Simulation-extrapolation method to address errors in atomic bomb survivor dosimetry on solid cancer and leukaemia mortality risk estimates, 1950-2003.

Analyses of the Life Span Study (LSS) of Japanese atomic bombing survivors have routinely incorporated corrections for additive classical measurement errors using regression calibration. Recently, several studies reported that the efficiency of the simulation-extrapolation method (SIMEX) is slightly more accurate than the simple regression calibration method (RCAL). In the present paper, the SIMEX and RCAL methods have been used to address errors in atomic bomb survivor dosimetry on solid cancer and leukaemia mortality risk estimates. For instance, it is shown that using the SIMEX method, the ERR/Gy is increased by an amount of about 29 % for all solid cancer deaths using a linear model compared to the RCAL method, and the corrected EAR 10(-4) person-years at 1 Gy (the linear terms) is decreased by about 8 %, while the corrected quadratic term (EAR 10(-4) person-years/Gy(2)) is increased by about 65 % for leukaemia deaths based on a linear-quadratic model. The results with SIMEX method are slightly higher than published values. The observed differences were probably due to the fact that with the RCAL method the dosimetric data were partially corrected, while all doses were considered with the SIMEX method. Therefore, one should be careful when comparing the estimated risks and it may be useful to use several correction techniques in order to obtain a range of corrected estimates, rather than to rely on a single technique. This work will enable to improve the risk estimates derived from LSS data, and help to make more reliable the development of radiation protection standards.

DNA repair polymorphisms in B-cell chronic lymphocytic leukemia in sufferers of Chernobyl Nuclear Power Plant accident.

An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.

Radiation-induced leukemia: lessons from history.

Beginning in 1895, with the discovery of x-rays, alpha and beta radiation, uranium, radium, thorium, and polonium, the fascinating story of the beginning of knowledge concerning the existence of ionizing radiation unfolds. This brief history of radiation and leukemia is divided into two main parts: the first 50 years, which deals with the confusion regarding radiation effects and the failure to clearly recognize that exposure to ionizing radiation may induce leukemia. The second part focuses on the last 60 years, when the radiation induction of leukemia was accepted and some progress achieved in understanding the clinical and pathophysiological characteristics of radiation-induced leukemia. Particular attention in this is paid to the effects of radiation on the survivors of Hiroshima and Nagasaki. The discussion in this section also covers some concepts of radiation-induced cell damage and ruminations on unanswered questions.

Delayed effects of external radiation exposure: a brief history.

Within months of Roentgen's discovery of X rays, severe adverse effects were reported, but not well publicized. As a result, over the next two decades, fluoroscope operators suffered lethal skin carcinomas. Later, case reports appeared concerning leukemia in radiation workers, and infants born with severe mental retardation after their mothers had been given pelvic radiotherapy early in pregnancy. Fluoroscopy and radiotherapy for benign disorders continued to be used with abandon until authoritative reports were published on the adverse effects of ionizing radiation by the U.S. NAS-NRC and the UK MRC in 1956. Meanwhile, exposure to the atomic bombs in Japan had occurred and epidemics of delayed effects began to be recognized among the survivors: cataracts (1949), leukemia (1952) and severe mental retardation among newborn infants after intrauterine exposure (1952). No statistically significant excess of germ-cell genetic effects was detected by six clinical measurements (1956), the F1 mortality (1981), cytogenetic studies (1987) or biochemical genetic studies (1988). Somatic cell effects were revealed by long-lasting chromosomal aberrations in peripheral lymphocytes (1968), and somatic cell mutations were found at the glycophorin A locus in erythrocytes (1992). Molecular biology is a likely focus of new studies based on the function of the gene for ataxia telangiectasia (1995), a disorder in which children have severe, even lethal acute radiation reactions when given conventional doses of radiotherapy for lymphoma, to which they are prone. Also, obligate heterozygote female relatives can be studied for increased susceptibility to radiation-induced breast cancer, as suggested by clinical studies. The tumor registries in Hiroshima and Nagasaki now provide incidence data that show the extent of increases in eight common cancers and no increase in eight others (1994). The possibility of very late effects of A-bomb exposure is suggested by recent reports of increased frequencies of hyperparathyroidism, parathyroid cancers and certain causes of death other than cancer.

John R. Goldsmith on the usefulness of epidemiological data to identify links between point sources of radiation and disease.

Sometimes the demonstration of a plausible risk is met with inappropriate attempts to explain it away rather than to protect the health of the public. This may have occurred in the case of leukemia in the vicinity of nuclear installations. In 1989, John Goldsmith prepared a document on this topic for the World Health Organization that persuasively argued for the association to be examined vigorously and to be taken seriously as a potential health risk. However, other commentators on the problem have seemed intent on raising unsubstantial methodological objections and insisting on standards of evidence inappropriate to the justification of action intended to protect the health of the public. Recommendations for resolving this specific issue are made, but the overriding concern is that the level of proof required to justify action for health protection should be less than that required to constitute causation as a scientific principle.

The epidemiology of leukemias (past, present, future).

There are three periods of the history of the epidemiology of leukemias. The first period is characterized by 3 features: the description of the occupational leukemias (radiations, benzene) with more recently the war leukemias (Hiroshima), the leukemia induced by chemotherapy; the description of the leukemias of animals induced by viruses (chicken, mice and more over cats); and the concept of the geographical hematology. The second period may be called "Burkitt period" so important are the consequences of the discoveries made in Uganda. The third period is Japanese and American with the leukemias induced by the virus HTLV 1 and the recent extensions. Such is the past. The present is defined by strong data (diversity of causes, diversity of the combinations of causes, of the etiologic pluralism), and by persisting weaknesses (epidemiology, classification of leukemias). Three ways for the future: induction, prediction, and correlation with the hope of an efficient prevention.