The hormesis concept holds that low doses of toxic substances and radiation elicit modest biological responses opposite to those caused by higher doses of the same agents. This concept stands in contrast to the prevailing views that a threshold model predicts most responses to toxicants at low doses and that linear extrapolation best predicts mutagenic and carcinogenic responses. Beyond the scientific considerations, there has been concern that inclusion of the hormesis model in risk assessment would raise complex ethical questions, pose serious challenges for policy makers, and threaten public safety. This article briefly reviews the growing evidence for hormesis and offers a perspective on the related ethical and societal issues. Complexities stem from the nature of biphasic curves, in which biological responses fall both above and below background levels. The monotonic responses of the threshold and linear models lend themselves to a single policy objective – avoiding harm associated with exposures. The biphasic responses of the hormesis model, however, suggest the possibility of accruing benefit as well as avoiding harm. The prospect of applying the hormesis model to public health policy is impeded by insufficient ability to identify the hormetic and toxic zones with precision. Moreover, heterogeneity among individuals in susceptibility to toxicants suggests that benefit and risk may be distributed unequally in the population. The potential shift in policy objectives associated with hormesis is considered relative to the difficulty of balancing the ethical principles of nonmaleficence and beneficence while maintaining a higher priority on the former.
The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of genetic damage in a wide variety of assays. The radioprotectors cysteamine (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in Go human lymphocytes. By contrast, WR-1065 is reported to reduce the induction of hprt mutations by BLM in Chinese hamster cells. To elucidate the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yeast Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependent increase in the frequency of mitotic gene conversion and gene mutations. Unlike its potentiation of BLM in Go lymphocytes, WR-1065 protected against the recombinagenicity of BLM in yeast. CSM was also strongly-antirecombinagenic under, some conditions, but the nature of the interaction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygen-rich conditions CSM potentiated the genetic activity of BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-induced damage. Aminothiols may potentiate the effect of BLM by acting as an electron source for the activation of BLM and/or by causing conformational alterations that make DNA more accessible to BLM. The results indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreover, the modulation differs markedly depending on physiological conditions. Thus, yeast assays help to explain why aminothiols have been observed to potentiate BLM in some genetic systems and to protect against it in others.
Dimethylsulfoxide (DMSO) and WR-1065 are radioprotectors, in that they reduce the effectiveness with which ionizing radiation causes genetic damage. Unlike their protective effects with radiation, these agents potentiate the induction of micronuclei by bleomycin in the cytokinesis-block assay in G0 human lymphocytes. High concentrations of DMSO (1 M) are required to cause potentiation. In contrast, WR-1065 causes dose-dependent potentiation at relatively low concentrations (1.25 to 10 mM). Cytogenetic analysis supports the results from the micronucleus assay, showing higher levels of genetic damage induced by the combination of bleomycin with DMSO or WR-1065 than by bleomycin alone. Possible mechanisms of potentiation are proposed.
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