Eric J. Hall

Background: In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation.Methods: Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons.Results: Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis.Conclusions: Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.

The biological effects of radiation result primarily from damage to DNA. There are three effects of concern to the radiologist that determine the need for radiation protection and the dose principle of ALARA (As Low As Reasonably Achievable). (1) Heritable effects. These were thought to be most important in the 1950s, but concern has declined in recent years. The current ICRP risk estimate is very small at 0.2%/Sv. (2) Effects on the developing embryo and fetus include weight retardation, congenital anomalies, microcephaly and mental retardation. During the sensitive period of 8 to 15 weeks of gestation, the risk estimate for mental retardation is very high at 40%/Sv, but because it is a deterministic effect, there is likely to be a threshold of about 200 mSv. (3) Carcinogenesis is considered to be the most important consequence of low doses of radiation, with a risk of fatal cancer of about 5%/Sv, and is therefore of most concern in radiology. Our knowledge of radiation carcinogenesis comes principally from the 60-year study of the A-bomb survivors. The use of radiation for diagnostic purposes has increased dramatically in recent years. The annual collective population dose has increased by 750% since 1980 to 930,000 person Sv. One of the principal reasons is the burgeoning use of CT scans. In 2006, more than 60 million CT scans were performed in the U.S., with about 6 million of them in children. As a rule of thumb, an abdominal CT scan in a 1-year-old child results in a life-time mortality risk of about one in a thousand. While the risk to the individual is small and acceptable when the scan is clinically justified, even a small risk when multiplied by an increasingly large number is likely to produce a significant public health concern. It is for this reason that every effort should be made to reduce the doses associated with procedures such as CT scans, particularly in children, in the spirit of ALARA.

In recent years, there has been a rapid increase in the number of CT scans performed, both in the US and the UK, which has fuelled concern about the long-term consequences of these exposures, particularly in terms of cancer induction. Statistics from the US and the UK indicate a 20-fold and 12-fold increase, respectively, in CT usage over the past two decades, with per caput CT usage in the US being about five times that in the UK. In both countries, most of the collective dose from diagnostic radiology comes from high-dose (in the radiological context) procedures such as CT, interventional radiology and barium enemas; for these procedures, the relevant organ doses are in the range for which there is now direct credible epidemiological evidence of an excess risk of cancer, without the need to extrapolate risks from higher doses. Even for high-dose radiological procedures, the risk to the individual patient is small, so that the benefit/risk balance is generally in the patients' favour. Concerns arise when CT examinations are used without a proven clinical rationale, when alternative modalities could be used with equal efficacy, or when CT scans are repeated unnecessarily. It has been estimated, at least in the US, that these scenarios account for up to one-third of all CT scans. A further issue is the increasing use of CT scans as a screening procedure in asymptomatic patients; at this time, the benefit/risk balance for any of the commonly suggested CT screening techniques has yet to be established.

Protons represent a logical step forward as a modality for radiotherapy because it is possible to concentrate dose in the tumor region and minimize dose to normal tissue. The pencil beam emerging from a cyclotron or synchrotron needs to be expanded to a larger size to cover tumors of realistic size. Ideally, this should be accomplished by scanning the pencil beam using magnetic fields, but this is technically challenging. The simpler method is to use passive modulation, the downside of which is that neutrons are produced in the scattering foil, which results in a total body dose to the patient. Neutrons are highly effective at inducing second cancers and so, for the full potential of protons to be realized, spot scanning is essential.

Radiation-induced bystander mutagenesis at a relatively low dose range was investigated using low LET β-particles in a three-dimensional cell culture model. CHO cells were labeled with 0, 0.5, 1.0 or 5.0 μCi tritiated thymidine (³HdTTP) for 12 h and subsequently incubated with A_L cells for 24 h at 11°C. The cell mixture was centrifuged to produce a spheroid of 4 × 10⁶ cells of which there was five times more A_L than CHO cells. The short-range β-particles emitted by ³HdTTP result in self-irradiation of labeled CHO cells, thus biological effects on neighboring A_L cells can be attributed to the bystander response. To evaluate such response, non-labeled bystander A_L cells were isolated from among labeled CHO cells and studied independently for survival and mutagenesis. Treatment of CHO cells with ³HdTTP resulted in a dose-dependent increase in bystander mutation incidence among neighboring A_L cells compared to controls. In addition, multiplex PCR analysis revealed the types of mutants to be significantly different from those of spontaneous origin. These data provide evidence that low dose low LET radiation can induce bystander mutagenesis in a three-dimensional model. The results of this study will address the relevant issues of actual target size and radiation quality, and are likely to have a significant impact on our current understanding of radiation risk assessment.