A.C. Lee

Cataractogenesis from high-LET radiation and the Casarett model.

Space radiations, especially heavy ions, constitute significant hazards to astronauts. These hazards will increase as space missions lengthen. Moreover, the dangers to astronauts will be enhanced by the persistence, or even the progression, of biological damage throughout their subsequent life spans. To assist in the assessment of risks to astronauts, we are investigating the long-term effects of heavy ions on specific animal tissues. In one study, the eyes of rabbits of various ages were exposed to a single dose of Bragg plateau 20Ne ions (LET infinity approximately equals 30 keV/micrometer). The development of cataracts has shown a pronounced age-related response during the first year after irradiation, and will be followed for two more years. In other studies, mice were exposed to single or fractionated doses of 12C ions (4-cm spread-out Bragg peak; dose-averaged LET infinity = 70-80 keV/micrometer) or 60Co gamma-photons (LET infinity = 0.3 keV/micrometer). Measurements of the frequency of posterior lens opacification have shown that the tissue sparing observed with dose fractionation of gamma-photons was absent when 12C-ion doses were fractionated. Development of posterior lens cataracts was also followed for long periods (up to 21 months) in mice exposed to single doses of Bragg plateau HZE particles (40Ar, 20Ne and 12C ions: LET infinity approximately equals 100, 30 and 10 keV/micrometer, respectively) or 225 kVp X-rays. Based on average cataract levels at the different observation times, the RBEs (RBE = relative biological effectiveness) for the ions were circa 5, 3 and 1-2, respectively, over the range of doses used (0.05-0.9 Gy). Investigations of cataractogenesis are useful for exploring the model of radiation damage proposed by Casarett and by Rubin and Casarett with a tissue not connected directly to the vasculature.

Cataractogenic potential of ionizing radiations in animal models that simulate man

Aspects of experiments on radiation-induced lenticular opacification during the life spans of two animal models, the New Zealand white rabbit and the rhesus monkey, are compared and contrasted with published results from a life span study of another animal model, the beagle dog, and the most recent data from the ongoing study of the survivors from radiation exposure at Hiroshima and Nagasaki. An important connection among the three animal studies is that all the measurements of cataract indices were made by one of the authors (A.C.L.), so variation form personal subjectivity was reduced to a minimum. The primary objective of the rabbit experiments (radiations involved: 56Fe, 40Ar and 20Ne ions and 60Co gamma photons) is an evaluation of hazards to astronauts from galactic particulate radiations. An analogous evaluation of hazards from solar flares during space flight is being made with monkeys exposed to 32, 55, 138 and 400 MeV protons. Conclusions are drawn about the proper use of animal models to simulate radiation responses in man and the levels of radiation-induced lenticular opacification that pose risks to man in space.

Late effects from particulate radiations in primate and rabbit tissues

Optic tissues in groups of New Zealand white rabbits were irradiated locally at different stages throughout the median life span of the species with a single dose (9 Gy) of 425 MeV/amu Ne ions (LET infinity approximately 30 keV/micrometer) and then inspected routinely for the progression of radiation cataracts. The level of early cataracts was found to be highest in the youngest group of animals irradiated (8 weeks old), but both the onset of late cataracts and loss of vision occurred earlier when animals were irradiated during the second half of the median life span. This age response can have serious implications in terms of space radiation hazards to man. Rhesus monkeys that had been subjected to whole-body skin irradiation (2.8 and 5.6 Gy) by 32 MeV protons (range in tissue approximately 1 cm) some twenty years previously were analysed for radiation damage by the propagation of skin fibroblasts in primary cultures. Such propagation from skin biopsies in MEM-alpha medium (serial cultivation) or in supplemented Hams F-10 medium (cultivation without dilution) revealed late damage in the stem (precursor) cells of the skins of the animals. The proton fluxes employed in this experiment are representative of those occurring in major solar flares.

Selected Examples of Degenerative Late Effects Caused by Particulate Radiations in Normal Tissues

When astronauts undertake lengthy missions in outer space, they will receive extended (chronic) exposure to a spectrum of cosmic radiations that contains a substantial component of highly energetic particles, including heavy ions. That aspect of space flight was illustrated by the flicker-flash phenomenon observed by ‘dark-adapted’ members of the crews of the lunar (Apollo) missions. Many of the heavy ions (HZE particles) are so penetrating that attempting to shield against them through space vehicle design is impractical at the present time. Fluxes of protons can become a major hazard if astronauts are caught during extravehicular activity (EVA) by the radiations associated with a major solar flare. To ensure the safety of astronauts and space workers, a scientific determination is needed of the health risks arising from anticipated exposures to space radiations during future space missions of long duration. From that information, an adequate risk/benefit analysis can be formulated. The best risk analysis available currently to NATO, which arose from the deliberations of subcommittee #75 of the National Council on Radiation and Protection, is but a step in the process.

Effects of Heavy Ions on Rabbit Tissues: Damage to the Forebrain

As part of a study of progressive radiation effects in normal tissues, the forebrains of New Zealand white rabbits (Oryctolagus cuniculus) (about 6 weeks old) were irradiated locally with single acute doses of 60Co gamma-photons (LET infinity = 0.3 keV/micron), Ne ions (LET infinity = 35 +/- 3 keV/microns) or Ar ions (LET infinity = 90 +/- 5 keV/microns). Other rabbits received fractionated doses of 60Co gamma-photons according to a standard radiotherapeutic protocol. Irradiated rabbits and appropriately aged controls were sacrificed at selected intervals, and whole sagittal sections of their brains were examined for pathological changes. Forebrain damage was scored with subjective indices based on histological differences between the anterior (irradiated) and posterior (unirradiated) regions of the brain. Those indices ranged from zero (no apparent damage) to five (severe infarctions, etc.). At intermediate levels of forebrain damage, the relative biological effectiveness (r.b.e.) of each heavy ion was similar to that found for alopecia and cataractogenesis, and the early expression of the damage was also accelerated as the LET infinity increased. Late deterioration of the forebrain appeared also to be accelerated by increasing LET infinity, although its accurate quantification was not possible because other priorities in the overall experimental design limited systematic sacrifice of the animals.

Late cataractogenesis caused by particulate radiations and photons in long-lived mammalian species

Radiation cataractogenesis induced by small acute doses of particulate radiations and photons in the New Zealand white (NZW) rabbit (Oryctolagus cuniculus), the beagle dog (Canis familiaris) and the rhesus monkey (Macaca mulatta) is discussed in the context of the use of animal models to assess the radiation hazards faced by humans during lengthy sojourns in deep space. Attention is paid to: 1) the importance of lifespan studies with long-lived species--the above animals have median lifespans in captivity of 5-7, 13-14 and approximately 25 years, respectively; 2) the magnitudes of possible dose thresholds for cataractogenesis from sparsely ionizing radiations and the modifications of those thresholds by the late degenerative phase of the phenomenon.

Risks of radiation cataracts from interplanetary space missions

Recognition of the human risks from radiation exposure during manned missions in deep space has been fostered by international co-operation; interagency collaboration is facilitating their evaluation. Further co-operation can lead, perhaps by the end of this decade, to an evaluation of one of the three major risks, namely radiation cataractogenesis, sufficient for use in the planning of the manned mission to Mars.

Radiobiological Risk Estimates for Space Flight Based on Long-Term Studies in Proton-Irradiated Primates

Abstract : Between 1963 and 1969, 301 young rhesus monkeys were exposed to low and intermediate doses of X-rays, protons or electrons to simulate space radiation hazards, 57 control animals were incorporated in the experimental design, and both sexes were represented. The subjects have been followed for nearly 30 years, and major findings of the study include: (1) highly significant incidence of glioblastoma mutliforme (high-grade astrocytoma) in male animals exposed to 55-MeV protons; (2) highly significant incidence of severe endometriosis in female subjects exposed to different radiation energies and doses; (3) development of significant late lenticular opacifications (cataracts) in monkeys 20+ years following exposures to low and intermediate doses of protons. As the animals age, abundant data are expected to provide additional insights into the late stochastic (probabilistic) and deterministic effects induced in primates by exposures to low and intermediate doses of particulate radiations. Refined space radiobiological risk estimates, based on a long-lived primate model closely resembling the-human in many of its responses to ionizing radiations, will enable scientists and engineers to design spacecraft and associated hardware to maximize the short- and long-term safety of personnel participating in lengthy space missions.... Late Effects, Proton Irradiation, Endometriosis, Radiation Carcinogenosis, Cataracts, Aging

Delayed Effects of Proton Irradiation in the Lens and Integument: A Primate Model

In 1964, the NASA Manned Spacecraft Center Biomedical Research Office and the USAF School of Aerospace Medicine inaugurated an experiment in Space Radiation Biology which now is approaching completion. Rhesus monkeys were irradiated “whole body” with X-rays (2 MeV), electrons (1.6 and 2 MeV), and protons of energies ranging from 10–2300 MeV; e.g. Dalrymple and Lindsay (1966), Krupp (1976), and Yochmowitz et al. (1985). Individual animals that received low and intermediate doses have been monitored for over 20 years, and those animals, together with age-matched controls, are known as the Chronic Radiation Colony (CRC).