C. Medvedovsky

Cataracts among Chernobyl Clean-up Workers: Implications Regarding Permissible Eye Exposures

Abstract Worgul, B. V., Kundiyev, Y. I., Sergiyenko, N. M., Chumak, V. V., Vitte, P. M., Medvedovsky, C., Bakhanova, E. V., Junk, A. K., Kyrychenko, O. Y., Musijachenko, N. V., Shylo, S. A., Vitte, O. P., Xu, S., Xue, X. and Shore, R. E. Cataracts among Chernobyl Clean-up Workers: Implications Regarding Permissible Eye Exposures. Radiat. Res. 167, 233–243 (2007). The eyes of a prospective cohort of 8,607 Chernobyl clean-up workers (liquidators) were assessed for cataract at 12 and 14 years after exposure. The prevalence of strictly age-related cataracts was low, as expected (only 3.9% had nuclear cataracts at either examination), since 90% of the cohort was younger than 55 years of age at first examination. However, posterior subcapsular or cortical cataracts characteristic of radiation exposure were present in 25% of the subjects. The data for Stage 1 cataracts, and specifically for posterior subcapsular cataracts, revealed a significant dose response. When various cataract end points were analyzed for dose thresholds, the confidence intervals all excluded values greater than 700 mGy. Linear-quadratic dose–response models yielded mostly linear associations, with weak evidence of upward curvature. The findings do not support the ICRP 60 risk guideline assumption of a 5-Gy threshold for “detectable opacities” from protracted exposures but rather point to a dose–effect threshold of under 1 Gy. Thus, given that cataract is the dose-limiting ocular pathology in current eye risk guidelines, revision of the allowable exposure of the human visual system to ionizing radiation should be considered.

Quantitative comparisons of continuous and pulsed low dose rate regimens in a model late-effect system

PURPOSE There is increasing interest and usage of pulsed low dose rate (PDR) brachytherapy, in which a single source is shuttled through the catheters of an implant, typically for about 10 min each hour. This study was designed to compare the late effects produced in various PDR regimens with those from the corresponding continuous low dose rate (CLDR) regimens. METHODS AND MATERIALS A model late-responding system was used, namely, cataract induction in the rat lens. This system has the advantage of being highly quantifiable. The rats eyes were exposed to a total dose of 15 Gy either continuously over 24 h, or with three different PDR regimens, all with the same total dose and overall time. We addressed three questions: (a) are late effects increased when a CLDR regimen is replaced with 10-min pulses repeated every hour? (b) Are late effects increased if hourly 10-min pulses are replaced with 10-min pulses repeated every 4 h? (c) Are late effects increased if 10-min pulses are replaced with 100-s pulses? RESULTS We found that the four regimens under test, continuous, 10-min pulses each hour, 10-min pulses every 4 h, and 100-s pulses every hour, showed no significant differences in cataractogenic potential, as estimated with the Wilcoxon-Gehan test. Power tests indicated that the experimental design was adequate to detect relatively small differences in cataractogenicity between regimens. CONCLUSIONS The equality of late effects from CLDR and PDR in these experiments must imply that sublethal damage repair is quite slow in this model late-responding system, in agreement with trends observed in the clinic for sublethal damage repair of late sequelae. Such trends would suggest that PDR is unlikely to produce significantly worse late effects than the corresponding CLDR regimen, which is in agreement with early clinical data using PDR. Caution, however, is strongly recommended.

Dosimetry for a Study of Low-Dose Radiation Cataracts among Chernobyl Clean-up Workers

Abstract Chumak, V. V., Worgul, B. V., Kundiyev, Y. I., Sergiyenko, N. M., Vitte, P. M., Medvedovsky, C., Bakhanova, E. V., Junk, A. K., Kyrychenko, O. Y., Musijachenko, N. V., Sholom, S. V., Shylo, S. A., Vitte, O. P., Xu, S., Xue, X. and Shore, R. E. Dosimetry for a Study of Low-Dose Radiation Cataracts among Chernobyl Clean-up Workers. Radiat. Res. 167, 606– 614 (2007). A cohort of 8,607 Ukrainian Chernobyl clean-up workers during 1986–1987 was formed to study cataract formation after ionizing radiation exposure. Study eligibility required the availability of sufficient exposure information to permit the reconstruction of doses to the lens of the eye. Eligible groups included civilian workers, such as those who built the “sarcophagus” over the reactor, Chernobyl Nuclear Power Plant Workers, and military reservists who were conscripted for clean-up work. Many of the official doses for workers were estimates, because only a minority wore radiation badges. For 106 military workers, electron paramagnetic resonance (EPR) measurements of extracted teeth were compared with the recorded doses as the basis to adjust the recorded γ-ray doses and provide estimates of uncertainties. Beta-particle doses to the lens were estimated with an algorithm devised to take into account the nature and location of Chernobyl work, time since the accident, and protective measures taken. A Monte Carlo routine generated 500 random estimates for each individual from the uncertainty distributions of the γ-ray dose and of the ratio of β-particle to γ-ray doses. The geometric mean of the 500 combined β-particle and γ-ray dose estimates for each individual was used in the data analyses. The median estimated lens dose for the cohort was 123 mGy, while 4.4% received >500 mGy.

Accelerated heavy particles and the lens. III. Cataract enhancement by dose fractionation

For a number of biological end points it has been shown that, in contrast to low linear energy transfer (LET) radiation, dose fractionation of high-LET radiation does not result in a reduction in overall effectiveness. Studies were conducted to determine the effect of fractionating the exposures to heavy ion doses on the development of cataracts. Rat eyes were exposed to single doses of 1, 5, and 25 cGy of 570 MeV/amu40Ar ions and to 2, 4, and 10 Gy of 250 kVp X rays. These were compared to unirradiated controls and eyes which were exposed to the same total dose delivered in four fractions over 12 h. While in all cases fractionation of the exposure to X rays produced significant reduction in cataractogenic potential, fractionating doses of 40Ar ions caused a dose- and stage-dependent enhancement in the development of cataracts.

Accelerated Heavy Particles and the Lens: I. Cataractogenic Potential

The effect of varying doses of accelerated (570 MeV/ amu ) argon ions on the rat lens is described with detailed observations on the sequence of development of the cataracts, the time-dose relationship, and the analysis of their cataractogenic potential. The relative biological effectiveness (RBE) of the heavy particles for cataract production, compared to low linear energy transfer (LET) radiation (X rays), has been established. These data indicate that, as with neutrons, the RBE increases with decreasing dose and that at a dose of 0.05 Gy an RBE of about 40 was observed.

Quantitative Assessment of the Cataractogenic Potential of Very Low Doses of Neutrons

We report on the prevalence and relative biological effectiveness (RBE) for various stages of lens opacification in rats induced by very low doses (2 to 250 mGy) of medium-energy (440 keV) neutrons, compared to those for X rays. Neutron doses were delivered either in a single fraction or in four separate fractions and the irradiated animals were followed for over 100 weeks. At the highest observed dose (250 mGy) and at early observation times, there was evidence of an inverse dose-rate effect; i.e., a fractionated exposure was more potent than a single exposure. Neutron RBEs relative to X rays were estimated using a non-parametric technique. The results were only weakly dependent on time postirradiation. At 30 weeks, for example, 80% confidence intervals for the RBE of acutely delivered neutrons relative to X rays were 8-16 at 250 mGy, 10-20 at 50 mGy, 50-100 at 10 mGy and 250-500 at 2 mGy. The results are consistent with the estimated neutron RBEs in Japanese A-bomb survivors, though broad confidence bounds are present in the Japanese results. Our findings are also consistent with data reported earlier for cataractogenesis induced by heavy ions in rats, mice, and rabbits. We conclude from these results that, at very low doses (<10 mGy), the RBE for neutron-induced cataractogenesis is considerably larger than the RBE of 20 commonly used, and use of a significantly larger value for calculating equivalent dose would be prudent.

G₀/G1 Arrest of Cell Proliferation in the Ocular Lens Prevents Development of Radiation Cataract

Exposure of the eyes of young frogs and rats to X-rays (12–25 Gy) causes posterior cataracts to appear several weeks later. Hypophysectomized frogs do not develop these opacities, but hypophysectomized rats do. In the former, but not the latter animals, the operation completely stops lens mitosis, the epithelial cells being largely confined to the G₀/ G1 phase of the cell cycle.

Accelerated heavy particles and the lens. VIII. Comparisons between the effects of acute low doses of iron ions (190 keV/microns) and argon ions (88 keV/microns).

The nature of the RBE-LET relationship for radiation-induced effects in vivo is not well known in the high-LET range above about 100 keV/microns. Here, we compare the cataractogenic effects of acute doses of 190 keV/microns iron ions on the eyes of rats with those of 88 keV/microns argon ions. The RBEs of the two radiations cannot be distinguished statistically, both being between 50 and 200 at our lowest dose of 0.01 Gy and decreasing to between 2 and 14 at our highest dose of 0.5 Gy; these values are consistent with results obtained in vivo, both for cataractogenesis and for oncogenesis. For this end point, therefore, the RBE-LET relationship probably varies very slowly between 88 and 190 keV/microns. On the basis of these studies with acute doses of 88 and 190 keV/microns particles, the detailed distribution in LET of the very high-LET galactic cosmic-ray dose to which astronauts in deep space are exposed may not be critical for the prediction of biological hazard. Such a conclusion might simplify the task of high-LET radiation risk estimation in space.

Radiation cataractogenesis in the amphibian lens.

This report describes a reproducible and characteristic sequelae for radiation cataractogenesis in the amphibian. The development of lens opacification was investigated as a function of dose and time after X-irradiation of the eye of postmetamorphic bullfrogs. It was found that the development of radiation cataracts in frogs is both age and dose dependent. It was also determined that, far from being radiation resistant, frog lenses are sensitive to doses that are moderately cataractogenic for mammals.

Stationary radiation cataracts: An animal model

The restitution of normal fibergenesis that occurs in stationary radiation cataracts provides a unique opportunity to study the cytopathomechanism of radiocataractogenesis. Previous attempts at investigating this phenomenon have been limited by the lack of an appropriate animal model. This report describes the induction of stationary radiation cataracts in postmetamorphic bullfrogs following ocular irradiation with a 10 Gy (1 Gy = 100 rads) dose of X-rays. The eyes of non-irradiated animals and animals irradiated with 25 Gy (an established dose known to induce progressive cataracts in frogs) served as controls. Animals were followed biomicroscopically and histopathologically over 79 weeks. As previously described, the cataracts developed in a dose-dependent manner. The 25 Gy irradiated lenses rapidly progressed to complete opacification (4+) by 26 weeks, while lenses exposed to 10 Gy advanced to the 2.5+ stage by 35 weeks and progressed no further. In the lower dose lenses, transparent cortex began to appear anteriorly and posteriorly between the capsule and opaque fibers at 45 weeks. As the clear fibers accumulated, the disrupted region came to occupy increasingly deeper cortex. Histologically, opacities in both groups were preceded by disorganization of the bow cytoarchitecture, meridional row disorganization, and the appearance in the lens epithelium of nuclear polymorphism, fragmented nuclei, micronuclei, clusters of nuclei, and abnormal mitotic figures. In the lenses exposed to the 25 Gy dose, this damage continued to worsen, so that the 4+ stage was characterized by extensive epithelial cell death, absence of the lens bow, degenerated fiber masses, and liquefied substrata. In contrast, prior to the appearance of transparent cortex in the 10 Gy group, the lens epithelial aberrations, are of the bow, and meridional row disorganization were all observed to improve. Further, by 69 weeks, the lens epithelium appeared as a largely homogeneous population, and the meridional rows and the are of the bow had become reestablished. The details of these observations and their possible relationship to the cytopathomechanism of radiation cataract formation are discussed.