DRAFT June 17, 2002

Table 3. Estimates of RBE, and RBE,, of fission neutrons for life-shortening in various
strains of mice derived from analysis of selected studies by Edwards (1999)*

RBE, RBEy
Mouse strain/Reference LL> Mean “UL? LL’ Mean’ UL?

RF/Un, Upton et al. (1967)° 2.5 3.5 4.5 2 3.5 4.5
Female 5 15 55

REM, Storer et al. (1979) 21 2.4 27 6.7 75 8.3
Female

BALB/c, Storer and Ullrich (1983) 3.5 45 5.5 12 15 18
Female

B6CF1, Carnes et al. (1989)
Male 7 8 9 35 50 65
Female 8.5 9.5 10.5 34 45 56

“See Table 3 of Edwards (1999). RBE, is RBE at high doses and high dose rates of reference
high-energy gamma rays, and RBEy is RBE at low doses and low dose rates obtained by extrapolation of
data on dose-response for neutrons and the reference radiation. Life-shortening in these studies was due
mainly to induction of cancers. When two sets of values are given, they represent alternative
interpretations that are consistent with the data.

®LL and UL are lower and upper 68% confidence limits on the mean, respectively, corresponding
to one standard error.

‘Results from study using X rays as reference radiation are omitted.

The data in Tables 3-5 illustrate two points noted previously. First, RBEs at high doses
and high dose rates, RBE,, usually are less than the extrapolated values at low doses and dose
rates, RBEy, due primarily to the influence of DDREF of the reference radiation on RBEy.
Second, the variability in RBE, is less than the variability in RBE,,, due primarily to the reduced
influence at high doses and dose rates of differences in DDREFs of the reference radiations. For
example, in the studies summarized in Tables 3 and 4, DDREF estimated as the ratio of the mean
value of RBE,, to the mean value of RBE, varies from | to nearly 20.

The available data for fission neutrons also indicate that RBEs for leukemias and related
diseases tend to be less than RBEs for solid tumors (NCRP, 1990; Edwards, 1997; Edwards,
1999). This difference is indicated, for example, by the RBEs for specific cancers in RF/Un and
REM mice given in Table 4. Given this difference, we have developed separate probability
distributions for solid tumors and leukemias based on RBEs for the two types of cancers.

14


DRAFT June 17, 2002

Table 1. Values of effective quality factor, @, and radiation weighting factor, w,, for
selected radiation types currently recommended for use in radiation protection®

Effective quality factor’ Radiation weighting factor‘
Radiation type (Q) (Wp)
Photons
All energies 1
> 30 keV4 1
Electrons
All energies* 1
> 30 keV 1
Tritium beta particles
Neutrons
Unknown energy’ 25
<10keV 5
10-100 keV 10
100 keV-2 MeV 20
2-20 MeV 10
> 20 MeV 5
Alpha particles 25 20

“Distinction between effective quality factor and radiation weighting factor is described in
footnote 8 of main text. Recommended effective quality factors and radiation weighting factors for other
radiation types, including protons and ions heavier than alpha particles, are not listed.

Values recommended by ICRU (1986) based on calculation of quality factor vs. lineal energy in
a 1-1m diameter sphere of tissue-equivalent material.

“Values recommended by ICRP (1991) and NCRP (1993).

At photon energies less than 30 keV, calculated effective quality factor increases with

decreasing energy (see Fig. 1).
“Auger electrons emitted in decay of radionuclides incorporated into DNA are excluded, see

paragraphs A13 and B67 of ICRP (1991).
When neutron energy at location of interest in tissue is known, energy dependence of effective

quality factor shown in Fig, 2 can be used.

The next section presents the equations used in IREP (Land et al., 2002) to calculate the
risk of a specific cancer resulting from a given absorbed dose of a particular radiation type.
These risk estimates provide the basis for calculations of probability of causation. The equations
illustrate how REFs are used in calculating risk, and they indicate the particular kinds of REFs
that are developed for each radiation type. The following sections then present the probability
distributions of REFs for neutrons, alpha particles, photons, and electrons.


DRAFT June 17, 2002

Log RBE

Log NEUTRON DOSE

Fig. 3. Schematic representation of increase in RBE for fission neutrons with decreasing dose given in
Fig. C-2 of ICRU (1986). Maximum values at low doses are values of RBEy.

Table 2. Summary of estimates of RBE,, for fission neutrons relative
to high-energy gamma rays given by expert groups*

Biological response ICRU (1986) NCRP (1990)
Tumor induction ~3 - ~200 16-59
Life shortening 15-45 10-46
Transformation 35-70 3-80"
Cytogenetic studies® 40-50 34-53
Genetic endpoints 10-45 5-70°

“Estimates of RBE,, apply at low doses and low dose rates, and are obtained by extrapolation of
data on dose-response for neutrons and the reference radiation at higher doses and dose rates; estimates
of RBE,, generally are greater than the corresponding estimates of RBE at higher doses and dose rates
(see Fig. 3). Only estimates of RBE,, for stochastic endpoints obtained from studies in mammalian
systems are listed.

°Value of 80 was derived from one set of experiments only.

*Studies in human lymphocytes in culture.

“Studies in mammalian systems only; range of values for genetic endpoints in plant systems
estimated by NCRP (1990) is 2-100.

“Value of 70 derived from data on specific locus mutations in mice is not necessarily an RBEy.


DRAFT June 17, 2002

CALCULATION OF CANCER RISKS

Different approaches are used in IREP to calculate risks of solid tumors and leukemias,
based on assumptions that the dose-response relationships in the Japanese atomic-bomb
survivors who received high acute doses of high-energy gamma rays are linear for solid tumors
but linear-quadratic for leukemias (Land et al., 2002), and that these relationships apply at lower
doses. Two additional assumptions are made. First, for any cancer type, the dose-response
relationships for neutrons and alpha particles are linear at any dose and dose rate. Second, for a
particular cancer type and conditions of exposure, the dose-response relationships for photons
and electrons have the same form (i.e., linear or linear-quadratic).

Based on these assumptions, cancer risks in exposed individuals are calculated using one
of the following equations:

Solid tumors —

R
R = REF, x —4_ x D (2)
DDREF,
® = REF, x Ruy xD (3)
Leukemias —
® = a(REF, x D) + b(REF, x D)? (4)
8 = ax REF, x D (5)
In these equations —
. MR is the risk of a particular cancer (i.e., the excess relative risk, ERR) due to
exposure to a particular radiation type;
. R,y is the risk coefficient (ERR per Gy) for a particular solid tumor at high acute

doses of high-energy gamma (y) rays, which have a defined biological
effectiveness of 1.0;

° the subscript L or H in the radiation effectiveness factor indicates that the REF is
derived based on estimates of RBE at low doses and low dose rates or at high
doses and high dose rates of the reference high-energy gamma rays, respectively;

° DDREF, is the dose and dose-rate effectiveness factor, which takes into account
that, for solid tumors, the ERR per Gy at low doses and low dose rates of photons
(and electrons) may be less than the values of R,,, at high acute doses obtained
from studies of exposed populations;


DRAFT June 17, 2002

2
is
=

15-4
Q
ea
2 4
=
ld
=
5 o5 4
&
wo

o T ee ee ea ee ee oe ee |

10° 10° 10°

PHOTON ENERGY/keV

Fig. 1. Calculated effective quality factor, 0, vs. photon energy under conditions of charged-particle
equilibrium given in Fig. 3 of ICRU (1986). Values are normalized to unity at energies of
orthovoltage X rays often used in radiobiological studies; energies of gamma rays emitted in
decay of ®Co are at right end of curve.

26
1s
= 20 -
x
E 15+
Ss 10
is2}
FO
=
=)
oO-7TTTMMT TOTTI a

10° 10° 10*
NEUTRON ENERGY/keV

Fig. 2. Calculated effective quality factor, Q, vs. neutron energy under conditions of charged-particle
equilibrium given in Fig. 4 of ICRU (1986).


DRAFT June 17, 2002

exposures to neutrons. This factor, which is a multiplier on the right-hand side of these
equations, is discussed in the sections that present the REFs for these radiation types.

Given an estimate of the excess relative risk, ERR, for a particular cancer type, the
probability of causation (PC) is estimated as PC = ERR/(ERR + 1) (Land et al., 2002).

NEUTRONS

Approaches to Estimating RBEs

RBEs for neutrons have been estimated in many radiobiological studies involving
different organisms, stochastic endpoints (responses), and doses and dose rates. Most studies
used fission neutrons or other neutrons of comparable energies; relatively few studies used
neutrons of lower or higher energies. Extensive reviews and evaluations of these data have been
presented by the ICRU (1986), the NCRP (1990), and the NRPB (Edwards, 1997).

In most studies, the doses and dose rates of neutrons and the reference radiation were
substantially above levels that are encountered in routine exposures of workers and the public.
Furthermore, as illustrated in Fig. 3, RBEs for neutrons generally increase with decreasing dose.
Therefore, an important focus of radiobiological studies and the primary concern of reviews by
expert groups has been to develop estimates of RBE that are appropriate at low doses and dose
rates. These RBEs are obtained by extrapolation of data on dose-response for neutrons and the
reference radiation at higher doses and dose rates. An RBE at low doses and dose rates obtained
by this extrapolation usually is denoted by RBE,,."? Summaries of estimates of RBE,, for fission
neutrons developed by the ICRU (1986) and the NCRP (1990) are given in Table 2."

From an evaluation of estimates of RBE, obtained from studies that are deemed relevant
to estimating cancer risks in humans, a representative probability distribution of REF at low
doses and low dose rates, which we denote by REF,, could be developed. This distribution could
be used to estimate cancer risks in accordance with eq. (2) for solid tumors or eq. (5) for
leukemias. As indicated by the summary in Table 2, estimates of RBE, for fission neutrons
obtained from different radiobiological studies vary widely. Thus, a probability distribution of
REF, that would represent these data would span a wide range of values.

"The subscript M denotes that an RBE at low doses and dose rates of the reference radiation is a
maximum value (see Fig. 3).

In some cases, such as studies of tumor induction in mice summarized in Table 6.3 of NCRP
(1990), particular values of RBE,, lie outside the range given in Table 2. Furthermore, the ranges in
Table 2 generally are based on central estimates of RBEy, and values well outside these ranges cannot be
ruled out when uncertainties in the data are taken into account.

9


DRAFT June 17, 2002

RADIATION EFFECTIVENESS FACTORS (REFs) FOR USE IN CALCULATING
PROBABILITY OF CAUSATION OF RADIOGENIC CANCERS

David C. Kocher, A. Iulian Apostoaei, and F. Owen Hoffman
SENES Oak Ridge, Center for Risk Analysis’

INTRODUCTION

Workers and members of the public can be exposed to various types of ionizing radiation
(e.g., photons, electrons, and alpha particles) that may differ in their biological effectiveness.
That is, for a given absorbed dose in tissue, the probability of a stochastic response (e.g., cancer)
may depend on the radiation type, and sometimes its energy, as well as the absorbed dose.
Differences in biological effectiveness of different radiation types must be taken into account in
estimating cancer risks and the probability of causation of radiogenic cancers in humans.

This report presents so-called radiation effectiveness factors (REFs) which are intended to
represent the biological effectiveness of different types of ionizing radiation for the purpose of
calculating the probability of causation of specific cancers in humans. REFs are expressed as
probability distributions, taking into account uncertainties in relevant radiobiological data and
other judgments involved in evaluating available information. The different types of ionizing
radiation considered in this report include photons (gamma rays and X rays),” electrons, alpha
particles, and neutrons. Except in cases of exposure of the lung to alpha particles emitted by
short-lived decay products of radon in air, probability distributions of REFs are intended to be
applied in calculating the probability of causation of radiogenic cancers in any organ or tissue
and for any exposure situation? The REFs developed in this report are incorporated in the
Interactive RadioEpidemiological Program (IREP).*

'SENES Oak Ridge, Inc., Center for Risk Analysis, 102 Donner Drive, Oak Ridge, TN 37830.
Phone, (865)483-6111; fax, (865)481-0060; email, senesor@senes.com. Research sponsored by National
Institute of Occupational Safety and Health (NIOSH) under contract with SENES Oak Ridge, Inc.

?Gamma rays are the electromagnetic radiations emitted in de-excitation of atomic nuclei,
whereas X rays are the electromagnetic radiations emitted in de-excitation of atomic electrons, often
referred to as characteristic X rays, or produced in deceleration of charged particles (e.g., electrons) in
passing through matter, often referred to as continuous X rays or bremsstrahlung.

5The probability of causation of lung cancer due to inhalation of radon and its decay products in
air is calculated based on an estimate of the risk per unit exposure to the short-lived alpha-emitting decay
products in Working Level Months (WLM), and an REF for alpha particles that would be applied to
estimates of absorbed dose in the lung is not used.

4Methods used in IREP to calculate the probability of causation of radiogenic cancers may be
found on the Internet at http://216.82.51.38/irep_niosh and in Appendix F of Land et al. (2002).

1



DRAFT June 17, 2002

LO

Fission neutrons

O08 F

250 kV x rays
0.6 |-

Dicentrics per celt

0.2
x rays linear component

1 !
lo) a 2 3
Dose, Gy

Fig. 4. Representation of linear and linear-quadratic dose-response relationships for fission neutrons and
X rays, respectively, given in Fig. 1 of Edwards (1997). Separation of two curves at different
levels of response illustrates dependence of RBE on dose (see Fig. 3); RBE at low doses, RBEy,
is determined by separation of neutron curve and linear component of X-ray curve.

L-
7
a

a 4 U=aD+6D?
JS

S
8 a“
3 Linear, No Threshold a“
3 lope a,
£ a
Ss
# Le Slope.a, —
g a peers ”

OO eT

7 <

Absorbed dose (D) ————— >

Fig. 5. Representation of linear-quadratic dose-response relationship for low-LET radiations given in
Fig. 2 of CIRRPC (1995). Dose and dose-rate effectiveness factor (DDREF) is ratio of linear
extrapolation at high doses, 0,;, to slope of dose-response curve at low doses, o,; DDREF thus is
a function of dose given by 1 + (B/a)D.


DRAFT June 17, 2002

In most radiobiological studies, the dose-response relationship for neutrons is linear at
absorbed doses of a few Gy or less, whereas the dose-response relationship for the low-LET
reference radiation is linear-quadratic in form (ICRU, 1986; NCRP, 1990); see Fig. 4. The
variability in estimates of RBE,, for neutrons obtained from different studies is due in part to
pronounced differences in the linear-quadratic dose-response relationships for the reference
radiation, which result in a wide range of DDREFs for these radiations when calculated as
indicated in Fig, 5 (CIRRPC, 1995; Edwards, 1997; Edwards, 1999). That is, RBE, is sensitive
to variations in biological effectiveness at low doses of the reference radiation, with higher
values of RBEy associated with high DDREFs and lower values with low DDREFs. Since the
DDREFs for the reference radiation embodied in values of RBE,, for neutrons generally are not
the same as a DDREF, that might be used to adjust observed cancer risks in humans at high acute
doses of high-energy gamma rays to obtain estimates of risk at low doses and low dose rates (see
footnote 11), a probability distribution of REF, that is based on the variability in estimates of
RBE, may not provide the best representation of the biological effectiveness of low doses of
neutrons in humans relative to low doses and dose rates of gamma rays.

Difficulties with developing a representative probability distribution of REF, based on
highly variable estimates of RBE,, obtained from different studies can be addressed by using an
alternative approach recommended by CIRRPC (1995) and discussed by Edwards (1997; 1999).
This approach is based on the view that the assumed REFs for neutrons should be consistent with
the data used to estimate cancer risks from exposure to photons. That is, the appropriate REFs
are values based on RBEs at high doses and high dose rates of reference high-energy gamma
rays, because this was the condition of exposure of the Japanese atomic-bomb survivors from
which most estimates of cancer risks in humans have been derived; we denote these REFs by
REF, Then, if DDREF for neutrons is assumed to be unity, based on the observation that the
dose-response relationship usually is linear at absorbed doses of a few Gy or less and the usual
presumption of linearity at low doses for all high-LET radiations, a probability distribution of
REF, that represents RBEs at high doses and high dose rates of reference high-energy gamma
rays could be used to estimate cancer risk at any dose and dose rate of neutrons in accordance
with eq. (3), for example. Thus, estimates of cancer risk from exposure to neutrons can be based
directly on estimated RBEs at high doses and high dose rates, rather than extrapolated values at
low doses and dose rates, and without the need to apply an uncertain DDREF to the risk
coefficient at high acute doses of the reference radiation.

When the alternative approach described above is used to estimate cancer risk, there still
is considerable variability in RBEs for neutrons at high doses and high dose rates of the reference
high-energy gamma rays, RBE,. This variability is due to several factors including the variety of
biological systems and stochastic endpoints studied, as well as the dependence of RBE on dose
when the dose-response relationship for the reference radiation is non-linear (see Figs. 3 and 4).
However, the variability in RBE, is considerably less than the variability in RBE,, due mainly to
the reduced influence at high doses of differences in the DDREFs for the reference radiation in
the various studies. Therefore, the uncertainty in a representative value of REF, to be used in
estimating cancer risks in humans should be less than the uncertainty in REF,.

11


DRAFT June 17, 2002

° aand b are the coefficients of the linear and quadratic terms, respectively, in the
assumed linear-quadratic dose-response relationship for leukemias under
conditions of acute exposure to high-energy gamma rays; and

. Dis the absorbed dose of the radiation type of concern.

The equation selected depends on the radiation type and cancer of concern. For solid
tumors, eq. (2) is used in cases of exposure to photons, electrons, and alpha particles, and eq. (3)
is used in cases of exposure to neutrons; the different approach to estimating risk from exposure
to neutrons is discussed in the next section. For leukemias, eq. (4) is used in cases of acute
exposure to photons and electrons, and eq. (5) is used in cases of chronic exposure'® to photons
and electrons and any exposures to alpha particles and neutrons; for this type of cancer, the
assumed dose-response relationships for photons and electrons are different under conditions of
acute and chronic exposure (linear-quadratic for acute exposure, but linear for chronic exposure).

The dose and dose-rate effectiveness factor (DDREF) is applied to radiations with a low
linear energy transfer (LET) in tissue and is based on observations that dose-response
relationships at low doses and low dose rates of photons often are different than at high doses
and dose rates, with the response per unit dose usually lower at low doses and dose rates (ICRP,
1991; NCRP, 1993),'' A DDREF is used to estimate risk for solid tumors only, and only when
the REF for the radiation type of concern is derived based on estimates of RBE at low doses and
low dose rates of the reference radiation. When the dose-response relationship for high-energy
gamma rays is assumed to be linear, DDREF renormalizes the risk coefficient at high acute
doses, R,,;, as obtained mainly from studies of the Japanese atomic-bomb survivors, to give a risk
coefficient at low doses and dose rates that is compatible with an REF at low doses and dose
rates, REF,. A DDREF is not used to estimate risk of leukemias. However, a similar effect is
obtained by assuming that the dose-response relationship under conditions of acute exposure to
low-LET radiations is linear-quadratic, and that the dose-response relationship under conditions
of chronic exposure is linear and is defined by the linear term in the dose-response relationship
for acute exposure.

A DDREF is not used in cases of exposure to high-LET alpha particles and neutrons.
However, a factor representing an inverse dose-rate effect, which is not shown in eqs. (2), (3),
and (5), is applied to all exposures to alpha particles emitted in radioactive decay and to chronic

An exposure is considered to be chronic if the absorbed dose rate, averaged over a period of a
few hours, is less than 6 mGy/h.

"For purposes of radiation protection, the ICRP (1991) and the NCRP (1993) currently
recommend a DDREF, of 2; i.e., estimated cancer risks per unit dose in the atomic-bomb survivors are
reduced by a factor of 2in estimating risks from exposure to gamma rays and other low-LET radiations at
lower doses and dose rates. In IREP, DDREF, is treated as an uncertain parameter at doses and dose
rates less than those experienced in the atomic-bomb survivors (Land et al., 2002).

8


DRAFT June 17, 2002

types considered in this report, the values of @ recommended by the ICRU (1986), which were
developed by a Joint Task Group of the ICRP and the ICRU, and the values of wz currently
recommended by the ICRP (1991) and the NCRP (1993) are given in Table 1. Although there is
general agreement between the two sets of recommendations, there are some differences,
especially in the recommendations for photons of energy less than 30 keV and low-energy beta
particles emitted in decay of tritium @H). There also are differences in the recommendations for
alpha particles and neutrons.

Although consistency between the REFs developed in this report and the effective quality
factors and radiation weighting factors recommended by national and international authorities
may be desirable, there are two important issues to be considered. First, point values of radiation
protection quantities do not reveal the state of knowledge (uncertainty) in the values, including
uncertainties in RBEs obtained from relevant radiobiological studies and uncertainties in other
judgments used to develop the point values. A full accounting of uncertainties in all parameters
is essential when estimating probability of causation for the purpose of evaluating claims by
individuals that their cancer was caused by radiation exposure.

Second, for some radiations, it is evident that the recommended point values of radiation
protection quantities given in Table 1 are not consistent with the preponderance of relevant
radiobiological information. For example, based on a review of available data, the ICRU (1986)
concluded that there is clear evidence that the biological effectiveness of orthovoltage X rays is
approximately twice that of high-energy “Co gamma rays. This conclusion is consistent with a
calculation of the energy dependence of the effective quality factor for photons shown in Fig. 1.
Nonetheless, neither the ICRU nor the ICRP and the NCRP have incorporated this difference in
their current recommendations. Similarly, the current ICRP and NCRP recommendations do not
take into account the clear evidence from many studies that beta particles emitted in decay of *H
are biologically more effective than high-energy gamma rays.”

It is important to recognize that the needs of radiation risk assessment and calculations of
probability of causation in cases where actual exposures of specific individuals are of concern
differ significantly from the needs of radiation protection. The primary concern in radiation
protection is control of exposures based on evaluations of compliance with applicable limits on
radiation dose and other radiation protection requirements, and the use of standard assumptions
for this purpose is appropriate. However, as noted above, estimates of probability of causation
must be based on the state of knowledge of actual doses and risks to exposed individuals. Thus,
we have not assumed a priori that effective quality factors or radiation weighting factors
developed for use in radiation protection provide “best” estimates of REFs for the purpose of
calculating probability of causation. Rather, we have developed probability distributions of
REFs based primarily on data obtained from relevant radiobiological studies.

°In earlier recommendations (ICRP, 1960), absorbed dose from 7H beta particles was modified by
a factor N = 1.7 in calculating dose equivalent to account for an increased biological effectiveness of
these radiations, but such a modifying factor is not included in current ICRP recommendations.

4


DRAFT June 17, 2002

Table 4. Estimates of RBE, and RBE), of fission neutrons for induction of specific cancers
in various strains of mice derived from analysis of selected studies by Edwards (1999)*

RBE, RBEy
Mouse
strain Cancer LL’ Mean’ (UL? LL’ Mean’ «UL!
RF/Un Myeloid Jeukemia 1.7 2.8 4.7 9 19 38
Lymphoma 2.2 2.9 3.7 2.7 4.7 5.6
RFM
Male Myeloid leukemia 2.2 2.8 3.8 — — —
Female Thymic leukemia 3.3 4.1 5.1 12 29 64
Harderian gland tumor 7 9 il 22 33 47
Pituitary tumor 5 7 10 17 120 °°
BALB/c
Female Lung adenocarcinoma 5.5 15 10 12 20 30
Mammary tumor 2 ia 18 7 41
CBA/H Myeloid leukemia 4 7 10 14 21 36
SAS/4
Male Lung adenocarcinoma 3 5 9 _ _ _
Female Lung adenocarcinoma 5 8 14 _ _ _—

“See Table 4 of Edwards (1999). RBE, is RBE at high doses and high dose rates of reference
high-energy gamma rays, and RBEy is RBE at low doses and low dose rates obtained by extrapolation of
data on dose-response for neutrons and the reference radiation. When two sets of values are given, they
represent alternative interpretations that are consistent with the data. Analysis was based on data given
in Upton et al. (1970), Ullrich et al. (1976; 1977; 1979), Ullrich (1980; 1984), Ullrich and Preston
(1987), Mole and Davids (1982), Mole et al. (1983), and Coggle (1988).

°LL and UL are lower and upper 68% confidence limits on the mean, respectively, corresponding
to one standard error.

15


DRAFT June 17, 2002

The probability distributions of REFs for induction of cancers in humans presented in this
report are based primarily on published reviews and evaluations of radiobiological studies. For
the most part, we relied on reviews by such expert advisory groups as the International
Commission on Radiological Protection (ICRP), the International Commission on Radiation
Units and Measurements (ICRU), the National Council on Radiation Protection and
Measurements (NCRP), the U.K.’s National Radiological Protection Board (NRPB), and the
Committee on Interagency Radiation Research and Policy Coordination (CIRRPC), as well as
reviews by the U.S. Environmental Protection Agency (EPA) and individuals who are recognized
experts. We used other information from the primary literature only to a limited extent.

It cannot be overemphasized that the development of probability distributions of REFs
relies to a significant extent on subjective scientific judgment. The most important judgment is
an assumption that RBEs obtained from studies of a number of stochastic responses in a variety
of biological systems are applicable to induction of cancers in humans. This assumption is
necessitated by the lack of data on RBEs for cancer induction in humans. Scientific judgment
also is applied by experts and expert groups in their reviews and evaluations of published studies,
and in the conclusions they draw from these reviews. Finally, we have applied our own scientific
judgments in developing probability distributions of REFs, and we recognize that knowledgeable
individuals could reach different conclusions based on the same body of information.

Given the importance of subjective scientific judgment, it also should be emphasized that
the probability distributions of REFs developed in this report are nothing more than a
representation of the current state of knowledge of the effectiveness of different radiation types in
inducing cancers in humans; they are not intended to represent uncertainty in a strict statistical
sense. That is, the assumed probability distributions of REFs are not intended to represent a
frequency distribution of actual outcomes that would be obtained if repeated experiments to
estimate the biological effectiveness of different radiation types in humans were performed.

Tn developing probability distributions of REFs for use in calculating probability of
causation of radiogenic cancers, an important consideration is the extent to which these
distributions should be consistent with recommendations developed by national and international
advisory groups for purposes of radiation protection. In radiation protection, the quantities that
are analogous to an REF are the effective quality factor, @ (ICRU, 1986), and the radiation
weighting factor, w, (ICRP, 1991; NCRP, 1993).3

Effective quality factors and radiation weighting factors used in radiation protection are
prescribed point values that are intended to represent relevant data on RBE. For the radiation

®Effective quality factors are intended to be applied to radiations at the Jocations in tissue where
an absorbed dose is delivered, and are used to calculate dose equivalent at a point (ICRU, 1986), whereas
radiation weighting factors are intended to be applied to radiations incident on the body or emitted by
internally deposited radionuclides, and are used to calculate equivalent dose in an organ or tissue from
the average absorbed dose in that organ or tissue (ICRP, 1991).

3


DRAFT June 17, 2002

The probability distributions of REFs developed in this report are based in large part on
data on the relative biological effectiveness (RBE) of different radiation types obtained from
relevant radiobiological studies. The RBE of radiation i compared with a reference radiation, r,
is defined as the absorbed dose of the reference radiation (D,) required to produce a specific level
of response relative to the absorbed dose of the radiation of concern (D,) required to produce an
equal response:

RBE, = —, a)

with all physical and biological variables, except differences in radiation type, being held as
constant as possible. The definition of RBE as a ratio of doses that produce an equal response
does not depend on the dose-response relationships for the two radiation types being the same, or
that either dose-response relationship be linear. Values of RBE are specific to each study, and
they generally depend on the biological system and specific response under study, the magnitude
of the absorbed doses, the dose rate, and the dose per fraction if the dose is fractionated.>

In most radiobiological studies to estimate RBEs, the reference radiation is either
orthovoltage (deeply penetrating) X rays, usually 180-250 kVp,° or higher-energy gamma rays
produced in decay of Co (photon energies of 1.2 and 1.3 MeV) or, less often, '°’Cs (0.66 MeV).
Knowledge of the reference radiation in any study is important because, as discussed in this
report, the biological effectiveness of X rays apparently is greater than that of higher-energy
gamma rays. In this report, the reference radiation is taken to be high-energy gamma rays,
specifically gamma rays emitted in °Co decay, at high doses and high dose rates. This choice is
appropriate for the purpose of calculating the probability of causation of cancers because
estimates of cancer risks in humans are based primarily on data obtained from studies of the
Japanese atomic-bomb survivors who received high acute doses of high-energy gamma rays.’

5It is because the term “RBE” strictly applies only to results of specific radiobiological studies
under controlled conditions that the new term “radiation effectiveness factor” (REF) is used in this
report. REFs for induction of cancers in humans are assumed values based primarily on evaluations of
RBEs obtained from studies of a variety of stochastic responses in other biological systems, augmented
in a few cases by information obtained from epidemiological studies of human populations.

The term “kVp” denotes the maximum potential difference in kilovolts (kV) across an X-ray
tube during an exposure; this potential difference determines the maximum electron energy in keV. The
average energy of the continuous spectrum of bremsstrahlung produced when the electrons are stopped in
a target is a fraction of the peak tube potential in kVp.

"In IREP, the only cancer risks that are not estimated based on data in the Japanese atomic-bomb
survivors, in addition to risks of lung cancer from inhalation of radon and its short-lived decay products,
are risks of thyroid cancer resulting from exposure in childhood (Land et al., 2002). These risks are
estimated based primarily on studies of children exposed to X rays.

2


DRAFT , June 17, 2002

It is important to emphasize that estimates of cancer risks at low doses and low dose rates
of neutrons obtained using the alternative approach represented by eq. (3) would be the same as
risks estimated using the conventional approach represented by eq. (2) if the DDREFs for the
reference radiation embodied in the estimates of RBE,, were the same as the value of DDREF,
that is used to adjust observed risks at high acute doses of high-energy gamma rays in humans to
obtain estimates of risk at low doses and dose rates. The advantage of the approach represented
by eq. (3) is that it is directly compatible with the data in the Japanese atomic-bomb survivors
who were exposed at high acute doses. Again, these are the data from which most estimates of
cancer risks in humans are obtained.

In principle, the alternative approach of estimating cancer risks from exposure to neutrons
based on probability distributions of REF, obtained from RBEs at high doses and high dose rates
of reference high-energy gamma rays could be used for any cancer type. However, as indicated
in the previous section, the alternative approach is used only to estimate risks of solid tumors.
The approach is particularly suitable in such cases because the dose-response relationships for
gamma rays are assumed to be linear and risk coefficients at high acute doses of gamma rays thus
are defined. The conventional approach of estimating cancer risks from exposure to neutrons
based on probability distributions of REF, obtained from RBEs at low doses and low dose rates
of the reference radiation is used for leukemias, essentially because the dose-response
relationship for acute exposure to gamma rays is assumed to be linear-quadratic. Consequently,
if the alternative approach were used for leukemias, estimated risks from exposure to neutrons
would have an additional uncertainty arising from the dependence of the risk on the choice of a
reference “high” acute dose of gamma rays in the Japanese atomic-bomb survivors.

Data on RBE Used in Analysis

In this analysis, probability distributions of REFs for fission neutrons are developed based
on data on RBE obtained from studies of life-shortening and induction of specific cancers in
mice. Since life-shortening in mice was due mainly to induction of cancers, the different
endpoints are closely related. Furthermore, compared with studies of other endpoints in various
biological systems, RBEs obtained from studies of life-shortening and cancer induction in mice
should be the most relevant to estimating REFs for induction of cancers in humans.

Available data on RBE for life-shortening and induction of specific cancers in mice have
been reviewed and analyzed by Edwards (1999); see also a report of the NRPB (Edwards, 1997).
Estimates of RBE at high acute doses of the reference high-energy gamma rays, RBE,, and
extrapolated values at low doses and low dose rates of the reference radiation, RBE,,, obtained by
Edwards are given in Tables 3-5."

“Estimates of RBE, given by Edwards (1997) incorporate an assumed DDREF of 2 for the
reference radiations and, thus, are a factor of 2 higher than the values given in the later paper (Edwards,
1999). The values in Edwards (1999) are the appropriate ones for use in this analysis.

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