Radiation Exposure and Adaptive Processes

Kenneth L. Mossman, Ph.D. and Linda M. Ledesma

Arizona State University

Office of Radiation Protection

Tempe, AZ 85287-2701

Tel: (602) 965-0584/6140

Fax: (602) 965-6609

Email: ken.mossman@asu.edu



When cells are first exposed to a small dose of radiation and then to a larger dose a few hours later, the biological response may be less than if the cells were exposed to the larger dose alone. This adaptive response was first described by Olivieri et al. (1984) for radiation-induced chromosomal aberrations in human lymphocytes. Adaptive processes have since been demonstrated for a wide variety of endpoints including carcinogenesis (reviewed in UNSCEAR, 1994). Ionizing radiation, including x rays and g rays, produce biological damage by the formation of ions and free radicals as a consequence of energy absorption by biological material. Unlike toxic chemicals, ionizing radiation produces damage randomly and does not target specific molecules in cells. Damage to DNA (produced by direct action or by indirect action via aqueous radiolytic products) is a key step in mutagenesis, carcinogenesis, and cell lethality. The adaptive response is one of several cellular processes that can repair damage to DNA.

"Adaptive response" may be defined as the induction of repair by small doses of radiation. Operationally, adaptive response is the decrease in biological effect when a radiation "test" dose is preceded by a small "conditioning" dose by several hours. The nature of the molecular "lesion" or its repair cannot be discerned from such experiments. However, adaptive processes in human lymphocytes appear to be enzymatically mediated by the repair enzyme poly-ADP-ribose polymerase since the effect may be prevented by treating cells with 3-aminobenzamide, an inhibitor of poly ADP-ribosylation (Wiencke et al., 1986). In addition to DNA repair, adaptive processes have also been associated with stimulation of cellular proliferation, enhancement of immune responses, and reduction in mortality from infectious diseases (UNSCEAR, 1994).

The adaptive response apparently occurs only under specific experimental conditions. Conditioning doses in the range of a few tens of milligray1 delivered at a dose rate of at least 50 mGy/minute are required to elicit the response. Test doses greater than 500 mGy are also required. Even if the conditioning dose is adequate, test doses less than 500 mGy do not produce the adaptive response. Furthermore, the effect appears to last no more than a few hours; if the test dose follows the conditioning dose by more than about 6-10 hours, the adaptive response is extinguished (UNSCEAR 1994).

1. How does the dose that induces the adaptive response relate to human and environmental (ecological) exposures?

Radiation doses that induce adaptive responses in experimental systems are in the range of a few tens of milligray (UNSCEAR, 1994). Accordingly, adaptive processes are probably not induced by the natural background or by exposures in occupational settings because average doses are in the range of a few mGy per year and are delivered at dose rates much lower than 50 mGy/minute (Table 1). The entire population is exposed to natural background radiation including cosmic rays and radiation emanating from terrestrial radionuclides. Inhaled radon gas is the single largest source of natural background radiation. Significant numbers of individuals are exposed to various occupational sources in addition to the natural background. The largest group is medical workers. However, only workers in the commercial nuclear power industry get an average annual occupational dose that exceeds the annual dose from natural background.

Even if environmental or occupational exposures were large enough to induce the adaptive response, the effect is not likely to be observed because it only occurs following relatively large "test" doses of 500 mGy and higher (UNSCEAR 1994). Test doses below 500 mGy either do not produce the adaptive response, or current experimental methods are not sensitive enough to detect the small changes in response reflective of adaptive processes. There are no occupational exposure settings that would result in such large exposures because of regulatory limits on occupational exposure. In unusual circumstances, radiation accidents may result in large enough doses to produce adaptive responses. For instance, it has been estimated that about 115,000 persons were exposed to doses up to 250 mGy following the 1986 Chernobyl nuclear accident (UNSCEAR 1993). There have been no published studies suggesting that adaptive responses occurred in this or other exposed populations.





2. What are the potential up and down sides of having ones adaptive response induced?

It is unclear what the potential benefit may be of exposing individuals to small doses of radiation (a few tens of milligray) in order to elicit the adaptive response. Although adaptive responses may be a common feature of cellular response to damage (UNSCEAR, 1994), there is no firm evidence that adaptive processes reduces health risks from exposures to low doses of radiation. Further, adaptive processes appear to be highly transient. The adaptive response lasts no more than a few hours following conditioning dose exposure (UNSCEAR 1994).

There is also little evidence that the small conditioning doses of radiation needed to elicit the adaptive response increase the risk of cancer or other detrimental health outcomes. Nevertheless, current radiation protection standards and practices are based on the premise that any dose, no matter how small, can result in detrimental health effects. Accordingly, individuals should not be exposed to small doses of radiation for the purposes of inducing adaptive processes, if there is no benefit regardless of the magnitude of the risk.

3. Can the induction of adaptive response be manipulated for medical and other beefits?

The idea of inducing adaptive processes for medical benefit is intriguing particularly in the context of cancer radiotherapy. Radiation therapy plays a major role in the treatment of cancer patients. More than half of all cancer patients (about 500,000 per year) will require radiation therapy during their management (Cumberlin et al., 1989).

In external beam radiotherapy patients are typically given daily doses of 2 Gy to the tumor to a total dose up to 70 Gy depending on the type and site of the cancer. The fractionated treatment regimen takes advantage of the greater repair capability of normal tissues compared to that of the tumor. Theoretically, the effectiveness of the therapy (measured by the therapeutic ratio) may be enhanced by increasing this difference in repair capacity.

On its surface, stimulating adaptive processes in normal tissues would appear to be feasible. A few hours prior to the daily treatment the patient would be given a small conditioning dose of radiation to stimulate adaptive processes in the diseased area. The daily treatment dose (~2 Gy) would be high enough to produce the adaptive response. However, it would be difficult to avoid stimulating adaptive processes in the tumor because it is surrounded by healthy normal tissue.

Unless adaptive processes could be induced in normal tissue and not in the tumor, there would be little clinical advantage. It should be emphasized that the adaptive process is a laboratory phenomenon and has not been demonstrated in the clinical setting. Adaptive responses occur when clearly defined conditions of controlled doses and time restraints are met (UNSCEAR , 1994).

4. How does the adaptive response relate to the concept of hormesis?

Adaptive response is a repair phenomenon resulting in a diminution of radiation damage (e.g., chromosomal aberrations) but usually not below levels that occur spontaneously. High "test" doses (often > 1 Gy) are necessary in order to observe a reduction in measurable radiation damage when adaptive processes are induced (UNSCEAR, 1994).

Hormesis may be defined as stimulation (beneficial effects) by low doses followed by inhibition (detrimental effects) by higher doses (Stebbing, 1982). Radiation hormesis has been observed in some experimental settings in which small doses (usually <100 mGy) result in a reduction of harmful effects below spontaneous or background levels (e.g. cancer rates are lower than in unexposed groups).

Figure 1 distinguishes hormesis and adaptive response. Hormesis occurs following small doses of radiation (usually <100 mGy) and results in a reduction in the incidence of health outcomes found in unexposed groups. Adaptive processes may be induced by small doses of radiation similar to doses causing hormesis, but the adaptive response cannot be observed unless a large test dose (usually >500 mGy) is given within a few hours of the conditioning exposure.



Figure 1. Idealized curves for the adaptive response and hormesis. Relative risk (RR) is plotted against total radiation absorbed dose. The line at RR=1 indicates no radiation effect. Below the line radiation responses are beneficial; above the line effects are detrimental. Curve "A" represents hormesis. Hormesis predicts the existence of a "threshold "dose below which radiation effects are beneficial. Curve "B" is the linear no-threshold model. Curve "C" is the adaptive response defined as a reduction in radiation effects compared to effects predicted by the linear no threshold model when a test dose(>0.5 Gy) is preceded by a relatively small conditioning dose.

Stimulated cell repair processes induced by small conditioning doses of ionizing radiation may reduce the risk of carcinogenic effects (UNSCEAR, 1994). If adaptive response reflects enhanced repair of DNA damage, it may be an important mechanism in radiation hormesis. However, it is unclear whether the natural incidence of cancer and other detrimental health outcomes can be reduced by adaptive processes since they currently cannot be measured in the dose range associated with hormesis.

5. Should a knowledge of the adaptive response affect current risk assessment methods for carcinogens?

Although the adaptive response has been well-characterized in mammalian cell culture systems, its relevance to radiogenic cancer risk in humans remains uncertain. There is no evidence to support the assumption that adaptive processes influence radiogenic risk. However, maintenance and repair of DNA are important in reducing cancer risk as demonstrated in several human diseases including xeroderma pigmentosum, Bloom's syndrome, Fanconi's anemia, and ataxia telangiectasia (AT). A common feature of these diseases is a heightened risk for cancer and an abnormally high rate of genetic damage in affected individuals. AT is a particularly interesting disease because it is also characterized by increased radiosensitivity. The AT gene may be found in approximately 1% of the population but may be present in 9-18 % of persons with breast cancer in the U.S. (Swift et al., 1991). Although yet to be confirmed, this finding suggests that cancer is not homogeneously distributed within the population but appears to be clustered in predisposed subgroups.

Although adaptive processes do not appear to influence radiogenic risk, further study of the phenomenon is warranted nonetheless. Current estimates of radiation risk are based on epidemiological studies of humans exposed to relatively high doses of radiation. Little direct evidence of risk is available at low doses because of the limited statistical power of epidemiological studies in the low dose range. Molecular biology studies and studies of DNA repair including adaptive processes may be important in identifying unique biomarkers of radiogenic disease and in clarifying the magnitude of radiation risk at low doses.



Footnotes

1 Radiation units used in this article are defined as follows: Absorbed dose is the radiation energy absorbed per unit mass. The unit of absorbed dose is the joule per kilogram with the special name "gray." 1 Gy is equal to 1000 milligray (mGy). The weighted absorbed dose, to account for differences in biological effectiveness of various ionizing radiation types, is termed equivalent dose. The unit of equivalent dose is the joule per kilogram with the special name "sievert." 1 Sv is equal to 1000 millisievert (mSv). For the purposes of this article, Sv and Gy may be considered equivalent.



REFERENCES

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National Council on Radiation Protection and Measurements (NCRP). Exposure of the Population in the United States and Canada from Natural Background Radiation. NCRP Report No. 94. Bethesda, MD: NCRP; 1987.

National Council on Radiation Protection and Measurements (NCRP). Exposure of the U.S. Population from Occupational Radiation. NCRP Report No. 101. Bethesda, MD: NCRP; 1989.

Olivieri, G., Bodycote, J., Wolff, S. Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science 233: 594-597; 1984.

Stebbing, A.R.D. (1982). Hormesis-The stimulation of growth by low levels of inhibitors. Sci. Total Environ. 22: 213-234.

Swift M., Morrell D., Massey R.B., Chase R.L. Incidenceof cancer in 161 families affected by telangiectasia. New England Journal of Medicine 325: 1831-1836; 1991.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and Effects of Ionizing Radiation, UNSCEAR 1993 Report to the General Assembly, with Scientific Annexes. New York: United Nations, 1993.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and Effects of Ionizing Radiation, UNSCEAR 1994 Report to the General Assembly, with Scientific Annexes. New York: United Nations, 1994.

Wiencke J.K., Afzal V., Olivieri G., Wolff, S. Evidence that the [3H] thymidine-induced adaptive response of human lymphocytes to subsequent doses of x-rays involves the induction of a chromosomal repair mechanism. Mutagenesis 1: 375-380; 1986.