Toxicology rewrites its history and rethinks its future: Giving equal focus to both harmful and beneficial effects

Abstract

Abstract-This paper assesses how medicine adopted the threshold dose-response to evaluate health effects of drugs and chemicals throughout the 20th century to the present. Homeopathy first adopted the biphasic dose-response, making it an explanatory principle. Medicine used its influence to discredit the biphasic dose-response model to harm homeopathy and to promote its alternative, the threshold dose-response. However, it failed to validate the capacity of its model to make accurate predictions in the low-dose zone. Recent attempts to validate the threshold dose-response indicate that it poorly predicts responses below the threshold. The long marginalized biphasic/hormetic dose-response model made accurate predictions in these validation studies. The failure to accept the possibility of the hormetic-biphasic dose-response during toxicology's dose-response concept formative period, while adopting the threshold model, and later the linear no-threshold model for carcinogens, led toxicology to adopt a hazard assessment process that involved testing only a few very high doses. This created the framework that toxicology was a discipline that only studied harmful responses, ignoring the possibility of benefit at low doses by the induction of adaptive mechanisms. Toxicology needs to assess the entire dose-response continuum, incorporating both harmful and beneficial effects into the risk assessment process. Environ. Toxicol. Chem.

Hormesis: why it is important to biogerontologists

“…The proximate mechanisms may be either ''receptor-or non-receptor'' based (Calabrese 2008a). The consistency of the quantitative features of the hormetic dose responses at the cell, organ and organismic level may be mediating the effects of upstream and highly conserved allometric gene clusters that control and direct the allocation of biological resources within complex biological systems (Calabrese 2011). At the evolutionary level, hormesis may be viewed as an adaptive response which mediates cellular stress involved in a plethora of preventive, reparative and signaling activities (Mattson and Calabrese 2010).…”

HORMESIS: A Fundamental Concept with Widespread Biological and Biomedical Applications

“…During this period, multiple large-scale efforts were made to create databases of hormetic dose responses using very rigorous a priori entry and evaluative criteria for the assessment of hormetic dose responses in the biological and biomedical literature [16,17,18,19,20]. In addition, detailed and systematic assessments were made of the history of the dose response to better understand the scientific development of dose response concepts and how judgements were rendered concerning which dose response models would be adopted by the scientific, medical and regulatory communities [9,21]. As a result of these efforts, it was learned that the biphasic dose response was commonly reported in the biological and biomedical literature, that it is highly generalizable, being widely reported in plants, microbes, invertebrates and vertebrates, including humans [15,22,23].…”

“…Hormesis has come to eventually replace the use of the earlier descriptive terms, probably because the Arndt-Schulz Law had its origins steeped in historical controversies between allopathic (i.e. now called traditional medicine) and the therapeutic practice of homeopathy [9,10], while Hueppe's Rule lacked the primacy of the Arndt-Schulz Law, reducing its acceptance.…”

Improving the scientific foundations for estimating health risks from the Fukushima incident

“…Added to this controversial use of LNT for carcinogen risk assessment by regulatory and public health agencies worldwide are recent revelations that this model became incorporated into regulatory use in the 1950s as a result of ideological motivations and manipulations of the scientific literature at the highest possible levels. Such manipulation of the risk assessment process has now become codified in most regulatory agencies (17)(18)(19). Objective attempts to resolve such contentious historical and scientific disputes are critical to issues made even more urgent by the Fukushima incident.…”