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Within the past three years there has been a spate of historical discoveries by our research team on various different facets of the historical foundations of cancer risk assessment. This series of discoveries was stimulated by the creation of a 22-episode documentary of the historical foundations of cancer risk assessment by the US Health Physics Society and the need to provide documentation. This process yielded nearly two dozen distinct historical findings which have been published in numerous papers in the peer-reviewed literature. These discoveries are itemized and summarized in the present paper, along with the significance of each discovery within the historical context of ionizing radiation research and cancer risk assessment., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The genetic load hypothesis of Hermann Muller raised the profound question of possible species extinction, even for humans, following a prolonged accumulation of recessive genes due to ionizing radiation exposure within the population. Two major mouse radiation research teams in the United States provided the most extensive tests of Muller's hypothesis. One group continued its study for more than two decades, over 82 consecutive generations, approximating 2500 human years. Even though Muller had stressed for decades his fear of species-threatening effects, no significant effects were observed for related factors such as reproductive fitness and longevity. Yet, the paper presenting the data of the 82-generation negative study has only been cited five times in 45 years. Altogether numerous laboratories worldwide collected vast amounts of data on mice, rats, and swine in an unsuccessful attempt to see if there was convincing evidence to support the genetic load theory and claims that species might deteriorate or be rendered extinct. This paper re-examines Muller's genetic load hypothesis with a new evaluation of how that hypothesis was tested and the significance of the findings, with most of those studies being completed before the BEIR I Committee Report in 1972. That committee briefly discussed the available evidence, mostly ignoring those results as they proceeded to make hereditary risk estimates both for (1) the first generation after a radiation exposure and (2) for the time, in the distant future, when a hypothetical genetic equilibrium would be reached. Their estimates assumed accumulation of harmful mutations and a linear no-threshold dose response extending all of the way down to a single ionization. More recent data on induction by ionizing radiation of dominant mutations that affect the skeletons of mice provide further robust supporting evidence that the generationally cumulative and LNT-based assumptions underpinning Muller's genetic load hypothesis are not correct., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The present paper highlights numerous publications of Hermann J. Muller with a focus on his opinions concerning the validity of the linear no-threshold dose response model for hereditary and cancer risk assessment. These comments reflect a very consistent and powerfully supporting position for the LNT model. However, newly discovered correspondence between Muller and Robley D. Evans reveals that Muller was highly uncertain about the supportive science, and therefore hid his real opinions, deliberately misleading the scientific community and governmental agencies. Of further historical value is that in the correspondence with Evans, Muller proposed what might be the first articulation of an environmentally based Precautionary Principle. These perspectives have remained unknown since Muller requested Evans to keep this letter private., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This paper clarifies scientific contributions and deceptive/self-serving decisions of William L. Russell and Liane Russell that led to the adoption of the linear non-threshold (LNT) model for cancer risk assessment by the US EPA. By deliberately failing to report an extremely large cluster of mutations in the control group of their first experiment, and thereby greatly suppressing its mutation rate, the Russells incorrectly claimed that the male mouse was 15-fold more susceptible to ionizing-radiation-induced gene mutations as compared with fruit flies. This self-serving error not only propelled their research program into one of great prominence, but it also promoted the LNT-based doubling dose (DD) concept in radiation genetics/cancer risk assessment, by the US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel (1956). The DD concept became a central element in their recommendation that regulatory agencies switch from a threshold to an LNT model. This error occurred because of a decision by W. Russell not to report that a large cluster of control group mutations found in an experiment for which preliminary results were reported in 1951. This failure to report that cluster and similar clusters continued throughout the careers of the Russells, resulting in massive overestimation of low dose radiation risks supporting the LNT. The Russell database and the repeated claim that those data show that there is no threshold dose rate for mutation in irradiated mouse stem-cell spermatogonia, have provided mechanistic validation supporting the epidemiological LNT hypothesis for radiation-induced leukemias and cancers. This reanalysis supports the threshold model for both males and females, thereby rebutting epidemiological extrapolations from the NAS and EPA claiming support for the LNT hypothesis for cancer risk assessment. The implications of the Russell errors/deceptions, how/why they occurred, and their impact upon society are enormous and need to be addressed by scientific/regulatory agencies, affecting regulatory and litigation activities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This paper identifies the occurrence of six major conceptual scientific errors of Hermann Muller and describes how these errors led to the creation of the linear no-threshold (LNT) dose response historically used worldwide for cancer risk assessments for chemical carcinogens and ionizing radiation. The paper demonstrates the significant role that Muller played in the environmental movement, affecting risk assessment policies and practices that are in force even now a half century following his death. This paper lends support to contemporary research that shows significant limitations of the LNT model for cancer risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This paper provides historical review and evaluation of the development, adoption, and advocacy of the linear non-threshold (LNT) dose response model for cancer risk assessment as applied in practices and policies worldwide. It extends previous historical assessments and provides novel insights regarding: 1) how LNT bias became institutionalized in US governmental agencies, 2) how improper editorial practices at the journal Science promoted the adoption of LNT, 3) how a Nobel Prize winning scientist unjustifiably espoused and influenced support for replacing the threshold dose response model with the LNT model, 4) how the cover-up of striking and substantial experimental cancer data by US government scientists reduced support for the threshold dose response model at a critical period of cancer risk assessment policy adoption, and 5) how these events have negatively influenced cancer risk assessment practices and environmental and public health decisions for decades. These findings are presented to illustrate how profound and recognized mistakes, biases and unethical activities, inclusive of frank scientific misconduct, converged, and should motivate regulatory agencies worldwide to critically evaluate any existing policies that apply the LNT model as well as to serve as object lessons for current and future ethical conduct of research, and the provision of ethico-legal education in and across scientific curricula and institutions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This paper reports that William Russell, Oak Ridge National Laboratory (ORNL), conducted a large-scale lifetime study from 1956 to 1959 showing that exposure of young adult male mice to a large dose of acute X-rays had no treatment effects on male and female offspring concerning longevity or the frequency, severity, or age distribution of neoplasms and other diseases. Despite the scientific, societal and crucial timing significance of the study, Russell did not publish the findings for almost 35 years, nor did he inform governmental advisory committees, thereby significantly biasing decisions made during this period which supported the adoption of LNT for risk assessment. Of further significance, Arthur Upton, an ORNL colleague of Russell during this study and later Director of the US National Cancer Institute (NCI), was also fully knowledgeable of this study, its findings and its negative impact on the acceptance of LNT. Upton later worked along with Russell to publish these data (i.e., Cosgrove et al., 1993) to dispute the case-specific claim that children developed cancer because of the radiation exposure of their fathers as workers at the Sellafield nuclear plant. Thus, while Russell's data were available, but were not used to challenge the key radiation and leukemia paper of Edward B. Lewis, (1957) when LNT was being adopted by regulatory agencies, they were used in a major trial in the United Kingdom (UK) for the client (i.e., British Nuclear Fuels Plc) that hired Upton. While the duplicity of Russell's and Upton's actions is striking, the key finding of the present paper is that Russell and Upton intentionally orchestrated and sustained an LNT cover up during the key period of LNT adoption by regulatory agencies, thereby showing an overwhelming bias to enhance the adoption of LNT., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The reported untreated mouse control data from the Oak Ridge National Laboratory assessment of dominant damage (ADD) experiments demonstrate a strong negative correlation between body weight at 4, 5, 7, 9, and 11 weeks of age and number in litter at 3 weeks of age. Independently from the above finding, mother mice are also shown to differ substantially as to the mean weights of their litters. Much literature suggests that, as a general rule, (a) heavier mice are more likely to develop spontaneous and induced tumors earlier and (b) caloric restriction decreases body weights and tumor incidences and increases longevity. The above findings make it likely that many experiments that have been interpreted to demonstrate radiation-induced transgenerational carcinogenesis have instead merely illustrated a confounding effect of extensive induced dominant lethality. That is, because of induced dominant lethality, experimental groups contain heavier mice or rats, which accordingly develop more spontaneous tumors at a faster rate than control groups, with the increased tumor rates having nothing to do with induction of dominant tumor mutations. Our findings prompt suggestions as to possible modifications in the analysis and experimental design of such experiments.

Assessment-of-Dominant-Damage (ADD) experiments explored induction by proven specific-locus mutagens of dominant mutations that cause skeletal anomalies, cataracts, and stunted growth in offspring of mutagenized male mice. The data set reported here includes 6134 offspring. Mutagenic treatments included 600 R (i.e., approximately 6 Gy) of X-rays delivered in about 7 min, 600 R of gamma rays delivered over about 110 days, and four weekly intraperitoneal (i.p.) injections of 77.5 mg/kg of ethylnitrosourea (ENU). The results reported in this paper are restricted to mutations induced in stem-cell spermatogonia and to the 34 more common skeletal anomalies (i.e., those found in 0.5% or more of the control offspring). Mutation induction was demonstrated for eight anomalies in the acute X-ray experiment and for 17 anomalies (including those same eight anomalies) in the ENU experiment. In spite of the surprisingly high mutation rates found for these treatments, there was no hint of any induction of such dominant mutations by 600 R of chronic gamma radiation. Our results suggest that several anomalies related to variation in the sacralization pattern may be particularly useful for revealing induction of dominant mutations.

Germinal mosaicism is a well-established mechanism by which new spontaneous mutations enter the human population, but it is only rather recently that clusters of mutations arising in that way have been acknowledged and dealt with in specific-locus experiments on male mice. This paper reports the first cluster of germinal mosaic mutations to have been identified in experiments on the induction of dominant skeletal mutations. The mutation was detected in six offspring of a control male from the radiation part of an Assessment-of-Dominant-Damage (ADD) experiment. Reasons are provided to explain why this one litter of six mutants was excluded from the analysis of induction of dominant mutations causing the more common skeletal anomalies, which is reported in another paper. The effects of excluding this litter from that analysis are fully described. There is discussion of why such clusters should be included in some analyses but omitted in others. They should certainly always be reported because, in some cases, they can have a major impact on conclusions. Details on this one cluster of FCGM mutations provide numerous examples of how a dominant skeletal mutation that causes rare effects can also cause many of the more common anomalies.