Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses.

Ionizing radiation is known to potentially interfere with cellular functions at all levels of cell organization and induces DNA lesions apparently with an incidence linearly related to D, also at low doses. On the other hand, low doses have also been observed to initiate a slowly appearing temporary protection against causation and accumulation of DNA lesions, involving the radical detoxification system, DNA repair and removal of DNA damage. This protection apparently does not operate at high doses; it has been described to be nonlinear, increasing initially with D, beginning to decrease when D exceeds approximately 0.1-0.2 Gy, and eventually disappearing at higher D. The various adaptive responses have been shown to last individually from hours to weeks in different cell types and resemble responses to oxidative stress. Damage to DNA is continuously and endogenously produced mainly by reactive oxygen species (ROS) generated in a normal oxidative metabolism. This endogenous DNA damage quantitatively exceeds DNA damage from low-dose irradiation, by several orders of magnitude. Thus, the protective responses following acute low-dose irradiation may be presumed to mainly counteract the endogenous DNA damage. Accordingly, the model described here uses two dose-effect functions, a linear one for causing and a nonlinear one for protecting against DNA damage from whatever cause in the irradiated cells and tissues. The resulting net dose-risk function strongly suggests that the incidence of cancer versus dose in the irradiated tissues is much less likely to be linear than to exhibit a threshold. The observed cancer incidence may even fall below the spontaneous incidence, when D to cells is below approximately 0.2 Gy. However incomplete, these data support a reexamination of the LNT hypothesis.

Relative biological effectiveness of ionizing radiations determined in tissue (RBE) fails in assessing comparative relative effectiveness in the tissue cells.

The value of the RBE of a test radiation is conventionally determined against a known standard radiation for a chosen response of a selected biological tissue and is expressed as the ratio of tissue absorbed doses at equal effect, or as ratio of magnitudes of the effect at equal absorbed dose. If such an effect is observable as a consequence of responses of individual elements of this tissue, namely the cells, such as induction of cancer that arises from a single cell, the relative biological effectiveness should be expressed as the ratio of the incidences of the effects at equal mean absorbed dose to the cells rather than at equal absorbed dose to tissue. This cell based relative biological effectiveness is here termed the relative local efficiency. Since tissue absorbed dose is a product of the number of energy deposition events in cells of that tissue (N(H)) and the mean absorbed dose to these cells in the exposed tissue (z(1)), per tissue mass equal tissue absorbed doses from different radiation qualities have different values of N(H) and z(1) As a result, for pink mutations in Tradescantia cells, the relative biological effectiveness of 0.43 MeV neutrons is 48 but the relative local efficiency in fact is 2.8.

The use of cell-oriented factors and the hit size effectiveness function in radiation protection.

It has long been argued that ionizing radiation can be considered to interact with matter in discrete, randomly occurring energy transferring events ("hits") and that the resulting microscopically nonuniform pattern of energy deposition strongly influences the biological effect of a given exposure. Microdosimetric measurements combined with cellular biological response data in the form of a "hit size effectiveness function" (HSEF) suggest a possible cell-oriented alternative method of correlating exposure with effect at low levels of any radiation or mixture of radiations. The instrumentation required, the validity of the approach, and its practical usefulness in radiation protection are examined, and its application to space radiation exposure is proposed as a test case.

The meaning of linear dose-response relations, made evident by use of absorbed dose to the cell.

Experimental evidence shows that if the probability of biological response is plotted against the absorbed dose from ionizing radiation, and if both dose and response are determined at the same level of biological organization (e.g., cell or organ-organism) the result appears as a sigmoid, medical-toxicological type of "dose-response" function when plotted using linear coordinates. However, if the biological response expressed at the cellular level is similarly plotted against the average absorbed dose expressed at the organ-organism level, a linearly proportional, "non-threshold" function is obtained. To explain this marked difference in curve shape, the absorbed dose at the organ level in terms of its meaning at the cellular level was examined, and both dose and response were put on the latter level. The result is consistent with the conclusion that absorbed dose at the organ-organism level can be treated, at the cellular level, as the product of two quantities: 1) the mean energy concentration or dose in a cell from a deposition event, i.e., "hit size" (the frequency-averaged specific energy in a reference cell target), and 2) the number of deposition events, or "hits," on the exposed cells. When the mean hit size for a given radiation remains constant, and the number of hits is increased, the total number of responses follows a linearly proportional "hit number response function." However, if the hit number is held constant or normalized to a given value, and the hit size is varied, the resulting probability of cell response again plots as the apparently sigmoid curve mentioned above, which has been termed the "hit size effectiveness function." With decreasing hit size, the probability of a cellular response appears to decrease asymptotically, and become indistinguishable from zero before zero dose is reached. It follows from this inherent relationship between the two kinds of functions that a sufficiently extensive set of data on a population of cells permits either type of function to be produced at will. These findings bear on the interpretation of the "linear, non threshold" hypothesis.

Cellular mechanisms of protection and repair induced by radiation exposure and their consequences for cell system responses.

The complex biological systems that constitute living organisms operate at various levels of organization, from the atomic-molecular to the cellular to the organ-organism level. The response of an organism to disturbances that are detrimental to structure and function generally begin at the level of organization where the primary injury has occurred. Detriment that occurs from simultaneous or sequential, or single or multiple interactions at a relatively low level of organization tends to be transferred to higher levels. However, at each level of organization there is a given probability of such detriment being removed according to the tolerance to injury that is peculiar to that level. There is thus a direct relationship between the frequency of injurious events at a lower level of organization, and the degree of structural complexity of the system at the high level at which such detriment is eventually manifested. The extent of structural disruption at any given level determines the degree of functional failure at that level. In the exposure of tissue to ionization radiation, the primary injury begins with energy deposition events (tracks or hits) consisting of many ionizations and excitations in localized clusters of submicroscopic dimensions at the atomic-molecular level of organization within the cell, and the cell is affected as a whole. The cell is the elementary unit of life and the sum of the individual cell responses determines the response of the tissue and the organism. Individual cell responses are nevertheless found to differ in type and degree depending on the absorbed dose. With decreasing values of absorbed dose to the tissue, the probability of a cell being hit by an energy deposition event decreases linearly. At very low values of absorbed dose to tissue, only a fraction of the total cell population experiences single hits and these are of different sizes. The size distribution or spectrum of these hits is invariant, independent of their total number over a considerable range at low-dose levels and is determined only by the type and quality of the given radiation. The probability that a hit cell will suffer a given detriment such as a chromosomal aberration, gene mutation or death has been shown to increase in a sigmoid fashion with increasing hit size.(ABSTRACT TRUNCATED AT 400 WORDS)

A different perception of the linear, nonthreshold hypothesis for low-dose irradiation.

Two equally useful dosimetric quantities, both of which are called dose, are used in toxicology. With radiation measurement, only one--the energy per unit mass D--is called dose. The other--the total energy in the irradiated system--is here distinguished from D by assigning it the name collective energy, epsilon. The collective energy is a more complete statement of dose because it is the product of the energy concentration D and the mass irradiated m. Especially in radioepidemiology, in which epsilon is the total energy imparted to all persons irradiated, the quantity m must be specified because it is situation specific and thus highly variable. At present, radioepidemiological dose-response curves are given only in terms of the toxicological model--i.e., the fraction (probability) of radiation-attributable cancers occurring as a function of D. Because this relation does not involve the number of persons at each value of D, it fosters the illusion that any dose, no matter how small, can result in cancer. However, we show that if the dose-response relationship is expressed in terms of the absolute number of attributable cancers as a function of epsilon, cancer occurs, on average, only if the collective energy exceeds a relatively large minimum value, the magnitude of which will be estimated. Therefore, we conclude that the nonthreshold aspect of the linear hypothesis is misleading and quite probably invalid. For example, in or around a facility in which exposure of humans to relatively low values of D occurs, attributable cancers are most unlikely to appear unless the epsilon to the irradiated population exceeds this minimum value.

Cell-oriented alternatives to dose, quality factor, and dose equivalent for low-level radiation.

Randomly occurring energy deposition events produced by low levels of ionizing radiation interacting with tissue deliver variable amounts of energy to sensitive target volumes within a small fraction of the tissue cell population. A model is described in which an experimentally derived function relating event size to cell response probability operates mathematically on the microdosimetric event size distribution characterizing a given irradiation and thus determines the total fractional number of responding cells; this fraction measures the effectiveness of the given radiation. Applying this cell response or hit size effectiveness function (HSEF) to different radiations and normalizing to equal numbers of responses produced by each radiation should define its radiation quality, or relative effectiveness, on a more nearly absolute basis than do the absorbed dose and dose equivalent, both of which are confounded when applied to low-level irradiations. Similar cell response probability functions calculated from different experimental data are presented.

Microdosimetric concepts applied to hormesis.

With radiation, unlike chemicals, a small absorbed organ dose can deliver amounts of energy to macromolecular cell targets so great that, if the relevant target is hit, even the best efforts of any repair processes probably cannot prevent cell transformation. Data are shown for both mutagenesis and carcinogenesis, indicating that, in this respect, even the smallest average organ absorbed dose can be effective, particularly for high-LET radiation. Thus while hormesis-enhanced protective processes may render ineffective marginally large amounts of energy deposition per cell target and thus perhaps reduce the incidence of carcinogenesis and mutagenesis, a goal of zero incidence is most likely unrealistic for at least high-LET radiation. The usefulness of the radiation hormesis concept may well be decided on these questions because of the general awareness that even a moderate average life lengthening in the population would not eliminate marked shortening of useful life in the young with induced cancer or serious genetic defects.

Intracellular stimulation of biochemical control mechanisms by low-dose, low-LET irradiation.

Non-specific generation of intracellular free radicals in excess of normal levels, e.g. by the acute radiation absorption event in cells, has led to a delayed and temporary inhibition of thymidine kinase. The enzyme activity reaches a minimum at 4 h even after a low-level exposure with full recovery soon thereafter. This process appears to represent a biochemical response to an initial physical event, but must be distinguished from the response of the DNA repair enzyme system. A reduction of cellular thymidine kinase activity is expected to cause a temporary reduction of DNA synthesis and may be of advantage to the cell. Such a response may be regarded as an instance of radiation hormesis in the sense that such a compensatory response to the stimulus of irradiation may confer protection against a repeated increase in free radical concentration whether by renewed radiation exposure or by metabolism in general. An improvement of the efficiency of repair or an increased level of free radical detoxification should be of benefit to both the individual cell and to the organism as a whole.

Common misinterpretations of the "linear, no-threshold" relationship used in radiation protection.

Absorbed dose D is shown to be a composite variable, the product of the fraction of cells hit (IH) and the mean "dose" (hit size) z to those cells. D is suitable for use with high level exposure (HLE) to radiation and its resulting acute organ effects because, since IH = 1.0, it approximates closely enough the mean energy density in the cell as well as in the organ. However, with low level exposure (LLE) to radiation and its consequent probability of cancer induction from a single cell, stochastic delivery of energy to cells results in a wide distribution of hit sizes z, and the expected mean value, z, is constant with exposure. Thus, with LLE, only IH varies with D so that the apparent proportionality between "dose" and the fraction of cells transformed is misleading. This proportionality therefore does not mean that any (cell) dose, no matter how small, can be lethal. Rather, it means that, in the exposure of a population of individual organisms consisting of the constituent relevant cells, there is a small probability of particle-cell interactions which transfer energy. The probability of a cell transforming and initiating a cancer can only be greater than zero if the hit size ("dose") to the cell is large enough. Otherwise stated, if the "dose" is defined at the proper level of biological organization, namely, the cell and not the organ, only a large dose z to that cell is effective.

Growth hormone secretion in the stunted head-irradiated rat.

Pulsatile secretion profiles of pituitary growth hormone (GH) and size and number of cells of brain, heart ventricles, liver, kidney, and gastrocnemius muscle were determined in male Long-Evans rats which received 600 rad x-irradiation to the head only at 2 days of age. Controls consisted of sham-irradiated littermates. The irradiated rats showed significant stunting of body weight and tail length beginning prior to weaning and lasting throughout the period (64 days) of observation. In irradiated rats at 20-21 days of age, just prior to weaning, organ weight was significantly reduced in all organs studied. Brain showed a decrease in organ/body ratio (p less than 0.0005) and in total DNA content (p less than 0.0005), but these values were not significantly changed in the other organs. DNA/organ ratio was increased significantly in heart (p less than 0.025) and gastrocnemius muscle (p less than 0.025); brain, liver, and kidney had nonsignificant increases. Protein/DNA ratios were decreased significantly in brain (p less than 0.005), heart (p less than 0.01), and gastrocnemius muscle (p less than 0.05); liver and kidney had nonsignificant decreases. Blood samples were removed for GH determination from cannulated undisturbed irradiated and control rats at 15-min intervals for 18-h periods (9 h light and 9 h dark) at 47-64 days of age. Irradiated rats had normal periodicity of bursts of GH secretion. The area under the curve of GH concentration versus time of the irradiated rat was decreased in light (p less than 0.025) and in dark (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

An alternative to absorbed dose, quality, and RBE at low exposures.

The microdosimetric distribution of event sizes, especially for small exposures and high-LET radiation, represents both a fractional involvement of the exposed cell population and variable amounts of energy transferred to the "hit" cells. To determine the fraction of cells that will respond quantally (be transformed) after receiving a hit of a given size, a hit size effectiveness function (HSEF) which appears to have a threshold has been derived from experimental data for pink mutations in Tradescantia. The value of the HSEF at each event size, multiplied by the fractional number of cells hit at that event size, and summed over all event sizes, yields a single value representing the fractional number of quantally responding cells and thus the population impairment for a given exposure. The HSEF can be obtained by unfolding (deconvoluting) several sets of biological and microdosimetric data obtained with radiation of overlapping event size distributions.

Model identification and estimation of organ-function parameters using radioactive tracers and the impulse-response function.

Examination of the input-output events in functioning organs by the use of the impulse-response function (IRF) for a radioactive tracer is gaining more and more ground in nuclear medicine. This study summarizes the development of deconvolution analysis, laying special stress on the 'model-free' approach. System linearity and time invariance are discussed, and means of eliminating noise in IRFs originating from the input and organ-time-activity curves are outlined. Typical IRFs are illustrated by flow diagrams, time-domain curves, and their representation by Laplace transforms. The cases of nondiffusible and diffusible tracers as well as parenchymally extracted and transported substances are discussed. Methods for the derivation of models and for the calculation of physiologically important parameters from the IRFs are suggested.

Cartilage metabolism during growth retardation following irradiation of the head of the neonatal rat.

The heads of 2-day-old male and female rats were irradiated with a single dose of 600 rads X irradiation, a dose which is known to stunt body weight, tibial length, and tail length, in order to ascertain its effects on synthesis by cartilage of sulfated proteoglycans, DNA, chondroprotein, and collagen as determined by utilization of [35S]sulfate, [Me-3H]thymidine, [1-14C]leucine, and [3,4-3H]proline, respectively. Data have been collected at 20-21, 23, 41-45, and 70-71 days of age. In comparison to controls, growth in body weight, tibial length, and tail length was significantly retarded in irradiated rats of both sexes. Although slow catch-up growth was observed with respect to tail length in both sexes and tibial length in females, a significant deficit in body weight in irradiated rats in both sexes remained at 70-71 days. Cartilage metabolism as evidenced by incorporation of the labeled substances showed no significant disturbance just prior to weaning (20-21 days) or after completion of the principal growth surge (70-71 days). Reduced sulfate and thymidine incorporation attributable to a brief period of undernutrition associated with weaning occurred in head-irradiated rats immediately following weaning (23 days). Increased isotope incorporation occurred at 41-45 days of age in cartilage of irradiated rats incubated with labeled sulfate, leucine, and proline; it did not increase with labeled thymidine. We conclude that neonatal head irradiation slows the rate of growth through the age of most rapid postnatal growth in normal rats. The pattern of cartilage metabolism during this time can be the result either of stimulation by a factor other than somatomedin, or selective inhibition of cartilage thymidine incorporation acting in combination with somatomedin.

The effect of neonatal head-irradiation and subsequent fasting on the mechanisms of catch-up growth.

The heads of 2 day old male and female rats were X-irradiated with 600 rad. Non-irradiated littermates served as controls. At 40 days of age groups of irradiated and non-irradiated rats were subjected to a 48 hour fast. Non-fasted groups of irradiated and non-irradiated rats were fed ad lib. and were used for comparative studies. Growth of body weight and tail length was recorded at intervals through 70 days of age. At sacrifice, pituitary weight, tibial length, and tibial epiphyseal width were also determined. The results confirm earlier findings that whole head irradiation produces reduced growth of body weight and of tail length which remains uncompensated by catch-up growth. After fasting and then refeeding normal catch-up growth acceleration occurred in both male and female irradiated and nonirradiated animals. The fasted non-irradiated animals caught up to the non-irradiated control rat size for both body weight and tail length. Similarly, the fasted irradiated rats caught up to the irradiated, non-fasted rat size, but did not catch up to the size of the non-irradiated controls. Pituitary weight and tibial length were significantly reduced in irradiated males and females. At sacrifice, no significant difference existed between the fasted and non-fasted subgroups. The tibial epiphyseal growth plate was not narrowed in irradiated rats; fasted rats had increased epiphyseal width during recovery in only one group. We conclude that the catch-up growth control is intact in the head-irradiated stunted rat. The findings suggest that the mechanism which recognizes normal body size (set-point for body size) and which determines the limit of catch-up growth acceleration is reset for a smaller body size by the head-irradiation.

Cosmic radiation exposure in subsonic air transport.

This FAA- and NASA-sponsored study of cosmic radiation doses recieved by United States residents flying in commercial jet aircraft is the most extensive to date and combines computer calculations with experimental data. Data derived from 1973 statistics on 2.99 million intercity flights carrying 468 million seats were included in the calculations, yielding a total of 581 billion seat-kilometer. The average flight was 1,084 km in length, was flown at an altitude of 9.47 km, and lasted 1.41 h. The average dose rate was 0.20 mrem/h, resulting in an average passenger dose of 2.82 mrem/year and an average crewmember dose of 160 mrem/year. The average radiation dose to the total U.S. population was 0.47 mrem/person/year. These results are in good agreement with data from several experiments performed by us and others in aircraft at various altitudes and latitudes. The significance of these doses to the population is discussed.