Risks and Modeling at Low Doses

Sunday, October 16, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP037) Transcriptional responses in humans following in vivo exposure to ionizing radiation.

Goldberg, Zelanna*,1, Rocke, David2, Schwietert, Chad1, Stern, Robin1, Lehmann, Joerg1, Jones, Angela1, Santana, Alison1, 1 Dept. of Radiation Oncology, Sacramento, CA, USA2 Division of Biostatistics, Sacramento, CA, USA

ABSTRACT- We report here the transcriptomic profile of the effects of low dose ionizing radiation (LDIR) when exposure is in vivo in solid tissue in humans under normal physiologic conditions. Low dose ionizing radiation (LDIR) in the 1-10 cGy range and even more moderate doses in the 100 cGy range have largely unknown biological activity in the human. Current modeling for health and safety regulations, as well as prediction of carcinogenesis, presupposes a linear, no-threshold model of radiation effects, which estimates the effect and risk at low dose by extrapolation from measured effects at high doses. Little is known regarding individual variability to radiation exposure. We undertook a unique approach by direct measurement after controlled radiation exposure in human subjects. By obtaining full thickness skin biopsies from men irradiated for the treatment of prostate cancer (IRB approved, HIPPA compliant), pretreatment samples were compared to biopsies taken after in vivo doses of 1, 10 and 100 cGy (skin point dose). The biopsies were 3 mm in diameter. Total RNA was then extracted and subject to comprehensive analysis using the Affymetrix HGU133 Plus 2.0 expression array platform. This cohort consisted of eight men, with four biopsies each. The changes were surprisingly subtle. Importantly, the human results were significantly different in time course and magnitude than cell culture results. To address inter-individual variation results were analysed by gene groups and functional pathways. We identified 19 gene groups that had been reported in the literature to be affected by LDIR, of which 11 were confirmed in the human studies, including zinc finger proteins, S100, TNF, GADD45 and many cytokines and heat shock proteins. Of 7 pathways, 6 showed significant transcriptional responses including the Akt/PI3 kinase, fibronectin, TGfb/cyclin/ubiquitin pathways. These data suggest that current models regarding radiation risk at low doses may overestimate biologic response.

Key words: transcriptomics, low dose radiation response, humans

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2005 RRS