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Biomedical subjects

L A Braby

Publications and source records attributed to L A Braby.

9 recordsLinked to original sources
PubMed1992

Microbeam studies of the sensitivity of structures within living cells.

Determining the biological effects of low doses of radiation with high linear energy transfer (LET) is complicated by the stochastic nature of charged-particle interactions. Populations of cells exposed to very low radiation doses contain a few cells which have been hit by a charged particle, while the majority of the cells receive no radiation damage. At somewhat higher doses, a few cells receive two or more events. Because the effects of damage produced by separate events can interact in the cell, we have had to make assumptions about the nature of these interactions in order to interpret the results of the experiments. Many of those assumptions can be tested if we can be sure of the number of charged-particle events which occur in individual cells, and correlate this number with the biological effect. We have developed a special irradiation facility at Pacific Northwest Laboratory (PNL) to control the actual number of charged particle tracks that pass through cell nuclei. The beam from a 2 MeV tandem accelerator is collimated to approximately 5 microns. Cells, grown in special dishes with 1.5 microns thick plastic bottoms, are positioned so that the desired portion of the cell aligns with the collimator. A shutter in the beam line is opened and closed after the desired number of particle tracks has been counted. This approach can be used to investigate the effects of the interaction between irradiated and unirradiated cells in an organized system, as well as to study the effects of spatial and temporal distribution of radiation damage within single cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Phenomenological models.

The biological effects of ionizing radiation exposure are the result of a complex sequence of physical, chemical, biochemical, and physiological interactions which are modified by characteristics of the radiation, the timing of its administration, the chemical and physical environment, and the nature of the biological system. However, it is generally agreed that the health effects in animals originate from changes in individual cells, or possibly small groups of cells, and that these cellular changes are initiated by ionizations and excitations produced by the passage of charged particles through the cells. One way to begin a search for an understanding of health effects of radiation is through the development of phenomenological models of the response. Many models have been presented and tested in the slowly evolving process of characterizing cellular response. Different phenomena (LET dependence, dose rate effect, oxygen effect etc.) and different end points (cell survival, aberration formation, transformation, etc.) have been observed, and no single model has been developed to cover all of them. Instead, a range of models covering different end points and phenomena have developed in parallel. Many of these models employ similar assumptions about some underlying processes while differing about the nature of others. An attempt is made to organize many of the models into groups with similar features and to compare the consequences of those features with the actual experimental observations. It is assumed that by showing that some assumptions are inconsistent with experimental observations, the job of devising and testing mechanistic models can be simplified.

Animals↗
PubMed1990

Multiple components of split-dose repair in plateau-phase mammalian cells: a new challenge for phenomenological modelers.

Split-dose experiments using starved plateau-phase Chinese hamster ovary cells have been used to investigate the kinetics of repair, expressed in terms of enhancement of reproductive survival. The results show two distinct components of repair, one having a characteristic time of just over 1 h for the removal of a lesion, the other, about 18 h. The rate at which each component removes damage and the fraction of the total damage that each removes appear to be independent of the initial amount of damage produced, i.e., dose. This lack of dose dependence is not consistent with some simple models of ionizing radiation damage and repair, such as those which assume that saturation of a repair process, depletion of enzyme pools, or the interaction of pairs of sublesions is responsible for the curvature in the dose-response relationship. However, the relationship between the amounts of each type of damage and dose appears to be consistent with models that assume that only a portion of the initial damage is directly accessible to the repair systems or that the initial damage consists of a mixture of potentially lethal and sublethal lesions.

Animals↗
PubMed1989

Analyzing the role of biochemical processes in determining response to ionizing radiations.

The interaction of biochemical processes and radiation damage appears to play a major role in determining long-term biological effects. It is responsible for both the removal of radiation-induced alterations in macromolecules and for the time-dependent changes in survival of irradiated cells. Restoration of macromolecules by such means as the rejoining of strand breaks in DNA suggests a variety of possible mechanisms which could lead to the observed enhancement of cell survival. However, even though a number of molecular repair mechanisms have been identified, specific links between any such mechanisms and a subsequent modification of cell survival have proved difficult, if not impossible, to demonstrate. Models of cellular response provide a means of attempting to establish this connection. Although details of radiation chemistry, chromatin structure, enzymatic repair, molecular genetics, and cell cycle kinetics are generally simplified, each individual model incorporates features based on a set of assumed mechanisms. For example, one group of models assumes that all damage is potentially lethal (capable of killing the cell unless it is repaired), while another assumes that part of the damage is sublethal (innocuous until it interacts with other damage). Using split-dose, dose-rate, and delayed-plating techniques, we have demonstrated two distinct components of repair in plateau-phase Chinese hamster ovary cells. One process has a characteristic time of about 1 h; the other, about 18 h. In both cases, the reaction rates and the fractions of damage repaired appear to be independent of the initial amounts of damage produced. These observations suggest that none of the simpler models adequately describes cell inactivation; i.e., reproductive death is inconsistent with all assumptions regarding any of them. Consequently, more-complex models involving combinations of sublethal and potentially lethal damage or multiple-step damage processes may be required. These findings help to define the effects of exposure at low doses and dose rates and to develop an understanding of the underlying biochemical mechanisms involved.

Animals↗
PubMed1988

Microdosimetric basis for exposure limits.

Consideration of the energy deposited by ionizing radiation in microscopic volumes has led to new insights into dosimetric concepts at the levels of interest in radiation protection. Large amounts of energy are deposited by the passage of low linear-energy-transfer (LET)-charged particles through small volumes. If a typical cell nucleus is considered to be about 7 micron, at an exposure rate of 2.5 X 10(-1) C kg-1 h-1 (1 mR hr-1) from a 60Co irradiation, the average cell nucleus receives one energy deposition event every 12.5 d. Biological processes, which modify radiation damage, typically occur in a few minutes to a few hours. Thus, at occupational exposure levels it is probably the irreparable or misrepaired effects of irradiation that determine the biological consequences. One goal of dosimetry is to measure the incident radiation, making it possible to predict biological risk and set meaningful exposure limits. These measurements must relate to the energy depositions that are responsible for radiation effects at low dose rates, yet the dosimetry system must not be excessively complex to allow use by operational health physicists. Furthermore, our description of the irradiation should be directly measurable. The use of quality factors based upon the energy deposition in a 1-micron-diameter volume of tissue as prescribed in International Commission on Radiation Units Report No. 40 (Joint Task Group 1986) satisfies these requirements. Instrumentation based upon measurement of lineal energy has already been successfully used in health-physics applications. Future changes in the quality factor can be accommodated by changing the algorithm in these microprocessor-based instruments.

Dose-Response Relationship, Radiation↗
PubMed1988

Microdosimetry near the trajectory of high-energy heavy ions.

Single-event energy distributions were measured in a 1.3-micron-diameter site as a function of radial distance from the trajectory of high-energy iron ions having an energy of about 600 MeV/amu. It was found that beyond distances of a few micrometers the average lineal energy of the (mostly single) secondary electrons (delta rays) is of the order of 3 keV/micron. This is similar to the value found in a medium irradiated by 170-keV photons. The frequency-mean specific energy for delta rays occurring at large distances from the path of the primary ion exceeds the calculated (radial) absorbed dose by two orders of magnitude.

Ions↗
PubMed1985

Dose-rate evidence for two kinds of radiation damage in stationary-phase mammalian cells.

Survival based on colony formation was measured for starved plateau-phase Chinese hamster ovary (CHO) cells exposed to 250 kVp X rays at dose rates of 0.0031, 0.025, 0.18, 0.31, and 1.00 Gy/min. A large dose-rate effect was demonstrated. Delayed plating experiments and dose response experiments following a conditioning dose, both using a dose rate of 1.00 Gy/min and plating delays of up to 48 hr, were also used to investigate the alternative repair hypotheses. There is clearly a greater change in survival in dose-rate experiments than in the other experiments. Thus we believe that a process which depends on the square of the concentration of initial damage, and which alters the effect of initial damage on cell survival is being observed. We have applied the damage accumulation model to separate the single-event damage from this concentration-dependent form and estimate the repair rate for the latter type to be 70 min for our CHO cells. Use of this analysis on other published dose-rate studies also yields results consistent with this interpretation of the repair mechanisms.

Animals↗