The Cancer Risk from Low Level Radiation

Bernard L. Cohen
Dept. of Physics
University of Pittsburgh
Pittsburgh, PA 15260

Telephone: (412)624-9245
FAX: (412)624-9163
e-mail: blc@pitt.edu

INTRODUCTION

	. It is commonly stated that “any radiation dose, no matter how small, can cause cancer”. The basis for that statement is the linear-no threshold theory (LNT) of radiation carcinogenesis. According to LNT, if 1 Gy (100 rads) of exposure gives a cancer risk R, the risk from 0.01 Gy (1 rad) of exposure is R/100, the risk from 0.00001 Gy (1 millirad) is R/100,000, and so on. Thus the cancer risk is not zero regardless of how small the exposure.
	However, over the past several years, a strong sentiment has developed in the community of radiation health scientists to regard risk estimates in the low-dose region based on LNT as being grossly exaggerated or completely negligible. For example, the 6000 member  Health Physics Society, the principal organization for radiation protection scientists, issued a position paper (HPS 1996) stating “Below 10 rad ….risks of health effects are either too small to be observed or are non-existent”. A similar position statement was issued by American Nuclear Society. When the Health Physics Society Newsletter asked for submission of comments on validity of LNT, there were about 20 negative comments submitted and only a single comment supportive of LNT. In a worldwide poll conducted by the principal on-line discussion group of radiation protection professionals (RADSAFE), the vote was 118 to 12 against LNT  A 2001 Report by the French Academy of Medicine concluded that LNT is “without any scientific validity, and an elaborate joint study by the French Academy of Medicine and the French Academy of Sciences (Aurengo et al 2005) strongly condemned the use of LNT. While U.S. official agencies have been slower to accept this position, the U.S, National Council on Radiation Protection and Measurements (NCRP) stated in NCRP Publication No. 121 (NCRP 1995)  “Few experimental studies and essentially no human data can be said to prove or even provide direct support for the [LNT] concept”, and in NCRP Publication No.136 (NCRP-2001) stated “It is important to note that the rates of cancer in most populations exposed to low level radiation have not been found to be detectably increased, and in most cases the rates appear to be decreased”. A group of scientists opposing use of LNT (Radiation Science and Health) submitted   several hundred papers supporting their position to National Research Council.
	Beyond failure of LNT, there is substantial evidence that low level radiation may be protective against cancer; a view known as “hormesis”. There is an International Hormesis Society which sponsors an annual International Scientific Conference and publishes a peer reviewed scientific journal and a regular newsletter
	The purpose of this paper is to review the basis for LNT and to present some of the mostly recent information that has caused this strong  shift in sentiment. Other recent reviews have been published with somewhat different approaches to similar objectives (Feinendegen 2005, 2005a, Tubiana 2005).

PROBLEMS WITH THE BASIS FOR LINEAR-NO THRESHOLD THEORY

	The original basis for linear-no threshold theory (LNT), as that theory emerged in the mid-twentieth century, was theoretical and very simple. A single particle of radiation hitting a single DNA molecule in a single cell nucleus of the human body can initiate a cancer. The probability of such a cancer initiation is therefore proportional to the number of such hits, which is proportional to the number of particles of radiation, which is proportional to the dose. Thus the risk is proportional to the dose – this is linear-no threshold theory.
	An important problem with this simple argument is that factors other than initiating events affect the cancer risk. Human bodies have biological defense mechanisms which prevent the vast majority of initiating events from developing into a fatal cancer (Pollycove 2001).  A list of some of the most important examples including how they are affected by low level radiation follows (Feinendegen 2005):
  --- Our bodies produce repair enzymes which repair DNA damage with high efficiency, and low level radiation stimulates production of these repair enzymes.
  ---Apoptosis, a process by which damaged cells “commit suicide” to avoid extending the effects of the damage, is stimulated by low level radiation. A similar effect is achieved by premature differentiation and maturation to senescence.
  ---The immune system is important for preventing mutations from developing into a cancer; there is abundant evidence that low level radiation stimulates the immune system, but high radiation levels depress it.
  ---The overwhelmingly most important cause of DNA damage is corrosive chemicals (reactive oxygen species -ROS); there are processes for scavenging these out of cells, and low level radiation stimulates these scavenging processes (Kondo 1993). Elevated ROS levels have been shown to initiate a broad array of biochemical reactions that are stress responses, leading to the conclusion that “the best protection against stress is stress itself” (Finkel 2000)..
  ---Radiation can alter cell cycle timing. This can extend the time before the next cell division (mitosis). Damage repair is most effective before the next mitosis, so changing this available time can be important (Elkind M, personal communication).Altered cell timing can also affect DNA repair processes in many ways by changing chemical processes (Boothman 1996)
 ---Various other effects of low level radiation on cell survival have been observed and are referred to as “low dose hypersensitivity”, “increased radiation radioresistance”, and “death inducing effects” (Bonner 2004)
	It is now recognized that development of cancer is a much more complex process than was originally envisioned. The role of “bystander effects”, signaling between neighboring cells relevant to their radiation experiences, is now recognized to be an important, albeit poorly understood, factor In fact it seems that tissue response, and even whole organ response, rather than just cellular response, must be considered (Aurengo et al 2005) .
	There is also apparently obvious evidence for failure of the original simple model. For example, the number of initiating events is roughly proportional to the mass of the animal – more DNA targets mean more hits. Thus the simple theory predicts that the cancer risk should be approximately proportional to the mass of the animal. But the cancer risk in a given radiation field is similar for a 30 g mouse and a 70,000 g human. As another example, our very definition of dose, based on the energy absorbed per unit mass of tissue, which is proportional to the number of radiation hits per unit target mass, would be misleading if only the total number of hits (which is proportional to the number of initiating events) were relevant regardless of the target mass.
	A detailed theoretical approach to evaluating the validity of LNT is based on the commonly accepted idea that double strand breaks (DSB) in DNA molecules are the principal initiating event in causing cancer. But DSB are also caused by endogenous corrosive chemicals, reactive oxygen species (ROS).In fact the DNA damage caused by radiation is mostly due to the production of ROS by the ionizing effects of the radiation on omnipresent water. It is estimated  that endogenous ROS causes about 0.1 DSB per cell per day, whereas 100 mSv (10 rem) of radiation, which is close to the upper limit of what is normally called low level radiation, causes about 4 DSB per cell (Feinendegen 2005). Assuming that the number of cancers is proportional to the number of DSB, a 100 mSv dose of radiation would increase the lifetime (28,000 days x 0.1 DSB/day) risk of cancer by only about (4 / 2800=) 0.14%, whereas LNT predicts an increase of 1%. From this it is concluded that the underlying assumption of LNT that cancer initiating events are the controlling factor in determining the dose-response relationship for radiation is a serious over-simplification

DIRECT EXPERIMENTAL CHALLENGES TO THE BASIS FOR LNT

	A direct demonstration of the failure of the basis for LNT derives from microarray studies determining  what genes are up regulated and down regulated by radiation.. It is found that generally different sets of genes are affected by low level radiation than by a high level dose. For example, in one study of mouse brain (Yin et al 2003), 191 genes were affected by a dose of 0.1 Sv but not by a dose of 2.0 Sv, 213 genes were affected by 2.0 Sv but not by 0.1 Sv, while 299 genes were affected by both doses. The 0.1 Sv dose induced expression of genes involved in protective and repair functions while down-modulating genes involved in unrelated processes.
	A similar study with even lower doses on human fibroblast cells (Golder-Novoselsky et al 2002) found that a dose of 0.02 Sv caused more than 100 genes to change their expression, and these were generally different than the genes affected by 0.5 Sv. The former group was heavily weighted by stress response genes
	Several other microarray studies have shown that high radiation doses which serve as the calibration for application of LNT, are not equivalent to an accumulation of low radiation doses (Tubiana 2005).
	Sophisticated experimental techniques have been developed for observing the effects of a single alpha particle hitting a single cell. It was found (Miller 1999) that the probability for transformation to malignancy from N particle hits on a cell is much greater than N times the probability for transformation to malignancy from a single hit. This is a direct violation of linear-no threshold theory, indicating that estimated effects based on extrapolating the risk from high exposure, represented by N hits, greatly exaggerates the risk from low level exposure as represented by a single hit.
	 A very clear demonstration of a threshold response, in contrast to LNT, was found in tumor induction by irradiation throughout life of mouse skin (Tanooka 2001). For irradiation rates of 1.5 Gy/week, 2.2 Gy/week, and 3 Gy/week, the percentage of mice that developed tumors was 0%, 35%, and 100% respectively.. 

EFFECTS OF LOW LEVEL RADIATION ON BIOLOGICAL DEFENSE MECHANISMS

Adaptive response
	An important type of biological defense mechanism is known as “adaptive response” (UNSCEAR 1994) - exposing a cell to a stress like radiation stimulates the natural defense against such stresses and hence protects against subsequent further stresses. On an experimental basis, this is most easily studied by exposing cells to a low dose to prime the adaptive response and then later exposing it to a high radiation “challenge dose”; the adaptive response is observed as the reduced effect of the challenge dose in comparison with a similar challenge exposure without the priming dose. 
	The most widely studied examples have involved observations on chromosome aberrations, perhaps the simplest tool for detecting genetic damage. It has long been recognized that radiation increases the number of these aberrations. However, an in vitro study on human lymphocyte cells (Shadley and Dai 1992) shows, in Table 1, how that process is affected if the high dose is preceded a few hours before by a low dose. We see that the number of chromosome aberrations caused by the high dose is substantially reduced. This is an example of adaptive response. 
	As an example of an in vivo  experiment (Cai and Liu 1990), it was found that exposure of mouse cells to 65 cGy (65 rad) caused chromosome aberrations in 38% of bone marrow cells and in 12.6% of spermatocytes, but if these exposures are preceded 3 hours earlier by an exposure to 0.2 cGy, these percentages are reduced to 19.5% and 8.4% respectively.  There are many other examples of such experiments, both in vitro  and in vivo (UNSCEAR 1994), and the results are usually explained as stimulated production of repair enzymes by low level radiation
	The effects of adaptive response in protecting against chromosome aberrations were observed for in-vivo human exposures in comparing residents of a high background radiation area (1 cGY/year) and a normal background radiation area (0.1 cGy/year) in Iran (Ghiassi-nejad et al  2001). When lymphocytes from these groups were exposed to 1.5 Gy (150 rad), the mean frequency of chromosome aberrations per cell was 0.098 +/- 0.012 for the high background area versus 0.176 +/- 0.017 for the low background area, a 4 standard deviation difference. Presumably adaptive response induced by radiation in the high background area protected its citizens against chromosome aberrations induced by the 1.5 Gy dose.
	A microarray study on human lymphoblastoid cells (Coleman et al 2005), was carried out to investigate the processes involved in adaptive response. A 0.05 Sv priming dose was followed by a 2.0 Sv challenge dose, and adaptive response was measured by the reduction of chromosome aberrations; the goal was to identify genes involved in adaptive response and determine how their states of activation were affected by the priming dose. It reported that 145 genes were affected by the priming dose, generally up-regulated for protein synthesis -- a key element in DNA repair -- and down-regulated for metabolic and signal transduction, perhaps as a means to conserve resources for devotion to DNA repair. Many genes associated with DNA repair, stress response, cell cycle control and apoptosis were strongly affected by the priming dose. The specifics of the process were found to be highly complex and sometimes pointing in different directions; For example, the TP53 gene which can act as either a tumor promoter or a tumor suppressor plays an important but not clearly defined role.
	Apart from studies using chromosome aberrations, another type of experiment that reveals effects of “adaptive response” involves detection of genetic mutations.  As an example of an in vitro  experiment (Kelsey 1991), it was found that an X-ray exposure of 300 cGy to human lymphocytes induced a frequency of mutations at the hprt  locus of 15.5 x 10-6, but if this large exposure was preceded 16 hours earlier by an exposure of 1 cGy, this frequency was reduced to 5.2 x 10-6.  
	As an in vivo  example (Fritz-Niggli 1991), it was found that the percentage of dominant lethal mutations in offspring resulting from exposures of female drosophila to 200 cGy of X-rays before mating was substantially reduced by preceding this high dose with an exposure to 2 cGy; for different strains of drosophila and different oocyte maturities these percentages were reduced from 42% to 27%, from 11% to 4.5%, from 40% to 36%, from 32% to 12.5%, from 42% to 30%, and from 51% to 22%.
	A technique has been developed for directly observing repair of DNA base damage (Le 1998). It was found that preceding an exposure to 2 Gy of gamma radiation with 0.25 Gy  4 hours before reduced the time for 50% DNA lesion removal from 100 minutes to 50 minutes. The progression of the repair vs time is shown in Fig. 1 with and without the 0.25 Gy priming dose.
	From the types of data discussed above, one might consider the possibility that adaptive response is only effective in protecting against damage caused by subsequent large doses of radiation. But there are data on its effectiveness against spontaneous transformation to malignancy on cells with a predisposition to such transformation. This was shown (Azzam 1996) for exposures of C3H 10T1/2 mouse cells where one day after exposure to low doses of radiation  the rate of spontaneous neoplastic transformation was reduced by 78%. In a similar experiment (Redpath 1998) with human HeLa x skin fibroblast cells, the reduction was by 55%. The dependence on dose for this cell type is shown in Fig.2 (Redpath 2003) with error bars indicating 95% confidence intervals. We see there that the effect is statistically indisputable even at very low doses, below 1 cGy.
	The question has been raised as to how long adaptive response persists following a priming dose. In one in vivo experiment (Zaichkina et al 2003) measuring chromosome damage in bone marrow cells of mice, both spontaneously and by a challenge dose, adaptive response was found after 1, 3, 6, 9, and 12 months following priming doses of 0.1 and 0.2 Gy, and the protection against spontaneous damage persisted to the end of life (20 months).
	This adaptive response protection against spontaneous development of cancer may be understood from effects of radiation on corrosive chemicals (ROS). Since ROS is the dominant cause of spontaneous cancers through initiating DNA damage, reducing the amount of ROS and increasing the amount of antioxidants that scavenge them out of cells is protective against development of spontaneous cancers. The results of a study of these on rat cells (Yamaoka 1991) are shown in Fig. 3. We see there that 50 cGy of X-ray exposure decreases the amount of the oxidant lipid peroxide by about 20%, and increases the amount of the antioxidant SOD by about 25%, and that these beneficial effects are appreciable over the entire dose range up to above 100 cGy. . Many other studies with similar results have been summarized and extended in a recent report (Yukawa et al 2005). .

	Stimulation of the immune system

	Since the immune system destroys cells with persistent DNA damage and is thus important in protecting against the development of cancer, the effects of low level radiation on it are relevant here.  Such effects on several different measures of the immune response (Liu 1992) are listed in Table 2.  We see that by each of these measures, the immune response is increased by low level radiation, and increasingly so at least up to 7.5 cSv.
	The results of one study of this effect over a wide range of radiation doses (Makinodan 1990) is shown in Fig. 4. We see there increases in immune response by 80% in vitro  and by 40% in vivo  at about 20 cGy followed by a rapid decrease to well below the unirradiated level at doses above 50 cGy.
	In a review (Liu 2003) of extensive mouse studies utilizing about 10 levels of whole body radiation exposure, effects on 52 immunologic parameters were analyzed to determine dose-response curves for two categories of these The first category included 20 parameters which would lead to decreased immune activity, for which the results are shown in the upper part of Fig 5, and the second category included the remaining 32 parameters that would lead to increased immune activity for which the results are shown in the lower part of Fig. 5. We see from Fig. 5 that low doses down-regulate the parameters indicative of decreased immune activity, and that these low doses up-regulate parameters indicative of increased immune activity. In both cases, these effects are reversed for high level radiation exposure. The conclusion is that low level radiation increases immune activity and high level exposures reduce immune activity, in agreement with what is seen in Fig. 4.	
	Contrary to expectations from the basic assumption of LNT that the cancer risk depends only on total dose, effects on the immune system are very different for the same total dose given at low dose rate vs high dose rate. In a study of effects on various indicators of immune response in several wild-type mouse strains (Ina and Sakai 2005), continuous whole body irradiation at 1.2 mGy per hour stimulated immune response as shown for a few example indicators in Fig. 6, but the same doses given at a high rate had the opposite effect.
	Further information on the dose rate dependence was reported in a mouse study of thymic lymphomas (Ina et al 2005). Acute challenge doses totaling 7.2 Gy induced tumors in 90% of the mice, but if the mice were previously exposed at a rate of 1.2 mGy per hour for 258 days (a total of 7.2 Gy) prior to the 7.2 Gy challenging dose, only 43% developed such tumors -- this may seem like an extreme case of adaptive response although the priming dose is equal to the challenge dose and doubling the total dose resulted in far fewer tumors. But most significantly for the present discussion, the low dose rate exposure, even extended to 450 days for a total exposure of 12.6 Gy, resulted in no tumors without a challenging dose. Various indicators of immune response were significantly increased by the continuous whole body radiation, and the authors attribute their observations to stimulation of the immune system by this radiation
	Several studies have shown that the immune system provides resistance to metastasis of tumors; one example is shown in Fig. 7. When tumor cells are transplanted into the groins of mice, the rate of their metastasis into the lung is cut about in half by total body irradiation with 15-30 cGy 12 days after the transplantation (Sakamoto 1997). Doses above 50 cGy on the other hand, reduce the immune response, leading to increased rates of metastasis. A study in rats (Hashimoto 1999) showed that total body irradiation – but not tumor irradiation – with low level radiation reduces the rate of metastasis and increases infiltration into the tumor of immune system agents (Makinodan and James 1990).
	Studies on naturally cancer-prone mice (Mitchel et al 2003) found that, while low level radiation exposure does not prevent eventual development of cancer, it delays the process substantially. Total body irradiation with low level radiation has also been shown to reduce tumor size (Makinodan 1992, Anderson 1992). The only reasonable explanation for such effects of total body low level radiation would seem to be stimulation of the body’s immune system.

CANCER RISK VS DOSE IN ANIMAL EXPERIMENTS

	There have been numerous direct studies of cancer risk vs dose, testing the validity of LNT, with animals exposed to various radiation doses. An example was a series of external gamma ray exposure studies at Oak Ridge National Laboratory, for which one result (Ullrich and Storer 1979) is shown in Fig. 8; we see there clear evidence for failure of LNT in the low dose region. In those experiments, exposed animals lived considerably longer (up to 40%) than their controls. Another example was a series of animal studies at Argonne National Laboratory in the 1950s qnd 1960s with injection of radioactive materials; these are reviewed by Finkel and Biskis (1962,1969). The results of one of these studies, for bone cancers in mice injected with radioactive isotopes of calcium and strontium (Finkel and Biskis1968), is shown in Fig. 9. Nearly all of these studies indicate, with high statistical significance, that linear-no threshold theory over-estimates the cancer risk from low level radiation, generally suggesting a threshold.
	A review of over 100 such experiments (Duport 2001) involved a total of 85,000 exposed animals with their 45,000 corresponding controls, with a total of 60,000 and 12,000 cancers in exposed and control animals respectively. In cases where cancers were observed in control animals, either no effect or an apparent reduction in cancer risk was observed in 40% of the data sets for neutron exposure, 50% of the data sets for X-rays, 53% of the data sets for gamma rays, and 61% of the data sets for alpha particles. 

CANCER Risk vs dose:  data from human exposures 

Data cited as supportive of LNT

	The principal data that have been cited by those in influential positions to support LNT are those for solid tumors (all cancers except leukemia) among the Japanese A-bomb survivors. The data up to 1990 (Pierce 1996) are shown in Figure 10, where the error bars represent 95% confidence limits (2 standard deviations).  If error bars are ignored, the points do indeed suggest a linear relationship with intercept near zero dose.
	But the data themselves give no statistically significant indication of excess cancers for doses below about 25 cSv. This conclusion applies to the incidence data as well as to the mortality data (Heidenreich 1997).  In fact, it was shown (Cohen 1998) that considering the three lowest dose points alone (i.e. up to 20 cSv), the slope of the dose-response curve has a 20% probability of being negative (risk decreasing with increasing dose). A recent update (Preston et al 2004) of the data on A-bomb survivors has been published but with insufficient detail to repeat the above analysis. a crude preliminary analysis indicates that the above conclusions will not be appreciably changed
	The data on leukemia among A-bomb survivors (Pierce 1996) are shown in Figure 11, with error bars indicating 95% confidence limits.  These data strongly suggest a threshold above 20 cSv, and this difference from LNT expectations is recognized by the authors and by all widely recognized reviews.
	The principal other evidence that has been widely cited as supporting LNT is the IARC (International Association for Research on Cancer) studies of monitored radiation workers. The first and most fully reported (Cardis 1995) was a study of 95,673 monitored radiation workers in U.S., U.K., and Canada.  For all cancers except leukemia, there were 3,830 deaths but no excess over the number expected.  The risk is reported as -0.07/Sv with 90% confidence limits 
(-04 , +0.3). There is surely no support for LNT here.
	However, for the 146 leukemia deaths, they did report a positive risk versus dose relationship and vociferously claimed that this supports LNT.  Their data are listed in Table 3.  It is obvious from those data that there is no indication of any excess risk below 40 cSv (even the excess for >40 cSv is by only 1.4 standard deviations).  The conclusion by the authors that this supports LNT is based on an analysis which arbitrarily discards the data in Table 3 for which o/e (observed/expected) is less than unity! They thus arbitrarily discard three of the seven data points.
	A follow-up study by the same group involved 407,000 monitored workers in 154 facilities spread through 15 countries, and reported results only as excess risk per Sv, assuming LNT. Thus a data display similar to that in Table 3 cannot be given here, but since the lead author is the same, it seems reasonable to assume that similar questionable procedures were used. No information on smoking status, an important risk factor for cancer, was collected. There was no consideration given to non-occupational exposure; the average occupational exposure was 2 cSv and 90% were below 5 cSv, whereas the average person is exposed throughout life to about 25 cSv of non-occupational radiation with large variations, typically at least 10 cSv, depending on geography and medical treatment. Thus the “signal” is very much smaller than the noise, making any conclusions about validity of LNT highly debatable. Another weakness is that most of the data were derived from photographic film badges which are sensitive to humidity and temperature; the films were handled differently in the 15 different countries (and also frequently by different organizations in the same country) which reduces the reliability of the results. There are other inherent problems in combining data from many different sources such as differences in ethnicity and socioeconomic status. If the data from just one of the 15 countries, Canada, are excluded, the excess risk is no longer statistically different from zero
	Many other studies have been reported on cancer risk vs dose for such normal occupational exposures. In response to heavy media coverage of some non-scientific reporting, a $10 million study (Matanoski 1991) was carried out by the U.S. Center for Disease Control and Prevention of workers in eight U.S. Navy shipyards involved in servicing nuclear-propelled ships. The study included 28,000 exposed workers and 33,000 age- and job-matched controls who worked on non-nuclear ships. The former group all had exposures above 0.5 cSv and average exposures of 5 cSv. The cancer mortality rate for the exposed was only 85% of that for the unexposed, a difference of nearly two standard deviations. Hiring procedures, medical surveillance, job type, and other factors were the same for both groups, so the often used explanation of “healthy worker effect” does not apply here - the study was specifically designed to eliminate that factor. The issue of non-occupational exposure was not addressed, but there was a high degree of homogeneity among the different worker groups being compared.
	More discussion of “healthy worker effect” may be appropriate here. In studies comparing mortality rates among employed workers with those for the general population, it is invariably found that employed workers have lower mortality, and it is widely understood that this results from the fact that unemployed persons may be unemployed because of health problems which lead to their earlier demise. However it has been pointed out (Monson 1986) that healthy worker effect should not apply to cancers occurring long after their initial employment because health problems leading to such cancers would not be apparent in a pre-employment medical exam. A direct test of this in Sweden (Gridley 1999) comparing 545,000 employed women with 1,600,000 unemployed women found that the standardized cancer incidence rate for employed women was 1.05 (1.04-1.06) times higher than for the unemployed women. This would certainly seem to eliminate healthy worker effects for cancer.
	Several other studies of cancer rates among people whose employment involves radiation exposure have been published:
	---Studies of British radiologists compared with other British medical practitioners (Berrington et al 2001) found that radiologists who began work in earlier years, when radiation exposure restrictions were much looser than recent standards, did experience excess cancers. But among the most recent cohort, radiologists who began work between 1955 and 1979, cancer mortality was only 0.71 (95% confidence limits, 0.49 - 1.00) times that of other medical practitioners who presumably had considerably lower radiation exposures.
	 ---A study of medical X-ray workers in China (Wang 2002) used cancer incidence rather than mortality, and a comparison group of workers in the same hospitals who were not involved with X-rays. The relative risks for earlier workers whose average exposure was 55 cGy were 2.4 for leukemias and 1.2 for solid cancers, while for the more recent workers whose average exposure was only 8.2 cGy, these risks were 1.73 for leukemias (based on 11 cases) and 1.06 (based on 232 cases) for solid cancers. For the recent workers, the differences from 1.0 are not statistically significant. 	
	---A U.S. study of 146,000 radiologic technologists (Mohan 2003) used only the total U.S. population as a comparison group and reported an SMR of 0.82 for all cancers, but a statistically significant increase among those first employed before 1940 as compared with those who began work after 1960.
	---A review of studies of 8 cohorts of radiologists and radiological technologists in various countries, comprising 270,000 monitored radiation workers (Yoshinaga 2004), concluded that there was good evidence for excess cancers among the early workers, but no such evidence among more recent workers.
	---A study of 22,000 monitored workers in the French nuclear power industry (Rogel 2005) found that the cancer mortality rate was only 0.58 (90% confidence interval 0.49 to 0.68) times that for the general population of France. The authors attribute this to healthy worker effect, but such an explanation seems like an extreme “stretch” for explaining such a large effect. There was no evidence for increased cancer as a function of increasing radiation exposure.
	Perhaps the most reasonable conclusion from studies of normally exposed radiation workers is that they give no conclusive information on effects of low level radiation. There is as much information suggesting zero or negative risk as information indicating the increased risk claimed by the IARC study. In any case, the fact that the monitored radiation received by the subjects was much lower than their non-occupational unmonitored exposures, make these data inherently of marginal significance.

Data contradictory to LNT
 	There are substantial statistically robust human data contradictory to LNT. One example is for breast cancer among Canadian women exposed to frequent X-ray fluoroscopic examinations in a tuberculosis sanitorium  (Miller 1989); the data for them are shown in Figure 12. While the statistical uncertainties are substantial, there seems to be a decrease in risk with increasing dose at least up to about 25 cSv.
	The data on lung cancer among these Canadian women (Howe 1995), and also a one point study of 10,000 individuals in Massachusetts (Davis 1989) are shown in Figure 13. Here again we see a decrease in the low dose region, in this case extending at least up to 100 cSv.  In Figure 13, these data are compared with lung cancer data for the Japanese A-bomb survivors, and we see there a difference between the two data sets that is clearly statistically significant; the A-bomb survivor data gives a much higher risk at all doses.  This is probably explained by the difference between the very high dose rate to the A-bomb survivors and the low dose rate from protracted fluoroscopic exams extending over many weeks. In any case, Figure 13 must give one pause before accepting the widely practiced approach of using A-bomb survivor data to predict risks from low dose rate low level radiation...Other arguments confirming the importance of dose rate, rather than only of total dose, have been expounded elsewhere (Tubiana 2005).
	In 1957, there was an explosion in an incredibly mismanaged radioactive waste storage facility at the U.S.S.R. Mayak nuclear weapons complex in the Eastern Urals of Siberia, causing large radiation exposures to people in nearby villages. A follow-up on 7852 of these villagers (Kostyuchenko 1994) found that the rate of subsequent cancer mortality was much lower among these than among unexposed villagers in the same area. The ratio for exposed to unexposed was 0.73 +/- 0.07 for 4 cGy, 0.61 +/- 0.07 for 12 cGy, and 0.72 +/- 0.12 for 50 cGy (here, +/- indicate one standard deviation).
	Studies are underway on the workers at this Mayak complex (Koshurnikova 2002), among whom there have been many excess cancers, but exposures were generally quite high and the data reported give little information on the dose-response relationship in the low dose region.
	Stimulation of the immune system by low level radiation is being used on an experimental basis for medical treatment of non-Hodgkin’s lymphoma with total body and half body (trunk only) irradiation. This radiation was administered  to one group of patients (“irradiated” group), but not to an otherwise similar “control” group, before both groups were given similar other standard treatments such as chemotherapy with or without accompanying high radiation doses to tumors. In one such study (Sakamoto 1997), after 9 years, 50% of the control group, but only 16% of the irradiated group had died. In a 25 year old study (Chaffey 1976) with different standard treatment, 4-year survival was 70% for the irradiated group versus 40% for the controls. In another study in that time period (Choi 1979) with a more advanced chemotherapy, 4-year survival was 74% for the irradiated group versus 52% for the control group. The information in the scientific literature is very supportive of using whole body or half body low level radiation to stimulate the immune system. U.S. physicians have not utilized it but further applications are underway in Japan.
	Potentially very significant human data on low level radiation is still in the preliminary research stage, but the results (Chen 2004) seem to be extremely interesting. In Taipai and other nearby areas of Taiwan, 1700 apartment units were built using steel contaminated with Cobalt-60, exposing 10,000 occupants for up to 20 years to an average of 40 cSv in total. From national Taiwan statistics, 232 cancer deaths  would be expected from natural sources, and according to LNT, there should have been 70 additional  cancer deaths due to this radiation.  However a total of only 7 cancers have occurred among these people. Differences in the age distribution of the affected people as compared with the general population have not been carefully investigated, but preliminary estimates are that this might reduce the expected number of cancers by about 20%, a relatively insignificant change. It would seem to be very important to do a full epidemiological study of this situation, but the funding agencies have not been cooperative, despite heavy pressures from some segments of the scientific community.
	The above described data deal with radiation by X-rays and gamma rays (and some neutrons for the A-bomb survivors). There are also impressive relevant data from radiation with alpha particles. One such study is of bone and head cancers among dial painters, chemists, and others occupationally exposed to ingested radium (Evans 1974).  There were no tumors among those with exposures below 1,000 cGy, but for dose ranges centered about 1800, 3500, 7500, and 20,000 cGy, 25% to 38% in each category developed tumors. Elaborate analyses of these data shows that a linear-no threshold fit is statistically unsupportable and a threshold behavior is strongly suggested.
	Several studies have reported that workers who inhaled plutonium, resulting in sizable radiation exposures to their lungs, have equal or lower lung cancer mortality rates than those not so-exposed (Tokarskaya 1997, Voeltz 1983, Gilbert 1989)
	Very strong evidence against LNT is provided by a very extensive study of lung cancer mortality rates, m, versus average radon exposure in homes for 1729 U.S. counties -- more than half of all U.S. counties, and including 90% of the U.S. population (Cohen 1995, 2005).  Plots of age-adjusted rates are shown in Figures 14a and 14c where, rather than showing individual points for each county, these are grouped into intervals of radon exposure (shown on the base-line along with the number of counties in each group) and plotted as the mean value of m for each group, its standard deviation indicated by the error bars, and the first and third quartiles of the distribution.  Figures 14b and 14d show these data corrected for prevalence of cigarette smoking. Note that when there is a large number of counties in an interval, the standard deviation of the mean is quite small. We see, in Figure 14, a clear tendency for lung cancer rates, with or without correction for smoking prevalence, to decrease with increasing radon exposure, in sharp contrast to the increase expected from LNT, shown by the lines labeled “Theory”. These data have been analyzed for over 500 possible confounding factors, including socioeconomic, geographic, environmental and ethnic associations (Cohen 2000), and the possible effects of an unrecognized confounding factor were investigated (Cohen 2005), but the conclusion remains firm that LNT fails very badly by grossly over-estimating the cancer risk from low level radiation.
	What has been interpreted as conflicting results were derived from a pooled study of seven case-control studies (Krewski 2005); shown in Table 4. We see there that none of the data points give a very statistically significant excess lung cancer risk, but the pattern  suggests an excess risk from radon exposures, although not necessarily increasing with exposure at least for the four lowest points which comprise the region of significance in Fig 14. A pooled study includes many complicated adjustments for differences among the different studies in the pool, and potential confounding factors with the adjustments for the few of them that are recognized might be a problem. If there is a conflict with Fig. 14, each of the several attempts to explain it as a problem with the latter have been shown to be completely implausible (Cohen 2005). Actually it is not clear that there is a conflict, because Fig. 14 is not a dose-response relationship for individuals exposed to radon, but rather is an experimental observation with extremely high statistical significance, to be compared with the prediction from LNT. That comparison indicates that the theory fails very badly, grossly over-estimating the risk from low level exposure. The results in Table 4 can hardly be interpreted as a test of LNT.
	
Dependence of latent period on dose

	There is a substantial body of data, both on animals and on humans, indicating that the latent period between radiation exposure and cancer death increases with decreasing exposure; these have been reviewed by Cohen (1980) and by Raabe (1994). An example of results for dogs injected with alpha particle emitters (Dougherty and Mays 1969) is shown in Fig. 15. These observations lead to the obvious conclusion that for low enough exposures, the latent period exceeds the normal life span, so no actual cancers develop.  Thus there is an effective threshold.
	This effect alone, even in the absence of all considerations discussed previously, would invalidate linear-no threshold theory as applied to low level radiation.

CONCLUSION

	The conclusion from the evidence reviewed in this paper is that the linear-no threshold theory (LNT) fails very badly in the low dose region, grossly over-estimating the risk from low level radiation. This means that the cancer risk from the vast majority of normally encountered radiation exposures is much lower than given by usual estimates, and may well be zero or even negative.

ACKNOWLEDGEMENT
The author acknowledges a great debt to Myron Pollycove and James Muckerheide for help in pointing out references involved in this paper.

TABLES 

Table 1: Effects of pre-exposure to 5 cGy on two types of chromosome aberrations in human lymphocyte cells, induced by 400 cGy of X-rays 6 hours later (Shadley 1992)

		     dicentrics & rings		           	 deletions
donor		400 cGy	(5 + 400) cGy		400 cGy	(5+400)cGy
#1		136	                 92				     52		       51
#2		178		    120				     62		       46
#3		  79		      50				      39		       15
#4		172		      42				      46		       34
#5		134		     106			      58		        41

Table 2: Effects of radiation on immune response.  Different columns are percent of response to various tests in unexposed mice, to response in mice exposed as indicated (Liu 1992). PFC = plaque forming cell; MLC = mixed lymphocyte culture, used as  test of T-cell function; Con A = concanavalin-A,  lectin that stimulates T-lymphocytes; NK = natural killer cells which recognize and kill tumor cells; ADCC = anti-body dependent cell mediated cytotoxicity, which assists NK activity.

Test			  2.5 cGy			5 cGy			       7.5cGy
PFC Reaction	  110				143				174
MLC Reaction	  109				133				122
Reaction to Con A      191				155				530
NK activity		  112				109				119
ADCC Activity	  109				128				132

Table 3: Leukemia deaths from International Association for Research on Cancer (IARC) Study (Cardis 1995). The final column is the ratio of observed to expected, O/E

Dose (cSv)			     Observed		     Expected		           	O/E

0-1					72			75.7				0.95
1-2					23			21.2				1.08
2-5					20			21.8				0.92
5-10					12			11.3				1.06
10-20					 9			  7.8				1.15
20-40					 4			  5.5				0.73
>40					 6 			  2.6 				2.3

Table 4: Odds ratios for lung cancer vs residential radon exposure from seven pooled case-control studies (Krewski 2005)

Radon level (Bq/m3)	    Odds ratio (95% C.I.)
	<25			1.00
	25-49			1.13 (0.95-1.35)
	50-74			1.09 (0.89-1.34)
	75-99			1.16 (0.91-1.48)
	100-149		1.24 )0.96-1.60)
	150-199		1.22 (0.87-1.71)
	>199			1.37 (0.98-1.92)

FIGURE CAPTIONS

Fig. 1: Comparison of removal of thymine glycol by A549 cells after 2 Gy irradiation, with (open squares) or without (shaded circles) a 0.25 Gy priming dose given 4 hours before (Le 1998).

Fig. 2: Transformations per surviving cell as a function of dose for HeLa x skin fibroblast human hybrid cells irradiated with gamma rays (Redpath 2003). Upper plot is of same data on an expanded scale. Error bars represent 95% confidence limits.

Fig. 3: Antioxidant SOD and lipid peroxide response to age and radiation of rat brain cortex (Yamaoka 1991)

Fig. 4: Immune system response to radiation. Mouse splenic cells primed with antigenic sheep red blood cells (Makinodan and James 1996)

Fig. 5: Dose-response curves constructed from multiple parameters of the immune system following whole body irradiation of C57BL/6 and Kunming mice (Liu 2003). Upper figure is for 20 parameters that lead to decreased immune activity, and lower figure is for 32 parameters that lead to increased immune activity

Fig. 6: Solid lines show activation by continuous low-dose-rate γ irradiation at 1.2 mGy hour−1 from 5 weeks of age, of three different immune cell populations in the spleens of C57BL/6 mice challenged intraperitoneally by SRBC; data are plotted as a function of irradiation time. Dashed lines are the same for un-irradiated control mice (Ina and Sakai 2005).

Fig.7: Spontaneous lung metasteses after total body irradiation of mice, given 12 days after tumor transplantation into groin (Sakamoto 1997) 

Fig. 8: Relative risk of lung cancer in mice following gamma ray exposure (Ullrich and Storer 1979)

Fig.9: Osteogenic sarcomas produced in CF1 female mice by injection of Sr-90 and Ca-45 at age 70 days (Finkel 1968). Sr-90 experiments used 810 mice and 150 controls; results for 1.3, 4.5, and 20 microcuries/kg, not shown on the plot, had ordinate values zero. 

Fig. 10: Excess deaths from solid tumors per 100 “expected” among Japanese A-bomb survivors (1950-1990) versus their dose (Pierce 1996). Error bars are 95% confidence limits.

Fig. 11: Excess deaths from leukemia per 100 “expected” among Japanese A-bomb survivors (1950-1990) versus their dose (Pierce 1996). Error bars are 95% confidence limits.

Fig. 12: Standardized death rates per million person-years from breast cancer among Canadian women after irradiation in fluoroscopic examinations versus their radiation dose (Miller 1989). Error bars are 95% confidence limits.

Fig. 13: Relative risk of mortality from lung cancer versus dose to lung, with 95% confidence limits. In upper figure with expanded vertical scale, circles are from (Howe 1995) and diamond is from (Davis 1989). In lower figure (Howe 1995), solid line connects data from Canadian fluoroscopy patients, and dashed line connects data from A-bomb survivors. 

Fig. 14: Age-adjusted lung cancer mortality rates, with and without correction for smoking prevalence, versus average radon level in homes for U.S. counties (Cohen 1995). See explanations in text. Fig. 14a and 14c are without smoking correction, for males and females respectively, and Fig. 14b and 14d are with smoking correction for males and females respectively.

Fig. 15: Survival time for beagle dogs who developed bone cancer from injections of various alpha emitting radioactive isotopes, vs dose to their bone at one year before death (Dougherty and Mays 1969).

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