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September 2022

Drug Metab Rev. 1988 ; 19(2): 195-229.

Hormesis, Gompertz functions, and risk assessment.

Boxenbaum H, Neafsey PJ, Fournier DJ.

Drug Metabolism Department, Merrell Dow Research Institute, Cincinnati, Ohio 45215-6300.

A historical survey of the literature indicates that benefits derived from low doses of toxic substances have been reported over many centuries. Hippocrates, Paracelsus, Arndt, Schulz, and Hahnemann (founder of homeopathy) have all reported that low doses of toxic substances may be "stimulatory" or otherwise beneficial. Assessment of mortality data from modern-day bioassay studies indicates that low-dose animal exposure to a variety of toxic agents can, through an unknown mechanism, also induce beneficial changes which promote health and prolong life (longevity hormesis). This nonspecific and apparently reversible phenomenon has been modeled kinetically through use of age-specific mortality rate and a generalized Gompertz function; the basic assumption is that mortality in an interval is a function of the weighted sum of intensities of physiologic injury during that interval. It was assumed that longevity-enhancing hormetic reduction in population injury may be decremented from life-shortening injury produced through the aging process and concomitant toxicity. At low exposure levels, a net reduction in age-specific mortality rate can sometimes be observed. The implications for risk assessment are significant. It is tacitly assumed in generating virtually all estimates of risk that toxic manifestations observed at higher doses are the sole effects elicited at lower doses. This appears to be qualitatively incorrect.

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