nor the inverse dose-rate phenomenon should have any significant effect on the dose-response for cancer induction in humans. Furthermore, molecular mechanisms associated with the two phenomena have not been delineated, and it is not known whether HRS for cell lethality would cause an increase in deleterious effects in surviving cells or would actually decrease deleterious effects by increased killing of damaged cells. Also, it is not known what effect HRS for signal transduction pathways will have in mitigating or increasing deleterious effects. Most important, it is not known if HRS plays a role when radiation doses <100 mGy are delivered over weeks to months, which could be relevant for low doses of low-LET radiation. Finally, until the molecular mechanisms responsible for HRS are understood, its role in low-dose radiation carcinogenesis is uncertain.

Results of experiments that quantified chromosomal aberrations, malignant transformation in vitro, or mutations induced by relatively low total doses or low doses per fraction indicate that the dose-response relationship over a range of 20–100 mGy is most likely to be linear and not affected significantly by either an adaptive or a bystander effect. No data are available in this dose range for radiation-induced genomic instability. Furthermore, as stated previously, studies of malignant transformation in immortalized (already-transformed) cell lines may have little relevance to malignant transformation of normal nonimmortalized cells, especially in vivo where complex interactive processes can occur. However, the results from these in vitro transformation studies may have relevance for effects involved in promoting the immortalization process, possibly through the induction of genomic instability. Thus, the question of the shape of the dose-response relationship up to about 20 mGy remains, although several of the dose-response relationships described above appear to be consistent with extrapolation linearly down to about 5 mGy. The shape of the dose-response relationship up to 5 mGy might be determined with in vitro and in vivo experiments in which multiple doses of about 1–5 mGy are delivered over a long period. However, this question should be addressed rigorously by defining the molecular processes responsible for the end points in question at these very low doses.

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