Radiobiology for the Radiologist, 8th Edition
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Chapters 8, 9, 15, and 16, are so specifically oriented towards radiotherapy that
the diagnostician may omit them without loss of continuity.
A word concerning reference material is in order. The ideas contained in this
book represent, in the author’s estimate, the consensus of opinion as expressed in
the scientific literature. For ease of reading, the text has not been broken up with
a large number of direct references. Instead, a selection of general references has
been included at the end of each chapter for the reader who wishes to pursue the
subject further.
I wish to record the lasting debt that I owe my former colleagues at Oxford
and my present colleagues at Columbia, for it is in the daily cut and thrust of
debate and discussion that ideas are formulated and views tested.
Finally, I would like to thank the young men and women who have regularly
attended my classes. Their inquiring minds have forced me to study hard and
reflect carefully before facing them in a lecture room. As each group of students
has grown in maturity and understanding, I have experienced a teacher’s
satisfaction and joy in the belief that their growth was due in some small
measure to my efforts.
E. J. H.
New York
July 1972
5
Preface
The eighth edition is a significant revision of this textbook and includes new
chapters that were not included in the seventh edition. We have retained the
same format as the seventh edition, which divided the book into two parts.
Section I contains 16 chapters and represents both a general introduction to
radiation biology and a complete self-contained course in the subject, suitable for
residents in diagnostic radiology and nuclear medicine. It follows the format of
the syllabus in radiation biology prepared by the Radiological Society of North
America (RSNA). Section II consists of 12 chapters of more in-depth material
designed primarily for residents in radiation oncology.
Dickens’s famous beginning to a Tale of Two Cities, “It was the best of
times, it was the worst of times, it was the age of wisdom, it was the age of
foolishness, it was the epoch of belief, it was the epoch of incredulity . . . ,” very
much applies to the current world order. Although medical science and
technology have made great advances in alleviating disease and suffering,
irrational and unpredictable events occur quite frequently, instilling fear and
apprehension about potential nuclear terrorism. The eighth edition contains a
new chapter (Chapter 9) on “Medical Countermeasures to Radiation Exposure”
that summarizes the current therapies available to prevent or mitigate radiation
damage to normal tissues. This chapter nicely complements Chapter 14 on
“Radiologic Terrorism.”
Due to the strong request for including more information on molecular
techniques, we have included a new Chapter 17 on “Molecular Techniques in
Radiology.” The techniques described in this chapter should be useful to both the
novice as well as the skilled practitioner in molecular biology.
In this edition, we have eliminated the chapter on “Molecular Imaging.” The
basis for this decision was that the subject matter covered in this chapter does not
involve any radiobiologic principles, and in any case, there are several textbooks
devoted solely to the subject of molecular imaging. For these reasons, we have
decided to remove this chapter from the eighth edition. Overall, we believe that
this new edition represents a well-balanced compilation of both traditional and
molecular radiation biology principles.
The ideas contained in this book represent, we believe, the consensus of
opinion as expressed in the scientific literature. We have followed the precedent
of previous editions, in that, the pages of text are unencumbered with flyspeck-
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like numerals referring to footnotes or original publications, which are often too
detailed to be of much interest to the general reader. On the other hand, there is
an extensive and comprehensive bibliography at the end of each chapter for
those readers who wish to pursue the subject further.
We commend this new edition to residents in radiology, nuclear medicine,
and radiation oncology, for whom it was conceived and written. If it serves also
as a text for graduate students in the life sciences or even as a review of basic
science for active researchers or senior radiation oncologists, the authors will be
doubly happy.
Eric J. Hall
Columbia University, New York
Amato J. Giaccia
Stanford University, California
October 2017
7
Acknowledgments
We would like to thank the many friends and colleagues who generously and
willingly gave permission for diagrams and illustrations from their published
work to be reproduced in this book.
Although the ultimate responsibility for the content of this book must be
ours, we acknowledge with gratitude the help of several friends who read
chapters relating to their own areas of expertise and made invaluable suggestions
and additions. With each successive edition, this list grows longer and now
includes Drs. Ged Adams, Philip Alderson, Sally Amundson, Joel Bedford,
Roger Berry, Max Boone, Victor Bond, David Brenner, J. Martin Brown, Ed
Bump, Denise Chan, Julie Choi, James Cox, Nicholas Denko, Bill Dewey, Mark
Dewhirst, Frank Ellis, Peter Esser, Stan Field, Greg Freyer, Charles Geard,
Eugene Gerner, Julian Gibbs, George Hahn, Simon Hall, Ester Hammond, Tom
Hei, Robert Kallman, Richard Kolesnick, Norman Kleiman, Gerhard Kraft,
Adam Krieg, Edward LaGory, Dennis Leeper, Howard Lieberman, Philip Lorio,
Edmund Malaise, Gillies McKenna, Mortimer Mendelsohn, George Merriam,
Noelle Metting, Jim Mitchell, Thomas L. Morgan, Anthony Nias, Ray Oliver,
Stanley Order, Tej Pandita, Marianne Powell, Simon Powell, Julian Preston,
Elaine Ron, Harald Rossi, Robert Rugh, Chang Song, Fiona Stewart, Herman
Suit, Robert Sutherland, Roy Tishler, Len Tolmach, Liz Travis, Lou Wagner,
John Ward, Barry Winston, Rod Withers, and Basil Worgul. The principal credit
for this book must go to the successive classes of residents in radiology,
radiation oncology, and nuclear medicine that we have taught over the years at
Columbia and Stanford, as well as at American Society for Radiation Oncology
(ASTRO) and RSNA refresher courses. Their perceptive minds and searching
questions have kept us on our toes. Their impatience to learn what was needed of
radiobiology and to get on with being doctors has continually prompted us to
summarize and get to the point.
We are deeply indebted to the U.S. Department of Energy, the National
Cancer Institute, and the National Aeronautical and Space Administration, which
have generously supported our work and, indeed, much of the research
performed by numerous investigators that is described in this book.
We owe an enormous debt of gratitude to Ms. Sharon Clarke, who not only
typed and formatted the chapter revisions but also played a major role in editing
and proofreading. Our publisher, Lauren Pecarich, guided our efforts at every
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stage.
Finally, we thank our wives, Bernice Hall and Jeanne Giaccia, who have
been most patient and have given us every encouragement with this work.
9
Contents
Preface to the First Edition
Preface
Acknowledgments
SECTION I For Students of Diagnostic Radiology, Nuclear
Medicine, and Radiation Oncology
1 Physics and Chemistry of Radiation Absorption
TYPES OF IONIZING RADIATIONS
Electromagnetic Radiations
Particulate Radiations
ABSORPTION OF X-RAYS
DIRECT AND INDIRECT ACTION OF RADIATION
ABSORPTION OF NEUTRONS
ABSORPTION OF PROTONS AND HEAVIER IONS SUCH AS
CARBON
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
2 Molecular Mechanisms of DNA and Chromosome Damage and Repair
GENERAL OVERVIEW OF DNA STRAND BREAKS
MEASURING DNA STRAND BREAKS
DNA REPAIR PATHWAYS
Base Excision Repair
Nucleotide Excision Repair
DNA Double-Strand Break Repair
Nonhomologous End-Joining
Homologous Recombination Repair
Crosslink Repair
10
Mismatch Repair
RELATIONSHIP BETWEEN DNA DAMAGE AND CHROMOSOME
ABERRATIONS
CHROMOSOMES AND CELL DIVISION
THE ROLE OF TELOMERES
RADIATION-INDUCED CHROMOSOME ABERRATIONS
EXAMPLES OF RADIATION-INDUCED ABERRATIONS
CHROMOSOME ABERRATIONS IN HUMAN LYMPHOCYTES
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
3 Cell Survival Curves
REPRODUCTIVE INTEGRITY
THE IN VITRO SURVIVAL CURVE
THE SHAPE OF THE SURVIVAL CURVE
MECHANISMS OF CELL KILLING
DNA as the Target
The Bystander Effect
Apoptotic and Mitotic Death
Autophagic Cell Death
Senescence
SURVIVAL CURVES FOR VARIOUS MAMMALIAN CELLS IN
CULTURE
SURVIVAL CURVE SHAPE AND MECHANISMS OF CELL DEATH
ONCOGENES AND RADIORESISTANCE
GENETIC CONTROL OF RADIOSENSITIVITY
INTRINSIC RADIOSENSITIVITY AND CANCER STEM CELLS
EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTION
REGIMEN
CALCULATIONS OF TUMOR CELL KILL
11
Problem 1
Answer
Problem 2
Answer
Problem 3
Answer
Problem 4
Answer
THE RADIOSENSITIVITY OF MAMMALIAN CELLS COMPARED
WITH MICROORGANISMS
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
4 Radiosensitivity and Cell Age in the Mitotic Cycle
THE CELL CYCLE
SYNCHRONOUSLY DIVIDING CELL CULTURES
THE EFFECT OF X-RAYS ON SYNCHRONOUSLY DIVIDING CELL
CULTURES
MOLECULAR CHECKPOINT GENES
THE EFFECT OF OXYGEN AT VARIOUS PHASES OF THE CELL
CYCLE
THE AGE-RESPONSE FUNCTION FOR A TISSUE IN VIVO
VARIATION OF SENSITIVITY WITH CELL AGE FOR HIGH–LINEAR
ENERGY TRANSFER RADIATIONS
MECHANISMS FOR THE AGE-RESPONSE FUNCTION
THE POSSIBLE IMPLICATIONS OF THE AGE-RESPONSE
FUNCTION IN RADIOTHERAPY
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
5 Fractionated Radiation and the Dose-Rate Effect
12
OPERATIONAL CLASSIFICATIONS OF RADIATION DAMAGE
Potentially Lethal Damage Repair
Sublethal Damage Repair
MECHANISM OF SUBLETHAL DAMAGE REPAIR
REPAIR AND RADIATION QUALITY
THE DOSE-RATE EFFECT
EXAMPLES OF THE DOSE-RATE EFFECT IN VITRO AND IN VIVO
THE INVERSE DOSE-RATE EFFECT
THE DOSE-RATE EFFECT SUMMARIZED
BRACHYTHERAPY OR ENDOCURIETHERAPY
Intracavitary Brachytherapy
Permanent Interstitial Implants
SUMMARY OF PERTINENT CONCLUSIONS
Potentially Lethal Damage Repair
Sublethal Damage Repair
Dose-Rate Effect
Brachytherapy
BIBLIOGRAPHY
6 Oxygen Effect and Reoxygenation
THE NATURE OF THE OXYGEN EFFECT
THE TIME AT WHICH OXYGEN ACTS AND THE MECHANISM OF
THE OXYGEN EFFECT
THE CONCENTRATION OF OXYGEN REQUIRED
CHRONIC AND ACUTE HYPOXIA
Chronic Hypoxia
Acute Hypoxia
THE FIRST EXPERIMENTAL DEMONSTRATION OF HYPOXIC
CELLS IN A TUMOR
13
PROPORTION OF HYPOXIC CELLS IN VARIOUS ANIMAL TUMORS
EVIDENCE FOR HYPOXIA IN HUMAN TUMORS
TECHNIQUES TO MEASURE TUMOR OXYGENATION
Oxygen Probe Measurements
Markers of Hypoxia
REOXYGENATION
TIME SEQUENCE OF REOXYGENATION
MECHANISM OF REOXYGENATION
THE IMPORTANCE OF REOXYGENATION IN RADIOTHERAPY
HYPOXIA AND CHEMORESISTANCE
HYPOXIA AND TUMOR PROGRESSION
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
7 Linear Energy Transfer and Relative Biologic Effectiveness
THE DEPOSITION OF RADIANT ENERGY
LINEAR ENERGY TRANSFER
RELATIVE BIOLOGIC EFFECTIVENESS
RELATIVE BIOLOGIC EFFECTIVENESS AND FRACTIONATED
DOSES
RELATIVE BIOLOGIC EFFECTIVENESS FOR DIFFERENT CELLS
AND TISSUES
RELATIVE BIOLOGIC EFFECTIVENESS AS A FUNCTION OF
LINEAR ENERGY TRANSFER
THE OPTIMAL LINEAR ENERGY TRANSFER
FACTORS THAT DETERMINE RELATIVE BIOLOGIC
EFFECTIVENESS
THE OXYGEN EFFECT AND LINEAR ENERGY TRANSFER
RADIATION WEIGHTING FACTOR
SUMMARY OF PERTINENT CONCLUSIONS
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BIBLIOGRAPHY
8 Acute Radiation Syndrome
ACUTE RADIATION SYNDROME
EARLY LETHAL EFFECTS
THE PRODROMAL RADIATION SYNDROME
THE CEREBROVASCULAR SYNDROME
THE GASTROINTESTINAL SYNDROME
THE HEMATOPOIETIC SYNDROME
THE FIRST AND MOST RECENT DEATHS FROM THE
HEMATOPOIETIC SYNDROME
PULMONARY SYNDROME
CUTANEOUS RADIATION INJURY
SYMPTOMS ASSOCIATED WITH THE ACUTE RADIATION
SYNDROME
TREATMENT OF RADIATION ACCIDENT VICTIMS EXPOSED TO
DOSES CLOSE TO THE LD50/60
TRIAGE
SURVIVORS OF SERIOUS RADIATION ACCIDENTS IN THE
UNITED STATES
RADIATION EMERGENCY ASSISTANCE CENTER
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
9 Medical Countermeasures to Radiation Exposure
INTRODUCTION AND DEFINITIONS
THE DISCOVERY OF RADIOPROTECTORS
MECHANISM OF ACTION
DEVELOPMENT OF MORE EFFECTIVE COMPOUNDS
AMIFOSTINE (WR-2721) AS A RADIOPROTECTOR IN
RADIOTHERAPY
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AMIFOSTINE AS A PROTECTOR AGAINST RADIATION-INDUCED
CANCER
A NEW FAMILY OF AMINOTHIOL RADIOPROTECTORS
RADIATION MITIGATORS
RADIONUCLIDE ELIMINATORS
DIETARY SUPPLEMENTS AS COUNTERMEASURES TO
RADIATION
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
10 Radiation Carcinogenesis
TISSUE REACTIONS (DETERMINISTIC EFFECTS) AND
STOCHASTIC EFFECTS
CARCINOGENESIS: THE HUMAN EXPERIENCE
THE LATENT PERIOD
ASSESSING THE RISK
COMMITTEES CONCERNED WITH RISK ESTIMATES AND
RADIATION PROTECTION
RADIATION-INDUCED CANCER IN HUMAN POPULATIONS
Leukemia
Thyroid Cancer
Breast Cancer
Lung Cancer
Bone Cancer
Skin Cancer
QUANTITATIVE RISK ESTIMATES FOR RADIATION-INDUCED
CANCER
DOSE AND DOSE-RATE EFFECTIVENESS FACTOR
SUMMARY OF RISK ESTIMATES
SECOND MALIGNANCIES IN RADIOTHERAPY PATIENTS
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Second Cancers after Radiotherapy for Prostate Cancer
Radiation Therapy for Carcinoma of the Cervix
Second Cancers among Long-Term Survivors from Hodgkin Disease
DOSE–RESPONSE RELATIONSHIP FOR RADIATION
CARCINOGENESIS AT HIGH DOSES
CANCER RISKS IN NUCLEAR INDUSTRY WORKERS
EXTRAPOLATING CANCER RISKS FROM HIGH TO LOW DOSES
MORTALITY PATTERNS IN RADIOLOGISTS
CHILDHOOD CANCER AFTER RADIATION EXPOSURE IN UTERO
NONNEOPLASTIC DISEASE AND RADIATION
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
11 Heritable Effects of Radiation
GERM CELL PRODUCTION AND RADIATION EFFECTS ON
FERTILITY
REVIEW OF BASIC GENETICS
MUTATIONS
Mendelian
Chromosomal Changes
Multifactorial
RADIATION-INDUCED HERITABLE EFFECTS IN FRUIT FLIES
RADIATION-INDUCED HERITABLE EFFECTS IN MICE
RADIATION-INDUCED HERITABLE EFFECTS IN HUMANS
INTERNATIONAL COMMISSION ON RADIOLOGICAL
PROTECTION ESTIMATES OF HEREDITARY RISKS
MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORS
CHANGING CONCERNS FOR RISKS
EPIGENETICS
Imprinted Genes
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SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
12 Effects of Radiation on the Embryo and Fetus
HISTORICAL PERSPECTIVE
OVERVIEW OF RADIATION EFFECTS ON THE EMBRYO AND
FETUS
DATA FROM MICE AND RATS
Preimplantation
Organogenesis
The Fetal Period
EXPERIENCE IN HUMANS
Survivors of the A-Bomb Attacks on Hiroshima and Nagasaki Irradiated
In Utero
Exposure to Medical Radiation
COMPARISON OF HUMAN AND ANIMAL DATA
CANCER IN CHILDHOOD AFTER IRRADIATION IN UTERO
OCCUPATIONAL EXPOSURE OF WOMEN
THE PREGNANT OR POTENTIALLY PREGNANT PATIENT
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
13 Radiation Cataractogenesis
CATARACTS OF THE OCULAR LENS
LENS OPACIFICATION IN EXPERIMENTAL ANIMALS
RADIATION CATARACTS IN HUMANS
THE LATENT PERIOD
DOSE–RESPONSE RELATIONSHIP FOR CATARACTS IN HUMANS
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
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14 Radiologic Terrorism
POSSIBLE SCENARIOS FOR RADIOLOGIC TERRORISM
AVAILABILITY OF RADIOACTIVE MATERIAL
HEALTH EFFECTS OF RADIATION
EXTERNAL EXPOSURE TO RADIATION AND CONTAMINATION
WITH RADIOACTIVE MATERIALS
EXTERNAL CONTAMINATION
INTERNAL CONTAMINATION
MEDICAL MANAGEMENT ISSUES IN THE EVENT OF
RADIOLOGIC TERRORISM
FURTHER INFORMATION
SUMMARY OF PERTINENT CONCLUSIONS
BIBLIOGRAPHY
15 Doses and Risks in Diagnostic Radiology, Interventional Radiology and
Cardiology, and Nuclear Medicine
DOSES FROM NATURAL BACKGROUND RADIATION
Cosmic Radiation
Natural Radioactivity in the Earth’s Crust
Internal Exposure
Areas of High Natural Background
COMPARISON OF RADIATION DOSES FROM NATURAL SOURCES
AND HUMAN ACTIVITIES
DIAGNOSTIC RADIOLOGY
Dose
Effective Dose
Collective Effective Dose
INTERVENTIONAL RADIOLOGY AND CARDIOLOGY
Patient Doses and Effective Doses
Dose to Personnel
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