Summary and Comments

Charles A. Waldren, Ph.D.

Email: Cwaldren@cvmbs.colostate.edu

The authors of these six papers* provided interesting and thoughtful answers to five questions concerning adaptive response (AR) and hormesis elicited by ionizing radiation (IR). The questions were: (1) How does the dose that induces AR relate to human and environmental (ecological) exposure? (2) What are the potential up- and down-sides of having one's adaptive response induced. (3) Can the adaptive response be manipulated for medical and other benefits? (4) How does the adaptive response relate to the concept of hormesis?, and (5) Should knowledge of the adaptive response affect current risk assessment methods for carcinogenesis?

The consensus response to Question #1 was that doses known to induce the adaptive response (a few cGy delivered acutely or over a few hours) are several orders of magnitude higher than those likely to be encountered by most humans via acute exposures, and are, in fact, about equal to the average human life-time exposure. These doses are, therefore, irrelevant to induction of AR. Regarding Question #2 Up and down side of AR stimulation and Question #3, can AR simulation be manipulated for medical & other benefits? The upside most mentioned was possible protection against radiation-induced tumors: the down side was that long-duration AR, if such existed, might protect tumors against eradication by radiation therapy. But the underlying theme in the responses to these two questions, and the others as well, was that much more knowledge of genetic mechanisms is needed before the effects of AR stimulation can be accurately predicted. Question #4 (relationship of AR to the concept of hormesis). [Stebbings defined hormesis, as the stimulatory effects caused by low levels of potentially toxic agents (1)]. The general feeling was that AR and hormesis could have common features and mechanisms but what these might be can be determined only by continued detailed studies of the mechanisms that underlie AR and hormesis. These authors largely agreed that while there is substantial evidence for the existence of radiation hormesis , including features of certain dose response curves and epidemological studies, it suffers from an almost complete lack of mechanistic understanding. So while the consensus was that radiation AR response has been demonstrated beyond dispute (but not at all understood mechanistically), the majority view was that hormesis is a fascinating concept with tantalizing and highly important implications for radiation risk assessment, which will remain only a concept until its underlying mechanisms are elucidated. Question #5: Should AR affect current risk assessment methods for carcinogenesis? Opinion was split on this important issue. Cai and Ikusshima argued that the case for AR effects is so compelling that the linear, non-threshold dose response model should be reconsidered immediately. Olivieri, Rigaud, Skov and Mossment, on the other hand, felt strongly that changes in policy should not be made until reasonable progress has been made in unraveling mechanisms underlying AR. The majority point of view was summarized by Mossman & Ledesma : "Although adaptive response is well chronicled, its relevance to radiogenic cancer risk in humans remains uncertain," and by Skov "(We) do not know enough about AR (or hormesis) to modify the entire set of guidelines."

The latter two view points seem to me the more prudent since it is clear that while low doses can ameliorate the genotoxic effects of subsequent larger doses, they can, on the other hand, also induce chromosome aberrations and other kinds of mutations that could well be carcinogenic. For example, 10 cGy of gamma irradiation clearly induces mutations and chromosome aberrations (2,3) and the lowest possible "dose" of alpha radiation, one a particle traversal through the nucleus (4) or the cytoplasm (7), is highly mutagenic. To quote Olivieri: "The current state of understanding requires an open mind in designing and interpreting new experiments."

So, despite much hard work by many talented investigators, the situation is not much different than that enunciated by Loken & Feinendeger (5) who said in 1993: "Because of the strong scientific evidence in support of radiation hormesis, we can no longer ignore this concept. There is, however, need for additional carefully documented investigations in selected biological systems .....if the matter of radiation hormesis is to be settled once and for all." These considerations pertain to AR as well.

A question that might profitably have been explicitly asked was: What experimental approaches should be employed to shed light on mechanisms controlling AR and which could provide guidance in attempts similarly to understand regulation of hormesis? An example of such an approach would be to build on prodecures used to understand adaptive responses induced by alkylating agents by exploiting cells from certain humans (6) and rodents in which AR can not be induced. These "mutant" cells could be transfected with a human cDNA library and transformants selected in which AR now occurred. Genetic and biochemical characterization of the transformants and their transforming gene(s) would be a step toward a mechanistic understanding of AR and perhaps of hormesis as well.

Footnotes

REFERENCES

1. A.R. Stebbing, Science of the Total Environment 22, 213 (1982).

2. C. Waldren, T.T. Puck, Somat.Cell Mol.Genet. 13, 411 (1987).

3. T.T. Puck, R. Johnson, P. Webb, G. Yohrling, Somat.Cell Mol.Genet. 24, 1 (1998).

4. T.K. Hei, et al, Proc. Natl. Acad. Sci.USA 94, 3765 (1997).

5. M.K. Loken, L.E. Feinendegen, Investigative Radiology 28, 446 (1993).

6. A. Bosi, G. Olivieri, Mutation Res. 211, 13 (1989).

7. T. K. Hei, et al, Proc. Natl. Acad. Sci., In Press (1999).