Modelling radiobiology effects of X-rays in small laboratory animals to develop guidelines for preclinical computed tomography imaging

Why did we fund this fellowship?

This award aims to develop guidelines for small animal computer tomography (CT) imaging to minimise effects caused by high levels of X-ray doses, refining the use of animals in these procedures.

CT imaging is a non-invasive method used to monitor disease progression and response to drugs. The technique also enables longitudinal studies, reducing the number of animals required in a study overall. However, there are few guidelines available about the X-ray doses animals are exposed to during CT imaging, despite evidence that high levels of X-ray can cause DNA and cellular damage. This can be exacerbated by longitudinal studies, where animals are imaged at various timepoints increasing the risk of detrimental effects to the animals’ welfare. During her NC3Rs-funded PhD, Dr Wendy McDougald developed a 3D rodent “phantom” with tissue equivalent material to simulate specific organs and tissues. These phantoms were able to be used in place of animals to calibrate instruments and standardise PET/CT imaging protocols between preclinical research sites.

During this Fellowship, Wendy will use radiation simulation software to evaluate DNA damage caused by X-ray doses and assess the levels of cellular, single and double strand DNA damage. She will then use the previously developed imaging phantom in combination with nanoDots® to monitor the radiation levels animals are exposed to during preclinical research. The doses measured will be compared to the simulation parameters. Using this data, Wendy will develop guidelines to prevent overexposure to radiation during CT imaging. Wendy will develop skills in computer aided design, 3D printing and computational modelling.

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 (ionising radiation) dose a person receives is regulated. This is not true in preclinical research where overexposure to ionising 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 minimise 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 ionising radiation causes cell/DNA damage. For instance, ionising 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 exists 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 ionising radiation damage. This project is designed to use these simulation techniques to evaluate the impact of preclinical ionising 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 recognises the need for and is pursuing improvements in imaging methods and ionising 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).

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Fellowship

Status:

Active

Principal investigator

Dr Wendy McDougald

Institution

University of Edinburgh

Grant reference number

NC/T00245X/1

Award date:

Apr 2020 - Mar 2022

Grant amount

£126,846