Human Equivalent Radiation Dose Response in the Rat Mandible
Purpose: Current studies looking at the effects of radiation (XRT) on the murine mandible have focused on sub-therapeutic dosages when compared to equivalent dosing in the human. A reproducible animal model demonstrating a human equivalent radiation dose is lacking in the current literature. The objective of this study was to establish a rat model of mandibular XRT that would correlate with the dose given to the human mandible during treatment for head and neck cancer (HNC) as well as doses above and below the target dose in order to establish a dose response.             
Methods: 3 groups of five male Sprague-Dawley rats underwent 5 days of fractionated XRT of the left mandible. Groups 1, 2, 3 received 5.91 Gy, 7 Gy, and 8.89 Gy per day respectively. These doses were calculated using a formula for Biologically Equivalent Dosing (BED = n * d * (1 + d/(a/b )) in order to approximate 75, 100 and 150% of the dose administered to humans for HNC. Tissue was harvested fifty-six days after radiation was completed. Gross, radiologic, mechanical and histological evaluations were undertaken and compared with non-radiated controls. Mandibles were scanned with micro-CT and the region of interest was evaluated for bone mineral density (BMD), bone volume fraction (BVF) and tissue mineral density (TMD).
Results: No deaths occurred during or following treatment. Groups 2 and 3 demonstrated signs of severe stress, and alopecia. All animals developed mucositis and weight loss, in proportion to dose, beginning at post-radiation day four which improved by post-radiation day eleven. All animals eventually gained weight and surpassed their pre-treatment weight. Gross, radiologic and histological evaluations were undertaken. At time of harvest, all animals exhibited bony atrophy in proportion to dosages. In the highest treatment group the mandibles appeared nearly translucent at time of harvest and were markedly more brittle compared with control animals. Using micro-CT analysis, groups 1, 2 and 3 demonstrated TMD of 0.9097±0.016, 0.9045±0.012 and 0.9005±0.015 compared with 0.9222±0.009 for controls. BMD was measured for the groups as 0.7605±0.040, 0.7330±0.018 and 0.7539±0.037 respectively, compared with 0.7739±0.015 for controls. Histogram analysis illustrated a clear shift in the pictorial representation of the bone density to the left with radiation compared to controls, graphically illustrating that the radiated bone measured lower on the Hounsfield unit scale than controls. Furthermore, the peaks of the curves diminished with higher doses of radiation, with a larger difference seen between groups 1 and 2, than between groups 2 and 3.
Conclusion: This set of experiments establishes a valuable dose response analysis of XRT in a rodent model at doses equivalent to, and greater than that used for humans in the treatment of HNC.  By demonstrating tolerance of a human equivalent dose of XRT in a murine mandible a translational approach can be utilized to formulate strategies to assuage the effects of radiation on bone in the clinical arena.