Research on the Adaptive Response Induced by Low-Dose Radiation: Where have we been and where should we go?
Lu Cai, Ph.D.
Norman Bethune University of Medical Sciences
Institute of Radiation Medicine
Changchun 130021, P. R. China
Tel: (519) 661-2030
Fax: (519) 661-3370
Adaptive response (AR) induced by low-dose radiation (LDR), originally described by Olivieri et al. in 1980's, is the induction of cellular resistance to genotoxic effects caused by subsequently high-dose radiation (HDR). Doses which are effective in inducing AR are called adapting dose or AR dose. So far, AR has been characterized both in vitro with human, rabbit and calf lymphocytes, normal or tumor cell lines, and in vivo with mouse bone marrow cells, splenocytes and germ cells (Cai & Liu 1990; Wolff 1998). AR could be expressed in multiple biological end-points including unscheduled DNA synthesis, micronuclei, chromosome aberrations, gene mutation and cell survival (figure 1).
Illustration of adaptive response (AR) by low-dose radiation (LDR) or low-dose chemicals (LDch) to high-dose radiation (HDR) or high-dose chemicals (HDch), and the possible mechanisms.
LDR-induced AR made cells more resistant not only to radiation, but also to hydrogen peroxide (H2O2) and anticancer drugs. Similarly, AR caused by exposure to subtoxic levels (or low dose) of non-radiation agents such as H2O2, anticancer drugs and hyperthermia could protect against radiation-induced damage (Cai & Jiang 1995; Wolff 1998). AR doses were found to be between 0.05 0.20 Gy for a single exposure to low LET radiation, which is just within the definition of LDR by UNSCEAR (0.2 Gy). Within 0.2 Gy AR was negatively correlated with AR doses (Cai & Liu 1990). The range of chronic AR doses is relatively broad. An optimal range of AR doses to induce AR is required (figure 2), and might vary depending on the exposure dose rate.
U-shaped curve of chronic AR doses for inducing AR. Data were obtained in rabbit lymphocytes. Lymphocytes were
pre-exposure to chronic LDR (0.05 Gy/9h.day) for different times, and were collected. They were irradiated by HDR (1.5 Gy) at G2 phase of cell cycle. S-value means the ratio of total chromosome aberrations in the groups with LDR plus HDR to that in group only with HDR.
Mechanisms underlying AR induced by LDR are still unclear, but several hypotheses have been considered (figure 1). LDR enhances DNA repair ability and antioxidant activity, and produces protective proteins to minimize the indirect damaging effects of subsequent HDR (Yamaoka et al., 1994, 1998; Cai et al., 1999). Increase in apoptotic cell death considered another mechanism for the induction of cytogenetic AR (Cregan et al., 1994; Pottern et al., 1994). Although further studies are required to illustrate both phenomenological features and the mechanism of LDR-induced AR, it is important that the biological significance and implications of AR need to be addressed. In this review, therefore, I would like to discuss the following questions.
Humans live with a background radiation which may play an essential role in human health
Humans have always lived in the presence of LDR from natural sources including cosmic rays, materials in the earth, our own bodies, and also additional sources from man-made radiation such as medical, occupational and accidental exposure. Natural radiation exposure, 80 - 90 % of the total annual exposure of population to environmental radiation, is 2.4 mSv/year in average throughout the world, although this varies considerably in different specific geographic locations. Average exposure of the population to natural exposure is 3.0 mSv for U.S.A, 2.6 mSv for U.K., 2.0 for Canada and 6.4 mSv for Yangjiang, China. Some areas, with enhanced radiation exposure by a factor of 10, are called as high natural radiation background areas (HNRBA), such as Yangjaing, China (Wei et al., 1996). The average annual exposure to populations in the HNRBA is 17.11 mSv, about seven-times higher than that of normal areas. However, no harmful biological effects of the enhanced radiation in HNRBA were found, and even an adverse effect of exposure to reduced radiation in low natural radiation background areas (LNRBA) was found (Luckey 1996; Wei et al., 1996; Jagger 1998). These suggest: (1) that a certain range of radiation exposures does not cause harmful effects for humans; and (2) that our body has the potential to tolerate exposure to low levels of environmental radiation and other environmental agents.
During the development of life, we have build up comprehensive defense mechanisms to adapt to a variety of environmental agents. The phenomenon that some agents are beneficial at a low-level exposure but are adverse effects at high-level exposure, was called hormesis. A common example is the consumption of alcohol. Heavy alcohol consumption is definitely harmful, but small amounts and long-term consumption could stimulate our body's function, resulting in reducing the risk of mortality, cardiovascular and coronary diseases (Gaziano 1995). Similarly, LDR can also stimulate certain functions in our body, as "radiation hormesis", which has been confirmed by the evidence from HNRBA, atomic bomb (A-bomb) survivors, occupational workers and laboratory studies with animals (Liu 1989; Hattori 1994; Luckey 1996). LDR can also activate some protective mechanisms, AR, to reduce the damage caused by subsequent HDR or other toxic agents (figure 1).
Radiation hormesis means the stimulatory effect by LDR and inhibitory effect by HDR. AR is sometimes used as synonyms for hormesis (Luckey 1996). In my personal opinion, hormesis is a wide concept and AR is concrete one as a special expression of hormesis. All the possible mechanisms for AR induction are associated with the stimulatory mechanism (hormesis) induced by LDR (figure 1). In other words, hormesis is the first response after exposure to AR doses, and some of the stimulatory effects then result in AR to subsequent HDR. Therefore, in the most cases AR doses are also effective in inducing hormesis (Liu et al., 1989; Cai & Liu 1990; Luckey 1996).
Induction of a radioprotective mechanism by LDR has important implications for human health. However, the data from epidemiological studies of human are still insufficient to define the implications for human health, therefore, the results from animal experiments are extremely important to investigate the effects of AR to humans.
Based on most studies of short-term effects, AR apparently contributes a beneficial effect to mammals and humans. AR reduces radiation-induced gene mutation, DNA damage and chromosome aberrations. AR doses do not induce, in general, marked adverse effects, and even reduce spontaneous oxidative damage (Cai & Liu 1990; Azzam, et al., 1996; Redpath & Antoniono 1998). Occupational exposure of workers to LDR was able to induce AR, reducing the genotoxic effects of subsequent exposure to HDR and also other genotoxic agents (Gourabi & Mozdarani 1998).
As compared to somatic cells, germ cells are of greater relevance for evaluation of genetic risk because it is possible that the DNA or chromosome damage induced in germ cells may be transmitted to the next generation and cause adverse heritable effects in their offspring. Thus, germ cells were chosen to study LDR-induced cytogenetic AR in our studies (Cai & Liu 1990; Cai & Wang 1995) and others. To date, the reducing effects of AR on subsequent HDR-induced genotoxic effects were predominant, with less protection observed for decreased testis weight and sperm count, sperm abnormalities, and the formation of lipid peroxidation in the testis. HDR-induced dominant lethality in Drosophila and mice was also prevented partially by LDR-induced AR. Human data from A-bomb survivors and occupational workers, and from HNRBA, also showed no marked genetic effect (reproductive ability and congenital abnormality) in the offspring of these LDR exposed individuals (Wei et al., 1996; Green et al., 1997).
To evaluate the effects of LDR-induced AR, we should consider the contribution of AR doses on irradiated individuals, and, more importantly, on their offspring (Cai & Wang 1995). Exposure to LDR prolonged animal survival time, which was reported for the first time by Lorenz et al. in 1950's and confirmed by later extensive studies (see ref. cited by Caratero et al., 1998).
Cancer mortality in the animals exposed to LDR was decreased as compared to control animals (Bhattacharjee 1996; Ishii et al., 1996). After mice were exposed to 2 or 3 Gy g-rays, thymic lymphoma developed in both males and females, but this could be markedly reduced by pre-exposure to LDR (single 0.01 Gy, or 5 and 10 mutiple 0.01 Gy). This suggests an important role of AR in inhibiting the acute effect of radiation, i.e., the onset of thymic lymphoma. Human epidemiological studies also showed the low incidence of cancer in HNRBA (Jagger 1998), in A-bomb survivors (Hoel & Li 1998; Mossman 1998) and workers occupationally exposed to LDR (Forastiere et al., 1998).
No significant difference for genetic disorders and tumor formation was found between controls and offspring of irradiated male mice (Cosgrove et al., 1993), and of A-bomb survivors (Neel & Schull 1991). Very low incidence of heritable effects were noted in the offspring of paternal exposure to low- or moderate-level radiation. This may be due to the efficiently selective elimination of cells with genomic abnormality probably by apoptotic cell death. A doubling dose for germ-line mutation induction at mouse minisatellite loci by acute irradiation with X-rays was 0.33 Gy (Dubrova et al., 1998). Using genomic instability, Luke et al. (1997) found that preconceptional paternal exposure to 0.1 Gy g-rays did not increase any risk, and even decreased mutations (genomic instability) in F1 offspring, but exposure to 1- 4 Gy caused a markedly increased effect. These suggested that the AR dose (<0.2 Gy) should not significantly increase the risk for the genomic alteration in the offspring of paternally exposed individuals. In early 1990's, Gardner and colleagues found an association between leukaemia and non-Hodgkin lymphoma in young people and relatively high doses of fathers irradiated during work at the Sellafield nuclear plant before conception of the child, which was called the Gardner hypothesis. But, this hypothesis was not confirmed by subsequent studies in the offspring of (a) occupationally exposed groups in Canada, Scotland, England, Germany, France and Britain (Zadeh & Briggs 1997; Draper et al., 1998; Michaelis 1998); (b) individuals who received the diagnostic contrast medium Thorotrast (Zadeh & Briggs 1997); and (c) of A-bomb survivors (see ref. cited by Drapper et al., 1998).
Using human lymphocytes and other cell lines, AR was found in cell survival with or without cytogenetic AR. The increase in nonaberrant cells was not sufficient to account for the increase in cell survival, suggesting that reducing cell death by AR was due to reducing lethal genomic damage including gene and DNA damage. For short-term, these adaptive survival responses (ASRs) are beneficial in certain situations. For example, our recent study showed that mice receiving an AR dose of X-ray showed high resistance to subsequent HDR-induced hematopoietic depression as compared to those only irradiated by HDR, resulting in high animal survival rate (Wang et al., unpublished data). This result seems to have the potential implication for preventing normal tissues from toxicity following cancer radiotherapy. In the view of long-term effect, however, Boothman et al. (1998) assumed that the increased survival does not necessarily mean that the treatment is beneficial since they indicated at the molecular level that ASRs are the result of misregulated cell cycle checkpoint responses, occurring in the G1 phase of the cell cycle after IR. ASRs, therefore, may be beneficial for survival, but the rescued cells might pass abnormal genome into following generation cells, resulting in carcinogenesis. However, this was not supported by two recent in vitro studies where AR doses reduced the spontaneous neoplastic transformation in vitro (Azzam, et al., 1996; Redpath & Antoniono 1998). As mentioned above, exposure of mice to LDR also caused a lower incidence of tumors as compared to control mice, and also reduced subsequent radiation-induced tumors (Bhattacharjee 1996; Ishii et al., 1996). All these strongly suggest the beneficial effect of AR doses in long-term effects. In addition, extensive studies were presented from Dr. Joiner's group, for the existence of an extreme hypersensitivity for cell death at very low doses of 0.1-0.3 Gy (Short & Joiner 1998). Under this dose range, cell death may occur mainly through an apoptosis mechanism (Normura et al., 1992; Potten et al., 1994; Mothersill et al., 1995). Furthermore, pretreatment with LDR or mild hyperthermia sensitized cells to become apoptotic after HDR (Gregan et al., 1994). Apoptotic cell death may remove the genetically damaged cells and result in the cytogenetic AR. This includes the reduction of the delayed genomic instability (see 4th IC-HLNR, 1996, Watanable et al.), which may lead to a reduction in carcinogenesis. In the International Symposium on Health Effects of Low Doses of Ionizing Radiation: Research Directions into the New Millennium, organized by the International Center for Low Dose Radiation Research, Ottawa, June 8, 1998, Dr. R. Mitchel from Chalk River Laboratories, AECL, Canada, reported that LDR reduces the subsequent HDR-induced leukemia, and the major mechanism may involve the increase in the apoptosis.
Since extensive scientific evidence shows the stimulation of immunological function, antioxidant activity and DNA repair ability, the induction of AR and the hypersensitivity of cell death to LDR, it can be beneficially used in medical practice and public health. One has to distinguish the difference between these responses in normal and tumor tissues, since AR in tumor cells will contribute to the drug- or radio-resistance. We have to develop the strategies to stimulate the immunological and hematopoietic functions, and to enhance the drug- or radio-resistance in normal tissues without AR in tumor tissues. Although we have not yet understood all characteristics mentioned above, the available data have shown promising perspectives.
A few earlier documents indicated that if mice received a total body irradiation in low dose (LD-TBI) before implanted tumor cells, the development of tumors was markedly inhibited as compared to control mice. Similar results have been found in our institute as shown in figure 3, that exposure to LD-TBI before implanting tumor cells (1) inhibited the formation and growth rate of the tumor as compared to control mice, and mortality rate of 40 days was 66.7% of control mice (figure 3A,B); (2) depressed the metastasis of injected tumor cells into veins (figure 3C); and (3) enhanced the treatment efficiency of radio- or chemo-therapy (figure 3D).
Effect of LDR on the formation (A), growth rate (B), and metastasis (C) of tumor and the efficiency of radiotherapy (D). A:
LD-TBI (0.05 Gy) was given before mice (C57BL/6J and Kunming mice) were implanted with tumor cells. At 12 days after
implanting, the rate of tumor formation in the mice with LD-TBI was compared with control mice. B: C57BL/6J mice pre-irradiated by 0.05
Gy LD-TBI were implanted with tumor cells and 5 days later tumor size was measured and calculated into tumor weight. C: Mice
were irradiated by different doses of LD-TBI and 24 h later were injected intravenously with two tumor cells (Lewis lung cancer and
B16 melanoma). They were killed 14 days after injecting, and check the nodules of tumors in lung. The ratio of nodule number
in mice with LD-TBI to control was presented. D: Tumor-bearing mice were treated with (1) 1 Gy/day x 5 (D2); (2) with single
0.05 Gy LD-TBI before 1 Gy/day x 5 (D1a + D2); and (3) with 0.05 Gy LD-TBI before each 1 Gy /day for 5 times (D1b + D2).
T.w-A: tumor weight was direct weighed after mice were killed. T.w-B: Tumor weight was calculated based on the size before mice
were killed. The ratio of tumor weight in radiotherapy groups to control was presented.
In clinical implications, LD-TBI has been suggested for use in non-Hodgkin's lymphoma patients for about two decades. But until two recent studies (Travis et al., 1996; Richau et al., 1998), no definite benefit was found, probably due to the limited number of cases and different stages of patients. The main reason against use of LD-TBI before radiotherapy or chemotherapy is probably the increase in the risk of secondary myeloproliferative disorders in the patients with LD-TBI plus radio- or chemotherapy. However, these two studies did not show any increase in the risk for the secondary leukemia by LD-TBI and LD-TBI plus radiotherapy with excellent clinical tolerance. Most patients showed efficient responses, in particular for follicular lymphoma. They lived without any acute nonlymphoblastic leukemia or myelodysplasic syndrome with a median follow-up of 88 months (Travis et al., 1996), and 56.2 months (Richau et al., 1998). Although they did not discuss any issues related to LDR-induced AR or hormesis for the mechanism of this beneficial effect, this may suggest a role of LDR hormesis in immunity and AR in the hematopoietic tolerance in this efficient treatment.
LDR-induced AR showed a wide cross-resistance to oxidative damage from other clastogens as shown in figure 1 (Cai & Jiang 1995; Wolff 1998). Induction of metallothionein (MT), as an adaptive mechanism, plays an important role in preventing DNA or cells from a variety of oxidative stressors (Cai et al., 1999). Ischemic reperfusion injury, known to have a significant oxidative damage component, can be decreased by ischemic preconditioning as a kind of AR (Hawaleshka & Jacobsohn 1998). MT and other antioxidants (SOD, catalase and GSH) have been found to be very important in protecting the myocardium in vivo or cultured cardiomyocytes in vitro from ischemia, and other oxidative stress. Therefore, enhancing antioxidant activity by LDR exposure may be a strategy to prevent the heart from oxidative injury since the induction of these antioxidants by LDR was indicated in animal studies (Yamaoka, et al., 1994,1998). Similar hypotheses have arisen to prevent Alzhemer's disease (AD) since the main pathogenesis of AD is due to oxidative damage, causing cell loss. If LDR enhanced activity of antioxidants in the brain (Yamaoka et al., 1994) and prevented brain cells from oxidative damage it would be a new field for investigation. Human epidemiological studies have shown a lower incidence of AD (4.39%, 25/570) in HBRA as compared to controls (4.95%, 25/505). The Wechsler Intelligence Scale for Children-Verbal (WISC-V) performed better in the children of HBRA than those in control population (4th IC-HLNR 1996; Wei et al., 1996). For other possible implications, Dr. Yamaoka and his colleagues have demonstrated the protection of the enhanced antioxidants from diseases such as alloxan-induced diabetes (Takehara et al., 1995; Yamaoka et al., 1996).
Because of the strong scientific evidence in support of LDR hormesis and AR, we can no longer ignore this concept. Although there is need for additional, carefully documented investigations in selected biological systems exposed to LDR to address the phenomenological features, mechanisms and implications of AR or hormesis, we should draw attention to its beneficial, at least non-harmful, effects of exposure to LDR. The linear, non-threshold (LNT) dose response model was currently used to regulation for protection of workers and the public from harmful effects of LDR. The LNT model was based on three fundamental assumptions: (1) Cancer may result from a single ionizing event in a critical cell, i.e., any radiation dose, no matter how small, is potentially harmful. (2) The probability of adverse health outcomes is linearly related to absorbed dose. If the absorbed dose is doubled, the risk is doubled. (3) Radiation damage is not repairable. Now, we know that radiation-induced DNA damage is repairable and LDR, in particular AR dose of radiation, is able to activate the DNA repair mechanisms. In addition, LDR could up-regulate the apoptotic cell death mechanism to remove the cells with genomic abnormality (figure 1). As summarized by Dr. Lutz (1998), if a carcinogen increases antioxidative effects at low dose, the carcinogenic dose-response should be a J-shaped (or U-shaped) curve with a decrease of the spontaneous tumor incidence at low doses, which includes ionizing radiation. Therefore, the appropriateness of the LNT theory as a predictive model in radiation protection should be reconsidered (Strom et al., 1998; Webster 1998). Based on a number of epidemiological studies of A-bomb survivors and workers exposed to LDR, most of researchers considered that the estimated cancer incidence from LNT models over-predicted the observed cancer incidence in the lowest exposure group. The LNT philosophy is overly conservative, and LDR may be less dangerous than commonly believed (Hoel & Li 1998; Mossman 1998; Sinclair 1998; Nussbaum 1998). In my personal opinion, I agree with the suggestion of Dr. Mossman. We can not ignore the fundamental scientific evidence that certain LDR is not harmful, even beneficial to human health. The LNT model is simplistic and provides a very conservative estimate of risk. Abandoning the LNT philosophy and relaxing regulations would have enormous economic implications. Although we do not have a perfect model to estimate the risk of LDR, perhaps exposure limits should be based on model-independent approaches since there is no requirement that exposure limits be based on any predictive model. I think it is a realistic suggestion that exposure limits might be based on the average natural background levels to population (2-3 mSv/year).
Finally, I would like to say that although we already have fundamental scientific evidence about the beneficials effects of AR or AR exposure, further studies, more important, using animal models are still required to illustrate LDR-induced AR or hormesis, and its mechanism. However, the matter of benefits derived from AR or AR exposure need be addressed without delay since it will have major economic and epidemiological implications. The LDR-induced AR should be elevated to a position of scientific and societal respectability, like radiation hormesis (Hendee 1998).
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