The Eighth

International Congress of Radiation Research

Patron: H . R . H . The Duke of Edinburgh, K . G .

The Eighth International Congress of Radiation Research was organized by the Association of Radiation Research at the invitation of the International Association for Radiation Research. The Officers of the Congress were appointed by the Association for Radiation Research.

G . E . Adams , President Sir Alastair Curr ie and L o r d Dainton , Hon . Vice Presidents

Ε . M . Fie lden, Secretary-General

O R G A N I Z I N G C O M M I T T E E : The Officers and

I . V . Chapman (Local Committee) J . F . Fowler (Scientific Programme) A . Tallentire (Fund Raising) P. Wardman (Treasurer) D . K . Bewley Ν . M . Bleehen

J . A . Dennis Ν . E . Gil l ies J . H . Hendry J . L . Moore Sir Oliver Scott

I N T E R N A T I O N A L A S S O C I A T I O N F O R R A D I A T I O N R E S E A R C H

A . C . Upton ( U . S . A . ) — President

A S S O C I A T I O N F O R R A D I A T I O N R E S E A R C H

A . Tallentire — Chairman

Radiation Research

Proceedings of the 8th International Congress of Radiation Research

Edinburgh, July 1987

VOLUME 2

Edited by

E . M . Fielden J . F . Fowler J . H . Hendry

D . Scott

Taylor & Francis

London · New York · Philadelphia

Contents

O P E N I N G L E C T U R E : A Glance at 25 years o f Radiation Research J. W. Boag 1

1. R A D I A T I O N C H E M I S T R Y 9

1.1 Track Effects in Radiation Chemistry (Symposium) Theoretical aspects of heavy-ion tracks in radiation chemistry

A. Mozumder and J. A. La Verne 11 A n overview of the oxidation o f ferrous ions in the Fricke dosimeter

by heavy ions J. A. La Verne and R. H. Schuler 17

Chemical aspects o f high energy heavy ion tracks A.Appleby 23

Biophysical aspects o f track structure G. Kraft and W. Kraft- Weyrather 29

1.2 New Trends in Radiation Chemistry Congress Lecture: The Chemistry o f Synchrotron Radiation

Y. Hatano 35

SYMPOSIUM: N E W T R E N D S IN R A D I A T I O N C H E M I S T R Y 1 G E N E R A L

Modern trends in experimental radiation chemistry R. H. Schüler 42

New trends in radiation chemistry: aqueous radiation chemistry K-D.Asmus 48

Some aspects o f the radiation chemistry o f ethanol and cyclic organic amides

G.A.Salmon 54 Gas phase pulse radiolysis

C. D. Jonah, A.Liu and W. A. Mulac 60

SYMPOSIUM: N E W T R E N D S IN R A D I A T I O N C H E M I S T R Y II

P R I M A R Y / R E A C T I V E S P E C I E S

New trends in radiation chemistry I I Ν. V. Klassen 66

Excited states in hydrocarbons S. Lipsky 72

Chemical reactivities o f radical anions studied by pulse radiolysis S. Takamuku 78

1.3 Redox Processes, Free Radicals and Oxygen Toxicity

SYMPOSIUM: R A D I A T I O N I N D U C E D R E D O X P R O C E S S E S

Mechanisms o f electron transfer between radicals and molecules: The addition-elimination route (inner-sphere electron transfer)

S. Steenken 84 The radiolytic approach to the understanding o f model photochemical

systems for energy conversion and storage Q. G. Mulazzani 90

Effects of energy, distance and orientation on electron transfer rates studied by pulse radiolysis in organic media

J. R. Miller 96 Congress Lecture: Radiation Chemistry in Microheterogeneous Systems

M.A.J. Rodger s and S. M. Hubig 102

SYMPOSIUM: F R E E R A D I C A L S A N D O X Y G E N T O X I C I T Y

Radiobiology and the superoxide radical LFridovich 109

Generation and reactivity o f activated oxygen species — the influence o f hyperthermic conditions

E. Lengfelder and R. M. Fink 116 Progress and trends in superoxide research

B.H.J. Bielski 122 The function o f specific genes to enhance tolerance to oxygen

M.Morimyo 128 1.4 Peptides, Proteins, D N A and Cell Death

SYMPOSIUM: R A D I A T I O N E F F E C T S IN P E P T I D E S A N D P R O T E I N S

Radical transformations in peptides and proteins W.A.Prutz 134

Peptide irradiation products and crosslinking mechanisms M. G. Simic, L . R. Kar am and M. F. Desrosiers 140

Radiation effects in histone octamer complexes and in isolated histones W. Schnabel L . Katsikas and K.-H. Deeg 146

χ Radiation-induced pro te in -DNA interactions H. Schuessler 152

\ Congress Lecture: D N A strand break formation and biological consequences

D. Schulte-Frohlinde 158 Congress Lecture: Radiation chemical mechanisms of cell death

J.F.Ward 162

SYMPOSIUM: R A D I A T I O N D A M A G E IN DNA

The mechanism by which metal compounds cause site specific D N A damage G. Czapski a fid S. Goldstein 169

Radiation damage o f the nucleobases in D N A C. von Sonntag 175

Direct effects o f ionising radiation on D N A and related compounds J. Cadet, A. Shaw, M. Berger, C. Decarroz, J. R. Wagner and J. van Lier 181

Radiation damage and biologically active D N A Μ. V. Μ. Lafleur, J. Retel and H. Loman 187

1.5 Industrial Applications of Radiation Chemistry

SYMPOSIUM: R A D I A T I O N C H E M I S T R Y AND T H E N U C L E A R I N D U S T R Y

Radiation chemistry in the nuclear industry W.G.Burns 193

The radiation chemistry o f water and aqueous solutions at elevated temperatures

K. Sehested and H. Christensen 199 The effect of radiolysis on the chemical forms of iodine species in

relation to nuclear reactor accidents K. Ishigure 205

Radiation-induced formation and dissolution of colloidal transition-metal oxides

G. V. Buxton, D. W. Cartmell andR. M. Sellers 212

SYMPOSIUM: A NEW L O O K A T T H E R A D I A T I O N P R E S E R V A T I O N

O F F O O D

Food preservation by irradiation G. Campbell-Platt 218

Public health aspects o f food irradiation Ε. H. Kampelmacher 224

The identification of irradiated foods W. Bogl 230

Assessment o f the wholesomeness o f irradiated food

D. W. ihayer 236

2. P H Y S I C S , B I O P H Y S I C A L M O D E L S A N D M I C R O D O S I O M E T R Y 243

2.1 Physics Congress Lecture: Prospects and Problems o f Fusion Power

W. M. Lomer 244

SYMPOSIUM: F U N D A M E N T A L R A D I A T I O N P H Y S I C S

Introductory review: Physics o f electron slowing-down processes M. Inokuti 250

Time dependent degradation o f energetic electrons in gaseous and condensed media

M. Dillon and M. Kimura 255 Experimental studies on the interactions of slow electrons wi th

molecules in solid films L . Sanche 260

Differential inelastic scattering cross sections for low energy (100 eV—few keV) electrons in solids

S. Tougaard 266

SYMPOSIUM: C H A R G E T R A P P I N G A N D M I G R A T I O N O F E N E R G Y

Charge migration and localisation /. M. Warman 272

Theoretical aspects o f trapping and transfer o f charge W. M. Bartczak 278

Charge trapping and migration in liquids Υ. N. Molin 284

Charge trapping and migration in solids M.C.R. Symons 290

2.2 Quantitative Models of Radiation Action Kaplan Lecture: Target Theory, Linearity and Repair/Misrepair

in Radiobiology Μ. M. Elkind 296

SYMPOSIUM: B I O P H Y S I C A L M O D E L S O F R A D I A T I O N A C T I O N

Biophysical models o f radiation act ion—Introductory review D. T. Goodhead 306

The cellular consequences o f binary misrepair and linear fixation o f initial biophysical damage

S. B. Curtis 312 Pairwise lesion interaction — extension and confirmation o f Lea's model

D. Harder 318 A concept relating D N A repair, metabolic states and cell survival

after irradiation Κ. T. Wheeler 325

2.3 Microscopic Deposition of Radiation Energy

SYMPOSIUM: A P P L I C A T I O N S O F M I C R O D O S I M E T R Y

Applications o f microdosimetry J. Booz and L . E. Feinendegen 331

Microdosimetry: Recent trends and applications to radiation biology and radiation chemistry

A. M.Keller er 338 Applications of microdosimetry in radiation protection

H. G. Menzel 345 Applications o f microdosimetry in radiation therapy

A. Wambersie 351

SYMPOSIUM: E F F E C T S O F I N T E R N A L A U G E R E M I T T E R S

Effects o f internal Auger emitters D. Ackery and K. F. Β averstock 357

Local effects o f Auger electron cascades D. E. Charlton 363

Radiobiological effects o f Auger emitters in vitro and in vivo D. V. Rao and K. S. R. Sastry 369

3. C E L L U L A R A N D D N A R E P A I R 375

Congress Lecture: Aspects of D N A Damage, D N A Repair and Radiosensitivity: Responses o f Mammalian Cells to Acute Doses of Radiation

J. T. Lett, A. B. Cox, R. Okayasu and M. D. Story 376

3.1 Inducible Repair of Damage Caused by Ionising and Non-ionising Radiation (Symposium)

recA -dependent repair o f D N A gaps and double-strand breaks after U V irradiation

K. C. Smith, T-C. V. Wang and R. C. Sharma 382 Cellular functions required for U V and chemical mutagenisis in

Escherichia coli J. R. Battista, T. Nohmi, C. E. Donnelly and G. C. Walker 388

Inducible D N A repair o f ultraviolet light damage in E. coli and related species

S. G. Sedgwick 394 Non-ionizing radiation and inducible responses in eucaryotes

R. M. Tyrrell and S. M. Keyse 400

3.2 Molecular Studies on D N A Repair in Mammalian Cells (Symposium) Reversion and interspecies transfer o f genes responsible for repair in

xeroderma pigmentosum /. E. Cleaver, D. Karentz, L . H. Lutze, A. N. Player and D. L . Mitchell 406

Homology of mammalian, Drosophila, yeast and E. coli repair genes D. Bootsma, Μ. Η. M. Koken, Μ. van Duin.A- Westerfeld, A. Yasui,

S. Prakesh and J. H. J. Hoeijmakers 412 D N A repair in tissue specific genes in cultured mouse cells

C. M. Haqq and C. A. Smith 418

3.3 Radiosensitive Human Cells (Symposium) The radiosensitivity o f cultured human cells

C.F.Arlett 424 Novel pattern of post-y ray D N A replicative synthesis in cultured

radioresistant fibroblasts from affected members o f a cancer-prone family

M. C. Paterson and R. Mirzayans 431 The human genetic disorder ataxia-telangiectasia ( A - T ) : New insights

into the basis o f radio-sensitivity P. G. Debenham and J. Thacker 437

High sensitivity to radiation and chemicals in relation to cancer and mutation

H. Takebe, K. Tatsumi,A. Tachibana and C. Nishigori 443

3.4 Fractionation, Low-dose Rate and Repair Kinetics (Symposium) Repair kinetics in normal tissues

H. D. Thames 449

The dose-rate effect and recovery in human tumour cells G. G. Steel, A. M. Cassoni,J. M. Deacon, G. M. Duchesne,

A. Horwich, L . R. Kelland and J. H. Peacock 455 The influence o f proliferative status on responses to fractionated and

low dose rate irradiation /. S. Bedford 461

Chromosome break rejoining and cellular recovery from X-rays Μ. N. Cornforth 468

4. O N C O G E N E S I S A N D M U T A G E N E S I S 475

4.1 Cellular and Molecular Aspects of Oncogenesis Congress Lecture: Genetic and Epigenetic Influences on Oncogene Act iv i ty

J. A. Wyke, J. Akroyd,A. Green, C. Poole and M. Welham 476

SYMPOSIUM: C E L L U L A R AND M O L E C U L A R A S P E C T S O F O N C O G E N E S I S

Search for genes involved in thymic lymphomagenesis M. Janowski, B. Borremans, R. Hooghe, J. Merregaert, P. Reddy,

J. Boniver and M. P. Defresne 482 Radiation-induced carcinogenesis in dogs

Μ. E. Frazier, Τ. M. Seed, L . L . Scott and G. L . Stiegler 488 Studies on radiation myeloid leukaemogenesis in the mouse

A. Silver, G. Β reckon, W. K. Masson, D. Malowany and R. Cox 494 The action o f chemical carcinogens and oncogenic retroviruses in

mouse skin tumour induction Α. Β almain, Κ. Brown, R. Bremner, Μ. Quintanilla and Μ. Archer 501

4.2 Oncogenic Transformation Congress Lecture: Oncogenic Transformation by Radiation and Chemicals

E. J. Hall and Τ. K. Hei 507

SYMPOSIUM: C E L L T R A N S F O R M A T I O N BY R A D I A T I O N

Cell kill ing in radiation tumorigenesis M.M.Elkind 513

Somatic mutation and cell differentiation in neoplastic transformation E. Huberman and F. R. Collart 519

Mechanisms and modifications of radiation induced neoplastic transformation

J. B. Little 526 In vivo activation o f mouse oncogenes by radiation and chemicals

L . E. Diamond, E. W. Newcomb, L . E. McMorrow, J. Leon, S. Sloan, I . Guerrero and A. Pellicer 532

4.3 Cellular and Molecular Aspects of Mutagenesis (Symposium) LacI sequence changes and the mechanisms of U V mutagenesis in E. coli

C. W. Lawrence, J. E. LeClerc, J. R. Christensen, R. B. Christensen, P. V. Tata and S. K. Banerjee 538

Radiation mutagenesis in bacteria and mammalian cells Thacker 544

New methods o f analysis o f radiation mutagenesis in mammalian cells: Shuttle virus

C. F. M. Menck, M. R. James and A. Sarasin 550 Mechanisms o f gamma ray mutagenesis inferred from changes in

D N A base sequence F. Hutchinson and K. R. Tindall 557

Ionizing radiation induced point mutations in mammalian cells B. W. Glickman, E. A. Drobetsky, J. de Boer and A. J. Grosovsky 562

4.4 Application of Cytofluorimetry Congress Lecture: Chromosome Abnormalities, Transformation and

Reproductive Death in Mammalian Cells Studied wi th Different Radiations and Flow Karyometry

G. W. Barendsen 568 Congress Lecture: Analyt ical cytology applied to detection o f induced

cytogenetic abnormalities /. W. Gray, J. Lucas, T. Straume and D. Pinkel 574

5. R A D I A T I O N E X P O S U R E A N D R I S K 581

5.1 Radiation Exposure Congress Lecture: Recent Reactor Accidents and Their Effects

L . B. Sztanyik 582 Congress Lecture: Revisions in the Dosimetry of the Α - B o m b Survivors

at Hiroshima and Nagasaki and Their Consequences W. K. Sinclair and D. L . Preston 588

Congress Lecture: Radiation Effects in Space R.J. M. Fry 595

SYMPOSIUM: R A D I A T I O N L E V E L S IN T H E E N V I R O N M E N T

Introductory review: Radiation and the Environment H. J. Dunster 601

The radiological impact o f the Chernobyl accident in O E C D member countries

O. llari 608 Radiation in the global environment

A. A. Cigna 614 Lung cancer risk from environmental exposure to radon daughters

W.Jacobi 620 5.2 Radiation Risks and Epidemiology (Symposium)

The status o f the assessment o f radiation risks to humans W.J.Schull 627

Methods and models in the epidemiological assessment o f radiation risks C. E. Land 634

Probability o f causation in radiation injury and its application S. Jablon 640

5.3 Animal Studies and Extrapolation to Man (Symposium) Some aspects of extrapolation o f late effects studies to man

R. H. Mole 646

Consequences of prenatal irradiation in mice: Cancer and C N S damage as a basis for human risks

S. Sasaki 652 The role o f pathology in late effect studies

W. Gossner, A.Luz and A. B. Murray 658 Experimental radiation carcinogenesis

A. C. Upton 664

6. M O D I F I C A T I O N O F R A D I O S E N S I T I V I T Y , I N V I T R O A N D I N V I V O 671

6.1 Sulphydryls and Radiation Response (Symposium) Molecular and cellular aspects o f the role o f thiols in radiation response

B. D. Michael 672 Role o f glutathione and other thiols in cellular response to radiation and drugs

J. E. Biaglow, M. E. Varnes, E. P. Clark and E. R. Epp 677 Radiation response o f human cells genetically deficient in glutathione

M.R.Edgren 683 Interactions o f radioprotectors and oxygen in cultured mammalian cells

K. D. Held 689 6.2 Oxygen and Radiation Responses

SYMPOSIUM: T I S S U E O X Y G E N A T I O N A N D H Y P O X I A

Tissue oxygenation and hypoxia in tumours D. G. Hirst 695

Determinants o f spheroid oxygenation W. Mueller-Klieser 701

Tissue oxygenation o f primary and xeno-transplanted human tumours P. Vaupel and F. Kallinowski 707

New trends in improving oxygen delivery to tumour tissues D. W. Siernann 713

SYMPOSIUM: M A N I P U L A T I O N O F T I S S U E O X Y G E N A T I O N F O R

T H E R A P E U T I C B E N E F I T

Benefit Exploitation o f bioreductive agents wi th vasoactive drugs J.M.Brown 719

Oxygen delivery and tumour response R. P. Hill and D. Stirling 725

Hypoxia-targetted chemotherapy: a role for vasoactive drugs D. J. Chaplin 731

Manipulation o f tumour oxygenation by hydralazine increases the potency o f bioreductive radiosensitizers and enhances the effect of melphalan in experimental tumours

/. /. Stratford, J. Godden, N. Howells, P. Embling and G. E. Adams 737

6.3 Chemical Modification of Radiation Response Congress Lecture: Recent Developments in Combinations o f

Radiotherapy and Chemotherapy M. Tubiana 743

SYMPOSIUM: C H E M I C A L M O D I F I C A T I O N O F R A D I A T I O N R E S P O N S E

The non-hypoxic cell sensitizers: Their use in radiobiology and in radiotherapy

E. P. Malaise 750 Predictive assays for identifying tumours which might benefit from

radiotherapy wi th sensitizers and/or protectors J. D. Chapman, J. H. L . Matthews and R. C. Urtasun 756

Radiosensitization - the clinical position 1987 S. Dische 762

The influence o f thiol modulation on the chemotherapy and radiation response J. B. Mitchell, J. A. Cook and A. Russo 768

7. I N V I V O R A D I O B I O L O G Y A N D R A D I O T H E R A P Y 775

7.1 In Vivo Radiobiology

SYMPOSIUM: N E W D E V E L O P M E N T S IN I N T E R P R E T A T I O N S

O F N O R M A L T I S S U E R E S P O N S E

New developments in interpretations o f normal tissue responses J. H. Hendry 776

Radiosensitivity and kinetics o f target cells in relation to tissue responses —as exemplified by the epidermis and the intestine

C. S. Pot ten 782 The role o f the vasculature in normal tissue responses

J. W. Hopewell 789 The tissue rescuing unit

E. L . Travis 795

SYMPOSIUM: V A S C U L A T U R E - M E D I A T E D A S P E C T S OF T U M O U R

R E S P O N S E

Attacking tumour vasculature J. Denekamp 801

Effectiveness o f interventional radiology K. Jonsson 807

Tumour blood flow response to hyperthermia and pharmacological agents R. K. Jain 813

Angiogenesis and anti-angiogenesis P. Twomey 819

SYMPOSIUM: P R E D I C T I V E A S S A Y S O F H U M A N T U M O U R R E S P O N S E

Predictive assays of human tumour response - Introductory review C. Streffer 825

Prediction o f tumour radiation response from radiosensitivity o f cultured biopsy specimens

L . J. Peters, F. L . Baker, H. Goepfert, Β. H. Campbell, T.A. Rich and W. A. Brock 831

Assessing radiation sensitivity o f human tumour subpopulations by proliferating status, D N A content and monoclonal antibodies

P.C.Keng 837 Measurements o f human tumour cell proliferation in vivo

N. J. McNally and G. D. Wilson 843 7.2 Radiotherapy, Low L E T Radiation

Congress Lecture: Physical Advances in Radiation Therapy M. Goitein 849

Congress Lecture: Biological Advances in Radiation Therapy H. D. Suit 856

Congress Lecture: Ant ibody Directed Radioisotopes and Chemotherapy K. D. Bagshawe 862

Congress Lecture: Dose Per Fraction, Overall Time and Volume Effects in Radiotherapy

H. R. Withers 869

SYMPOSIUM: T O T A L BODY A N D T O T A L L Y M P H O I D I R R A D I A T I O N

Clinical application o f immunological effects o f T L I E. van der Schueren, M. Waer, Y. Vanrenterghem,

M. Vandeputte and P. Michielsen 875 Immune modulating effects o f fractionated total lymphoid irradiation

( T L I ) : Experimental Studies M. Waer, E. van der Schueren and M. Vandeputte 880

Early blood cell kinetics after total body irradiation - Biological and clinical significance

/. Dutreix, Th. Girinski, D. Hubert, G. Socie and J. M. Cosset 885 Total lymphoid irradiation combined with total body irradiation preceding

bone marrow transplantation for chronic myeloid leukaemia N. D. James, J. F. Apperley, K. C. Kam, S. Mackinnon, J. M. Goldman,

A.W.G. Goolden andK. Sikora 891 7.3 Radiotherapy, High L E T Radiation

Congress Lecture: Problems of Neutron Capture Therapy Y. S. Ryabukhin 898

Congress Lecture: A n Update o f Fast Neutron Therapy Results R. D. Errington and Η. M. Warenius 904

SYMPOSIUM: C L I N I C A L R E S U L T S WITH C H A R G E D P A R T I C L E BEAMS

Clinical results o f charged particle radiotherapy J. R. Castro, T. L . Phillips, P. Petti, J. M. Collier, S. D. Henderson,

S. Pit luck and M. Reimers 910 Clinical results o f proton beam radiotherapy in Boston

J. E. Munzenrider, M. Austin-Seymour, E. S. Gragoudas, J. M. Seddon, L . J. Verhey, M. Goitein, R. Gentry, M. Urie, D. Ruotolo, S. Birnbaum, Κ. Johnson, J. M. Sister son, P. McNulty, H. D. Suit and A. M. Koehler 916

Clinical results o f proton radiotherapy in Japan H. Tsunemoto, S. Morita, K. Kawachi, T. Kanai, K. Kawashima,

T. Hiraoka, S. Furukawa, T. Kitagawa and T. Inada 922 Clinical evaluation o f Pimeson radiotherapy at T R I U M F

G. B. Goodman, R. Harrison, R. O. Kornelsen, G. Κ. Y. Lam C. Ludgate, L . D. Skarsgard and F. J. Vernimmen 928

7.4 Diagnosis Congress Lecture: Magnetic Resonance Measurements o f Physiological

and Metabolic Factors G. K. Radda 934

8. H Y P E R T H E R M I A 941

SYMPOSIUM: H Y P E R T H E R M I A : C L I N I C A L , P H Y S I C A L , /./V VITRO

A N D A N I M A L

Clinical hyperthermia - an update J. Overgaard 942

Physical and engineering aspects o f hyperthermia R.B.Roemer 948

Hyperthermic effects studied in vitro W. C. Dewey 954

Hyperthermia in animals S. B. Field and S. P. Hume 960

9. S U B J E C T I N D E X 967

10. A U T H O R I N D E X 981

M I C R O D O S I M E T R Y

R e c e n t T r e n d s a n d A p p l i c a t i o n s t o R a d i a t i o n B i o l o g y

a n d R a d i a t i o n C h e m i s t r y

A . M . K e l l e r e r I n s t i t u t für Med. S t r a h l e n k u n d e , U n i v e r s i t y o f Würzburg

1. H i s t o r i c a l N o t e

A quarter of a century ago microdosimetry had j u s t been con­ceived by Harald H.Rossi and h i s colleagues (1,2), but i t was s t i l l unnamed, and 1962, a t the Second I n t e r n a t i o n a l Congress of Radiation Research - the f i r s t i n t h i s country - a sympo­sium could w e l l have been devoted to 'Stochastic Dosimetry and i t s A p plications'. The top i c would have been appropriate and the designation might have been equally f i t t i n g , s i n c e Otto Hug had noted, a t about the same time, that the Greek word 'stochazein' had the two meanings of ' h i t t i n g a target' and 'making a guess' (3,4), two processes c e n t r a l to target theory and r a d i a t i o n biology (5,6,7).

That the d i f f e r e n t term 'microdosimetry' was chosen for the new branch of science, may not have been e n t i r e l y the i n t e n t i o n of i t s inventor. However i t gave due regard to the remarkable f a c t that a c t u a l energy concentrations could henceforward be mea­sured i n microscopic regions which correspond to c e l l u l a r or s u b c e l l u l a r domains. Experimental microdosimetry developed ex­p l o s i v e l y i n these l a s t twenty-five y e a r s . I t was recognized that s t o c h a s t i c q u a n t i t i e s can be more r e a l and more rele v a n t to r a d i a t i o n biophysics than t h e i r more t r a c t a b l e and more r e a d i l y understood mean values. S u r p r i s i n g as i t may have been at f i r s t , the ICRU has even ranked the s t o c h a s t i c microdosime-t r i c v a r i a b l e s among the fundamental r a d i a t i o n q u a n t i t i e s ( 8 ) .

I n the pragmatic a p p l i c a t i o n s to r a d i a t i o n protection and to the c l i n i c a l uses of i o n i z i n g r a d i a t i o n s , microdosimetric con­cepts and techniques have found a number of important and l a s t i n g a p p l i c a t i o n s . Many of these a p p l i c a t i o n s are unspecta­c u l a r , because they are n a t u r a l . When i t i s proposed by a

338

Microdosimetry - recent trends 339

l i a i s o n committee of ICRP and ICRU that the q u a l i t y f a c t o r i n r a d i a t i o n p r o t e c t i o n be l i n k e d to l i n e a l energy, r a t h e r than LET, (9) no fundamental change from present p r a c t i c e s i s i n t r o ­duced. I n f a c t i t i s merely suggested that measured q u a n t i t i e s - often i n unknown r a d i a t i o n f i e l d s - need not be a r t i f i c i a l l y c o r rected to transform a c t u a l energy concentrations i n t o values of a more a b s t r a c t parameter. But t h i s i n t e r p r e t a t i o n does not mean th a t LET can not serve u s e f u l purposes; i n f a c t i t can be shown that LET and l i n e a l energy are interchangeable under c e r t a i n conditions (10,11). S i m i l a r l y , i n medical p h y s i c s mi-crodosimetric measurements have become e s s e n t i a l and even rou­t i n e , because they are the most d i r e c t way to c h a r a c t e r i z e the properties of the r a d i a t i o n f i e l d a t d i f f e r e n t l o c a t i o n s i n a beam.

Microdosimetry may have been l e s s s u c c e s s f u l where the aims and expectations were f a r more ambitious. To understand the reason fo r such f a i l u r e , or seeming f a i l u r e , may be c r u c i a l f o r the future development not only of microdosimetry, but of r a d i a t i o n biology i n general.

I t i s , therefore, important to consider the e s t a b l i s h e d uses of microdosimetrie data i n r a d i a t i o n biology ( s e c t i o n 2) , but equally the more t e n t a t i v e a p p l i c a t i o n s towards the e l u c i d a t i o n of molecular mechanisms of r a d i a t i o n a c t i o n ( s e c t i o n 3) .

2 . E s t a b l i s h e d Uses o f M i c r o d o s i m e t r y

One of the simplest uses of microdosimetry has proved to be p a r t i c u l a r l y important. I o n i z i n g r a d i a t i o n s impart energy to matter i n f i n i t e portions, and on the s c a l e of the c e l l and of s u b c e l l u l a r s t r u c t u r e s these portions can be very s u b s t a n t i a l . At doses r e l e v a n t to r a d i a t i o n protection one deals frequently with a s i t u a t i o n , where most c e l l s or c e l l n u c l e i r e c e i v e no energy a t a l l , while few c e l l s which are traversed by a charged p a r t i c l e r e c e i v e d i s p r o p o r t i o n a l l y large amounts of energy. The q u a l i t y of the r a d i a t i o n , not the dose, determines then the f a t e of the a f f e c t e d c e l l s ; dose determines merely t h e i r number. Whether t h i s condition p r e v a i l s , can be a s c e r t a i n e d on the b a s i c of microdosimetric data. I f i t p r e v a i l s , any dose-e f f e c t r e l a t i o n f o r c e l l u l a r e f f e c t s must be l i n e a r , a con­c l u s i o n fundamental to r i s k assessment, and even a h i g h l y p o l i t i c a l i s s u e i n the past year. The dependences can be non­l i n e a r , i f the f a t e of the c e l l i s co-determined by energy deposition i n the cytoplasm, by energy deposition i n adjacent

MO A.M. K e l l e r e r

c e l l s , or, f i n a l l y , by r e a c t i o n s of the i r r a d i a t e d t i s s u e . Whether a c t i o n on 'autonomous' c e l l s - to use a phrase coined by Harald R o s s i (12) - can be assumed or an e x t r a c e l l u l a r e f f e c t of the exposure needs to be taken i n t o account, i s to be judged on the b a s i s of microdosimetric data.

I n experiments on the induction of mammary tumours i n r a t s by 430 keV neutrons (13,14), which were thoroughly randomized stu d i e s , a dose dependence with negative curvature i n the region of 1 to 16 mGy was found. T h i s implied that the e f f e c t can not be merely a matter of inducing i n d i v i d u a l c e l l s which then have a small dose independent p r o b a b i l i t y to cause a neoplasm. Microdosimetric data have i d e n t i f i e d the problem; tumour biology has not y e t provided the answer.

S i m i l a r microdosimetric considerations have been important with the f i n d i n g by H i l l , Han, and E l k i n d of a s t r i k i n g reversed dose-rate efSect for the transformation of mammalian c e l l s by small doses of neutrons (15). I t has been suggested that such a dose-rate e f f e c t i s incompatible with the paucity of multiple events i n the c e l l nucleus. Measured nuclear areas and microdo­s i m e t r i c data f o r event frequencies have then shown that event frequencies are indeed higher (16) than o r i g i n a l believed, and that the e f f e c t might therefore be due to the induction of a r e p a i r system by one p a r t i c l e and i t s influence on a subsequent event. The molecular mechanisms remain unresolved, and i t i s puzzling why an analogous e f f e c t i s not seen i n the same c e l l system when i t i s exposed to α-particles (17). Even with a-p a r t i c l e s there are s t i l l s u f f i c i e n t events that a dose-rate e f f e c t , on the b a s i s of c e l l u l a r mechanisms, i s conceivable at a dose of 100 mGy.

A r e l a t e d example are the astonishing r e s u l t s by Wolff and h i s colleagues (18,19), that human lymphocytes are s u b s t a n t i a l l y l e s s s e n s i t i v e to i o n i z i n g r a d i a t i o n s many hours a f t e r being exposed to the t i n y dose of only 10 or even 5 mGy of gamma-rays. At t h i s dose the mean number of charged p a r t i c l e s i n the c e l l nucleus i s c l o s e to unity and i t w i l l , therefore, be of p a r t i c u l a r i n t e r e s t to seek analogous e f f e c t s with densely i o n i z i n g r a d i a t i o n s , and to assess the observations i n terms of microdosimetric information on event frequencies i n the nucleus or the cytoplasm.

Event frequencies i n c e l l u l a r or s u b c e l l u l a r domains are im­portant parameters. However, microdosimetry provides the f u l l spectrum of events i n a s i t e . Various attempts have been made to u t i l i z e t h i s information, and the d i v e r s i t y of approaches precludes t h e i r d e t a i l e d consideration. I n a c e r t a i n over-

Microdosimetry - recent trends 341

g e n e r a l i z a t i o n , one may s t a t e that such attempts have f a i l e d , or are bound to f a i l , when they aim at c o r r e l a t i n g the r e a c t i o n of the c e l l with ' c e l l dose' - presumably the s p e c i f i c energy i n some subregion of the nucleus. One knows too l i t t l e about the d i s t r i b u t i o n of the s e n s i t i v e DNA or DNA-membrane s t r u c t u r e s to make r e a l i s t i c models, but one knows that the d i s t r i b u t i o n throughout the nucleus, and the d i s t r i b u t i o n on the micrometer to the nanometer s c a l e needs to be taken i n t o account. The c e l l has no uniform g r o s s - s e n s i t i v e volume, nor does i t c a r r y one or a few s p h e r i c a l or c y l i n d r i c a l t a r g e t s .

I n a f u r t h e r s l i g h t overstatement one may say that microdosi-metric arguments can merely exclude c e r t a i n assumptions and thereby narrow down the range of p o s s i b l e models. But t h i s negative function can be e s s e n t i a l . Even wrong models - and every model i s u l t i m a t e l y wrong - can serve a u s e f u l purpose, i f they have s u f f i c i e n t l y few parameters to be f a l s i f i a b l e . Dual a c t i o n i n i t s o r i g i n a l formulation (20) was the postulate of a second order process dependent on the square of energy concentrations measured over regions of the order of a microme­t e r . I t was a wrong model with a minimum of free parameters, and i t did permit f a l s i f i c a t i o n through s e v e r a l i n t r i g u i n g experiments (21,22). I n being p a r t l y disproved, i t l e d to modified analyses which are l e s s f a l s i f i a b l e , but may s t i l l be u s e f u l . They are c l o s e l y linked to more recent trends of micro­dosimetry.

3 . R e c e n t T r e n d s

Continued e f f o r t s have been made i n microdosimetry to extend the measurements to submicroscopic regions of l e s s than 50 nm or even to molecular dimensions. None of these e f f o r t s have been s u c c e s s f u l . However, a great change has been brought about by the advance of computational methods to simulate charged p a r t i c l e t r a c k s (23) . Some of the information may s t i l l be t e n t a t i v e and cross s e c t i o n s often p e r t a i n to gasses r a t h e r than condensed media. However, the remaining u n c e r t a i n t i e s may be of minor importance, si n c e microdosimetric information i s mainly used to compare the e f f e c t s of d i f f e r e n t types of i o n ­i z i n g r a d i a t i o n s and to c o r r e l a t e them with c h a r a c t e r i s t i c d i f f e r e n c e s i n the patterns of energy deposition; such d i f f e r ­ences depend l i t t l e on the s u b t i l i t i e s of track s t r u c t u r e .

342 A.M. K e l l e r e r

While there i s adequate physics information, there i s a l s o a curious imbalance i n pragmatic a p p l i c a t i o n s . I n r a d i a t i o n che­mistry i t i s s t i l l common to quantify energy concentrations i n terms of 'blobs' and 'spurs', while microdosimetric functions show that one deals with a continuum of energy d e n s i t i e s , not with d i s t i n c t c l a s s e s of events. Developments towards a more qu a n t i t a t i v e d e s c r i p t i o n (24) show that more use needs to be made of mathematical functions that describe the s p a t i a l cor­r e l a t i o n of energy t r a n s f e r s i n charged p a r t i c l e t r a c k s .

I n the much l e s s q u a n t i t i v e s t u d i e s of radiobiology there i s a strangely reversed s i t u a t i o n . I t i s not uncommon that exact information from simulated t r a c k s i s applied to models which invoke thresholds of energy f o r the r e a c t i o n of assumed spheres or c y l i n d e r s - or p a i r s of such c o n s t r u c t s . The exactitude of the p h y s i c a l d e s c r i p t i o n i s then i n marked contrast to the uncertainty of the r a d i o b i o l o g i c a l assumptions.

The use of r e l a t i v e l y crude t o o l s i n the more exact i n v e s t i g a ­t i o n s , and the a p p l i c a t i o n of p r e c i s e data to the more q u a l i ­t a t i v e s t u d i e s may r e f l e c t the unavoidable imbalance of a developing f i e l d of study, but i t i n d i c a t e s the need for more systematic and concise a p p l i c a t i o n s of microdosimetric data. Few steps have yet been done i n the d i r e c t i o n of a mathematical theory of the random patterns of energy deposition. But c e r t a i n notions, such as the d i s t r i b u t i o n s of nearest neighbours among the energy t r a n s f e r s i n charged p a r t i c e t r a c k s (23,25), are c l o s e l y r e l a t e d to d i s t r i b u t i o n s and parameters f a m i l i a r i n the s t o c h a s t i c geometry of point s e t s (see e.g. ( 2 6 ) ) . Of even broader a p p l i c a b i l i t y i s the proximity function. I t i s linked to M.J.Berger's concept of the geometric reduction f a c t o r and i t has been u t i l i z e d i n a general formulation of dual action that accounts for the steep s p a t i a l gradient of the i n t e r a c t i o n p r o b a b i l i t i e s between l e s i o n s i n the c e l l (27). The function i s l a r g e l y equivalent to the s p a t i a l a u t o - c o r r e l a t i o n function which has wide a p p l i c a t i o n i n the a n a l y s i s of any random pro­cess and s p a t i a l or temporal pat t e r n ; i t a l s o equals the point-p a i r distance d e n s i t y of a s t r u c t u r e times i t s content. In s t o c h a s t i c geometry, the mathematical theory of random s e t s , a corresponding quantity i s c a l l e d covariance of a point process. I t i s of considerable i n t e r e s t t h a t notions evolved i n microdo­simetry are c l o s e l y p a r a l l e l to a v a r i e t y of concepts i n other f i e l d s .

A fundamental r e l a t i o n i n microdosimetry (see e.g. (28)) shows that the y i e l d of a second order process i s a simple i n t e g r a l over the proximity function of a r a d i a t i o n and the correspond­ing function that c h a r a c t e r i z e s the i r r a d i a t e d s t r u c t u r e or

Microdosimetry - recent trends 343

s u b s t r a t e . T h i s dependence and a modified formula apply to such d i v e r s e mechanisms, as the r e a c t i o n of two free r a d i c a l s , the combination of two adjacent DNA breaks i n misrepair, or the f a r more complex process of the f u s i o n of two chromosome breaks. The same theorem app l i e s to a l l problems that a r i s e when a r b i ­t r a r y s t r u c t u r e s are randomly superimposed (29). The r e l a t i o n expresses the weighted average (and a l s o the second moment) of the i n t e r s e c t i o n , u, of two bodies Τ and S (of contents V T and V s) under uniform i s o t r o p i c randomness i n terms of the point-p a i r d i s t a n c e d i s t r i b u t i o n s Pp(x) and p s ( x ) of the two bodies:

p s ( x ) p T ( x )

This fundamental r e l a t i o n , and s i m i l a r r e s u l t s and t h e i r i m p l i ­cations can not be elaborated i n t h i s b r i e f d i s c u s s i o n . But t h e i r existence needs to be noted, i f uses of microdosimetry are sought which go beyond a merely d e s c r i p t i v e c o r r e l a t i o n between the patterns of energy deposition and the varying degrees of e f f e c t i v e n e s s of d i f f e r e n t i o n i z i n g r a d i a t i o n s . Methods and concepts of s t o c h a s t i c geometry are bound to deter­mine the f u r t h e r development of microdosimetry and i t s u t i l i z a ­t i o n i n r a d i o b i o l o g i c a l or radiochemical s t u d i e s .

R e f e r e n c e s

1) R o s s i , H.H., Radiat. Research, 10, 522-531, 1959. 2) R o s s i , H.H., Radiat. Research, Suppl. 2, 290-299, I960. 3) K e l l e r e r , A.M., Hug, 0., Biophysik 1, 33-50, 1963. 4) Hug, 0., K e l l e r e r , A.M., Stoc h a s t i k der Strahlenwirkung,

Springer Verlag, Berlin-Heidelberg-New York, 1966. 5) Dessauer, F., Quantenbiologie, Springer, 1964. 6) Timofeeff-Ressowsky, N.V., Ivanov, V . l . , Korogodin, V.J.,

Die Anwendung des T r e f f e r p r i n z i p s i n der Strahlenbiologie, F i s c h e r , Jena, 1972.

7) Lea, D.E., Actions of Radiations on L i v i n g C e l l s , Cambridge U n i v e r s i t y Press, London, 2nd ed., 1955.

8) ICRU, Report 33, Radiation Q u a n t i t i e s and Units, 1980.

u z / u = V T V S

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ICRU, Report 40, The Quality Factor i n Radiation Protection, 1986. Blohm, R., Harder, D., Rad.Prot.Dosimetry 13, 377-381, 1985. K e l l e r e r , A.M., Hahn, Κ., Considerations on a Revision of the Quality Factor, submitted f o r p u b l i c a t i o n , 1987. Rossi, H.H., K e l l e r e r , A.M., B i o p h y s i c a l Aspects of Radi­ation Carcinogenesis, Cancer 1, 2nd ed., 569-616, 1982. Shellabarger, C.J., Chmelevsky, D., K e l l e r e r , A.M., J.Nat. Cancer I n s t . 64, 821-833, 1980. Shellabarger, C.J., Chmelevsky, D., K e l l e r e r , A.M., Stone, J.P., Holtzman, S., J.Nat. Cancer I n s t . 69, 1135-1146, 1982. H i l l , C.K., Han, Α., E l k i n d , M.M., I n t . J . Radiat. B i o l . 46, 11-15, 1984. Rossi, H.H., K e l l e r e r , A.M., I n t . J . Radiat. B i o l . 50, 353-361, 1986. Hieber, L., Ponsel, G., Roos, Η., Fenn, S., Fromke, E., K e l l e r e r , A.M., Absence of a Dose-Rate E f f e c t i n the Trans­formation of C3H 10T1/2 C e l l s by α-Particles, I n t . Journal Radiat. B i o l , to appear. Shadley, J.D., Wolff, S., Mutagenesis 2, 95-96, 1987. Wolff, S., A f z a l , V., Wiencke, J.K., O l i v i e r i , G., Michaeli, Α., I n t . J . of Radiat. B i o l . , 1987. K e l l e r e r , A.M., Rossi, H.H., Current Topics i n Radiation Research Quarterly, 8, 85-158, 1978. Rossi, H.H., B i r d , R., Colvett, R.D., K e l l e r e r , A.M., Rohrig, H., Lam, Y.-M.P., Proc. 6th Symp. on Microdosimetry 2, 937-947, Harwood, London, 1978. Goodhead, D.T., Thacker, J . , Cox, R., Proc. 6th Symposium on Microdosimetry 2, 829-843, Harwood, London, 1978. Paretzke, H.G., Radiation Track Structure Theory, I n : Kine­t i c s of Nonhomogeneous Processes, Ed. by Gordon R. Freeman, John Wiley & Sons, 89-170, 1986. Maggee, J.L., Chatterjee, Α., Track Reactions of Radiation Chemistry, I n : K i n e t i c s of Nonhomogeneous Processes, John Wiley & Sons, 171-214, 1986. Berger, M.J., Proc. 7th Symp. of Microdosimetry 1, 521-531, EUR 7147 d-e-f, Harwood, London, 1981. Stoyan, D., Kendall, W.S., Mecke, J . , S t o c h a s t i c Geometry and I t s Applications, John Wiley & Sons, 1987. K e l l e r e r , A.M., Rossi, H.H., Rad. Res. 75, 471-488, 1978. K e l l e r e r , A.M., Models of C e l l u l a r Radiation Action, I n : K i n e t i c s of Nonhomogeneous Processes, John Wiley & Sons, 305-375, 1986.

29) K e l l e r e r , A.M., J.Appl.Prob. 23, 307-321, 1986.