Flaws in the LNT single-hit model for cancer risk: An historical assessment

Attached is the latest in a series of publications by Ed Calabrese, clarifying how the erroneous Linear No-Threshold (LNT) Model had become entrenched in all laboratory-animal chronic cancer and toxicity studies performed during the past 5-6 decades. This story strikes near-and-dear to my heart because Ernst Caspari was my genetics mentor at Wesleyan University; Professor Caspari never revealed to me all the details, but implied that “not all radiation-mutation data from past decades can be trusted.”

In 1946, the young geneticist Ernst Caspari reported to his supervisor, Curt Stern, that his experiment on gamma-ray-induced mutations in Drosophila had produced results that neither scientist had anticipated. Caspari had fully expected to replicate the 1944 study of Ray-Chaudhuri who had shown that total X-ray/gamma-ray dose was the best predictor of mutational events in mature Drosophila spermatozoa. To corroborate the 1944 study was important, because it would confirm evidence that the dose-response for ionizing radiation-induced mutations was cumulative, irreversible, independent of the dose-rate, and linear at low doses. However, in contrast to Ray-Chaudhuri’s earlier results, Caspari found that the dose-rate (rather than the total dose) determined the dose-response and that –– for a sufficiently low dose-rate –– no response could be detected. Caspari’s data revealed an apparent threshold response for gamma-ray-induced mutations.

The Caspari studies were part of the Manhattan Project and, as such, were generally stronger scientifically than those of most independent, single researchers –– including the studies of Ray-Chaudhuri. For example, as compared to the Ray-Chaudhuri study, the Caspari study had a more robust design, used larger numbers of flies, exerted superior oversight and guidance, applied better quality control, and assessed a notably lower dose and dose-rate, among other factors. The Caspari findings produced considerable alarm and concern throughout the radiation genetics community fearing now that the LNT single-hit model might not replace the currently accepted threshold doseresponse model.

One especially succinct and notable response came from Milisav Demerec who asked Caspari, “What can we do to save the one-hit model?” The above cited papers document prestigious members of the radiation geneticist community –– including a Nobel Laureate, and an expert Genetics Panel of the U.S. National Academy of Sciences, who saved the “hit” model by obfuscating, deceiving and misrepresenting the scientific record. Sadly, these ideologically based and scandalous manipulations of the scientific record proved highly successful; they quickly infiltrated and affected the highest levels of regulatory policy in the US Government, where they still remain in place today.

The attached paper examines a surprisingly under-researched and critical aspect of the cancer risk assessment process by seeking answers to the following questions: [a] what was the genesis of the LNT Single-hit Hypothesis, [b] what was its scientific basis, and [c] how and when was itvalidated? To address these questions it is necessary to re-examine the discovery of X-ray-induced heritable mutations by Hermann J. Muller, to assess the scientific validity of Muller’s findings and interpretations, and, finally, to understand how the scientific community reacted to and accepted Muller’s personal account of his results. Acceptance by the scientific community essentially affirmed a biological basis for the Single-hit Model and, at the same time, reassured the public of its “legitimate” use in cancer risk assessment for decades to come.

Lewis J. Stadler, a plant geneticist of comparable standing to Muller within the radiation geneticist community, challenged Muller’s 1927 claim of having induced gene mutations with X-rays and, as a result, initiated a fierce data-driven debate that only ended much later with he 1954 death of Stadler. Although Muller’s views would eventually predominate, the experimental data and arguments offered by Stadler were formidable. The 25-year Muller-Stadler debate generated a unique scientific record that has never been used to re-evaluate the LNT single-hit model and, therefore, validate its application in the process of cancer risk assessment; this is quite astonishing –– considering that the LNT single-hit model would emerge primarily from the decades-long Muller-Stadler debate. Although Muller’s views eventually prevailed, the questions raised herein are why they prevailed, should they have prevailed and, if not, then what does this mean for us today? This assessment concludes that the arguments of Stadler were based on stronger data and were more scientifically persuasive than were Muller’s. Yet, in spite of Stadler’s superior arguments, his views would show little penetration and have no impact today on risk assessment policy.

Detailed evaluations by Stadler over a prolonged series of investigations revealed that Muller’s experiments had induced gross heritable chromosomal damage –– instead of specific gene mutations, as had been claimed by Muller in his Nobel Lecture. These X-ray-induced alterations became progressively more frequent and were of larger magnitude (more destructive) with increasing doses. Thus, Muller’s claim of having induced discrete gene mutations represented a substantial speculative overreach and was, in fact, without proof. The post hoc arguments of Muller to support his gene mutation hypothesis were significantly challenged and weakened by a series of new findings in the areas of cytogenetics, reverse mutation, adaptive and repair processes, and modern molecular methods for estimating induced genetic damage. These findings represented critical and substantial limitations to Muller’s hypothesis of X-ray-induced gene mutations.

Furthermore, they challenged the scientific foundations used in support of the LNT single-hit model by severing the logical nexus between Muller’s data on radiation-induced inheritable alterations and the LNT single-hit model. These findings exposed fundamental scientific flaws that undermined not only the seminal recommendation of the 1956 BEAR I Genetics Panel to adopt the LNT single-hit Model for risk assessment but also any rationale for its continued use today..!!

Environ Res July 2o17; 158: 773-788


Env Res threshold v LNT Pa~1.pdf‎ (123 KB‎)[Open as Web Page]; Env Res threshold v LNT- P~1.pdf‎ (2 MB‎)[Open as Web Page]

For those who wish to read even more about the “power politics” involved in pushing through the Linear No-Threshold Model –– despite the lack of sufficient scientific evidence to confirm the LNT Model –– attached are two more recent publications. These represent “additional nails in the coffin.”

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