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COMPARATIVE RISK ASSESSMENT OF RADIATION AND OTHER MUTAGENIC AGENTS. LOW DOSE RELATIVE RISK OF DIFFERENT IONIZING RADIATIONS AND COMPARISON WITH UV RADIATION

Objective

THE EVENTUAL AIM OF THIS PROJECT IS THE DEVELOPMENT OF A NEW COMPREHENSIVE CONCEPTUAL APPROACH TO PERMIT A COMPARATIVE RISK ASSESSMENT OF THE CELLULAR EFFECTIVENESS OF RADIATIONS AND OTHER MUTAGENIC AGENTS ON THE BASIS OF THE MECHANISMS OF ACTION. IT IS ENVISAGED THAT THE DEVELOPMENT OF THE CONCEPTUAL APPROACH WILL PROCEED IN PHASES BY THE CONSOLIDATION AND EXTRAPOLATION OF THE METHODOLOGY USED TO ANALYSE RADIATION EFFECTS.
IN PREVIOUS CONTRACTS A THEORY OF RADIATION ACTION HAS BEEN DEVELOPED BASED ON THE ASSUMPTION THAT DNA DOUBLE STRAND BREAKS FORM THE CRUCIAL RADIATION INDUCED LESIONS(1). THE THEORY SATISFIES THE NEED FOR A SMALL TARGET FOR THE ALPHA-COEFFICIENT (DNA SMALLER THAN 2NM) BUT RESTRICTS THE WAY IN WHICH DIFFERENT INDUCTION PROCESSES AND REPAIR PROPERTIES CAN INFLUENCE THE ALPHA-COEFFICIENT AND ESPECIALLY THE BETA-COEFFICIENT.
IN THE CONTRACT 1983-1984 A RADIATION TRACK STRUCTURE MODEL, WHICH DESCRIBES THE SPATIAL ASSOCIATION OF ENERGY DEPOSITION EVENTS AT NANOMETER DIMENSIONS, HAS BEEN REVISED AND IS BEING USED TO CALCULATE THE EFFICIENCY OF DNA DOUBLE STRAND BREAK PRODUCTION FOR DIFFERENT RADIATION TYPES AND COMPARE THIS WITH THE RADIATION QUALITY DEPENDENCE OF THE LOW DOSE CELL KILLING (ALPHA-COEFFICIENT). IN ADDITION, A MODEL HAS BEEN DEVELOPED FOR UV CELL KILLING, WHICH RELATES CELL KILLING TO THE SQUARE OF UV EXPOSURE. A COMPARISON OF THE BETA-COEFFICIENTS FOR UV AND IONIZING RADIATION REVEALS SOME SIMILARITIES BUT ALSO ESSENTIAL DIFFERENCES. BOTH BETA-COEFFICIENTS ARE DERIVED FROM A COMBINATION OF TWO DNA SINGLE STRAND LESIONS AND INTERACTION BETWEEN UV AND X-RAYS IS ANTICIPATED.
THE ESSENTIAL DIFFERENCE BETWEEN THE THEORETICAL PREDICTIONS FOR THE BETA-TERM FOR IONIZING AND UV RADIATION IS THAT IN THE CASE OF IONIZING RADIATION THE OCCURRENCE OF THE "SECOND" SINGLE STRAND BREAK IN THE PROXIMITY OF THE "FIRST" CONVERTS THE "FIRST" TO A DOUBLE STRAND BREAK WHEREAS IN THE CASE OF UV THE TWOO PYRIMIDINE DIMERS ARE NOT RECOGNIZED AS A CRUCIAL PAIRED
A track structure model in liquid water is being developed and improved to calculate radiation effectiveness of X-rays, gamma-rays, electrons, ions and neutrons. This includes the application of the track model to demonstrate the behaviour of the linear term of the radiobiological dose effect relationship for different ionising radiations, and the development of a stationary cellular system to compare directly the effects on survival of the repair of sublethal, and potentially lethal, damage following ultraviolet (UV) radiation and gamma-rays.
METHODOLOGY
CALCULATIONS
THE TRACK STRUCTURE MODEL DEVELOPED TO CALCULATE THE INDUCTION OF DNA DOUBLE STRAND BREAKS BASED ON THE ENERGY DEPOSITION PROCESSES IN WATER WILL BE FURTHER EXPANDED TO DETERMINE THE DISTANCE FROM THE DNA HELIX OVER WHICH WATER RADIOLYSIS PRODUCTS CAN BE EFFECTIVE. IN ADDITION THE ROLE OF DIRECT ENERGY DEPOSITION PROCESSES IN THE DNA MOLECULE WILL ALSO BE TAKEN INTO ACCOUNT. THE MODEL WILL BE USED TO CALCULATE THE ALPHA-COEFFICIENT FOR CELL KILLING IN DIFFERENT CELL SYSTEMS FOR A VARIETY OF RADIATION TYPES. WHERE AVAILABLE, DATA FOR OTHER BIOLOGICAL END-POINTS SUCH AS CHROMOSOMAL ABERRATIONS AND MUTATIONS WILL ALSO BE COMPARED WITH THE CALCULATIONS. THE MODEL WILL BE FURTHER DEVELOPED TO INCLUDE MONO-ENERGETIC NEUTRON BEAMS AND FISSION-SPECTRUM NEUTRONS.
IN THE SECOND PHASE OF THE PROJECT THE TRACK STRUCTURE MODEL WILL BE USED TO CALCULATE THE DEPENDENCE OF THE BETA-COEFFICIENT OF THE BIOLOGICAL EFFECTS ON RADIATION QUALITY TAKING INTO ACCOUNT THE POTENTIAL ROLE OF DIFFERENT WATER RADIOLYSIS PRODUCTS AND POSSIBLE ENERGY TRANSFER DOWN THE DNA.
EXPERIMENTS
IN A SERIES OF SPECIALLY DESIGNED EXPERIMENTS THE INFLUENCE OF REPAIR PROCESSES ON FRACTIONATION AND POST-IRRADIATION STORAGE EFFECTS FOR CELL KILLING WILL BE INVESTIGATED ESPECIALLY IN STATIONARY MAMMALIAN CELL CULTURES FOR UV AND X-RAYS. THE REPAIR OCCURRING BETWEEN FRACTIONS WILL BE COMPARED WITH THE POST-IRRADIATION REPAIR TO LOOK FOR DIFFERENCES BOTH IN THE TWO TYPES OF REPAIR AND BETWEEN THE TWO TYPES OF RADIATION. THE ROLE OF THE S-PHASE WILL BE EXPLOITED TO PROVIDE EVIDENCE ON WHETHER THE CURVE-LINEAR FORM OF THE X-RAY EFFECT IS REALLY A TWO-HIT EFFECT OR A RESTRICTED REPAIR EFFECT.
IN A SECOND PHASE OF THE EXPERIMENTAL WORK THE EFFECT OF COMBINED TREATMENT OF UV AND X-RAYS ON THE STATIONARY CELLS WILL BE INVESTIGATED WITH RESPECT TO THE SEQUENCE OF EXPOSURES AND THE TIME BETWEEN EXPOSURES. HERE AGAIN THE PREDICTIONS OF THE THEORETICAL MODELS WILL BE USED TO ANALYSE THESE RESULTS IN AN ATTEMPT TO PROVIDE A COHERENT PICTURE OF THE MECHANISM OF ACTION OF UV AND X-RAYS. EVENTUALLY A SECOND END-POINT SUCH AS CHROMOSOMAL ABERRATIONS OR MUTATIONS MAY BE INVESTIGATED.

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RIJKSINSTITUUT VOOR VOLKSGEZONDHEID EN MILIEUHYGIENE
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