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Biomedical subjects

A B Cox

Publications and source records attributed to A B Cox.

At least 37 records · Page 2Linked to original sources
PubMed1986

Use of primary cell cultures to measure the late effects in the skins of rhesus monkeys irradiated with protons.

Previous pilot investigations of the uses of primary cell cultures to study late damage in stem cells of the skin of the New Zealand white (NZW) rabbit and the rhesus monkey, have been extended to individual monkeys exposed to 55 MeV protons. Protons of this energy have a larger range in tissue of (approximately 2.6 cm) than the 32 MeV protons (approximately 0.9 cm) to which the animals in our earlier studies had been exposed. Although the primary emphases in the current studies were improvement and simplification in the techniques and logistics of transportation of biopsies to a central analytical facility, comparison of the quantitative measurements obtained thus far for survival of stem cells in the skins from animals irradiated 21 years ago reveals that the effects of both proton energies are similar.

Animals↗
PubMed1986

Morphometric studies of heavy ion damage in the brains of rodents.

As an approach to determining the relative biological effectiveness (RBE) of each of five different heavy ions for the mammalian brain, histological preparations of brains from mice exposed to various HZE particles at different doses and primary LETinfinity values were examined by means of semi-automated image analysis for volume changes in specific regions of the olfactory bulb. The mice were irradiated at 100 days of age and euthanatized about 500 days (16 months) later. Exposures were: 60Co gamma photons (LETinfinity = 1-2 keV/micrometer), 4He (LETinfinity = 6 keV/micrometer), 12C (LETinfinity = 80 keV/micrometer), 20Ne (LETinfinity = 150 keV/micrometer), 56Fe (LETinfinity = 180 keV/micrometer), and 40Ar (LETinfinity = 650 keV/micrometer). Animals receiving particle radiation were exposed in an extended Bragg peak region except for iron where the plateau region was used. The zones measured in the olfactory bulb were 1) the external plexiform layer (zone) and 2) an internal region consisting of the granule cells, internal plexiform layer, and layer of mitral cells. These studies indicated that volume changes did indeed occur, not only in absolute terms but also when expressed as the ratio of the structures to each other and to the bulb as a whole. Although this study is exploratory in character, the data obtained may nevertheless contribute to a determination of risk factors due to late effects from HZE articles.

Animals↗
PubMed1986

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.

Animals↗
PubMed1985

Some perspectives on cataractogenesis from heavy charged particles.

Two sets of observations on cataractogenesis in the New Zealand white (NZW) rabbit (Oryctolagus cuniculus) following localized exposure of optic and proximate tissues to heavy ions are reported. The experiments involved measurements of lenticular opacification in young (ca. 9 weeks old) rabbits caused by graded doses (0.5-5.0 Gy) of 460 MeV/u (incident energy) 56Fe ions and the effects of animal age (9 +/- 0.3 week, 1 +/- 0.5 year, and 4.5 +/- 1.3 year) on lenticular opacifications caused by 9 Gy of 400 MeV/u (incident energy) 20Ne ions. In substantiation of earlier results from NZW rabbits exposed to other low- and high-LET radiations, there was a dose-dependent onset of cataractogenesis following 56Fe-ion irradiation, with the highest doses causing the earliest appearance of cataracts. The level of stationary cataracts was also dependent on dose, and preliminary estimates of RBE yield values comparable to those found at similar doses (0.5-5.0 Gy) by others with populations of cultured cells. With increasing age at the time of exposure to 20Ne ions, the onset of lenticular opacification was delayed progressively and the level of stationary cataracts was reduced, but the onset and progression of late cataractogenesis was most rapid in the oldest group of animals. A discussion of the use of cataract measurements in risk assessment is included in this article.

Age Factors↗
PubMed1984

Quantitation of heavy ion damage to the mammalian brain: some preliminary findings.

Histological preparations of brains from rabbits and mice exposed to different doses of various HZE particles or to low-LET photons have been subjected to preliminary quantitation of radiation-induced morphometric changes. Computer assisted measurements of several brain structures and cell types have been made using the KONTRON Automated Interactive Measurement System (IBAS, Carl Zeiss, Inc., Thornwood, N.Y. 10594 U.S.A.). New Zealand white rabbits irradiated at approximately 6 weeks of age were euthanatized 6.5-25 months after exposure to 60Co gamma photons (LET infinity = approximately 0.3 keV/micrometer, 20Ne particles (LET infinity = 35 +/- 3 keV/micrometer), or 40Ar particles (LET infinity = 90 +/- 5 keV/micrometer). Measurements of stained sections of the olfactory bulbs of those animals indicate that the mean size (volume) of olfactory glomeruli is reduced in a dose-dependent (and perhaps an LET-dependent) manner as soon as 6.5 months after irradiation. Differences between mean volumes of additional structures have been noted when histological preparations of control mouse brains were compared with irradiated specimens. Quantitation of intermediate and late changes in nervous (and other) tissues exposed to low- and high-LET radiations will improve our ability to predict late effects in tissues of astronauts and others exposed to the radiation hazards of the space environment.

Animals↗
PubMed1984

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 Ham's 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.

Age Factors↗
PubMed1984

Further evidence that the survival of irradiated mammalian cells is controlled by temporal processes.

Theories of mammalian cellular radiosensitivity that exclude metabolic modification of radiation damage are untenable (Nagasawa et al., 1980). Evidence supporting that conclusion has been obtained from experiments with a radiosensitive, proliferating cell, the S/S variant of the L5178Y murine leukaemic lymphoblast, and a radioresistant, nondividing cell, the retinal photoreceptor (rod) of the rabbit. When S/S cells (mid-) G1 + 8 h in the cycle, at the peak of radioresistance, were X-irradiated at 37 degrees C and then treated hyperthermically (12 h, 38.7-40.3 degrees C), the survival curve, which has a shoulder at 37 degrees C, changed progressively to the simple exponential obtained for G1 cells. Under conditions where Ne ions (LET = 35 keV microns-1) have a relative biological effectiveness (RBE) of approximately 2 for normally radioresistant cells in vitro and in situ, the RBE for G1 S/S cells was approximately 1. Neon ions (1-50 Gy) caused similar amounts of DNA damage in S/S cells and photoreceptors, but the cellular responses were very different. After 5 Gy, the surviving fraction of asynchronous S/S cells was 10(-5), DNA structures were not restored and by 8 h post-irradiation extensive DNA degradation was evident; in the retina, however, the photoreceptor complement was unchanged for greater than 1 year, DNA structures appeared to be restored and remained so (many months) until late DNA degradation began. These phenomena can be explained satisfactorily only if temporal processes play a significant role in cellular radiosensitivity.

Animals↗
PubMed1983

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 RBE's (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.

Age Factors↗
PubMed1983

Late skin damage in rabbits and monkeys after exposure to particulate radiations.

Skin biopsies were taken from the central regions of the ears of New Zealand white rabbits following localized exposure of one ear of each rabbit to 530 MeV/amu Ar or 365 MeV/amu Ne ions. The unirradiated ears served as controls. Biopsies were taken also from the chests and inner thighs of rhesus monkeys after whole-body exposure to 32 MeV protons and from unirradiated control animals. The linear energy transfers (LET infinity's) for the radiations were 90 +/- 5, 35 +/- 3, and approximately 1.2 keV/micrometer, respectively. In the rabbit studies, explants were removed with a 2 mm diameter dermal punch at post-irradiation times up to five years after exposure. Similar volumes of monkey tissue were taken from skin samples excised surgically 16-18 years following proton irradiation. Fibroblast cultures were initiated from the explants and were propagated in vitro until terminal senescence (cessation of cell division) occurred. Cultures from irradiated tissue exhibited decreases in doubling potential that were dependent on radiation dose and LET infinity and seemed to reflect damage to stem cell populations. The implications of these results for astronauts exposed to heavy ions and/or protons in space include possible manifestations of residual effects in the skin many years after exposure (e.g. unsatisfactory responses to trauma or surgery).

Age Factors↗
PubMed1982

Effects of heavy ions on rabbit tissues: cataractogenesis.

As part of an investigation of the responses of optic and proximate tissues to heavy-ion irradiation, the lenses of New Zealand white rabbits were exposed to the Bragg plateau regions of 530 MeV/amu Ar ions and 365 MeV/amu Ne ions and also to 60Co gamma-photons. The linear energy transfers (LET infinity s) for the radiations were 90 +/- 5, 35 +/- 3, and 0.3 keV/micrometer, respectively. After irradiation, lenticular opacities were monitored through their incipient and/or clinical stages (less than or equal to 5 years) by slit-lamp biomicroscopy and scored with subjective, but well-defined, indices. Cataractogenesis, which progressed according to the model proposed by Rubin and Casarett (1968), was modified by radiation quality in the following ways. (1) The rate of development of the early (acute) stage increased with the LET infinity of the incident radiation; (2) at the intermediate (plateau) stage, the values for the relative biological effectiveness (r.b.e.) of the heavy ions were similar to those reported for proliferating cells in culture; (3) for a given intermediate level, the onset of late cataractogenesis occurred earlier the higher the LET affinity of the radiation involved. As with alopecia, the r.b.e.s for cataractogenesis varied with post-irradiation time.

Animals↗
PubMed1982

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.

Animals↗
PubMed1981

Effects of heavy ions on rabbit tissues: alopecia.

During extended investigations of the radiation responses of optic and proximate tissues of New Zealand white rabbits (Oryctolagus cuniculus), the skin surrounding the eyes was exposed to the Bragg plateau regions of 530 MeV/amu Ar ions and 365 MeV/amu Ne ions, and also to 60Co gamma rays. The linear energy transfers (LET infinity s) for the radiations were 90 +/- 5, 35 +/- 3, and 0.3 keV/micron, respectively. Alopecia was measured after irradiation with subjective indices of baldness (0-5) that were calibrated against hair loss in other rabbits irradiated with Ne and Ar ions at the central region of the ear. The patterns of post-irradiation alopecia, which conformed to the model proposed by Casarett (1963) for the long-term expression of radiation damage in proliferating animal tissues, were modified by radiation quality in the following ways: (1) For acute (early) losses, the magnitude of the recovery phase decreased as the LET infinity of the incident radiation increased; (2) In the intermediate or plateau phase of radiation response, the values of relative biological effectiveness (r.b.e) approached those reported for proliferating cells in culture, but differences were found that may be related to the changes in the magnitude of the recovery phase; (3) For a given level of intermediate damage, the onset of the late degenerative phase of radiation response, which was expressed years after irradiation, occurred earlier the higher the LET infinity of the incident radiation. Taken overall, the most important finding of these experiments was that the r.b.e.s for alopecia varied with post-irradiation time.

Alopecia↗
PubMed1980

Late degeneration in rabbit tissues after irradiation by heavy ions.

In 1974, using the rabbit as a model, we began long-term experiments designed to help in the evaluation of the hazards to man from extended exposure to heavy ions in space. Such exposure would occur, for example, during the construction of solar power stations in stationary orbits or on round trips to Mars. Our experiments with 400 MeV/nucleon Ne ions and 570 MeV/nucleon Ar ions have shown that true late effects of a degenerative nature are manifested only years after irradiation. At the appropriate doses (the high end of the experimental dose range), the magnitudes of the late effects are comparable with those encountered in human patients given radiation therapy with neutrons. Such comparisons show that the rabbit experiments are applicable to man. Given that basis, the results from the low end of the experimental dose range lead to the conclusion that astronauts subjected to the radiation fluxes anticipated during flights of the above duration could experience late radiation effects one or more decades after exposure. Late degenerative changes will occur in tissues of the central nervous system, terminally differentiating systems and stem cell populations. The studies also indicate that individual tissues may be "prematurely aged" by radiation in the sense that the "life spans" of those tissues can be decreased without the appearance of malignancies.

Alopecia↗