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Correspondence re: W. Paile’s Letter to the Editor. Cancer Res., 60: 1146, 2000.

Institute of Urology and Nephrology Academy of Medical Sciences of Ukraine 9a, Yu. K otzuinsky Street 04053 Kiev, Ukraine

Keiichirou Morimura and Shoji Fukushima

Department of Pathology Osaka City University Medical School I-4-3 Asahi-machi, Abeno-ku Osaka 545-8585, Japan

The most serious accident in the history of the nuclear industry occurred in April 1986 at the Chernobyl power plant in Ukraine (70 km from Kiev). It took 10 days to control the disaster, and during this time, large quantities of radionuclides (about 300 MCi, 11 x 10¹⁸ Bq) were released into the environment, with radiocontamination of more than 50.5 thousand km² or 20% of the entire Ukraine territory (1) . About 17.5 million people from the Ukraine, Russia, and Belarus now live in radiocontaminated areas (2) . It is important to note that radioactive contamination still exists and continuously impacts the health of the exposed populations.

Our subjects were selected according to the contamination level of the inhabited area (Ci/km²). The BPH¹ patients in groups I and II have lived for many years in radiocontaminated areas with densities of ¹³⁷Cs contamination of 5–30 Ci/km² (group I) and 0.5–5 Ci/km² (group II). Patients living in so-called "clean" areas of Ukraine were included as the controls (group III). The Ukrainian Legislation states that the radiocontaminated areas are those that have levels of ¹³⁷Cs on the ground of more than 37 kBq/m² (1 Ci/km²).

It can readily be imagined that the total doses in 1986–1987 received by people living in radiocontaminated areas were undoubtedly much greater than now, and the total exposure has been chronically adding up now for many years. In addition, the patients who were the subjects of this study suffered from BPH and therefore might have had urinary retention, by which radiation exposure to the urothelium would have been enhanced.

Unfortunately, we have no means to determine what radiation dose our patients received. Recently, however, we obtained results for ¹³⁷Cs measurement in a 1-day urine of the same patients with BPH in groups I and II; these values are summarized in Table 1 , which will be published in our next paper.²

In addition to the effect of chronic long-term exposure to low doses of ionizing radiation, the synergistic influence of other ecological hazards (chemical pollution and cigarette smoking) in Ukraine has to be taken into consideration.

The Institute of Urology and Nephrology in Kiev during 1994–1997 collected all BPH patients who underwent open transbladder adenomectomy, and all of these patients were included in our study, without exception. We have now a computerized register of the patients enrolled from 1994 until now. The bladder samples from all these patients were examined in a blinded fashion by a number of well-known urological pathologists from different countries: (a) Dr. Christer Busch (Medical University, Uppsala, Sweden); (b) Dr. Gregor Mikuz (Medical University, Innsbruck, Austria); (c) Dr. Shoji Fukushima (Osaka City University Medical School, Osaka, Japan); and (d) Dr. Alina Romanenko (Institute of Urology and Nephrology, Kiev, Ukraine). All of them diagnosed multiple areas of dysplasia and carcinoma in situ of urothelium in the majority of patients from radiocontaminated areas of Ukraine and Kiev city, with these lesions demonstrating strong p53 protein nuclear overexpression (3 , 4) .

We agree that the term "irradiation cystitis," which reflects a reactive epithelial proliferation associated with hemorrhage, fibrin deposits, fibrinoid vascular changes, and multinuclear stromal cells (5) , is not appropriate and now prefer the term "Chernobyl cystitis." In our latest study,² we have documented for the first time that chronic long-term (maximum of 15 years after Chernobyl accident) low-dose ionizing radiation leads to the development of a previously unknown urinary bladder disease—radiation chronic proliferative atypical cystitis, or Chernobyl cystitis, in humans. This is characterized by multiple areas of dysplasia and carcinoma in situ of the urinary bladder urothelium in strong association with sclerosis of connective tissue and strongly increased angiogenesis without any marked inflammatory reaction. Our radiometric study mentioned above showed a significant increase of ¹³⁷Cs in the urine of patients from groups I and II who were suffering from BPH and presumably therefore had urinary retention, which enhanced radiation exposure of the urothelium. Such male patients with BPH have to be the group with the highest risk of Chernobyl cystitis.

It is interesting to note that the epidemiological study of atomic bomb survivors of the Hiroshima and Nagasaki tumor registries in 1958–1987 also showed a significant risk of bladder cancer morbidity (6) . The contamination level of the long-lived radiation element ¹³⁷Cs is thousands of times greater in Ukraine than in the two Japanese cities (7, 8, 9) . The total amount of radionuclides produced by the Hiroshima bomb was less than 1 MCi, and during the Chernobyl nuclear accident in 1986, more than 300 MCi of radionuclides were released into the environment, with serious consequences to health, the environment, and the social and economic life of the people in Ukraine. The magnitude of the collective effective exposure dose of the Ukrainian population has been estimated as 50,000 mSv over 10 years (National Report of Ukraine, Vienna, 1996). The collective thyroid exposure dose (in 21 areas of Ukraine and Kiev city) was estimated to be 1,306,000 mGy (2) .

According to the annual reports published by the Ukrainian Ministry of Health, based on epidemiological coefficients generally accepted in Ukraine, the incidence of bladder cancer in the years 1986–1996 actually increased gradually from 26.2 to 36.1 and then to 43.3 in 2000 per 100,000 people (10) . The percentage of histologically confirmed cases of bladder cancer in Ukraine in 1986 and 1998 was 74.6% and 90.3%, respectively (11) . Recently a significant increase in bladder cancer morbidity in people from radiocontaminated areas in Belarus compared with pre-Chernobyl years has been shown (12 , 13) . Analogous data have been accepted concerning the incidence of bladder cancer in people from the radiocontaminated areas of Ukraine (10) . Unfortunately, the well-known decreased level of health care in post-Soviet countries does not permit a conclusion of improved cancer registration to account for the increase.

The Chernobyl accident is a unique 20th century catastrophe, not only in terms of scale, but as the first catastrophe to generate the new problem of the chronic long-term effects of low doses of ionizing radiation on humans (14) . The well-established cancer risk with high doses of ionizing radiation implies that low doses also constitute a hazard. The recent observations of Trosko et al. (15 , 16) have provided evidence that low doses of ionizing radiation can act not only as a progressor but also as an initiator or a promoter of carcinogenesis. Our recent data also support this conclusion for chronic low-level radiation and urinary bladder carcinogenesis in the Ukraine and point to a significant relationship between oxidative stress induced by long-term, low-dose ionizing radiation in people living for more than 13 years in radiocontaminated (¹³⁷Cs) areas and the development of preneoplasia in the urinary bladder (17) . Mutational inactivation of the p53 gene (G:C to A:T transitions at CpG dinucleotides) was shown in our previous study (18) , and this is typical for NO-mediated DNA deamination (19) . The suggested interaction between toxic NO peroxynitrites, 8-hydroxy-2'-deoxyguanosine, and p53 gene offers an explanation of the molecular mechanisms of multistep carcinogenesis in human bladder cancer (17) .

FOOTNOTES

¹ The abbreviation used is: BPH, benign prostatic hyperplasia.

² A. Romanenko, K. Morimura, H. Wanibuchi, M. Wei, W. Zaparin, W. Vinnichenko, A. Kinoshita, A. Vozianov, and S. Fukushima, unpublished data.

Received 9/28/00. Accepted 7/16/01.

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