REDUCED RADIO-BIOLOGICAL EFFECTIVENESS AT LOW-RATE, LOW-DOSE
EXPOSURES [DREF] : An Unwarranted Conjecture
Rudi H. Nussbaum, Portland State University, Portland OR 97205-0751/USA
and Wolfgang Köhnlein, Universität Münster/Germany
After the use of the A-bombs and the follow-up of its after-effects among a large group of survivors of Hiroshima and Nagasaki, (the LSS cohort), there has never been any doubt about the disastrous short- and long-term effects of exposures to high doses of radiation, nor about the numerical relation between high-dose exposure and excess risk. However, subsequent public acceptance of escalating billion-dollar investment in nuclear weapons production, in civilian nuclear energy and also in nuclear medicine, was predicated on the confident assurances of enthusiastic radiation experts that added exposures at dose levels acceptable to industry, would not be found detrimental to human health, they might even be beneficial !
Premature evaluations of the delayed effects of radiation among the Japanese survivors, as well as transference to humans of radiation effects in animals, lead to strongly-held optimistic convictions. For decades, any challenge to these tenets based on extrapolations by epidemiologic studies among populations with occupational and environmental exposures were received with enmity and rejection rather than as opportunities to test new hypotheses and increase our understanding. Nevertheless, optimistic expectations had to be scaled back continuously as a result of long-delayed excess cancers among the Japanese survivor population.
Direct Information on the relation between human cancer induction and radiation dose, in particular at low doses and low dose-rates, should be considered as the most reliable foundation for estimating occupational and environmental exposure risks from radiation releases during the various stages in nuclear technology - from uranium mining, to weapons testing, waste disposal and decommissioning. During these various phases, which include accidents, workers and the general public can be at risk by external and/or internal exposure to various ionizing radiations. Historically, at the time of most rapid build-up of this technology, when exposure standards for radiation protection had to be formulated, there were several major barriers to such a direct approach. First, there has been a scarcity of epidemiological studies among occupationally or environmentally exposed populations with sufficiently long follow-up times. Decades of follow-up are required to allow for long and varying periods of latencies for most malignancies. In the context of the times authoritative scientists asserted that low-dose studies would never be able to detect significant excess radiogenic incidence or mortality.
Probably the most important barrier to direct information on human cancer induction and radiation dose was the concentration in radiation epidemiology on the post 1950 follow-up of a large population of Japanese A Bomb Survivors. Early findings of the A-bomb study, strongly weighted toward medium to high doses, in combination with high-dose animal data, have continued to dominate the thinking about radiation health effects. Over recent decades, in view of long-delayed and still increasing excess cancer mortalities among the LSS cohort of A-bomb survivors, official cancer risks per unit exposure have had to be revised upward several times. Significantly, the models postulated for extrapolating A-bomb exposure risks downward to the occupationally relevant dose range, are based on transference of observed dose- and dose-rate effects in animals or animal cells under exposures to very high doses (several hundreds of cGy). A majority of radiation experts used these extrapolation models from animal and radio-biological findings to crystallize into firm expectations of much reduced biological effects per unit dose at low doses and low dose-rates (dose fractionation) in people.
A consequence of this mind set was that any epidemiologic evidence from studies of populations with occupational and environmental exposures most relevant to risk assessment, which were inconsistent with the above tenets, have routinely been received with angry rejection by a majority of experts and established radiation effects commissions. These groups refused to recognize that apparent discrepancies in findings among vastly different populations could serve as opportunities to test alternate hypotheses and to gain insight into poorly understood physico-chemical interactions of ionizing radiation with human health. Focus on the paradigm has meant that much less is known by radiation experts about the potentially much wider spectrum of health effects related to distributed or selectively concentrated radio-isotopes ingested into the body. In part, this is due to the lack of reliable methods of internal dosimetry. Yet many ailments are now showing up among atomic veterans, so-called downwinders of weapons production plants, and populations exposed to the Chernobyl fallout. Nevertheless, official scientific bodies have repeatedly denied any possible connection with radiation.
Thus, two basic assumptions have endured in slightly varying versions in all recent authoritative radiation effects reports such as UNSCEAR (1988), BEIR V (1990) or ICRP (1990) :
(1) that a linear, no-threshold dose-effect relation, fitted to the A-bomb mortality data over the complete dose range 0 - 400 cGy (Fig. 1, curve L) would overestimate occupational and environmental risks per unit dose by at least a factor two or more. Hence, low-dose risk (equivalent to the slope of the curve) should rather be determined from a concave dose-effect relation with steadily reduced slope at reduced dose, approximating the existence of a threshold dose range (Fig. 1, curve Q).
(2) that independent of the relation describing low dose effects, the "biological effectiveness" per unit dose is considerably lower (by at least a factor two) for fractionated or extended than for single exposures.
Therefore, reductions of linear risk estimates by so-called "Dose and Dose Rate Effectiveness Factors" or DREFs (ICRP), (UNSCEAR)  between 2-10 have remained part of risk evaluations by most official radiation protection commissions. For example, the authoritative BEIR V report (p. 22) states: "There are scant human data that allow an estimate of the dose-rate effectiveness factor." Nevertheless, in its Executive Summary, the most quoted part of this report, the committee recommends use of a DREF of at least two for environmental and occupational exposures . Again, the 1990 ICRP Recomendations  incorporate a DREF of two in their tables of occupational risk estimates.
The primary sources for the above two tenets (1) and (2) had been the concave dose relation for leukemia mortalities found at very high doses among the A-bomb survivors and animal, as well as animal cell studies at varying dose rates and total doses of several hundred cGy.
As an alternative to the representation of dose-effect relations as shown in Fig. 1, a more effective distinction between different risk models can be obtained by a loglog plot of excess relative risk per unit dose DR/DD (essentialiy the slope of the dose response curve) versus dose for different dose-dependencies (Fig. 2).
Let us now examine the above listed persistent assumptions (1) and (2) in the light of some relevant recent research outcomes:
A-bomb Survivors (LSS cohort)
1. A linear model of risk (L-model, Fig. 1, curve L or Fig. 2, curve 1) gives an excellent fit to the A-bomb data, when they are restricted to doses <200 cGy, both for leukemia and for all cancers. Adding a positive quadratic term (LQ-model, see Fig. 1, curve L or Fig. 2, curve 2 does not improve the fit. In fact, any DREF factor of much above one to correct for a presumed so-called "linear extrapolation overestimation" of risk, is quite inconsistent with the data, according to RERF scientists [5,6].
2. Kerma doses below 5 cGy and probably as low as 1.6 cGy have produced excess cases of acute lymphoid and chronic myeloid leukemia among A-bomb
survivors . Certainly, such a significant risk at very low single doses of exposure leaves little room for a "safe" (very low slope) range in the dose-effect relation.
3. When Aggregate cancer mortalities 1950-85 are plotted against mean kerma or organ absorbed dose for the dose subcohorts in the 0 - 100 cGy range, we find a strong indication for an initialiy much steeper slope below 10 cGy in the dose-effect relation (Figs. 3, 4), exactly the opposite of the postulated concave curve, illustrating the generally accepted LQ-model [8, 9]. Given the confidence limits of the 1950 - 85 cancer mortality data for the lowest LSS dose groups, together with documented nonuniform under-estimates of the mean doses for the control and the lowest exposure groups, a linear model with a single slope down to zero dose can not be excluded on the 95% level of confidence (p=0.05). However, consistency of our linear slope for the range 6- 69 cGy with that obtained by RERF scientists for the entire dose range under 200 cGy, strongly suggests a steeper initial slope, thus higher risk per unit dose, for the very low dose range 0 - 10 cGy resulting from a single A-bomb exposure (see Fig. 1, curve P; Fig. 2, curve 3 and Fig. 5) [8,9].
4. Another independent analysis of the same low-dose A-bomb data suggests a best fit to a convex mortality-dose relation of the form m = mo + aDb (b
5. One of the chief analysts of RERF data, D.A. Pierce, applied RERF's model, stratified for background rates according to age at time of bombing, sex, city and follow-up period, to the LSS dose groups below 100 cGy. He confirmed improvement in the fit (p=0.25) for that dose range, if instead of simple proportionality with dose, he assumed excess relative risk to be proportional to the square root of dose (Fig. 5) . The same convex dose dependence had earlier been suggested for the excess radiation risk in a mortality analysis of Hanford nuclear workers at very low accumulated doses (see below and Fig. 5) . On the basis of stringent statistical criteria, such convex (supra-Iinear) dose-effect curves from studies of these two very different populations are strongly suggestive, but not compelling. However, together with additional epidemiologic and radio-mutagenic evidence, a picture emerges which by its consistency, supports the hypothesis of an increased biological effectiveness per unit dose at very low doses, contrary to assumption (1) above.
1. There is now a large body of studies on childhood cancers following prenatal exposures, the first of which was Stewart and Kneale's Oxford Survey of Childhood Cancers. They all show significant excess risks for X-ray exposures down to fractions of a cGy,[13,14,15,16] thus leaving no room for a "safe" dose range for human exposure.
2. A 28-50 year follow-up study of over 31,000 Canadian women, following X-ray fluoroscopy as part of treatment for Tuberculosis, with doses ranging from 10 cGy or less per treatment to over 1,000 cGy accumulated dose, showed breast cancer mortalities most consistent with a simple linear dose-response model over the entire dose range . Considering the fractionation of dose in that study and the large range of accumulated doses, there is no support for either the quasi-threshold notion of the LQ model at low doses, or any reduced cancer induction at fractionated exposures in this study of female breast tissue.
3. The occupational radiation study by Mancuso, Stewart and Kneale (MSK) of Hanford nuclear workers, already mentioned above , was rejected and maligned by the community of radiation experts when it suggested that official risk estimates, based on extrapolations from the A-bomb study, implicitly using the above tenets, were off by at least a factor ten. Recent reanalysis by the same researchers, including updated Hanford mortality statistics, reconfirmed most of the earlier findings. A just completed DOE-sponsored mortality analysis for Oak Ridge nuclear workers 1943 - 84, using more conventional statistical methods, confirmed the much higher radiation risks at very low and protracted exposures found in the MSK Hanford study . These US worker data are also consistent with some studies of British nuclear workers  (Table 1 and Fig. 5). The most recent British nuclear worker study, involving a much larger study population, while broadly consistent with the US studies, would need further statistical refinement to be comparable in detail to the Oak Ridge study . However, that British study, too, found evidence for an association between radiation exposure and moriality from cancer, in particular leukemia and multiple myeloma, at very low accumulated doses, protracted over long periods of time . Neither of these recent epidemiological data do allow a statisticaily robust distinction between a linear and a convex dose-response relation. However, the values of excess relative risk DR/DD versus mean dose D in the representation suggested in Figs. 2 and 5 for three of the nuclear worker studies mentioned, as well as for the low-dose A-bomb data (see also Figs. 3, 4) are consistent with a convex (supra-linear) dose-effect relation (Fig. 5). Leaving the question of the correct shape of this curve aside for the moment (it is likely different for different populations), the aggregate of findings does establish significant excess risks for any dose over and above background and at background exposure rates, even in populations selected for good health (in US studies a 25% lower mortallty for all causes among nuclear workers compared to the general population) which clearly contradicts both tenets (1) and (2) and thus undermines the concept of "safe" occupational or environmental exposure levels. In addition, the mutually consistent magnitudes of the excess risk per cGy in these worker studies, in , comparison with the somewhat lower risks from the low-dose A-bomb data for a single exposure above 6 cGy mean dose (Table 1 and Fig, 5), suggest an increased, not a reduced risk per unit dose at very low and fractionated exposures. All serious challenges to the Oak Ridge data, attempting to dismiss them as "singular" or seeking to "reconcile" them with the A-bomb data,. have been effectively refuted by the authors of the study .
4. Also contrary to assumed reduced biological effectiveness at lower dose-rates, a survey of lung cancer studies among uranium miners found that relative risk for internal alpha radiation exposures increases significantly with decreasing exposure rates .
Mutational and Animal Data
While epidemiological studies involve whole organisms in the context of complicated co-exposures, selection, susceptibility factors, etc., studies of mutagenesis deal with greatly simplified systems, usually cell cuItures, Thus, in these studies there is greater opportunity for experlmental control and reliable measurement, however, their outcomes yield only an indirect and poorly known link to factors determining human health. Some animal studies are considered to provide closer models for human reactions to radiation exposures.
High-dose animal and radio-biological data on cell mutations have been the primary evidence cited for the two-fold DREF hypotheses (1) and (2). Several recent findings in these fields, however, contradict these assumptions:
1. Waldren et al.  have demonstrated that conventional methods for measuring mutagenesis in mammallan cells seriously underestimate the contribution of radiation to cancer and genetic diseases. They observed at least a 200-fold higher mutation frequency in the 0-50 cGy range than some previous conventional studies. Also, they find a supra-Iinear mutation-rate-dose relation (Fig.6). This study deserves confirmation, in particular at very low doses and varying dose-rates.
2. Grosovsky and Little studied mutagenesis in human lymphoblast cells over a wide range of doses and dose-rates. They found a linear dose dependence and no indication of a change in mutation frequency per unit dose between single and fractionated doses (Fig. 7) [23, 24]. Also, exposures to tritiated water and X-rays over a range of dose rates yielded no deviation from a proportional relation between mutation frequency and total dose .
3. Little showed significant differences, with regard to inhibitory effects of DMSO, dose response and the effects of changes in dose-rate for radiogenic induction of mutations in rodent, compared to human cells. While he confirms reduced effects in rodent cells with reduced dose rates at high total doses, no such effects are found in human cells and the dose response is linear in the range 0 - 250 cGy (Fig. 8a, b) . These results make the transference of rodent exposure findings to humans extremely questionable.
4. A recent radiation study on 378 beagle dogs with accumulated doses between 450 - 3000 cGy at varying rates of 3.8 - 26.3 cGy/day shows no relationship between tumor mortality and dose rate but a clear linear relation with accumulated dose .
Vigorous rejection by a majority of radiation experts of suggestions that the two long-held tenets mentioned above are inconsistent with current human data epidemiologic or mutagenic - may in part be based on the recognition that a convex dose-effect relation, especially at very low doses, cannot be reconciled with the long-known linear mutagenic effect of ionizing radiation, down to the lowest doses. In fact, any observed increased biological effectiveness per unit dose at near-background exposures which may well rapidly saturate at doses below 10 cGy, followed by a linear relation (as suggested by the A-bomb mortalities), would indicate the existence of one or several hitherto unrecognized pathways toward cancer induction, especially effective at very low exposures (where the linear effect is relatively small) and highly non-linear in dose  *' (footnote)
This is not the only evidence that our understanding of the radiation - chromosome interactions is rather incomplete. Other examples are: the association between the father's exposure to relatively low doses of external radiation and leukemia in his offspring , or genetic abnormalities that express themseives only after several generations of cell divisions in mouse cells after exposure to alpha particles  and also in hamster cells after exposure to X-rays [30, 31]. Finally, a new mechanism of inflammatory reactions in human blood has been found in the ultra-low dose range 5.4 - 235 microGy, with a linear dose-effect relation up to 100 microGy, followed by a plateau. This mechanism in blood is quite distinct from the effects of exposures at higher doses .
To summarize: for decades radiation researchers have focused their attention somewhat myopically on delayed cancer and genetic effects among A-bomb survivors - a highly selected group of individuals - and on much animal and radio-biological
research at very high doses. Specific low-dose or low dose-rate studies of populations or human ceils, that suggested that ionizing radiation might actually have an increased rather than a reduced biological effectiveness at low doses, have either been rejected outright, or ignored in reviews of radiation health effects. Only very recently have there been persistent suggestions in the literature that such unexpected effects which clash with firmly held beliefs among a majority of radiation experts, might involve hitherto unknown and rapidly saturating complex radio-biophysical or radiobiochemical mechanisms at very low doses, very different from the well-known mutational effects, proportional to dose,
" Two recent independent studies of correiations between neo-natal deaths and radioactive contamination of the environment by nuclear tests and the Chernobyl explosion, are consistent with the implications of Petkau's work on the effect on cell membranes of low-dose, low-rate exposures. lt is wellknown that membrane functions play a crucial role in the effective operation of the human immune system. All of these studies strongljy suggest much higher low-dose effects than a linear extrapolation from higher doses would predict. (see also refs. 9, 10, 12, 18,19-21):
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see also the book by GOULD JM and GOLDMAN BA, Deadly Deceit,- Low Level Radiation, High Level Cover-up. New York, Four Walls Eight Windows, 1990.
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