The European Radiobiology Archives (ERA)--content, structure and use illustrated by an example.

The European Radiobiology Archives (ERA), supported by the European Commission and the European Late Effect Project Group (EULEP), together with the US National Radiobiology Archives (NRA) and the Japanese Radiobiology Archives (JRA) have collected all information still available on long-term animal experiments, including some selected human studies. The archives consist of a database in Microsoft Access, a website, databases of references and information on the use of the database. At present, the archives contain a description of the exposure conditions, animal strains, etc. from approximately 350,000 individuals; data on survival and pathology are available from approximately 200,000 individuals. Care has been taken to render pathological diagnoses compatible among different studies and to allow the lumping of pathological diagnoses into more general classes. 'Forms' in Access with an underlying computer code facilitate the use of the database. This paper describes the structure and content of the archives and illustrates an example for a possible analysis of such data.

Options for the modified radiation weighting factor of neutrons.

The recent ICRP Report 92 has noted that the current radiation weighting factor, wR, depends on the energy of the incident neutrons in a manner that differs substantially from the dependence, which results from the current convention, QL. At all neutron energies, but most conspicuously below 1 MeV, the values of wR exceed those of the effective quality factor, qE. The discrepancy is largely due to the fact that--in the absence of computed values of the effective quality factor for neutrons--wR has been patterned after the values of the ambient quality factor, which accounts insufficiently for the low-linear energy transfer (LET) gamma ray component from neutron capture in the human body. There are different options to remove the discrepancy. Option 1 is to reduce wR substantially at all neutron energies to make it equal to qE for a standard condition, such as isotropic incidence of the neutrons. Since such a reduction may cause problems in those countries where the current wR values are already legally implemented, ICRP 92 has proposed what is here termed Option 2. It recommended to replace QL by the increased value 1.6 QL - 0.6 and, accordingly, to make the radiation weighting factor equal to 1.6 qE - 0.6. With Option 2 the radiation weighting factor needs to be decreased appreciably at low neutron energies, but for fission neutron spectra the overall changes are minor. To guide--regardless which option is chosen--the selection of the numerical values, the effective quality factor, qE, is computed here for different directional distributions of neutrons incident on the anthropomorphic phantoms ADAM and EVA. None of the sex averaged numerical values is found to deviate much from those for isotropic incidence. Isotropic incidence can, thus, be used as an adequate standard condition. A numerical approximation is proposed for the standard qE that is nearly equivalent to a formula invoked by ICRP 92, but is somewhat simpler and provides realistic values of qE even for the extremely high neutron energies in space. In line with ICRP 92, it is emphasised that wR needs to be seen as a derived quantity related to the LET-dependent weighting factor.

Error bands for the linear-quadratic dose-effect relation.

Least square or maximum likelihood fits to the linear-quadratic dose-effect relation are common in experimental radiobiology and in radio-epidemiology. The fit procedure provides the estimates of the linear and the quadratic dose coefficients, a and b, as well as their standard errors, s(a) and s(b). The magnitude of the standard errors s(a) and s(b) is partly determined by the fact that-for a given data set-different parameter combinations (a, b) can produce rather similar fits, i.e. larger values of a can be roughly compensated by smaller values of b. The values s(a) and s(b) are, because of this interrelation, unsuitable to determine error bands of the dose-effect relation. The exact analysis accounts for the co-variance of the parameters, but it is rarely employed. To avoid the consideration of co-variances a simple parameter change is introduced here that replaces the dose-squared coefficient, b, by a+ bDelta. This term is the effect-to-dose ratio at the reference dose Delta, and can thus be termed reference slope. With the proper value of Delta-which is readily determined for a data set, and is 2 Gy for the dicentric chromosome data which are used as example-the two parameters initial slope, a, and reference slope are then orthogonal, i.e. there is no inter-dependence of the parameter values, and their uncertainties can be treated as independent. In the case of three-model parameters, e.g. the linear-quadratic model with an intercept term, c, the same type of parameter change can be applied to make both the first and the third parameter orthogonal to a. The curve fit is then performed conveniently with the standard computer routines, and parameter uncertainties are obtained that provide by simple error propagation the equations for the standard error or confidence bands of the dose-effect relation. Appendix A gives the numerical scheme.

Lung cancer mortality among nuclear workers of the Mayak facilities in the former Soviet Union. An updated analysis considering smoking as the main confounding factor.

A new analysis of lung cancer mortality in a cohort of male Mayak workers who started their employment in the plutonium and reprocessing plants between 1948 and 1958 has been carried out in terms of a relative risk model. The follow-up has been extended until 1999, moreover a new dosimetry system (DOSES2000) has been established. Particular emphasis has been given to a discrimination of the effects of external gamma-exposure and internal alpha-exposure due to incorporated plutonium. This study has also utilized and incorporated the information from a cohort of Mayak reactor workers, who were exposed only externally to gamma-rays. The influence of smoking as the main confounding factor for lung cancer has been studied. The baseline lung cancer mortality rate was not taken from national statistics but was derived from the cohort itself. The estimated excess relative risk for the plutonium alpha-rays was 0.23/Sv (95%CI: 0.16-0.31). The resulting risk coefficient for external gamma-ray exposure was very low with a statistically insignificant estimate of 0.058/Sv (95%CI: -0.072-0.20). The inferred relative risk for smokers was 16.5 (95%CI: 12.6-20.5).

Microdosimetry: reflections on Harald Rossi.

This and twelve previous Symposia reflect the evolution of microdosimetry, a field of research that has determined major new developments in radiation research, radiation protection, and radiology during the past four decades. The concepts of microdosimetry and its techniques were developed almost single handedly by H. H. Rossi. This memorial lecture outlines some of the ideas and some of the work of Harald Rossi that led to microdosimetry. It describes its major impact on radiobiology and, especially, its impact on studies with fast neutrons and on risk assessment. Microdosimetry was primarily designed as a tool for the elucidation of basic mechanisms of radiation action, but it has found its most important applications in the dosimetric measurement techniques that have become indispensable in radiation protection and in the dosimetry for radiation therapy. The advances of molecular biology are now providing new possibilities for a quantitative application of microdosimetry to radiobiology along the lines that Harald Rossi defined.

Heavy ion RBE and microdosimetric spectra.

Reliable values for the relative biological effectiveness (RBE) of the complex field of heavy ions is essential for radiation therapy with carbon beams. Clinical experience with this novel form of therapy is still quite narrow and it is, therefore, desirable to compare and combine relevant clinical findings and theoretical approaches. One major source of available information comes from neutron therapy. The approach towards the determination of RBE for neutron therapy is, therefore, tentatively applied to the heavy ion therapy. This includes the determination of microdosimetric spectra and their numerical evaluation towards the determination of RBE. A microdosimetric detector on the basis of a tissue-equivalent proportional counter (TEPC) was developed for measurements in the heavy ion fields of the GSI, Darmstadt. Measurements were performed first near the perspex phantom surface with carbon ion energies between 89 MeV.amu-1 and 430 MeV.amu-1. Subsequently, measurements were taken at various depths in the neighbourhood of the Bragg region. The numerical techniques that were developed for neutron therapy lead to tentative values of the RBE that are compared to the RBE values from the biophysical model developed at the GSI. The comparison is still preliminary but can be helpful in modifying the microdosimetric approach for its application in heavy ion therapy.

The Southern Urals radiation studies. A reappraisal of the current status.

In the late 1940s and early 1950s the nuclear workers of the Mayak Production Association in the Southern Urals were exposed to high doses from gamma-rays and from incorporated plutonium. In addition, the population of the Techa riverside downstream of the plutonium-production sites received continued exposures from external gamma-rays due to fission products released into the river and from the internal radiation due to incorporation of the fission products. Based on two international coordination meetings in 1998 and 2000, a synopsis has been given recently in this journal of the radioepidemiological studies on these exposed populations. This commentary describes the current status of these singular investigations with regard to the dosimetry, the assessment of late health effects, and the risk estimation both for the Mayak nuclear workers and the Techa riverside population. A central issue are newly published reduced estimates of the external dose to the Techa riverside population which imply substantially increased risk coefficients for solid cancer. Unless the new dosimetry system, TRDS-2000, has missed a major dose contribution, there is now conspicuous disagreement with current risk estimates. Unaccounted doses from atmospheric releases of fission products and from radiological screening of the Techa riverside population need to be explored, but underestimation of the short lived fission products released into the river appears to be a more critical factor. It is furthermore argued that even if TRDS-2000 were confirmed it would remain questionable whether risk estimates can be based on organ-specific doses when they are obtained in a population with a much higher bone-marrow exposure that may possibly have caused an 'abscopal' radiation effect.

Risk estimation for fast neutrons with regard to solid cancer.

In the absence of epidemiological information on the effects of neutrons, their cancer mortality risk coefficient is currently taken as the product of two low-dose extrapolations: the nominal risk coefficient for photons and the presumed maximum relative biological effectiveness of neutrons. This approach is unnecessary. Since linearity in dose is assumed for neutrons at low to moderate effect levels, the risk coefficient can be derived in terms of the excess risk from epidemiological observations at an intermediate dose of gamma rays and an assumed value, R(1), of the neutron RBE relative to this reference dose of gamma rays. Application of this procedure to the A-bomb data requires accounting for the effect of the neutron dose component, which, according to the current dosimetry system, DS86, amounts on average to 11 mGy in the two cities at a total dose of 1 Gy. With R(1) tentatively set to 20 or 50, it is concluded that the neutrons have caused 18% or 35%, respectively, of the total effect at 1 Gy. The excess relative risk (ERR) for neutrons then lies between 8 per Gy and 16 per Gy. Translating these values into risk coefficients in terms of the effective dose, E, requires accounting for the gamma-ray component produced by the neutron field in the human body, which will require a separate analysis. The risk estimate for neutrons will remain essentially unaffected by the current reassessment of the neutron doses in Hiroshima, because the doses are unlikely to change much at the reference dose of 1 Gy.

Instability of microsatellites in radiation-associated thyroid tumours with short latency periods.

PURPOSE: To determine the instability of microsatellite sequences in post-Chernobyl thyroid tumours from children and young adults, and to ascertain whether they correlated with the age of the patient at the time of the accident and the tumour latency period. MATERIALS AND METHODS: The stability of 26 microsatellite markers was investigated in 122 radiation-associated thyroid tumours (96 children, 26 adults) from Belarus and 39 spontaneous thyroid tumours (adults) from Munich without radiation history. RESULTS: A significant correlation between patient age at the time of the accident and the instability of microsatellite sequences was established. Also, a high instability of microsatellite sequences was found in 28 early thyroid tumours from Belarus with latency periods of 6-8 years, in contrast to a low instability of microsatellites in 94 tumours emerging 9-11 years after the accident. Microsatellite instability in the reference group from Munich proved similar to the early thyroid tumours from Belarus. CONCLUSION: Early, fast-growing and aggressive post-Chernobyl thyroid tumours are characterized by an increase in microsatellite instability.

On the conversion of solid cancer excess relative risk into lifetime attributable risk.

Risk coefficients representing the lifetime radiation-induced cancer mortality (or incidence) attributable to an exposure to ionizing radiation, have been published by major international scientific committees. The calculations involve observations in an exposed population and choices of a standard population (for risk transportation), of suitable numerical models, and of computational techniques. The present lack of a firm convention for these choices makes it difficult to inter-compare risk estimates presented by different scientific bodies. Some issues that relate to a necessary harmonization and standardization of risk estimates are explored here. Computational methods are discussed and, in line with the approach utilized by ICRP, conversion factors from excess relative risk (ERR) to lifetime attributable risk (LAR) are exemplified for exposures at all ages and for occupational exposures. A standard population is specified to illustrate the possibility of a simplified standard for risk transportation computations. It is suggested that a more realistic perception of lifetime risk could be gained by the use of coefficients scaled to the lifetime spontaneous cancer rates in the standard population. The resulting quantity lifetime fractional risk (LFR) is advantageous also because it depends much less on the choice of the reference population than the lifetime attributable risk (LAR).

Childhood leukemia in Belarus before and after the Chernobyl accident: continued follow-up.

Earlier assessments led to the conclusion that due to the added radiation after the Chernobyl accident, childhood leukemia in Belarus was not recognisably increased in the years 1987-1994 compared to the years 1982-1986, i.e. the period before the accident. The present paper gives the data of the continued follow-up (1995-1998) which was conducted by the Institute of Haematology and Blood Transfusion, Minsk. In line with the earlier observations no increase has been identified. The incidence rates have been compared to the data of the newly established Belarussian Childhood Cancer Registry and a tentative explanation is given for apparent differences between the rates from our follow-up and the data reported earlier by the Belarussian Childhood Cancer Registry.

Neutron RBE for induction of tumors with high lethality in Sprague-Dawley rats.

The effectiveness of fission neutrons is compared to that of gamma rays and X rays with regard to the induction of malignancies in male Sprague-Dawley rats. The analysis is based on autopsy results. It is focused on tumors that tend to be present in animals dying early, which is indicative of a high degree of lethality. The relative biological effectiveness (RBE) is deduced from a comparison of the cumulative hazard functions. Different nonparametric models-the constant relative risk model, a time shift model, and an acceleration model-are employed in the comparison, and the resulting values of RBE are seen to be substantially independent of the choice of model. The results are in good agreement with earlier studies of nonlethal lung tumors in the same series of experiments. At neutron doses of 20 to 60 mGy, the RBE of fission neutrons is about 50.

The LNT-controversy and the concept of "controllable dose".

There is no firm scientific information on the potential health effects, such as increased cancer rates, due to low doses of ionizing radiation. In view of this uncertainty ICRP has adopted as a prudent default option the linear no-threshold (LNT) assumption and has used it to derive nominal risk coefficients. Subsequent steps, such as the comparison of putative fatality rates in radiation workers with observed accident rates in other professions, have given the risk estimates a false appearance of scientific fact. This has encouraged meaningless computations of radiation-induced fatalities in large populations and has caused a trend to measure dose limits for the public not against the magnitude of the natural radiation exposure and its geographic variations, but against the numerical risk estimates. In reaction to this development, opposing claims are being made of a threshold in dose for deleterious health effects in humans. In view of the growing polarization, ICRP is now exploring a new concept "controllable dose" that aims to abandon the quantity collective dose, emphasizing, instead, individual dose and, in particular, the control of the maximum individual dose from single sources. Essential features of the new proposal are here examined, and it is concluded that the control of individual dose will still have to be accompanied by the avoidance of unnecessary exposures of large populations, even if their magnitude lies below that acceptable to the individual. If a reasonable cut-off at trivial doses is made, the collective dose can remain useful. Misapplications of collective dose are not the deeper cause of the current controversy; the actual root is the misrepresentation of the LNT-assumption as a scientific fact and the amplification of this confusion by loose terminology. If over-interpretation and distortion are avoided, the current system of radiation protection is workable and essentially sound, and there is no need for a fruitless LNT-controversy. The new concept of controllable dose promises simplifications and improvements, but any major change of principles needs to be carefully considered in a broad discussion that ICRP is presently seeking.

Lung cancer mortality among male nuclear workers of the Mayak facilities in the former Soviet Union.

An analysis of lung cancer mortality in a cohort of 1,669 Mayak workers who started their employment in the plutonium and reprocessing plants between 1948 and 1958 has been carried out in terms of a relative risk model. Particular emphasis has been given to a discrimination of the effects of external gamma-ray exposure and internal alpha-particle exposure due to incorporated plutonium. This study has also used the information from a cohort of 2,172 Mayak reactor workers who were exposed only to external gamma rays. The baseline lung cancer mortality rate has not been taken from national statistics but has been derived from the cohort itself. For both alpha particles and gamma rays, the results of the analysis are consistent with linear dose dependences. The estimated excess relative risk per unit organ dose equivalent in the lung due to the plutonium alpha particles at age 60 equals, according to the present study, 0.6/Sv, with a radiation weighting factor of 20 for alpha particles. The 95% confidence range is 0.39/Sv to 1.0/Sv. For the gamma-ray component, the present analysis suggests an excess relative risk for lung cancer mortality at age 60 of 0.20/Sv, with, however, a large 95% confidence range of-0.04/Sv to 0.69/Sv.