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No Validity to No Safe Dose: Part I - The Flawed Linear No Threshold Model of Carcinogenesis

A Commentary by Mark G. Zellmer ofHnsch Blackwell LLP Author bio on page 9

he Linear No Threshold model Various organizations and agencies use • How LNT is now applied to all of carcinogenesis (“LNT”)1 LNT to justify findings on carcinogens carcinogens? holds that all exposures to car­ and thereby give support, whether con­ • What is the evidence of thresholds cinogens cumulatively increase sciously or otherwise, to the claims of or safe doses? the risk of cancer in a linear, proportion­ plaintiffs’ attorneys. For example, since • Why LNT is still utilized? al relationship to dose, even at the lowest 1975, the Occupational Safety and possible levels of exposure. The LNT Health Administration (OSFIA) has The conclusion is simply that LNT has model, first postulated in the 1920s, is “assumed” that there is “no safe thresh­ no basis in science. not the product of well-founded science old” for exposure to any carcinogen.4 In and is subject to clear refutation by con­ its response to public comments advocat­ cepts of science today. In fact, the gene­ ing that there is a threshold for causation Defining LNT sis, and then acceptance, of LNT is the of mesothelioma by chrysotile asbestos, result of decades of bluster, literal bully­ the EPA rejected any such notion citing Although not always defined in the same ing (both verbal and financial in the sci­ “accepted models for cancer” as well as terms, the Linear No Threshold model of entific community), non-disclosure, and the “linear” dose response model.5 The carcinogenesis always involves the follow­ even deception. World Health Organization (WHO) ing concepts:7 rejects any concept of a “threshold” for Tire importance of LNT in asbestos, as the carcinogenic risk of asbestos.6 1. Carcinogens can, and do, cause well as other toxic tort, litigation is obvi­ damage to DNA. ous. Plaintiffs’ attorneys and their experts The LNT model is used to support such have a mantra recited repeatedly in depo­ statements and views expressed by plain­ 2. The damage is irreparable and sitions, reports, affidavits, and trials tiffs’ attorneys and their experts, as well irreversible. regarding asbestos or, for that matter, any as various agencies and organizations. toxic tort: “there is no safe dose of a car­ Even when not mentioned expressly, 3. The damage is cumulative, i.e. cinogen.” In somewhat more lengthy LNT is the basis for what plaintiffs’ higher or additional doses constantly terms, they explain that there is “no attorneys argue in asbestos cases. Indeed, add to the risk regardless of time threshold below which an exposure to a much of what plaintiffs’ attorneys say in frame. carcinogen will not cause cancer.” In the asbestos litigation would fail without the 216 pages of one of Dr. Arthur Frank’s LNT concept. 4. Ihe risk of cancer increases in a affidavits, he mentions that there is “no linear relationship to cumulative safe dose” of asbestos 37 times.2 This does This article will discuss the concepts dose. not even count the number of times that underlying LNT and why the science he opines that there is no “threshold” for supports a view clearly contrary to LNT: 5- Risk increases at any exposure exposure to asbestos. In the standard 46- exceeding zero, i.e. there is no page report of Dr. Edwin Holstein, he • How LNT is defined? threshold or safe dose. mentions “no safe dose” of asbestos 11 • What is the history of LNT? times.3

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Testing these concepts is not straightfor­ ward. Errors in testing or in the interpre­ “In the EPA’s recent response to public tation of results can lead to erroneous comments on its 2020 proposed findings. And, indeed, as research relating to LNT has progressed over the years, findings on asbestos, it dismissed pages errors happened for any number of rea­ sons. Anyone looking at this issue must and pages of critical comments by a understand some sense of the complexity simple and short reference to its of testing the concept of a linear no threshold model. For example, the study acceptance of the linear no threshold of carcinogenic exposure of cells that can­ model of carcinogenesis. All of this not repair DNA will not give worthwhile information on the cumulative nature of creates a problem. LNT was originally gene mutation. In a case-control animal developed as a radiation model. study, if the control group of animals is not well controlled, the results may show If the basis for LNT is not scientifically risks where none actually exist. valid for radiation, it should not be Such testing involves test tubes and petri valid for other carcinogens. dishes or long observation of large num­ bers of animals. On the other hand, researchers have long recognized that the most relevant information on carcinogen­ science. The story is illuminating and fas­ had only induced large chromosomal esis in man comes from man himself.8 cinating. At its heart, it tells what can go deletions, not point gene mutations.14 In Determination of the risk of disease from wrong with science. Anyone wanting a 1946, based upon radiation experiments past exposure can require estimates of more in-depth explanation can look to that were part of the Manhattan Project, exposure that is uncertain at best. Non- one or more of his many excellent arti­ Ernest Caspari reported to his superior, fatal occurrence of damage to DNA has- cles.111 If you prefer to learn by listening, Curt Stern, that the total dose did not been hypothesized to affect oft-spring for he has an online lecture on the subject cause genetic change and that there was generations, but accounting for such that runs for almost an hour.11 in fact a threshold or “tolerance” dose. occurrences among oft-spring requires Despite having the Caspari data in his careful, long-term observation. In 1927, based on experiments subjecting possession, Muller lauded LNT in his male fruit flies to high dose X-rays, 1946 Nobel Prize acceptance speech. The Maybe most importantly of all, LNT Hermann J. Muller found phenotypic12 Caspari data never had much impact. assumes that the total dose is key to the changes in subsequent generations and Caspari’s superior, Stem, along with a occurrence of cancer. Failing to consider published his finding as proof of “artifi­ co-author, published support for the the time over which a dose of carcinogen cial transmutation of the gene,” in other LNT model in Science. While mention­ is experienced (rate of administration of words, gene mutations.15 Although ing Caspari’s work, the underlying data the doses) can leave this emphasis on Muller’s studies used very high doses of from Caspari was not included, giving a total dose essentially unchallenged. radiation, he assumed that the dose false impression of support for the response was linear down to a single radi­ model.13 The Historical ation event at the lowest dose. Based Perspective on LNT upon further work of Muller’s under­ In the early 1950s, Detlev Bonk, study, Ray-Chaudhuri, Muller proposed President of the Rockefeller Institute and that the damage from radiation was the National Academy of Science, Much, if not all, of what follows in this cumulative, meaning that the total dose appointed Warren Weaver to chair the section comes from what Edward J. created the gene mutation. There was dis­ Biological Effects of Atomic Radiation Calabrese'' has found regarding the devel­ sent. Lewis J. Stadler’s work at the (BEAR I) Genetics Panel. Prior to this opment and acceptance of the Linear No University of Missouri involved 13 doses Panel, medical professionals accepted a Threshold model of carcinogenesis. The of radiation to barley with the lowest threshold model. Government agencies credit for uncovering so many of the ele­ doses “showing no enhanced mutation utilized a threshold model. As part of an ments of this story goes to him. His work over the control.” He argued that Muller effort to negotiate the adoption of LNT, and writing are equal parts history and

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the human data was too uncertain and that the fruit fly work was more reliable. Its importance in the context of this His Nobel Prize as well as his command­ ing personality gave him the power to article is not the effect of hormesis redirect the discussion in favor of LNT and away from the findings of Neel, a from asbestos but rather the lack of younger and less well-known researcher.1'

any validity of the LNT model if In the late 1950s, William Russell and co-authors at the Oakridge National hormesis is correct The Laboratory published the results of ioniz­ ing radiation to spermatogonia (undiffer­ inconsistency is obvious. If low level entiated male germ cells) and oocytes exposures are beneficial in the (loosely, female cells in the ovary) in a mouse model. The data for the oocytes, prevention of mutation and cancer, when analyzed by comparison to the con­ trol animals, showed that gene mutation low level exposures cannot create was dependent upon dose rate. This meant that DNA damage was not cumu­ the risk of cancer lative, was reversible, and could not be assumed to be in linear relation to dose alone. There was a threshold."1 The data Weaver made his position clear at the level of uncertainty of the calculations on the spermatogonia was less clear. start of the proceedings of the BEAR I from 4000-fold to 750-fold. The esti­ Russell soft pedaled his data, saying that Genetics Panel. Those who wanted fund­ mates that were ultimately published it needed to be interpreted carefully as a ing should align their views to the were by fiat dropped to a 100-fold level threshold may not be “a necessary conse­ accepted model, namely LNT. of uncertainty.16 quence.”19 Once again, Muller fought to Thereafter, Muller’s colleague, Tracy protect the LNT model, both in writing Sonneborn, defined LNT for the Panel James Neel of the University of Michigan and presentations. Russell, the much explaining that all mutational radiation was one of the geneticists who refused to younger scientist, like Neel before him, damage was “cumulative, irreversible, and participate. Muller had found genera­ mainly deferred to Muller, the more sen­ lacking repair” with dose related to dam­ tional gene mutation from irradiation of ior, Nobel Prize winning researcher.*0 age in a “linear” manner “down to a sin­ fruit flies. The use of the atomic bomb at gle ionization.” Not unexpectedly, the the end of World War II created the What came next should have put an end Panel adopted LNT. To prove LNT, opportunity to study the generational to LNT. First, it was discovered that the Weaver asked the 12 members of the effects of radiation, not on animals, but work of Ray-Chaudhuri, upon which Panel to estimate genetic damage over 10 humans. The sample size was substantial: Muller placed so much reliance, had been generations from a radiation event to the approximately 70,000 children born over done with mature spermatozoa which American public. Three Panelist refused a decade. Ultimately, the study extended had no ability to repair DNA damage.*1 to participate because any such estimates over six decades. Neel and others did the A threshold exists because DNA damage would be too uncertain to be reliable. study under the auspices of the Atomic can be repaired. Muller and Ray- James Crow reviewed the submitted esti­ Bomb Casualty Commission of the Chaudhuri, by using cells without the mates and told Weaver that there was so National Academy of Science. The study ability to repair DNA damage, did not much variation in the estimates that revealed no statistically significant results have evidence to deny the existence of a LNT would have little credibility if the from the radiation event (i.e., dropping threshold or to support a linear relation­ estimates were published. To save LNT, the atomic bomb) even though the radia­ ship between dose and genetic damage the BEAR Genetics Panel published the tion experienced was much higher than causing cancer. Second, after 25 years estimates, but only after eliminating the necessary to cause DNA damage in stem had elapsed from the revelations of three lowest estimates and without dis­ cells. When speaking in panels and at Russell’s mouse data, Paul Selby, a stu­ closure of the refusal of some Panel conferences and when writing in letters dent of Russell, also at Oakridge, discov­ members to participate. Elimination of to colleagues, Muller successfully blunted ered a misconstruction in the mouse con­ these estimates brought the statistical the bomb research results, arguing that trol group. Correcting the misconstruc­

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tion meant that the male mutation inci­ the EPA on cancer risk assessment, four pleural cancers with four cases of dence was just as low as the female inci­ asserted that genetic mutation, the cause mesothelioma. The pleural cancers could dence. Hence, there was a threshold, of cancer, is “linear with radiation dose” be mesothelioma, but they could also be consistent for both male and female and then further stated that the “differ­ pseudo-mesotheliomatous lung cancer or mouse mutations. Unfortunately, prior to ence between chemical carcinogens and metastasis from renal cancer or some­ the reconstruction of the Russell mouse ionizing radiation could be waved aside thing else entirely. When only the four data, the Biologic Effects of Ionizing as they both cause genetic damage.”2’ In cases of mesothelioma were included, the Radiation (BEIR I) Genetics Sub-com­ the EPA’s recent response to public com­ relative risk of developing mesothelioma mittee recommended LNT. BEIR I ments on its 2020 proposed findings on was not statistically significant.29 jumped to a conclusion supporting LNT asbestos, it dismissed pages and pages of before the full meaning of Russell’s data critical comments by a simple and short An analysis of cohorts with chrysotile was understood.22 Without reopening the reference to its acceptance of the linear exposure led Pierce and co-authors to matter for further scientific evaluation no threshold model of carcinogenesis.25 conclude in 2016 that the risk of and discussion, the EPA and other agen­ All of this creates a problem. LNT was mesothelioma will not increase from cies have adopted LNT. originally developed as a radiation model. chrysotile exposure when the cumulative If the basis for LNT is not scientifically dose is less than approximately 200 f/cc- Calabrese gives this conclusion about valid for radiation, it should not be valid years.30 The work of Pierce has been criti­ LNT: for other carcinogens. cized because their identification of a “No-Observed-Adverse-Effects-Level” or “The LNT single-hit dose-response NOAEL is confusing animal toxicology model for cancer risk assessment was Thresholds, with human epidemiology. Such criti­ conceived, formulated, and applied NOAELs, and More cism is not fair. Even the EPA in its IRIS in a manner which is now known to database uses the term “NOAEL” with­ have been scientifically invalid. . . out distinction between animals and The work of Stadler, Caspari, Neel, [T]he concept of LNT ... is shown humans.31 Russell, and now Calabrese as well as to have multiple flaws that reveal its many others ultimately led to the dual lack of scientific validity. . . [TJhe Likely, the most persuasive data comes conclusions that cells repair damage to basis for cancer risk assessment as from the Canadian chrysotile mining DNA done by carcinogens and that the recommended by NAS BEIR I cohort. Even with known contamination capability to repair damage to DNA Subcommittee and accepted by vir­ of the ore with tremolite, no case of leaves no doubt about the existence of a tually all regulatory agencies, is mesothelioma “was identified in some threshold dose. What is known about demonstrably incorrect."23 4000 men employed less than two such thresholds for carcinogens, particu­ years. larly asbestos? To play upon and inflame fears in a jury, plaintiffs’ attorneys claim that there is Lung Fiber Burden Epidemiology “no safe dose,” citing regulatory pro­ When parenchymal lung tissue is As mentioned earlier, the most relevant nouncements based upon the scientifical­ removed and weighed, the tissue may be information on carcinogenesis in man ly invalid LNT model. dissolved leaving the asbestos fibers to be comes from man himself.26 On that sub­ counted.33 In 1960, Christopher Wagner ject, the epidemiology of chrysotile Application to first published on the relationship of asbestos is most illuminating.27 All Carcinogens mesothelioma and asbestos when he found numerous cases of mesothelioma Study of the chrysotile miners at in the crocidolite mining district of The historical perspective emphasizes Balangero found that the relative risk of South Africa. On the other hand, he radiation and rightly so. Radiation was mesothelioma from chrysotile exposure firmly believed that chrysotile was largely the focus of much of the 1940s, 1950s, was statistically significant only when not responsible for the causation of and 1960s due to the bomb and nuclear exposures reached 346 f/cc-years.2* mesothelioma.3'1 Gathering the evidence energy. Agencies such as the EPA, like Epidemiology on the North Carolina tex­ from lung digestion studies, human epi­ plaintiffs’ attorneys, do not limit the use tile cohort found that the statistically sig­ demiology, animal studies, and other of LNT to radiation alone, but, rather, nificant relative risk of mesothelioma sources, he estimated that mesothelioma apply it to all carcinogens. In 1994, Roy from chrysotile exposure was 1.15 for would “occur when the fiber concentra­ E. Albert, who at one time worked for 100 f/cc-years of cumulative exposure. tion is more than 1 million/g dry weight This result came from the inclusion of of [amphibole] fibers longer that 5.0

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[microns] and diameter smaller than 0.25 biologic mode of action that links DNA Hermann Muller) suffer negative effects [micron].”35 damage to the development of HCC.”37 on “fitness-related traits” from “lower- than background radiation levels.” In In 2019, Louis Anthony Cox returned to Hormesis effect, stressing the system earlier in life the issue of the number of fibers neces­ Hormesis is the beneficial “biologic can prepare the organism for stress later sary to cause mesothelioma. He noted at process in which low doses of toxins elicit in life.40 the outset that the LNT model posited a protective response [against] a higher that a “single fiber” increased the risk of dose of the same toxins.”38 Hormesis is A Lesson From Bruce Ames lung cancer and mesothelioma. His protective against various maladies Bruce Ames is likely the scientist most approach to test the LNT model varied including cancer.35 Its importance in the deserving of the Nobel Prize who has from anything that had come before. He context of this article is not the effect of never won it. His Ames test is an expedi­ recognized that inflammatory response, hormesis from asbestos but rather the tious and inexpensive method to deter­ and specifically chronic inflammation, lack of any validity of the LNT model if mine mutagenicity and thereby carcino­ induced by asbestos fibers was the key hormesis is correct. The inconsistency is genicity of substances. Despite his atten­ mediator in the development of one or tion to issues of cancer, he is extraordi­ more mutations and then cancer. The narily cautious about overstatement of chronic inflammation was the result of the dangers of carcinogens: “cancer esti­ the long-recognized problem of “frustrat­ “To win on a causation mates for toxin control programs are ed phagocytosis” in which macrophages defense in toxic tort worst-case, hypothetical estimates, and cannot engulf and destroy the long, bio- the true risks at low dose are often likely persistent fibers. He then determined, by cases, and specifically to be zero.”41 a mathematical model, that the threshold in asbestos cases, level for chronic inflammation in the tar­ So, Why LNT? get organ was at least hundreds of thou­ defense attorneys must sands to millions of these long, bio-per­ be prepared to If the LNT model is so bereft of validity, sistent fibers per gram of dry weight lung 9 why has it not been supplanted already? tissue.36 The conclusions of Wagner and challenge plaintiffs Cox are consistent. constant refrain of fno First, the reason that it was adopted in a safe dose* with a regulatory context still holds sway at this Animal Studies refrain of their own. time. It is “extremely simple” to apply. In 2014, Johnson et al. tested the linear That was the honest explanation given by no threshold hypothesis. Noting that Thresholds are real. Roy Albert from his involvement in the others have challenged the no “safe level” LNT is not valid. early days of the EPA’s early risk assess­ or “no-threshold” assumption, the ment.42 There is certainly not much sci­ researchers administered F344 rats with It is plaintiffs entific validity attended to a model used aflatoxin B1 (AFB1), a potent hepatic selling a fiction because it is simple. toxin and carcinogen. They treated one group of rats with CDDO-Im, a drug Second, the adage of “follow the money” known for its chemoprotective efficacy is applicable here. Regulators justify their obvious. If low level exposures are benefi­ against hepatocellular carcinoma induced work, and even their existence by scaring cial in the prevention of mutation and by AFB1. Of the rats with no CDDO- the public with overblown pronounce­ cancer, low level exposures cannot create Im treatment, 96 percent developed liver ments of the risks of cancer. Plaintiffs’ the risk of cancer. cancer. Of the rats treated with CDDO- attorneys make a fine living telling juries Im, none contracted liver cancer. If the just how afraid that they must be of car­ There is plenty of evidence of hormesis. LNT model was correct about the effect cinogens. Government money seldom Studies have shown a lack of any differ­ of low dose exposure to carcinogens with flows to those scientists who advocate ences of DNA damage, cancer markers, no threshold at all, at least some of the lesser risk from carcinogens. There is an or chromosomal aberrarions between rats with CDDO-Im treatment should unconscious network of those that close people living in areas of high background have suffered liver cancer. The authors ranks and criticize any challenge to radiation versus those living in areas of concluded that “the absence of cancer . . LNT.43 . supports the concept of a threshold for low background radiation. In fact, organ­ isms, including fruit flies (remember

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Third, there is inertia. It is hard to give and Disposition for Asbestos Part I: scientific foundations.” Chemico- up on a model having promoted it lor Cbrysotile Asbestos at 135, 175 (December Biological Interactions. Vol. 301 (2019) at decades, even though it is wrong. This is 2020). It is notable that the EPA uses the 6. a certain intellectual stubbornness that is term “model” appropriately understand­ natural among us humans but needs to ing its unproven status. "See YouTube: be resisted in the interests of science. https://www.bing.com/videos/search?q=y f'World Health Organization. Cbrysotile ou+Tube+Edward+J.+Calabrese&dodd= Conclusion Asbestos at 4 (2004). 608028964334800059&mid=943D36D A6E4EED098715943D36DA6E4EED0 This article is only Part I. In the next Albert, R.E. “Carcinogen Risk 98715&view=detail&FORM=VIRE article, Part II, which will run in the Assessment in the U.S. Environmental April 2021 issue of COLUMNS-Asbestos, Protection Agency.” Critical Reviews in 12 Phenotypic trait is an obvious or the LNT model will be compared to epi­ Toxicology. Vol. 24(1) (1994 at 75, 80). observable or measurable trait in an demiology that plaintiffs so often present organism. and rely upon. However, that epidemiol­ “Calabrese, E.J. “The Muller-Neel ogy does not support and is inconsistent Dispute and the fate of cancer risk assess­ "Calabrese, E.J. “Was Muller’s 1946 with the LNT model. ment.” Environmental Research. Vol. 190 Nobel Prize Research for radiation- (2020) at 3 citing to statements by Tracy induced gene mutations peer-reviewed?” A conclusion can be drawn at this point: Sonneborn and James Neel. Philosophy, Ethics, and Humanities in to win on a causation defense in toxic Medicine. tort cases, and specifically in asbestos ’Department of Environmental Health https://doi.org/10.1186/sl 3010-018- cases, defense attorneys must be prepared Sciences, University of Massachusetts 0060-5 (2018) at 1. to challenge plaintiffs’ constant refrain of Amherst. “no safe dose” with a refrain of their "Id. at 2. own. Thresholds are real. LNT is not 10Id. Calabrese, E.J. “The linear No valid. It is plaintiffs selling a fiction. Threshold dose response model: A com­ 15 Calabrese, Comprehensive Assessment, prehensive assessment of its historical and supra, at 6-12. Endnotes

1 The term “model” is used intentionally rather the term “theory.” In science a Mark G. Zellmer is a Partner in the St Louis, Missouri, office of Husch theory is a coherent proposition or group Blackwell LLP. He is admitted to practice in Missouri (1982) and Illinois (1978) as of propositions formulated to explain well as in federal courts in those states. Zellmer facts or phenomena that has been repeat­ earned his J.D. from Saint Louis University School edly tested and confirmed either through of Law (1978). He earned his B.A. from the experiment or observation. A model is a University of Notre Dame (1975). concept to explain a process that has not yet been confirmed by testing or observa­ Zellmer speaks and writes extensively on products tion. A model can become a theory but liability law and asbestos litigation. Such writing and only after a process of scientific confirma­ presentation on asbestos litigation include subjects tion. such as premises liability, application of statutes of limitations, medical causation, the litigation in histor­ 2 Affidavit of Arthur L. Frank, M.D., ical context, and exclusivity of remedies under Ph.D., dated December 20, 2016. workers1 compensation.

’Report of Dr. Edwin C. Holstein, dated Zellmer defends toxic tort cases, particularly relating to asbestos, as well as other September 30, 2020. substances and chemicals. Zellmer also defends various defendants in product liability regarding vehicular and industrial equipment. Zellmer's trial practice is "51 F.R. 22612 at 5 Qune 20, 1986). active in state and federal courts from coast to coast, and he has acted as nation­ al counsel in asbestos litigation. 5 LJ.S.E.P.A. Summary of External Peer Review and Public Comments for Asbestos

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16Id. at 12-15. 30 Pierce, J. et al. “An Updated Evaluation asbestos likely necessary to cause of Reported No-Observed Effect Level mesothelioma, not against the amount of 17 Calabrese, Muller, supra. Many years for Chrysotile Asbestos for Lung Cancer background asbestos exposure to be later, the EPA also rejected reliance on and Mesothelioma.” Critical Reviews of found without the effects of occupational the atomic bomb data. Toxicology. or even para-occupational exposure. http://dx.doi.org/10:3109/10408444.201 18 Calabrese, Comprehensive Assessment, 6.1150960 (2016) at 1, 14. 36 Cox, L.A. “Dose-response modeling of supra, at 17. NLRP3 inflammasome-mediated dis­ 31https://ofmpub.epa.gov/sor_internet/reg eases: asbestos, lung cancer, and malig­ 19 Russell, W.L. et al. '‘Radiation Dose istry/termreg/searchandretrieve/glos- nant mesothelioma as examples.” Critical Rate and Mutation Frequency.” Science. sariesandkeywordlists/search.dojjsession- Reviews in Toxicology. Vol. 49(7) (2019) Vol. 128 (December 19, 1958) at 1546, id=UixiOY4UxBenOZQ7LkFOHoAiwYZ at 614-635. 1550. T4xUcAQDURVd 1 Jpi_cBd69lfS! 12903 9450?details=&vocabName=IRIS%20Gl “Johnson, N. M. et al. “Complete pro­ 20 Calabrese, Comprehensive Assessment, ossary&filterTerm=no-observed-adverse- tection against aflatoxin B(l)-induced supra, at 15-19. effect- liver cancer with a triterpenoid: DNA level&checkedAcronym=false&checkedT adduct dosimetry, molecular signature, uId. erm=false&hasDefinitions=false&filterTe and genotoxicity threshold.” Cancer rm=no-observed-adverse-effect- Prevention Research. Vol. 7(7) (2014) at 22 Id. level&filterMatchCriteria=Contains 658-665.

23 Id. at 21. “McDonald, A.D., et al. “Mesothelioma 38 Lopez-Otin, C. et al. “Hallmarks of in Quebec Chrysotile Miners and Health.” Cell. Vol. 184 0anuary 7, 2’Albert, supra, at 78. Millers: Epidemiology and Aetiology.” 2021) at 1, 19. Annals of Occupational Hygiene. Vol. 25U.S.E.P.A., Comments, supra. 41(6) (1997) at 707-719. 39 Id. at 20.

“Calabrese, Muller, supra, at 3. “This process of lung digestion and fiber 4“Constantini, D. et al. The linear no­ counting varies somewhat from laborato­ threshold model is less realistic than 27 Others have presented data supporting ry to laboratory. One aspect is important threshold or hormesis-based models: An thresholds for causation of mesothelioma at the outset. Some laboratories weigh evolutionary perspective. Chemico- by other types of asbestos. For example, the lung tissue before the water is Biological Interactions. Vol 301 (2019 at see Ilgren, E.B. and Browne, K. removed while other laboratories remove 26-33. “Asbestos-Related Mesothelioma: the water and weigh the tissue dry. Wet Evidence for a Threshold in Animals and means that the lung tissue is heavier and, 41 Ames, B. et al. “Environmental Humans.” Regulatory Toxicology and hence, fewer fibers per gram of tissue. Pollution, Pesticides, and the Prevention Pharmacology Vol. 13 (1991) at 116-132. The number of fibers per gram of lung of Cancer: Misconceptions.” Tire FASEB tissue dry versus wet is approximately ten Journal. Vol 11 (November 1997) at 28Ferrante, D. et al. “Mortality and to one. 1042, 1050. Mesothelioma Incidence among Chrysotile Asbestos Miners in Balangero, 34Wagner, C. “Historical Background 42 Albert, supra, at 78. Italy: A Cohort Study.” American Journal and Perspectives of Mesothelioma.” in of Industrial Medicine. Vol. 63 (2020) at Marie-Claude Jaurand and Jean Bignon, 43 Cox, supra, at 625. 135-145. editors, The Mesothelial Cell and Mesothelioma. Vol. 78 (1994) at 8. 29Loomis, D. et al. “Quantitative Interestingly, although the number of Relationships of Exposure to Chrysotile chrysotile fibers may predominate in the Asbestos and Mesothelioma Mortality.” lung, by a calculation of mass, chrysotile American Journal of Industrial Medicme. will be “far less” than amphiboles. Vol. 62 (2019) at 471-477. The authors did not address confounding by use of 35Id. at 10. Wagner measures the content amphiboles even though amphiboles of the lung against the amount of were used at the facility.

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