C.A. Sondhaus

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.

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.

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.

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.