PERSPECTIVES 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 ___________ 4___________ www.harrismartin.com HaiwsMartin columns PERSPECTIVES 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 ASBESTOS • MARCH 2021 www.harrismartin.com PERSPECTIVES 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.