A retrospective audit of cumulative ionising radiation levels in hospitalised pregnant patients.

BACKGROUND: Among hospitalised patients, diagnostic radiation is possibly used least on pregnant patients due to the fear of ionising radiation on the fetus; however, what levels are currently being prescribed. AIMS: To assess the cumulative levels of ionising radiation received by pregnant patients during a single admission to a tertiary hospital. MATERIALS AND METHODS: A retrospective audit of pregnant patients admitted to Flinders Medical Centre, South Australia, Australia, between 2013 and 2017 inclusive was performed. All procedures utilising ionising radiation were collected including conventional radiology, computed tomography, fluoroscopy and nuclear medicine. Individual and cumulative effective doses for mother and fetus were calculated using patient dose reports and published conversion factors. RESULTS: From 547 patients, the median cumulative effective dose was 0.02 mSv and only five patients received more than 10 mSv, with 19.07 mSv the highest dose received. The median fetal cumulative effective dose was 0.01 mSv but only three fetuses received more than 10 mSv, likely due to fetal exclusion in some procedural fields of view. Stays longer than ten days were associated with significantly higher cumulative effective dose, as did those with maternal cardiovascular related admission, for both maternal and fetal exposures. CONCLUSION: These results suggest that pregnant patients are exposed to low doses of ionising radiation, in both individual procedures and cumulative doses. The detrimental risks associated with these levels of ionising radiation are not overt and so clinicians should question which risk is higher, the ionising radiation from the radiological procedures received or the lack of diagnostic information if avoided?

Unchanged cardiovascular and respiratory outcomes in healthy C57Bl/6 mice after in utero exposure to ionizing radiation.

BACKGROUND: Advancements in medical technologies that utilize ionizing radiation have led to improved diagnosis and patient outcomes, however, the effect of ionizing radiation on the patient is still debated. In the case of pregnancy, the potential effects are not only to the mother but also to the fetus. The aim of this study was to determine if exposure from ionizing radiation during pregnancy alters the development of the cardiovascular and respiratory system of the offspring. MATERIALS AND METHODS: Pregnant C57Bl/6 mice were whole-body irradiated at gestational day 15 with a 137Cs gamma radiation emitting source at 0 mGy (sham), 50 mGy, 300 mGy, or 1000 mGy. Post weaning weight and blood pressure measurements were taken weekly for both male and female pups until euthanasia at 16-17 weeks postnatal age. Immediately following, the trachea was cannulated, and the lungs and heart excised. The lung was then examined to assess respiratory physiological outcomes. RESULTS AND CONCLUSIONS: In utero exposures to 1000 mGy caused significant growth reduction compared to sham irradiated, which remained persistent for both male and female pups. Growth restriction was not observed for lower exposures. There was no significant change in any cardiovascular or respiratory outcomes measured. Overall, intrauterine exposures to ionizing radiation does not appear to significantly alter the development of the cardiovascular and respiratory system in C57Bl/6 pups up to 17 weeks postnatal age.

A radon chamber specifically designed for environmentally relevant exposures of small animals.

In order to facilitate direct testing of the biological effects of radon, we designed and constructed a 3.1 m3 radon chamber specifically for radon exposures to small animals. The chamber is designed to operate as a sealed enclosure with a controlled atmosphere containing a known concentration of radon and its radioactive decay products. Sensors for air flow rate, temperature, humidity, HEPA filter and differential pressure ensure an optimal environment for exposure subjects. The radon gas is supplied to the chamber from a generator containing Radium-226 in a dilute acid solution. Air containing radon can be pumped continuously using a constant flow rate to maintain a steady state supply. The source flow rate was partitioned to achieve a chamber concentration at 200 Bq/m3 (R2 = 0.9341) or 1000 Bq/m3 (R2 = 0.9715). Small particles are injected into the re-circulating air stream via a particle generator to provide condensation nuclei for attachment of radon decay products as they form in the chamber atmosphere. Particles measured at 0.3 µm, 0.5 µm and 5.0 µm averaged concentrations 5.7 ± 0.6 × 107/m3, 2.5 ± 0.7 × 107/m3 and 2.3 ± 2.4 × 103/m3, respectively. A desired Equilibrium Factor can easily be achieved by varying the air circulation rate through the chamber. The Equilibrium Factor ranged from 0.4 to 0.8 at 200 Bq/m3 and 0.5 to0.6 at 1000 Bq/m3. The chamber was designed to conduct short term exposures to assess the acute cellular changes induced by radon exposure. To our knowledge, this is currently the only radon chamber designed specifically to investigate environmentally relevant exposure time and doses of radon gas and decay products in small animal models.

Cumulative radiation in critically ill patients: a retrospective audit of ionising radiation exposure in an intensive care unit.

OBJECTIVE: Ionising radiation is a valuable tool in modern medicine including for patients in an intensive care unit (ICU). However, clinicians are faced with a trade-off between benefit of information received from procedure versus risks associated with radiation. As a first step to understanding the risk and benefits of radiation exposure to ICU patients, we aimed to assess the cumulative levels of ionising radiation patients receive during their ICU stay. DESIGN: Retrospective audit. SETTING: A single tertiary care ICU in South Australia. PARTICIPANTS: This audit included 526 patients admitted to the ICU at Flinders Medical Centre, Adelaide, SA, for longer than 120 hours (long stay) over a 12-month period from April 2015 to April 2016. MAIN OUTCOME MEASURES: Cumulative radiation exposure to ICU patients. RESULTS: The 526 patients audited underwent 4331 procedures totalling 5688.45 mSv of ionising radiation. The most frequent procedure was chest x-ray (82%), which contributed 1.2% to cumulative effective dose (CED). Although only 3.6% of the total procedures, abdominal and pelvic computed tomography (CT) contributed the most to CED (68%). Over 50% of patients received less than 1 mSv CED during their stay in the ICU. However, 6% received > 50 mSv and 1.3% received > 100 mSv CED. Trauma patients received significantly higher CED compared with other admission diagnoses, and CED increased with length of stay. CONCLUSION: Most ICU patients received low CED during their stay, with the majority receiving less than the recommended limit for members of the public (1 mSv). These results may educate clinicians regarding radiation exposures in ICU settings, highlighting the relatively low exposures and thus low risk to the patients.

Acute pulmonary and splenic response in an in vivo model of whole-body low-dose X-radiation exposure.

Purpose: Diagnostic radiation is an important part of patient care in the Intensive Care Unit; however, there is little data on the acute effects of exposure to these doses. We investigated pulmonary and splenic response 30 minutes, 4 hours or 24 hours after exposure to 2 mGy, 20 mGy, 200 mGy or 4 Gy whole-body X-radiation in a Sprague Dawley rat model. Materials and methods: Lung injury was assessed via respiratory mechanics, pulmonary edema, cellular, and proteinaceous fluid infiltrate and protein expression of oxidative stress markers. The radiation effect on the spleen was determined via proliferation, apoptosis and protein expression of oxidative stress markers. Results: All measurements of the lung did not differ from sham animals except for an increase in catalase after high dose exposure. Stimulated splenocyte proliferation increased after sham and low dose exposure, did not change after 200 mGy exposure and was significantly lower after 4 Gy exposure. The number of apoptotic cells increased 4 hours after 4 Gy exposure. There were fewer apoptotic cells after low dose exposure compared to sham. Both catalase and MnSOD were increased after 4 Gy exposure. Conclusion: There was no measured effect on pulmonary function while there was an impact to the spleen after low and high dose exposure.

Deterministic Effects to the Lens of the Eye Following Ionizing Radiation Exposure: is There Evidence to Support a Reduction in Threshold Dose?

Ionizing radiation exposure to the lens of the eye is a known cause of cataractogenesis. Historically, it was believed that the acute threshold dose for cataract formation was 5 Sv, and annual dose limits to the lens were set at 150 mSv. Recently, however, the International Commission on Radiological Protection has reduced their threshold dose estimate for deterministic effects to 0.5 Gy and is now recommending an occupational limit of 20 mSv per year on average. A number of organizations have questioned whether this new threshold and dose limit are justified based on the limited reliable data concerning radiation-induced cataracts. This review summarizes all of the published human epidemiological data on ionizing radiation exposure to the lens of the eye in order to evaluate the proposed threshold. Data from a variety of exposure cohorts are reviewed, including atomic bomb survivors, Chernobyl liquidators, medical workers, and radiotherapy patients. Overall, there is not conclusive evidence that the threshold dose for cataract formation should be reduced to 0.5 Gy. Many of the studies reviewed here are challenging to incorporate into an overall risk model due to inconsistencies with dosimetry, sample size, and scoring metrics. Additionally, risk levels in the studied cohorts may not relate to occupational scenarios due to differences in dose rate, radiation quality, age at exposure and latency period. New studies should be designed specifically focused on occupational exposures, with reliable dosimetry and grading methods for lens opacities, to determine an appropriate level for dose threshold and exposure limit.

Low dose X-radiation adaptive response in spleen and prostate of Atm knockout heterozygous mice.

PURPOSE: To investigate the effect of being heterozygous for a knockout mutation in the ataxia telangiectasia (Atm) gene on radiation adaptive response. MATERIALS AND METHODS: DNA recombination, as measured by pKZ1 inversion frequency, was quantified by histochemistry in Atm knockout heterozygous prostate and spleen 3 days after treatment with a priming dose of 0.01 or 10 mGy X-radiation 4 h prior to a challenge dose of 1,000 mGy. RESULTS: In spleen and prostate, a single dose of 0.01 mGy caused an induction in inversion frequency but a dose of 10 mGy prevented the induction of a proportion of endogenous inversions. Both doses induced an adaptive response, of similar magnitude, to a subsequent high challenge dose for chromosomal inversions in both spleen and prostate. The adaptive response completely prevented the induction of inversions from a 1,000 mGy challenge dose and also a proportion of endogenous inversions. The adaptive responses and distribution of inversions across gland cross-sections observed here in Atm knockout heterozygote prostate were similar to those induced in Atm wild-type prostate in a previous study. CONCLUSIONS: Being heterozygous for a knockout mutation in the Atm gene does not affect the endogenous pKZ1 inversion frequency, the inversion response to single low radiation doses used here, or the induction of a radiation adaptive response for inversions in pKZ1 mouse spleen or prostate.

Adaptive response for chromosomal inversions in pKZ1 mouse prostate induced by low doses of X radiation delivered after a high dose.

Adaptive responses are induced by stress such as X radiation and result in a lower than expected biological response. Two-dose adaptive response experiments typically involve a low priming dose followed by a subsequent high radiation dose. Here, we used a sensitive in vivo chromosomal inversion assay to demonstrate for the first time an adaptive response when a low dose (0.01-1 mGy) was given several hours after a high 1000-mGy radiation dose. The adaptive responses in this study were of similar magnitude to the two-dose adaptive responses previously observed in this test system when the low dose was given first. A chromosomal inversion adaptive response was also induced by two 1000-mGy doses and when a 1-mGy dose was preceded or followed by a dose of 0.01 mGy, but not by two 4000-mGy doses. This is also the first example of an adaptive response when both doses are low. Our data agree with previous reports of an on-off mechanism of adaptive response. The induction of an adaptive response by a low dose after a high damaging dose provides evidence that the mechanisms underlying radiation adaptive responses are not due to prevention of damage induced by the high dose but to modulation of the cellular response to this damage.

Extremely low doses of X-radiation can induce adaptive responses in mouse prostate.

The pKZ1 mouse chromosomal inversion assay is the only assay that has detected modulation of a mutagenic endpoint after single whole body X-irradiation with doses lower than 1 mGy. A non-linear dose response for chromosomal inversion has been observed in spleen and prostate between 0.001 mGy and 10 mGy, with doses between 0.005-0.01 mGy causing an increase in inversions and doses between 1-10 mGy causing a reduction below spontaneous inversion frequency. An adaptive response is a decreased biological effect induced by a low radiation dose. Adaptive responses contradict the linear-no-threshold model of risk estimation. We demonstrated that very low (0.001 mGy, 0.01 mGy, 1 mGy and 10 mGy) doses of X-radiation induced a chromosomal inversion adaptive response as measured by a reduction in the frequency of subsequent high dose (1000 mGy) induced inversions in prostate. These are the lowest X-radiation doses reported to induce an adaptive response for any endpoint. Adaptive response experiments were also performed where the high dose was administered four hours prior to a low dose of 0.01 mGy or 10 mGy In both cases an adaptive response was observed. Identification of the modifying factors involved in the adaptive response may provide candidates for radioprotection.

Extremely low priming doses of X radiation induce an adaptive response for chromosomal inversions in pKZ1 mouse prostate.

An adaptive response is a response to a stress such as radiation exposure that results in a lower than expected biological response. We describe an adaptive response to X radiation in mouse prostate using the pKZ1 chromosomal inversion assay. pKZ1 mice were treated with a priming dose of 0.001, 0.01, 1 or 10 mGy followed 4 h later by a 1000-mGy challenge dose. All priming doses caused a similar reduction in inversions compared to the 1000-mGy group, supporting the hypothesis that the adaptive response is the result of an on/off mechanism. The adaptive response was induced by a priming dose of 0.001 mGy, which is three orders of magnitude lower than has been reported previously. The adaptive responses completely protected against the inversions that would have been induced by a single 1000-mGy dose as well as against a proportion of spontaneous background inversions. The distribution of inversions across prostate gland cross sections after priming plus challenge irradiation suggested that adaptive responses were predominantly due to reduced low-dose radiation-induced inversions rather than to reduced high-dose radiation-induced inversions. This study used radiation doses relevant to human exposure.

Non-linear chromosomal inversion response in prostate after low dose X-radiation exposure.

Somatic intrachromosomal recombination can result in inversions and deletions in DNA, which are important mutations in cancer. The pKZ1 chromosomal inversion assay is a sensitive assay for studying the effects of DNA damaging agents using chromosomal inversion as a mutation end-point. We have previously demonstrated that the chromosomal inversion response in pKZ1 spleen after single low doses of X-radiation exposure does not follow the linear no-threshold dose-response model. Here, we optimised a chromosomal inversion screening method to study the effect of low dose X-radiation exposure in pKZ1 prostatic tissue. In the present study, a significant induction in inversions was observed after ultra-low doses of 0.005-0.01 mGy or after a high dose of 1000 mGy, whereas a reduction in inversions to below the sham-treated frequency was observed between 1 and 10 mGy exposure. This is the first report of a reduction to below endogenous frequency for any mutation end-point in prostate. In addition, the doses of radiation studied were at least three orders of magnitude lower than have been reported in other mutation assays in prostate in vivo or in vitro. In sham-treated pKZ1 controls and in pKZ1 mice treated with low doses of 1-10 mGy the number of inversions/gland cross-section rarely exceeded three. Up to 4 and 7 inversions were observed in individual prostatic gland cross-sections after doses < or =0.02 mGy and after 1000 mGy, respectively. The number of inversions identified in individual cross-sections of prostatic glands of untreated mice and all treated mice other than the 1000 mGy treatment group followed a Poisson distribution. The dose-response curves and fold changes observed after all radiation doses studied were similar in spleen and prostate. These results suggest that the pKZ1 assay is measuring a fundamental response to DNA damage after low dose X-radiation exposure which is independent of tissue type.

In vivo mutagenic effect of very low dose radiation.

Almost all of our knowledge about the mutational effect of radiation has come from high dose studies which are generally not relevant to public exposure. The pKZ1 mouse recombination mutagenesis assay enables study of the mutational effect of very low doses of low LET radiation (microGy to cGy range) in a whole animal model. The mutational end-point studied is chromosomal inversion which is a common mutation in cancer. We have observed 1) a non-linear dose response of induced inversions in pKZ1 mice exposed to a wide dose range of low LET radiation, 2) the ability of low priming doses to cause an adaptive response to subsequent higher test doses and 3) the effect of genetic susceptibility where animals that are heterozygous for the Ataxia Telangiectasia gene (Atm) exhibit different responses to low dose radiation compared to their normal litter-mates.

The linear no-threshold model does not hold for low-dose ionizing radiation.

Almost all of the data on the biological effects of ionizing radiation come from studies of high doses. However, the human population is unlikely to be exposed to such doses. Regulatory limits for radiation exposure are based on the linear no-threshold model, which predicts that the relationship between biological effects and radiation dose is linear, and that any dose has some effect. Chromosomal changes are an important effect of ionizing radiation because of their role in carcinogenesis. Here we exposed pKZ1 mice to single whole-body X-radiation doses as low as 1 microGy. We observed three different phases of response: (1) an induction of inversions at ultra-low doses, (2) a reduction below endogenous inversion frequency at low doses, and (3) an induction of inversions again at higher doses. These results do not fit a linear no-threshold model, and they may have implications for the way in which regulatory standards are presently set and for understanding radiation effects.

Cancer-associated genes can affect somatic intrachromosomal recombination early in carcinogenesis.

The pKZ1 recombination mutagenesis model has provided a sensitive assay where we study somatic intrachromosomal recombination (SICR) as a mutation end-point. SICR is associated with non-homologous end-joining repair of double-strand breaks and can result in chromosomal inversions and deletions, both of which are common chromosomal aberrations identified in cancers. It has been difficult to study the effect of cancer-associated genes on chromosomal changes prior to tumour formation in vivo because of a lack of appropriate test systems. We hypothesised that cancer-associated genes play a role in formation of chromosomal aberrations and that the pKZ1 model would provide a system in which such a role could be studied in the initial steps of carcinogenesis. Transgenic tumour model mice were bred to pKZ1 mice to produce double transgenic animals. SICR inversion events were scored in mouse tissues at an early time, prior to evident tumour formation, and compared with endogenous pKZ1 SICR levels. Over-expression of the c-myc proto-oncogene resulted in a significant 2.1-fold increase in SICR in spleen. Loss of Msh2 and expression of the SV40 T antigen resulted in a significantly reduced SICR frequency (0.3 of the endogenous frequency in pKZ1 mice) in spleen and prostate respectively. Therefore SICR was affected in the case of all three cancer-associated genes studied. We hypothesise that the increase and decrease in SICR in the presence of cancer-associated genes results from incorrect repairing of double-strand breaks. The data presented here suggest that the pKZ1 model may provide a powerful tool for studying the effect of cancer-associated genes on chromosomal changes in the early stages of carcinogenesis.

Dose-dependent increase or decrease of somatic intrachromosomal recombination produced by etoposide.

Chromosomal inversions and deletions can occur via somatic intrachromosomal recombination (SICR), a mechanism known to be important in mutagenesis and carcinogenesis. Here, we demonstrate a dose-dependent increase or decrease in SICR inversion frequency both in vivo and in vitro after treatment with etoposide, using the pKZ1 mouse mutagenesis model. pKZ1 mice received a single intraperitoneal injection of etoposide dose ranging from 0.0005 to 50mg/kg. Animals were sacrificed 3 days after treatment and the spleen was analysed for SICR. A significant 1.4-3.1-fold induction of SICR inversion events was detected in pKZ1 mice after treatment with etoposide doses ranging from 0.05 to 50 mg/kg etoposide. However, inversion frequencies after treatment with 0.0005 and 0.005 mg/kg etoposide decreased significantly to 0.67 and 0.43 of the levels observed in control animals, respectively. A pKZ1 mouse hybridoma cell line was exposed to etoposide (1-1000 nM) and a similar pattern of SICR response to that detected in vivo was observed. A significant 2.3-4.6-fold induction of SICR inversions was observed in pKZ1 cells treated with 100 and 1000 nM etoposide. Inversion frequencies after treatment with 1 and 10nM etoposide decreased significantly to 0.31 and 0.5 of the level observed in control cell lines. Our in vitro studies complement our in vivo studies and exclude a kinetic phenomenon as the responsible mechanism of reduction in SICR in response to low dose etoposide. Determination of the exact mechanism and significance of recombination suppression at low doses of etoposide treatment requires further investigation.