PARENT SESSION
9:00 AM to 11:00 AM
Sunday, April 21, 2002
Symposium 5
Biologic Responses to Low Doses of Low LET Ionizing Radiation
Room: Nevada 6-7
Chair: Redpath, Les²²Department of Radiation Oncology, Irvine, CA, Co-Chair: Amundson, Sally³³National Institutes of Health, Bethesda, MD
Speakers: Amundson, Sally⁴; Boothman, David⁵; Joiner, Michael⁶; Redpath, Les⁷; Mitchel, Ronald⁸⁴National Institutes of Health, Bethesda, MD⁵Departments of Radiation Oncology and Pharmacology, Cleveland, OH⁶Dept of Radiation Biology, Detroit, MI⁷Department of Radiation Oncology, Irvine, CA⁸Department of Radiation Biology and Health Physics, Chalk River, ON

(S05-4) Adaptive response to radiation in vivo.

Mitchel, R.^*,1, ¹ Atomic Energy of Canada, Chalk River, ON Canada

ABSTRACT-
The Linear No Threshold hypothesis, used in all radiation protection practices, assumes that all doses, no matter how low, increase the risk of cancer. In vitro cell based experiments show adaptive processes in response low doses and dose rates of low LET radiation, and do not support the hypothesis. This talk will present animal experiments that test the hypothesis in vivo. A single low dose (100 mGy) of low LET radiation delivered to the skin reduced the frequency of pre-malignant skin tumors in mice subsequently initiated by a single topical dose of MNNG, indicating that ionizing radiation can reduce the risk of tumor initiation by a chemical mutagen. In contrast, a single, low, whole body dose (100 mGy) of low LET radiation did not alter frequency but did increase the latency for acute myeloid leukemia, initiated by a subsequent large dose. This indicates that low doses also reduce the rate at which initiated cells become genomically unstable and consequently reduce risk in genetically normal mice. This reduction in the progress of genomic instability also occurred in cancer prone Trp53 heterozygous mice, where a single 10 mGy dose again had no effect on spontaneous cancer frequency, but significantly increased latency for spontaneous osteosarcomas, lymphomas and hemangiosarcomas. Latency was also increased for undifferentiated sarcomas initiated by physical irritation. The protective effect of this adaptive response lasted for the entire lifespan of all the animals that developed these tumors, effectively restoring a portion of the mean loss of life attributed to Trp53 heterozygosity in the absence of radiation exposure. Increasing the dose 10 fold to 100 mGy produced variable results, with increased risk (decreased latency) for some tumors but increased latency for other tumors, indicating that this higher dose was in a transition zone between reduced and increased risk. In fetal mice, prior low doses could also protect against radiation induced teratogenic effects resulting from both Trp53 dependent and independent apoptotic processes, but the protective effects varied with both Trp53 status and gestational time. Overall, the results demonstrate that the assumption of a linear relationship between dose and risk in vivo is not warranted, and that low doses actually reduce risk.

KEYWORDS: Adaption, in vivo, Trp53, mice