Richard B. Richardson

Requirements for radiation emergency urine bioassay techniques for the public and first responders.

Following a radiation emergency, the affected public and the first responders may need to be quickly assessed for internal contamination by the radionuclides involved. Urine bioassay is one of the most commonly used methods for assessing radionuclide intake and radiation dose. This paper attempts to derive the sensitivity requirements (from inhalation exposure) for the urine bioassay techniques for the top 10 high-risk radionuclides that might be used in a terrorist attack. The requirements are based on a proposed reference dose to adults of 0.1 Sv (CED, committed effective dose). In addition, requirements related to sample turnaround time and field deployability of the assay techniques are also discussed. A review of currently available assay techniques summarized in this paper reveals that method development for ²⁴¹Am, ²²⁶Ra, ²³⁸Pu, and ⁹⁰Sr urine bioassay is needed.

Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans

Domination of cell proliferation over cell death is a driving force for carcinogenesis, whereas reduced cell proliferation and increased cell death are characteristic of ageing. We employed published data to estimate representative mean values of cell turnover times for 31 different organs and tissues in adult humans and animals (when data in humans were lacking) as well as functional mass loss for 5 organs, accounting for actual mass loss and tissue conversion to fat, in humans over the adult period, age 25 to 70. We found that greater actual and functional mass loss was significantly associated (P=0.001 and P<0.0001, respectively) with the log of shorter cell turnover times. We propose that this is characteristic of stem cell exhaustion and replicative senescence. In addition, we provide quantitative evidence that, in many organs, involution is evident even in young adults. On the basis of published mass measurements of major organs, by analysis of covariance, we identified examples of significant (P≤0.05), accelerated actual or functional mass loss and ageing from early to late adulthood. We hypothesise and quantitatively demonstrate that functional mass loss accelerates with ageing by incorporating the contribution of actual mass loss, tissue conversion to fatty or fibrous tissue, and the presence of apoptotic, necrotic and senescent cells. We propose that mass loss, linked to replicative senescence, is an evolutionary adaptation that effectively limits cancer in young adults, as mass loss is first apparent soon after the end of the growth period, accelerating in the more elderly as biological conditions deviate away from those prevailing in youth, when the selective pressure on pleiotropic genes is greatest.

p53 mutations associated with aging-related rise in cancer incidence rates.

TP53’s role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer’s TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies other than TP53 that reduce p53 activity.

Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2- to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Pagets disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches.

Promotional etiology for common childhood acute lymphoblastic leukemia: The infective lymphoid recovery hypothesis

This paper speculates on the role of infection in modifying a young childs risk of promoting precursor B-cell acute lymphoblastic leukemia (ALL). It is suggested that the heat shock instigated by infections, particularly in infancy, stimulates Th1 pro-inflammatory cytokines and an apoptosis-inhibitory environment. This infective stress also increases the number of cooperating oncogenic mutations in pre-leukemic cells, especially if the primary adaptive immune response is delayed. The glucocorticoid release that follows leads to acute thymic involution, a decline in antitumor immunity, and maturation arrest of B-lymphocytes. The infective lymphoid recovery hypothesis addresses an apparent contradiction-that a non-hygienic environment primes the adaptive immune response and is protective against childhood ALL, while multiple infections occurring later increase the risk of childhood ALL. In affluent (compared to less-affluent) societies, the characteristic ALL incidence peak in early childhood, and the shortened time to diagnosis, arise from surviving recurrent infections and the accumulated loss and recovery of lymphoid tissue. Evidence supporting the hypothesis, such as the role of lymphoid tissue reconstitution cytokines that stimulate proliferation stress on B-cell progenitors, comes from the study of children with congenital syndromes that are susceptible to leukemia.

Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part A: Dose from radon and thoron

Purpose: There is mounting evidence that a significant fraction of radiation-induced mortality and years-life lost are non-cancerous in nature. This study quantifies the radon dose to the coronary artery walls, especially the intimal layer, vunerable to the development of atherosclerosis, and associated cardiovascular disease (CVD). Two accompanying papers determine the oxygen levels (Part B) in coronary arteries and the oxygen effect for radon and other exposures (Part C). Materials and methods: The alpha-radiation dose to coronary artery walls was calculated from the proportion of inhaled radon (222Rn), thoron (220Rn) and their short-lived progeny, which was not deposited in the lung and passed into blood. Age- and gender-dependent morphology and composition for the wall layers of coronary arteries were developed from published data for a normal population and also for individuals with cardiovascular disease. The alpha particle dose to the coronary artery walls was evaluated taking account the diffusion of radon from blood and the solubility of radon-gas in tissues. Results: Diseased arteries exhibited a moderate increase in the solubility of lipophylic radon (190%) in arteries with 88% luminal narrowing, as the high Rn solubility in fat was partially offset by the lower solubility in calcium deposits. The average worldwide dose rate to the diseased intimal layer from 222Rn and its short-lived progeny was estimated to be as high as 68 μSv y−1 per 40 Bq m−3 in air, whereas the corresponding dose rate from 220Rn per 0.3 Bq m−3 in air was ≤0.1% in comparison. Gender had little influence on the dose. Conclusion: The Rn dose to the coronary arteries is significant, but has a large uncertainty due to poor knowledge of Rn and its progeny concentrations in the body.

A physiological skeletal model for radionuclide and stable element biokinetics in children and adults.

A physiological skeletal model (PSM) is described that represents the skeletal uptake, retention, and clearance of both bone-surface-seeking and bone-volume-seeking radionuclides and stable elements. A key objective of the PSM is to model the higher skeletal growth and bone turnover in infants and children (compared to adults) in order to account for their greater uptake and cancer risk from bone-seeking contaminants such as lead and plutonium. The PSM is a compartmental model that allows for the incorporation of organic and inorganic material in the bone volume via quiescent bone surfaces, forming bone surfaces and the lacuno-canaliculi system. The model uniquely incorporates a tertiary phase of mineralization via bone fluids. The PSMs structural concepts and biokinetic parameters--such as realistic mass transfers, organ and tissue masses, and bone remodeling half-times--are selected mainly on the basis of physiological and anatomical criteria. For brevity, model parameter values are evaluated for adults only. The PSM is an improvement on existing skeletal models that are based more on compartment structures and pathways that rendered good fits to biokinetic data rather than on being anatomically and physiologically accurate.

Electron absorbed fractions of energy and S-values in an adult human skeleton based on µCT images of trabecular bone

When the human body is exposed to ionizing radiation, among the soft tissues at risk are the active marrow (AM) and the bone endosteum (BE) located in tiny, irregular cavities of trabecular bone. Determination of absorbed fractions (AFs) of energy or absorbed dose in the AM and the BE represent one of the major challenges of dosimetry. Recently, at the Department of Nuclear Energy at the Federal University of Pernambuco, a skeletal dosimetry method based on µCT images of trabecular bone introduced into the spongiosa voxels of human phantoms has been developed and applied mainly to external exposure to photons. This study uses the same method to calculate AFs of energy and S-values (absorbed dose per unit activity) for electron-emitting radionuclides known to concentrate in skeletal tissues. The modelling of the skeletal tissue regions follows ICRP110, which defines the BE as a 50 µm thick sub-region of marrow next to the bone surfaces. The paper presents mono-energetic AFs for the AM and the BE for eight different skeletal regions for electron source energies between 1 keV and 10 MeV. The S-values are given for the beta emitters (14)C, (59)Fe, (131)I, (89)Sr, (32)P and (90)Y. Comparisons with results from other investigations showed good agreement provided that differences between methodologies and trabecular bone volume fractions were properly taken into account. Additionally, a comparison was made between specific AFs of energy in the BE calculated for the actual 50 µm endosteum and the previously recommended 10 µm endosteum. The increase in endosteum thickness leads to a decrease of the endosteum absorbed dose by up to 3.7 fold when bone is the source region, while absorbed dose increases by ∼20% when the beta emitters are in marrow.

Dose to the cell nucleus from exposure to tritiated pump oil or formaldehyde.

Abstract—A Monte Carlo simulation of tritium decays in a cell composed of two parts, a nucleus and surrounding cytoplasm, was developed to evaluate the beta-radiation dose to the nucleus. A dose modifying factor (DMF), which is a ratio of the average nuclear dose to the whole-tissue dose, after skin-contact exposure of rats to tritiated pump oil or tritiated formaldehyde was estimated. Biokinetic data characterizing the retention of tritium in liver were available in the form of tritium-specific activities and biological half-times for tritiated water and five macromolecular species (DNA, RNA, acid-soluble fraction, acid-insoluble protein, and lipids). The spatial distribution of tissue-free water and macromolecular species in the nucleus and cytoplasm of rat liver cells was based on published data. In the case of exposure to tritiated pump oil, tritium incorporated into lipids provides the largest percentage (60%) of the absorbed dose to the nucleus. For the tritiated-formaldehyde exposure, the tritium dose to the nucleus is overwhelmingly contributed by tritiated water (58%) and in acid-insoluble proteins (40%). For both these tritiated organic exposures, the tritium-labeled DNA has a negligible effect on the DMF. The DMF for the tritiated pump oil and formaldehyde exposures was estimated as 0.81 and 1.05, respectively: the DMF of both exposures was close to unity. Given the other uncertainties in tritium dosimetry, our results suggest that for these skin-contact exposures a uniform distribution of tritium in tissue is an adequate assumption for dosimetry.

Toxicity of irradiated advanced heavy water reactor fuels.

AbstractThe good neutron economy and online refueling capability of the CANDU® heavy water moderated reactor (HWR) enable it to use many different fuels such as low enriched uranium (LEU), plutonium, or thorium, in addition to its traditional natural uranium (NU) fuel. The toxicity and radiological protection methods for these proposed fuels, unlike those for NU, are not well established. This study uses software to compare the fuel composition and toxicity of irradiated NU fuel against those of two irradiated advanced HWR fuel bundles as a function of post-irradiation time. The first bundle investigated is a CANFLEX® low void reactor fuel (LVRF), of which only the dysprosium—poisoned central element, and not the outer 42 LEU elements, is specifically analyzed. The second bundle investigated is a heterogeneous high-burnup (LEU,Th)O2 fuelled bundle, whose two components (LEU in the outer 35 elements and thorium in the central eight elements) are analyzed separately. The LVRF central element was estimated to have a much lower toxicity than that of NU at all times after shutdown. Both the high burnup LEU and the thorium fuel had similar toxicity to NU at shutdown, but due to the creation of such inhalation hazards as 238Pu, 240Pu, 241Am, 242Cm, and 244Cm (in high burnup LEU), and 232U and 228Th (in irradiated thorium), the toxicity of these fuels was almost double that of irradiated NU after 2,700 d of cooling. New urine bioassay methods for higher actinoids and the analysis of thorium in fecal samples are recommended to assess the internal dose from these two fuels.