Answer Explanations 6

Not Likely to Be Carcinogenic to Humans
Expert 3
1,3-D has been well studied in 2 species, using multiple routes of exposure with no data to support concern for carcinogenic hazard to humans. Positive results in early studies are consistent with confounding by the stabilizer, epichlorohydrin and the inconsistent observation of benign liver tumors in F344 may be attributable to strain-specific responses to doses above the MTD. 1,3-D does not appear to be DNA-reactive and metabolic clearance through the glutathione pathway appears to be effective in the test species. No alternative modes of carcinogenic action have been discussed but positive limited positive results are detected only when the MTD is exceeded.
Not Likely to Be Carcinogenic to Humans
Expert 8
My recommendation is for a classification of "Not Likely to Be Carcinogenic for Humans, Under Expected Conditions of Exposure". Please note the amendment I added. The White Paper does not present all the arguments that I feel are needed to support this classification , and it does present some arguments that I don't think support the category. But I think the information on studies is sufficient to support the classification. A systematic evaluation of MOA was not done, and I find this to be a major difficulty in establishing any classification.
Not Likely to Be Carcinogenic to Humans
Expert 4
For reasons noted above I agree with the conclusions in the white paper given that the: 1) WOE indicates the absence of tumorigenic effects at doses or below the MTD; 2) in vivo genotoxicity data indicate no mutagenic or DNA reactive potential 3) lack of any liver or lung toxicity effects in carcinogenicity studies below the MTD or KMD 4) large PODs for both the oral and inhalation routes of exposure a compelling case is made to conclude that 1,3-D's tumorigenic potential is not likely at human exposure levels and a threshold risk assessment is both supported and protective NOTE TO SCIPINION - I have no changes to my original answer to this question. However I do have changes for my comment and have included them below if you wish to note such changes. If not disregard: re: answer 6, regulatory agencies focus on risk assessment which is a careful and detailed evaluation of both exposure and hazard to estimate risk and not simply hazard characterization of the inherent property of the substance to cause disease at some level of exposure that may greatly exceed that ever seen by humans. Regulatory Agencies use conservative assumptions and safety factors to ensure that allowable use levels have large margins of exposures that protect public health. They also recognize that at very high exposure levels xenobiotics can overwhelm detoxification and repair systems causing diseases, such as cancer, that simply would never happen at the levels encountered in the environment. IARC and NTP can be very helpful to EPA, FDA and other regulators around the world by conducting tests to identify chemicals that can cause tumors at any exposure level in a hazard identification manner. Their use of terms like "Possibly (or Probably) carcinogenic to humans" means that the substance so identified has the potential to cause cancer in humans without regard to the exposure levels required to produce the tumors. They do not consider whether such levels might ever be encountered by humans. Their role is to alert regulatory authorities that cancer is a possibility for that substance (i.e. there is a potential hazard). The regulatory agencies then take the results and conditions of the study into account and carefully evaluate this in light of the potential exposure levels that humans will encounter in as a result of the manufacture, use and disposal of the substance to judge it’s risk. However, in addition to providing this benefit the IARC and NTP hazard only classification approach can also create unintended negative consequences, such as categorizing a chemical substance that has been tested many times with negative results as a possible human carcinogen and inadvertently alarming the public. For instance, glyphosate has been studied in nearly two score cancer bioassays almost all of which were negative. Every regulatory authority around the world concluded that if used according the the pesticide label requirements glyphosate is safe. However, based on their categorization scheme IARC labeled glyphosate as a possible human carcinogen, because of a positive cancer bioassay. The tumors primarily occurred at the high dose level in this study which was something like 5000 mg/kg/d, a dose far above the 1000 mg/kg/d maximum dose level the EPA requires as the top dose for cancer studies. Based on the IARC classification EPA and other regulatory authority around the world are re-evaluating their data sets and indications are that they will still conclude that glyphosate is safe to use under the conditions and restrictions on its the label. The IARC classification has not resulted in any regulatory changes. Despite this the IARC it was successfully used in a lawsuit to claim that a worker’s cancer was caused by exposure to glyphosate. Given the dichotomy between the hazard only categorizations used by IARC/NTP, and the risk categorization (i.e. hazard x exposure = risk) approaches used by regulatory agencies, at best one compares apples to oranges when applying the IARC/NTP classifications with those used by regulatory agencies such as EPA. While those who feel that it is irresponsible not to use IARC type hazard identification alone to restrict exposure to substances that might cause cancer under any circumstance, because we just don't know everything about the initiation and progression of the disease, it is also important to note that it is irresponsible to regulate a substance without consideration of the exposure levels required to cause the tumors because of the societal benefits the substance provides (e.g., the public health benefits from disease control).
Not Likely to Be Carcinogenic to Humans
Expert 5
The available data strongly indicate 1,3-D is not likely present a cancer risk in humans. However, one must still be cognizant that we are extraoplating from rodents to humans.
Not Likely to Be Carcinogenic to Humans
Expert 7
I like to stress that stand alone hazard classifications do not convey the nuances around intrepretative information nor puts hazard in the context of exposure which is critical because the cancer WoE is a judgement of not only the significance of the laboratory animal findings for humans, but also for the potential of risk at lower exposures (ie those encountered by humans vs high animal treatment doses). There is sufficient evidence to make a projection about human hazard and risk. My choice of “Not likely” is based on the following key points: 1. Several well-designed and well-conducted studies using representative technical material, observed no treatment related responses in two oral mouse bioassays for both sexes (Redmond 1995 and Kelly 1998), an inhalation rat bioassay for both sexes (Lomax 1987), and an inhalation mouse bioassay for females (Stott 1987). 2. Although there were some positive findings at the highest treatment dose/concentration, the liver tumors in the oral rat study by Scott 1995 were only benign ( late stage onset), and occurred slightly above the lab historical controls in males at a dose that exceeded the MTD; and the slight increase in benign lung tumors in male mice in the inhalation mouse study (Stott 1987) is of questionable human relevance given that this species/sex is highly susceptible to this tumor (ie high background) and that the response was found at terminal sacrifice at a high concentration that exceeded GSH saturation (the predominant metabolic pathway protective of toxicity). 3. In vivo mammalian mutation and DNA adduct studies using routes, species and target tissues of interest, as a whole, indicate that 1,3 D is not a mutagenic concern for humans nor would it act via a DNA reactive mode of action for cancer. 4. Although some short comings in the oral in vivo micronucleus assay and inhalation dominant lethal test were pointed out in the peer review, both studies used representative material and were clearly negative. The overall weight of evidence (TK, genotoxicity, cancer bioassay findings) does not support a concern for clastogenicity in humans. 5. Metabolism studies demonstrate that metabolic profiles are similar for rats and mice, TK is also similar for oral and inhalation routes of exposure, GSH detoxification is a predominant pathway and a protective mechanism, and TK inhalation studies have identified a KMD around 20 ppm, indicating that high exposure specific toxicities exceeding the KMD are not relevant to human risk.
Suggestive Evidence of Carcinogenic Potential
Expert 2
I am puzzled by the lack of an option that in fact characterizes many, if not most, of all substances evaluated by IARC, NTP, and others: namely "POSSIBLY (or PROBABLY) CARCINOGENIC TO HUMANS." I would have chosen this option if available-- more than "suggestive" but less than "likely." I believe that 8 bioassays, 4 of them with some positive responses (Scott, NTP rat, NTP mouse, Stott), cannot all be deemed "not likely" (which is the technical euphemism for "likely NOT to be carcinogenic") for the panoply of unrelated and not entirely convincing reasons given in the white paper. There remains the response of "inadequate." Here I think the survey is also not precise, because NTP and IARC use "inadequate" generally to refer to situations where key information is simply absent. In the case of 1,3-D we have 30 years of information of all types-- it is not definitive, but I think we should be choosing between "likely not to be" and "possible/probable/likely" (one of these) given what we do know. ADDENDUM ADDED MAY 1 BASED ON ROUND 4: I remain convinced that "not likely" is simply not appropriate given all the data and evidence-- in light of the troubling findings that have been convincingly discounted and those that have *not* been. I would prefer being able to choose "possible" rather than either "likely" or "suggestive" (I regard "possible" as in between these two categories). If there is to be a summary conclusion from all reviewers, I hope the writer(s) will document the range of views among us, even if I remain an outlier.
0
Expert 4
04/22/2019 12:55

re: answer 6, regulatory agencies focus on risk assessment which is a careful and detailed evaluation of both exposure and hazard to estimate risk and not simply hazard characterization or the inherent property of the substance to cause disease at some level of exposure that may greatly exceed that ever seen by humans. Regulatory Agencies use conservative assumptions and safety factors to ensure that allowable use levels have large margins of exposures that protect public health. They also recognize that at very high exposure levels, xenobiotics can overwhelm detoxification and repair systems causing diseases, such as cancer, that simply would never happen at the levels encountered in the environment. IARC and NTP can be very helpful to EPA, FDA and other regulators around the world by conducting tests to identify chemicals that can cause tumors at any exposure level in a hazard identification manner. Their use of terms like "Possibly (or Probably) carcinogenic to humans" means that the substance so identified has the potential to cause cancer in humans, without regard to the exposure levels required to produce tumors and whether such levels might ever be encountered by humans, to alert regulatory authorities that cancer is a possibility for that substance (i.e. there is a potential hazard). The regulatory agencies then take the results and conditions of the study into account and carefully evaluate potential exposures to the substance in context with the levels that humans will encounter to judge the substance's risk. In addition to providing this benefit the IARC and NTP approach can also create unintended negative consequences, such as categorizing a chemical substance that has been tested many times with negative results as a possible human carcinogen because of one positive study employing very high doses that greatly exceed that maximum dose levels required to be tested. For instance, glyphosate has been studied in nearly two score cancer bioassays almost all of which were negative. Every regulatory authority in countries around the world had concluded that if used according the the pesticide label requirements, which is the law, glyphosate could be used safely. However, based on one lifetime study using something like 5000 mg/kg/d cancers were found in the high dose level, far above the 1000 mg/kg/d maximum dose level the EPA requires to be used, and thus according to their categorization scheme IARC categorized it as a possible human carcinogen. This was of use to EPA, and every other regulatory authority around the world (some 30 odd countries) because they now knew it could cause cancer at least under very high dose exposures. They then evaluated the data sets within the requirements of their own countries laws and regulations and unanimously concluded, that glyphosate is safe to use under the conditions and restrictions on its the label (i.e., while glyphosate may pose a hazard at very high dose levels the risk assessments conducted in some 30 odd countries all said its safe to use as directed on the label because the exposures encountered by humans will be orders of magnitude less ). On the other hand that same IARC hazard identification classification of possibly carcinogenic was also successfully used in a lawsuit to claim that a worker got cancer from its use despite unanimous agreement among regulatory agencies worldwide that it does not and will not do so. Given the dichotomy between hazard only categorizations vs. hazard x exposure = risk categorizations at best one compares apples to oranges when applying the IARC, NTP classifications with those of organizations such as EPA. While those who feel that it is irresponsible not to use hazard identification alone to restrict exposure to substances that might cause cancer under any circumstance, because we just don't know everything about the initiation and progression of the disease there is another side to the argument. One can also argue that it is irresponsible to regulate a substance without consideration of the exposure levels required to cause the tumors , because of the societal benefits the substance provides (e.g., the public health benefits from disease control).

0
Expert 2
04/23/2019 11:07

I appreciate much of the comment (user-125195 [Expert 4] ) above, which seems to be in response to my "suggestive evidence" classification in Round 2. For clarification, I would classify 1,3D as "possibly carcinogenic", NOT because of the arguments in the white paper that the human threshold dose is far below current exposure levels (I don't fully agree with that logic anyway...), but because I see the bladder carcinomas, lung adenomas, and perhaps other findings among the 8 bioassays as of concern and NOT sufficiently debunked by the arguments in the white paper.

So the interesting issues in the above comment (what to do about a substance that CAN cause an effect in humans but can't if "used safely"?), don't apply to my original response to this particular question. I will note, however (albeit with ZERO knowledge of the lawsuit #125195 [Expert 4] refers to), that there is nothing inconsistent about (1) saying a substance poses no human risk as long as exposures are low; and (2) compensating a plaintiff whose exposures were NOT low!

0
Expert 7
04/24/2019 09:32

First, I agree that hazard needs to be put in context of exposure, and risk is more informative. Also, I did not take issue with the WOE classifications provided in Q5.8 because a WoE needs to come to a judgement of whether there is sufficient evidence to make a projection of human risk (ie “Likely” or “not likely”) or there is not a sufficient basis to support a reliable projection of human risk given the nature of the responses/data (ie suggestive, inadequate).

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