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A M Kellerer

Publications and source records attributed to A M Kellerer.

At least 37 records · Page 2Linked to original sources

Risk estimates for radiation-induced cancer--the epidemiological evidence.

The risk of low-dose radiation exposures has--for a variety of reasons--been highly politicised. This has led to a frequently exaggerated perception of the potential health effects, and to lasting public controversies. A balanced view requires a critical reassessment of the epidemiological basis of current assumptions. There is reliable quantitative information available on the increase of cancer rates due to moderate and high doses. This provides a firm basis for the derivation of probabilities of causation, e.g. after high radiation exposures. For small doses or dose rates, the situation is entirely different: potential increases of cancer rates remain hidden below the statistical fluctuations of normal rates, and the molecular mechanisms of cancerogenesis are not sufficiently well known to allow numerical predictions. Risk coefficients for radiation protection must, therefore, be based on the uncertain extrapolation of observations obtained at moderate or high doses. While extrapolation is arbitrary, it is, nevertheless, used and mostly with the conservative assumption of a linear dose dependence with no threshold (LNT model). All risk estimates are based on this hypothesis. They are, thus, virtual guidelines, rather than firm numbers. The observations on the A-bomb survivors are still the major source of information on the health effects of comparatively small radiation doses. A fairly direct inspection of the data shows that the solid cancer mortality data of the A-bomb survivors are equally consistent with linearity in dose and with reduced effectiveness at low doses. In the leukemia data a reduction is strongly indicated. With one notable exception -- leukemia after prenatal exposure--these observations are in line with a multitude of observations in groups of persons exposed for medical reasons. The low-dose effects of densely ionizing radiations--such as alpha-particles from radon decay products or high-energy neutrons--are a separate important issue. For neutrons, there is little epidemiological information. This has facilitated exaggerated claims of high neutron effects with reference to alleged dangers from transports of reactor fuel. However, in spite of limited information, it can be shown that the data from Hiroshima exclude the stated claims. New dosimetric information on neutrons may turn out to be highly informative with regard to an upper limit for the potential effects of neutrons and equally with regard to a reassessment--and a possible reduction--of risk estimates for gamma-rays.

Breast Neoplasms↗

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.

Humans↗

Induction of malignant bone tumors in radium-224 patients: risk estimates based on the improved dosimetry.

Mainly between 1945 and 1955, several thousand German patients with ankylosing spondylitis, tuberculosis, or--in a few cases--other diseases received multiple injections of the short-lived alpha-particle emitter radium-224. In the early 1950s, the follow-up of 899 patients was initiated, and the study has continued since then. It includes most of the high-dose patients and nearly all of those treated as children or juveniles, i.e. under the age of 21. In the study cohort, 56 malignant bone tumors occurred in a temporal wave that peaked 8 years after exposure, whereas less than one case would have been expected during the follow-up. Most of the malignant bone tumors were osteosarcomas and fibrous-histiocytic sarcomas. A new analysis has now been performed, primarily because an improved dosimetry resulted in modified bone surface doses, especially for those treated at younger ages. A significant increase in bone tumor risk with decreasing age at exposure is now demonstrated. The earlier finding of an inverse protraction factor is confirmed. In the new formulation, the dependence on dose rate or duration applies only at higher doses; i.e., the initial slope of the dose dependence is unrelated to dose rate or exposure duration, which is in contrast to earlier analyses but is in agreement with microdosimetric considerations and general radiobiological experience.

Adolescent↗

Radiation dose dependences in the atomic bomb survivor cancer mortality data: a model-free visualization.

Chomentowski, M., Kellerer, A. M. and Pierce, D. A. Radiation Dose Dependences in the Atomic Bomb Survivor Cancer Mortality Data: A Model-Free Visualization. The standard approach to obtaining nominal risk coefficients for radiation-related cancer involves fitting linear or linear-quadratic dose-response functions. This is usually complemented by a more direct visualization where the data are subdivided into distinct dose categories and the effect level is quantified for each of these categories. Such model-free computations, however, can be quite dependent on the arbitrary choice of the cutpoints in dose. The method proposed here largely avoids this arbitrariness by choosing a dose category width-constant on a log scale-to obtain the desired degree of smoothing, and then superimposing results for all placements of the resulting log-dose grids. The method is applied to leukemia and solid cancer mortality of the A-bomb survivors.

Cohort Studies↗

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.

Alpha Particles↗

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.

Animals↗

Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus.

Rearrangements of the ret oncogene were investigated in papillary thyroid carcinomas (PTC) from 51 Belarussian children with a mean age of 3 years at the time of the Chernobyl radiation accident. For comparison, 16 PTC from exposed Belarussian adults and 16 PTC from German patients without radiation history were included in the study. ret rearrangements were detected and specified by RT-PCR and direct sequencing using specific primers for ret/PTC1, 2 and 3. Only ret/PTC1, and no ret/PTC3, was found in the adult patients, with a frequency of 69% for the Belarussian cases, but of only 19% in the German patients. In contrast, 13 ret/PTC3 (25.5%) and 12 ret/PTC1 (23.5%) rearrangements were present in PTC from Belarussian children. Thus, our study reveals about a 1:1 ratio of ret/PTC3 and ret/PTC1, in contrast to earlier studies with lower numbers of cases and exhibiting a high predominance of ret/PTC3 (ratio about 3:1). A ratio (2.5:1) similar to that in earlier investigations (diagnosed 1991-94) was obtained for cases included in our study that were diagnosed in 1993/94. The present data suggest that ret/PTC3 may be typical for radiation-associated childhood PTC with a short latency period, whereas ret/PTC1 may be a marker for later-occurring PTC of radiation-exposed adults and children.

Adenocarcinoma, Follicular↗

Cytogenetic changes in radiation-induced tumors of the thyroid.

Thyroid carcinoma incidence is increased significantly after ionizing irradiation; however, the possible mechanisms have not yet been identified. To provide clues for an understanding of the radiation-induced transformation of thyroid epithelium, we analyzed the karyotypes of 56 childhood thyroid tumors that appeared in Belarus after the Chernobyl nuclear accident in 1986. We also studied eight secondary thyroid tumors that developed after radiotherapy. Metaphase preparations obtained from primary cultures were analyzed by G-banding. Clonal structural aberrations were found in 13 of 56 Belarussian cases and in 6 of 8 secondary tumors that developed after radiotherapy. Furthermore, we detected multiple chromosomal aberrations as well as complex rearrangements in some of these tumors and performed a detailed analysis of marker chromosomes from a single case using spectral karyotyping and comparative genomic hybridization in a childhood tumor from Belarus with a near-triploid karyotype. Both comparative genomic hybridization and spectral karyotyping analysis revealed structural alterations affecting identical chromosomes 1, 2, 9, and 13, among others. In addition to the known hot spots of alterations in papillary thyroid carcinomas on chromosomes 1q and 10q, a comprehensive breakpoint analysis in the pooled data set revealed novel breakpoints on chromosomes 4q, 5q, 6p, 12q, 13q, and 14q. The chromosomal aberrations in these tumors may provide suitable starting points for the positional cloning of genes involved in radiation-induced tumorigenesis.

Adolescent↗

International radiobiology archives of long-term animal studies: structure, possible uses and potential extension.

Animal experiments have contributed a great deal to our information on effects and risks arising from exposure to radionuclides. This applies, in particular, to alpha-emitting radionuclides where information from man is limited to thorotrast, 224Ra and 226Ra. The late C.W. Mays was the first to suggest that animal data in conjunction with epidemiological data could allow estimates of human risks for radionuclides - predominantly from actinides - where information in man is scarce. The 'International Radiobiology Archives of Long-term Animal Studies' were created through the combined efforts of European, American and Japanese scientists and aim to safeguard the large amount of existing data on long-term animal experiments and make them available for, among others, an improved assessment of risks from alpha-emitting radionuclides. This paper summarizes the structure of the archives and reviews their present status and future plans. It also demonstrates the extensive information available in these archives on alpha-emitting radionuclides which is suitable for further analysis. Also, the structure of the animal archives could - in a slightly modified form - accommodate the epidemiological data available on 224Ra and thorotrast and, thus, facilitate a direct comparison of data from man, dogs and rodents.

Animals↗

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

Animals↗

[Long-term radiation damage to the skin and eye after combined beta- and gamma- radiation exposure during the reactor accident in Chernobyl].

BACKGROUND: In April 1986, numerous reactor workers and firemen were exposed to high doses of ionizing radiation during the Chernobyl nuclear power plant accident. Apart from high ambient gamma-ray exposures they received inhomogeneous contamination with beta-rays from fission products, resulting in severe skin exposure. PATIENTS AND METHODS: Sixteen of these so called Liquidators were repeatedly examined between 1991 and 1996. Their doses ranged from 0.35 to 9 Gy, partly confirmed by determination of chromosomal aberrations. Ophthalmologic examination included non-subjective assessment of lenticular radiation damage with an electronic Scheimpflug camera system. Digital image analysis allowed the comparison of opacification units to previous and normal findings. RESULTS: Four Liquidators had posterior subcapsular opacifications in different degrees, one presented only after cataract extraction. One patient had dense corticonuclear cataracts and pseudoexfoliation-like changes. Three men had severe dry eye syndrome. Eight men had no ocular complications. Retinal radiation damages were absent. 15 Liquidators suffered from severe chronic cutaneous radiation damage, which led to amputations in 3 cases. CONCLUSIONS: A relation between ocular and dermatological findings was not expected and could, in fact, not be seen. The comparison of posterior subcapsular opacification and doses revealed no distinct relation, although it indicates a correlation that is here not quantified. The doses represent organ doses for the bone marrow which is primarily exposed to deeper penetrating gamma-radiation. Thus they need not be correlated with combined beta- and gamma-doses in organs such as skin and eye because the superficial exposure due to beta-radiation may differ greatly form the whole body exposure as reflected in bone marrow doses.

Accidents, Occupational↗

Microsatellite instability and loss of heterozygosity in radiation-associated thyroid carcinomas of Belarussian children and adults.

DNA from 129 paired thyroid tumorous and non-tumorous tissue samples of Belarussian children (102 patients; age at surgery </=18 years) and adults (27 patients; age at surgery 19-35 years), who had been exposed to radioactive fallout from the Chernobyl reactor accident in 1986, was examined for microsatellite instability (MSI) and loss of heterozygosity (LOH). Twenty-eight microsatellite markers were chosen because of their vicinity to DNA repair genes or genes involved in tumorigenesis as well as regions of chromosomal breakpoints in thyroid tumours. In 40 patients (31% of 129) we detected a total of 73 alterations, 80% of which were classified as LOH and only 20% as MSI. Amongst these 40 patients we identified a subgroup of 11, mainly young female patients (8.5% of 129), exhibiting alterations in at least two microsatellite markers. For comparison we examined samples from spontaneous thyroid carcinomas without radiation history from 20 adult patients from Munich (mean age at surgery 56 +/- 13 years). None of the tumour samples investigated showed evidence of alterations in the 28 microsatellite markers tested. Taken together our data indicate an increased instability of microsatellite markers in thyroid cancers from Belarussian patients. At present, it is uncertain whether the increased genome instability observed in Belarussian patients is the result of the exposure to radioactive iodine from the Chernobyl reactor accident or due to the young age of the patients.

Adolescent↗

Malignancies in patients treated with high doses of radium-224.

Predominantly from 1945 to 1955, a group of patients in Germany was treated with multiple injections of the short-lived alpha-particle emitter (224)Ra. The patients suffered from ankylosing spondylitis, tuberculosis and in a few cases from other diseases. The "Spiess study" (study I) follows up the health of 899 of these patients; it includes most of the patients who were treated with high doses (mean bone surface dose: 30 Gy, mean specific activity: 0.66 MBq/kg), and nearly all of those treated under the age of 21 years. The most striking consequence of the (224)Ra injections was the occurrence of 56 malignant bone tumors. They appeared in a temporal wave that peaked around 8 years after exposure. A new analysis was recently performed, because a reassessment of the dosimetry resulted in changed bone surface doses, especially for the patients treated at younger ages. Averaged over all ages at exposure, the estimated risk coefficient is in general agreement with earlier analyses. However, there is now an increase in bone tumor risk that is significantly greater for younger ages at exposure. The earlier finding of an inverse protraction factor is confirmed. During the most recent years of follow-up, a significant excess of nonskeletal solid malignancies has become manifest. In 1998, a significant increase of breast cancer incidence, of soft tissue malignancies, of thyroid carcinomas, and of liver, kidney and bladder cancer was found. An eightfold increased risk of mammary cancers in those treated at a young age is particularly striking. Equally notable are two cases of breast cancer in male patients. To identify potential confounders, a control group of tuberculosis patients not treated with (224)Ra was established. The comparison confirms that the (224)Ra treatment is responsible for most of the excess of mammary cancer.

Adolescent↗

Late effects in ankylosing spondylitis patients treated with 224Ra.

This study is comprised of 1577 ankylosing spondylitis patients from 9 German hospitals who have been treated with multiple injections of (224)Ra. The majority of the patients, most of them treated in the years 1948-1975, received one series of 10 weekly intravenous injections of about 1 MBq of (224)Ra each. This dose leads to a mean absorbed dose due to alpha-particle radiation of 0.56 Gy to the marrow-free skeleton of a 70- kg man (mean bone surface dose of about 5 Gy). To provide comparative information on causes of death and on health effects possibly related to the basic disease itself, a control group of 1462 ankylosing spondylitis patients with roughly the same age distribution has been established. By the end of 1998, 649 patients in the exposed group and 762 control patients had died. Among other observations, it is of particular interest that 13 cases of leukemia in the exposed group have been observed. This is a highly significant excess (P < 0.001) compared to a standard population, but only a marginally significant excess in comparison to the seven cases observed in the control group. Subclassification of the leukemias shows a clear preponderance of the myeloid leukemias in the exposed group (8 cases observed compared to 1.7 cases expected, P < 0.001), whereas in the control group the observed cases are within the expected range for myeloid leukemia (3 cases observed compared to 2.2 cases expected, P = 0.3). The (224)Ra cohort of the earlier study (higher-dose group) has provided a risk coefficient that predicts about 8 excess malignant bone tumors for the irradiated cohort in this study. In actuality, 4 cases of malignant tumors in the skeleton have been observed so far. However, excess of breast cancer has not been observed in either the irradiated or the control group, which is in contrast to the findings in the earlier (224)Ra cohort of Study I.

Adult↗

Lung cancer in nuclear workers of Mayak. A comparison of numerical procedures.

Lung cancer mortality was analyzed among 4279 nuclear workers of the Mayak facilities in the former Soviet Union, who were exposed to chronic irradiation both externally and internally from incorporated plutonium. The analysis was carried out in terms of a relative risk model. It was shown that an earlier estimate of the excess relative risk for lung cancer, that exceeds the value employed by ICRP by a factor of roughly 2, as well as an earlier estimated latency period of 24 years for lung cancer induction were the result of the numerical procedure chosen. In another recently published case control study, a purely quadratic, threshold-type dose response to incorporated plutonium was deduced. In the present calculations, no evidence for a departure from linearity in dose response was suggested. Principal aim of this study has been the comparison to methods used in the earlier cohort analysis. More detailed risk modelling on the basis of the most recent follow-up will be required.

Colorado↗

Infant leukemia in Belarus after the Chernobyl accident.

Petridou et al. [1] have reported an increase in infant leukemia in Greek children born between 1/7/86 and 31/12/87 and have linked this increase to in utero radiation exposure due to the Chernobyl accident. Subsequently, Michaelis et al. [2] have reported a similar trend for Germany but found that it was not correlated to the levels of contamination. For Belarus, which was much more severely affected, a similar but much weaker trend is found.

Cohort Studies↗

Consideration on a limit for lifetime occupational radiation exposure.

Annual dose limits in occupational radiation exposure are merely a secondary constraint in addition to the primary rule of dose reduction and justification. The limits may, therefore, be reached only in rare, special cases. However, in principle, there might be cases in which the annual limit is continuously exhausted throughout a working life; a high total dose of 0.8 Sv could then be reached. In view of this possibility, there have been considerations of an added restriction by limiting the lifetime occupational dose to 0.4 Sv. The implications of such lifetime doses are considered, and it is shown that an exposure up to the maximum of 0.8 Sv will lead to the need for compensation, if a leukaemia were to occur in the exposed worker. A lifetime dose of 0.4 Sv equally spread over a working life will not lead to the critical value of the probability of causation in excess of 0.5. Nevertheless, it could cause such critical values when it is accumulated during shorter periods. More decisive than the probabilities of causation are, however, the absolute numbers of excess cases of leukaemia due to the occupational exposure. It is seen that less than one excess case would be expected if a group of 100 workers were all exposed to the maximum of 0.8 Sv. Since lifetime doses of 0.8 or 0.4 Sv will be accumulated in very few cases and only with special justification, there appears to be little need to introduce a further limit of lifetime exposure in addition to the current annual limit.

Adult↗