Adaption By Low Dose Radiation Exposure: A Look at Scope and Limitations for Radioprotection.

The procedures and dose limitations used for radiation protection in the nuclear industry are founded on the assumption that risk is directly proportional to dose, without a threshold. Based on this idea that any dose, no matter how small, will increase risk, radiation protection regulations generally attempt to reduce any exposure to "as low as reasonably achievable" (ALARA). We know however, that these regulatory assumptions are inconsistent with the known biological effects of low doses. Low doses induce protective effects, and these adaptive responses are part of a general response to low stress. Adaptive responses have been tightly conserved during evolution, from single celled organisms up to humans, indicating their importance. Here we examine cellular and animal studies that show the influence of radiation induced protective effects on diverse diseases, and examine the radiation dose range that is effective for different tissues in the same animal. The concept of a dose window, with upper and lower effective doses, as well as the effect of multiple stressors and the influence of genetics will also be examined. The effect of the biological variables on low dose responses will be considered from the point of view of the limitations they may impose on any revised radiation protection regulations.

Radiation induced bystander effects in mice given low doses of radiation in vivo.

The 'bystander effect' phenomenon has challenged the traditional framework for assessing radiation damage by showing radiation induced changes in cells which have not been directly targeted, but are neighbors to or receive medium from directly hit cells. Our group performed a range of single and serial low dose irradiations on two genetically distinct strains of mice. Bladder explants established from these mice were incubated in culture medium, which was used to measure death responses in a keratinocyte reporter system. The study revealed that the medium harvested from bladder tissues' (ITCM) from acutely irradiated C57BL6 but not Balb/c mice, was able to induce clonogenic death. Administration of a priming dose(s) before a challenge dose to both C57BL6 and Balb/c mice stimulated reporter cell survival irrespective of the time interval between dose(s) delivery. When ITCM corresponding to both strains of mice was measured for its calcium mobilization inducing ability, results showed an elevation in intracellular calcium levels that was strain dependent. This indicates that genotype determined the type of bystander signal/response that was produced after exposure to low and acute doses of radiation. However, serial exposure conditions modified bystander signal production to induce similar effects that were characterized by excessive growth.

Increased skin carcinogenesis in caspase-activated DNase knockout mice.

Caspase-activated DNase (CAD), also called DNA fragmentation factor (DFF), is the enzyme responsible for DNA fragmentation during apoptosis, a hallmark of programmed cell death. CAD/DFF has been shown to suppress radiation-induced carcinogenesis by preventing genomic instability in cells. In this study, we have investigated the role of CAD in chemical carcinogenesis using CAD-null mice and two-stage model of skin carcinogenesis. After topical treatment of mouse skin with dimethylbenz[a]anthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 4-fold increase in the number of papillomas per mouse and 50.8% increase in the incidence of papilloma formation in the CAD knockout mice compared with wild-type littermates. The papillomas in CAD-null mice grew faster and reached larger sizes. These data indicate that loss of CAD function enhances tumorigenesis induced by a chemical carcinogen in the DMBA/TPA two-stage model of skin carcinogenesis in mice.