MODELLING RADIOBIOLOGY EFFECTS OF X-RAYS IN SMALL LABORATORY ANIMALS TO DEVELOP GUIDELINES FOR PRECLINICAL COMPUTED TOMORGRAPHY IMAGING

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

Images acquired by X-rays provide doctors with anatomical information and assist in diagnoses or progression of health problems. In a similar manner, this imaging technique is used for clinical and preclinical research. When used by doctors or in clinical research the amount of X-ray (ionizing radiation) dose a person receives is regulated. This is not true in preclinical research where overexposure to ionizing radiation occurs since X-ray doses are unknown, unregulated and there are no guidelines. Overexposure potentially causes unnecessary suffering to animals and may impact research results, especially in longitudinal studies. The goal of this project is to set X-ray (CT) dose guidelines in order to minimize or eliminate any animal suffering and reduce the number of animals used by refining CT imaging experimental methods. It has been known for years that ionizing radiation causes cell/DNA damage. For instance, ionizing radiation is used as a cancer treatment to kill cells.
Worldwide Cancer Research and Cancer Research UK are advocating for continued preclinical cancer research but seek improved, more reliable results. A major part of preclinical cancer research is drug development, testing, tumour treatment and radiotherapy. This type of research generally includes CT, PET/CT or SPECT/CT. Reviewing 10 of the most recent preclinical cancer studies using rodents (>536,000, 5yrs) the average per study was n=60 rodents. This equates to >32,000,000 rodents. Locally, 250 rodents were used in PET/CT research studies over 1 year. Refining the CT method potentially would reduce the number of rodents used by 20% to 200 rodents. Using the 20% metric and similar research trend, the potential to save >6,000,000 rodents exits in cancer studies. Furthermore, drug research extends beyond cancer treatment with over 286,000 preclinical studies done in the last 5 years. With the same metrics and n=50, >14,000,000 rodents could be reduced to <12,000,000 in drug research. Along with the demand for increased research the demand for understanding the impact of X-rays is needed.
Understanding can be gained with well-established radiation simulation software used routinely in clinical research and cancer treatment planning. Simulation tools have 20 years of valid, reliable and consistent predictions with dose calculation algorithms accuracies better than 1%, providing details on organ, cell and DNA ionizing radiation damage. This project is designed to use these simulation techniques to evaluate the impact of preclinical ionizing radiation along with X-ray beam measurements for validation. Radiation simulations completely replace animals, determine radiation thresholds and set foundational preclinical CT dose regulations. Knowing the biological effects of preclinical X-ray doses provides answers, refines CT experimental methods, improves robustness and reliability of outcomes; reducing number of animals.
Additionally, last year >100,000 rodents received a CT, PET/CT or SPECT/CT in studies unrelated to cancer or drug research. This demonstrates CT is widely used, potentially 100,000 rodents may have suffered unnecessarily and possibly 20,000 rodents weren't needed. The preclinical research community recognizes the need for and is pursuing improvements in imaging methods and ionizing standards. Recently, several avenues for dissemination of research in this regard opened up. The European Society for Molecular Imaging (ESMI) and the Society of Nuclear Medicine and Molecular Imaging set up specific committees and conference forums. This funding body offers publication support and dissemination of results through blogs and the F1000 gateway open access. A key opportunity for dissemination, policy making and implementation is in the EMSI STANDARD committee, which this applicant is a lead member. Results from this project will have a substantial future impact on preclinical imaging in the UK, Europe and USA. (Searches:ISI Web of Science 8/2019).

Technical Summary

Main objective: Establish preclinical X-ray dose guidelines/regulations for the refinement of CT experimental methods, minimize potential suffering caused by overexposure of ionizing and reduce of the number of animals used. Study design replaces rodents with DNA damage simulations, phantom X-ray dose measurements and absorbed dose calculation. Aim 1: Evaluate DNA damage caused by energy deposited in cells from ionising radiation using Monte Carlo simulation and radiobiological models. Simulations represent current preclinical X-ray tube voltages (kVp), exposure times (ms) and projections acquired. Simulations include rat and mouse models with the option of varying CT focal points, amperage (mA), filtering and binning as deemed necessary for greater understanding of damage. Cell and DNA damage will be quantitative events of segment damage for classified as no damage, single strand break, or double strand break. Aim 2: Measure absorbed ionising radiation doses at preclinical tube voltage ranges using newly developed 3D printed anthropomorphic rodent phantom. For comparative analysis and dose guideline validation, measure absorbed ionized radiation at preclinical tube voltage ranges (35 to 80kVp) will be measured. Previous studies assessing DNA damage by ionized radiation have shown single/double strand damage is done with high doses and low doses. Low doses can cause damage by scatter directly to the cell or a neighbouring cell. Therefore, measurements will include additional CT parameters which are "low-dose" or soft X-rays with the ion chamber and verified by the nano-Dots. Additionally, projections and exposure times will be set at constant to check for linearity. Measured dose will be compared to simulation parameter doses. Aim 3: In conjunction with aims 1&2, calculate expected absorbed doses to specific rodent organs. Simulations parameters will include both settings from aim 1 & 2 with the intentions as noted in the Summary, absorbed radiation are in mGy.

Publications

10 25 50