Nicholas D. Priest

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice

Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNFα, INFγ, IL-1β, TGFβ, INFγ, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025–0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025–2.0 Gy. In contrast, an enhancement of MCP-1, TNFα and fibrinogen at 0.05–2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.

Characterization of neutron fields from bare and heavy water moderated 252Cf spontaneous fission source using Bonner Sphere Spectrometer

In this work a calibrated Bonner Sphere Spectrometer (BSS), together with ISO shadow cones, was used to quantify the total and scattered components of bare and heavy water moderated (252)Cf neutron fields. All measurements were performed with a BSS that was calibrated at the National Physical Laboratory (NPL), Teddington, UK, which is a global primary standard laboratory and world-leading facility for neutron metrology and neutron instruments calibration. The fields were characterized for source-spectrometer distances of 80, 100, 150 and 200cm; and at heights of 103 and 200cm from the facility floor. As expected, the scattered contribution was greatest at the farthest distance from the source and closer to the floor. Hence, at a distance of 200cm and a height of 103cm, the scatter added to the direct field up to 162% of the total neutron fluence and up to 61% of the ambient dose equivalent, while at the same distance and height of 200cm above the floor, these values were up to 146% and 52%, respectively. In the case of heavy water moderated (252)Cf neutron fields, a shadow cone subtraction technique could not be implemented, however Monte Carlo simulations were utilized in order to differentiate between the direct and scatter components of the neutron fields. In this case, at a source-detector distance of 200cm and a height of 103cm, the scatter added to the direct field up to 148% of the total neutron fluence and up to 45% of the ambient dose equivalent, while at the same distance and a height of 200cm above the floor, these values were up to 134% and 42%, respectively.

Relative toxicity of 45Ca β-particles and 242Cm α-particles following their intravenous injection into mice as radiolabelled FAP

Purpose: To determine the relative toxicity of α- and β-radiations under conditions of controlled temporal and spatial dose distribution. Methods: Fused aluminosilicate particles were radiolabelled with either 45Ca (a β-emitter) or 242Cm (an α-emitter). These were injected into CBA/Ca mice to give lifespan, whole-body doses of ∼0.5, 1.0 or 1.5 Gy. Most animals were entered into a lifespan toxicity study, but some were killed for radiochemical analysis and autoradiography. Results: Twenty-seven tumour types were identified. The most common malignant tumours were: Mammary carcinoma; liver carcinoma; malignant lymphoma; uterine histiocytic sarcoma. Excess relative risk (strictly hazard ratio) was higher for radiation-induced carcinomas than for sarcomas. The carcinomas, but not sarcomas showed a reduction in relative risk at the highest radiation dose employed. This reduction was most easily attributed to a systemic effect. The highest relative toxicity measured was for liver carcinoma (5.9, 95% confidence intervals [CI] 2.4, 14) and the lowest for uterine carcinoma (0.6, CI 0.03, 9.7). Overall, the excess relative risk ratio for survival was 1.9 (CI 1.1, 3.2), for all carcinoma was 2.3 (CI 1.7, 3.0) and for all sarcoma was 2.7 (CI 0.72, 10). Conclusions: The 10-fold variability in the observed toxicity ratio for different tumour endpoints shows that tissue sensitivity is a more important determinant of relative toxicity than radiation quality. The use of single radiation-weighting (wR) factors for radiation risk prediction and for radiological protection dosimetry is inconsistent with scientific observation.

Tritium ( 3 H) Retention In Mice: Administered As HTO, DTO or as 3 H-Labeled Amino-Acids

Abstract The objective of this study was to compare the biokinetics of injected 3H-labeled light (HTO) and heavy (DTO) water in CBA/CaJ mice and to compare the organ distribution and/or body content of 3H administered by chronic ingestion for 1 mo to C57Bl/6J mice, as either 3H-labeled water or 3H-labeled amino acids (glycine, alanine and proline). HTO and DTO were administered to CBA/CaJ mice by single intraperitoneal injection and body retention was determined for up to 384 h post-injection. Tritium-labeled water or 3H-labeled amino acids were given to C57Bl/6J mice ad libitum for 30 d in drinking water. Body content and organ distribution of 3H during the period of administration and subsequent to administration was determined by liquid scintillation counting. No differences were found between the biokinetics of HTO and DTO, indicating that data generated using HTO can be used to help assess the consequences of 3H releases from heavy water reactors. The results for 3H-water showed that the concentration of radionuclide in the mice reached a peak after about 10 d and dropped rapidly after the cessation of 3H administration. The maximum concentration reached was only 50% of that in the water consumed, indicating that mice receive a significant fraction of their water from respiration. Contrary to the findings of others, the pattern of 3H retention following the administration of a cocktail of the labeled amino acids was very little different from that found for the water. This is consistent with the suggestion that most of the ingested amino acids were rapidly metabolized, releasing water and carbon dioxide.

Environmentally Relevant Chronic Low-Dose Tritium and Gamma Exposures do not Increase Somatic Intrachromosomal Recombination in pKZ1 Mouse Spleen.

The toxicity of tritium is a public health concern given its presence and mobility in the environment. For risk predictions using radiological protection models, it is essential to allocate an appropriate radiation weighting factor (WR). This in turn should be consistent with the observed relative biological effectiveness (RBE) of tritium beta radiation. Although the International Commission on Radiological Protection (ICRP) currently recommends a WR of 1 for the calculation of committed effective dose for X rays, gamma rays and electrons of all energies, including tritium energies, there are concerns that tritium health risks are underestimated and that current regulatory tritium drinking water standards need revision. In this study, we investigated potential cytotoxic and genotoxic effects in mouse spleen after one month and eight months of chronic exposure to low-dose tritiated water (HTO). The dose regimes studied were designed to mimic human chronic consumption of HTO at levels of 10 kBq/l, 1 MBq/l and 20 MBq/l. The total doses from these radiation exposures ranged from 0.01 to 180 mGy. We also compared the biological effects of exposure to HTO with equivalent exposure to external whole-body 60Co gamma rays. Changes in spleen weight and somatic intrachromosomal recombination (DNA inversions) in spleen tissue of pKZ1Tg/+ mice were monitored. Our results showed no overall changes in either spleen organ weights and no increase mouse splenic intrachromosomal recombination frequencies, indicating that current drinking water standards for tritium exposure in the form of HTO are likely to be adequately protective against cytotoxic and genotoxic damage in spleen. These results demonstrate no evidence for cytotoxicity or genotoxicity in mouse spleen following chronic exposures to HTO activities (or equivalent gamma doses) up to 20 MBq/L.

Correction: Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice.

[This corrects the article DOI: 10.1371/journal.pone.0119661.].

A Pilot Study Measuring Aluminum in Bone in Alzheimer’s Disease and control Subjects Using in vivo Neutron Activation Analysis

Aluminum, being the most abundant metal in the earths crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimers disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimers disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimers disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimers disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance.

Optimisation of nasal swab analysis by liquid scintillation counting.

When responding to an emergency radiological incident, rapid methods are needed to provide the physicians and radiation protection personnel with an early estimation of possible internal dose resulting from the inhalation of radionuclides. This information is needed so that appropriate medical treatment and radiological protection control procedures can be implemented. Nasal swab analysis, which employs swabs swiped inside a nostril followed by liquid scintillation counting of alpha and beta activity on the swab, could provide valuable information to quickly identify contamination of the affected population. In this study, various parameters (such as alpha/beta discrimination, swab materials, counting time and volume of scintillation cocktail etc) were evaluated in order to optimise the effectiveness of the nasal swab analysis method. An improved nasal swab procedure was developed by replacing cotton swabs with polyurethane-tipped swabs. Liquid scintillation counting was performed using a Hidex 300SL counter with alpha/beta pulse shape discrimination capability. Results show that the new method is more reliable than existing methods using cotton swabs and effectively meets the analysis requirements for screening personnel in an emergency situation. This swab analysis procedure is also applicable to wipe tests of surface contamination to minimise the source self-absorption effect on liquid scintillation counting.

In vivo animal studies help achieve international consensus on standards and guidelines for health risk estimates for chronic exposure to low levels of tritium in drinking water: Health Risks of Chronic Exposure to Tritium

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta‐emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low‐level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi‐partner collaborations allow evaluation of a great variety of health‐related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586–594, 2018.

Chronic Exposure to External Low-Dose Gamma Radiation Induces an Increase in Anti-inflammatory and Anti-oxidative Parameters Resulting in Atherosclerotic Plaque Size Reduction in ApoE–/– Mice

Populations living in radiation-contaminated territories, such as Chernobyl and Fukushima, are chronically exposed to external gamma radiation and internal radionuclide contamination due to the large amount of 137Cs released in the environment. The effect of chronic low-dose exposure on the development of cardiovascular diseases remains unclear. Previously reported studies have shown that low-dose radiation exposure could lead to discrepancies according to dose rate. In this study, we examined the effect of very low-dose and dose-rate chronic external exposure on atherosclerosis development. ApoE–/– mice were chronically irradiated with a gamma source for 8 months at two different dose rates, 12 and 28 μGy/h, equivalent to dose rates measured in contaminated territories, with a cumulative dose of 67 and 157 mGy, respectively. We evaluated plaque size and phenotype, inflammatory profile and oxidative stress status. The results of this study showed a decrease in plaque sizes and an increase in collagen content in ApoE–/– mice exposed to 28 μGy/h for 8 months compared to nonexposed animals. The plaque phenotype was associated with an increase in anti-inflammatory and anti-oxidative gene expression. These results suggest that chronic low-dose gamma irradiation induces an upregulation of organism defenses leading to a decrease in inflammation and plaque size. To our knowledge, this is the first study to describe the possible effect of chronic external very low-dose ionizing radiation exposure for 8 months. This work could help to identify the potential existence of a dose threshold, below that which harmful effects are not exhibited and beneficial effects are potentially observed. Furthermore, these findings permit consideration of the importance of dose rate in radiation protection.