Current problems of estimation of genetic risk of human exposure to radiation

The methodology of assessing the genetic risk of radiation exposure is based on the concept of "hitting the target" in development of which N.V. Timofeeff-Ressovsky has played and important role. To predict genetic risk posed by irradiation, the UN Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has worked out direct and indirect methods of assessment, extrapolational, integral and populational criteria of risk analysis that together permit calculating the risk from human exposure on the basis of data obtained for mice. Laboratory mice are the main objects in studying radiation mutagenesis due to the fact that the data on the frequency of radiation-induced human mutations are rather scarce. The method of doubling dose based on the determination of a dose doubling the level of natural mutational process in humans is the main one used to predict the genetic risk. The evolution of views about the genetics risk of human exposure to radiation for last 40 years is considered. Till 1972 the main model for assessing the genetic risk was the "human/mouse" model (the use of data on the spontaneous human variability and data on the frequency of induced mutations in mice). In the period form 1972 till 1994 the "mouse/mouse" model was intensively elaborated in many laboratories. This model was also used in this period by UNSCEAR experts to analyze the genetic risk from human irradiation. Recent achievements associated with the study of the molecular nature of many hereditary human diseases as well as the criticism of number fundamental principles of the "mouse/mouse" model for estimating the genetic risk on a new basis. The estimates of risk for the different classes of genetic diseases have been obtained using the doubling-dose method. The estimate of doubling dose used in the calculations is 1 Gy for low dose/chronic low-LET radiation conditions.     

Radiation protection in space

The challenge for planning radiation protection in space is to estimate the risk of events of low probability after low levels of irradiation. This work has revealed many gaps in our knowledge that require further study. Despite investigations of several irradiated populations, the atomic-bomb survivors remain the primary basis for estimating the risk of ionizing radiation. Compared with previous estimates, two new independent evaluations of available information indicate a significantly greater risk of stochastic effects of radiation (cancer and genetic effects) by about a factor of three for radiation workers, including space travelers. This paper presents a brief historical perspective of the international effort to assure radiation protection in space.Invited paper presented at the International Symposium on Heavy Ion Research: Space, Radiation Protection and Therapy, Sophia-Antipolis, France, 21–24 March 1994     

Estimating clear-day solar radiation: An evaluation of three models

Three models for estimating clear-day solar radiation were compared to one another and to values of solar radiation measured at Ft Collins, Colo. The models of Campbell (1977), Gates (1962) and McCullough and Porter (1971) all correlate closely with measurements of clear-day solar radiation. The Campbell and the Gates models require less technical expertise and less expensive computations to produce estimates of the direct component of solar radiation. All of the models appear to require calibration in order to correct estimates of the input variables to measured values of irradiance so that accurate calculations of direct solar radiation can subsequently be made. The best estimates of the diffuse component of solar radiation are obtained from the model of McCullough and Porter. The easiest and most accurate predictions of total solar radiation can be obtained from the direct-radiation models of Campbell (1977) and Gates (1962) and a modification of the diffuse-component model of McCullough and Porter (1971).     

Estimates of absolute cause-specific risk in cohort studies

In this paper we study methods for estimating the absolute risk of an event c1 in a time interval [t1, t2], given that the individual is at risk at t1 and given the presence of competing risks. We discuss some advantages of absolute risk for measuring the prognosis of an individual patient and some difficulties of interpretation for comparing two treatment groups. We also discuss the importance of the concept of absolute risk in evaluating public health measures to prevent disease. Variance calculations permit one to gauge the relative importance of random and systematic errors in estimating absolute risk. Efficiency calculations were also performed to determine how much precision is lost in estimating absolute risk with a nonparametric approach or with a flexible piecewise exponential model rather than a simple exponential model, and other calculations indicate the extent of bias that arises with the simple exponential model when that model is invalid. Such calculations suggest that the more flexible models will be useful in practice. Simulations confirm that asymptotic methods yield reliable variance estimates and confidence interval coverages in samples of practical size.     

Clinical and epidemiological analysis of possibility of acute myocardial infarction development in personnel of radiation dangerous plants

According to the data of cohort and to the "case-control" studies, dynamics of an acute myocardial infarction (AMI) morbidity during the period 1998-2002 and role of radiation factor in AMI development among personnel of radiation dangerous plants (by the example of Siberian Group of Chemical Enterprises (SGCE) exposed to a long-term impact of ionizing radiation in the range of "low" doses) were being carried out. It was determined that in personnel of the main production (working in contact with IR sources) the gradient increase of AMI morbidity was registered during the study period. Personnel of the main production in comparison to personnel of support production (correlating age, sex and examination level) have statistically significant increase of standardized relative risk coefficients of AMI development. When evaluating standardized relative risk coefficient depending on the cumulative dose of external y-radiation, it was impossible to determine the reliance between the rate of increase of radiation dose and standardized relative risk coefficient. According to logistic regression, was determined that individual features of dose load formation are of great significance in AMI development for the personnel of the main production. Absolute values of standardized regression coefficients peculiar to the values characterizing technogenic impact, exceed correspondent values for "traditional" risk factors to be the components of the regression equation, two-three times as much. The combination of these factors allowed to prognosticate AMI development in 94.3% cases. Obtained data made possible to conclude that in pathogenesis of acute coronary diseases ionizing radiation acts as a factor that aggravate negative influence of "traditional" risk factors of cardio-vascular diseases through pleiotropic effects.     

Addressing the dosimetric impact of bone cement and vertebroplasty in stereotactic body radiation therapy

PurposeBone cement used for vertebroplasty can affect the accuracy on the dose calculation of the radiation therapy treatment. In addition the CT values of high density objects themselves can be misrepresented in kVCT images. The aim of our study is then to propose a streamlined approach for estimating the real density of cement implants used in stereotactic body radiation therapy.MethodsSeveral samples of cement were manufactured and irradiated in order to investigate the impact of their composition on the radiation dose. The validity of the CT conversion method for a range of photon energies was investigated, for the studied samples and on six patients. Calculations and measurements were carried out with various overridden densities and dose prediction algorithms (AXB with dose-to-medium reporting or AAA) in order to find the effective density override.ResultsRelative dose differences of several percent were found between the dose measured and calculated downstream of the implant using an ion chamber and TPS or EPID dosimetry. If the correct density is assigned to the implant, calculations can provide clinically acceptable accuracy (gamma criteria of 3%/2 mm). The use of MV imaging significantly favors the attribution of a correct equivalent density to the implants compared to the use of kVCT images.ConclusionThe porosity and relative density of the various studied implants vary significantly. Bone cement density estimations can be characterized using MV imaging or planar in vivo dosimetry, which could help determining whether errors in dose calculations are due to incorrect densities.     

A Bayesian hierarchical approach to account for left-censored and missing radiation doses prone to classical measurement error when analyzing lung cancer mortality due to γ-ray exposure in the French cohort of uranium miners

Epidemiological data on cohorts of occupationally exposed uranium miners are currently used to assess health risks associated with chronic exposure to low doses of ionizing radiation. Nevertheless, exposure uncertainty is ubiquitous and questions the validity of statistical inference in these cohorts. This paper highlights the flexibility and relevance of the Bayesian hierarchical approach to account for both missing and left-censored (i.e. only known to be lower than a fixed detection limit) radiation doses that are prone to measurement error, when estimating radiation-related risks. Up to the authors’ knowledge, this is the first time these three sources of uncertainty are dealt with simultaneously in radiation epidemiology. To illustrate the issue, this paper focuses on the specific problem of accounting for these three sources of uncertainty when estimating the association between occupational exposure to low levels of γ-radiation and lung cancer mortality in the post-55 sub-cohort of French uranium miners. The impact of these three sources of dose uncertainty is of marginal importance when estimating the risk of death by lung cancer among French uranium miners. The corrected excess hazard ratio (EHR) is 0.81 per 100 mSv (95% credible interval: [0.28; 1.75]). Interestingly, even if the 95% credible interval of the corrected EHR is wider than the uncorrected one, a statistically significant positive association remains between γ-ray exposure and the risk of death by lung cancer, after accounting for dose uncertainty. Sensitivity analyses show that the results obtained are robust to different assumptions. Because of its flexible and modular nature, the Bayesian hierarchical models proposed in this work could be easily extended to account for high proportions of missing and left-censored dose values or exposure data, prone to more complex patterns of measurement error.

     

Regeneration of the sciatic nerve in the progeny of female rabbits irradiated prior to mating

A study was made of the sciatic nerve regeneration after smooth cutting thereof in 198 young chinchillas whose mothers were subjected to whole-body single irradiation with doses of 0.05, 0.15, 0.5 or 1.5 Gy one week before mating. The statistically significant data obtained may be used in estimating a risk from ionizing radiation and ensuring the radiation security standards.     

Radiation injury: some aspects of the oncogenic effects.

The late effects or irradiation stem from cell killing, mutation, and malignant transformation. Cancer is the major somatic late effect of exposure to low dose levels of radiation, and estimates of risk of cancer in man after irradiation are based entirely on human experience. The data for dose-response relationships for the induction of tumors by external irradiation in man have been obtained from a single exposure or a small number of exposures delivered at high dose rates. In contrast, exposure to environmental irradiation is mainly protracted over a long period of time and is delivered at a low dose rate. As yet no allowance has been made for the effect of protraction of the exposure time in estimating the risk of cancer, although an adjustment has been made in the case of estimates of genetic risk. Incidence of tumors has been the only parameter used for risk estimates, but latent period and degree of malignancy, which are probably both dose and dose-rate dependent, influence the nature of the risk from radiation. As the knowledge about the effects of low-level radiation has been accumulated and assimilated over the last 70 years, so has the concern for reasonable standards of safety. There are still problems in the estimation of radiation risks, but at least many of the relevant questions can now be framed. The problems of estimating risks for chemical carcinogens are clearly greater, but the experience gained from radiation studies should help in the design of the necessary experiments.     

Pitfalls of hypothesis tests and model selection on bootstrap samples: Causes and consequences in biometrical applications

The bootstrap method has become a widely used tool applied in diverse areas where results based on asymptotic theory are scarce. It can be applied, for example, for assessing the variance of a statistic, a quantile of interest or for significance testing by resampling from the null hypothesis. Recently, some approaches have been proposed in the biometrical field where hypothesis testing or model selection is performed on a bootstrap sample as if it were the original sample. P‐values computed from bootstrap samples have been used, for example, in the statistics and bioinformatics literature for ranking genes with respect to their differential expression, for estimating the variability of p‐values and for model stability investigations. Procedures which make use of bootstrapped information criteria are often applied in model stability investigations and model averaging approaches as well as when estimating the error of model selection procedures which involve tuning parameters. From the literature, however, there is evidence that p‐values and model selection criteria evaluated on bootstrap data sets do not represent what would be obtained on the original data or new data drawn from the overall population. We explain the reasons for this and, through the use of a real data set and simulations, we assess the practical impact on procedures relevant to biometrical applications in cases where it has not yet been studied. Moreover, we investigate the behavior of subsampling (i.e., drawing from a data set without replacement) as a potential alternative solution to the bootstrap for these procedures.     

Trace metal levels of X-ray technicians' blood and hair

Medical X-ray technicians are exposed to low-level ionizing radiation in their occupational field. There are very few data on low-dose radiation effects. The present study was designed to estimate a few vital trace metals (Zn, Cu, Fe) in indicator tissues (blood and hair) of X-ray technicians and non-X-ray technicians (hospital employees were used as controls) by Atomic Absorption Spectrometry (AAS). This analysis noted a significant increase in Zn, Cu, and Fe concentrations in X-ray technicians' hair. But in blood, Zn and Cu were depleted, whereas Fe was increased. Such changes in trace metal concentrations among X-ray technicians were noted where occupational exposure to radiation was for longer than three years. Through composite risk analysis, by using Zn:Fe as an indicator, it was noted that blood gave a stronger indication than hair in analyzing and estimating risk.     

Estimating glomerular filtration rate in diabetes using serum cystatin C

Chronic kidney disease (CKD) is a major public health problem, especially for people with diabetes. Not only is it a risk factor for end-stage renal disease (ESRD) but it is also a major cardiovascular disease (CVD) risk factor. Methods that accurately and simply estimate glomerular filtration rate (GFR) are therefore needed to optimise the detection and management of CKD in people with diabetes. One of the main failures of commonly used creatinine-based methods for estimating renal function is that they lack applicability across the full range of GFR values and underestimate GFR levels >60 mL/min/1.73m(2). Methods for accurately estimating an early pathological decline in GFR (i.e. ΔGFR >3.3 mL/min/year before reaching a GFR <60 mL/min/1.73m(2)) are especially needed as appropriate interventions have been shown to retard progression to ESRD and reduce CVD risk in people with diabetes. In contrast, recent studies have suggested that estimates of GFR based on serum cystatin C concentration might provide a simple and accurate method for detecting and monitoring an early decline in renal function.     

Relevance of Internal Bremsstrahlung photons from 90Y decay: an experimental and Monte Carlo study

Internal Bremsstrahlung (IB) is a continuous electromagnetic radiation accompanying beta decay; however, this process is not considered in radiation protection studies, particularly when estimating exposure from beta-decaying radionuclides.The aims of the present work are: i) to show that neglecting the IB process in Monte Carlo (MC) simulation leads to an underestimation of the energy deposited in a ionization chamber, in the case of a high-energy pure beta emitter such as Yttrium-90 (⁹⁰Y), and ii) to determine the most reliable choice of source term for ⁹⁰Y IB to be used in MC simulations.For this radionuclide, commonly employed in nuclear medicine and radiochemistry applications, experimental data acquired with a well ionization chamber have been compared with Monte Carlo (MC) calculations carried out in the GAMOS framework. Simulations that do not include the effect of the IB process, are found to give results underestimating the experimental values by 12–14%.Consequently, two models for the IB energy spectra, previously described by Italiano et al. [1], have been implemented using MC simulation and a good agreement has been achieved with one of them.We therefore conclude that inclusion of IB process in Monte Carlo simulation packages is advisable for a more accurate and complete treatment of electromagnetic interactions.     

A reanalysis of liver cancer incidence in Danish patients administered thorotrast using a two-mutation carcinogenesis model

In recent years, a two-mutation carcinogenesis (TMC) model has been used to analyze epidemiological data and estimate the radiation risks at low doses for the organs affected. Here the TMC model was used to reanalyze the liver cancer incidence in the Danish population in general and in patients administered Thorotrast, and to estimate the radiation risks for the liver. The data for 807 patients for whom sufficient data on the injected volumes of Thorotrast were available were used in this reanalysis. These data were combined with data on liver cancer incidence in the Danish population as the baseline or background incidence. Because males and females show different baseline liver cancer incidences, separate fits were made for males and females. The fits showed that the radiation effect could be ascribed entirely to the radiation dependence of the first mutation rate of the TMC model, which was higher for females than for males. The second mutation rate was not significantly dependent on dose. The radiation risks for the liver were calculated on the basis of the model parameters. These risks for lifetime exposures are about the same for males and females and are between a factor of 2 and 10 higher than current estimates. The discrepancy between the model results and previous risk estimates probably arises because the model calculations give more complete lifetime radiation risk estimates. For short-term exposures of the liver to ionizing radiation, the maximum radiation-induced excess liver cancer risk per unit dose applies to exposures at the age of about 10; exposures at ages above 35 have a radiation effect of less than approximately 15% of this maximum.     

Estimation of radiation resistance values of microorganisms in food products

Several statistical methods, including the conventional technique of Schmidt and Nank, were evaluated for estimating radiation resistance values of various strains of Clostridium botulinum by the use of partial spoilage data from an inoculated ham pack study. Procedures based on quantal response were preferred. The tedious but rigorous probit maximum likelihood determination was used as a standard of comparison. Weibull's graphical treatment was the method of choice because it is simple to utilize, it is mathematically sound, and its ld(50) values agreed closely with the reference standard. In addition, it offers a means for analyzing the type of microbial death kinetics that occur in the pack (exponential, normal, log normal, or mixed distributions), and it predicts the probability of microbial death with any radiation dose used, as well as the dose needed to destroy any given number of organisms, without the need to assume the death pattern of the partial spoilage data. The Weibull analysis indicated a normal type kinetics of death for C. botulinum spores in irradiated cured ham rather than an exponential order of death, as assumed by the Schmidt-Nank formula. The Weibull 12D equivalent of a radiation process, or the minimal radiation dose (MRD), for cured ham was consistently higher than both the experimental sterilizing dose (ESD) and the Schmidt-Nank average MRD. The latter calculation was lower than the ESD in three of the five instances examined, which seems unrealistic. The Spearman-K?rber estimate was favored as the arithmetic technique on the bases of ease of computation, close agreement with the reference method, and providing confidence limits for the ld(50) values.     

Computational method for relative binding energies of enzyme-substrate complexes.

A computational method for estimating the relative binding free energies of enzyme-substrate complexes is described that combines electrostatic and solvation models and X-ray crystallographic data. The polar contribution is evaluated by the Poisson-Boltzman equation. The nonpolar contribution is evaluated by solvent transfer data and surface area calculations. This algorithm was used to calculate the relative binding energies of 63 pairs of nine different mutant proteins with seven different substituted R-malate substrates of Escherichia coli isocitrate dehydrogenase. Comparison of calculated values with the experimentally observed values shows a high degree of correlation.     

The risk of chronic myeloid leukemia: can the dose-response curve be U-shaped?

Chronic myeloid leukemia (CML) is caused by a BCR-ABL chromosome translocation in a primitive hematopoietic stem cell. The number of hematopoietic stem cells in the body is thus a major factor in CML risk. Evidence suggests that the number of hematopoietic stem cells in the body is only loosely regulated, having a broad "dead-band" of physiologically acceptable values. The existence of a dead-band is important, because it would imply that low levels of hematopoietic stem cell killing can be permanent; i.e., it would imply that low doses of ionizing radiation can cause permanent reductions in the total number of CML target cells and thus permanent reductions in the subsequent risk of spontaneous CML. Such reductions in risk could be substantial if hematopoietic stem cells are also hypersensitive to radiation killing at low dose. Our calculations indicate that, due to dead-band hematopoietic stem cell control, if hematopoietic stem cells are as hypersensitive to killing at low doses as epithelial cells, reductions in the spontaneous CML risk could exceed the low-dose risks of induced CML; i.e., the net lifetime CML risk could have a U-shaped dose-response curve.     

The remote effects of chronic exposure to ionizing radiation and electromagnetic fields with respect to hygienic standardization

A variety and rate of non-cancer diseases occurred in humans as a result of chronic exposure to ionizing radiation or to electromagnetic radiation (EMR) of high and superhigh frequency have been compared. The intensity of EMR was slightly higher than a sanitary standard for population. A risk of health impairments in workers having occupational exposure to EMR was assessed on the basis of Selie's concept of development of non-specific reaction of the body to chronic stress factors (general adaptation syndrome), models of changes in the body compensatory reserves and calculations of radiation risk after severe and chronic exposure to ionizing radiation.     

Determination of erythema-effective solar radiation in Japan and Germany with a spore monolayer film optimized for the detection of UVB and UVA – results of a field campaign

The available physical and biological broadband radiometers designed to determine erythema-effective radiation do not show any response or over/underestimate the biologically effective radiation to a high extent in the ultraviolet (UV)A spectral region. The data presented in this paper demonstrate that the biological system used in this study is the first one to make possible measurements of erythema-effective radiation in the sun in the UVA and UVB spectral region. These measurements were performed with a spore-film filter system as well as with spectroradiometers. It was demonstrated that this biotechnological method could be used to determine exact values expressed as minimal erythemal dose (MED). The spore-film system was tested in various field campaigns performed in Germany and in Japan. The seasonal daily variation of UV radiation in Germany determined in the period November 1995 to December 1996 using the spore-film filter system in sunny conditions tallied well with model calculations. The daily dose in Germany measured with the spore-film system close to the summer solstice, in sunny conditions (20.45 MED), was approximately 20 times higher than the lowest value measured close to the winter solstice (0.82 MED), a result which was in accordance with model calculations. The data determined with the spore-film filter system in Sapporo and Naha, Japan, fitted to the erythema-weighted data calculated from spectroradiometric measurements (Brewer), even at low solar radiation angles in a solar spectrum with less UVB but significant UVA. The spore-film dosimeter values were about 103 ± 8% of the integrated dose of the Brewer instrument. The standard deviation of the spore-film measurements obtained in Japan was 12.8%. The responsivity of the spore-film system towards longer wavelengths within the UVA spectrum was tested with the Okasaki Large Spectrograph with monochromatic radiation. At a wavelength of 365 nm – in a spectral region which is dominant in many tanning lamps and with minor importance for solar radiation in summer conditions – the tested spore-film system gave results that were close (112% compared to the calibration dose) to the calibration dose which was used for irradiation. Received: 27 January 1998 / Received last revision: 21 July 1998 / Accepted: 29 July 1998