Hormesis, biological plasticity, and implications for clinical trial research

Edward J Calabrese; Peter Pressman; A Wallace Hayes; Gaurav Dhawan; Rachna Kapoor; Vittorio Calabrese; Evgenios Agathokleous; Ivo Iavicoli; James Giordano

doi:10.1016/j.arr.2023.102028

Hormesis, biological plasticity, and implications for clinical trial research

Ageing Res Rev. 2023 Sep:90:102028. doi: 10.1016/j.arr.2023.102028. Epub 2023 Aug 6.

Authors

Edward J Calabrese¹, Peter Pressman², A Wallace Hayes³, Gaurav Dhawan⁴, Rachna Kapoor⁵, Vittorio Calabrese⁶, Evgenios Agathokleous⁷, Ivo Iavicoli⁸, James Giordano⁹

Affiliations

¹ Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA. Electronic address: edwardc@schoolph.umass.edu.
² University of Maine, 5728 Fernald Hall, Room 201, Orono, ME 04469, USA.
³ Center for Environmental Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, USA.
⁴ Stantec (ChemRisk), Boston, MA, USA.
⁵ Saint Francis Hospital and Medical Center, Hartford, CT, USA.
⁶ Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Via Santa Sofia 97, Catania 95123, Italy.
⁷ Department of Ecology, School of Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing 210044, China.
⁸ Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy.
⁹ Departments of Neurology and Biochemistry, and Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington, DC 20007, USA.

PMID: 37549872
DOI: 10.1016/j.arr.2023.102028

Abstract

The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity.

Keywords: Clinical trial; Dose response; False negative; Hormesis; Limits of epidemiology; Weight-of-evidence.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Clinical Trials as Topic*
Hormesis*
Humans

Grants and funding

UL1 TR001409/TR/NCATS NIH HHS/United States