Adaptive Response and Its Relationship to Hormesis and Low Dose Cancer Risk Estimation

Gregorio Olivieri, Ph.D.

Instituto di Genetica

Dip. to Genetica e Biol Molec.

Universita' di Roma La Sapienza

P. le Aldo Moro 3

Italia 00185, Roma, Italy

Tel: 06-49-912-470

Fax: 06-44-568-66



In introducing my presentation I wish to state that I shall be dealing specifically with the adaptive response (AR) to low doses of ionizing radiation (IR). There are analogies between AR to IR and that after exposure to chemical mutagens and carcinogenic agents or various types of stress. This has been demonstrated among other things by the occurrence of cross-adaptation phenomena (Wolff et al., 1988; Vijayalaxmi and Bukart, 1989) and by the fact that the cascade of events underlying the various AR go through several common stages. Nevertheless, in my opinion, it is more useful to separate the treatment of AR to IR in view of several characteristics possessed by the latter, namely: their background presence in the environment which cannot be eliminated under normal conditions; the long coexistence of living matter with IR, which has necessarily affected its evolution; the easy dosimetry and extensive information gathered on IR; its usefulness and economic impact in medicine, industry, etc.

1. The doses used to induce AR experimentally are usually in the range of 1-2 cGy. Doses of 0.1 to 10 cGy have also been used. The doses are generally administered in an acute fashion at a variable dose rate that however usually exceeds 20 cGy/minute. These doses can thus not be compared with that of natural background exposure. They may be compared only to the doses used in a number of diagnostic tests. However, even though the doses usually used to induce AR are of a different order of magnitude, the fact remains that cohorts of individuals after chronic overexposure to occupational doses at a low dose rate have been described whose lymphocytes treated in vitro show signs of the presence of an AR (Tuschl et al., 1980; Barquinero et al., 1996; Gourabi and Mozdarani, 1998). The results obtained in other cases of overexposure other than occupational exposure are not always in agreement (Tedeschi et al., 1996; Pelevina et al., 1997). In some cases, however, such as individuals exposed to the Chernobyl incident, it is difficult to assess the conditioning dose. In other cases, it is difficult to establish the boundary between AR and hormetic phenomena (Kondo, 1993; Cohen, 1995).

It is thus conceivable that the underlying mechanisms of AR observed in vitro differ in some respects from the situation observed after chronic exposure to a very low dose rate. It must be born in mind that the AR observed in vitro is a transient phenomenon that persists after induction for only a limited number of cell divisions (Shadley et al., 1987) and that, in the course of conditioning treatment in vitro, both the overall dose and the dose rate were found to be critical (Shadley and Wiencke, 1989).

2. In my opinion the potential associated with AR will be understood only when the underlying mechanisms of this phenomenon have been grasped more fully. In other words, it is necessary to understand more clearly which sensors are activated by the conditioning dose, the cascade of events leading to the modulation of the activity of certain genes, the duration of this modulation and the function of the induced proteins, as well the relations between this cascade of events and other inducible responses to DNA damage, such as apoptosis, the activation of cell cycle checkpoints and "induced radioresistance" (Joiner et al., 1996). Only when these phenomena have been fully understood will it be possible to have a clear idea of the positive and negative potential of AR.

3. The preceding section applies also the use of AR in medicine and in the sector of protection. It must not be overlooked in this connection that AR has been observed also in the case of germ cells (Cai and Wang, 1995). Indeed the stimulation of certain genes may be exploited in the medical field or in other sectors provided that it is fully understood which genes are actually involved and the functions they control.

4. The phenomena associated with AR are, in my opinion, closely linked to hormetic phenomena. AR may be viewed as a special hormetic response: in other words, in addition to the effect of a low dose on growth, development, reproduction, etc. we must consider also the stimulating action on cell defences against any subsequent mutagenic treatment. Underlying all this is probably the same stimulating action as is postulated in hormesis on certain genes which may have a knock-on effect on physiological phenomena such as the former, as well as on such an exceptional event as exposure to high doses of a mutagen. What AR and hormesis have in common and which represents a new and very important acquisition in biology is the fact that low doses (specifically?) modulate the action of certain genes. It is on this extremely important acquisition that we must base all our considerations and experimental activity in this field.

5. AR has been investigated ever since its discovery above all with regard to the endpoints associated with genetic damage. Some evidence is now available concerning cell transformation as well (Azzam et al., 1996; Redpath and Antoniono, 1998). If we accept that acute or chronic exposure to a mutagen, in this case IR, can condition the subsequent response to the same or another mutagen, and that in any case such a conditioning exposure (temporarily?) modulates the activity of certain genes, we must also accept several implications concerning the evaluation not only of the genetic risk but also the carcinogenic risk due to small doses of IR or chemical carcinogenic agents. The likelihood of low doses having a different action from that which may be extrapolated from high doses (Sugahara, 1997) must, in my opinion, be accepted by the biologist in order to enable experimentation to be performed that does not exclude a priori any of the possible results. It therefore becomes necessary: a) to examine with an open mind the results referring to every point on the dose effect curve, paying special attention to the lower doses, and thus design experiments that take this situation into account (Calabrese and Baldwin, 1998), b) to investigate with particular thoroughness the action of these low doses, taking into account all the implications of any effects they may have. These effects may be positive, in the sense of improving the response to any subsequent exposure, thereby reducing the risks thereof; it is however necessary to examine carefully also other possibilities that imply further study of the mechanism of action of the conditioning treatment. In this connection, it should be pointed out that cases of synergism have been described between the first treatment and the subsequent ones (Wolff et al., 1988; Olivieri et al., 1994; Sasaki, 1995) and that considerable inter-individual variability has been observed in the human species also as far as AR is concerned (Olivieri and Bosi, 1990; Vijayalaxmi et al., 1995).


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