Comprehensive toxicology: Ionized Radiation as Carcinogen.

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From Jones, J. A., Karouia, F., Cristea, O., Casey, R. C., Popov, D., & Maliev, V.
(2018) Ionizing Radiation as a Carcinogen. In: McQueen, C. A., Comprehensive Toxicology,
Third Edition. Vol. 7, pp. 183–225. Oxford: Elsevier Ltd.
ISBN: 9780081006016
Copyright © 2018 Elsevier Ltd. All rights reserved.
Elsevier Science
Author's personal copy

7.09 Ionizing Radiation as a Carcinogenq
JA Jones, Baylor College of Medicine- Center for Space Medicine, Urology, Houston, Texas, USA
F Karouia, NASA Ames Research Center, Moffitt Field, California, USA
O Cristea, University of Ottawa, Ottawa, Ontario, Canada
RC Casey, University Space Research Associates, NASA- Johnson Space Center, Houston, TX, USA
D Popov, Advanced Medical Technologies & Systems, Richmond Hill, Ontario, Canada
V Maliev, Vladicaucasian Scientific Center of Russian Academy of Sciences, Vladicaucas, North Ossetia–Alania, Russia
© 2018 Elsevier Ltd. All rights reserved.
7.09.1 Introduction 190
7.09.2 Radiation Spectrum 191
7.09.2.1 Units 192
7.09.2.2 Dose and Dose Rate 192
7.09.2.3 Biophysical Damage Mechanisms 193
7.09.2.4 Atomic Ionization 195
7.09.3 Radiobiology 196
7.09.3.1 Primary Versus Secondary Damage 196
7.09.3.2 Mechanisms of Damage From Ionizing Radiation 196
7.09.3.3 Direct DNA Damage 196
7.09.3.4 Indirect DNA Damage or Oxidative Injury 198
7.09.3.5 Epigenetic Effects 198
7.09.3.6 Bystander Effects 198
7.09.3.7 Adaptive Response 199
7.09.4 Evidence for Radiation Carcinogenesis 200
7.09.4.1 Human Data 200
7.09.4.2 Atomic/Nuclear Weapon Survivors 200
7.09.4.3 Industrial Accidents 201
7.09.4.3.1 Chernobyl and JCO nuclear criticality accident 201
7.09.4.3.2 Techa River Basin 202
7.09.4.4 Medical Radiation Therapy and Cancer Risk 202
7.09.4.5 Medical Conditions Predisposing to Radiation-Induced Cancer 203
7.09.4.6 Radiation Carcinogenesis in Animal Models 203
7.09.4.7 In Vitro Evidence for Radiation Carcinogenesis 204
7.09.4.7.1 Chromosome Aberrations 204
7.09.4.7.2 Cell Transformation 205
7.09.4.7.3 Mutagenesis in Somatic Cells 206
7.09.4.7.4 Gene Expression 206
7.09.4.7.5 Biological Effects Occurring in Nonirradiated Cells 207
7.09.5 Molecular Biology of Radiation Carcinogenesis 207
7.09.5.1 Cell Cycle Delay and Gene Induction 207
7.09.5.2 Oncogenes in Radiation Carcinogenesis 208
7.09.5.2.1 Ras genes 209
7.09.5.2.2 c-myc gene 209
7.09.5.2.3 bcl-2 genes 209
7.09.5.2.4 erbB2 genes 210
7.09.5.2.5 Oncogenes in Radiation Resistance 210
7.09.5.3 Tumor Suppressor Genes 210
7.09.5.3.1 BRCA1/2 genes 210
7.09.5.3.2 p53 genes 211
7.09.5.4 Interactions Between Oncogenes and Tumor Suppressor Genes in Radiation-Induced Cancer 211
7.09.5.5 Genomic Instability 211
7.09.6 Radiation Carcinogenesis Risk Modeling 211
7.09.6.1 Risks Effect Definition 212
7.09.7 Projecting Lifetime Carcinogenesis Risk 212
q
Change History: February 2017, JA Jones and F Karouia updated the text and the references.
This is an update of JA Jones, RC Casey, F Karouia, Ionizing Radiation as a Carcinogen, Comprehensive Toxicology, Second Edition, edited by Charlene A.
McQueen, Elsevier, Oxford, 2010, Volume 14, Pages 181–228.
183
Comprehensive Toxicology, Third Edition, 2018, 183–225

7.09.8 Radiation Protection from Ionizing Radiation 214
7.09.8.1 Shielding 214
7.09.8.2 Dose Limitation 215
7.09.8.3 Radioprotectants/Chemoprevention 215
7.09.8.4 Immunoprotection Strategies 216
7.09.9 Conclusions 216
References 219
Glossary
Absorbed dose Mean energy imparted by ionizing radiation to an irradiated object per unit mass. Units: gray, rad. Thus,
absorbed dose is the amount of energy deposited by a radiation in a quantity of material (e.g., tissue) through ionization and
excitation. Units of measurement are rad/mrad or Gy/mGy (SI unit). 1 Gy¼100 rad or 10 mGy¼1 mrad. Absorbed dose is
a useful parameter for determining the likelihood and severity of acute radiation effects. A typical chest X-ray yields $10 mrad
of dose.
Acute effects of radiation Effects that occur shortly after exposure to radiation, usually within a week. These acute effects result
from exposure to radiation at relatively high doses, usually greater than 1 Gy. They are usually due to the killing cell in critical
tissues in the body.
Alpha radiation Type of particulate radiation that is released from a radioactive atom. Alpha particles are helium nuclei. Alpha
particle radiation is densely ionizing (high LET) radiation and can be very damaging, but it is very limited in its ability to
penetrate tissue. For example, alpha radiation will not penetrate the outer layers of the skin.
Background radiation Radiation received by the entire human population due to natural occurring radiation and radioactive
materials in the environment. The three major sources of natural background radiation are (1) cosmic radiation, (2) radiation
from naturally occurring radioactive elements in the Earth’s surface, and (3) internal radiation arising from radioactive atoms
normally present in foodstuffs or in the air.
Cell transformation A process by which cells in vitro, which have a limited ability to divide, are altered by radiation or
chemicals so as to have an unlimited division potential.
Comet assay Comet assay, also called single cell gel electrophoresis (SCGE), is a sensitive and rapid technique for quantifying
and analyzing DNA damage in individual cells. As such, this is one of the techniques used in the area of cancer research for the
evaluation of genotoxicity and effectiveness of chemoprevention. Swedish researchers Östling and Johansson developed this
technique in 1984. Singh et al. later modified this technique, in 1988, as the alkaline comet assay. The resulting image that is
obtained resembles a “comet” with a distinct head and tail. The head is composed of intact DNA, whereas the tail consists of
damaged (single-strand or double-strand breaks) or broken pieces of DNA. While most of the applications of the comet assay
have been to study animal eukaryotes, there have been reports of successful application in the study of plant cells. Individual
cells are embedded in a thin agarose gel on a microscope slide. All cellular proteins are then removed from the cells by lysing.
The DNA is allowed to unwind under alkaline/neutral conditions. Following the unwinding, the DNA undergoes electro-
phoresis, allowing the broken DNA fragments or damaged DNA to migrate away from the nucleus. After staining with a DNA-
specific fluorescent dye such as ethidium bromide or propidium iodide, the gel is read for amount of fluorescence in head and
tail and length of tail. The extent of DNA liberated from the head of the comet is directly proportional to the amount of DNA
damage.
Cross section Probability of a nuclear interaction within a defined region of a more stable material. Likewise, the chloride atom
has seven electrons in the outermost electron orbit. Gaining one electron fills the orbit with eight electrons, which makes the
atom more stable. Thus, the give and take of selected electrons is ordinarily involved in the formation of ions.
Curie Unit of measurement of radioactivity. In modern nuclear physics, the curie is precisely defined as the amount of
a substance in which 37 billion atoms per second undergo radioactive disintegration. A curie was originally defined as the
amount of radon in equilibrium with 1 g of radium, or the amount of any radioactive substance that undergoes the same
number of radioactive disintegrations in the same time as 1 g of radium. When it is defined this way, the unit is still used as
a measure of radiation dosage in medicine. The Becquerel is the preferred unit of measure for radioactivity in SI units. One curie
equals 3.7Â10À10
Bq.
Deterministic effects Effects formally known as nonstochastic effects that may appear early or late after irradiation. There is
a threshold dose above which both the probability of occurring and the severity of the effects increase. Most deterministic
effects involve cell killing.
DNA fingerprint Some minisatellites share a repeating unit similar in base sequences. Such minisatellites can be examined
using a common probe and 10–20 minisatellite bands of different sizes are detected on a Southern filter. The band pattern is
extremely variable among different individuals and is quite useful for molecular identification of individuals, thus the term
DNA fingerprints.
Dose See absorbed dose.
184 Ionizing Radiation as a Carcinogen

Dose effect (dose–response) model Mathematical formulation used to predict the magnitude of an effect that would be
produced by a given dose of radiation.
Dose equivalent Amount of biologically effective dose deposited by an ionizing radiation. Dose equivalent is only valid for
assessing the risk of cancer or genetic effects in humans as a result of radiation exposure. It is computed by multiplying the
absorbed dose by a radiation species-dependent quality factor. Quality factors can range from 1 to 20. Units of measurement
are rem/mrem or Sv (SI unit). 1 Sv¼100 rem or 10 mSv¼1 mrem. A typical chest X-ray yields $10 mrem of dose equivalent.
Dose rate Quantity of absorbed dose delivered per unit of time.
Dose rate effectiveness factor (DREF) Factor by which the effect caused by a specific dose of radiation changes at low dose
rates as compared with high dose rates.
Energetic solar particle event Events characterized by >100 MeV proton flux greater than or equal to 1 p.f.u. at
geosynchronous orbit as measured by a GOES satellite. Energetic SPE flux can range from $1 to 550 p.f.u. (or higher).
Energetic SPEs can persist from several hours (very small events) to several days. Energetic SPEs are believed to result from the
propagation of fast interplanetary shocks formed by CMEs.
eV Kinetic energy of charged particles, which is measured in units of eV. Multiples of eV are frequently used. These include:
keV ¼ 1000 eV;
MeV ¼ 1000000 eV;
GeV ¼ 1000000000 eV,
Excess risk Refers to the excess cases of a particular health effect associated with exposure to radiation. Excess risk can be
described in various ways including the (1) difference in the rate of occurrence of a particular health effect in an exposed
population and an equivalent population with no radiation exposure (rate difference or absolute risk, the unit for which is
excess number of cases per person-year-sievert); (2) ratio of the rates in exposed and unexposed populations (relative risk, a unit
of no dimension); and (3) ratio of the rate difference to the rate in an unexposed population (excess relative risk, i.e., relative risk
minus 1). Excess risk can depend on various factors including radiation dose, age at exposure, time since exposure, current age,
and sex. Assessments of the risk among the atomic bomb survivors are carried out using regression methods, and risk estimates
are usually reported for a specific dose (often 1 Gy or 1 Sv) for a specified combination of other important factors. In general, it
is not possible to summarize the excess risk associated with a single factor.
Fluence Rate at which particles are incoming, measured in number of particles per second.
Flux Density at which particles are incoming, measured in number of particles per square centimeter.
Gamma rays Short-wavelength EMR of nuclear origin with an energy range of about 10 keV–9 MeV.
Gray (Gy) Quantity of energy imparted by ionizing radiation to a unit mass of matter. A gray (abbreviated as Gy) is the amount
of energy deposited in tissues; technically, one joule of energy per kilogram of tissue. When ionizing radiation passes through
a body, some of its energy is imparted to the surrounding tissue. The average cumulative radiation doses from natural, medical,
and occupational sources are estimated to be about 2 mGy (or 0.002 Gy) per year for humans. Gray is used in the SI system, the
term “rad” used in the USA, is replaced by gray (Gy) and is defined as:
1 Gy ¼ 1 J kgÀ1
Since 1 rad ¼ 10À2 J kgÀ1
;
1 Gy ¼ 100 rad
High-Z, high energy (HZE) particles Heavy (high atomic number), high energy particles, such as carbon or iron nuclei, with
an energy range in cosmic rays between approximately 102
and 103
MeV per nucleon.
Ionization An ion is an atom or a molecule that has an unequal positive and negative charge. The negative electrical charge is
derived from electrons and the positive charge is derived from protons in the nucleus. An example of an ion is sodium chloride
(NaCl). When NaCl is dissolved in water, sodium and chloride separate to form two kinds of ions: Naþ
and ClÀ
. The sodium
loses one electron and the chloride gains one electron. Why does this happen? Because the sodium atom has a single electron in
the outermost electron orbit, losing it makes the atom more stable. Likewise, the chloride atom has seven electrons in the
outermost electron orbit. Gaining one electron fills the orbit with eight electrons, which makes the atom more stable. Thus, the
give and take of selected electrons is involved in the formation of ions ordinarily.
Isotropic Radiation with the same magnitude (values) from all axes (directions).
JCO On Sep. 30, 1999, a criticality accident occurred at the Tokai nuclear fuel plant in Japan. The plant operated by JCO Co.
Ltd, a 100% subsidiary of Sumitomo Metal Mining Co. Ltd, converts enriched uranium hexafluoride (UF6) to uranium dioxide
(UO2) for use in nuclear fuel. Criticality accidents involve a self-sustaining chain reaction caused from handling of too large
amounts of enriched uranium. The chain reaction continued for around 20 h, before it could be stopped.The uranium pro-
cessed was enriched to 18.8% of uranium-235, rather than the 3%–5% used for commercial light water reactor fuel. Material of
this high enrichment grade was being produced for the experimental Joyo Fast Breeder reactor.The plant has an annual
production capacity of 715 tonnes of uranium for light water reactors and 3 tonnes of uranium for fast breeder reactors.The
chain reaction caused heavy releases of gamma and neutron radiation. Three workers were exposed to doses of up to 17 Sv
(sieverts), causing severe radiation sickness. The worker exposed to the highest dose died on Dec. 21, 1999. The worker exposed
Ionizing Radiation as a Carcinogen 185

to the second highest dose of 6–10 Sv died on Apr. 27, 2000. Sixty-eight other persons were irradiated at lower levels. Among
them were the workers who stopped the chain reaction: they were exposed to doses of up to 119.79 mSv, exceeding the
100 mSv limit for emergency situations. The annual dose limit for workers is 50 mSv (while ICRP currently recommends
20 mSv). As of Oct. 7, 1999, radiation levels remained high inside the plant building, preventing inspection of the damage
inside the plant.On Nov. 4, 1999, the Science and Technology Agency submitted a report to the Nuclear Safety Commission,
containing estimates of radiation exposures during the criticality accident, based on an analysis of uranium solution sampled
from a tank inside the fuel processing plant and the neutron levels monitored around the plant. The report says that1. the
radiation dose received at a distance of 80 m from the accident site (that is the nearest boundary of the plant) was estimated at
75 mSv (this figure was revised to 30 mSv, according to Yomiuri Shimbun of Dec. 12, 1999; details are not known yet) for the
first 25 min of the criticality accident and 160 mSv for the whole criticality period of 20 h; and 2. the radiation dose received at
a distance of 350 m from the plant (that was the evacuation boundary) was estimated at almost equal to the annual
permissible dose of 1 mSv for the first 25 min and 2 mSv for the whole event.Since the evacuation started only 5 h after the
beginning of the criticality accident, residents may have received doses of more than 75 mSv, that is, 75 times the permissible
annual dose of 1 mSv.The government has so far said 69 people were exposed to radiation, but the latest survey says the
number of affected people could increase.
LET Quantifies the amount of energy deposited per unit length of particle track. This factor increases with the square of the
charge and is inversely proportional to the energy of the radiation particle. The influence of the electric force field depends on
the velocity of the particle. Slower moving charged particles will produce more ionizations per unit path length than faster
moving ones. LET accounts for all energy transfers along the particle path, irrespective of mechanism. Thus, LET of protons,
deuterons, alpha particles, and other heavy, charged particles lose kinetic energy rapidly as they penetrate matter. Most of this
energy is lost as the particles interact inelastically with electrons of the absorbing medium. Energy transferred to an electron in
excess of its binding energy appears as kinetic energy of the ejected electron. An ejected electron and the residual positive ion
constitute an ion pair; for example, an average energy of 33.7 eV, termed the W-quantity or W, is expended by charged particles
per ion pair produced in air. The specific ionization (SI) is the number of primary and secondary ion pairs produced per unit
length of path of the incident radiation. LET is the average loss in energy per unit length of path of the incident radiation. The
LET is the product of the specific ionization and the W-quantity:
LET ¼ SIð Þ Wð ÞLET ¼ SIW
where SI is the specific ionization and W is the W-quantity of the medium.The range of ionizing particles in a particular
medium is the straight line distance traversed by the particles before they are stopped completely. For heavy particles with
energy E, the range in a particular medium may be estimated from the average LET:
range ¼ E=LETrange ¼ E=LET
The SI and LET are not constant along the entire path of monoenergetic charged particles traversing a homogeneous medium.
The increase in SI near the end of the path of the particles reflects the decreased velocity of the particles as they traverse the
medium. As the particles slow, the SI increases because nearby atoms are influenced for a longer period. The region of increased
SI is termed the Bragg Peak.
Linear dose response Relationship between dose and biological response, which is a straight line. In other words, the rate of
change (slope) in the response is the same at any dose. A linear dose response is written mathematically as follows: If Y
represents the expected or average response and D represents dose, then
Y ¼ aDY ¼ aD
where a is the slope, also called the linear coefficient.
Linear quadratic dose response Relationship between dose and biological response that is curved. This implies that the rate of
change in response differs at different doses. The response may change slowly at low doses, for example, but rapidly at high
doses. A linear quadratic dose response is written mathematically as follows: If Y represents the expected or average response
and D represents dose, then
Y ¼ aD þ bD2
Y ¼ aD þ bD2
where a is the linear coefficient (or slope) and b is the quadratic coefficient (or curvature).
microsatellite The genome contains sequences consisting of two to five base repeats, shorter than minisatellite core sequences,
which are thus called microsatellites. In contrast to minisatellites, microsatellites distribute evenly throughout the genome and
are frequently used as landmarks for gene mapping. Human hereditary diseases caused by unusual expansion of three base
repeats are now known (e.g., CGG repeats in fragile X syndrome, CAG repeats in Huntington’s disease). The number of repeats
varies among normal individuals, as well as among family members of the affected individuals and even among somatic cells
of an individual. The inheritance pattern of the repeats does not seem to follow Mendelian rules. Patients of hereditary
nonpolyposis colon cancer are known to show instability in microsatellite repeat number. Radiation effects on microsatellite
instability are not known.
Monte Carlo Statistical method that evaluates a probability distribution by means of random sampling.

Multiplicative interaction model A model in which the relative risk (the relative excess risk plus 1) resulting in exposure to two
risk factors is taken to be the product of the relative risks from the two factors taken separately.
Neutron Uncharged subatomic particle capable of producing ionization in matter by collision with charged particles.
Nonstochastic effect See deterministic effects.
Nuclide Species of atom characterized by the constitution of its nucleus, which is specified by the atomic mass (M) and atomic
number (Z).
Organ dose Used interchangeably at the Radiation Effects Research Foundation (RERF) with the terms “mean organ dose” or
“dose.” It is defined as the energy absorbed in a specific organ divided by its mass, that is, the average energy absorbed per unit
mass. This quantity is expressed in gray or its submultiples. The organ dose calculation allows for effects of external shielding
and shielding provided by other tissues.
Photon Unit of EMR. One g-ray is a photon of EMR.
Quality factor (Q) Function of the particle LET, as determined by the charge and energy of radiation particles. This factor,
which accounts for differences in the biological effectiveness of different particles, is used to convert an absorbed dose into
a dose equivalent. The Q is based on observations of RBE. ICRP, 1991 defined Q for use in risk (R) estimates for radiation
protection practice as R¼k2QÂD/DREF, where k is the dose rate risk coefficient for high-rate g-rays and D is the adsorbed dose.
H is the term for dose equivalent, where H¼QD. The unit for H is rem or Sv. Current values for the quality factor may range
from 1 to 20. X-rays are assigned a value of unity (1). Quality factor values as high as 100 may be deemed appropriate as
additional research continues.
Rad (United States)/gray (international) The absorbed dose, rad, is the amount of energy absorbed from radiation per mass
of material (1 rad¼100 ergs gÀ 1
). The SI unit for absorbed dose is the gray (1 gray or Gy¼100 rad). Chemical and biological
changes in tissue exposed to ionizing radiation depend upon the energy absorbed in the tissue from the radiation rather than
upon the amount of ionization that the radiation produces in air. To describe the energy absorbed in a medium from any type
of ionizing radiation, the quantity of radiation should be described in units of rads. The rad, which was originally an acronym
for radiation absorbed dose, is a unit of absorbed dose and represents the absorption of 10À 2
Joules of energy per kilogram (or
100 ergs gÀ1
) of absorbing material:
1 rad ¼ 10À2
J kgÀ1
¼ 100 ergs gÀ1
The absorbed dose D in rads delivered to a small mass m in kilograms is
D rad ¼ E=m Ä 10À2
J kgÀ1
where E, the absorbed energy in joules, is “the difference between the sum of the energies of all directly and indirectly ionizing
particles which have entered the volume and the sum of the energies of all those which left it minus the energy equivalent of
any increase in rest mass that took place in nuclear or elementary particle reactions within the volume.” This definition means
that E is the total energy deposited in a small volume of irradiated medium, corrected for energy removed from the volume in
any way.
Radiation weighting factor (Wr) Factor, established by consensus and used in radiation protection, to weight the absorbed
dose averaged over an organ to obtain the equivalent dose on a common scale for types of ionizing radiation.
Radioisotope Radioactive species of an element with the same atomic number and identical chemical properties.
Radionuclide Radioactive species of an atom characterized by the constituents of its nucleus (atomic number).
Radiosensitivity Relative susceptibility of cells, tissues, organs, and organisms to the injurious action of radiation.
Radiosensitivity and its antonym, radioresistance, are used in a comparative sense rather than an absolute sense.
Relative biological effectiveness (RBE) Chemical and biological effects of irradiation depend not only on the amount of
energy that is absorbed in an irradiated medium but also on the distribution of absorbed energy within the medium. For equal
absorbed doses, various types of ionizing radiation often differ in the efficiency with which they illicit a particular chemical or
biological response. RBE describes the effectiveness or efficiency with which a particular type of radiation evokes a certain
chemical or biological effect. It is computed by comparing results obtained with the radiation in question to the results
obtained with a reference radiation (e.g., medium energy X-rays):
RBE ¼ dose of reference radiation=dose of experimental radiationð Þ to produce the same end point.
For a particular type of radiation, the RBE may vary from one chemical or biological response to another. The RBE dose in rem
is the product of the RBE and the dose in rad.
RBE dose remð Þ ¼ absorbed dose radð Þ Â RBE
The concept of RBE dose should be limited to the discipline of radiation biology.
Relative risk Expression of risk relative to the underlying (baseline) risk. If the relative risk is 2, the excess risk equals the
baseline risk.

rem (United States)/sievert (international) The biological equivalent dose, rem (Roentgen equivalent man), is the absorbed
dose adjusted for biological effectiveness of the particular type of radiation. It is the product of the absorbed dose and the
quality factor. The SI unit for biological equivalent dose is sieverts (1 sievert or Sv¼100 rem):
rem ¼ rad Â quality factor
sievert ¼ gray Â quality factor
Replication Cellular process of DNA synthesis (duplication) from DNA template. It involves unwinding of the DNA helix and
separation of the strands to expose the complementary base for nucleotide addition, one at a time, and requires the enzyme
DNA polymerase in eukaryotes.
Risk coefficient Increase in the incidence of disease or mortality per person exposed per unit equivalent dose. The relative risk
coefficient is the fractional increase in the baseline incidence or mortality rate for a unit dose.
Risk estimate Number of cases (or deaths) projected to occur in a specified exposed population per unit of collective dose for
a specified exposure regime and expression period, for example, number of cases per person (in gray).
Roentgen One of the oldest units of radiation measurement (W. K. Roentgen discovered X-rays in 1895). The Roentgen is
a measure of the quantity of ionization induced in air from radiation exposure.
Sievert (Sv) In the SI system, the sievert (Sv) replaces the rem (1 Sv¼100 rem). Often, the effectiveness with which the
different types of radiation produce a particular chemical or biological response varies with the LET of the radiation. The dose
equivalent (DE) in rem is the product of the dose in rad and a quality factor (QF) that varies with the LET of the radiation:
DE remð Þ ¼ D radð Þ Â QF
The dose equivalent reflects a recognition of differences in the effectiveness of different radiations to inflict overall biological
damage and is used in computations associated with radiation protection and safety. The sievert unit of radiation dose is used
for radiation protection purposes. When an individual is exposed to mixed sources of radiation, the total biologically effective
dose is calculated by multiplying the physical dose (expressed in units called gray) of each kind of radiation by a corresponding
factor (the Q-factor) specified for the type of radiation and its energy, after which these amounts are summed. The factor for g-
rays is 1; therefore, 1 Sv¼1 Gy. The factor for the neutrons in atomic bomb radiation is 10; therefore, 1 Sv¼0.1 Gy.
Solar flare Sudden release of energy across the electromagnetic spectrum from a relatively small region of the Sun. Flares are
important because they are believed to be a manifestation of solar processes that produce SPEs. Ground-based observatories
and the GOES continuously monitor for solar flares. Flares are often characterized by brightening in an optical wavelength (H-
a, a red wavelength) or soft X-rays (1–8 Å). NOAA characterizes flares by their soft X-ray intensity as measured by the GOES X-
ray detector. Flares are classified on a logarithmic scale using B, C, M, and X designations for very small, small, moderate, and
large X-ray flares.
Solar particle event (SPE) Events characterized by the >10 MeV proton flux greater than or equal to 10 p cmÀ 2
- sÀ1
srÀ1
(p.f.u.) at geosynchronous orbit as measured by a GOES. SPE flux can range from $10 to 40 000 p.f.u. (or higher). SPEs, which
can persist from several hours (very small events) to a couple of weeks, are believed to result from the propagation of moderate
to fast interplanetary shocks formed by CMEs.
Stochastic effects Random events leading to effects whose probability of occurrence in an exposed population of cells or
individuals (rather than severity in an affected cell or individual) is a direct function of dose. These effects are commonly
regarded as having no threshold. Hereditary effects are regarded as being stochastic. Some somatic effects, especially
carcinogenesis, are regarded as being stochastic.
Target theory (hit theory) Explains some biological effects of radiation on the basis that ionization, which occurs in a discrete
volume (the target) within a cell, directly causes a lesion that later results in a physiological response to the damage at that
location. One, two, or more hits (ionizing events within the target) may be necessary to elicit this response.
Threshold dose Dose level below which there is no effect of radiation on the biological response. It is often difficult to
distinguish between a threshold and a linear quadratic dose response, where the response changes only slightly at low doses. A
threshold model postulates that radiation does not cause the effect at any level below the threshold. Radiation thresholds are
generally thought to be limited to acute (short-term) effects that are called deterministic, because they require depletion of
certain cells in the body to below a critical number in a given organ or tissue. These effects include radiation sickness (nausea
and vomiting), infection and bleeding, and loss of hair.
Transcription Cellular process of making RNA from the DNA template. This type of RNA is called messenger RNA (mRNA).
Translation Cellular process of synthesizing proteins from the mRNA template in ribosomes.
Transport calculation Calculation of particle distributions and energy behind a specific shield. Transportation calculation is
derived from the basic nuclear cross sections for interaction and fragmentation in shielding.

Abbreviations
AP Apurinic/apyrimidic
ASA Acetylsalicylate
AT Ataxia telangiectasia
ATM Ataxia telangiectasia mutated
bFGF Basic fibroblast growth factor
CI Confidence interval
CDKN1A Cyclin-dependent kinase inhibitor 1A
CNS Central nervous system
CSF Colony-stimulating factor
DDC Diethyldithiocarbamate
DMSO Dimethylsulfoxide
DNA Deoxyribonucleic acid
DNA-PK DNA-dependent protein kinase
DREF Dose rate effectiveness factor
DSB Double-strand break
EGCG Epigallocatechin gallate
EGF Epidermal growth factor
EGR-1 Epidermal growth factor receptor
EMR Electromagnetic radiation
ERR Excess relative risk
FGF Fibroblast growth factor
FISH Fluorescence in situ hybridization
GCR Galactic cosmic radiation
GJIC Gap junction intercellular communication
GM-CSF Granulocyte/macrophage colony-stimulating factor
GPX Glutathione peroxidase
Gy Gray
HGF Hepatocyte growth factor
HNSCC Head and neck squamous cell carcinoma
HO2* Peroxy radical
HPRT Hypoxanthine-guanine phosphoribosyl transferase
HZE High Z, high energy
HZETRN High Z, high energy transport code
IAEA International Atomic Energy Agency
ICRP International Commission on Radiological Protection
IGF-1 Insulin-like growth factor-1
IL Interleukin
IR Infrared
ISS International Space Station
JCO JCO Company Limited (a company operating the Tokai nuclear fuel plant in Japan, where a radiation release accident
occurred in 1999)
LD50 Median lethal dose (lethal for 50% of test subjects)
LET Linear energy transfer
LLR Long-lived organic radical
LSS Life Span Study
MAP Mitogen-activating protein
MW Microwave
NAS National Academy of Sciences
NCI National Cancer Institute
NCRP National Council for Radiation Protection and Measurement
NHEJ Nonhomologous end joining
NIH National Institutes of Health
NSAIA Nonsteroidal anti-inflammatory agent

OH* Hydroxyl radical
OSHA Occupational Safety and Health Administration
PARP Poly(ADP-ribose) polymerase
PC Probability of causation
PCNA Proliferating cell nuclear antigen
PGE2 Platelet granule extract 2
PKC Protein kinase C
PYSv Person-year sieverts
rad Radiation absorbed dose
RBE Relative biological effectiveness
REID Risk of exposure-induced death
rem Roentgen equivalent man
RNA Ribonucleic acid
RNS Reactive nitrogen species
ROS Reactive oxygen species
RR Relative risk
SCE Sister chromatid exchange
SI International unit of measurement
SRD Specific radiation determinant
SSB Single-strand break
TNF Tumor necrosis factor
UV Ultraviolet
VEGF Vascular endothelial growth factor
XRT X-ray telescope
Nomenclature
l Wavelength
c Speed of light
H Dose equivalent
h Planck’s constant
Hz Hertz
k Dose rate risk coefficient for high rate g-rays
Sv Sievert
f Frequency
7.09.1 Introduction
Ionizing radiation is generally considered to be any form of radiation exposure that will produce a subatomic ionization event.
Ionizing radiation may be in the form of either electromagnetic waves or particles; however, it must have sufficient energy to
cause ionization in the target molecule. For electromagnetic radiation (EMR), the wavelength is usually shorter and therefore the
energy is higher than for nonionizing radiation; thus, ionizing radiation is more likely to produce a biological effect. Ultraviolet
(UV) EMR is intermediate in wavelength and energy and is typically considered as nonionizing; however, it is clearly mutagenic,
can produce ionization, and should be considered as a carcinogen. (Nonionizing radiation is discussed elsewhere in the textbook.)
Although, perhaps, recognized later than its chemical counterparts, ionizing radiation is now regarded as a carcinogen and can act
independently or synergistically with other carcinogens to produce neoplasia in living systems via its unique mechanisms of muta-
tion and biological effect. This article discusses the carcinogenic nature of ionizing radiation.
This article will first describe the physical interaction between the different forms of ionizing radiation and cellular and subcel-
lular components, as well as the factors that are likely to produce an elevated risk of neoplasia. Next, the biological and molecular
effects of radiation within living systems will be examined, followed by a presentation of the epidemiological evidence for radiation
as a carcinogen in animals and humans. Some risk models for carcinogenesis following an exposure to ionizing radiation, as well as
some strategies for protection against radiation-induced biological damage, are included. Important new avenues of research and
some of the controversial issues surrounding radiation carcinogenesis are brought forth. Finally, the significance of ionizing
radiation-induced carcinogenesis to the understanding and management of the broader issue of the etiology of human cancer
will be addressed.

7.09.2 Radiation Spectrum
Radiation is a form of energy that is emitted or transmitted in the form of electromagnetic waves and/or particles. The electromag-
netic spectrum is a continuum of all electromagnetic waves according to frequency and wavelength. EMR can be described in terms
of a stream of photons, which are massless particles, each traveling in a wave-like pattern and moving at the speed of light. Elec-
tromagnetic energy at a particular wavelength l (measured in meters) has an associated frequency f (measured in cycles per seconds,
i.e., hertz) and photon energy E (measured in electron volts). Thus, the electromagnetic spectrum may be expressed in terms of any
of these three quantities. They are related by the following equations:
l ¼
c
f
and E ¼ hf or E ¼
hc
l
where c is the speed of light (299,792,458 m sÀ 1
) and h is the Planck’s constant (hz6.62Â10À 34
J s).
Thus, high-frequency electromagnetic waves have a short wavelength and high energy, whereas low-frequency waves have a long
wavelength and low energy. Therefore, a shorter wavelength corresponds to more energetic radiation and an increased potential for
biological harm. The electromagnetic spectrum is divided into different types of radiation based on wavelength ranges and encom-
passes a wide range of terrestrial applications. These different types of radiation, expressed as a function of decreasing wavelength,
include radio, microwave (MW), infrared (IR), visible, UV, X-ray, and g-ray (Fig. 1).
Fig. 1 The electromagnetic spectrum. The diagram shows the entire spectrum of the electromagnetic waves. The scale at the bottom indicates
representative objects that are equivalent to the wavelength scale and their respective energy. Reproduced from NASA (http://son.nasa.gov/tass/
content/electrospectrum.htm).

Ionizing radiation is composed of either particles or photons that have enough energy to ionize an atom or molecule by
completely removing an electron from its orbit, thus creating a more positively charged atom. The ionization of matter can be
divided into two processes: indirect and direct ionization (BEIR-VII, 2006). Certain types of EMR, such as X- and g-rays, are termed
indirectly ionizing because part or all the photon energy is transferred to the electrons in the cell’s molecules, which, upon release,
produce the bulk of subsequent ionization events. In contrast to this, charged particles, such as high-energy electrons, protons,
a-particles (a helium atom nucleus moving at a very high speed), b-particles (a high-speed electron or positron), and fast heavy
ions, are termed direct ionizing radiation because while they traverse the cell, they ionize numerous molecules by direct collisions
with their electrons.
Nonionizing radiation includes the spectrum of UV, visible light, IR, MW, radiofrequency, and extreme low frequency (Fig. 1).
Nonionizing radiation is present in a wide range of occupational settings and can pose a considerable health risk. UV is classified
into near-, medium-, and far UV according to energy level, where near UV is nonionizing. However, medium- and far UV radiation
may carry enough energy per quantum to ionize atoms and molecules. Thus, UV radiation can also be considered within the spec-
trum of ionizing radiation.
7.09.2.1 Units
Some biophysical notions are fundamental to an effective understanding of ionizing radiation carcinogenesis. In the context of bio-
logical systems, ionizing radiation must be understood in terms of the radioactivity of the source, the energy of the radiation, the
level of background radiation, and the level of radiation energy absorbed. The latter, from an occupational exposure point of view, is
the most important parameter. By definition, the common unit of measure for energy present in ionizing radiation is the electron
volt (eV). One eV equals 1.6Â10À12
ergs or 1.6Â10À 19
J. Other parameters, apart from the energy level of a particular type of radi-
ation, are important to the understanding of the biological effects of ionizing radiation (Table 1). A distinction is made between
sparsely ionizingdor low linear energy transfer (LET)dand densely ionizingdor high LETdradiation. The LET of an ionizing
charged particle is defined as the average energy lost by the particle due to electronic interactions per unit length of its trajectory;
it is expressed in kiloelectronvolts per micrometer (keV mmÀ1
) (BEIR-VII, 2006). High-energy EMR, such as X- and g-rays, is sparsely
ionizing since, in cells, it results in the release of fast electrons that have low LET. In contrast to this, a-particles, neutrons, and heavy
particles (HZE) are densely ionizing because, in cells, they can release fast protons and heavier atomic nuclei that have high LET
(Fig. 2).
7.09.2.2 Dose and Dose Rate
The absorbed dose D, measured in gray (Gy), is the amount of energy deposited per unit mass of material (e.g., living tissue). One
gray is equivalent to 1 J of radiation energy absorbed per kilogram of tissue (1 J kgÀ 1
¼6.25Â1018 eV kgÀ 1
), and one centigray
(0.01 Gy) is equivalent to a rad. However, the types of radiation are diverse in how they deposit energy; therefore, the absorbed
dose is a poor descriptor of biological effects (Durante and Cucinotta, 2008). A dose of energetic particles normally causes more
damage than an equivalent dose of energetic photons (X- or g-rays). If the same biological event is induced by a dose of a standard
radiation (e.g., X-rays) and by a dose of a test radiation (e.g., HZE ions), then the ratio of the standard to test radiation dose is
defined as the relative biological effectiveness (RBE) of the test radiation. The RBE depends on several parameters, including
Table 1 The main parameters relevant to ionizing radiation
Parameter Radioactivity Absorbed dose Dose equivalent Exposure Energy
Definition The spontaneous
disintegration of
atomic nuclei. The
nucleus emits a-,
b-particles, or
electromagnetic rays
during the process
The mean of energy
absorbed per unit
mass of material
The estimate of radiation
risk that accounts for
the differences in the
biological effectiveness
of different types of
radiation that produce
the absorbed dose
Quantity that expresses
the ability of radiation
to ionize air
The ability
to do work
Common
units
Curie (Ci),
1 Ci¼3.7Â1010 Bq
Radiation absorbed
dose (rad), 1 rad¼100
ergs gÀ1
¼0.01 J kgÀ1
Roentgen equivalent
man (rem)
Roentgen (R) Joule (J)
International
System of
unit
Bequerel (Bq), 1 Bq
equals 1 event of
radiation emission
per second
Gray (Gy), 1 Gy¼100 rad Sievert (Sv), 1 Sv¼100
rem
Coulomb/kilogram (C kgÀ1
),
1R¼2.58Â10À4
C kgÀ1
of air
Electronvolt (eV)
1.6Â10À19
J
Modified from Rask, J., Elland, C., Vercoutere, W. (2006). Radiation biology educator guide. National Aeronautics and Space Administration (NASA).

LET, particle velocity and charge, dose and dose rate, biological end point, and oxygen concentration. To estimate biological effects
it is customary to scale the absorbed dose by a quality factor Q(LET), which is estimated from the measured RBE values for late
effects (Table 2). Current values for Q range from 1 at low LET (<10 keV mmÀ 1
) to 30 at high LET (around 100 keV mmÀ1
) and
then decrease at very high LET values because of what is called overkill or wasted energy (Durante and Cucinotta, 2008). The
dose equivalent or biologically dose equivalent, H¼DÂQ, represents the absorbed dose adjusted for the biological effectiveness
of a particular type of radiation. H is measured in sievert (Sv) and the centisievert (0.01 Sv) is equivalent to a rem (rad equivalent
in humans). Thus, the dose equivalent is intended to encompass all aspects of a certain radiation exposure influencing a biological
effect. Finally, another important factor needs to be introduced to understand the influence of dose rate on biological effect. The
dose rate effectiveness factor (DREF) measures the difference between acute exposures (a single large exposure) and chronic expo-
sures (an exposure fractionated over time) of the same type of radiation at the same dose. Similar to RBE, the DREF is expressed as
a ratio and is therefore an important scaling factor for the physician, allowing meaningful comparisons to be made between acute
exposure events for which there is historical evidence linking outcome and dose (e.g., atomic bomb survivors) and long-term expo-
sures involving low dose rates (e.g., long duration human spaceflight) (Jones et al., 2008).
7.09.2.3 Biophysical Damage Mechanisms
A full description of radiation physics and the interaction between radiation and target atoms is beyond the scope of this article and
can be found elsewhere (Jones et al., 2008). However, some of the relevant biophysical damage mechanisms need to be covered to
appreciate the processes important in energy deposition. Incident ionizing radiation can interact with matter by being either
Fig. 2 Comparison of particle tracks in human cells and nuclear emulsions. The figure emphasizes the biological impacts as a function of charged
particle tracks. (A–C) The DNA double-strand break distribution in human fibroblasts is depicted in situ by g-H2AX immunofluorescence staining
(every green focus corresponds to a DNA double-strand break). The different patterns of energy deposition (LET) for various particles is shown in the
different distribution of DNA double-strand break in cells. (A) The cells are exposed to sparsely ionizing, that is, low LET, g-rays. DNA breaks are
uniformly distributed in the nucleus. (B) The cells are exposed to densely ionizing, that is, high LET, one silicon nuclei particle. (C) The cells are
exposed to densely ionizing, that is, high LET, three iron nuclei particles. Cells exposed to high energy heavy ions show DNA damage along the path
traveled by the particles. Additionally, cellular biological damage (DNA double-strand break) increases as a function of LET. (D) The damage tracks of
different ions, from proton to iron, are seen in nuclear emulsions and show the increasing ionization density (LET) as charge, Z, increases. Our
understanding of biological knowledge decreases with increasing atomic number. A cell has been drawn to scale for comparison purposes.
Reproduced from Cucinotta, F. A.; Durante, M. (2006). Lancet Oncology 7, 431–435.

scattered or absorbed. As such, it can interact with one of the atomic components (i.e., nucleus or electrons), which usually produce
secondary radiation following the destruction of the incident radiation, the target, or both. Additionally, it can also interact with
atomic components that usually change the target atoms and lose energy via a complex chain reaction of radiation events (Jones
et al., 2008). The mechanisms of absorption are of particular interest because (1) absorption in body tissue may result in physio-
logical injury, (2) absorption is a phenomenon upon which the detection of ionizing radiation is based, and (3) the degree of
absorption, or type of interaction, is a primary factor in determining shielding requirements (NCRP, 1993).
The transfer of energy from an incident photon or particle to atoms of an absorber (e.g., tissue) may occur by excitation loss and
ionization. The process of excitation involves the addition of energy to an atomic or molecular system, thereby transferring it from
its ground or stable state to an excited or unstable state. Depending upon the type of interaction, either the atomic nucleus or one of
its orbital electrons may absorb the excitation energy. An excited electron will not retain its energy but will tend to return to its orig-
inal energy level either by emitting the excess energy in the form of a photon (e.g., X-ray) or by transferring its energy to the electrons
of other atoms or molecules. As indicated previously, ionization is any process that results in the removal of an electron from an
atom or molecule, thereby leaving the atom or molecule with a net positive charge. Ionization occurs if a- or b-particles, or g-
photons, transfer sufficient energy to dislodge one of the electrons from the outer orbital shells of the target atom. Each ionization
event produces an ion pair consisting of a free electron and the positively charged remainder of the atom.
As discussed in the previous sections, photons produced from EMR play an important role in the ionizing process. In the inter-
actions of photons with matter, the energy of the photons is transferred via collision; usually these collisions occur with orbital
electrons in an atom of the absorbing medium. The most relevant energy transfer processes whereby photons of sufficient energy
eject electrons from an atom, which can then interact with other atoms and molecules to produce a cascade of alterations that ulti-
mately lead to observable biological effects, will be described. These are the photoelectric effect, Compton scattering, and pair
production (BEIR-VII, 2006; Jones et al., 2008).
At low energies (<0.1 MeV), the photoelectric effect dominates in tissue. A photon interacts with and ejects an electron from one
of the inner shells of an atom. The photon is extinguished, and most of its energy is imparted to the ejected electron as kinetic
energy. As outer electrons fill the vacancy, this energy change is balanced by the emission of a photon. In tissue, this type of photon
emission has a low energy, typically 0.5 keV, and is of little biological consequence.
At medium photon energies (about 0.5–3.5 MeV), Compton scattering is the most probable event. Compton scattering occurs
when an incoming photon’s energy greatly exceeds the electron-binding energy of the affected atom. In this case, the energy of the
incoming photon is converted into the kinetic energy of an ejected electron and a secondary “scattered” photon. Hence the products
of Compton interactions are a scattered, less energetic photon of reduced wavelength, a high-speed electron, and an ionized atom.
The ejected electron will travel some distance in matter, producing ionizations along its track. In the course of this travel, the photon
Table 2 Quality factors associated with various types of radiation
Radiation type and energy range Source/occurrence Penetration properties in human Quality factor, Q
X-rays X-ray machine and accelerators, Van
Allen belts, solar radiation,
electromagnetic processes
X- and g-rays penetrate deeply (only a
fraction of the rays interact with
each layer of tissue)
1
g-rays Radioisotopes decay, Van Allen belts,
solar radiation, electromagnetic
processes
b-particles Radioisotopes decay, Van Allen belts,
solar radiation, galactic
cosmic radiation
The level of penetration depends on the
energy but is usually limited to less
than 8 mm in tissue
1
Neutrons: <10 keV Nuclear reactor, accelerators,
radiation therapy, atmosphere, Van
Allen belts, solar radiation, galactic
cosmic radiation
Neutrons penetrate deeply (only a fraction
of the neutrons interact with
each layer tissue)
5
Neutrons:10–100 keV 10
Neutrons: 100 keV
to 2 MeV
20
Neutrons:2–20 MeV 10
Neutrons: >20 MeV 5
Protons of energy >
2 MeV
Accelerators, radiation therapy, Van Allen
belts, solar radiation, galactic cosmic
radiation
The level of penetration depends
on the energy
2
a-Particles, fission
fragments, heavy
nuclei
Radioactive decay, solar radiation,
galactic cosmic radiation
The level of penetration depends on
the energy but is limited to about the
thickness of the epidermis
for a-particles
!20
Modified from Jones, J., Karouia, F. (2008). In: Barratt, M., Pool, S. (Eds.). Principles of clinical medicine for space flight, 1st ed. Springer, pp. 475–519.

may undergo additional Compton collisions until its energy is sufficiently degraded for the photoelectric process to predominate.
Thus, the photons in this energy range have their energy distributed over a relatively large volume of matter and may therefore have
significant biological effects.
At energies greater than 1.02 MeV, pair production can occur. A photon interacts with an atomic nucleus, and the photon energy
is converted into a positron and an electron. The photon energy above 1.02 MeV is converted into the kinetic energy of the newly
created particles. The electron and the positron interact with and can ionize other molecules until the excess kinetic energy is
exhausted.
7.09.2.4 Atomic Ionization
The so-called heavy nuclei are the nuclei of ordinary atoms of high atomic number whose electrons have been stripped away
yielding a very heavy, highly charged particle. Energy from a heavy ion is deposited along the core of the track, where the ionization
events produced in glancing collisions are quite dense. The core can be as wide as a few nanometers (Fig. 2D). Surrounding the core
is a penumbra of low LET energetic electrons (d-rays), where the density of ionization events is much less than that in the core but
extends for many microns (Cucinotta et al., 2000; Kramer and Kraft, 1994). These features allow even a single heavy ion particle to
affect many cells in an irradiated tissue, which make the biological effects of heavy ions different from those of other radiation
phenomena. As such, heavy ions are several times more effective than X-rays in terms of inducing radiation effects on small
DNA segments (Cucinotta et al., 2000; Goodhead, 1994, Fig. 3).
In addition to natural background radiation, the general population is exposed to low- and high LET radiation from man-made
sources such as X-ray equipment and radioactive materials used in medicine, research, and industry. The man-made ionizing radi-
ation exposure of the population of the United States has been estimated to account for 18% of the total annual US population
exposure, whereas the remainder originates from background radiation (Fig. 3) (NCRP, 1987). Fig. 4 illustrates the relative contri-
butions of the various man-made forms of radiation to the US population.
People working in medical facilities, mining, milling, or with nuclear material are required to protect themselves from occupa-
tional exposures to radiation. Therefore, the Occupational Safety and Health Administration (OSHA) strictly regulates the maximal
amount of radiation that workers can receive in connection with their occupation. The limits are 50 mSv yearÀ1
for the whole body
for terrestrial radiation workers and 50 cSv for astronauts (BEIR-VII, 2006; CERSSE, 2008).
As we have seen earlier, predicting the risks associated with exposure of biological tissue to a given quantity of radiation is
a complicated process. The current preferred measure of risk is the risk of exposure-induced death (REID) and has been imple-
mented by data originated from studies of Japanese atomic bomb survivors, animals, and cell cultures. REID quantifies the risk
of an exposed individual dying from a certain cancer as a function of the effective dose (Jones et al., 2008). Of note, cancer in
the United States was reported to account for 23% of all deaths in 2004 (CERSSE, 2008).
Fig. 3 The natural background exposure worldwide. The figure depicted here illustrates the relative contributions of natural sources to the global
population exposure. The present estimate of the central value of background radiation is 2.4 mSv. More than half of the total exposure comes from
exposure to radon gas and its decay products. Cosmic radiation is subsequently the next highest percentage of natural ionizing radiation exposure.
Reproduced from UNSCEAR (2000). Source and effects of ionizing radiation, vol. 1. United Nations Scientific Committee on the Effects of Atomic
Radiation. United Nations Publications: New York.

7.09.3 Radiobiology
7.09.3.1 Primary Versus Secondary Damage
A cell’s sensitivity to radiation is influenced by its stage in the cell cycle, its state, and the component of the cell that was exposed.
With regard to cell cycle stage, cells are generally most sensitive to reproductive death when irradiated during M phase (mitosis), to
chromosomal damage and division delay when irradiated during G2, and to problems with DNA synthesis during early G1. They
are most resistant during late S phase and during G0 (Prasad, 1995). The timing of irradiation also affects the progression of the cell
through the cell cycle in a way that is dependent upon the normal rate of division in a given cell line; for example, low dose radiation
stops slowly dividing cellsdbut not rapidly dividing onesdin G1. With regard to cell state, cells irradiated in vitro are more radio-
sensitive than those irradiated in vivo (Jones et al., 2008). Amplification of the expression of specific oncogenes (e.g., ras, especially
when myc is coexpressed, or raf) or the presence of radiosensitive or radioprotective genes can affect the radioresistance of cells.
With regard to cellular components, the nucleus is more sensitive to both low- and high LET radiation than the cytoplasm. Redun-
dancy in the number of mitochondria may confer radioresistance; for example, lymphocytes contain few mitochondria and are
exquisitely sensitive to irradiation. Another factor affecting radiation-induced cell death or inactivation is the oxygen tension in
the cellular environment; many cells are more sensitive to irradiation under normoxic conditions as compared to hypoxic environ-
ments (Jones et al., 2008).
7.09.3.2 Mechanisms of Damage From Ionizing Radiation
The main cellular effects of ionizing radiation relate to specific ionization events that produce molecular alterations. Space radia-
tion, as opposed to typical terrestrial sources, contains a much greater proportion of particulate radiation. Of greatest concern are
HZE particles: high LET radiation particles, which produce dense ionization tracks. Cells exposed to radiation have one of four fates:
(1) complete recovery to the preradiation state; (2) partial recovery with repair of injury but with diminished functionality; (3)
mutations caused by incomplete or erroneous repair; or (4) cell death (Jones et al., 2008).
Incident radiation injures cells both directly and indirectly. Approximately one-third of biological damage from low LET radi-
ation is thought to be from direct ionization, with the remainder incurred from indirect damage. The vast majority of damage from
high LET radiation results from direct ionization. The following sections outline the mechanisms by which radiation directly and
indirectly induces genetic damage (i.e., damage to a cell’s DNA), followed by a brief review of mechanisms of additional epigenetic
damage (Jones et al., 2008).
7.09.3.3 Direct DNA Damage
Ionizing radiation can penetrate the cytoplasm of a cell and interact with the molecularly rich cell nucleus, which is packed with
DNA, histone proteins, and nuclear matrix. The severity of the injury depends on the track, the cross section, and the LET of the
particle. When electromagnetic or particle radiation strikes the DNA and other macromolecules directly, molecular damage occurs
in the form of ionization and, possibly, molecular bond breaks (Turner, 1995). The hydrogen bonds (including hydrogen–
hydrogen (H–H) and sulfhydryl (SH)) are the weakest in the macromolecular structure and are therefore the most vulnerable to
disruption by ionizing radiation. Breaks in these bonds lead to changes in the secondary and tertiary structure of proteins and
enzymes, which in turn lead to decreases or loss of functional activity. Cellular proteins may express alterations in their viscosity,
conductivity, and other physical properties. The side chains of amino acids are the most radiosensitive portions of proteins. Large
Fig. 4 Relative contributions of the man-made radiation to the US population. The figure shows the relative contributions of man-made radiation.
Medical X-rays and nuclear medicine account for about 79% of the man-made radiation exposure. Elements in consumer products, such as tobacco
and domestic water supply, account for 16%. Occupational exposures, fallout, and nuclear fuel cycle account for the remaining. Reproduced from
NCRP (1987). Ionizing radiation exposure of the population of the United States. National Council on Radiation Protection and Measurements, Report
No. 93, Washington, DC.

macromolecules with repeated identical units often show disruption in the same bond, suggesting that the energy absorbed in the
molecule can be transmitted down the molecular chain to the weakest bond. Histone proteins may lose their associations with
DNA, and the secondary and tertiary DNA structure may be altered with disruption of the hydrogen bond linkage between base
pairs; both effects can lead to errors in transcription and translation (Prasad, 1995).
Molecular disruptions in the DNA molecule are characterized as strand breaks (single or double), apurination, or deamination.
Strand breaks often occur between a sugar (ribose) and a phosphate, although these breaks will often rejoin if the broken end is not
peroxidized by a reactive oxygen species (ROS). Radiation of energy as low as 30–40 eV can produce a break in one of the two
strands of DNA (a single-strand break (SSB)), and an exposure of a cell to 0.01 Sv (1 rem) can be expected to produce 10–20
SSBs (Fig. 5). Double-strand breaks (DSBs) can occur when two SSBs are juxtaposed or when a single densely ionizing particle
(HZE with >500 eV) produces a cluster of ionization within a span of about 20 degrees. High LET radiation, at a given energy,
will induce more non-rejoining strand breaks than will low LET radiation, and non-rejoining strand breaks are more likely to
lead to cell death. Another mechanism of DNA damage is cross-linking, an irreversible binding between chemically active loci
produced in adjacent molecules or within the same molecule. Base pair dimerization, a type of cross-linking from an ionizing expo-
sure, can easily produce a downstream mutation (Jones et al., 2008).
Radiation-induced SSBs between a sugar and the phosphate group of the nucleotide can readily be repaired with high ﬁdelity,
since the template for the nucleotide is preserved. Occasionally, if SSBs occur in adjacent sister chromatid regions, the affected DNA
segments undergo a process called sister chromatid exchange (SCE). However, when an ionization event leads to a DSB, the
template is lost and errors in repair are much more likely, producing a point or segmental mutation. Such injuries or mutations
can be lethal if the DNA damage is severe enough to cause the loss of function of one or several key proteins, or if repair is not
possible and the chromosomal elements beyond the break are lost. A process similar to SCE that preserves the broken chromosome
can sometimes remove DSBs, but such repair may place genes under different control mechanisms (as can happen with genetic
recombination), which can also lead to changes in cellular activity and phenotype (Jones et al., 2008; Prasad, 1995).
Single hits within chromosomes are more likely to be repairable by normal cellular mechanisms, but multiple hits in the same
region of a chromosome may require more complex repair mechanisms or may not be repairable at all. Depending on the path of
the ionizing particle, multiple damage sites can occur in proximity to one another. If the sites are located less than 20 degrees apart,
the ionization event is usually lethal to the cell, whereas injuries to sites separated by more than 80 degrees are usually survivable
but are likely to lead to mutations.
HZE exposure tends to produce more complex nuclear biochemical events than those produced by low LET radiation. The
complex events can lead to “unfaithful” or non-rejoining strand breaks and clusters of injury (e.g., base damage, SSBs, DSBs).
Speciﬁc postexposure chromosomal aberrations observed in cytogenetic analysis of lymphocytes include inversions, dicentrics,
fragments, rings, and translocations (Prasad, 1995).
Fig. 5 Diagram of DNA lesion by direct effects. Reproduced from SRHWG (2001). Space radiation health project description. Houston,
TX: NASA/JSC.

If the cell survives the damage event, several downstream effects may occur. Translation errors can be seen if a DSB occurred in
a coding region of the DNA, leading to mutated or truncated proteins with aberrant or lost function and subsequent alterations in
phenotype. Mutations can also result in replication errors during mitosis. Errors in replication, if they occur in a sensitive region of
the genome, can cause further mutations in daughter cells through rearrangements; such errors are the root of potential carcinogen-
esis in these cells (Jones et al., 2008).
In addition to overt injury, incidental radiation exposure can induce genomic instability. This can be produced with as little as
0.2–0.3 Gy (20–30 rem) of high LET radiation in mammary and other cell lines (Fry et al., 1983; Hall et al., 2001). In one exper-
iment, transplanted bronchial epithelial cells that were irradiated with 0.3 Gy of 56Fe (<1 particle per cell) and, 6 months later,
with 1 Gy of X-rays developed tumors in three of seven animals upon implantation; no tumors formed when cells had been irra-
diated with either 0.3 Gy of 56Fe or 1 Gy of X-rays immediately before transplantation (Hei et al., 1998). These results imply that
exposure to as little as a single HZE particle may render a cell genetically more sensitive or unstable for months and, therefore, at
greater risk for subsequent neoplastic initiation events. Recent animal models of tumorigenesis have also demonstrated the extent to
which high LET particle radiation is, itself, highly carcinogenic, with evidence suggesting that there is an increased risk of solid tumor
formation subsequent to exposure to high LET particle radiation, as compared to g-rays or X-rays (Datta et al., 2013; Weil et al.,
2014; Wang et al., 2015). In one study, groups of mice were irradiated with 28Si, 56Fe, protons, or g-rays at doses ranging from
0.01 to 0.3 Gy; mice irradiated with 28Si and 56Fe ions demonstrated a markedly higher incidence of hepatocellular carcinoma,
as compared to mice irradiated with protons or g-rays administered at the same doses (Weil et al., 2014). The mechanism for
high LET-induced genomic instability is not fully understood, but this phenomenon may account for the carcinogenic side effect
of such irradiation. This condition seems to persist for several generations of cellular offspring after exposure. However, cells trans-
formed by high LET radiation cannot be distinguished phenotypically from those transformed by low LET radiation.
7.09.3.4 Indirect DNA Damage or Oxidative Injury
Ionizing radiation can interact with other parts of the cell besides the nucleus. The nucleus-to-cytoplasm ratio of cells varies from 1:5
to less than 1:1 depending on the cell type and maturity. For the majority of cells, the probability of radiation interacting with cyto-
plasmic organelles and molecular species is statistically much larger than that of interacting with nuclear species. Damage to either
the cytoplasm or the nucleus by ionizing radiation can result not only from direct damage but also from secondary reactive species.
Radiation exposure results in energy being released into cellular materials, causing excitation of electrons or secondary ionization
(Turner, 1995). In addition to the formation of ions, radiation can cause the loss of an electron from an atom or molecule, resulting
in an unstable, highly reactive entity called a free radical. The unpaired outer shell electron of these electrically neutral radicals causes
them to react very quickly with one another or with stable molecules (Jones et al., 2008). Since the human body consists of about
70% water, such events primarily involve aqueous products, particularly the highly reactive hydroxyl (OH) and peroxy (HO2
l
)
radicals.
Reactive species such as the oxidizing agents OH and HO2
l
and the reducing agent H can propagate and disseminate, interacting
with various parts of the cell such as cytosolic proteins and other macromolecules, membrane constituents such as lipids, and
nuclear contents, including DNA. The base structures are particularly susceptible to direct damage by OH radicals, and the pyrim-
idine bases are almost twice as sensitive to radiation effects as are the purines. In macromolecules, radicals can cause hydrogen bond
breakage, molecular degradation or breakage, and intra- and intermolecular cross-linking (Conklin and Walker, 1987). Hydroxyl
species produced by g-irradiation can induce DNA–protein cross-links, which tend to occur mostly in areas of the genome that
are being actively transcribed (Xue et al., 1994). Components of these links, known as DNA adducts (e.g., 8-OHdG), can be quan-
tified as an indication of the extent of DNA damage from chemical or radiation exposure.
7.09.3.5 Epigenetic Effects
As noted above, reactive species can be generated anywhere in the cell and can propagate and disseminate, eventually interacting
with chromosomal elements, including the DNA itself. Such interactions can create DNA adducts and (hypo- or hyper-)methylation
events, which do not mutate the structure of the DNA but change the pattern of expression of the affected genes. Epigenetic effects
arise from one of the three mechanisms: (1) modifications of nongenetic nuclear proteins (histones or nonhistones) that affect tran-
scriptional or translational activities or prolong the activity of protein kinases; (2) binding between carcinogens and tRNA, which
can change amino acid codons, or binding between carcinogens and RNA polymerases, which can increase the expression of enzy-
matic proteins; and (3) the action of cocarcinogens such as hormonal transcription factors (Jones et al., 2008).
7.09.3.6 Bystander Effects
The DNA-centric paradigm that the nucleus is the quintessential target for radiation damage had prevailed among radiobiologists
for some time, and earlier observations of nontargeted effects were not integrated into the mainstream of their studies (Hamada
et al., 2007). Subsequently, advances in nonuniform radiation fields and microbeams have allowed for the emergence of new
interest in ionizing radiation-induced bystander effects: the fact that deposition of energy in a cell not only alters that individual
cell but also triggers signal pathways that can result in alterations in nonhit cellsdthat is, bystander cells (Brooks, 2005). The
bystander effect was first demonstrated when monolayer cell cultures were exposed to mean a-particle doses in which only

0.1%–1% of the cell nuclei were traversed by a single a-particle track; this resulted in an enhanced frequency of SCEs in 20%–40%
of Chinese hamster ovary cells (Nagasawa and Little, 1992). Furthermore, exposure to both particulate and EMR has demonstrated
the occurrence of in vitro and in vivo bystander effects in a wide variety of cell types (Azzam and Little, 2004; Azzam et al., 2004;
Hei, 2006; Kassis, 2004; Mothersill and Seymour, 2004). Bystander studies have revealed that the resulting effects are manifested as
the expression of a wide variety of end points, such as SCEs (Nagasawa and Little, 1992), mutagenesis (Nagasawa and Little, 1999;
Zhou et al., 2000), chromosomal and genomic instability (Hall and Hei, 2003; Lorimore et al., 2003), micronucleus formation
(Belyakov et al., 2005; Prise et al., 1998; Shao et al., 2001), neoplastic transformation (Mothersill and Seymour, 2004; Sawant
et al., 2001a), proliferation and differentiation (Azzam et al., 2004; Iyer et al., 2000; Mothersill and Seymour, 2004; Shao et al.,
2003), decreased clonogenic survival (Liu et al., 2006; Mothersill and Seymour, 1997, 1998; Mothersill et al., 2004; Sawant
et al., 2002), and apoptosis (Lyng et al., 2006). Multiple intercellular and intracellular signal transduction pathways have been
implicated in the bystander response (Hamada et al., 2007). The cellular communication bringing about the radiation-induced
bystander responses is thought to occur through direct physical connections between cells, such as gap junction intercellular
communications (GJICs), or through the culture medium (Ballarini et al., 2002; Little, 2006). Four possible models for intercellular
signal pathways capable of producing the radiation-induced bystander response have been proposed (1) through the GJIC, (2)
through interactions between ligands and their specific receptors, (3) through interactions between the secreted factors and their
specific receptors, and (4) directly through the plasma membrane (Hamada et al., 2007; Matsumoto et al., 2007).
Irrespective of whether the cytoplasm or nucleus is targeted by ionizing radiation, irradiated cells release signals in the form of
cytokines, growth factors, membrane-permeable reactive species (e.g., H2O2 and NO), and other factors that include long-lived
organic radicals (LLRs) (Hamada et al., 2007). More recently, microarray analysis of irradiated and bystander fibroblasts in
confluent cultures has shown different expression profiles; this implies that intercellular signaling between irradiated and bystander
cells activate intracellular signaling, leading to the transcriptional stress response in bystander effects (Iwakawa et al., 2008). Finally,
selective induction of DNA damage levels, global DNA methylation, cell proliferation, and apoptosis has been correlated to gender
differences in exposed and bystander spleen tissue of male and female mice induced by ionizing radiation (Koturbash et al., 2008a).
Interestingly, the gender specificity of radiation-induced bystander effects may be due to gender-specific microRNAs involved in gen-
otoxic stress responses and may help to explain gender specificity of radiation-induced carcinogenesis (Koturbash et al., 2008b).
7.09.3.7 Adaptive Response
The radiation-induced adaptive response is described as the reduced effect of radiation received as a challenging dose in instances
where there has been previous induction by a low radiation dosedthe so-called priming or conditioning dose (Tapio and Jacob,
2007). The adaptive response is the only radioprotective mechanism that has been formally recognized by international organiza-
tions and agencies, such as the International Atomic Energy Agency and World Health Organization (Leonard, 2007). Adaptive
responses have been observed in vitro and in vivo using various end points, such as cell lethality, chromosomal aberrations, muta-
tion induction, radiosensitivity, and DNA repair (Cai, 1999; Cai and Liu, 1990; Cramers et al., 2005; Gajendiran et al., 2001; Shad-
ley and Wiencke, 1989; Yonezawa et al., 1996). Additionally, radioadaptive responses have been observed to both low LET (X-rays,
g-rays, b-particles) (Azzam et al., 1994; Olivieri et al., 1984; Shadley and Wiencke, 1989) and high LET (neutrons, a-particles) radi-
ation (Gajendiran et al., 2001; Sawant et al., 2001b). In cellular studies, values of priming doses and doses rates resulting in adaptive
behavior have been found to range from 0.01 to 0.5 Gy and from 0.01 to 1 Gy minÀ1
, respectively (Tapio and Jacob, 2007).
Although the mechanisms responsible for the radioadaptive response are not fully understood, this phenotype has been associated
with an increase of certain cellular functions such as DNA repair (e.g., poly (ADP-ribose) polymerase (PARP), apurinic/apyrimidic
(AP) endonuclease, DNA-dependent protein kinase (DNA-PK)) (Coleman et al., 2005; Iyer and Lehnert, 2002a,b; Takahashi et al.,
2002; Wiencke et al., 1986), cell cycle function (e.g., M phase phosphoprotein) (Coleman et al., 2005), and transducers (e.g., ataxia
telangiectasia mutated (ATM), and p53) (Coleman et al., 2005; Sasaki et al., 2002; Takahashi, 2002). Such adaptive cellular
responses have been mediated either by the release of diffusible signaling molecules or by GJICs (Coates et al., 2004). In contrast
to cellular studies, where the adaptive response lasts from a few hours to only one cell cycle, the adaptive response in animals, and
probably in humans, can be maintained from several weeks to several months, and, in some cases, throughout the entire life span
(Tapio and Jacob, 2007). The factors determining the length of the adaptive response remain unclear; however, reactive oxygen and
nitrogen species (ROS and RNS) may contribute to this response by (1) directly inducing DNA damage that initiates the radioadap-
tive response; (2) inducing DNA damage that brings about the transcriptional/posttranscriptional regulation of certain genes that
confer radioprotective properties to cells or enhance the functions of certain proteins to promote radioadaptive responses; and (3)
inducing certain proteins (e.g., transcriptional factors) that induce the cellular events necessary to conduct a radioadaptive response
(Matsumoto et al., 2007). Additionally, ROS/RNS may be the link between the adaptive response and bystander effects (Matsumoto
et al., 2007; Tapio and Jacob, 2007). Animal studies indicate a possible role of the radioadaptive response in the development of
various cancers, as well as in the induction of radioresistance, probably via the induction of the immune activation (Ina et al., 2005).
The main demonstrated in vivo effect of a low-dose exposure is a reduction in the rate at which spontaneously initiated cells prog-
ress to malignancy (Mitchel et al., 2003). Persons living in high natural radiation areas have been shown to have an induced
immune response (Tapio and Jacob, 2007). More recently, an Australian study found that while increased levels of solar UV expo-
sure were associated with increased chromosome breakage, there was also an unexpected association with a decrease in the rate of
DNA strand break misrepair (Nadir-Shaliker et al., 2012). However, the broader subject of radiation hormesisdthat is, the notion
that there are health benefits that arise from exposure to low-dose ionizing radiationdremains controversial and in need of further

study. In a well-publicized example, thousands of Taiwanese residents were exposed to low-dose g-radiation over a period of years
when the steel used to construct a number of apartment buildings was inadvertently contaminated with radioactive cobalt-60
during the early 1980s. A subsequent investigation of this population revealed increased risks of leukemia and thyroid cancer
but, surprisingly, a decreased risk of all other malignancies and solid tumors (Hwang et al., 2006). As the authors note, these
results may be subject to confounders and must be interpreted with caution. Nevertheless, others have called for a reevaluation
of our approach to the risk assessment of low dose radiation exposure (Chen et al., 2007; Scott, 2008). Moving forward, the
role of the radioadaptive response in carcinogenesis will be more effectively understood by embracing a more systemic
approach. Such an approach will take account of the potential benefit of the adaptive response to human health and may
demonstrate a possible reduction in natural-occurring carcinogenic diseases (Leonard, 2007).
7.09.4 Evidence for Radiation Carcinogenesis
7.09.4.1 Human Data
As discussed in many articles of this volume, there are a number of accepted criteria for determining whether a particular agent is
a human carcinogen. The most convincing argument, of course, comes from empirical evidence, usually epidemiologic, that the
agent has caused cancer in humans. For the case of ionizing radiation, such evidence is, unfortunately, plentiful (Table 3). Several
populations have been exposed, often deliberately, to ionizing radiation, sometimes at very high doses. The number of such groups
is sufficiently large to allow epidemiologists to derive fairly detailed information concerning the effects of radiation dose and
quality, age at exposure, and other variables on cancer incidence in a large variety of organs. Based on data collected from exposed
cohorts over several decades, it appears that ionizing radiation is a potent carcinogen with no organ or tissue specificity, other than
as determined by the circumstances of exposure such as the site and manner of irradiation (Boice and Fraumeni, 1984; Burns et al.,
1986; Upton et al., 1986).
In addition, reports are appearing that select groups may, due to their occupational level of radiation exposure, have an increased
incidence of certain types of cancer. A prominent example is the recent number of manuscripts inferring that flight crews (pilots and
flight attendants) have, due to their altitude-based exposures, especially with polar flight routes, a higher incidence of solid tumors,
especially breast cancer in the female crewmembers (Barr et al., 2007; Rafnsson et al., 2000).
7.09.4.2 Atomic/Nuclear Weapon Survivors
Although the use of atomic weapons constitutes a grim wartime event, the information available from their use can be used to
benefit those in radiation occupations or those who suffer inadvertent exposures. The Radiation Effects Research Foundation
(formerly the Atomic Bomb Casualty Commission) is a binational organization formed to evaluate the medical effects of radiation
on humans and on diseases affected by radiation. Laboratories in Hiroshima and Nagasaki are dedicated to studying the acute and
chronic effects of the atomic detonations in those cities. Epidemiologic tracking of the survivors has allowed for the study of the
relationship between estimated radiation dose and the development of leukemias and solid tumors (Thompson et al., 1994).
The acute, annual, and career radiation exposure limits recommended by organizations such as the International Commission
on Radiological Protection (ICRP) and the National Council for Radiation Protection and Measurement (NCRP) are largely based
on findings from this cohort of acutely exposed individuals (ICRP, 1991).
By examining the fate of family members who were located in the same houses during the atomic bomb explosions, it has been
estimated that doses of 2.7–3.1 Gy (270–310 rad) to the bone marrow caused death within 2 months in some 50% of cases. Esti-
mates of the LD50/60 (death of 50% of the exposed population within 60 days), generated by the United Nation’s Scientific
Table 3 Cancer associated with exposure to ionizing radiation populations
Cancer type AB AS PM TC TH RP UM RD
Leukemia þ þ þ þ
Thyroid þ þ
Breast þ þ
Lung þ þ þ þ
Bone þ
Stomach þ þ
Esophagus þ þ
Lymphoma þ þ þ
Brain þ þ
Liver þ
Skin þ þ þ
AB, atomic bomb survivors; AS, ankylosing spondylitis patients; PM, postpartum mastitis patients; TC, tinea capitis patients; TH, patients receiving thorotrast; RP, radium dial
painters; UM, underground miners; RD, radiologists.

Committee from the information on atomic bomb survivors, accidental radiation exposure cases, and radiation therapy studies,
suggest that the LD50/60 is 2.5–3.2 Gy (250–320 rad) to the bone marrow when little medical assistance is available, and about
5 Gy (500 rad) when extensive medical care is provided (Petersen and Abrahamson, 1998). Animal studies have shown that admin-
istering various growth factors to stimulate surviving blood-forming stem cells in the bone marrow facilitates more rapid recovery
from radiation injury, and the lives of 100% of the exposed population can be saved after a whole-body dose of up to about 10 Gy
(1000 rad).
An excess risk of leukemia was one of the earliest delayed effects of radiation exposure observed in the victims of the atomic
bombs dropped on Hiroshima and Nagasaki in Aug. 1945. Now, more than 50 years after these events, this excess risk is widely
seen as the most apparent long-term effect of radiation. As of 1990, 176 of the 50, 113 survivors in the Life Span Study who
had significant exposures (0.005 Gy or 0.5 rad) had died of leukemia, and about 90 of these deaths were attributable to radiation
exposure. This excess was especially apparent because much of these occurred during the first 10–15 years after exposure. Unlike the
dose–response curves for other types of cancer, the leukemia dose–response curve seems to be nonlinear, with low doses being less
effective than would be predicted by a simple linear dose response. With regard to other types of cancer, 4687 people in the Life
Span Study had died of nonleukemic forms of cancer by 1990, which represents an excess of 381 deaths as compared with an esti-
mated 4306 deaths in a population that had not been exposed (Pierce and Vaeth, 2003; Pierce et al., 1996). A comparison of excess
deaths in the Life Span Study population between 1950 and 1990, according to radiation dose, is shown in Table 4; the number of
deaths sorted by the type of cancer is shown in Table 5.
7.09.4.3 Industrial Accidents
7.09.4.3.1 Chernobyl and JCO nuclear criticality accident
Nuclear power accidents, such as those of the Japan Nuclear Fuel Conversion Company (JCO) (Tokaimura, Japan, Sep. 1999) and
Chernobyl, have resulted in population exposures that are being medically monitored. Acute exposure of 600 workers at the
Table 5 Cancer deaths between 1950 and 1990 among life span study survivors according to cancer
site
Type of cancer Total number of deaths Estimated excess deaths Evidence for effect
Stomach 2529 65 Strong
Lung 939 67 Strong
Liver 753 30 Strong
Uterus 476 9 Moderate
Colon 347 23 Strong
Rectum 298 7 Weak
Pancreas 297 3 Weak
Esophagus 234 14 Strong
Gallbladder 228 12 Moderate
Breast (female) 211 37 Strong
Ovary 120 10 Strong
Bladder 118 10 Strong
Prostate 80 2 Weak
Bone 32 3 Moderate
Other solid tumors 948 47 Strong
Lymphoma 162 1 Weak
Myeloma 51 6 Strong
Modified from Pierce, D. A., Shimizu, Y., Preston, D. L., Vaeth, M., Mabuchi, K. (1996). Radiation Research 146, 1–27.
Table 4 Cancer deaths between 1950 and 1990 among life span study survivors according to dose
0.005–0.2 Sv 0.2–0.5 Sv 0.5–1 Sv 1 Sv
Number of deaths from leukemia 70 27 23 56
Estimated excess deaths 10 13 17 47
Percent attributable to radiation (%) 14 48 74 84
Number of deaths from all other cancers 3391 646 342 308
Estimated excess deaths 63 76 79 121
Percent attributable to radiation (%) 2 12 23 39
Modified from Pierce, D. A., Shimizu, Y., Preston, D. L., Vaeth, M., Mabuchi, K. (1996). Radiation Research 146, 1–27.

Chernobyl site on Apr. 26,l 1986 resulted in 134 cases of radiation sickness due to high exposure and 31 deaths (28 in the first
3 months and 3 delayed), according to the 2000 UNSCEAR report to the general assembly (Holm, 2001; NEA95, 1995).
Several studies have concluded that Chernobyl accident-generated radioactive iodine has resulted in an increased incidence of
thyroid cancer among the exposed population, especially among children in neighboring Belarus, where the winds took the vast
majority of the radioactive cloud and large amounts of 131I were concentrated in cow’s milk (Farahati et al., 2000; Jacob et al.,
2000; Rybakov et al., 2000; Williams, 1994). The thyroid cancer rate in persons less than 18 years of age, in the region surrounding
Chernobyl, increased from 9 cases per the 5-year interval pre-exposure (1981–1985) to 37 in the 1986–1990 interval and 177 in the
1991–1995 interval. The incidence rate was still high more than 10 years after exposure, with 116 reported cases during the 3-year
interval from 1996 to 1998 (Rybakov et al., 2000). At least 1800–2000 thyroid tumors are attributed to the Chernobyl accident-
associated radiation exposure (Williams, 1994). The tumors in these patients were characterized by a shorter latency period and
increased aggressiveness at presentation, as measured by the extent of regional and distant metastases (Heidenreich et al., 1999;
Rybakov et al., 2000). The incidence and aggressiveness of regional urinary tumors (renal and bladder) were also increased in
the 13-year period after the accident, as measured by stage, histopathologic features such as grade, PCNA (proliferating cell nuclear
antigen), and K-ras expression, presumably due to ingestion and renal excretion of 137Cs (Romanenko et al., 2000, 2006). Most of
the radio-induced cancers occurred in individuals exposed to high dose rates of 100 mSv yearÀ1
(Masse, 2000).
Germline mutations at human minisatellite loci were studied in children born in the heavily polluted areas of the Mogliev
district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation was found to be twice as
high in the exposed families as in the control group (Dubrova et al., 1996; Weinberg, 2001). Researchers from Texas Tech University
did not find increased number of birth defects, physical deformities, or germline mutations in microsatellite DNA from exposed
embryos or micronucleus formation in exposed rodents versus unexposed counterparts (Baker, 2001).
In the JCO exposures, three workers who were not wearing exposure badges underwent postexposure biodosimetry to quantitate
their exposure by counting the number of chromosomal aberrations in peripheral blood lymphocytes. Biodosimetry is now widely
used in industry to correlate exposure to a toxicant (radiation, chemical, etc.) to the risk of the biological effects, inducing human
disease (Jones et al., 2008).
7.09.4.3.2 Techa River Basin
The Techa River Basin region in southwestern Siberia suffered from the environmental release of a large volumeda total of
7.6Â107 m3
, equating to 1017 Bq (2.75Â106 Ci)dof radioactive waste products over more than a decade, beginning in 1948.
The environmental releases from the plutonium processing facility from within 100 km of Chelyabinsk, Russia, resulted in contam-
ination of the local water system and widespread distribution into multiple villages along the Techa–Iset–Tobol river network of
tributaries. Approximately 95% of the release was between Mar. 1950 and Nov. 1951, with an average daily release of
1.6Â1014 Bq (4300 Ci). Subsequently, large populations of the local people and animals, across the age spectrum, were exposed
to external doses up to 1220 mGy yearÀ1
and internal doses up to 2260 mGy yearÀ1
. Some village residents received both internal
and external exposures. The sources were mostly g-emitters, with some b-emitters, but included 89Sr, 90Sr, 137Cs, 95Zr, 95Nb,
106Ru, and others, typically with long half-lives (Akleyev et al., 1995, 2002a,b). The cancer-specific mortality rate in the exposed
population was 24.89% versus 16.17% for the controls. The cancer-specific mortality (55 cancer death cases) in the exposed patients
with signs and symptoms of chronic radiation syndrome was 274.8 deaths per 100 000 person-years (206.92–357.79, 90% CI)
versus 189.9 (181.16–198.82, 90% CI) in the control population (1888 cancer death cases) (Akleyev et al., 1995, 2002a,b). The
older exposed age cohort had the highest cancer death rate at 602 deaths per 100 000 person-years. The largest differences in cancer
incidence of the exposed population versus the controls were for leukemiad25 per 100 000 person-years (8.09–58.20) versus 3.62
(2.53–5.01), female breastd14.99 (3.09–43.77) versus 3.42 (2.37–4.78), urinary organs (kidney, ureter, bladder)d29.98 (11.0–
65.36) versus 9.25 (7.45–11.34), lymphomad5.0 (0.12–27.85) versus 1.21 (0.63–2.12), and uterusd24.98 (8.09–58.2) versus
17.50 (15.10–20.30). The cancer specific mortality rate was dose dependent, being much higher in exposure doses 1.0 Gy, at
429.18Â10À3
versus 198.22Â10À 3
at doses 0.2 Gy (Akleyev et al., 1995, 2002a,b).
7.09.4.4 Medical Radiation Therapy and Cancer Risk
Medical exposuresdthe use of diagnostic and therapeutic radiation exposure in the form of 60Co, linear accelerators, injected and
ingested radionuclidesdhave been ongoing for many years and millions of patients. Studies of patients with ankylosing spondylitis
(a form of arthritis) treated with external beam external radiation therapy, or X-ray therapy (XRT), have shown an increased relative
risk (RR) of lung and other solid tumors of 1.5–1.8 at 8–20 years posttherapy. However, in contrast to the incidence data for atomic
bomb survivors, the RR began to decrease beyond 20 years postexposure. Scottish women who received pelvic irradiation for met-
ropathia hemorrhagica have a RR of 3.02 of developing bladder cancer, but the vast majority of these cancers were not observed
until 20 or more years after treatment (Darby and Inskip, 1995).
In the 1930s, before the effects of ionizing radiation were well understood, a number of people were exposed to radiation for
medical purposes (Holm, 2001; Mole, 1987; Mole and Major, 1983). In England, patients with ankylosing spondylitis were treated
with ionizing radiation from 1935 until 1954 (Smith and Doll, 1982). These patients were later found to have a fivefold higher
incidence of leukemia than expected. In Rochester, NY, ionizing radiation was given to women to treat postpartum mastitis, result-
ing in elevated breast cancer incidence (Mettler et al., 1990; Shore et al., 1977). In the United States and Israel, ionizing radiation
was used until 1960 as a treatment for children with tinea capitis or ringworm (Shore, 1990; Shore et al., 1976). Later, as adults,

Comprehensive toxicology: Ionized Radiation as Carcinogen.

Comprehensive toxicology: Ionized Radiation as Carcinogen.

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