Accommodative responses to chronic irradiation: effects of dose, dose rate, and pharmacological response modifiers.

Low-level radiation exposures are expected to have long-term health implications but few near-term effects that would impair function. These assumptions are based on extrapolation from acute exposure responses, not on studies of a larger array of exposure scenarios (e.g., protracted exposures) that might present as operational threats. Protracted exposure is one scenario that needs to be better defined in terms of both the initial effect and the long-term health consequences. Reported here are the near-term effects of chronic, low daily-dose gamma-irradiation (3-128 mGy per day) on the blood-forming system of canines. Change in hematopoietic capacity was monitored along with time of exposure and cumulative radiation dose. The rate, magnitude, and timing of suppression and accommodation were determined. The ability of periodic treatment with a lipopolysaccharide immunomodulator to alleviate the suppressive hematopoietic effects of chronic exposure was tested. The effects of other pharmacologics (amifostine, granulocyte colony-stimulating factor, cytokine) are projected on the basis of current research using rodent models. Results indicated that low but significant suppression of blood leukocyte and platelet levels occurred at 3 mGy per day. As the dose rate increased from 3 mGy to 128 mGy per day, the rate of suppression increased approximately eightfold, whereas the time to accommodate declined from 2,000 days to approximately 150 days. Within the time frame required to reach the upper limit of 700 mGy, none of the dose rates examined elicited blood cell decrements large enough to severely compromise near-term immune function. Pharmacological intervention with lipopolysaccharide minimized hematopoietic suppression in only a small fraction of the treated animals that displayed distinctive long-term survival and pathology patterns. Comparable short-term benefits of treatment with hematopoietic cytokines or chemoprotectants are predicted on the basis of responses noted in rodent models. Long-term benefits of such treatments remain to be determined. Future work will require the application of advanced molecular tools to more fully assess potential pathophysiological responses and their modulation after low-level radiation exposure.

New strategies for the prevention of radiation injury: possible implications for countering radiation hazards of long-term space travel.

New strategies for the prevention of radiation injuries are currently being explored with the ultimate aim of developing globally radioprotective, nontoxic pharmacologics. The prophylactic treatments under review encompass such diverse pharmacologic classes as novel immunomodulators, nutritional antioxidants, and cytokines. An immunomodulator that shows promise is 5-androstenediol (AED), a well-tolerated, long-acting androstene steroid with broad-spectrum radioprotective attributes that include not only protection against acute tissue injury, but also reduced susceptibility to infectious agents, as well as reduced rates of neoplastic transformation. Other potentially useful radioprotectants currently under study include the nutraceutical vitamin E and analogs, a chemically-engineered cytokine, interleukin-1beta, and a sustained-release formulation of an aminothiol, amifostine. Results suggest that a new paradigm is evolving for the prophylaxes of radiation injuries, based on use of newly identified, nontoxic, broad-spectrum prophylactic agents whose protective action may be leveraged by subsequent postexposure use of cytokines with organ-specific reparative functions.