Comments on gLow-dose Extrapolation of Radiation-Related Cancer Riskh Low Dose Radiation Research Center, Central Research Institute of Electric Power Industry Our comments are provided below. We hope Committee 1 will take our comments into account for a better foundation document. 1. Another Source of Epidemiological Data (Chapter 2) As the final goal of radiation biology in relation to radiological protection is to understand the effects of low level radiation on human beings, it is reasonable to have epidemiology at the beginning of the Report. Chapter 2 summarizes the epidemiological data among cohorts having received medical exposure and exposure under industrial situation as well as A-bomb survivors. Without doubt each of them is very informative; however, we have another set of data which should be taken into consideration. Those are data from research works on health effects of those living in high natural background radiation area. The strength of these data are as follows; (1) they cover both males and females, (2) they cover all ages, (3) the exposure is protracted one at low dose rate, and (4) the exposure was under non-stressful situation compared to medical exposures or the exposure from A-bombs. These data have accumulated and many qualified papers have been published. For example, in an epidemiological study on high background area in China gman-yearh reached nearly 2 million, and no radiation-related increase in cancer mortality was observed (Proceedings of the 6th International Conference on High Levels of Natural Radiation and Radon Areas, held in Osaka, Japan will be published shortly). 2. Evidence for Increased Cancer Risk from Doses on the Order of 10 mGy (Chapter 2) Increased risk of mammary tumors among women who received fluoroscopic exposures is described as an evidence for carcinogenesis by doses on the order of 10 mGy. However, most of these cases are exposed to multiple exposures and the total dose was much higher; in some cases the total dose reached a few Gy or more iRadiat. Res. 145: 694-707, 1996j. It should not be reasonable, therefore, to refer these cases as an example for the increase in cancer by exposure on the order of 10 mGy. 3. Origin of Intra-/Inter-Cellular Signals (Chapter 3) DSB of DNA is the most important cause of biological effects as described in Chapter 3. DSBs are also significant origin of intra-/inter-cellular signals; however, recently we have a lot of evidences that cellular membrane is also the origin of signals affecting cellular radiosensitivity (Cell Mol Biol 47, 473-84, 2001). Therefore, cellular membrane should also be considered as important origin of signals that affect responses of a cell or cell population to ionizing radiation. 4. Small Amount of Remaining Damage after Low Level Exposure (Chapter 3) As is discussed in Chapter 3, it was reported that DSB was not repaired when its amount was small. This result has sometimes been mentioned as an example that the DSB rejoining was not perfect; however, this phenomenon should be a part of the mechanism to remove those cells containing potentially carcinogenic damage as described the original paper (Proc. Natl. Acad. Sci. USA.100, 5057-5062, 2003). 5. Linearity of Dose Responses for Carcinogenesis (Chapter 3) As discussed in Chapter 3, LNT hypothesis is based on the facts that (1) even a single track of radiation would induce clustered damage, and that (2) the repair cannot be error-free. These discussions are reasonable at cellular level. In the process of tumorigenesis, however, certain defense mechanisms of higher level, including immune system, are involved. Therefore, consideration at cellular level is not enough in discussion of cancer risk as is discussed in Chapter 4. 6. Suppression of Tumorigenesis through Adaptive Responses (Chapter 4) As mentioned in Chapter 4, the adaptive responses as well as bystander effects and genomic instability, are relevant to radiological protection only if they affects and suppress the carcinogenesis in vivo. In addition to reports cited in the Report, another report showing the suppression of tumorigenesis by protracted irradiation at low dose-rate was published ( Radiat. Res. 163, 153-158, 2005). 7. Implication of Bystander Effects and Genomic Instability for Risk Assessment (Chapter 4) The bystander effects and genomic instability have generally been tended to be discussed in the context that they would increase the risk from low dose radiation. In the Report (Chapter 4), however, important points are made: (1) both responses are dependent of the genetic background and they cannot be a general rule. (2) Investigation should be continued on the mechanisms underlying these phenomena and their relevance in radiological protection should be discussed based on scientific data. 8. Sources of Uncertainty (Chapter 6) The importance of uncertainty in risk assessment is emphasized in Chapter 6. Those factors described in this chapter as sources of uncertainty include both intrinsically uncertain ones, such as that associated with dose estimation, and those uncertainties due to our limited knowledge. Among the uncertainty sources of the latter category, the difference between males and females, difference between populations should be taken into consideration in the radiological protection. Furthermore, the age dependency and the difference among individuals, though not mentioned in Chapter 6, should be taken into consideration if we are to establish individual-based radiological protection system. 9. Gradualism (Chapter 6) The concept of gradualism is very reasonable from the view of radiation biology. As discussed in Chapter 6 lots of data have suggested that the biological effect tend to be attenuated when dose and/or dose rate decrease. In other words, DDREF should be larger for lower dose and/or dose rate. Therefore, DDREF should be defined as a function of both dose and dose rate (e.g. Radiat. Res., 160, 543-538, 2003). Currently DDREF is 2; however, the value of DDREF should be much larger toward zero dose in the ggradualism functionh. Considering the importance of the concept of gradualism, it is very disappointing that further discussion of the gradualism was not made in the Report. Committee 1 should emphasize the importance of this concept and suggest a more reasonable basis for radiological protection based on the concept of the gradualism. 10DAppropriateness of LNT Hypothesis One of the most important conclusions of the present Report is that due to the uncertainty involved in the estimation of risks from low level radiation, we cannot conclude whether there is a threshold or not. This is a scientific conclusion and it proposes further investigation of radiation biology at low dose and dose rate. However, the conclusion gthe LNT hypothesis remains the most prudent risk model for guidance of radiation protection.h is not scientific, but practical, political, or even philosophical. The report from Committee 1 should exclusively discuss scientific basis for radiological protection. 11. Conclusion The Report is, as a whole, very informative review of current knowledge in radiation biology in relation to radiological protection. Especially, it should be greatly appreciated that the Report emphasized the importance of the concept of the uncertainty and the gradualism, which would have a great influence on the framework of radiological protection. These concepts should be taken into consideration for more reasonable system for radiological protection. In this sense, the choice of LNT hypothesis is not appropriate as a conclusion of the Report. The validity of the hypothesis should be discussed based not only on science, but also on social and economic situation; and this kind of discussion is a matter for, probably, the Main Commission. The Report from Committee 1 should provide basis for a more reasonable radiological protection system based on the uncertainty and the gradualism, not a support of LNT.