A comparison of the natural survival of beagle dogs injected intravenously with low levels of 239Pu, 226Ra, 228Ra, 228Th, or 90Sr

The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 +/- 0.04 kBq 239Pu/kg, 23 dogs injected with 2.31 +/- 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 +/- 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 +/- 0.030 kBq 228Th/kg, and 12 dogs injected with 21.13 +/- 1.74 kBq 90Sr/kg was evaluated statistically. The amounts of these radionuclides are related directly to the estimated maximum permissible body burdens for humans suggested in ICRP II (1959). They constitute a level of exposure that initially was assumed to cause no deleterious effects in dogs. This study had two objectives: (1) identification of homogeneous control groups against which to evaluate the survival of the irradiated groups and (2) comparison of the survival characteristics and estimation of mortality or hazard rate ratios for control dogs vs dogs injected with the baseline dosages given above. It was shown, by goodness-of-fit plots, that the Cox proportional hazards model was an appropriate method of analysis. Therefore, covariates that possibly could influence survival were tested for significance. Only the effects of grand mal seizure, which is caused in epileptic dogs by an external stimulus and can be fatal if untreated, were significant (P less than 0.0001). Consequently, in the final model, death from grand mal seizure was considered as accidental. After censoring the dogs dying from grand mal seizure, it was established that the data for the control groups from previous and contemporary experiments could be pooled. The change in hazard rates relative to controls resulting from exposure to the baseline radionuclide level was modest, 1.6 times for 239Pu (P = 0.033), 1.0(4) for 226Ra (P = 0.86), 1.9 for 228Ra (P = 0.035), 2.5 for 228Th (P less than 0.001), and 0.52 for 90Sr (P = 0.041). Bone tumor induction was clearly elevated in dogs injected with 239Pu and 228Th. When the effect of these bone tumors on survival was removed by censoring, the dogs injected with 239Pu were indistinguishable from the controls. In contrast, the effects of bone tumor on group survival of the 228Ra and 228Th dogs were not significant. Thus, no additional life-shortening effects beyond those attributable to bone tumor were suggested by these data for 239Pu, but other, as yet unspecified, confounders are suggested for 228Ra and 228Th.     

Two-mutation models for bone cancer due to radium, strontium and plutonium

Data from beagle experiments and radium dial painters were used to derive two-mutation carcinogenesis models for bone cancer induced by the bone-seeking radionuclides radium, strontium and plutonium. For all data, the model fits indicate that at low doses both mutation rates depend linearly and equally strongly on dose rate. For the high-LET alpha-particle emitters, a cell killing term reduces the second mutation rate at high dose rates. In all cases, the combined effect of both mutation rates is a linear-quadratic dose-effect relationship for cancer at low doses. This behavior may lead to experimental data that could be mistaken as showing a threshold below which no cancers are induced. Derived parameters such as toxicity ratios and tumor growth times compare well with values reported in the literature. Furthermore, results for plutonium indicate that rapid burial of the nuclide in the growing bones of juvenile beagles leads to a significant reduction of its toxicity, as was suggested previously. The results for radium in beagles compare well with those for humans and suggest that the models derived for strontium and plutonium in beagles may be translated to humans. The significant model parameters for the accurate animal data could then also be used to fit human epidemiological data.     

243,244Cm studies in C57BL/Do mice

Three groups of C57BL/Do mice were injected with different activities of 243,244Cm so that the long-term biological effects could be evaluated. The biological retention, R, of injected curium in the skeleton at t days after injection could be represented by the equations R = 0.245e-0.000379t and R = 0.208e-0.000494t for male and female mice, respectively. Effective skeletal retention equations were used to calculate the cumulative mean skeletal dose in rad at 140 days before death in each group of mice. The primary objective of this study was to determine the relative biological effectiveness (RBE) of 243,244Cm compared to 226Ra, using bone sarcoma induction as the end point. Combined data (bone sarcomas per 10(6) mouse-rad) for male and female mice permitted the RBE value +/- SD for 243,244Cm to be calculated as 4.4 +/- 1.8 compared to 1.0 for 226Ra. A comparison of RBE values form a previous study in this mouse strain and the value for 243,244Cm from this study suggests that the trivalent actinides 241Am, 243,244Cm, and 249Cf are about three times less effective for bone sarcoma induction than 239Pu.     

Vasoformative non-osteogenic (angio) sarcomas of bone-marrow stroma due to strontium-90.

In a series of experiments, mainly CBA/H, but also C2H/H, mice aged 3 months were injected intraperitoneally with solutions of 90Sr Cl2, the dose per mouse varying from 7 to 20 muCi, and compared with similar mice treated with 226Ra or 239Pu, discussed elsewhere. In male mice, the commonest tumour resulting at each dose of 90Sr was non-osteogenic (angio) sarcoma, a tumour not seen after 226Ra. In females, this tumour occurred far less frequently than osteosarcoma. In CBA mice of both sexes converted to radiation chimaeras (which are sterile) and similarly treated with 90Sr, the only skeletal tumours were osteosarcomas. When only half the body of CBA mice was X-irradiated with 1000 rad and the mice given 90Sr, non-osteogenic sarcoma occurred predominantly in those mice X-irradiated in the cephalic half. The results suggest that intact testes may provide co-factors for this type of neoplasm, whereas others have shown that oestrogens facilitate murine osteosarcoma. The non-osteogenic osteosarcomas arise from damaged stromal elements in bone-marrow of selected bones. The risk to this component of bone-marrow, as well as to haematopoietic tissue, should be considered in radiation protection.     

Interpretation of cytogenetic damage induced in the germ line of male mice exposed for over 1 year to 239Pu alpha particles, fission neutrons, or 60Co gamma rays

The relative biological effectiveness (RBE) of 239Pu alpha particles, fission neutrons (0.85 MeV), and 60Co gamma rays has been evaluated for the induction of reciprocal chromosome translocations in spermatogonia and of chromosome/chromatid fragments and chromatid rearrangements in the primary spermatocyte of adult male B6CF1 mice. Age concurrency was maintained for both internal and external radiations which were delivered at about 1 rad/week for 239Pu (single intravenous dose of 10 microCi/kg), 0.67, 1.67, and 2.67 rad/week for neutrons, and 6.95, 17.4, and 32 rad/week for gamma rays for at least 60 weeks. In terms of frequency of translocations, the response to the alpha emitter was nonlinear (concave downward) with little dose-response predictability; to cumulative neutron exposures the response was linear, without evidence of a dose-rate effect; and to gamma radiation the responses were linear, and a significant dose-rate effect was seen. RBE estimates are variable. For translocations, the n/gamma ratio is between 10 and 24, depending upon weekly dose level, and the ratio is 1 or less for the alpha particle relative to the neutron. For fragments, the n/gamma ratio is 18 to 22, depending upon age factors, and alpha/n is 1.5. For chromatid rearrangements, n/gamma is 7 and alpha/n is essentially indeterminate, but much below one. The overall response to the alpha emitter is interpreted to be a complex function of (a) microdosimetric heterogeneity, (b) a nearly invariant deposition pattern in the gonad, (c) the high sensitivity of differentiating spermatogonia to cell killing, and (d) the capacity of stem cells in relatively radiation-free areas to progressively assume the major spermatogenic role.     

A model-based Bayesian estimation of the rate of evolution of VNTR loci in Mycobacterium tuberculosis

Variable numbers of tandem repeats (VNTR) typing is widely used for studying the bacterial cause of tuberculosis. Knowledge of the rate of mutation of VNTR loci facilitates the study of the evolution and epidemiology of Mycobacterium tuberculosis. Previous studies have applied population genetic models to estimate the mutation rate, leading to estimates varying widely from around to per locus per year. Resolving this issue using more detailed models and statistical methods would lead to improved inference in the molecular epidemiology of tuberculosis. Here, we use a model-based approach that incorporates two alternative forms of a stepwise mutation process for VNTR evolution within an epidemiological model of disease transmission. Using this model in a Bayesian framework we estimate the mutation rate of VNTR in M. tuberculosis from four published data sets of VNTR profiles from Albania, Iran, Morocco and Venezuela. In the first variant, the mutation rate increases linearly with respect to repeat numbers (linear model); in the second, the mutation rate is constant across repeat numbers (constant model). We find that under the constant model, the mean mutation rate per locus is (95% CI: ,)and under the linear model, the mean mutation rate per locus per repeat unit is (95% CI: ,). These new estimates represent a high rate of mutation at VNTR loci compared to previous estimates. To compare the two models we use posterior predictive checks to ascertain which of the two models is better able to reproduce the observed data. From this procedure we find that the linear model performs better than the constant model. The general framework we use allows the possibility of extending the analysis to more complex models in the future.     

Comparative evaluation of 238U and 226Ra absorption by herbaceous and woody species under conditions of technogenic pollution

The results of studies on uranium and radium distribution in soil and vegetation at the territory contaminated by wastes of radium plant in 1930-1950 are presented. Specific activities of 226Ra and 238U in soil varied as 0.01-200 and 0.004-7.58 Bq/g per ash respectively. The radionuclides are mainly concentrated in the upper layer of soil profile. In the vegetation concentrations of 226Ra and 238U varied as 0.64-132 0.001-0.02 Bq/g per ash respectively. Among the woody species studied, Betula pubescens and Sorbus aucuparia are characterized by the highest absorption of radionuclides. For all plants studied a negative linear dependence is shown between logarithm of TF (TF = [226Ra, 238U in plant, Bq/g per ash]/[226Ra, 238U in soil, Bq/g per ash]) and logarithm of 226Ra and 238U concentrations in soil. The findings obtained can be used in modeling of biological absorption in radioecological investigations.     

Determination of the plutonium-239 content of the body

In order to increase the informativeness of the indirect dosimetric estimates of plutonium-239 body levels complex makers are widely used to enhance natural excretion of the radionuclide in urine, the ratio between 239Pu levels in urine and skeleton being measured. However, as the onset of chelate application is postponed its efficacy, with respect to the skeleton, sharply decreases making it impossible to obtain reliable information concerning plutonium 239 levels in bone tissues at later times.     

Lymphoid tumours and leukaemia induced in mice by bone-seeking radionucleides.

Single intraperitoneal doses of soluble 90Sr and monomeric 239Pu induced generalized lymphomatosis in laboratory mice. Leukaemogenesis due to soluble 226Ra was more uncertain. Clinical expression was variable, but as a generalization the disease was a lymphosarcoma with haematogenous (leukaemic) spread. Only rarely, unlike the commonly recorded forms of natural and X-ray-induced lymphosarcomas, was the thymus apparently the site of onset. The cell-type was lymphoblastic of undifferentiated null form (not T, not B). The average doses of alpha or beta radiation accumulated in the bone-marrow, the presumed site of induction, were at the time of diagnosis usually more than 2500 rad, but, if the cases occurring after radium or low activities of plutonium are accepted as induced, 300-1500 rad of alpha radiation. Mice converted to chimaeras only rarely exhibited any lymphoma, general or local. Abdominal lymphomas were not numerically increased by these radionucleides (perhaps due to shortening of life-span) though some may have been prematurely induced.     

Cytogenetic mechanisms of aneuploidy in somatic cells of chemonuclear industry professionals with incorporated plutonium-239

Risks related to occupational exposure of humans to ionizing radiation remains a focus of attention. Of special importance is the poorly understood effect of ionizing radiation on the rate of numerical chromosome aberrations in human somatic cells. The purpose of this study was characterization of a radiation-induced increase in the rate of aneuploidy induced by incorporated plutonium-239 (²³⁹Pu) in somatic cells of chemonuclear industry workers. Significant differences in the chromosome 2, 7, 8, 12, and Y aneuploidy rate have been found between subjects with incorporated ²³⁹Pu and control subjects have been demonstrated. Chromosome nondisjunction has been found to be the main mechanism of aneuploidy induced by incorporated ²³⁹Pu.     

Tempo and mode of synonymous substitutions in mitochondrial DNA of primates

Nucleotide substitutions of the four-fold degenerate sites and the total third codon positions of mitochondrial DNA from human, common chimpanzee, bonobo, gorilla, and orangutan were examined in detail by three alternative Markov models; (1) Hasegawa, Kishino, and Yano's (1985) model, (2) Tamura and Nei's (1993) model, and (3) the general reversible Markov model. These sites are expected to be relatively free from constraint, and therefore their tempo and mode in evolution should reflect those of mutation. It turned out that, among the alternative models, the general reversible Markov model best approximates the nucleotide substitutions of the four-fold degenerate sites and the total third codon positions, while the maximum likelihood estimates of the numbers of nucleotide substitutions along each branch do not differ significantly among the three models. It was further shown that the transition rate of these sites during evolution, and therefore transitional mutation rate of mtDNA, are higher in humans than in chimpanzees and gorillas probably by about two times. However, transversional mutation rate and amino acid substitution rate do not differ significantly between humans and the African apes. These and additional observations suggest heterogeneity of the mutation rate as well as of the constraint operating on the mtDNA-encoded proteins among different lineages of Hominoidea.      

Plutonium,241Am,90sr,and137cs concentrations in some antarctic matrices

A radioecological survey in Antarctica shows that the^239+240Pu,²³⁸Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs activities were detectable in nearly all the samples. The activity level of^239+240Pu,²⁴¹Am, and¹³⁷Cs in antarctic sediments was about 5–20 times lower than in the northern Adriatic Sea sediments, but the²³⁸Pu activities were relatively high. It was interesting to note that the⁹⁰Sr concentrations in all the sediments tended to be low, which could be the result of the easier exchangeable behavior of⁹⁰Sr in water. High concentrations were detected in mosses and lichens and their activity levels were comparable to those in central Italy. The radionuclide ratio analyses show that the major part of^239+240Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs was a result of nuclear weapon tests. The higher²⁴¹Am/^239+240Pu ratio was observed and it could perhaps be the result of fallout of nuclear weapon tests prior to 1962. The²³⁸Pu/^239+240Pu ratio in the antarctic matrices was about seven times higher than in the Northern hemisphere and it could be inferred that the major part of²³⁸Pu was originating from the SNAP-9A satellite accident.     

The levels of soil pollution with plutonium isotopes in the Bryansk Oblast (following the accident at the Chernobyl Atomic Electric Power Station)]

The estimates of plutonium concentration in soils of Western regions of Bryansk (Krasnogorsky, Novozybkovsky, Zlynkovsky and Klintsovsky) are presented. The levels of soil contamination with plutonium within the regions examined vary by 4-5 times, although no definite geographical direction of pollution intensity within the territory examined is noted. The cumulative concentration of isotopes (238Pu, 239Pu, and 240Pu) varies within 21-112 Bq/kg.     

90Sr, 137Cs, 238Pu, 239+240Pu,and 241Am radionuclides in macrophytes within the Krasnensky flood plain: species specificity of concentration and distribution in phytocenosis components

The analysis of the content of radionuclides 90Sr, 137Cs, 238Pu, 239 + 240Pu and 241Am in water vegetation of flood plain reservoirs has allowed studing features of radionuclide accumulation by various species of macrophytes and revealing bioindicators of radionuclide contamination. Thus species-specificity of radionuclide accumulation can essentially change the contribution of different species to a percentage ratio of the radionuclide content in phytomass of reservoirs in comparison with fund of higher aquatic plants.     

A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data

A generalization of the two-mutation stochastic carcinogenesis model of Moolgavkar, Venzon and Knudson and certain models constructed by Little is developed; the model incorporates progressive genomic instability and an arbitrary number of mutational stages. This model is shown to have the property that, at least in the case when the parameters of the model are eventually constant, the excess relative and absolute cancer rates following changes in any of the parameters will eventually tend to zero. It is also shown that when the parameters governing the processes of cell division, death, or additional mutation (whether of the normal sort or that resulting in genomic destabilization) at the penultimate stage are subject to perturbations, there are relatively large fluctuations in the hazard function for the model, which start almost as soon as the parameters are changed. The model is fitted to US Caucasian colon cancer incidence data. A model with five stages and two levels of genomic destabilization fits the data well. Comparison with patterns of excess risk in the Japanese atomic bomb survivor colon cancer incidence data indicate that radiation might act on early mutation rates in the model; a major role for radiation in initiating genomic destabilization is less likely.     

Sparing of bone marrow stem cells by long-term administration of Na-alginate to 226Ra contaminated mice.

226Ra toxicity studies form the experimental basis for the estimation of radiation risk from internal emitters in man. We investigated whether treatment with Na-alginate is able to protect haemopoietic bone marrow cells against alpha-irradiation from 226Ra contamination. Doses from 4 to 14 micronCi/kg were injected intraperitoneally in mice 12 days before the start of the treatment. Damage to marrow stem cells was assessed by the exogene clonal spleen technique. Collection of marrow cells by two methods was compared. In the lower dose groups no influence on stem cell survival is noticed. but from 9.0 micronCi/kg a decrease in the number of surviving stem cells is observable in non treated animals. while in animals treated with Na-alginate fewer stem cells are damaged. These preliminary data agree with the hypothesis that Na-alginate stimulates removal of 226Ra mainly from the endosteal bone surfaces, reducing the local 226 Ra dose which accounts for damage to marrow stem cells within the range of alpha-rays at the endosteal surfaces.     

Sources and fluxes of submarine groundwater discharge delineated by radium isotopes

This paper reports the results derived fromradium isotopes of a submarine groundwaterdischarge (SGD) intercomparison in thenortheast Gulf of Mexico. Radium isotopesamples were collected from seepage meters,piezometers, and surface and deep ocean waters.Samples collected within the near-shore SGDexperimental area were highly enriched in allfour radium isotopes; offshore samples wereselectively enriched. Samples collected fromseepage meters were about a factor of 2–3higher in radium activity compared to theoverlying waters. Samples from piezometers,which sampled 1–4 meters below the sea bed were1–2 orders of magnitude higher in radiumisotopes than surface waters. The twolong-lived Ra isotopes, ²²⁸Ra and²²⁶Ra, provide convincing evidence thatthere are two sources of SGD to the study area:shallow seepage from the surficial aquifer andinput from a deeper aquifer. A three end-membermixing model can describe the Ra distributionin these samples. The short-lived radium isotopes, ²²³Ra and²²⁴Ra, were used to establish mixing ratesfor the near-shore study area. Mixing wasretarded within 3 km of shore due to a strongsalinity gradient. The product of the mixingrate and the offshore ²²⁶Ra gradientestablished the ²²⁶Ra flux. This flux mustbe balanced by Ra input from SGD. The flux ofSGD within 200 m of shore based on the²²⁶Ra budget was 1.5 m³ min^?1.This flux agreed well with other estimatesbased on seepage meters and ²²²Rn.     

Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors

Estimation of population parameters for the common ancestors of humans and the great apes is important in understanding our evolutionary history. In particular, inference of population size for the human-chimpanzee common ancestor may shed light on the process by which the 2 species separated and on whether the human population experienced a severe size reduction in its early evolutionary history. In this study, the Bayesian method of ancestral inference of Rannala and Yang (2003. Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics. 164:1645-1656) was extended to accommodate variable mutation rates among loci and random species-specific sequencing errors. The model was applied to analyze a genome-wide data set of approximately 15,000 neutral loci (7.4 Mb) aligned for human, chimpanzee, gorilla, orangutan, and macaque. We obtained robust and precise estimates for effective population sizes along the hominoid lineage extending back approximately 30 Myr to the cercopithecoid divergence. The results showed that ancestral populations were 5-10 times larger than modern humans along the entire hominoid lineage. The estimates were robust to the priors used and to model assumptions about recombination. The unusually low X chromosome divergence between human and chimpanzee could not be explained by variation in the male mutation bias or by current models of hybridization and introgression. Instead, our parameter estimates were consistent with a simple instantaneous process for human-chimpanzee speciation but showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species.