Hormesis at a Glance 

   All living organisms evolved and exist in a sea of ionizing radiation, much of which is internal. It is a general belief that low doses of ionizing radiation produce detrimental effects proportional to the effects produced by high-level radiation. Over the past decades, however, some pioneer scientists reported that low-dose ionizing radiation is not only a harmless agent but often has a beneficial or hormetic effect. That is, low-level ionizing radiation may be an essential trace energy for life, analogous to essential trace elements. It has been even suggested that about one third of all cancer deaths are preventable by increasing our low dose radiation. 
 

Introduction

  Despite the fact that high doses of ionizing radiation are detrimental, substantial data from both humans and experimental animals show that biologic functions are stimulated by low dose radiation (Luckey 1980). The word "hormesis" is derived from the Greek word "hormaein" which means "to excite". It has long been known that many popular substances such as alcohol and caffeine have mild stimulating effects in low doses but are detrimental or even lethal in high doses. In the early 1940s C. Southam and his coworker J. Erlish found that despite the fact that high concentrations of Oak bark extract inhibited fungi growth, low doses of this agent stimulated fungi growth. They modified starling's word "hormone to "hormesis" to describe stimulation induced by low doses of agents which are harmful or even lethal at high doses. They published their findings regarding the new term "hormesis" in 1943 (Bruce M. 1987). Generally, hormesis is any stimulatory or beneficial effect, induced by low doses of an agent, that can not be predicted by the extrapolation of detrimental or lethal effects induced by high doses of the same agent.
  During the 1950`s, Luckey, a pioneer researcher in radiation hormesis, indicated that low dose dietary antibiotics caused a growth surge in livestock. Later he found that hormesis could be induced effectively by low doses of ionizing radiation. In 1980 the first complete report on radiation hormesis was published (Luckey TD 1980). In this report he reviewed numerous articles regarding radiation hormesis. Since the first reports, 3000 papers have been published on the benefits of low doses of ionizing radiation (for a review see Luckey 1980, Luckey 1982, Luckey 1991). The concept of radiation hormesis is usually applied to physiological benefits from low LET radiation in the range of 1-50 cGy total absorbed dose (Macklis 1991). It is widely believed that radiation biology in the future will be focused on biomolecular and genetic implications, problems of damage and repair and connected problems such as radiation hormesis and radioadaptive response. 
 
 

Hormesis and LNT Model

   In the early days of X-rays and radioactivity it was generally believed that ionizing radiation has numerous beneficial effects. It was claimed that blindness might be cured by X-rays. Ladies corsets contained radium! Drinking mineral water containing radium was very popular. People went to spas to drink radioactive water or stayed for hours in caves to be irradiated by ionizing radiation (for a review see Wolff 1992). Between 1925 and 1930 over 400,000 bottles of distilled water containing radium 226 and radium 228 were sold. It was advertised that some mixtures could treat over 150 disease, especially lassitude and sexually impotence (Macklis 1990). It is estimated that the collective skeletal radiation dose of victims of such radioactive medicine may had exceeded 350 Sv by the time the user died (Macklis 1991). Gradually people found that the improper use of ionizing radiation could lead to many complications and harmful effects. Later, In 1927 Herman J. Muller,a Nobel Prize winner, found that X-rays are mutagen and there is a linear relationship between mutation rate and dose. He proposed that mutations, which are induced by radiation (or other mutagens) are mostly detrimental. When it was generally accepted that excessive radiation may be harmful, the first regulations for dose limits were introduced. . Despite carcinogenicity of X-rays was observed as early as 1902 (Kathren 1996), the first radiation protection limits suggested in 1925 and for three decades these limits were based on the concept of a tolerance dose (Muller 1928). Surprisingly, until the end of World War II, ionizing radiation was considered agreat scientific miracle. After the war the development of nuclear weapons and later increased use of nuclear power changed this great miracle into radiophobia. At that time people became afraid of even very small doses of ionizing radiation.
   After the atomic bomb explosions in Hiroshima and Nagasaki, studies concerning life span of atomic bomb survivors showeda linear relationship between cancer mortality and high doses of radiation (Pollycove 1998). The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), then proposed the linear no-threshold (LNT) theory in 1958 (UNSCEAR 1958). According to LNT theory:
1-The effects of low doses of ionizing radiation can be estimated by linear extrapolation from effects observed by linear extrapolation from effects observed by high doses. 
2-There is not any safe dose because even very low doses of ionizing radiation produce some biological effect.
In1959 the international commission on radiation protection  (ICRP) adopted the LNT theory (ICRP 1959).
  The results of many investigations do not support the LNT theory (for an integrative review see Jaworowski 1997). Furthermore several studies including Cohen's studies of the relationship between environmental radon concentrations and lung cancer even contradict this theory and clearly suggest a hormetic effect. This contradictory evidence is discussed in the following section.
 

Extensive Evidence Suggesting Hormesis
 
 

1. Experimental Evidence 

1.1. Cancer Prevention 

   Bhattarcharjee in 1996 showed that when the mice preirradiated with just adapting doses of 1 cGy/day for 5 days (without a challenge dose), thymic lymphoma was induced in 16% of the animals (Bhattarcharjee 1996). Interstingly, when preirradiated mice were exposed to a 2 Gy challenge dose, thymic lymphoma was induced again in 16% of the animals. However, the challenge dose alone, induced thymic lymphoma in 46% of the mice. From these results, it can be concluded that the low dose preirradiation possibly cancel the induction of thymic lymphoma by the 2 Gy challenge dose. In 1996, Azzam and his colleagues showed that a single exposure of C3H 10T1/2 cells to doses as low as 0.1 cGy reduces the risk of neoplastic transformations. They suggested that a single low-dose at background or occupational exposurelevels, may reduce cancer risk. Recently, Redpath and his co-workers haveconfirmed the findings of Azzam and his coworkers (Azzam et al. 1996). To test the generality of the observations of Azzam and his colleagues, they used the Hela x skin fibroblast human hybrid cell. Using a similar experimental protocol, they demonstrated a significantly reduced transformation frequency for adapted to unirradiated cells (pooled data from four separate experiments).In addition, recently Mitchel and his co-workers in Canada have indicated that a low dose preirradiation (10 cGy, 0.5 Gy/h) modifies latency for radiation induced myeloid leukemia in CBA/H mice after exposure to a 1 Gy chronic radiation exposure (Mitchel et al. 1999). They showed that the latent period for development of acute myeloid leukemia (AML) was significantly increased by the prior low radiation dose. Interestingly, according to T.D. Luckey one third of all cancer deaths are premature and preventable by low-level ionizing radiation (Luckey 1994, 1997). 

1.2. Survival Rate 

 In 1996, Yonezawa and his colleagues indicated that when 21-ICR mice were exposed to a 8 Gy of X-rays, about 30% of the animals survived 30 days after the irradiation. However, when mice preirradiated with 5 cGy of X-rays, the survival rate increased to about 70% (Yonezawa et al. 1996).
 

2. Epidemiological Evidence 
 
 

 Although radiation hormesis data are still incomplete, extensive epidemiological studies have indicated that radiation hormesis is really exist. A briefreview on this irrefutable evidence is as follows: 

2.1. Japanese studies

1-According to UNSCEAR report (1994), among A-bomb survivors from Hiroshimaand Nagazaki who received doses lower than 200 mSv, there was no increase in the number of total cancer death. Mortality caused by leukemia was evenlower in this population at doses below 100 mSv than age-matched controlcohorts.
2-Mifune (1992) (Mifune et al. 1992) and his co-workers indicated that in a spa area (Misasa), with an average indoor radon level of 35 Bq/m³, the lung cancer incidence was about 50% of that in a low-level radon region. Their results also showed that in the above mentioned high background radiation area, the mortality rate caused by all types of cancer was 37% lower.
3-According to Mine et al. (1981), among A-bomb survivors from Nagasaki, in some age categories, the observed annual rate of death is less than what is statistically expected.
4-Kumatori and his colleagues (Kumatori et al. 1980) reported that according to their 25 year follow up study of  Japanese fishermen who were heavily contaminated by plutunium (hydrogen bomb test at Bikini), no one died from cancer.
 

2.2. Background Radiation Studies

1-In an Indian study, it was observed that in areas with a high-background  radiation level, the incidence of cancer and also the mortality rate due to cancer was significantly less than similar areas with a low backgroundradiation level (Nambi and Soman 1987).
2-In a very large scale study in U.S.A, it was found that the mortality rate due to all malignancies was lower in states with higher annual radiation dose (Frigerio 1976).
3- In a large scale Chinese study, it was showed that the mortality rate due to cancer was lower in an area with a relatively high background radiation (74,000 people), while the control group (78,000 people) who lived in anarea with low background radiation had a higher rate of mortality (Wei L 1990).
4-In the U.S.A., it was indicated that significantly, the total cancer mortalityis inversely correlated with background radiation dose (Cohen BL. 1993).
 

2.3. Nuclear Power Plant studies

1-In a Canadian survey the mortality caused by cancer at nuclear power plants was 58% lower than the national average (Abbat et al. 1983).
2-In U.K also it was indicated that cancer frequency among nuclear powerplant workers was lower than the national average (Kendal et al. 1992).
 

The Mechanism of Hormetic Phenomena

   Although still we do not know the entire mechanisms of radiation hormesis, the following theories may explain this process:

1-DNA repair (Mollecular level)
According to this theory, low doses of ionizing radiation induce the production of special proteins, that are involved in DNA repair processes (Ikushima 1996). Studies using two dimensional gel electrophoresis indicated new proteins in cells irradiated with low doses of radiation. Also, it was further shown that cycloheximide, a protein synthesis inhibitor blocks this hormetic effect. The function and importance of these radiation induced proteins is still unknown. Also it was foud that inhibitors of poly ADP-ribose polymerase, an enzyme implicated in DNA strand break rejoining could prevent the induction of adaptive response (for a review see Wolff 1998). 

2-Free radical detoxification (Molecular level)
In 1987 Feinendengen and his co-workers indicated that low doses of ionizing radiation cause a temporary inhibition in DNA synthesis (the maximum inhibitionat 5 hours after irradiation). This temporary inhibition of DNA synthesis would provide a longer time for irradiated cells to recover (Feinendengen et al. 1987). This inhibition also may induce the production of free radical scavengers, so irradiated cells would be more resistant to any further exposures.

3-Stimulation of immune system (Cellular level)
Despite the fact that high doses of ionizing radiation are immunosupressive, many studies have indicated that low doses radiation may stimulate the function of the immune system. In 1909 Russ first showed that mice treated with low-level radiation were more resistant against bacterial disease (Russ VK 1909).Later in 1982 Luckey published a large collection of references supporting immunostimulatory effects of low doses of ionizing radiation (Luckey TD 1982).

Conclusion

Our radiation protection policy is based on linear extrapolation from the dose-response data of high doses of ionizing radiation. According to the results of many worldwide studies, this assumption is not compatible with observed health effects of  low levels of radiation. Obviously LNT and current radiation protection regulations exaggerate the risk of low level ionizing radiation (in the range of 1-50 cGy) and cause radiophobia (Yalow RS 1990). It is concluded that according to new findings, the existence of radiation hormesis and adaptive response are not deniable and abandoning the LNT theory in low dose risk estimations will be a real nessecity in the near future.
 

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