Historical Foundations of the Linear Non-Threshold Dose Response Modle for Cancer Risk Assessment was presented by Dr. Edward J. Calabrese (Ph.D.), Professor of Toxicology of University of Massachusetts. edwardc@schoolph.umass.edu The 32nd Annual Meeting of the Japanese Society for Radiation Oncology was held at Nagoya on November 21-23, 2019.
The story of the dose response in biology and medicine seems like it should be simple and straight-forward. Yet, it is far from either, displaying a series of remarkably unique historical stages with each being controversial and highly contentious, in a struggle that has always been about what is the nature of the dose response in the low dose zone. It remains a problem yet to be resolved scientifically and/or politically and is still the object of Congressional Hearings in the United States Senate as recent as the fall of 2018 (Calabrese,
2018a).
With the emergence of the “modern” scientific era starting about 1880, the dose response concept found itself at the center of a war that would last almost another 50 years over who provides and controls medicine, its practice and drug enterprises. The battle
was between homeopathy, a once powerful entity, and what would become modern Western traditional medicine (EJ Calabrese, 2005; Calabrese, 2011a). The dose response concept would later become a central player for low dose radiation risk assessment in
the Manhattan Project when the United States produced the atomic bomb in World War II (Calabrese, 2011b) and in the subsequent high stakes game of above ground testing of nuclear weapons with worldwide radionuclide contamination. The dose response issue then quickly became the centerpiece of contemporary environmental risk assessment, being born again in the aftermath of Rachel Carson’s legendary book, Silent Spring. It is now renewing itself yet again, this time in the world of novel bio-pharmaceuticals and traditional herbal/Asian medicinal treatments that are being incorporated into modern Western medicine and lifestyles in an effort to enhance healthy aging.
However, there have been major episodes, or stages in the history of the dose response and multiple battles fought over the nature of the dose response in the low dose zone, affecting careers, national economies, health and safety regulations, the testing of chemicals and drugs and whether, if and when neuron saving drugs will transform human health.
Hormesis became significant the hard way, it was a concept that was the target of historical antipathies between homeopathy and what is now call traditional medicine. The discoverer of hormesis, Hugo Schulz, made a terrible historical blunder by claiming that his biphasic dose response provided the explanatory principle of homeopathy. Given that homeopathy was profoundly defeated in this economic and scientific battle by traditional medicine the hormetic-biphasic dose response had a decidedly disastrous entry into the scientific world. In fact, traditional medicine would never ease up on the opposition and neither homeopathy nor medicine could discern what hormesis was, how to study it and wherein its value might lie. It became an orphan dose response concept with an unrelenting enemy who nevertheless had long forgotten what the fight originally was about or that there actually had been a fight.
This lack of historical understanding (and memory) has ironically made the hormetic dose response challenge even more difficult to resolve. Thus, the road to significance for hormesis was unique, unfair, unpredictable and yet nonetheless, almost inevitable since science would be forced to eventually assess low doses and evolutionarily based adaptive responses. Thus, hormesis was marginalized for a long time but never knocked out as scattered researchers continued to report hormetic responses in a haphazard fashion while failing to understand its importance.
It took about 30 years from the time of the last hormesis failed resurgence (i.e., the Luckey/Stebbing attempt) for the significance of hormesis to be revealed by scientific findings and massive efforts to integrate this information in the presence of an overwhelmingly skeptical and often hostile and certainly data censored/brainwashed scientific, public health, medical, and regulatory agency communities. This time the science was sufficient and the strategy and tactics able to demonstrate the biological reality of hormesis, its generality, dose responses features, underlying mechanisms, vast practical applications, and superiority over the threshold and linear dose response models.
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