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OFFICIAL ORGAN OF THE RADIATION RESEARCH SOCIETY
RADIATION RESEARCH
MANAGING EDITOR: ODDVAR F. NYGAARD
Volume 55, 1973
Academic Press • New York and London A Subsidiary of Harcourt Brace Jovanovich, Publishers
Copyright © 1973 by A C A D E M I C PHKSS, I N C .
A L L R I G H T S R E S E R V E ! )
A r o part of this publication may be reproduced or transmitted i n any f o r m , or by any ?neans, electronic or mechanical, i n c l u d i n g photocopy, recording, or any I n f o r m a t i o n storage and r e t r i e v a l system, w i t h -oid permission i n w r i t i n q f r o m the Copyright owner.
Made in the United States of America
RADIATION RESEARCH
OFF1CIAL ORGAN OF THE RADIATION RESEARCH SOCIETY
BOARD OF EDITORS
M a n n g i n g Editor: O D D V A R F. N Y G A A R D , Department of Radiology, Gase Western Reserve University, Cleveland, Ohio 44106
J. G. C A R L S O N , University of Tennessee
R. A. C O N A R I ) , Brookhaven National Laboratory
C. C. C O N G D O N , Oak Ridge National Laboratory
S. B. C U R T T S , University of California
E . R. E P P , Sloan-Kettering Institute for Cancer Research
T . M . F L I E D N E R , Universi tät Ulm, Germany
J . A. G H O R M L E Y , Oak Ridge National Laboratory
M . L . G R I E M , University of Chicago
R. H . H A Y N E S , York University, Canada
R. F. K A L L M A N , Stanford University
A. M . K E L L E R E R , Columbia University
G . J . K O L L M A N N , Albert Einstein Medical Center
P. RIESZ, National Institutes of Health
G . SILINI, Centro di Studi Nucleari della Cassaccia, Roma, Italy
W. C. SNIPES, Pennsylvania State University
J . K . T H O M A S , University of Notre Dame
J. F . T H O M S O N , Argonne National Laboratory
H . R. W I T H E R S , M . D . Anderson Hospital
G. M . W O O D W E L L , Brookhaven National Laboratory
J . M . Y U H A S , Oak Ridge National Laboratory
OFFICERS Ö F TUE SOCIETY
President: V I C T O R P. B O N D , Brookhaven National Laboratory, Upton, Long Island, New York 11937
V i c e President (and President Elect): H A R A L D H . ROSSI, Columbia University, New York, New York 10032
Secretary-Treasurer: M A X R. Z E L L E , Dept. Rad. and Rad. Biol., Colorado State University, Fort Colli ns, Colorado 80521
M a n a g i n g Editor: O D D V A R F . N Y G A A R D , Gase Western Reserve University, Cleveland, Ohio 44106
Executive Secretary: R I C H A R D J . B U R K , JR. 4211 39th Street, N.W., Washington, D. C . 20016
A N N U A L MEETINGS
1974: July 13-20, Fifth International Congress of Radiation Research, Seattle, Washington
1975: May 11-15, Miami Beach, Florida
V O L U M E 55, 1973
Councilors Radiation Research Society 1973-1974
P H Y S I C S
R. J . Shalek, University of Texas S. B . Curtis, University of California at Berkeley
BlOLOGY
R. F . Kal lman, Stanford University G. W. Casarett, University of Rochester
M E D I C I N E
C . C . Lushbaugh, Oak Ridge Associated Universities J . I. Fabrikant, University of Connecticut
C H E M I S T R Y
Jack Schubert, University of Pittsburgh W. M . Garrison, University of California at Berkeley
A T - L A R G E
H . I. Adler, Oak Ridge National Laboratory A . P . Casarett, Cornell University
RADIATION R E S E A R C H 55, V - V Ü (1973)
CONTENTS OF VOLUME 55 NüMBER 1, JüLY 1973
B . E . L E O N A R D A N D J O H N W . B O R I N G . T h e Average Energy per I o n P a i r , W, for Hydrogen and Oxygen I o n s i n a Tissue E q u i v a l e n l Gas 1
T Z U - L I N T U N G A N D R O B E R T R . K U N T Z . T h e Reactions of Hydrogen Atoms i n Aqueous Solutions: T h i o l s 10
J . G I T S A N D G . B . G E R B E R . Electrolyte Loss, the M a i n Cause of D e a t h f r o m the Gastro-intestinal Syndrorne? 18
J A M E S M . P A R R Y AND E L I Z A B E T H M . P A R R Y . Allclic Interaction at the rad 1 Locus in
D i p l o i d Cultures of U V - I r r a d i a t e d Yeast 29 W A R R E N K . SINCLAIR. N - E l h y l m a l e i m i d e and the Cyclic Response to X - R a y s of Synchronous
Chinese Hamster Cells 41 S H I R L E Y H O R N S E Y . T h e Effectiveness of F a s t Neutrons Compared with Low L E T R a d i a t i o n
on C e l l S u r v i v a l Measured i n the Mouse J e j u n u m 58 N O R M A N N . L I C H T I N , J E C H I E L O G D A N , AND G A B R I E L S T E I N . Fast Inlramolecular Radical
Processes i n Reactions of Aqueous Solutions of Ribonuclease-S-Peptide and Ribonuclease-S - P r o l e i n W i t h H Atoms 69
M . D O M O N A N D A . M . R A U T H . C e l l Cycle Specific Recovery f r o m F r a c l i o n a t e d Exposures of U l t r a v i o l e l L i g h t 81
P A U L T O D D . F r a c l i o n a t e d U l t r a v i o l e l L i g h t I r r a d i a t i o n of C u l l u r e d Chinese Hamster Cells 93 T H O M A S J . D O U G H E R T Y . T r a n s a n n u l a r Peroxides as R a d i a l i o n Sensitizers 101 J . L . R E D P A T H . Radioproteclion of Enzyme and B a c l e r i a l Systems by D i t h i o t h r e i t o l 109 W A T A R U N A K A M U R A . Effect of Thrombocyte-Rich Plasma on X - R a y I n d u c e d Bone M a r r o w
D e a t h i n M i c e 118 N O R M A N C O H E N A N D M C D O N A L D E . W R K N N . Metabolie Characteristics of m A m in the
A d u l t Baboon 129 D . W . B A X T E R , M . W . R O S E N T H A L , AND A . L I N D E B A U M . Decorporation of Monomeric
P l u t o n i u m f r o m the D o g by G l u c a n and/or D T P A 144 S T A N L E Y R . N E L S O N . Effects of M i c r o w a v e I r r a d i a t i o n of Enzymes and Metabolites i n Mouse
B r a i n 153 I. M A L X T O V Ä , V . D V O R A K , AND L . P I F F L O V Ä . Assessmcnl of l h e 2 2 0 R n F r a c t i o n Retainedin
M i c e after a Single I n j e c t i o n of m R a 160 J O H N H . D A U G H E R T Y A N D C H A R L Y S 1). B A U M E S . Sites of R a d i a t i o n Scnsivility i n the V i s u a l
System as Assessed by D o u b l e L i g h t F a s h 169 F . W E N D L I N G , P . J U L L I E N , AND P . T A M B O U R I N . Hematopoietic C F A i n M i c e I n f e c t e d by the
Polycythemia-inducing F r i e n d V i r u s . I L S u r v i v a l of Lethally I n a d i a l e d M i c e G r a f t e d with Spleen or Bone M a r r o w Cells f r o m I n f e c t e d Donors 177
W . F . W A R D , R . K . M E Y E R , AND R . C . W O L F . D N A Synlhesis i n R a t Blastocycts X - I r r a d i -ated Düring Delayed I m p l a n a l i o n 189
C O R R E S P O N D E N C E
P . M . M C I L V A I N E , G . L E N G Y E L , AND V . H . H U T C H I S O N . Infrared-Induced Thermo-
electric Potentials i n E x t r a c e l l u l a r Recording Electrodes 197
A N N O U N C E M E N T 202
N U M B E R 2, A U G U S T 1973
M . ISAACSON, D . J O H N S O N , AND A . V . C R E W E . E l e c t r o n Beam E x c i t a l i o n and D a m a g e of B i o l o g i c a l Molecules; I i s I m p l i c a t i o n s for Specimen D a m a g e i n E l e c t r o n Microscopy 205
v
v i C O N T E N T S O F V O L U M E 55
E I N A U S A G S T U E N . E S R a n d I N D O - M O Sludics of R a d i c a l s a n d R a d i c a l Reactions i n I r r a d i a t e d S i n g l e Cryslals of 5 - N i t r o - G - M e t h y l u r a c i l 225
R . W . M A T T H E W S . Effect of Solide C o n c e n l r a t i o n a n d T e m p e r a t u r c on the C e r i c - C e r o u s Dosimeter 242
T Z Ü - L I N T Ü N G A N D R O B E R T R . K U N T Z . H y d r a t e d E l e c t r o n Reactions w i t h T h i o l s i n A c i d i c Aqueous Solutions 2 5 6
E R N E S T C . P O L L A R D AND E L K A N O R P . R A N D A L L . Sludics on the Inducible Inhibitor of
R a d i a t i o n - I nduced D N A D e g r a d a t i o n of Escherichia coli 265 C K O K G K M . H A H N , M A L C O L M A . B A G S H A W , RICHARD G . » A N S , AND L O U I S E F . G O K D O N .
R e p a i r of P o t e n t i a l l y L e l h a l Lesions i n X - I r r a d i a t e d , D e n s i t y - 1 n h i b i l e d Chinese H a m s t e r C e l l s : M e t a b o l i e Effects a n d H y p o x i a 280
A . B E C C I O L I N I , P . C A S T A G N O L I , L . A R G A N I N I , AND G . D E G I U L L Post-Irradiation Enzyme
Aclivüies of R a t S m a l l I n t e s t i n e : Effects of Dose F r a c l i o n a i i o n 291 A . F E R E N C Z , E . J . H I D V E G I , L . D . SZABÖ, AND V. V Ä U T E K E S Z . The Effect of Whole-Body
X - I r r a d i a t i o n of G u i n e a Pigs on the L i v e r Ribonuclease a n d R i b o n u c l e a s e - I n h i b i l o r System 304 Y U T A K A O K U M U R A , T O S H I T E H U M O R I T A , AND T A I J U M A T S U Z A W A . The Effects of Tempera
tur-e on the D y i n g Process of L e t h a l l y I r r a d i a t e d C u l l u r e d M o u s e M a m m a r y C a r c i n o m a Cells 3 1 8
A H M E D E L - M E T A I N Y , SHIGEMITSU T A N O , K E I J I Y A N O , AND H I K O Y U K I Y A M A G U C H I . Chemi
c a l N a t u r e of R a d i a t i o n - I nduced S i n g l e - S t r a n d B r e a k s i n the D N A of D o r m a n t B a r l e y Seeds in Vivo 324
C H R I S T O P H E R D . T O W N , K E N D R I C C . SMITH, AND H E N R Y S. K A P L A N . The Repair of DNA
fc{J^ S i n g l e - S t r a n d B r e a k s i n E . coli K-12 X - I r r a d i a t e d i n the Presence or Absence of O x y g e n ; fett the I n f l u e n c e of R e p a i r on C e l l S u r v i v a l 334
E M M A N U E L V A N D E R S C H U E R K N , K K N D R I C C . SMITH, A N D H E N R Y S. K A P L A N . Modification
of D N A R e p a i r a n d S u r v i v a l of X - I r r a d i a t e d pol, rec, a n d exr M u l a n t s of Escherichia coli K-12 by 2 , 4 - D i n i t r o p h e n o l 346
G U N N A R S A X E B 0 L , T H O R B . M E L 0 , AND T H O U M O D H K N U I K S E N . E l e c t r o n S p i n Resonance Studies of E l e c t r o n I n a d i a l e d Peptides. A S i n g l e C r y s l a l of N - A c e l y l g l y c i n e a t 7 7 K 356
R A Y M O N D P A G E A U . Effects of I r r a d i a t i o n Schcdules on a M u r i n e E p e n d y m o m a 3 6 9 T A K A S H I A O Y A M A A N D S H U N Z O O K A J I M A . E a r l y M o r p h o l o g i c a l Changes i n the C o r t i c a l a n d
M e d u l l a r y Thijmocytes of the R a t afler W h o l e - B o d y I r r a d i a t i o n . I L Q u a n t i t a t i v e I n v e s t i g a l i o n 3 7 9
C O R R E S P O N D E N C E
Luis F E L I P E F A J A R D O AND J . M A R T I N B R O W N . C a r d i a c M u r a l T h r o m b i Caused by R a d i a l i o n 387
O b i l u a r y f o r B e r n a r d S m a l l e r 3 9 0
N U M B E R 3, S E P T E M B E R 1973
H A Y A Z E M E L A N D P . N E T A . T h e M e c h a n i s m of O x i d a l i v e D e n i l r a t i o n of ö-Nitrouracil a n d b ~ - N i l r o - 2 - F u r o i c A c i d by H y d r o x y l R a d i c a l s 393
R . D . P H E M I S T E R , R . W . T H O M A S S E N , R . W . N O R R D I N AND R . S. J A E N K E . Renal Failure
i n P e r i n a l a l l y I r r a d i a t e d Beagles 399 I Z H A K J . P A U L A N D A R T H U R M . Z I M M E R M A N . M a c r o m o l e c u l a r Synthesis a n d C e l l D i v i s i o n
i n X - I r r a d i a t e d Tetrahymena 411 E R I C J . H A L L A N D A L B R E C H T M . K E L L E R E R . T h e B i o p h y s i c a l Properties of 3 . 9 - G e V N i t r o g e n
I o n s . I I I . O E R a n d R B E D e t e r m i n a l i o n s U s i n g Vicia Seedlings 422 E R I C J . H A L L A N D S H I R L E Y L E H N E R T . T h e B i o p h y s i c a l Properties of 3 . 9 - G e V N i t r o g e n I o n s .
I V . O E R a n d R B E D e t e r m i n a l i o n s U s i n g C u l l u r e d M a m m a l i a n Cells 431 A T G . U N D E R B R I N K , L . A . SCHAIRER, AND A . H . SPARROW. The Biophysical Properties
of 3 . 9 - G e V N i t r o g e n I o n s . V, D e t e r m i n a l i o n s of the R e l a t i v e B i o l o g i c a l Effectiveness f o r S o m a l i c M u l a t i o n s i n Tradescantia 437
C O N T E N T S O F V O L U M E 55 v i i
A L B R E C H T M . K E L L E R E R AND H A R A L D H . ROSSI. The Biophysical Properlies of 8.9-GeV
I o n s . V I . I n t e r p r e t a t i o n of Results 447 D . C . S W A R T Z E N D R U B E R AND K A R L F . H Ü B N E R . Effect of E x t e r n a l Whole-Body X - I r r a d i -
ation on G a l l i u m - 6 7 Retenlion i n Mouse Tissues 457 B . I V A N O V , A . L E O N A R D , AND G H . D E K N U D T . Blood Storage and the Rate of Chtomosome
Aberrations After i n Vitro Exposure to I o n i z i n g Radiations 469 IAN T A N N O C K AND A N T H O N Y H O W E S . T h e Response of V i a b l e T u m o r Cords lo a Single Dose
of R a d i a t i o n 477 C L A R E N C E E . S T Y R O N AND G L A D Y S J . D O D S O N . Responses of a Grassland Arthropod C o m
munity to Simulated Radioactive F a l l o u t 487 C O R R E S P O N D E N C E
E L I A N U N E S D E L A N G G U T H AND C A R L A . B E A M . T h e Effects of Ploidy lipon C e l l Cycle Dependent Changes i n X - R a y Sensitivity of Saccharomyces cerevisiae 501
Abstracls of T w e n t y - f i r s l A n n u a l M e e t i n g of the R a d i a t i o n Research Society, St. Louis, M i s souri, A p r i l 2 9 - M a y 3, 1 9 7 3 507
A N N O U N C E M E N T S 607
A U T H O R I N D E X 610
Subject Index for Volume 55 will appear in the December issue as part of a cumulative index for the year 1973.
RADIATION RESEARCH
OFFICIAL ORGAN OF THE RADIATION RESEARCH SOCIETY
BOARD OF EDITORS
M a n a g i n g Editor: O D D V A R F. N Y G A A R D , Department of Racliology, Case Western Reserve University, Cleveland, Ohio 44106
J. G . C A R L S O N , University of Tennessee
R. A. C O N A R D , Brookhaven National Laboratory
C. C . C O N G D O N , Oak Ridge National Laboratory
S. B. C U R T I S , University of California
E . R. E P P , Sloan-Kettering Institute for Cancer Research
Univers i tät Ulm, T. M . F L I E D N E R , Gennany
J. A . G H O R M L E Y , Oak Ridge National Laboratory
M . L . G R I E M , University of Chicago
R. H . H A Y N E 8 , York University, Canada
R. F . K A L L M A N , Stanford University
A. M . K E L L E R E R , Columbia University
G . J . K O L L M A N N , Albert Einstein Medical Center
P. RIESZ, National Institutes of Health
G . SILINI, Centro di Studi Nucleari della Cassaccia, Roma, Italy
W. C . SNIPES, Pennsylvania State University
J . K . T H O M A S , University of Notre Dame
J . F . T H O M S O N , Argonne National Laboratory
H . R. W I T H E R S , M . D . Anderson Hospital
G . M . W O O D W E L L , Brookhaven National Laboratory
J . M . Y U H A S , Oak Ridge National Laboratory
OFFICERS OF T H E SOCIETY
President: V I C T O R P. B O N D , Brookhaven National Laboratory, Upton, Long Island, New York 11937
V i c e President (and President Elect): H A R A L D H . ROSSI, Columbia University, New York, New York 10032
Secrelary-Treasurer: M A X R. Z E L L E , Dept. Rad. and Rad. Biol., Colorado State University, Fort Colli ns, Colorado 80521
M a n a g i n g Editor: O D D V A R F . N Y G A A R D , Case Western Reserve University, Cleveland, Ohio 44106
Executive Secretary: R I C H A R D J . B U R K , J R . 4211 39th Street, N.W., Washington, D. C . 20016
A N N U A L MEETINGS
1974: July 13-20, Fifth International Congress of Radiation Research, Seattle, Washington
1975: May 11-15, Miami Beach, Florida
VOLUME 55, NUMBER 2, AUGUST 1973
Radiation Research Volume 55, N ü r n b e r g , August 1973
CONTENTS
M . Isaacson, D . Johnson, and A . V . Crewe. E l e c t r o n Beam E x c i t a t i o n a n d D a m a g e of B i o l o g i c a l M o l e c u l e s ; I t s I m p l i c a t i o n s f o r Specimen D a m a g e i n E l e c t r o n M i c r o s c o p y . 205
Einar Sagstuen. ESR a n d I N D O - M O Stndies of R a d i c a l s a n d R a d i c a l React i o n s i n I r r a d i a t e d S i n g l e C r y s t a l s of 5 - N i t r o - 6 - M e t h y l u r a c i l . 225
R. W. Matthews. Effect of Solute C o n c e n t r a t i o n a n d T e m p e r a t u r e o n the C e r i c - C e r o u s D o s i m e t e r . 242
Tzu-L in Tung and Robert R . Kuntz . H y d r a t e d E l e c t r o n Reactions w i t h T h i o l s i n A c i d i c Aqueous S o l u t i o n s . 250
Ernest C. Pollard and Eleanor P. Randau. Studies o n the I n d n c i b l e I n h i b i t o r of R a d i a t i o n - I n d u c e d D N A D e g r a d a t i o n of Escherichia coli. 205
George M . Hahn, Malcolm A . Bagshaw, Richard G . Evans, and Louise F . Gordon. R e p a i r of P o t e n t i a l l y L e t h a l Lesions i n X - I r r a d i a t e d , D e n s i t y -I n h i b i t e d Chinese H a m s t e r C e l l s : M e t a b o l i e Effects a n d H y p o x i a . 280
A . Bccciolini, P . Castagnoli, L . Arganini, and G . De Giu l i . P o s t - I r r a d i a t i o n Enzyme A c t i v i t i e s of Rat S m a l l I n t e s t i n e : Effects of Dose F r a c t i o n a t i o n . 291
A . Ferencz, E . J . Hidvegi, L . D . Szab6, and V . Värtcresz. The Effect of Whole-Body X - I r r a d i a t i o n of G u i n e a P i g s o n the L i v e r Ribonuclease and, R i b o n u c l e a s e - I n h i b i t o r System. 304
Yutaka Okumura, Toshiteru Mori ta , and Tai ju Matsuzawa. The Effects of T e m p e r a t u r e o n the D y i n g Process of L e t h a l l y I r r a d i a t e d C u l t u r e d Mouse M a m m a r y C a r c i n o m a C e l l s . 318
Ahmed El-Metainy, Shigemitsu Tano, Ke i j i Yano, and Hikoyuk i Yama-guchi. C h e m i c a l N a t u r e of R a d i a t i o n - I n d u c e d S i n g l e - S t r a n d Breaks i n the D N A of D o r m a n t B a r l e y Seeds in Vivo . 324
Christopher D . Town, Kendric C. Smith, and Henry S. Kaplan . The R e p a i r of D N A S i n g l e - S t r a n d Breaks i n E . coli K - 1 2 X - I r r a d i a t e d i n the Presence o r Absence of O x y g e n ; the I n f t u e n c e of R e p a i r o n C e l l S u r v i v a l . 334
Emmanuel Van der Schueren, Kendric C. Smith, and Henry S. Kaplan . M o d i j i c a t i o n of D N A R e p a i r a n d S u r v i v a l of X - I r r a d i a t e d pol, rec, a n d exr M u t a n t s of Escherichia coli K - 1 2 by 2 , 4 - D i n i t r o p h e n o l . 34(>
Gunnar Saxeb0l, Thor B . Mel0, and Thormod Henriksen. E l e c t r o n Spin Resonance Studies of E l e c t r o n I r r a d i a t e d Peptides. A S i n g l e C r y s t a l of N-Acetißglycine a t 77 K . . . . ^
Raymond Pageau. Effects of I r r a d i a t i o n Schedules o n a M u r i n e Epen-dymoma. 369
Takashi Aoyama and Shunzo Okajima. E a r l y M o r p h o l o g i c a l Changes i n the C o r t i c a l and, M e d u l l a r y Thymocytes of the Rat after Whole-Body I r r a d i a t i o n . I I . Q u a n t i t a t i v e I n v e s t i g a t i o n . 379
Correspondencc Luis Felipe Fajardo and J . Mar t in Brown. C a r d i a c M u r a l T h r o m b i
Caused by R a d i a t i o n . 387 O b i t u a r y f o r B e r n a r d S m a l l e r . 390
Published monthly by Academic Press, Inc., 111 Fifth Avenue, New York, N . Y . 10003. 1973: Volumes 53-56. Price per yolume: $22.50. All correspondence and subscription Orders should be addressed to the office of the Publishers at
111 Fifth Avenue, New York, N . Y . 10003. Send notices of change of address to the office of the Publishers at least 4 weeks in advance. Please
include both old and new addi *esses. Second class postage paid at New York, N . Y. and at additionai mailing offices. Copyright © 1973 by Academic Press, Inc.
Radiation Research
Volume 55, Number 2, August 1973
Copyright © 1973 by Academic Press, Inc. All rights reserved
No part of this publication may be reproduced or transmitted in any form, or by any means, electronic or mechanical, including photocopy, re-cording, or any Information storage and retrieval System, without permission in writing from the Copyright owner.
RADIATION R E S E A R C H 55, 447-456 (1973)
The Biophysical Properties of 3.9-GeV Nitrogen Ions VI. Interpretation of Results1
A L B R E C H T M . K E L L E R E R A N D H A R A L D H . R O S S I
R a d i o l o g i c a l Research L a b o r a t o r y , D e p a r t m e n t of Radiology, C o l u m b i a University College of Physicians & Surgeons N e w Y o r k , N e w Y o r k 1 0 0 8 2
K E L L E R E R , A. M . , AND ROSSI, H . H . , The Biophysical Properties of 3.9-GeV Nitrogen Ions. VI . Interpretation of Results. R a d i a l . Res. 55, 447-456 (1973).
Biological data obtained on V i c i a f a b a , T r a d e s c a n t i a , and mammalian cells with a 3.9-GeV nitrogen ion beam are related to microdosimetric measurements. The relative biological effectiveness near the Bragg peak of the depth-dose curve can be explained on the basis of the microdosimetric data and the theory of dual radiation action. A comparison is performed with the results obtained on the same biological Systems with monoenergetic neutrons, and essential agreement is found with earlier conclusions derived from the comparison of track-segment experiments and neutron irradiations. The oxygen-enhancement ratio for the nitrogen ions is higher than expected from the microdosimetric data; this is taken as an indication that the oxygen effect may at least partly depend on the energy concentration over distances of the order of nanometers. The implications of the results to the use of heavy ions in radiotherapy are considered.
I N T R O D U C T I O N
Dosimetrie and microdosimetric analysis as well as radiobiological studies performed at the Princeton Particle Accelerator with nitrogen ions of 3.9-GeV initial energy have been described in previous publications ( 1 - 5 ) . This paper is an attempt to link the ph%ysics studies with the radiobiological results, and to comparc the observed relative biological effectiveness and oxygen enhance-ment ratio with the results which are expected on the basis of the microdosimetric data and also with results which have earlier been obtained for the same biological sj^stems with monoenergetic neutrons of various energics.
P R E D I C T I O N S B A S E D O N M I C R O D O S I M E T R I C D A T A
In an earlier analysis concerned with the theory of dual radiation action ( 6 ) it has been found that for a wide ränge of cellular radiation effects onc can assume that the yield of primär}^ lesions is proportional to the Square of the specific energy z in a site with a diameter of approximately 2 / i m :
e(z) = kz\ (1)
^ h i s investigation was supported by Contract AT-(ll-l)-3243 from the U.S. Atomic Energy Commission and Research Grant C A 12536 from the National Cancer Institute.
447
Copyright © 1973 by Academic Press, Inc. All rights of reproduetion in any form reserved.
448 K E L L E R E R A N D ROSSI
The specific energy, z, is defined as the ratio of energy imparted to a micro-scopic region to its mass (7). The mean value of this ran dorn variable is the absorbed dose, but z can deviate significantly from D .
Equation (1) provides a basis for the analysis of d o s e - R B E relations in a great variety of radiation effects on higher organisms. The }deld of primary cellular lesions, e ( z ) , can, however, in general not be equated to the observed effect, and the dose-effect relation is, therefore, not always directly obtained by averaging e(z) over the probability distribution, f ( z ; D ) , of the values of z which occur at a given dose. Dose-effect relations can be considerably more complicated not only because they depend on such factors as the oxygen con-centration and the position of the cells in their cycle but also because thejr are influenced b}' other stochastic factors in addition to the statistics of energy deposition; only the latter are accounted for by the integration of E q . (1) over the distribution of z. If, however, exponential or nearly exponential dose-effect curves are observed, as is frequently the case in cellular survival studies with densely ionizing radiation, one may assume that the statistics of the energy deposition is the dominant factor; one can then postulate an exponential relation between survival and primary cellular lesions:
S(z) = e-«^ = e-k'*2 with h ' = ck. (2)
Analogous relations can be assumed if exponential dose-effect relations are found for experimental endpoints other than cellular survival. As has been shown in earlier publications ( 8 , 1 0 ) , this is the case in the growth reduction of V i c i a f a b a by nitrogen ions.
A t small values of z E q . (2) reduces to proportionality between the observed effect, e.g., the reduction of survival, and the yield of primary cellular lesions. A t higher values of z the observed effect changes more slowly than the quantity t ( z ) , and one may, therefore, speak of a Saturation effect. Various interpreta-tions can be given to this Saturation effect ( 6 ) ; in the following only the basic formulae will be derived.
In order to facilitate the comparison of the microdosimetric studies with the L E T analysis which has been applied to cellular inactivation experiments based on the so-called track-segment method 2 (8) one can use the variable y instead of z. The lineal energy, y , is closely related to z and it refers to the same sitcs of approximately 2 jum; but it is defined as the energy deposited in one absorption event divided by the mean traversal length of the reference region (7, 9 ) . Formulated in terms of this variable y , which is the microdosimetric analoguc of L E T , E q . (2) for the survival probability takes the form:
S(y) = e-CWz/o)2. (3)
From an analysis of the cellular inactivation studies of Barendsen ( 8 ) and Todd 3 the value y 0 = 125 keV/jum has been deduced, and by application of this result to various observations obtained with monoenergetic neutrons it
2 P. N . Todd, Thesis, Univ. of California, Lawrence Radiation Laboratory, UCRL-1.1614 (1964).
3 P. N. Todd, Thesis, Univ. of California, Lawrence Radiation Laboratory, UCRL-11614 (1964).
P R O P E R T I E S O F N I T R O G E N IONS 449
has been concluded ( 6 ) that the same value of y 0 may also apply to other cellular effects such as growth reduction in V i c i a f a b a and to the induction of mutations in T r a o l e s c a n t i a .
A t any position in the beam one is dealing with a ränge of values of y ; these distributions have been given in an earlier publication ( 2 ) . One must integrate E q . (3) over the füll spectrum, f ( y ) , of the values of y produced in one event in order to obtain the survival probability S\ when one event has taken place:
S l = f e - ^ y ^ f { y ) c l y . (4)
l f one considers not the survival probability but the effect level, one has the following proportionality:
E\ - [ (1 - e-^y^)f(y)dy. (5)
Finally, if one wants to obtain the effect per unit absorbed dose, one has to multiply E i hy the event frequency, <£, per unit dose ( 9 ) . The event frequency per unit dose is proportional to the inverse of the mean value of y :
* - i / f yf(y)äy. (6)
Accordingly the effect probability per unit absorbed dose is proportional to the following quantity:
VA* = Vo2 f (1 - f(y)äy / [ yf(y)dy. (7)
This quantity can be considered as an effective lineal energy; the subscript A is used to indicate that the quantity refers to aerated conditions. For effects which are proportional to dose one expects the relation:
E = KIJA*D (8)
wliile in exponential dose-effect relations the exponent is proportional to y , *
S = E - < " A * D . (9)
The normalization constant y 0
2 has been inserted so that y A * is cqual to the so-called dose average yn ( 9 ) for sparsely ionizing radiations, i.e., if all values of y are small as compared to t/o and if, therefore, Saturation plays no role. The value of y A * can be calculated for any measured microdosimetric spectrum, and such calculations have been performed for the data ( 2 ) obtained on the nitrogen beam in various depths in the phantom.
The formulae given above apply to experiments performed under aerated conditions. A similar analysis has been performed with regard to hypoxic conditions. In this case one obtains a formula which is basically equivalent to
450 K E L L E R E R A N D ROSSI
1.0
P .5
1 0 100 1000 L INEAL ENERGY y ( k e V / / i m )
F I G . 1. Relation between the reduction factor p and the lineal energy y. This relation which has been deduced ( 6 ) from track-segment experiments is used in the computation of yfl*.
E q . (7), but which contains a reduction factor, p, for the production of primary lesions:
V i i * = y t j (1 - e - ^ ' y ^ ) S { y ) d y / J y f ( y ) d y . (10)
The simplest assumption would be that p is constant, i.e., indepcndent of the microdistribution of energy. The data obtained in the track segment experiments by Barendsen ( 8 ) and the observations obtained with monoenergetic neutrons indicate, however, that the reduction factor p varies with y } and the functional dependence in F ig . 1 has been found (6) to be in satisfactory agree-ment with the experimental data.
The fact that p tends towards 1 with increasing y is of considerable interest because it could mean that Saturation alone does not account fully for the observed small O E R for densely- ionizing radiation, and that one may have to invoke additional mechanisms (e.g., the production of oxygen in the tracks of densely ionizing particles). There is, however, an alternative interprctation of the increase of p. In the experiment of Barendsen as well as in the neutron experiments one deals with very narrow particle tracks when one approaches values of y in the vicinity of 100 keV/jum; this may lead to an increase in Saturation which would correspond to a smallcr value of ?/o. The two different possibilities can not readily be distinguished. The fact, however, that from Todd's data 3 no Variation of p can be deduced, favors the second interpretation. The analysis of Todd's data is complicated because in Iiis experiments the particle tracks are wide enough that the indirect events in which a particle does not enter the nucleus but injects ö-rays into it can not be neglected; y can, therefore, not simply be equated with L E T . An accurate analysis would have to be based on microdosimetric data; however, a study by Curtis ( 1 8 ) indicates that the diffcrencc between the data of Barendsen and Todd may indeed be partly due to the different lateral extension of the tracks in the two cases. In the next section the Situation wil l be examined in the light of the data obtained for nitrogen ions. To this purpose E q . (10) has been evaluated with the microdosimetric data ( 2 ) for the nitrogen ions and with the reduction factor given in F ig . 1. The resulting quantity y n * is presented in F ig . 2 together with y u and y A * . The quantity y D , which is obtained if Saturation is not taken into account, is given as a solid line for comparison with the quantities y A * (broken line) and y H * (dotted line).
P R O P E R T I E S O F N I T R O G E N I O N S 451
DEPTH IN WATER (cm)
F I G . 2. Dependence of the microdosimetric quautities #D, VA*, and yu* on depth in the phantom. The heavy dots indicate those positions where microdosimetric spectra have been determined. Toward their right end the cnrves have been extrapolated to values obtained at the depth of 15.1 cm.
C O M P A R I S O N O F E X P E R I M E N T A L A N D T H E O R E T I C A L D A T A
Figure 3 represents the observed effectiveness, a , for the growth reduction of V i c i a f a b a of the nitrogen beam as a function of depth in the phantom. The values a have been obtained by a least-squares fit (8) of the experimental data to dose-responsc curves of the form:
G = G 0 e - « D , (11)
where G is the observed growth and G0 is the least-squares estimate for the controls. The results are indicated by rhomboids. The horizontal extension of these rhomboids Covers the ränge of depths in the phantom occupied by the
io- 3
5-10" 4
OL
(rad"')
2-I0" 4
IO" 4
T 1 1 1 1 1 1 1 1
b) Hypoxie
• / v
. . . . i . . . . II 12 13
DEPTH IN WATER (cm)
F I G . 3. Dependence of the effectiveness of nitrogen ions, a, for the growth reduction of V i c i a seedlings on depth in the phantom. The rhomboids indicate the thickness of the irradiated sample« (horizontal extension) and the Standard deviation of a (vertical extension). The broken curves represent the theoretical relation a = K y A * for the aerated condition and C C = K I J H * for the hypoxic condition. The value 5 • 10~4 (keV/Vm) - 1 r a d - 1 for K has been assumed.
(rad"1)
10"
f^.\r\~
4.52 K E L L E R E R A N D ROSSI
DEPTH IN WATER(cm)
F I G . 4. Dependence of the oxygen enhancement ratio for nitrogen ions and the growth reduction of V i c i a seedlings on depth in the phantom. The rhomboids indicate the thickness of the irradiated samples (horizontal extension) and the Standard deviation of the O E R (vertical extension). The broken line represents the theoretical value y A * / y n * of O E R according to microdosimetric data. The dots indicate those positions where microdosimetric spectra have been determined.
plants; the vertical placement and extension corrcspond to the value of a and its Standard deviation, respectively. R B E is proportional to a ; the numerical relation between the two quantities for different effect levels has been given in the earlier publication ( 3 ) .
According to the considerations in the preceding section the observed values of a should be proportional to the microdosimetric quantity y A * . The broken line in Fig . 3a corresponds to the relation a = K y A * with the proportionalty constant K = 5-10"4 (keV//xm) _ 1 r a d - 1 . The ränge in depth as well as the Statistical accuracy of the data are not sufficient to verify or reject the propo-tionality between a and y A * ; the results are, therefore, neither a confirmation of the basic tenets of the considerations in the preceding section nor a confirmation of the numerical value of y 0 used in E q . (7). One may, however, accept the relation a = nyA* on the basis of the earlier evidence (6) from track-segment experiments and studies with monoenergetic neutrons ( 1 0 ) , and it is then of considerable interest to compare the values of K obtained with V i c i a f a b a in the present studies and in the earlier experiments with monoenergetic neutrons. The data obtained with monoenergetic neutrons are in near agree-ment with the relation a = K y A * . However, the decrease of a with increasing neutron energy is somewhat steeper than the decrease of y A * - In the energy ränge between 200 and 600 keV one obtains a value of K of about 9.3 • 10~4
(keV/Vm)- 1 rad" 1 while the value at 14 M e V is 6.2 -10~4 ( k c Y / p m ) - 1 r ad ' 1 . The reason for this finding is at present not completely clear; but one can think of two likely factors. One reason why the low-energy neutrons should be rela-tively more effective than expected could be that the charged particle secondaries have in this case ranges which are considerably smaller than the nuclear diameter of the cell. This would lead to a diminished Saturation effect and thereby to increased effectiveness. A t 14 M e V , on the other hand, almost all of the reeoil protons and most of the heavier charged particles have ranges comparable to the diameter of the cell nucleus and the Saturation effect should, therefore, be comparable to the one observed with charged particles in the experiments by Barendsen and Todd. Another possible reason is that at a given value of y or,
P R O P E R T I E S O F N I T R O G E N IONS 453
in the more conventional terminolog}', at a given L E T the radial profile of energy deposition around the particle track is narrower in the case of protons ncar their Bragg peak than in the case of hcavier charged particles of the same stopping power. Since protons near their Bragg peak are probably mainly responsible for the effects at low and intermediate neutron energies, one could expect a somewhat increased effectiveness due to this difference. It may, at present, not be possible to decide which of the two factors is more important. But independently of the answer to this question one would have to expect that due to the long ränge of the particles and the extended delta-ray halo the case of the nitrogen ions corresponds more closely to the case of 14-MeV neutrons than to that of the lower energy neutrons. This is indeed borne out in the experiments and one concludes that the theoretical considerations on R B E presented in the preceding section are equally consistent with the track-segment experiments, wi th the experiments with fast neutrons, and with the present studies with nitrogen ions.
Discrepancies both with the data of Barendsen and with the neutron data arise as far as the oxygen enhancement ratio is concerned. On the basis of E q . (10) and the value of K obtained under aerated conditions one predicts the effectiveness in anoxic conditions which is indicated by the broken line in Fig . 3b; this line corresponds to the quantity y n * plotted in F ig . 2, w rhich, in turn, is based upon the dependence of p on y (see F ig . 1) inferred from B a -rendsen's data and the experiments with monoenergetic neutrons. Although the experimental data and the theoretical predictions based on the microdosimetric measurements do not cover exactly the same depth ränge in the phantom, one must conclude that the observed effectiveness under anoxic conditions is below the calculated values. Figure 4 shows this somewhat more explicitly in a comparison of the oxygen enhancement ratio which is theoretically predicted and the values which are experimentally observed. One concludes that the observed values of O E R are higher than would correspond to B a -rendsen's observations of cellular inactivation by the so-called track-segment method. One could assume that this merely reflects a difference in the two biological Systems. However, the growth reduction studies with monoenergetic neutrons and V i c i a seedlings ( 1 0 ) have led to oxygen-enhancement ratios which are in agreement with the values predicted under the assumption of a variable p. The larger values of O E R obtained in the present experiments would indicate that p does not change with y , and this may be due to the more extended radial profile of energy deposition at a given L E T in the case of nitrogen ions. The results, therefore, support the conclusion ( 1 3 ) which has been drawn from the data obtained by Todd. One infers that the value of y in a region of one to scveral micrometers is not the only relevant quantity but that the effectiveness of dcnsely ionizing radiation is also influenced by the width of the track.
The other biological experiments performed with the nitrogen beam are less extensive than the studies performed on V i c i a f a b a but they conplement and support the basic conclusion reached for this System. In the induetion of pink mutations in T r a d e s c a n t i a by nitrogen ions (5) the geometrical extension of the irradiated samples is larger than in the case of V i c i a seedlings; consequently
454 K E L L E R E R A N D ROSSI
i t is more difficult to establish an accurate dependence between R B E and the depth of the sample in the phantom. One can, however, perform an overall fit of the observed yield, Y ( D ) , of pink mutations per stamen hair at small doses to the relation:
Y ( D ) = K y A * D , (12)
where y A * is the value of the microdosimetric quantity defined in E q . (7) at the mean depth of the sample. The resulting value is K = 1.8 - 1 0 - 4 ( k c V / V m ) - 1
r a d - 1 . Again, as in the case of the growth-reduction studies on V i c i a f a b a , a comparison with neutron data 4 shows that the value is only slightly smaller than the value (K = 2 - 1 0 - 4 (keV/ßm)'1 r ad - 1 ) obtained for 14-MeV neutrons but considerably smaller than the value for 430-keV neutrons (K = 5.2 -10 - 4
(keV/jum)""1 r ad - 1 ) . The experiments on the induction of pink mutants in T r a -d e s c a n t i a support, therefore, the conclusion that the analysis of R B E given in the preceding section applies equally to the track-segment method, to the experiments with high-energy neutrons, and to the present studies with nitrogen ions. The rather close agreement of the values K obtained with 14-MeV neutrons and with nitrogen ions is particularly significant in view of the fact that the microdosimetric distributions for 14-MeV neutrons and for nitrogen ions near their Bragg peak differ widely, as shown in the earlier report on the microdosimetric studies ( 2 ) . I t should be noticed that yz> which is the microdosimetric analog of the dose mean L E T , L D , and which varies rapidly near the Bragg peak is not correlated to the observed R B E in V i c i a seedlings and in T r a d e s -c a n t i a j while the explicit microdosimetric analysis which leads to the quantity y A * is in substantial agreement with the data.
N o experiments under anoxic conditions have been performed with T r a d e s -c a n t i a . But two dose-effect curves which have been obtained with mammalian cells as close as possible to the Bragg peak of the depth-dose curve have resulted in an oxygen enhancement ratio of 1.25. This is close to the predicted oxygen enhancement ratio, but because only one position has been tested, one cannot decide whether this agreement occurs only at the very close vicinity to the Bragg peak. It should also be pointed out that even with x-rays the O E R obtained with mammalian cells under the same expcrimental conditions is relatively low ( 1 0 ) .
DISCUSSION
As shown elsewhere ( 6 ) , E q . (1) can also be written in the form
e ( D ) = *(fD + JD«), (13)
where f is the dose average of individual increments of specific energy. This quantity can be expressed in terms of y ; for a unit density spherical volume
4 A . G . Underbrink, unpublished.
P R O P E R T I E S O F N I T R O G E N IONS 455
of diameter d one has ( 9 ) :
20.4 y 2 f ( y ) d y / f f = y f ( y ) d y
(14) 20.4
A t small doses one can disregard the quadratic component in E q . (13) and the relation then corresponds to the linear relation considered in the preceding section. However y D must be replaced by the quantity y A * [see E q . (7)] because of Saturation effects.
One interpretation of E q . (13) or of its modified forms is that the expression in the brackets represents the Square of the energy concentration in sites (which as mentioned above have dimensions of the order of micrometers) and K represents the effectiveness with which this energy inactivates loci within the site as well as the probability with which pairs of these loci interact within the site. I t was assumed that the loci are much smaller than the site and that in a first approximation K might be considered to be independent of radiation quality. In this case E q . (13) represents the dependence of biological effect on both dose and radiation quality with the latter entering only through f.
I t has already been pointed out that this first approximation may be in-adequate in somc instances ( 1 1 , 1 2 ) and it would appear that the experiments that have been analyzed here are an example where it is insufficient because of differences of energy concentration at the locus level (perhaps in the na-nometcr ränge) . One may also surmise that such differences are even more important in the absence of oxygen which by the agency of various active radicals might enhance radiation effects depending on energy concentrations within a typical diffusion distance of a few nanometers.
Although such a dependence of K on radiation quality might be an adequate qualitative explanation of the observed effects it must remain tentative until adequate quantitative Information is available. This underlines the need for microdosimetric data in the nanometer ränge.
Rcgardless of the reasons involved it is apparent that the O E R for these ions exceeds that for lighter ions of comparable L E T . This has negative im-plications for the utilization of 1 4 N ions in radiotherapy. However, i t might be expected that further enhancement of the L E T (e.g., in irradiation with argon ions) would overcome the difficulty. In this case delta rays wil l be spaced more closefy which makes the ionization density within individual delta rays less critical. The narrow Bragg peak for nitrogen ions would seem to require the use of heavier particles as well.
W i t h an increase in atomic number one could approach the Situation where the biological effectiveness per particle is substantially independent of energy (i.e., the R B E in the Bragg peak is less than further upstream) with a more extensive zone of uniform tissue destruetion. This, together with an antieipated
450 K E L L E R E R A N D ROSSI
O E R near 1.0 and minimal lateral scatter, should constitute conditions of con-siderable interest to radiotherapy.
R E C E I V E D : February 3, 1973
R E F E R E N C E S
1 . VV. G R O S S and R. D. C O L V E T T , The biophysical properties of 3.9-GeV nitrogen ions. I. Dosim-etry. R a d i a l . Res. 54, 3-11 (1973).
2 . Ii. C . R O D G E R S , J . F. D I C E L L O , and W. GROSS, The biophysical properties of 3.9-GeV ions. II. Microdosimetry. R a d i a l . Res. 54, 12-23 (1973).
3 . E . J . H A L L and A. M . K E L L E R E R , The biophysical properties of 3.9-GeV nitrogen ions. III. O E R A N D R B E determinalions using V i c i a seedlings. R a d i a l . Res. 55, 422-430 (1973).
4. E . J . H A L L and S. L E H N E R T , The biophysical properties of 3.9-GeV nitrogen ions. IV. O E R and R B E determinations using cultured mammalian cells. R a d i a t . Res. 55, 431-436 (1973).
5. A. G . U N D K R H R I N K , L . A. S C H A I R E R and A. H . SPARROW, The biophysical properties of 3.9-
GeV nitrogen ions. V. Relative biological effectiveness determinations in T r a d e s c a n t i a . R a d i a t . Res. 55, 437-446 (1973).
6. A. M . K E L L E R E R and H . H . Rossi, The theory of dual radiation action. C M / T . T o p . R a d i a t . Res., 8 (1972).
7. International Commission of Radiation Units and Measurements, Report 19, Washington, D C (1971).
8. B A R E N D S E N , G . W., In T h e o r e t i c a l a n d E x p e r i m c n t a l Biophysics, (A. Cole, Ed.), Dekker, New York, Vol. 1, p. 167 (1967).
9. A. M . K E L L E R E R and H . H . Rossi, In M i c r o d o s i m e t r y . P r o c . 2 n d Symp. on M i c r o d o s i m e t r y ( H . G . Ebert, Ed.) Euratom, Brüssels, 4452-d-f-e, 1970.
10. E . J . H A L L , H . H . ROSSI, A. M . K E L L E R E R , L . G O O D M A N , and S. M A R I N O , Radiobiological
studies with monoenergetic neutrons. R a d i a t . Res. 54, 431-443 (1973). 1 1 . H . H . Rossi, Dual radiation injury and its consequences. P r o c . Symp. Biophys. Aspects
R a d i a t . Q u a l . pp. 333-341, I A E A , Vienna, 1971. 1 2 . H . H . Rossi, The role of microdosimetry in radiobiology and radiation protection. P r o c .
Srd. Symp. M i c r o d o s i m e t r y (H. G. Ebert, Ed.), pp. 1-29. Euratom, Brüssels (1971). 1 3 . C U R T I S , S. B. The effects of track structure on O E R at high L E T , In C h a r g e d P a r t i c l e T r a c k s
i n Solids a n d L i q u i d s , The Institute of Physics and the Physical Society Conference Series No. 8, London (1970).
