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OCR for page 9
1
Background Information and
Scientific Principles
PHYSICS AND DOSIMETRY OF IONIZING RADIATION
All living matter is composed of atoms joined into molecules by elec-
tron bonds. Ionizing radiation is energetic enough to displace atomic
electrons and thus break the bonds that hold a molecule together. As
described below, this produces a number of chemical changes that, in the
case of living cells, can lead to cell death or other harmful effects. Ion-
izing radiations fall into two broad groups: 1) particulate radiations, such
as high energy electrons, neutrons, and protons which ionize matter by
direct atomic collisions, and 2) electromagnetic radiations or photons such
as x rays and gamma rays which ionize matter by other types of atomic
interactions, as described below.
Absorption and Scattering of Photons
Photons ionize atoms through three important energy transfer proc-
esses: the photoelectric process, Compton scattering, and pair production.
For photons with low energies (<0.05 megaelectron volt iMeVi) the pho-
toelectric process dominates in tissue. The photoelectric process occurs
when an incoming photon interacts with a tightly bound electron from
one of the inner shells of the atom, and causes the electron to be ejected
with sufficient energy to escape the atom. Characteristic x rays and Auger
electrons follow from this process, but the biological effects are due mainly
to excitations and ionizations in molecules of tissue caused by the ejected
electron. The probability of the photoelectric process occurring is strongly
9
OCR for page 10
10 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
dependent on the average atomic number of the tissue with an equally
strong inverse dependence on the photon energy.
At higher photon energies (0.1-10 MeV), Compton scattering is the
most probable process that takes place in irradiated tissue. It occurs when
the photon energy greatly exceeds the electron binding energy, so that an
orbital electron appears to the photon as a free electron. The photon
scatters off the electron, giving up part of its energy to the electron, which
proceeds to ionize and excite tissue molecules. The scattered photon with
reduced energy continues to interact with other electrons and repeats the
above process many times until the photon either escapes the absorbing
material or its energy is sufficiently degraded for the photoelectric process
to occur. Within the energy range of 0.1-10 MeV, the Compton process
has a modest dependence on energy and is almost independent of atomic
number.
Above a threshold energy of 1.02 MeV, the pair-production process is
possible. Here a photon converts its energy in the presence of an atomic
nucleus to a positron-electron pair, which, in turn, proceeds to interact with
tissue atoms and molecules, leading to eventual biological effects. When
the positron slows down it is almost always annihilated with an electron,
producing two 0.511 MeV photons. The probability of pair-production in
tissue increases slowly with photon energy but does not outweigh that of
the Compton process until the photon energy reaches 20 MeV The process
depends upon the average atomic number of the tissue.
Photon Spectral Distr~bui'ons
As seen from the description presented above, the absorption and
scattering of photons depend critically on photon energy. The initial photon
energy depends on the source of the radiation. Gamma rays resulting from
radioactive decay consist of monoenergetic photons with energies that do
not exceed several MeV in energy. Because of scattering and absorption
within the radioactive source itself and in the encapsulating material, the
photons that are emitted do have a spectrum of energies but it is fairly
narrow.
Relatively broad energy distributions are the rule for x-ray photons
produced from electrical devices. X rays are effectively produced by the
rapid deceleration of charged particles (usually electrons) by a material of
high atomic number. This results in a continuous distribution of energies
with a maximum at an energy about one third that of the most energetic
electron. As photons interact with matter, their spectral distribution is
further altered in a complex manner as the photons transfer energy to the
absorbing medium by the processes described above.
OCR for page 11
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
Electron Spectral Distributions and LET
11
When monoenergetic photons interact with a tissue medium, the elec-
trons that are set in motion, particularly from the Compton process, pro-
ceed to interact with the atoms and molecules of the medium, losing energr
through collisions and excitations, and are scattered in the process. The
result is a complex shower of electrons, the energy distribution of which is
continuously degraded as the electrons give up their energy to the medium
at a rate defined by the electron stopping power of the medium. As the
electron proceeds through tissue, it creates a track of excited and ionized
molecules that, for energetic electrons, are relatively far apart. For exam-
ple, the dimension of this spacing is such that there is a finite probability
that the energetic electron can pass through a DNA molecule, with about
3 rim separating the two strands, without releasing any of its energy and
therefore without causing damage. The spatial energy distribution, stated
in terms of the amount of energy deposited per unit length of particle
track, is defined as the linear energy transfer (LET) of the radiation. X rays
and gamma rays set in motion electrons with a relatively low spatial rate of
energy loss and thus are considered low LET radiations. The photon and
electron energy degradation processes described above result in a broad
distribution of LET values occurring in irradiated tissue. A typical value
of LET for the electrons set in motion by cobalt-60 gamma rays (average
energy 1.25 MeV) would be about 0.25 keV/pm. This can be contrasted
with a densely ionizing 2 MeV alpha particle which produces about 1000
times more ionization per unit distance, 250 keV/pm. Such particles are
characterized as high LET radiation. Knowledge of LET is important when
considering the relative biological effectiveness (RBE) of a given radiation;
LET is commonly used as a measure of radiation quality, as discussed
below.
Microdosimetry
Various limitations in the concept of LET and absorbed dose in sub-
cellular tissue volumes led to the introduction of microdosimetry. Mi-
crodosimetry takes account of the fact that energy deposition by ionizing
radiations is a stochastic (random) process. Identical particles of the same
energy interacting in a small volume of material deposit differing amounts
of energy due to chance alone. The specific energy, z, is defined as the
ratio c/m where ~ is the energy imparted by a single ionizing particle in
a volume element of mass m. The mean value of z for a large number
of particles is equal to the absorbed dose. The microdosimetric analogue
to LET is the quantity lineal energy, defined as c/d, where d is the mean
chord length in the volume occupied by mass m. Distributions of absorbed
dose in terms of lineal energy can be measured by proportional counters
OCR for page 12
12 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
filled with tissue-equivalent gas at pressure levels appropriate for simulating
spheres of tissue with diameters on the order of 1 ~m. The principles of
microdosimetry are extensively discussed in the BEIR IV report (NRC88)
and ICRU report 36 (ICRU83~.
Energy wander Kerma and Absorbed Dose
The transfer of energy from photons to tissue takes place in two stages:
(1) the interaction of the photon with an atom, causing an electron to be set
In motion, and then (2) the subsequent absorption by the medium of kinetic
energy from the high energy electron through excitation and ionization.
The first stage can be identified with the quantity called henna, K,
which stands for kinetic energy released in the material.
IT = dE~r/dm, where dE~r is the kinetic energy transferred from pho-
tons to electrons in a volume element of mass dm.
lithe second stage, energy absorption, is more important for under-
standing radiobiological effects. The absorbed dose, the energy absorbed
per unit mass, differs from kerma in that the dose may be smaller due
to lack of charged particle equilibrium, bremsstrahlung escaping from the
medium, etc. Another difference is that the kerma refers to energy trans-
fer at a point, whereas the energy is absorbed over a distance equal to
the electron range. Of the two quantities, absorbed dose is the easier
one to approach experimentally and can be determined by a number of
well-defined techniques, including gas ionization methods, calorimetry, and
thermoluminescent techniques. On the other hand, kerma is often more
easily calculated.
Radiation Chemical EHects Following Energy Absorption
After the electron produced by a photon interaction passes through
tissue, exciting and ionizing atoms and molecules, a number of important
chemical events that precede the biological effects take place. Most of
the energy absorption takes place in water, since cells are made up of
more then 70% water. When an ionizing particle passes through a water
molecule, it may ionize it to yield an ionized water molecule, H2O+, and
an electron by the reaction:
H O radiation H O+ +
The electron can be trapped, polarizing water molecules to produce the
so-called hydrated electron, eaq. On the other hand, the ionized water
molecule, H2O+, reacts at the first collision with another water molecule
to produce an hydroxyl radical, OH' according to the reaction:
OCR for page 13
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
H2O+ + H2O ) OH' + H3O+ .
13
The free radical OH' has an unpaired electron and is therefore highly
reactive as it seeks to pair its electron to reach stability. At the high
initial concentrations, certain back reactions occur producing hydrogen
molecules, hydrogen peroxide and water. The initial species produced in
water radiolysis can then be written as:
H2O , eat, H', H2O2, H2.
Instead of being ionized, the water molecule may simply be excited
according to the reaction:
H `' radiation H O*
where H2O* is the excited molecule. But H2O* soon breaks up into the
H' radical and the OH' radical according to:
H2O* ~ H' + OH' .
As a result of the above processes, three important reactive species are
produced: the aqueous electron, OH', and H', with initial relative yields
of about 45%, 45%, and 10%, respectively. These reactive species attack
molecules in the cell leading to the production of biological damage. The
OH' radical is believed to be the most effective of the three species in
causing damage. Because it is an oxidizing agent, it can abstract a hydrogen
atom from the deoxyribose moiety of DNA, for example, yielding a highly
reactive site on DNA in the form of a DNA radical. Since this process
arises from the irradiation of a water molecule rather than the DNA itself,
the process is known as the indirect effect. Electrons set in motion by
photons can, of course, directly excite or ionize cell macromolecules by
direct interaction with the critical molecule. This is called the direct elect.
Both mechanisms can produce cellular damage. There is strong evidence
that the DNA is the most critical site for lethal damage, but other sites
such as the nuclear membrane or the DNA-membrane complex may also
be important.
Ward (Wa88) has derived an approximation of the damage yields
expected in various moieties of DNA within an irradiated cell, in which
consideration is given to the direct deposition of energy in DNA and other
molecules. Able 1-1 shows the amount of energy deposited per Gray in
each moiety of DNA within a cell that is assumed to contain 6 pg of DNA.
OCR for page 14
14 EFFECTS OF EXPOSURE TO LOW LEVELS OF IONIZING RADIATION
TABLE 1-1 Amount of Energy Deposited in DNA
per Cell per Gray
Mass per Cell eV Number of
Constituent (pa) Deposited 60-eV Events
Deoxyribose 2.3 14,000 235
Bases 2.4 14,700 245
Phosphate 1.2 7,300 120
Bound water 3.1 19,000 315
Inner hydration 4.2 25,000 415
SOURCE: J. F. Ward, C. L. Limoli, P. Calabro-Jones, and J. W. Evans
(Wages.
Calculated from this is the number of events since 60 eV is the average
amount of energy deposited per event.
The yields of DNA damage necessary to kill 63% of mammalian
cells (63% of cells killed means that, on average, each cell has sustained
one lethal event) can be assessed for various lethal agents (Wa88), as
shown in Table 1-2. The high efficiency with which ionizing radiation (and
bleomycin) kill cells is not simply due to individual OH radical-induced
lesions, as witnessed by the large-scale production of single-strand breaks
with hydrogen peroxide. Ward et al. (WA87) suggest that the efficiency of
cell killing by ionizing radiation at relatively low levels of DNA damage is
due to the production of damage in more than one moiety in a localized
region, i.e., lesions resulting from multiply damaged sites in a single location
or locally multiply damaged sites (LMDS).
Recent studies (Wi85, Gr85, Ei81), as analyzed by Ward (Wage), sup-
port the importance of indirect effects of ionizing radiation in producing
damage to intracellular DNA. This is of particular significance in view of
the suggestion that most intracellular DNA damage is caused by direct
ionization and that radicals produced in water cannot access the macro-
molecule. It appears from the above analysis (Wa88) that the volume of
water in the DNA-histone complex (nucleosome) is at least equal to the
DNA volume and that radiation-produced OH radicals in the water volume
have ready access to the DNA molecule.
Some of the current assessments of DNA damage caused by ionizing
radiation in mammalian cells (Wa~) are as follows: (1) direct and indirect
effects are both important; (2) the quantity of damage produced by ionizing
radiation is orders of magnitude lower than for most other agents for equal
cell-killing efficiency; (3) individual damage moieties are not biologically
significant since they can be repaired readily by using the undamaged DNA
strand as a template; (4) LMDS are more likely the lethal lesion in cellular
OCR for page 15
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
TABLE 1-2 Yields of DNA Damage Necessary to Kill 63% of the
Cells Exposed
15
Agent
Number of Lesions
DNA Lesion per Cell per D37a
1,000
40
440
150
150
30
400,000
100
Ionizing radiation
Bleomycin A2
UV light
Hydrogen peroxide
go
37°C
Benzotaipyrene 4,5-oxide
Aflatoxin
1-Nitropyrene
Methylnitrosourea
ssB
dsB
Total LMDSb
Dpcc
ssB
dsB
TT dimer
ssB
ssB
?
Adduct 100,000
Adduct 10,000
Adduct 400,000
7-Methylguanine 800,0004
O6-Methylguanine 130,0004
3-Methyladenine 30,0004
2-(N-Acetoxy-N-acetyl~amino-fluorene Adduct 700,000
Other similar aromatic amides produce about the same number of adducts per lethal event
aD37 = dose of agent required to reduce survival of cells to 37% of the number exposed.
b Calculated, LMDS = locally multiply damaged sites.
c DPC = DNA-protein cross-links.
D37 calculated from individual exposures; no survival curves available.
SOURCE: J. F. Ward, C. L. Limoli, P. Calabro-Jones, and J. W. Evans (Wa884.
<2,600,000
DNA; these result from a high local energy deposition in the DNA (in
such a volume, multiple radicals cause multiple lesions locally); (5) the
individual lesions making up an LMDS can be widely separated on the
opposite strands of the DNA; if they are separated too much, they could
be repaired as individual lesions.
Physics and Dosimetry of High-LET Radiation (Neutrons)
Interactions of Neutrons with Tissue Elements
When neutrons impinge on a tissue medium, they will either penetrate
it without interacting with its constituent atoms or they will interact with
its atoms in one or more of the following ways: (1) elastically, (2) inelasti-
cally, (3) nonelastically, (4) by capture reactions, or (5) through spallation
processes.
OCR for page 16
16 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING EDITION
Elastic scattering is the most important interaction in tissue irradiated
with neutrons at energies below 20 MeV. This would include the energy
range for fission neutrons (~10 MeV), neutrons produced with 16 MeV
deuterons bombarding a beryllium target (<20 MeV), and neutrons pro-
duced with 150 keV deuterons on tritium (<20 MeV). The neutron, an
uncharged particle, interacts primarily by collisions with nuclei in the ab-
sorbing medium. If the total kinetic energy of the neutron and the nucleus
remains unchanged by the collision, the collision is termed elastic. During
an elastic collision, the maximum energy is transferred from the neutron to
the nucleus if the two masses are equal. In soft tissue, the most important
neutron interaction is with hydrogen. There are three reasons for this:
(1) Nearly two-thirds of the nuclei in tissue are protons, (2) the energy
transfer with protons is maximal (about one-half), and (3) the interaction
probability (cross-section) for hydrogen is larger than that for any other
element. The result is that about 90% of the energy absorbed in tissue from
neutrons with energy of less than 20 MeV comes from protons that are
recoiling from elastic collisions. The remaining energy is absorbed by other
recoiling tissue nuclei in the following decreasing order of importance:
oxygen, carbon, and nitrogen.
Inelastic scattering refers to reactions in which the neutron interacts
with the nucleus but is promptly reemitted with reduced energy and usually
with a changed direction. The scattering nucleus, which is left in an excited
state, then emits a nuclear deexcitation gamma ray. For neutrons with
kinetic energies of greater than 10 MeV, inelastic scattering contributes to
energy loss in tissue; about 30% of the energy deposited in tissue by 14-MeV
neutrons, for example, comes from inelastic interactions. The important
inelastic interactions of neutrons in soft tissue are not with hydrogen but
with carbon, nitrogen, and oxygen.
Nonelastic scattering defines reactions in which the neutron-nucleus
interaction results in the emission of particles other than a single neutron
such as alpha particles and protons [e.g., i60(n,c~3C, i4N(n,p)~4C]. The
cross-sections for nonelastic scattering in tissue become significant at en-
ergies greater than S MeV and increase as the neutron energy approaches
15 MeV. These reactions are usually accompanied by deexcitation gamma
rays, but their importance is due to the high LET of the charged particles
emitted, especially alpha particles. At neutron energies greater than 20
MeV, even though nonelastic cross-sections do not increase appreciably,
nonelastic processes become increasingly important contributors to the to-
tal dose because of the increased average energy of the charged particles
resulting from the interaction.
The capture of low-energy neutrons in the thermal and near-thermal
regions provides a significant contribution to tissue dose. The reactions of
importance are i4N(n,p)~4C and ~H(n,~y)2H. The former reaction produces
OCR for page 17
BACKGROUND INFORMATION AD SCIENTIFIC PRINCIPLES
17
locally absorbed energy of 0.62 MeV from the proton and the recoil nucleus.
The latter reaction yields a 2.2-MeV gamma ray that, in general, deposits
energy at a distance from the capture site and that has a reasonable
probability of escaping altogether from a mass as large as a rodent. For
thermal neutrons the i4N(n,p)~4C reaction is the major contributor of
absorbed energy in tissue samples with a dimension of less than 1 cm
because of the short range (<10 ~m) of the 0.58-MeV proton. However,
for larger masses of tissue (e.g., the human body), the 2.2-MeV gamma
rays from the ~H(n,:~2H reaction are a significant dose contributor.
In the spallation process the neutron-nucleus interaction results in the
fragmentation of the nucleus with the emission of several particles and
nuclear fragments. The latter are heavily ionizing, so the local energy
deposition can be high. Several neutrons and deexcitation gamma rays also
can be emitted, yielding energy carriers that escape local energy deposition.
The spallation process does not become significant until neutron energies
are much greater than 20 MeV
In summary, elastic and nonelastic scattering and the capture process
are by far the most important reactions in tissue for neutrons in the fission
energy range. Inelastic and nonelastic scattering begin at about 2.5 and 5
MeV, respectively, and become important at an energy of about 10 MeV
As the neutron energy goes higher, nonelastic scattering and spallation
reactions increase in importance, and elastic scattering becomes of less
importance for energies greater than 20 MeV.
POPULATION EXPOSURE TO IONIZING RADIATION
IN THE UNITED STATES
A new assessment of the average exposure of the U.S. population
to ionizing radiation has recently been made by the National Council on
Radiation Protection and Measurements (NCRP87b). Six main radiation
sources were considered: natural radiation and radiation from the following
five man-made sources: occupational activities (radiation workers), nuclear
fuel production (power), consumer products, miscellaneous environmental
sources, and medical uses.
For each source category, the collective effective dose equivalent was
obtained from the product of the average per capita effective dose equiv-
alent received from that source and the estimated number of people so
exposed. The average effective dose equivalent for a member of the U.S.
population was then calculated by dividing the collective effective dose
equivalent value by the number of the U.S. population (230 million in
1980~. As discussed below, the dose equivalent is defined as the product
of the absorbed dose, D, and the quality factor Q. which accounts for
OCR for page 18
18 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING ORATION
TABLE 1-3 Average Annual Effective Dose Equivalent of Ionizing
Radiations to a Member of the U.S. Population
Dose Equivalenta
Effective Dose Equivalent
Source mSvmrem mSv %
Natural
Radonb 242,400 2.0 55
Cosmic 0.2727 0.27 8.0
Terrestrial 0.2828 0.28 8.0
Internal 0.3939 0.39 11
Total natural 3.0 82
Artificial
Medical
x-ray diagnosis 0.3939 0.39 11
Nuclear medicine 0.1414 0.14 4.0
Consumer products 0.1010 0.10 3.0
Other
Occupational 0.0090.9 <0.01 <0.3
Nuclear fuel cycle <0.01<1.0 <0.01 <0.03
Fallout <0.01<1.0 <0.01 <0.03
MiscellaneousC <0.01< 1.0 <0.01 <0.03
Total artificial 0.63 18
Total natural and
artificial 3.6 100
aTo soft tissues.
b Dose equivalent to bronchi from radon daughter products. The assumed weighting factor
for the effective dose equivalent relative to whole-body exposure is 0.08.
c Department of Energy facilities, smelters, transportation, etc
SOURCE: National Council on Radiation Protection and Measurements (NCRP87b).
differences in the relative biological eRectiveness of different types of ra-
diation. The effective dose equivalent relates the dose-equivalent to risk.
For the case of partial body irradiation, the effective dose equivalent is
the risk-weighted sum of the dose equivalents to the individually irradiated
tissues.
As seen in Bible 1-3 and Figure 1-1, three of the six radiation sources,
namely radiation from occupational activities, nuclear power production
(the fuel cycle), and miscellaneous environmental sources (including nuclear
weapons testing fallout), contribute negligibly to the average effective dose
equivalent, i.e., less than 0.01 millisievert (mSv)/year (1 mrem/year).
A total average annual effective dose equivalent of 3.6 mSv (360
mrem)/year to members of the U.S. population is contributed by the other
three sources: naturally occurring radiation, medical uses of radiation, and
radiation from consumer products. By far the largest contribution (82%)
is made by natural sources, two-thirds of which is caused by radon and its
OCR for page 19
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
TERRESTRIAL 8%
INTERNAL 1 1%
(Inside
Human
Body)
Stocks
COSMIC 8%
(Outer Space)/ /
_
a\
if\
- _
-
RADON 55%
\ \
\
~ \
Strays 1 1%
NUCLEAR MEDIC
CONSUMER
PRODUCTS 3%
OTHER c 1%
Occupational
Fallout
Nuclear
Fuel Cycle
Miscellaneous
FIGURE 1-1 Sources of radiation exposure to the U.S. population (NCRP87b).
19
4%
0.3%
<0.3%
0.1%
0.1%
decay products. Approximately equal contributions to the other one-third
come from cosmic radiation, terrestrial radiation, and internally deposited
radionuclides. The importance of environmental radon as the largest source
of human exposure has only recently been recognized.
The remaining 18% of the average annual effective dose equivalent
consists of radiation from medical procedures (x-ray diagnosis, 11% and
nuclear medicine, 4%) and from consumer products (3%~. The contribution
by medical procedures is smaller than previously estimated. For consumer
products, the chief contributor is, again, radon in domestic water supplies,
although building materials, mining, and agricultural products as well as
coal burning also contribute. Smokers are additionally exposed to the
natural radionuclide polonium-210 in tobacco, resulting in the irradiation
of a small region of the bronchial epithelium to a relatively high dose (up to
0.2 Sv per year) that may cause an increased risk of lung cancer (NCRP84~.
Uncertainties exist in the data shown in Table 1-3. Uncertainties
for exposures from some consumer products are greater than those for
exposures from cosmic and terrestrial radiation sources. The estimates
for the most important exposure, that of lung tissue to radon and its
decay products, have many associated uncertainties. Current knowledge
OCR for page 54
54 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION
to be too sparse to merit further modeling by incorporating age. Good
human data on the Interaction between radiation and other exposures do
not appear to exist. The present Committee has therefore decided not to
pursue analysis of interaction effects further at this time.
Approaches to Model Fitting
The approach that is taken to fitting risk models to epidemiologic
data depends on the form in which the data are available. Some of the
more complex models require access to the raw data on individual subjects
and their entire history of exposures. However, most models can be fitted
with very little loss of information by placing the subjects into subgroups
with similar values of the relevant characteristics, particularly dose and
age at exposure, and then tabulating their person-years at risk and the
numbers of cases of each type of cancer as a function of age and time since
exposure. The study data can then be summarized by two arrays, one of
person-years, Yield, for dose group i, age at exposure group j, attained age
group k, and time since exposure interval 1, and one of numbers of cancers,
Nijk~m, in each subgroup ijkl from each type of cancer m. Admittedly, the
numbers of cases in most of the cells will be small, but this does not pose
a problem for the method of analysis to be used. Next, one assumes that
the numbers of cases in each cell follows a Poisson distribution, with the
expected value given by the product of the rate predicted by the model
and the person-years for that cell. The data can then be fitted by the
technique of maximum likelihood. The likelihood is the probability of the
observed data given a particular choice of model parameters, which, in this
circumstance, is obtained from the product of the Poisson probabilities for
each cell of the cross-tabulation. A Newton-Raphson search is used to find
the parameter values which maximize this likelihood. Confidence limits
and significance tests can be derived from large sample theory (Comb. The
committee used a computer program known as AMFIT for fitting a general
class of regression models for the Poisson data. Further details of the fitting
program can be found in Annex 4C to Chapter 4.
In any model fitting analysis, it is important to know how well the
model describes the data. There are several aspects to this question. First,
one would like an overall assessment of whether the model fits; such an
assessment is known as a goodness-of-fit test. A poor fit might be an
indication either that the chosen model is incorrect or that there is some
problem with the data; a good fit does not prove that the model is correct-
it simply means that there is insufficient evidence that the model is wrong.
Next, assuming that the model fits, one would like to know the range of
parameter values that is also consistent with the data; this range is known
as a confidence interval and is important in evaluating the uncertainty in
OCR for page 55
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
55
the fitted model. Next, one would like to be assured that the model is not
unduly influenced by a few observations at the expense of the bunk of the
data or by the inclusion of variables that are too highly correlated to be
separated. Techniques to identify these types of problems are known as
diagnostics and were used by the Committee throughout these analyses, as
discussed in Annex 4F.
Special Problems
Pooling Data From Multiple Studies For many cancer sites, information
was available from more than one epidemiologic study, raising the issue of
how these data should be combined for risk assessment purposes. Because
the studies generally differed in the nature of the exposures, the populations,
and numerous methodological details, it was considered inappropriate to
simply combine all of the raw data into a single data set. Instead, each
of the studies for which original data were available to the committee
were analyzed separately to obtain an estimate of the relevant parameters
and their uncertainties. Formal tests of homogeneity were carried out to
assess whether any differences in results could reasonably be ascribed to
chance. If the results appeared to be consistent, an overall estimate could
be obtained by a matrix weighted average and an estimate of the uncertainty
of the pooled estimate could easily be derived. On the other hand, if the
results appeared to be discrepant, the committee had to make a subjective
judgment as to the quality and relevance of each of the studies.
Use of Animal Data The committee felt strongly that its risk assess-
ments should be based on human data to the extent that they were available
and that animal data should be used only to address questions for which
human data were unavailable or inadequate. Questions in the latter cate-
gory included the RBE of neutrons and gamma rays and the effect of dose
rate.
Treatment of the RBE One of the problems for which the human data
are inadequate is that of estimating the RBE for neutrons. The BEIR
III Committee (NRC~) attempted to estimate the RBE for leukemia
from the data from Japanese atomic-bomb survivors and then applied their
estimate to the data on solid tumors. Aside from the inappropriateness of
treating this point estimate as if it were known with certainty, the approach
is no longer valid because reassessment of the atomic-bomb dosimetry
has largely eliminated the differences in responses between Hiroshima and
Nagasaki on which the previous estimate of the RBE was based. It therefore
became necessary for the present Committee to rely on animal data for this
purpose. For all analyses of the Radiation Effects Research Foundation
OCR for page 56
56 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
(RERF) data, a value of 20 for the RBE for neutrons was assumed as a
fixed constant. The justification for this choice is given in Chapter 4.
Projection of Lifetime Risk Estimates
Once the epidemiologic and animal data are summarized in the form
of an exposure-time-response model, the final stage of risk assessment
involves the calculation of lifetime risk for patterns of exposure of particular
interest. This is done with standard life table (mortality table) techniques
(Bugle. Consider the case of lifetime exposure at a constant annual rate.
A life table analysis would proceed as follows. Starting with a hypothetical
population of 1 million newborn infants, the first column in the life table
gives the number of infants that are expected to survive to each age.
The second column gives the cancer rate predicted by the exposure-time-
response model, and the third column gives the number of cases of cancers
that would result; this is given by the product of the first two columns.
The fourth column gives the number of deaths from other causes, based on
current mortality rates, which are not assumed to depend on radiation. The
number of survivors at the beginning of the next age interval is therefore
the number at the start of the interval minus the number of radiogenic and
nonradiogenic deaths, and the process continues until the entire cohort is
dead (although, in practice, the calculations are usually terminated at age
100~. The total number of excess cases of cancer is estimated by subtracting
the number of deaths obtained from a similar life table for persons with no
radiation exposure.
For protracted exposures, these calculations assume that each incre-
ment of exposure contributed independently to the cancer rates. Thus, the
risk at age T is given by the background rate plus the sum over the entire
exposure history of the excess rate attributable to each exposure increment;
that is, if D(t) represents the history of radiation doses at each age t and
[T~(t)] represents the postulated dependence of cancer rates on age and
each increment of exposure then the risk from the the entire history of
. .
exposure Is given fly:
rT
A[T, D] = Ao(T) + J {[I, D(t)]-Ao(t)}dt (1-7)
o
This implies that the rate is a function of cumulative exposure (possibly
weighted by a function of age at exposure or time since exposure). There
is evidence, however, that the contributions of extended exposures are not
simply additive: for low-LET radiation, protracted exposures appear to
be less hazardous than instantaneous exposures of the same total dose,
possibly because sublesions caused by the first event can be repaired before
additional events occur; for high-LET radiation, the effect may simply be
additive, or protracted exposures may even be more hazardous, possibly
OCR for page 57
BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES
57
because subsequent radiation exposure can promote already initiated cells.
The committee acknowledges this problem but, as explained earlier in
this chapter, it does not believe that sufficient information is available to
deal with this question in a definitive manner. The committee therefore
chose to retain the assumption of independence for the calculations but to
present the results in such a way that the reader can make adjustments for
protracted exposure when warranted.
Uncertainty of the Risk Estimates
Unlike the BEIR III Committee (NRC80) which presented a range
of lifetime risks based on relative and absolute risk models for several
choices of dose-response functions, the present committee has chosen to
assess the uncertainty of the projected lifetime risks by using a Monte Carlo
simulation approach. The committee's preferred exposure-time-response
model for a particular site of cancer or group of sites was characterized by
a vector of parameter estimates and a covariance matrix which describes
the uncertainty in each parameter. By repeated sampling from the set
of possible parameter values, with sampling probabilities determined by
their covariance matrices, 1,000 sets of possible parameters were obtained.
Each combination was then applied to the life table calculation described
above to obtain a set of predicted lifetime risks. The resulting distribution,
presented in Chapter 4, gives a measure of the statistical uncertainty in the
committee's risk estimates under the preferred model. Other sources of
uncertainty, external to the preferred model and its statistical uncertainty,
are discussed in Annex 4F.
A number of other models fit the data nearly as well. The Monte Carlo
simulation could, in principle, have been extended to include sampling over
alternative models. However the committee invoked a number of non-
statistical criteria, e.g., biological plausibility, to chose between alternative
models, and felt that using a simple goodness-of-fit criteria as weights in
the Monte Carlo simulation would not adequately reflect this process. Life
table results are presented in Annex 4D for a number of alternative models.
It is of interest that the range of life table risks estimated under these al-
ternative models is less than the uncertainty estimated by the Monte Carlo
simulation.
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Representative terms from entire chapter:
radiation protection
