Nghi Phan

Biological Effects and Adaptive Response from Single and Repeated Computed Tomography Scans in Reticulocytes and Bone Marrow of C57BL/6 Mice

This study investigated the biological effects and adaptive responses induced by single and repeated in vivo computed tomography (CT) scans. We postulated that, through the induction of low-level oxidative stress, repeated low-dose CT scans (20 mGy, 2 days/week, 10 weeks) could protect mice (C57BL/6) from acute effects of high-dose radiation (1 Gy, 2 Gy). The micronucleated reticulocyte (MN-RET) count increased linearly after exposure to single CT scans of doses ranging from 20 to 80 mGy (P = 0.033). Ten weeks of repeated CT scans (total dose 400 mGy) produced a slight reduction in spontaneous MN-RET levels relative to levels in sham CT-scanned mice (P = 0.04). Decreases of nearly 10% in γ-H2AX fluorescence levels were observed in the repeated CT-scanned mice after an in vitro challenge dose of 1 Gy (P = 0.017) and 2 Gy (P = 0.026). Spontaneous apoptosis levels (caspase 3 and 7 activation) were also significantly lower in the repeated CT-scanned mice than the sham CT-scanned mice (P < 0.01). In contrast, mice receiving only a single CT scan showed a 19% elevation in apoptosis (P < 0.02) and a 10% increase in γ-H2AX fluorescence levels after a 2-Gy challenge (P < 0.05) relative to sham CT controls. Overall, repeated CT scans seemed to confer resistance to larger doses in mice, whereas mice exposed to single CT scans exhibited transient genotoxicity, enhanced apoptosis, and characteristics of radiation sensitization.

Exercise training enhances the skeletal muscle response to radiation‐induced oxidative stress

Overproduction of reactive oxygen species (ROS) can damage cellular macromolecules and lead to cellular dysfunction or death. Exercise training induces beneficial adaptations in skeletal muscle that may reduce cellular damage from exposure to ROS. To determine the response of exercise‐conditioned muscle to acute increases in ROS, four groups of mice were used: non‐trained (NT, n = 12); NT + high‐dose radiation (HDR, n = 3); exercise‐trained (EX, n = 13, 3 days/week for 10 weeks, 10 m/min to 18 m/min); and EX + HDR (n = 3/group). Quadriceps muscle was harvested 3–5 days following the last exercise bout in the training program for measurement of antioxidant enzyme and metabolic enzyme activity. Total superoxide dismutase (41%), and manganese sodium oxide dismutase (51%) activities were significantly increased in radiation‐challenged EX mice as compared with unchallenged EX mice (all P ≤ 0.05). No such increase was observed in NT mice. Citrate synthase (42%) and cytochrome c oxidase (38%) activities were both elevated in radiation‐challenged EX mice as compared with unchallenged EX mice (both P < 0.05), and no such increase was observed in NT. We demonstrate that preconditioning skeletal muscle with EX enhances the response of antioxidant and mitochondrial enzymes to radiation. Muscle Nerve, 2011

HUMAN HEALTH AND THE BIOLOGICAL EFFECTS OF TRITIUM IN DRINKING WATER: PRUDENT POLICY THROUGH SCIENCE – ADDRESSING THE ODWAC NEW RECOMMENDATION

Tritium is a radioactive form of hydrogen and is a by-product of energy production in Canadian Deuterium Uranium (CANDU) reactors. The release of this radioisotope into the environment is carefully managed at CANDU facilities in order to minimize radiation exposure to the public. However, under some circumstances, small accidental releases to the environment can occur. The radiation doses to humans and non-human biota from these releases are low and orders of magnitude less than doses received from naturally occurring radioisotopes or from manmade activities, such as medical imaging and air travel. There is however a renewed interest in the biological consequences of low dose tritium exposures and a new limit for tritium levels in Ontario drinking water has been proposed. The Ontario Drinking Water Advisory Council (ODWAC) issued a formal report in May 2009 in response to a request by the Minister of the Environment, concluding that the Ontario Drinking Water Quality Standard for tritium should be revised from the current 7,000 Bq/L level to a new, lower 20 Bq/L level. In response to this recommendation, an international scientific symposium was held at McMaster University to address the issues surrounding this change in direction and the validity of a new policy. Scientists, regulators, government officials, and industrial stakeholders were present to discuss the potential health risks associated with low level radiation exposure from tritium. The regulatory, economic, and social implications of the new proposed limit were also considered. The new recommendation assumed a linear-no-threshold model to calculate carcinogenic risk associated with tritium exposure, and considered tritium as a non-threshold chemical carcinogen. Both of these assumptions are highly controversial given that recent research suggests that low dose exposures have thresholds below which there are no observable detrimental effects. Furthermore, mutagenic and carcinogenic risk calculated from tritium exposure at 20 Bq/L would be orders of magnitude less than that from exposure to natural background sources of radiation. The new proposed standard would set the radiation dose limit for drinking water to 0.0003 mSv/year, which is equivalent to approximately three times the dose from naturally occurring tritium in drinking water. This new standard is incongruent with national and international standards for safe levels of radiation exposure, currently set at 1 mSv/year for the general public. Scientific research from leading authorities on the carcinogenic health effects of tritium exposure supports the notion that the current standard of 7,000 Bq/L (annual dose of 0.1 mSv) is a safe standard for human health. Policy-making for the purpose of regulating tritium levels in drinking water is a dynamic multi-stage process that is influenced by more than science alone. Ethics, economics, and public perception also play important roles in policy development; however, these factors sometimes undermine the scientific evidence that should form the basis of informed decision making. Consequently, implementing a new standard without a scientific basis may lead the public to perceive that risks from tritium have been historically underestimated. It was concluded that the new recommendation is not supported by any new scientific insight regarding negative consequences of low dose effects, and may be contrary to new data on the potential benefits of low dose effects. Given the lack of cost versus benefit analysis, this type of dramatic policy change could have detrimental effects to society from an ethical, economical, and public perception perspective.

Single CT Scan Prolongs Survival by Extending Cancer Latency in Trp53 Heterozygous Mice

There is growing concern over the effects of medical diagnostic procedures on cancer risk. Although numerous studies have demonstrated that low doses of ionizing radiation can have protective effects including reduced cancer risk and increasing lifespan, the hypothesis that any radiation exposure increases cancer risk still predominates. In this study, we investigated cancer development and longevity of cancer-prone Trp53+/– mice exposed at 7–8 weeks of age to a single 10 mGy dose from either a diagnostic CT scan or gamma radiation. Mice were monitored daily for adverse health conditions until they reached end point. Although the median lifespan of irradiated mice was extended compared to control animals, only CT scanned mice lived significantly longer than control mice (P < 0.004). There were no differences in the frequency of malignant cancers between the irradiated and control groups. Exposure to a single CT scan caused a significant increase in the latency of sarcoma and carcinoma (P < 0.05), accounting for the increased lifespan. This study demonstrates that low-dose exposure, specifically a single 10 mGy CT scan, can prolong lifespan by increasing cancer latency in cancer-prone Trp53+/– mice. The data from this investigation add to the large body of evidence, which shows that risk does not increase linearly with radiation dose in the low-dose range.

Multiple CT Scans Extend Lifespan by Delaying Cancer Progression in Cancer-Prone Mice

Computed tomography (CT) scans are a routine diagnostic imaging technique that utilize low-energy X rays with an average absorbed dose of approximately 10 mGy per clinical whole-body CT scan. The growing use of CT scans in the clinic has raised concern of increased carcinogenic risk in patients exposed to ionizing radiation from diagnostic procedures. The goal of this study was to better understand cancer risk associated with low-dose exposures from CT scans. Historically, low-dose exposure preceding a larger challenge dose increases tumor latency, but does little to impact tumor frequency in Trp53+/– mice. To assess the effects of CT scans specifically on tumor progression, whole-body CT scans (10 mGy/scan, 75 kVp) were started at four weeks after 4 Gy irradiation, to allow for completion of tumor initiation. The mice were exposed to weekly CT scans for ten consecutive weeks. In this study, we show that CT scans modify cellular end points commonly associated with carcinogenesis in cancer-prone Trp53+/– heterozygous mice. At five days after completion of CT scan treatment, the multiple CT scans did not cause detectable differences in bone marrow genomic instability, as measured by the formation of micronucleated reticulocytes and H2AX phosphorylation in lymphoid-type cells, and significantly lowered constitutive and radiation induced levels of apoptosis. The overall lifespan of 4 Gy exposed cancer-initiated mice treated with multiple CT scans was increased by approximately 8% compared to mice exposed to 4 Gy alone (P < 0.017). Increased latency periods for lymphoma and sarcoma (P < 0.040) progression contributed to the overall increase in lifespan. However, repeated CT scans did not affect carcinoma latency. To our knowledge, this is the first reported study to show that repeated CT scans, when administered after tumor initiation, can improve cancer morbidity by delaying the progression of specific types of radiation-induced cancers in Trp53+/– mice.

The Influence of TRP53 in the Dose Response of Radiation-Induced Apoptosis, DNA Repair and Genomic Stability in Murine Haematopoietic Cells

Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/− mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01–2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/−) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/− between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/−. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.

Low-dose radiation from 18F-FDG PET does not increase cancer frequency or shorten latency but reduces kidney disease in cancer-prone Trp53+/- mice

There is considerable interest in the health effects associated with low-level radiation exposure from medical imaging procedures. Concerns in the medical community that increased radiation exposure from imaging procedures may increase cancer risk among patients are confounded by research showing that low-dose radiation exposure can extend lifespan by increasing the latency period of some types of cancer. The most commonly used radiopharmaceutical for positron emission tomography (PET) scans is 2-[(18)F] fluoro-2-deoxy-d-glucose ((18)F-FDG), which exposes tissue to a low-dose, mixed radiation quality: 634 keV β+ and 511 keV γ-rays. The goal of this research was to investigate how modification of cancer risk associated with exposure to low-dose ionising radiation in cancer-prone Trp53+/- mice is influenced by radiation quality from PET. At 7-8 weeks of age, Trp53+/- female mice were exposed to one of five treatments: 0 Gy, 10 mGy γ-rays, 10 mGy (18)F-FDG, 4 Gy γ-rays, 10 mGy (18)F-FDG + 4 Gy γ-rays (n > 185 per group). The large 4-Gy radiation dose significantly reduced the lifespan by shortening the latency period of cancer and significantly increasing the number of mice with malignancies, compared with unirradiated controls. The 10 mGy γ-rays and 10 mGy PET doses did not significantly modify the frequency or latency period of cancer relative to unirradiated mice. Similarly, the PET scan administered prior to a large 4-Gy dose did not significantly modify the latency or frequency of cancer relative to mice receiving a dose of only 4 Gy. The relative biological effectiveness of radiation quality from (18)F-FDG, with respect to malignancy, is approximately 1. However; when non-cancer endpoints were studied, it was found that the 10-mGy PET group had a significant reduction in kidney lesions (P < 0.021), indicating that a higher absorbed dose (20 ± 0.13 mGy), relative to the whole-body average, which occurs in specific tissues, may not be detrimental.