Document XO58Dakvd35kz1mVBGE0kzngg

To: Jackson, Ryan[jackson.ryan@epa.gov] From: Edward Calabrese Sent: Tue 10/10/2017 9:07:54 AM Subject: [SPAM] LNT history LNT History Abridged-1 .pdf Ryan: See the attached new paper (published today). Please share with your key people. Ed 17cv1906 Sierra Club v. EPA ED_001523_00000948-00001 Commentary The Mistaken Birth and Adoption of LNT: An Abridged Version Edward J. Calabrese1 Dose-Response: An International Journal October-December 2017:1-3 a The Authors) 2017 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1559325817735478 journals.sagepub.com/home/dos VISAGE Abstract The historical foundations of cancer risk assessment were based on the discovery of X-ray-induced gene mutations by Hermann J. Muller, its transformation into the linear nonthreshold (LNT) single-hit theory, the recommendation of the model by the US National Academy of Sciences, Biological Effects of Atomic Radiation I, Genetics Panel in 1956, and subsequent widespread adoption by regulatory agencies worldwide. This article summarizes substantial recent historical revelations of this history, which profoundly challenge the standard and widely acceptable history of cancer risk assessment, showing multiple significant scientific errors and incorrect interpretations, mixed with deliberate misrepresentation of the scientific record by leading ideologically motivated radiation geneticists. These novel historical findings demonstrate that the scientific foundations of the LNT single-hit model were seriously flawed and should not have been adopted for cancer risk assessment. Keywords risk assessment, mutation, linearity, history of science, cancer, X-rays In 1927, Herman Muller mistakenly asserted that he had used X-rays to induce "gene" mutations in Drosophila.1 Although flawed and unverified, this interpretation was well received and widely accepted by the scientific community.2 Both the 1930 "Proportionality Rule" of Muller and the 1935 "LNT Single Hit dose-response model" of Timofeeff-Ressovsky and colleagues3 were offspring to Muller's mistaken conception of X-ray-induced "gene" mutations.1 Critics from the genetics community, such as Lewis J. Stadler, Barbara McClintock, and others, soon argued convincingly that Muller's idea lacked scientific proof and could be alternatively explained by mechanisms involving gross chromosomal deletions and aber rations rather than mutations within specific genes.1 Respond ing to such criticisms, Muller quickly conducted research-- albeit experimentally limited--to support the accuracy of his conclusions on X-ray-induced "gene" mutations, specifically that mutational responses were cumulative (ie, that the total dose--and not dose rate--was important), irreversible, and linear with respect to dose4,5 Soon though, more experimen tally rigorous studies were performed under the oversight of the Manhattan Project and produced results that seriously chal lenged Muller's concept of "total dose"6 Sadly and shock ingly, influential leaders of the US radiation and genetics communities, including Stern and Muller, chose to misrepre sent and thereby marginalize the more carefully performed studies6-8 The alarming saga continues. In 1956, the prestigious NAS Biological Effects of Atomic Radiation (BEAR) I Genetics Panel deliberately misrepresented its own research to promote the acceptance of the linear nonthreshold (LNT) model by regulatory agencies.7,8 Moreover, the same NAS BEAR I scientists along with other experts from the scientific/regulatory communities9 "eagerly and wrongly" assumed that if the dose-response for X-ray-induced mutations in mature sperma tozoa was shown to be not only I near but also "independent" of dose rate, then this same dose-response relationship could be used in risk assessment to generalize across ail cell types, all doses, and all dose rates.7,8 In only a few years, mature sper matozoa were shown to be the exception and not the rule. Unlike most cells, mature spermatozoa were found to lack the ability to repair mutations induced by either chemicals or 1 Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Morrill I, Amherst, MA, USA Received 18 August 2017; accepted 22 August 2017 Corresponding Author: EdwardJ. Calabrese, Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Morrill I, Amherst, MA 01003, USA. Email: edwardc@schoolph.umass.edu Creative Commons CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (http://www.creativecommonsorg/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-acce-at-sage). 17cv1906 Sierra Club v. EPA ED_001523_00000949-00001 2 Dose-Response: An International Jbumal radiation,10,11 proving that the assumption of the NAS BEAR I Genetics Panel and its affiliates was wrong. In late 1958, Wil liam L. Russell showed that X-ray-induced mutations in the spermatogonia and oocytes of mice could indeed be repaired and--in direct contradiction to Muller's ideas of "total dose" and irreversibility--were dependent rather than independent of dose rates,10,11 at low levels of radiation. Fourteen years later, the Biological Effects of Ionizing Radiation I (BEIR I),12 Genetics Subcommittee acknowledged the "mistake" of the NAS BEAR I Genetics Panel on dose rate but nevertheless retained the LNT recommendation because the reduced mutation rate in spermatogonia, as shown by Rus sel I, had not regressed back to control values as it had for oocytes. Nonetheless, the BEIR I GerreticsSubcommitteegrudgingly indicated that, due to its repair capacity, spermatogonia rather than mature spermatozoa were better models for general izing mutational responses across somatic cells. Russell referred to fai led DNA repair capacity as an "odd phenomenon, restricted to spermatozoaand occasioned by the pecul iar nature of the specialized spermatozoan cell".10'11 In 1995, Paul B. Selby (1998a, b)13,14 detected a significant error that had routi nely occurred in the historical control groups of Russell's mouse-specific locus test. This final mistake was subsequently acknow ledgedand corrected by Russelland Russel I15 along with Selby.13,14 I f this mistakehad not occurred or had been corrected before the creation of BEIR I, then the mouse spermatogonia data that supported continuanceof the LNT model would have adjusted control mutational values to historical norms, support ing either a threshold or hormetic model depending on whether the correction of Russell or Selby, respectively, was used.10'11 To summarize, the successful birth and adoption of LNT for cancer risk assessment was due to (1) the mistaken assumption by Muller that he had discovered X-ray-induced "gene" muta tions, (2) the adoption of the "LNT single-hit model" that was based on Muller's mistaken assumption, (3) the mistake by BEAR I of generalizing DNA repair-deficient mature sperma tozoa as representative of all somatic cells, (4) the deceptions and misrepresentations of the scientific record by leaders of the radiation genetics community, including the NAS BEAR I Genetics Panel, and (5) the repeated mistakes made in asses sing the control responses in Russell's mouse-specific locus test. The EPA (1975, 1977)16,17 even extended and com pounded these mistakes in 1975 and 1977 by further adopting LNT for chemical- (Albert et al., 1977)18 as well as radiation- induced cancer risk assessments, stating that its LNT decision (later proven to be wrong by both Russell and Russell in 1996 and then by Selby in 1998a, b)13,14 was based on the dose-rate findings of Russell as cited in BEIR I (1972). If any one (or more) of these mistakes had been avoided, then an invalid LNT, its birth,and itsadoption by society would al I havelikely miscarried and been replaced by a more authentic dose response alternative, such as a threshold or hormetic model. Authors' Note The US Government is authorized to reproduce and distribute for governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the author and should not be interpreted as necessarily representing pol icies or endorsement, either expressed or impl led. Sponsor had no involvement in study design, collection, analysis, interpretation, writing, and decision to and where to submit for publication consideration. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research has been supported by awards from the US Air Force. References 1. Calabrese EJ. Flaws in the LNT single-hit model for cancer risk: an historical assessment. Environ Res. 2017a;158:773-788. 2. Campos LA. Radium and the Secret of Life. Chicago & London: University of Chicago Press; 2015. 3. Timofeeff-Ressovsky NW, Zimmer KG, Delbruck M. Nachrich ten von der gesellschaft der wissenschaften zu Gottingen. Uber die nature der genmutation und der genstruktur Biologie. 1935; 1(13): 190-245. 4. Ray-Chaudhuri SP. The validity of the Bunsen-Roscoe law in the production of mutations by radiation of extremely low intensity. Proceedings of the 7th International Congress on Genetics, Edin burgh 1939; 246. 5. Ray-Chaudhuri SP. The validity of the Bunsen-Roscoe law in the production of mutations by radiation of extremely low intensity. Proc Royal Soc Edinburgh. 1944;62:66-72. 6. Calabrese EJ. Key studies used to support cancer risk assessment questioned. Environ Mol Mutagen. 2011a;52(8):595-606. 7. Calabrese EJ. On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith. Environ Res. 2015;142:432-442. 8. Calabrese EJ. LNTgate: how scientific misconduct by the US NAS led to governments adopting LNT for cancer risk assess ment. Environ Res. 2016;148:535-546. 9. Anonymous. (Genetic Panel, W. Weaver, Chair). National Acad emy of Sciences (NAS), Biological Effects of Atomic Radiation (BEAR), Genetic Effects of Atomic Radiation. Science 1956; 123: 1157-1164. 10. Calabrese EJ. The threshold vs LNT showdown. Dose rate findingsexposed flaws in the LNT model. Part 1. The Russell-Muller debate. Environ Res. 2017b;154:435-451. 11. Calabrese EJ. The threshold vs LNT showdown. Dose rate find ings exposed flaws in the LNT model. Part 2. How a mistake led BEIR I to adopt LNT. Environ Res. 2017c; 154:452^58. 12. National Academy of Sciences (NAS)ZNational Research Council (NRC). The Effects on Populations of Exposure to Low Levelsof Ionizing Radiation (BEIR I). Washington, DC: National Academy; 1972. 17cv1906 Sierra Club v. EPA ED_001523_00000949-00002 Calabrese 3 13. Selby PB. Major impacts of gonadal mosaicism on hereditary risk estimation, origin of hereditary diseases, and evolution. Genetica 1998a;102/103(1 -6):445-462. 14. Selby PB. Discovery of numerous clusters of spontaneous mutations in the specific-locus test in mice necessitates major increases in esti mates of doubling doses. Genetica. 1998b;102/103(1-6):463-487. 15. Russell LB, Russell WL. Spontaneous mutations recovered as mosaics in the mouse specific-locus test. Proc Natl Acad Sci U S A 1996;93(23): 13072-13077. 16. United States Environmental Protection Agency. ORP policy statement on the relationship between radiation dose and effect. Fed Reg. 1975;41(133):28409. 17. United States Environmental Protection Agency. Excerpts from radiological quality in the environment of the United States. Office of Radiation Programs EPA; 1977. 902/4-78-002. 18. Albert E, Train E, Anderson E. Rationale developed by the Envi ronmental Protection Agency for the assessment of carcinogenic risks. J Natl Cancer Inst. 1977;58(3):1537-1541. 17cv1906 Sierra Club v. 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