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Ultralow-level stimuli. Death or hormesis?
Ultralow-level stimuli. Death or hormesis? Ultralow-level stimuli. Death or hormesis?

Schematic illustration of the molecular and cellular mechanisms triggered by low-dose and high-dose radiation. Source - [9].

Every day, we are exposed to a multitude of environmental factors. By their nature, these can be classified into physical, chemical, biological, and man-made. This article will look into physical ones, which, in particular, include electromagnetic radiation (EMR) of different wavelengths (X-rays, gamma rays, ultraviolet, visible and infrared light, and radio waves), acoustic (sound) and mechanical (e.g., vibrations) stimuli, and streams of particles (such as electrons, protons, alpha particles, and neutrons).

No one will question the impact exerted on the body by exposure to physical factors when their “strength” is high. A strong wind is able to knock people down and tear down ancient trees. However, are we affected by the slight, almost intangible movement of the air? Is it possible that even very low-dose exposure to physical stressors can affect living beings?

Today, we know from multiple studies conducted in different areas of biology that a linear impact exerted on a living organism can lead to a nonlinear biological response. For example, the bedrock principle running as “the severity of an effect decreases with dose” seems to no longer apply. Back in the second half of the 19th century, the German scientists Pflüger, Arndt and Schulz formulated a law stating that a living thing's activity is excited by weak, inhibited by moderate, and abolished by very strong stimuli1. That is, the response reverses with the intensity of the stimulus. Many experiments have demonstrated favorable effects of different low-dose metals and chemicals on the growth of plants, fungi, seaweeds, and bacteria, with negative effects observed for the same substances when used in higher doses.

In this regard, the experience with penicillin gives a remarkable example. During World War II, the shortage of antibiotics propelled doctors to use them sparingly and reduce the doses administered. It was thus discovered that low-dose penicillin did not suppress staphylococcal growth but, oppositely, stimulated it1. Eventually, the concept of hormesis emerged. The term ‘hormesis’, i.e. stimulating, beneficial effects produced on physiological systems by an agent which is toxic at high doses, was introduced in 1943 by C. Southam and J. Ehrlich.1 There are a whole number of factors currently known to trigger the hormetic mechanism within a biological system. These include physical stressors, the most intensely studied and controversial of which is ionizing radiation. T.D. Luckey, who summarized and furthered the knowledge of the low-dose biological effect of ionizing radiation2, introduced the term radiation hormesis in 1980.

The radiation is called ionizing because it is able to cause ionization of atoms and molecules in the substance that it is passing through. There are two major forms of ionizing radiation – electromagnetic radiation (streams of high-energy photons such as gamma rays and X-rays) and particulate form (accelerated particles and nuclei of various elements including α-particles (nuclei of helium) and β-particles (electrons and positrons). Gamma radiation has the highest penetrating power. While α-particles can easily be stopped by just a piece of paper and β-particles – by a few millimeters thick sheet of aluminum, it will require a few centimeters of lead to shield gamma radiation.3

The effects of medium- and high-dose radiation are quite well studied, and there is convincing evidence of their deleterious impact (which increases with dose) on various living organisms1, 3. However, what is known about the effects of low-dose radiation on biological systems?

First, it is necessary to ascertain what doses of radiation should be considered low. Throughout their lifetime, all living things on Earth are exposed to natural radiation, or background radiation, which occurs naturally and is estimated at an average of 2.4 mSv (millisieverts) per year (while in some inhabited regions the average background exposure is over ten times as high) 1,3. It should be explained here that the amount of radiation received by a target is normally measured in grays (i.e., a measure of absorbed energy per unit of mass (1Gy = 1J/1kg)). Sievert is a sort of ‘biological equivalent’ of the gray including the estimates of radiation quality factors for different tissues and body parts3. Probably, a low dose should be defined as an amount slightly higher than the natural background radiation level. However, the radio sensitivity of living organisms varies rather extensively, which means that an increase in background radiation that may be ‘slight’ for one will be fatal to another.

In this way, while lethal to a human, a dose of 10 Gy will be harmless to some reptiles and even beneficial for the growth and development of mustard seeds1. In the medical perspective, low doses, which do not contribute to cancer incidence, are currently defined as 100 mGy (according to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)), whereas the human effective dose must not exceed 1 mSv annually. We receive about 0.05 mSv when flying to the USA from Europe or about 0.5 mSv when undergoing a routine fluorographic examination) 1, 3, 4.

Despite the intense studies, ongoing for over half a century, scientists still have not agreed on how to assess low-dose biological effects of lionizing radiation. Two opposing viewpoints are currently available: the radiation hormesis concept and the concept of no-threshold radiation exposure4-6. Both are based on experimental evidence and epidemiological data, but it is the latter that is regarded as “official” and recognized by the UNSCEAR and the International Commission on Radiological Protection4-6.

Advocates of the radiation hormesis concept believe that low-dose radiation causes no harm, but rather acts as a sort of stimulus able to stimulate and boost biological objects, promoting their growth, development and resistance to adverse factors1-6. Back in 1956, N.V. Timofeev-Resovskij, a prominent Russian scientist, confirmed and theoretically explained the stimulation of plant growth by low-dose radiation. In the 60s, A.M. Kuzin, a top Soviet biophysicist, concluded that the stimulating effects of low-dose radiation on live processes have a universal biological meaning and are a rigorously demonstrated fact4. There has been evidence of increased life span in vertebrates (mice)1,5 or stimulated immunity,5-7 hematopoiesis and DNA repair6 following low-dose exposure to radiation, as well as even lower risk of cancer (e.g., lung cancer in Canadian workers, who are occupationally exposed to radioactive radon) and its progression6,8,9.

The no-threshold exposure concept relies on the assumption that there is no safe dose-level of ionizing radiation.4-6 Proponents of this officially accepted hypothesis state that low-dose radiation may cause indirect damage to living objects, through effects such as induced genome instability, the “bystander effect” (i.e., phenomenon in which irradiated cells “infect” nearby unaffected cells), raptured cell membranes, etc.

Some experiments have demonstrated negative and inhibiting effects of low-dose radiation on plants. The use of the lowest doses of very low-level radiation led to alterations in the DNA structure and cell membranes, as well as cell death and chromosome aberrations6, 10-16. Furthermore, changes caused by irradiation may persist long after the exposure was stopped and even be inherited11,14,16.

Numerous studies and experiments have shown that low-dose radiation exposure may result in the development of leukemia and any other type of cancerous tumors5,10,16,17. To note, according to epidemiological findings, the risk of cancer has only been plausibly demonstrated for ionizing radiation doses of above 50-100 mSv (with prolonged exposure) and 10-50 mSv (with acute exposure) 18. It has been suggested that the body’s repair systems are not responsive to low dose-rates. We are programmed to survive in certain environments, so the body cannot respond to any minor deviation from normality using its unique set of defense responses11.

To sum up, the data concerning low-dose biological effects of ionizing radiation are incredibly controversial and often conflicting. One thing that is clear is that low-dose effects are obviously nonlinear by their nature and cannot be obtained by merely extrapolating experimental data gathered for high, toxic doses1,9,11. Despite some instances of evidence supporting the radiation hormesis phenomenon, low-dose ionizing radiation should not be regarded as perfectly safe10,16.

The other types of EMR with wavelengths greater than X-rays are ultraviolet, visible and infrared light. It is commonly known that small doses of sunshine are beneficial and essential – to the synthesis of vitamin D and endorphins19-20. However, prolonged sun exposure increases the risk of skin cancer via the action of ultraviolet (UV) radiation (predominantly UVA rays) 19. Yet, low-dose ultraviolet radiation, apart from its physiological benefits, also has a therapeutic effect, such as the one used in the treatment of psoriasis and some other skin diseases21-22. It has been shown that low-dose exposure to ultraviolet radiation followed by stronger UV exposure can prevent the development of skin cancer23.

Studies examining the impact of low-level red and infrared radiation on biological systems have demonstrated adaptogenic and anticarcinogenic effects24-26. Pre-exposure of animal tissues to this type of radiation was observed to reduce the damage to bone marrow cells, protect the spleen and thymus against high-dose radiation, and inhibit malignant growth24. A systematic review of the effects of red and infrared light (low-power laser therapy) has shown that exposure to these light waves can significantly reduce pain and improve health status in chronic conditions of the joints27.

The risk of late effects of continuous low-level EMR on human health has been particularly relevant in recent years, due to rapid advances in electronic communications, television and radio broadcasting. It should be noted that long-term exposure to ostensibly safe and very low-intensity physical factors might have deleterious effects.

For example, 24 hours’ exposure to a low-intensity magnetic field of 0.01 mT (by comparison, the magnetic induction of a modern tomograph is usually up to 1-3 T, and the magnetic field intensity near Earth’s surface is about 50 µT) resulted in a significant increase in single- and double-strand DNA breaks in brain cells of the rat. With the exposure extended to 48 hours, the damage increased even more28. Prolonged combined exposure to low-intensity magnetic and electromagnetic fields can even affect a living organism’s metabolism. For instance, “omnivorous” bacteria were observed to take up more iron following the above treatment29.

Among studies of the low-dose effects of radio spectrum EMR, those examining mobile phone radiation are of particular interest. There are various data demonstrating negative effects of the latter. For example, even short-term exposure (about 20 min/day) to radio wave EMR adversely affected embryo development in chicken experiments, so it cannot be considered 100% safe30. The WHO's International Agency for Research on Cancer has even classified low-intensity radio frequency EMR, including mobile phone radiation, as potentially carcinogenic31.

Another physical factor that can exert low-dose effects on biological systems is vibration and sound. For example, there have been attempts to make use of it in the development of sustainable bioprocess intensification methods. In particular, low-level acoustic or electric treatment of barley grain enzymes improved germination and the quality of final malt. It also increased the activity of some lactic acid bacterial enzymes, resulting in faster milk fermentation32.

The use of ultrasound is another example of acoustic stimulation. It was revealed that low-level ultrasound increased neuronal activity in the hippocampus (an important brain structure responsible for short-term to long-term memory conversion), showing thereby that this easily accessible physical factor can be used to modulate neuronal activity33.

Low-dose effects are rarely straightforward. Predicting biological effects of low-level exposure of complex organisms to chemical or physical agents is complicated by many circumstances: a nonlinear dose-effect relationship for systems of different complexity, broadly varying manifestation of effects at low dose-rates, dependence of the magnitude and direction of an effect on the pre-exposure condition of the object, unpredictability of a combined effect when multiple factors coexist. All of this indicates that the mechanisms behind the effects exerted on biological objects by various low-dose factors are not yet sufficiently studied.


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