Editorial Review

The Low Dose Dilemma

G. J. Köteles

“Fodor József” National Center for Public Health, “Frederic Joliot-Curie” National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary

Corresponding author: Professor G. J. Köteles, MD, PhD, DSc, Director

“Frederic Joliot-Curie” National Research Institute for Rabiobiology and Radiohygiene

H-1775 Budapest, POB. 101. Hungary

Phone/Fax: 36-1-226-0026

CEJOEM 1998, Vol.4. No.2.:103-113

Key words: Ionizing radiation, low dose, biological effects, cellular effects, epidemiological effects

Introduction

The increasing use of ionizing radiations and nuclear energy all over the world induces an ever-increasing interest of the professionals as well as of the whole society in health protection and the risk due to these practices. Many international and national bodies and organizations are involved in the development of radiation protection philosophy, regulations for the safe use of radiations and the practical implementations of rules. One of the main forums devoted to the radiation protection is the International Commission on Radiological Protection (ICRP) founded in 1928. The Commission and its Committees have a leading role in elaborating the relevant recommendations. The latter are usually considered by other international, including intergovernmental organizations, scientific societies and last but not least by national authorities responsible for legislations. In the exponentially growing professional literature plenty of factual information, models and ideas have been accumulated in recent years concerning the biological effects of ionizing radiation including possible detrimental effects on human health. For the sake of safety the international radiological protection and dose limitation systems recommend their standards based on biological observations, experimental and epidemiological data (ICRP 1991; IAEA-IBSS 1996). In the trend of lowering the dose limits, however, the attributable risk to health might even get lower than in several other industrial or other activities of a civilized society. It also has to be noted that the implementation of increasing safety results in considerable financial burden to the national economies. Therefore, a rather wide discussion developed on the crucial points of radiation biology and radiation protection whether it is justified to assess the health risks by linear extrapolation of effects from large doses to low doses (Tubiana 1991, Gonzalez 1994, Streffer and Tanooka 1996; Duport 1996; Mossman et. al. 1996; IAEA 1997). Beside the scientific discussions it has also to be considered that there is a deepening gap between the risk assessment of the professionals and the risk perception of various groups of the society (UNEP 1985; Faragó and Engländer 1987; Köteles 1996).
The intention of the present review is to assist those who are interested but could not follow these emerging ideas. Accordingly, the review outlines the so-called dose-response models, the “low dose” levels, lists the main pro and contra arguments concerning the validity of linear-non threshold (L-NT) model of stochastic biological effects, and points out a few examples on the cellular reactivities at low doses. The advantages of maintaining the present view on the L-NT model as recommended by the ICRP and accepted widely are also raised.

The features of the main dose-response relationships

The biological effects of ionizing radiation for radiation protection considerations are grouped into two categories: the deterministic and the stochastic ones (Fig. 1).

Fig. 1. Schematic dose-response curves for the stochastic and deterministic effects of ionizing radiation

The deterministic effects occur when above a certain “threshold” an appropriately high dose (above 500–1000 mSv) is absorbed in the tissues and organs to cause the death of a large number of cells and consequently to impair tissue or organ functions early after exposure. The severity of injury depending on the absorbed dose according to an s-shaped dose-response curve might be manifested in the various syndromes of radiation illness, i.e. the bone marrow, the gastro-intestinal and the central nervous system-vascular syndromes. The effects can be detected by laboratory and clinical techniques.
    The stochastic effects might occur following low doses (below several tens or 100–200 mSv). The probability of consequences increases with the dose and the relationship between dose and effect is assumed to be linear. Accordingly, not having a “threshold” dose a certain risk – albeit very small – can be attributed to any low dose.
    Such late effects might be the development of malignant (cancerous) diseases and of the hereditary consequences. Here, it has to be mentioned that in human populations hereditary effects could not be detected even in the offsprings of the large population of A-bomb survivors in the first two generations. The possibility of hereditary alterations is known only from experimental observations in radiation biology.
    The model for assessing the detrimental health effects used for the deterministic effects is the non-linear-threshold (NL-T) model, while for the stochastic effects the linear-non-threshold “L-NT” one. In the low dose dilemma the problem raised is whether the use of the L-NT model is justified to attach any health risks to low doses.

WHAT IS “LOW DOSE”?

Low doses are considered by observations in epidemiology, cellular radiation biology and microdosimetry. The levels according to these views are demonstrated in Table 1.
    Based on epidemiological data of radiation-induced cancer occurrences, various authors agree that low dose is below 200 mGy as under this level the statistical evaluation of data becomes more and more uncertain (UNSCEAR 1994; Tubiana et. al. 1995; Heidenreich et. al. 1997). Accordingly, based on the frequency of cancer cases the extrapolation of risks from high doses to low ones is not justified.
    Certain cellular reactions like enzyme inductions, DNA-repair processes, adaptive responses, chromosome aberrations, etc. could already be observed between 10 and 100 mGy by various sensitive assay techniques (Table 2). Therefore this dose-range is considered low. In general, the doses causing fully recoverable cellular damages or alterations might be considered low doses in the cell biology.
    In microdosimetry the low dose is defined when 20 per cent of targets, i.e. cells in a tissue are hitted (Bond et al., 1988; Feinendegen et al., 1988; Booz and Feinendegen, 1988).
Table 1.
Dose ranges considered low in various approaches to biological effects of ionizing radiations


Approaches	mGy, mSv	References
For stochastic effects as carcinogenicity for gamma and x-rays for neutrons For cellular reactions By microdosimetrical consideration	200 200 50 10–100 when less than 20 % of “gross sensitive volume – GSV” (F target) will be hit once	NCRP 1980 ICRP 1991 Fry 1996 UNSCEAR 1994 UNSCEAR 1994 See Table 2 Feinendegen 1990
For comparison: The avarage natural background in a year in the life-time of a person “Insignificant individual dose” “De minimis” dose	3 50–200 0.01 0.01	Webb and McLean 1977 Kocher 1987

    Among the low dose radiation-induced cellular alterations recently special interest has been focussed toward the hormesis and adaptive responses. Although these phenomena, i.e. inducing stimulatory or beneficial effects are more and more targets for research, no direct evidence is available for their possible impact on human radiation protection.
    It is also worth mentioning that when individual radiosensitivity of persons was studied through the frequencies of radiation-induced lymphocytic micronuclei following in vitro irradiation of individual blood samples, below 200 mGy the responses were found to be unrelated to the absorbed dose (Köteles et al. 1997). These data suggest the importance of other factors in individual sensitivity besides the dose. On the other hand, the data point to the existence of dose-effect modifying biological factors making the response statistics uncertain like in epidemiology below the same dose range.
    In the foregoings the dose range was given in mGys. It has to be recalled that the natural background from cosmic and terrestrial sources is appr. 3 mGy in world average. This level means that 1 hit offends each of our cells once in a year! For comparison of considerations on low doses it has to be noted that earlier the opinion was expressed that 10 µSv for an individual is an “insignificant dose” (Webb and McLean 1977) or with an other wording 10 µSv is a “de minimis dose” (Kocher 1987). The expression comes from the language of jurisprudence, i.e. “De minimis non curat lex”, i.e. – the law does not care with minimal causes or effects. The limitations and consequences of these expressions have been outlined and criticized (Lindell 1989), still 10 mSv per year is considered to be a dose to any member of the public the source or practice of which may be exempted from requirements of radiation protection standards without further consideration (IAEA-IBSS 1996). At dose levels when “the collective dose committed by one year of performance of the practice is no more than about 1 man-sievert or an assessment for the optimalization of protection shows that exemption is the optimum option” the risk assessments based on the collective dose is not justified (IAEA-IBSS 1996).
Table 2.
Examples for cellular responses and alterations provoked by low doses


Response/alteration	Dose-range mGy	References
Free radicals granulocyte oxidant production increases superoxide dismutase in spleen increases oxidative stress increases Cellular responses Lymphocyte mitogenic stimulation by lectins increases Thymidin kinase activity Phospholipase C, Adenylatecyclase Guanilatecyclase increases Rosette formation CHO-CD2+ fenotype alteration Spleen colony formation stimulation Mutagenic alterations lymphoblast 6-thioguanin resistance (6-TG') mutant formation increases Nuclear structure chromatin conformation alteration Cytogenetic alteration micronucleus formation Cell membrane stucture and function lipid composition changes antioxidant capacity decreases micromorphological alteration lectin binding alteration Adaptive response develops Tumor metastasis reduced	0,1–1 100 50 10–40 10 2,5 10 6 10 40–250 >10 10–100 10–100 250 5–10 200	Vicker et al. 1991 Yamaoka et al. 1990 Emerit 1997 Makinodan and James 1990 Nogami et al. 1994 Feinendegen et al. 1988 Krymskx-Ruda et al. 1992 Kitsiou et al. 1993 Rozhdestvensky and Fomicheva 1995 Grosovsky and Little 1985 Belyaev and Harms-Ringdahl 1996 Köteles et al. 1997 Petcu et al. 1997 Bojtor and Köteles 1998 Burlakova 1992 Burlakova 1992 Köteles 1979 Kubasova et al. 1981 a,b Köteles 1982 UNSCEAR 1994 Mosoi and Sakamoto 1990

Beside the doses the biological responses depend also on the dose rates. At low doses the decreasing dose rate results in the reduction of biological damages, therefore, the ICRP has introduced the “dose-dose rate effectiveness factor DDREF” in the assessment of risk, when the absorbed dose is below 200 mGy and when the dose rate is less than 100 mGy per hour at higher ones. Though in cases of various detrimental effects the value of DDREF might vary, the value of 2 was selected (ICRP 1991).
As low dose rates the value of 0,1 mSv per minute was considered by the (UNSCEAR 1994) for low LET radiations. The natural radiation background dose rate is 1–3 mSv per year.

THE MAIN ARGUMENTS RAISED AGAINST THE L-NT MODEL

The arguments of those who are opposing the L-NT modell can be summarized as follows though not necessarily including all the available reasoning:

Below 200 mSv no cancer cases were found in a significantly increased frequency among the A-bomb survivors (UNSCEAR 1994; Duport 1996; Little and Muirhead 1996, Heidenreich et al. 1997a and b; Pierce and Preston 1997).
No higher risk could be detected at high natural background areas though they might be 3–10-times higher than the average level (Yalow 1986; Kondo 1993; UNSCEAR 1994).
The carcinogenesis is not a first order kinetic process, i.e. the hit of cellular genes at sensitive sites or the malignant transformation of one or a few cells does not lead necessarily to the clinical manifestation of a malignant disease (Duport 1996; Cox 1996; Pierce 1997; Mendelsohn 1997).
The repair of a few single strand breaks (SSB) in the DNA or double strand breaks (DSB) following a damage by low doses should not mean an overloading for repair capacity of a cell when the metabolism of cellular DNA and the repair of damages induced by other endogenous or exogenous factors is running with much higher intensity,
a real threshold might appear when the latency period is long enough compared with the life time of an individual,
by low dose exposures no detectable biological or health effects are provoked (Bond et al. 1996),
the L-NT model is for regulatory purposes as a tool for risk assessment but it is not verified scientifically or statistically in epidemiology (Becker 1997).

THE MAIN ARGUMENTS RAISED FOR THE L-NT MODEL

The arguments of those who are in favour of keeping this model further as valid for the risk assessment are mainly the followings:

The linearity is known and it has a great tradition in radiation biology since the epoch-making experimental results of Muller (1928) on the genetic effects on Drosophila.
For the stochastic effects the L-NT modell is used and recommended by the ICRP and it is widely used in assessment of health detriment.
In cellular radiation biology including observations on the survival of cells in culture, formation of cytogenetic aberrations and mutations many results can be fitted to a linear dose-response relationship or linear-quadratic one when the investigations are extended to higher doses, e.g. appr. above 1 Gy.
Recent data indicate significant increase of risk for thyroid cancer, breast cancer and malignancy to following in utero irradiations also in the range between 10 and 100 mGy (Clarke 1996; Sobolev et al. 1997; Miller and Boice 1997; Delongchamp et al. 1997).
Even among the A-bomb survivors the risk of cancer increased already above 50 mGy significantly, though it is obvious that the risk below 100 mGy is really small (Pierce et al. 1996).
Among the “liquidators” of the Chernobyl accident site increases of malignant tumours of the digestive system were observed up to 1995. The average dose of the studied cohort was 108 mGy (Ivanov et al 1998).
It is also repeatedly mentioned that the consequences of DSB if not repaired are more serious than the consequences of SSBs.

CONCLUSIONS

It is foreseen that the multisided debate will be continued but at this stage some views can be delineated as conclusions:
    Further research and investigations both on the cell biological as well as on the epidemiological aspects of health consequences of low doses are necessary (Little 1990; Clarke 1991; Oftedal 1991; Modan 1993; Schull 1996).
    It has to be realized that a biological response itself experienced following rather low doses does not mean detrimental health consequences.
    The L-NT model might be too conservative and unjustified but at present it seems to be safe enough to ensure the safe application and uses of ionizing radiation and nuclear energy.
    The rejection of the L-NT modell and the acceptance of a threshold in cases of stochastic effects would raise many questions concerning the regulatory actions. These foreseen questions like the safe thresholds for late effects, for different population groups, for various practices, etc. are hardly answerable at the moment. It seems to be easier, however, to reach an agreement on the level of acceptable risk instead of the risk threshold dose.
    The debate, however, reveals the important aspects of the risk assessment and risk perception of the society. The professionals themselves are grouped – certainly not halved as the opponents of L-NT are probably still in minority. It is, however, a warning not to overestimate the risk due to the use of ionizing radiation and nuclear technology especially when proper radiation protection services are provided. The use of fire is unavoidable for mankind, though also dangerous, therefore the human society elaborated ways and means of fire protection. A similar attitude is needed for the use of radiation.
    And last but not least the society at large has to perceive the various risks in an industrialized country in a comparative way. In this case, the real risks due to radiation are not at the first place as certain interviewed student groups have assessed it (UNEP 1985; Faragó and Engländer 1987).
    Professionals in occupational and environmental medicine might also assist in releasing the people from irrational anxieties, the latter being also an etiological contributor for many diseases.

REFERENCES

The References has intended to give only a few references out of the vast literature for the first orientation of the reader.

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