Criticality accident dosimetry by chromosomal analysis.

The technique of measuring the frequency of dicentric chromosomal aberrations in blood lymphocytes was used to estimate doses in a simulated criticality accident. The simulation consisted of three exposures; approximately 5 Gy with a bare source and 1 and 2 Gy with a lead-shielded source. Three laboratories made separate estimates of the doses. These were made by the iterative method of apportioning the observed dicentric frequencies between the gamma and neutron components, taking account of a given gamma/neutron dose ratio, and referring the separated dicentric frequencies to dose-response calibration curves. An alternative method, based on Bayesian ideas, was employed. This was developed for interpreting dicentric frequencies in situations where the gamma/neutron ratio is uncertain. Both methods gave very similar results. One laboratory produced dose estimates close to the eventual exercise reference doses and the other laboratories estimated slightly higher values. The main reason for the higher values was the calibration relationships for fission neutrons.

Bayesian methods for chromosome dosimetry following a criticality accident.

Radiation doses received during a criticality accident will be from a combination of fission spectrum neutrons and gamma rays. It is desirable to estimate the total dose, as well as the neutron and gamma doses. Present methods for dose estimation with chromosome aberrations after a criticality accident use point estimates of the neutron to gamma dose ratio obtained from personnel dosemeters and/or accident reconstruction calculations. In this paper a Bayesian approach to dose estimation with chromosome aberrations is developed which allows the uncertainty of the dose ratio to be considered. Posterior probability densities for the total and the neutron and gamma doses were derived.

Bayesian estimation of dose thresholds.

An example is described of Bayesian estimation of radiation absorbed dose thresholds (subsequently simply referred to as dose thresholds) using a specific parametric model applied to a data set on mice exposed to 60Co gamma rays and fission neutrons. A Weibull based relative risk model with a dose threshold parameter was used to analyse, as an example, lung cancer mortality and determine the posterior density for the threshold dose after single exposures to 60Co gamma rays or fission neutrons from the JANUS reactor at Argonne National Laboratory. The data consisted of survival, censoring times and cause of death information for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were 0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for neutron and gamma radiation were calculated with numerical integration and found to have quite different shapes. The density of the threshold for 60Co is unimodal with a mode at about 0.50 Gy. The threshold density for fission neutrons declines monotonically from a maximum value at zero with increasing doses. The posterior densities for all other parameters were similar for the two radiation types.

Bayesian analysis of overdispersed chromosome aberration data with the negative binomial model.

The usual assumption of a Poisson model for the number of chromosome aberrations in controlled calibration experiments implies variance equal to the mean. However, it is known that chromosome aberration data from experiments involving high linear energy transfer radiations can be overdispersed, i.e. the variance is greater than the mean. Present methods for dealing with overdispersed chromosome data rely on frequentist statistical techniques. In this paper. the problem of overdispersion is considered from a Bayesian standpoint. The Bayes Factor is used to compare Poisson and negative binomial models for two previously published calibration data sets describing the induction of dicentric chromosome aberrations by high doses of neutrons. Posterior densities for the model parameters, which characterise dose response and overdispersion are calculated and graphed. Calibrative densities are derived for unknown neutron doses from hypothetical radiation accident data to deterimine the impact of different model assumptions on dose estimates. The main conclusion is that an initial assumption of a negative binomial model is the conservative approach to chromosome dosimetry for high LET radiations.

Exact and approximate Bayesian estimation of net counting rates.

The stochastic fluctuations in the number of disintegrations, which had already been studied experimentally by Rutherford and other investigators at the beginning of the twentieth century, make estimation of net counting rates in the presence of background counts a challenging statistical problem. Exact and approximate Bayesian estimates of net count rates using Poisson and normal distributions for the number of counts detected during varying counting intervals are derived. The posterior densities for the net count rate are derived and plotted for uniform priors. The graphs for the exact, Poisson based, and for the approximate posterior densities of the background and net count rates, resulting from the normal approximation to the Poisson distribution, were compared. No practical differences were found when the number of observed gross counts is large. Small numerical differences in the posterior expectations and standard deviations of the counting rates appeared when the number of observed counts was small. A table showing some of these numerical differences for different background and gross counts is included. A normal approximation to the Poisson is satisfactory for the analysis of counting data when the number of observed counts is large. Some caution has to be exercised when the number of observed counts is small.

Synthesis of optically active alpha-methylene beta-lactams through lipase-catalyzed kinetic resolution.

A convenient method for the preparation of the hitherto unknown chiral alpha-methylene beta-lactam derivatives 5a,b is reported. The optically active alpha-methylene beta-lactams 5a-c, and their corresponding amino acids 6a-c have been readily made available through lipase-catalyzed kinetic resolution in high enantiomeric purity (up to 99% ee). The N-substituted beta-lactam derivatives 4a, b and 10 are not accepted by the lipases and were prepared in optically active form by chemical transformation.

Photochemical and photobiological studies with acridine and phenanthridine hydroperoxides in cell-free DNA.

The acridine and phenanthridine hydroperoxides 3 and 7 were synthesized as photochemical hydroxyl radical sources for oxidative DNA damage studies. The generation of hydroxyl radicals upon UVA irradiation (lambda = 350 nm) was verified by trapping experiments with 5,5-dimethyl-1-pyrroline N-oxide and benzene. The enzymatic assays of the damage in cell-free DNA from bacteriophage PM2 caused by the acridine and phenanthridine hydroperoxides 3 and 7 under near-UVA irradiation revealed a wide range of DNA modifications. Particularly, extensive single-strand break formation and DNA base modifications sensitive to formamidopyrimidine DNA glycosylase (Fpg protein) were observed. In the photooxidation of calf thymus DNA, up to 0.69 +/- 0.03% 8-oxo-7,8-dihydroguanine was formed by the hydroperoxides 3 and 7 on irradiation, whose yield was reduced up to 40% in the presence of the hydroxyl radical scavengers mannitol and tert-butanol. The acridine and phenanthridine hydroperoxides 3 and 7 also induce DNA damage through the type I photooxidation process, for which photoinduced electron transfer from 2'-deoxyguanosine to the singlet states of 3 and 7 was estimated by the Rehm-Weller equation to possess a negative Gibb's free energy of ca -5 kcal/ mol. Control experiments with the sensitizers acridine 1 and the acridine alcohol 4 in calf thymus and PM2 DNA confirmed the photosensitizing propensity of the UVA-absorbing chromophores. The present study emphasizes that for the development of selective and efficient photochemical hydroxyl radical sources, chromophores with low photosensitizing ability must be chosen to avoid type I and type II photooxidation processes.

Radium dial workers: issues concerning dose response and modeling.

The mortality pattern of women who began employment as luminizers in the radium dial industry before 1930 was followed through 1990. Hazard models with time-dependent covariates were used on mortality data either organized by individual death times or grouped into cross-classified person-year tables. These models were used to quantify trends in mortality associated with either death from or diagnosis of bone sarcoma or head carcinoma. The accumulation of skeletal doses from 226Ra and 225Ra was an important predictor of the risk of death from bone sarcoma. Women exposed to 226Ra at ages associated with active bone growth were at greater risk of bone sarcoma than women receiving even larger exposures at an age when their skeletons would have been fully developed. Exposure to only 226Ra was found to be an important predictor of risk for carcinoma of the mastoid air cells and paranasal sinuses. For the cranial sites, where adult dimensions are attained early in life, an effect of age at exposure could not be detected.

Measurement of airborne 218Po--a Bayesian approach.

The standard mathematical treatment of the buildup and decay of airborne radionuclides on a filter paper uses the solutions of the so-called Bateman equations adapted to the sampling process. These equations can be interpreted as differential equations for the expectation of an underlying stochastic process, which describes the random fluctuations in the accumulation and decay of the sampled radioactive atoms. The process for the buildup and decay of airborne 218Po can be characterized as an "immigration-death process" in the widely adopted, biologically based jargon. The probability distribution for the number of 218Po atoms, accumulated after sampling time t, is Poisson. We show that the distribution of the number of counts, registered by a detector with efficiency epsilon during a counting period T after the end of sampling, is also Poisson, with mean dependent on epsilon, t, T, the flowrate and N(o), the number of airborne 218Po atoms per unit volume. This Poisson distribution was used to construct the likelihood given the observed number of counts. After inversion with Bayes' Theorem we obtained the posterior density for N(o). This density characterizes the remaining uncertainty about the measured number of 218Po atoms per unit volume of air.

A Bayesian methodology for scaling radiation studies from animals to man.

This paper describes a Bayesian methodology for integrating studies in experimental animals and humans to obtain a risk estimate for a radionuclide for which no data or very limited human data are available. The method is quite general and is not limited to radiation studies. In fact, it was first developed for chemical toxicants. The methodology is illustrated using studies with rats, beagles, and humans exposed to isotopes of Ra and Pu. The goal is a quantitative risk estimate for bone cancer in humans exposed to internally deposited Pu. The choice of bone cancer as an end point and of Pu as the source of exposure was made partially because of its inherent interest but also because of issues of data availability and suitability. We performed Poisson regression analyses on 13 of 15 data sets. These analyses form the basis for the unifying method of interpreting the entire ensemble of studies. Each of the studies is summarized by the estimated dose-response slope and its estimated standard error. These summary statistics are combined with other available biological and physical information about species differences, physical and metabolic characteristics of isotopes, disease mechanisms, and the like. This information enters the analysis in the form of prior assumptions about the parameters of the Bayesian model combining the studies. The posterior distribution for the bone cancer rate in man from the Bayesian analysis of the 13 studies is updated with the limited data on Pu in humans. This update gives the final probability density for the bone cancer rate in humans exposed to internally deposited Pu. This density has a median of about three cancers per 100 Gy and has a 95% probability interval from 0.8 to 11 bone cancers per 100 Gy.

Current status of cytogenetic procedures to detect and quantify previous exposures to radiation.

The estimation of the magnitude of a dose of ionizing radiation to which an individual has been exposed (or of the plausibility of an alleged exposure) from chromosomal aberration frequencies determined in peripheral blood lymphocyte cultures is a well-established methodology, having first been employed over 25 years ago. The cytogenetics working group has reviewed the accumulated data and the possible applicability of the technique to the determination of radiation doses to which American veterans might have been exposed as participants in nuclear weapons tests in the continental U.S.A. or the Pacific Atolls during the late 1940s and 1950s or as members of the Occupation Forces entering Hiroshima or Nagasaki shortly after the nuclear detonations there. The working group believes that with prompt peripheral blood sampling, external doses to individuals of the order of about 10 rad (or less if the exposure was to high-LET radiation) can accurately be detected and measured. It also believes that exposures of populations to doses of the order of maximum permissible occupational exposures can also be detected (but only in populations; not in an individual). Large exposures of populations can also be detected even several decades after their exposure, but only in the case of populations, and of large doses (of the order of 100 to several hundred rad). The working group does not believe that cytogenetic measurements can detect internal doses from fallout radionuclides in individuals unless these are very large. The working group has approached the problem of detection of small doses (less than or equal to 10 or so rad) sampled decades after the exposure of individuals by using a Bayesian statistical approach. Only a preliminary evaluation of this approach was possible, but it is clear that it could provide a formal statement of the likelihood that any given observation of a particular number of chromosomal aberrations in a sample of any particular number of lymphocytes actually indicates an exposure to any given dose of radiation. It is also clear that aberration frequencies (and consequently doses) would have to be quite high before much confidence could be given to either exposure or dose estimation by this method, given the approximately 3 decades of elapsed time between the exposures and any future blood sampling.(ABSTRACT TRUNCATED AT 400 WORDS)

Temporal analysis of a dose-response relationship: leukemia mortality in atomic bomb survivors.

A data analysis that incorporates time dependencies is demonstrated for the dose response of leukemia mortality in the atomic bomb survivors. The time dependencies are initially left unspecified and the data on leukemia mortality--up to the end of 1978--are used to infer them. Several findings based on T65 revised doses (T65DR) are obtained. First, it is shown that the fits to the data of time-dependent L (linear in gamma dose)-Q (quadratic in gamma dose)-L (linear in neutron dose), L-L, and Q-L dose-response models are significantly improved (P less than 0.001) by using the corresponding time-dependent dose-response models. Second, it is shown that the increased risk of leukemia mortality due to gamma irradiation decreases in time while the increased risk due to neutron exposure decreases more slowly, if at all, in time. Consequently, relative biological effectiveness (RBE) of neutrons is shown to increase in time (P = 0.002) and the current definition of RBE as a time-independent quantity is therefore challenged. It is demonstrated with time-dependent models that the L-L model has a poor fit (P = 0.01) to the data for the first 7 years of study, but has an adequate fit for the remaining 21 years. In contrast the Q-L model has an adequate fit for the entire follow-up period (P greater than 0.30).

Dose-response curves and competing risks.

Points of the underlying dose-response curve of a lethal response or group of lethal responses induced by varying doses of a toxicant in a homogeneous population can be estimated from knowledge of the time of occurrence for all responses if the response(s) of interest is (are) statistically independent from the other competing responses (risks). In the case of statistical dependence, only tight upper and lower bounds can be established within which the points of the dose-response curve have to lie. These bounds for the response(s) of interest are far apart if the frequency of occurrence of the competing response(s) is large. In such situations, the shape of the underlying dose-response curve is only suggested by the imaginary band connecting the estimated bounds. The estimation procedures for both cases are illustrated with data from an experiment in which beagles received injections of 239Pu.