxic effects in humans. The wording was clarified and explained more thoroughly under Accidents, contamination episodes and occupational risks

Risks connected with lower exposures. Explanations requested have been added

The most conspicuous acute toxic effects. The text has been clarified

Peer review 3[edit]

Dioxins and dioxin-like compounds table - R3.pdf

A

Dioxins and dioxin-like compounds review - R3.pdf

B

Reviewer-annotated pdf file. A) First file B) Second file

Review by Helen Håkansson , Karolinska Institutet
This review was submitted on , and refers to this previous version of the article


Reviewer comments included as table and annotation comments in attached PDF.


Response

There is a misunderstanding in Peer review 3 that this is a wikipedia text. It is not, it is an independent review hopefully to be published in Wiki Journal of Medicine. The wikipedia article was in no part of the text used as a basis, nor was it intended that this text would directly be transfered to wikipedia. It is assumed to be one source among other secondary sources. It would be highly helpful if the reviewer would reconsider some points on this basis. Also changes have been made on basis of previous comments, so it would e useful to use the latest version.

Comments by Thomas Shafee

Apologies, this was my error. I had the article marked down as intended for re-integration into Wikipedia rather than as a stand-alone review article. I have re-contacted R3 to confirm this and to ask if they would be willing to provide an updated review with this in mind.

Response

This review 3 is still based on outdated version which was already edited after the first round of review. Most of the comments were accepted and the text adapted accordingly. If not, the reasons were explained.

Review by Helen Håkansson , Karolinska Institutet
This review was submitted on , and refers to this previous version of the article


This reviewer was first asked to review the preprint submission under the agreement that the submitted text was meant to replace the currently available text with the same title on Wikipedia. To this end a systematic comparison was done between the two texts, first taking into account structure and overall contents. When relevant, judgements were made on whether or not a merge of text from the two documents were favorable. In a next step more detailed commenting on the scientific content of the submitted preprint text was made. During this latter process, this reviewer was informed that the submitted text was not meant to replace the current text on Wikipedia but was submitted as an independent WikiJournal Review article and, that if accepted for publication, the intention is to cross reference between the two documents. As a result, this reviewer likes to add the following concluding comments/recommendations:

  • The WikiJournal submission requires major revision. In particular, since it is a Review article it is important to clearly distinguish between what is review material and what are author views.
  • Make sure that the title of the WikiJournal document is different from the Wikipedia page. The WikiJournal title should reflect the particular scope and intention of the review as such, and also as compared to the encyclopedic intention of the Wikipedia page.
  • Make sure the overlap in content between the WikiJournal and Wikipedia page is minimized to avoid confusion on which page is telling/representing what.
  • If possible and not beyond the scope of the WikiJournal submission, consider the possibility to add missing information on the Wikipedia page, which is now addressed in the WikiJournal text. E.g. currently the Wikipedia page have little information on Toxicity, Mechanisms etc  and would benefit largely from being enriched with such text.
Response

Thank you for very thorough reading of the preprint. A large majority of the comments were valid and useful, and I have adapted the text accordingly. On the other hand, we seem to have some philosophical differences in how to see toxicology and its role in risk assessment and risk management. I’ll try to explain this first and defend my approach.

General: Reviews, in my mind, best fulfil their purpose, if they are seen as a personal interpretation of the results of a number of studies. That means they are always biased, because interpretations vary among people, and this should be openly acknowledged. If somebody claims that he/she is only telling the truth without any personal impact, he/she is lying. Therefore review authors should take a risk of “painting with a broad brush”, rather than only repeating the details of referred papers. Secondly, in my interpretations I am bound to my training as a physician having seen the risks of real life. There I follow the path of my respected guides and old-day M.D. toxicologists John Doull and Bo Homstedt. We are also very interested in disease burden approach, i.e. relative impact of various risks on diseases at population level (measured e.g. by DALY, Disability Adjusted Life Years) which clearly show that a few major risks in the society are much more important than all hundreds of other risks together. As to environmental health, fine particulate matter is by far the most important and all individual chemicals follow very far. I cannot help approaching any topic in the framework of overall health, i.e. trying to understand the complicated interplay of diet, lifestyle, differences between individual, genetic and otherwise. This also means prioritization between risks. If you take very purist view from one single angle, there is a risk that the total health of people suffers. Precautionary approach does not work, if you are dealing with two alternative risks. To compare them, you have to use the best estimate of each, not the best estimate of one and a precautionary estimate of the other. I see a restricted view as a very real risk in toxicology. Every toxicologist seems to have a pet poison that MUST be very dangerous. Unfortunately I have been working with too many topics, on drugs, chemicals and public health risks (e.g. fine particulate matter, diet, alcohol) that I have too many pets. I once argued with a food control inspector, and she claimed that she is only responsible for chemical safety and not healthy diet. I see this as a very blinkered approach. Thirdly, and I admit this is very personal, I prefer reviews that are easy-reading and may be seen to some extent popularization of science, not to the same extent as science essays in newspapers or lay magazines, but using, as far as possible, common language rather than scientific jargon. Majority of readers are usually not particular experts of the particular issue of the review, and they have the right to obtain a general idea of what the scientists think. There are risks here, but then referees are useful in commenting what perhaps goes too far. It was not possible to comment separately each pdf note, but I have also made other changes not mentioned below. Unfortunately I could not read all of the pdf notes in full, so in some cases the end of the text might have escaped.

Abstract Persistence: this is a little semantics, but according to my logic something is persistent, because it is eliminated slowly. Not the reverse. Remaining wildlife risks: this is a good comment; I changed the wording to include a possibility of covert remaining risks. Debates among scientists and administrators: In 1990s there was a fierce fight in the US on the risks of dioxins, especially carcinogenic risks, involving both regulators and scientists, and I have heard some unhappy comments on the EFSA CONTAM panel proposal from some countries. I think this is normal, and a good argumentation will help clarifying the issue. As to AHR biology, dioxin risks cannot be treated in a balanced way without seeing the whole issue of AHR biology, although I agree that AHR part should not be excessively detailed.

General introduction: This chapter was intended to give a general flavour of what will follow. Therefore it is not meaningful to move individual parts to the relevant parts in later text. Some points were clarified as suggested.

Chemistry: AH receptors in plural does not refer to several types of AH receptors, but to a number of receptor molecules. The reviewer may be right in that using AH receptor consistently would be clearer to the reader than AHR. AHR was used for brevity only in the chapter Mechanism of action where the term is needed repeatedly.

Sources: Sediments: a good point, the text does not explain that the most recent surface sediments contain less dioxins that those in deeper layers. I also added another reference to better cover both PCDD/Fs and PCBs.

Mechanism of action Separation of physiological and toxic effects via AH receptors would be kind of artificial and also misleading to the readers, because it is a continuum of effects just as with physiological actions and toxic effects associated with e.g. retinoid receptors. Is this not what Paracelsus tried to say centuries back, it is the dose, not the agent that is harmful? Additional information on endocrine disruption, epigenetics, and hormonal cross-talk is a good point; some of this is discussed later in the chapter, but can be added here.

Toxicity equivalents Brominated compounds were shortly mentioned under Chemistry, but a sentence was added here on interim use of TEF values.

Toxic effects in wild animals Good point. The title has been amended, since intake and toxicity in humans were described in separate chapters, but this is not the case here. Difficulties caused by simultaneous exposures to many chemicals are very important to point out to give the reader a possibility to understand the difficulties in dose-response assessments. For comparison I think experimental results using a single chemical are important, although they are treated separately later. In ecology we seldom see pure effects of one factor; therefore it is important to remind of other simultaneous factors.

Human intake and concentrations Decrease in concentrations: good point, added the efforts

Elimination: elimination rate is primary (X=X0*e-ke*t), it is the sole reason for long half-lives (t½=0.693/ke) and thus persistence in the body. Accumulation is a function of half-life (and thus of elimination constant ke). Lipid solubility slows elimination, because it increases the volume of distribution, dioxin stored in fat is not available to enzymes. Absorption has no effect on accumulation rate; of course it enables the presence of the chemical in the body. In first-order elimination conditions, accumulation continues until steady state is reached, after about five elimination half-lives. Carry-over means the body burden accumulated in history during high intake, thus the present levels can be much higher than the present intake would cause. Therefore you cannot compare e.g. in epidemiological studies two populations from different decades (or of different age distribution). Transgenerational: wording was clarified, but it is essential here, because of its dependence on kinetics.

Toxic effects in humans Section on Toxic effects in humans etc. Frankly, I do not understand the point on missing section. Just a matter of title? Or should the effects be first and administrative part then? However, they are so intermingled that it would make it harder for the reader to follow. A separate chapter on effects would be kind of awkward, if the conclusion is that most of time there are no proven effects, only hypotheses. It is clearly stated, though, that the safety margins are not large.

Accidents etc. The concentrations were ten thousand fold the present concentrations, and estimated doses million fold the present daily doses. If this is not huge in toxicology, what is? This is not a value word, it is a fact. For a general reader this is essential information. Of course the absolute amounts are small, but still. The incidence etc: Again this is essential information, because e.g. during the Belgian catastrophe abortions were seriously discussed, and afterwards knowing the actual human concentrations it sounds ridiculous. This is an important learning issue for possible future accidents: short term exceedances of regulatory levels do not increase human levels, and drastic manoeuvres would only cause harm. This is not a matter of opinion. Soft-tissue sarcoma: we have a study with more sarcoma cases than all other studies in the world combined, and measured PCDD/Fs and PCBs in every single patient contrary to other studies. There was absolutely no positive association with dioxins or dioxins+PCBs. This is not a matter of opinion. Regulators should follow the science and not vice versa.

Risks connected with low exposures To help the reader, the order of paragraphs was edited starting with the effects. There is a misunderstanding with the panel: it met in 1998, the final publication in Food Additives and Contaminant in 2000 which is in the table. This should be clear from the references Van Leeuven and WHO Temporary Consultation Group. Also it should be clear that the last sentence of the para refers to ref. 4. The text has been clarified. To my knowledge the TWI is the opinion of the CONTAM panel, and waits to be instigated by authorities. Table: good point, sorry for my careless date input. EFSA-CSF was in fact 2001, and it was only referred to in the 2015 paper. This was already corrected in later versions of the text. Below the table: As to the CONTAM panel, you do not like criticizing authorities. I think this is exactly what all review authors should do if necessary. Authorities should follow the science; scientists should not follow the authorities. The whole review is my personal expression, a misunderstanding may be due to the concept that this is a Wikipedia article and it is not, it is a review. It should not be difficult for the reader to see easily where I agree with authorities and/or dioxin community and where I disagree based on clearly expressed reasons. As I explained in the General chapter in the beginning, I have reasons for that. Scientific debate paper is a good idea, but this article happened to be solicited this time. Other reviewers and consulted scientists were happy with the approach, and improved many details. As to cancer risk, the intention was not to minimise the importance of animal experiments, but to point out that both human evidence and animal experiments are based on high doses, and extrapolation is notoriously difficult. It should be clear that with dioxins linear extrapolation is not reasonable. Para: In conclusion the safety margins..: Again, scientists should never base their conclusions on administrative decisions; on the contrary the administrative bodies should base their assessments on scientist’s work. WHO panel was referred to, because it has been the scientific basis for all administrative decisions in Europe until the CONTAM panel. So this discussion in fact compares the conclusions of those two panels. My conclusion was that the truth is closer to the WHO panel than the CONTAM panel, and the latter seemed to apply precautionary principle preventing fair comparison of dioxin risks with competing risks. On the other hand, much of the vast literature survey performed by the panel is highly useful and there it has done plenty of good work. Para: The WHO..: The basis of WHO assessment was the risks to new-borns via placenta and breast feeding. A long breast feeding causes dioxin intake that is far higher than any intake later in life (e.g. milk with 10 pg/g TEQ in milk fat causes an intake of 240 pg/day assuming 3 % fat and 800 ml milk/day, in 3 kg baby this means 80 pg/kg daily dose, which then gradually decreases due to growth). The CONTAM panel calculates somewhat lower intakes for 6-kg child. If these are deemed safe for the baby, nobody else in the population is exposed even closely to similar amounts. Therefore the risks in other population groups are lower than in new-borns. Again, this is not an opinion, it is a fact. If followed literally, the new TWI recommendations would stop breast feeding in the world with catastrophic consequences. Precautionary principle cannot be used, if you compare two opposing risks.

Laboratory studies… Good point, the title was modified What is uncommon in dividing effects to toxic effects and other effects, it is done all the time in pharmacology? The only difference is that now we have adaptive effects that may be useful, in pharmacology we have therapeutic effects that may be useful. This separation was also very clear in the WHO consulting group work where the division was toxic effects and biochemical effects (WHO 2000, Food Add Contam 17:223-240). The wasting syndrome was added as suggested by another reviewer, thanks for noting a wrong reference.

The most conspicuous… Some wordings were softened a bit. Table 5. The subtitle was amended so that the most sensitive toxic effects are first and adaptive responses follow, not to give too much emphasis to adaptation only. Previously what is now called adaptive responses were called biochemical effects (WHO 2000, Birnbaum & Tuomisto, 2000). The differences between biochemical effects and acute toxicity were already predicted in Poland & Knutson review 1982, e.g. binding affinity to the receptors of guinea pig, mouse, rat, rabbit and hamster are close to each other despite a 5000-fold difference in LD50. Enzyme induction between rat, guinea pig and hamster occurs at similar doses (e.g. Kransler et al. 2007). The obvious deviation is the difference between C57BL/6 and DBA/2 mice, DBA being less sensitive to all effects, which is easy to explain, because receptor binding is different. In developmental toxicity there is little difference between species (Kransler et al, 2007, ref. added). So the term adaptive was used because not all of the sensitive effects are biochemical.

Developmental effects First line: for heaven’s sake, developmental effects were nowhere claimed to be adaptive. It is clearly stated that the most sensitive toxic effects take place at the same dose range as the adaptive effects. What is endocrine in strict sense? Endocrine means hormonal effect via blood circulation. Local hormone-like effects are often called paracrine. Endocrine disruption discussion has widened the use of the term in such a way that it is sometimes confusing.

Multigenerational … I do not quite understand the question on message. This is a general review on dioxins and dioxin-like compounds, and most aspects have been shortly described. This is not primarily on hazard or risk assessment, although these are also discussed to some extent. I see mechanisms more central than administrative specifics. On the other hand, an attempt was made to avoid highly sophisticated details to make the text also readable to non-experts. Therefore e.g. in vitro work has not been thoroughly discussed.

Interactions of dioxins… This is a highly interesting new area in dioxin research. Therefore I do not understand what is the motivation to delete all new information that does not strengthen the high dangers of dioxins, sounding rather personal and biased. Very precautionary approach is justified e.g. when accepting new chemicals to the market, but in case of chemicals existing in our environment very strict attitudes increase risks elsewhere and may be counterproductive. The attitude resembles vaccination aversions; even a slight possibility of vaccine risks is seen more important than the obvious high risks of the disease that the vaccines prevent. Unfortunately there is no risk-free world, and aiming at such may increase the risks substantially. We say, fleeing a wolf and running on a bear. To fully understand the toxicity of dioxins, one has to know something also on AH receptors and their functions outside the dioxin world. Compared with the other parts of the review, the treatise of AH receptors is in my mind not very lengthy.