DRAFT

Table 11. Estimates of RBE,, for X rays and induction of

dicentric chromosomes in human lymphocytes*

RBE,,
Reference X rays (68% Cl)’
Bauchinger (1984) 220 kVp 3.8
(2.5, 6.5)
Fabry et al. (1985) 250 kVp 15
(1.0, 2.2)
Lloyd et al. (1986) 250 kVp 2.6
(1.8, 3.8)
Littlefield et al. 220 kVp 2.8
(1989) (1.7, 5.1)
Brewen and 250 kVp 2.3
Luippold (1971); (1.8, 3.3)
Brewen et al.
(1972)
Lloyd et al. (1975) 250 kVp 3.0
(2.4, 3.8)

“RBE,, is RBE at low doses obtained by extrapolation of linear-
quadratic dose-response relationships for X rays and reference °Co

gamma rays.

First entry is point estimate calculated by NCRP (1990) as
a,/a,, where ay and a, are central estimates of coefficient of linear term
in dose-response relationship for X rays and gamma tays, respectively,

given in Table 10. Second entry in parentheses is 68% confidence

interval based on standard errors in o coefficients given in Table 10 and
calculated as described in text.

June 17, 2002

* A study of life-shortening in mice (Upton et al., 1967) summarized in Table 8.2 of NCRP
(1990), in which the radiations under study were neutrons, indicated that the RBE at low
doses and low dose rates of X rays was about 3 or less. A similar result was obtained
from an analysis of these data by Edwards (1999) to obtain estimates of RBE for neutrons
at high doses and high dose rates of the reference radiation, RBE, (see Table 3).

¢ A study of mutations in human lung fibroplasts (Cox and Masson, 1979) summarized in
Section 7, Paragraph 19, and Table 7.3 of Muirhead et al. (1993), in which the radiations
under study were alpha particles, indicated that the RBE of X rays was about 2.5 when

44


DRAFT June 17, 2002

It is questionable, however, whether an REF for alpha particles and leukemia inferred
from studies of Thorotrast patients can be applied to other exposures to alpha-emitting
radionuclides. The difficulty is that Thorotrast occurs as colloidal particles that mostly remain
suspended in bone marrow, whereas the various forms of alpha-emitting radionuclides normally
encountered in the workplace or the environment are deposited on bone surfaces and, in some
cases, are then distributed throughout the volume of cortical and trabecular bone (EPA, 1999).
Thus, Thorotrast may be substantially more effective in irradiating radiosensitive cells in bone
marrow than other forms of alpha-emitting radionuclides.

An indication that an REF for alpha particles and leukemia inferred from studies of
Thorotrast patients may not apply to exposures to more common forms of alpha-emitting
radionuclides is provided by the results of studies of other populations that were exposed to alpha
emitters. Specifically, studies of radium dial painters who ingested Ra and medical patients
who were administered ?Ra (National Research Council, 1988) have not shown an excess of
leukemias in these populations. When dosimetry models developed by the ICRP are used to
estimate an alpha dose to bone marrow from radium deposited in bone, an REF substantially
greater than unity (e.g., a central estimate of about 6 based on the Thorotrast data) implies that
the leukemia risk in these populations should have been comparable to the estimated risk of bone
cancer (EPA, 1999), but no such risk has been seen.

Based on the absence of excess leukemias in populations exposed to radium, the EPA.
(1999) concluded that an “effective RBE” of about 1 is an upper bound for leukemia in cases of
exposure to alpha-emitting radionuclides that deposit on bone surfaces or in bone, and that the
uncertainty in this “effective RBE” could be described by a uniform probability distribution
between 0 and 1. The EPA also emphasized, however, that this result does not imply that
radiosensitive cells in bone marrow are less sensitive to alpha particles than to gamma rays.
Rather, this result probably reflects the nonuniform distribution of alpha dose in bone marrow
when an alpha emitter is deposited on bone surfaces or in bone.

Interpretation of the studies of leukemias in populations exposed to radium also has its
difficulties. The high doses of alpha particles in some cases (e.g., the radium dial painters) may
have resulted in substantial cell killing that masked any leukemia risk at lower doses. The
potential importance of cell killing on the leukemia risk in Thorotrast patients was noted by
Muirhead et al. (1993). Another difficulty is that both the observed incidence of leukemias in the
exposed populations and the expected incidence in the absence of radiation exposure were low
(about 10 cases or less). Therefore, there is considerable uncertainty in estimates of leukemia
risk in these populations, and the possibility of a significant leukemia risk may not be completely
ruled out by the data. Finally, some leukemias may have been missed in the radium dial painters,
due to incomplete information on the identification of these workers and their causes of death,
especially during the early years of the last century.

A third source of information on the REF for alpha particles and leukemias is data on
RBEs for fission neutrons and leukemias in mice. These data are relevant because a large

35


DRAFT June 17, 2002

1.006 |
750 || | | |

S sod

S Q

]

e

25 Op L
000-5 | H t l 78

0.00 11.25 22.50 33.75 45.00

Fig. 17. Assumed probability distribution of REF, for alpha particles and leukemias modified by an
enhancement factor representing an inverse dose-rate effect under conditions of chronic exposure
shown in Fig. 16 displayed as a cumulative distribution.

Table 9. Summary of probability distributions of radiation effectiveness factors and
enhancement factor for alpha particles to be used in estimating cancer risks
and probability of causation in accordance with eq. (9) or (10)

Cancer type Probability distribution of radiation effectiveness factor (REF,)
Solid tumors Lognormal distribution having a 95% confidence interval between 3 and 80
Leukemias Hybrid distribution with —

50% weight to lognormal distribution having a 95% confidence
interval between 1.0 and 15;

25% weight to value 1.0;

25% weight to lognormal distribution having a 95% confidence
interval between 2.0 and 60

Enhancement factor representing inverse dose-rate effect for all exposures to alpha particles*

Discrete distribution with —
70% weight to value 1.0;
20% weight to value 1.5;
7.5% weight to value 2.0;
2.5% weight to value 3.0

“All exposures to alpha particles emitted by radionuclides are assumed to be chronic.

40


DRAFT June 17, 2002

and RBEs for fission neutrons and leukemias in mice represent the biological effectiveness of
alpha particles, given that the radiosensitive cells in bone marrow are irradiated.

Correction for Inverse Dose-Rate Effect

As in the case of neutrons discussed in the previous section, an additional consideration
in estimating cancer risks at low doses and dose rates of alpha particles is the possibility of an
inverse dose-rate effect, whereby the biological effectiveness at a given dose increases as the
dose rate decreases. An analysis of data in humans (underground miners) who were exposed to
elevated levels of radon has shown an inverse dose-rate effect that could be as much as a factor
of 3 but is more likely less than a factor 2 (Lubin et al., 1995).

Arguments can be made both for and against the need to account for an inverse dose-rate
effect in estimating cancer risks from chronic exposure to alpha particles. An argument in favor
is that since an inverse dose-rate effect has been observed in some studies of neutrons, the effect,
if it exists, should occur with other high-LET radiations. However, there are several opposing
arguments. First, an inverse dose-rate effect has not been observed in underground miners at
exposures to short-lived alpha-emitting radon decay products less than 50 Working Level
Months (WLM) (Lubin et al., 1995).'® Second, in contrast to studies of neutrons in small
mammals, all studies of alpha-emitting radionuclides involved protracted exposures, and
estimated RBEs obtained from these studies may already account for an inverse dose-rate effect.
Finally, again in contrast to neutrons, RBEs for alpha particles are extrapolated values at low
doses and dose rates, RBEy, and the highest values, which correspond to the highest DDREFs of
the reference low-LET radiations, may result in overestimates of cancer risks in humans.

We assume that the probability distributions of RBE, for alpha particles described
previously should be adjusted by a small factor representing a possible inverse dose-rate effect, to
be consistent with a similar assumption in cases of chronic exposure to neutrons. However, we
give less weight to a possible inverse dose-rate effect for alpha particles compared with neutrons
based mainly on two considerations discussed above. First, the data in underground miners do
not show an effect at low doses of concern in routine exposures of workers and the public.
Second, the probability distributions of REF, may already incorporate an inverse dose-rate effect
when the relevant studies involved protracted exposures to alpha particles. Specifically, we
assume a discrete probability distribution for the enhancement factor representing an inverse
dose-rate effect for alpha particles with 70% of the values at 1.0, 20% at 1.5, 7.5% at 2.0, and
2.5% at 3.0. The arithmetic mean of this distribution is about 1.2.

As noted previously, all exposures to alpha particles emitted by radionuclides are
assumed to be chronic. Therefore, the enhancement factor representing an inverse dose-rate

‘8Based on conversion coefficients given in Table 4 of ICRP (1987) and Table 6 of ICRP (1993),
an exposure to radon decay products of 50 WLM corresponds to an absorbed dose to the bronchial
epithelium, where lung carcinomas in underground miners ate observed to originate, of about 0.8 Gy.

37


DRAFT June 17, 2002

difference in the biological effectiveness of alpha particles and fission neutrons is not expected
and has not been demonstrated experimentally (ICRU, 1986; Sinclair, 1985). As noted above,
selected data in mice were used by the EPA (1999) to support an assumption about biological
effectiveness that applies to exposure situations represented by the Thorotrast patients, i.e.,
exposures to alpha emitters suspended in bone marrow.

Given the variety of information on the risk of leukemia from exposure to alpha particles
discussed above, some of which is seemingly contradictory, we have taken the approach of
developing a hybrid probability distribution of REF at low doses and dose rates of the reference
radiation, REF,, that gives some weight to all potentially relevant information. As discussed
above, the sources of information include (1) data in the Thorotrast patients, (2) data in other
populations exposed to alpha-emitting radionuclides, and (3) data for fission neutrons in mice.
We also assume that there is only a small probability that alpha particles would be less effective
than high-energy gamma rays in inducing leukemias.

Based on these considerations, we describe REF, for alpha particles and leukemias by the
following hybrid probability distribution:

fi] 50% weight to a lognormal distribution having a 95% confidence interval between
1.0 and 15, based on estimates of leukemia risk in Thorotrast patients;

[2] 25% weight to the value 1.0, based on the EPA’s evaluation of leukemia risks in
other populations and an assumption that the REF should not be less than 1.0;

{3] 25% weight to the lognormal probability distribution of REF, for fission neutrons
and leukemias, which has a 95% confidence interval between 2.0 and 60.

The median of this distribution is 3.6 and the 95% confidence interval lies between 1.0 and 33.
This distribution clearly is a subjective representation of the current state of knowledge, rather
than an expected frequency distribution of RBEs that would be obtained based on measurements.

The information on leukemia risks in populations exposed to radium discussed above
indicates that the assumed probability distribution of REF, could result in substantial
overestimates of risk to individuals exposed to common forms of alpha-emitting radionuclides
when alpha dose to bone marrow is estimated using dosimetry models developed by the ICRP.
That is, the “effective RBE” in these cases may be substantially less than unity (EPA, 1999).
However, we have given little weight to an assumption that the biological effectiveness of alpha
particles is less than that of high-energy gamma rays, essentially because we believe that possible
errors in estimating alpha dose to radiosensitive cells of bone marrow should not be incorporated
in a representation of biological effectiveness; i.e., considerations of biological effectiveness
should be separated from considerations of dosimetry. We have given some weight (25%) to an
assumption that alpha particles and gamma rays are equally effective in inducing leukemias, but
substantially more weight (75%) is given to an assumption that data in the Thorotrast patients

36


DRAFT June 17, 2002

02 ~ +

Probabili

: : : q

0.00 25.00 50.00 75.00 100.00

Fig. 15. Assumed probability distribution of REF, for alpha particles and solid tumors modified by an
enhancement factor representing an inverse dose-rate effect under conditions of chronic
exposure. Median of distribution is at 18, and 95% confidence interval lies between 3.4 and 101;
about 2.5% of values lie beyond 100.

194 r

145

097

Probabili

wa |
lite

0.00 11.25 22.50 33.75 45.00

Fig. 16. Assumed probability distribution of REF, for alpha particles and leukemias modified by an
enhancement factor representing an inverse dose-rate effect under conditions of chronic
exposure. Median of distribution is at 4.1, and 95% confidence interval lies between 1.0 and 42;
about 2.1% of values lie beyond 45.

39


DRAFT June 17, 2002

30

EFFECTIVE QUALITY FACTOR (Q)

28 -
26>
24 - eo

225

20-

t T T T T

4 5 6 7 8 9
Alpha Particle Energy/MeV

Fig. 14. Calculated effective quality factor, Q, vs. alpha particle energy given in Fig. 5 of ICRU (1986).
Values apply to entire range of alpha particles of given initial energy.

REF for Solid Tumors

Data on RBEs for alpha particles that are potentially relevant to induction of solid tumors
in humans have been reviewed by the NCRP (1990) and the NRPB (Muirhead et al., 1993); see
also Sinclair (1996). Compared with neutrons, a complicating factor in estimating RBEs for
alpha particles is that the reference radiation in most studies was not high-energy gamma rays. In
some studies in mammalian cells, the reference radiation was X rays, and in studies of bone or
lung tumors in mammals, the reference radiation usually was the continuous spectrum of beta
particles emitted in decay of Sr and °’Y, which have an average energy is 565 keV (Kocher,
1981), or other radionuclides. However, the difference between using electrons from beta decay
and high-energy gamma rays as the reference radiation may not be significant, because studies
discussed in Section 7.3 of NCRP (1990) indicated that beta particles from “Ce decay (average
energy of 226 keV) and protracted “Co gamma rays are equally effective in producing
chromosome aberrations in liver cells of hamsters.

The derivation of RBEs based on studies of induction of bone tumors in mammals by
alpha-emitting radionuclides compared with beta-emitting °°Sr and *°Y is further complicated by
differences in the distributions of the study and reference radionuclides in cortical and trabecular
bone compared with bone surfaces. These differences are important because the radiosensitive
tissues in bone are located near the surface and alpha particles and beta particles have short

31


DRAFT June 17, 2002

REF Based on Estimated RBEs for X Rays and Data in Humans

Studies of the biological effectiveness of 220-250 kVp X rays in inducing dicentric
chromosomes in human lymphocytes were reviewed and evaluated by the NCRP (1990). The
average energy of X-rays in these studies was about 50-65 keV (Stanton et al., 1979; NCRP,
1985). The dose-response relationships for the X rays and reference gamma rays in these studies
were assumed to be linear-quadratic; i.e., the response was assumed to be described by wD + BD’,
where D is the absorbed dose and a and f are coefficients obtained from fits to the data. The
data on dose-response for X rays and the reference gamma rays in the various studies are
summarized in Table 10. Point estimates of RBEy, calculated by the NCRP (1990) as a,/a,,
using the central estimates of the two coefficients in Table 10, are given in Table 11. Similar
values of RBEy, for X rays are indicated when estimates of RBE,, for neutrons and the same
endpoint obtained in studies using X rays as the reference radiation are compared with estimates
obtained using “Co gamma rays (Dobson et al., 1991; Schmid et al., 2000).

The NCRP’s point estimates of RBE,, in Table 11 do not take into account the reported
uncertainties in the coefficients ay and a, in the dose-response relationships for X rays and
gamma rays, respectively. We estimated the uncertainty in each value of RBE,, in the following
way. We assumed that the central estimates and standard errors of ay and a, given in Table 10
define 68% confidence intervals of lognormal probability distributions of these coefficients.”
We then used random sampling methods to calculate a probability distribution of RBE,, as the
ratio of the distributions of a, and a,, and the 68% confidence interval of this distribution thus
was obtained. These confidence intervals are given in parentheses in Table 11.

The estimates of RBE,, for X rays and their uncertainties summarized in Table 11 can be
represented by a lognormal probability distribution having a 95% confidence interval between
1.0 and 6.5. However, information obtained from other radiobiological studies should be taken
into account. This information is indirect, in that the radiation under study was not X rays or
gamma rays but both of these radiations were used as reference radiations. Inferences about the
biological effectiveness of X rays relative to gamma rays can be made by comparing RBEs for
the radiation under study relative to X rays with RBEs relative to gamma rays, provided the RBEs
apply to similar endpoints. Information obtained mainly from reviews of various studies by
experts and expert groups is summarized below.

¢ A study of induced pink mutation events in stamen hairs of Tradescantia (Underbrink et
al., 1970) discussed in Section 2.2.4 of NCRP (1990), in which the radiations under study
were neutrons, indicated that the RBE of X rays was about 1.7.

Uncertainties are described by lognormal probability distributions to avoid problems that arise
in calculating ratios of two normal distributions when very small or negative values are randomly
sampled from the distribution in the denominator.

42


DRAFT June 17, 2002

PHOTONS

Approach to Estimating RBEs

Compared with neutrons and alpha particles discussed previously and beta particles from
decay of 3H discussed in the following section, there are few measurements of the biological
effectiveness of orthovoltage X rays (and other lower-energy photons) relative to high-energy
gamma rays. Furthermore, a review by the NCRP (1990) indicated that only a single stochastic
endpoint in mammalian systems (induction of dicentric chromosomes in human lymphocytes)
has been studied extensively in investigating the biological effectiveness of X rays. Nonetheless,
we believe that the available data on chromosome aberrations, supplemented by information
obtained from studies of other radiations discussed in this section, provide sufficient evidence to
support an assumption that lower-energy photons have a substantially greater biological
effectiveness than high-energy gamma rays. As noted in the Introduction, the ICRU (1986)
reached the same conclusion. This assumption applies to orthovoltage X rays and other photons
of similar energies including, for example, 60-keV gamma rays emitted in decay of “!Am.

Cancer risks in humans from exposure to X rays and other lower-energy photons are
estimated using an approach represented by eq. (2), (4), or (5); eq. (2) is used to estimate risks of
solid tumors at any dose and dose rate of photons, and eq. (4) or (5) is used to estimate risks of
leukemias under conditions of acute or chronic exposure, respectively. For a given photon
energy, the same radiation effectiveness factor at low doses and low dose rates of the reference
high-energy gamma rays, REF,, is used for all cancer types. This approach to estimating cancer
risks is based on assumptions that the dose-response relationships for solid tumors and leukemias
are of the same form (linear or linear-quadratic) for photons of any energy, and that the same
dose and dose-rate effectiveness factor (DDREF) applies to all photons in estimating risks of
solid tumors.

Given the assumptions about the dose-response relationships and DDREF for photons of
any energy described above, there is no apparent advantage to deriving an REF at high doses and
high dose rates of reference high-energy gamma rays, REF, for use in the model represented by
eq. (3). Furthermore, an analysis to estimate RBEs of X rays at high doses and dose rates has not,
to our knowledge, been performed. An additional complication that discourages use of the
approach to estimating risks represented by eq. (3) is that, in the various radiobiological studies,
the reference gamma rays and X rays under study often exhibit non-linear dose-response
relationships. As a consequence, the DDREFs for the two radiations in a given study often differ
substantially from each other and from the nominal value of 2 normally used in radiation
protection (ICRP, 1991; NCRP, 1993), and the DDREFs for the two radiations also vary from
one study to another. The alternative approach to risk estimation involving use of REF, is most
appropriate when the dose-response relationship for the radiation under study is linear at any
dose and dose rate and DDREF for the radiation is unity. The following discussion focuses on
estimation of RBEs for lower-energy photons at low doses and low dose rates, RBE,,, and the
derivation of probability distributions of REF, based on these data.

41


DRAFT June 17,2002 |

effect for alpha particles is applied to the probability distributions of REF, for solid tumors and
leukemias in all cases. The resulting probability distributions are shown in Figs. 15 and 16. The
result for leukemias in Fig. 16 also is shown as a cumulative probability distribution in Fig. 17.
A cumulative distribution often is more informative when a single value is given a high weight
relative to all other values. The assumed probability distributions of REF, for alpha particles,
when adjusted to account for an inverse dose-rate effect, encompass the recommended point

values of the effective quality factor, Q, and the radiation weighing factor, wp, for alpha particles
given Table 1.'°

Summary

Except in cases of exposure of the lung due to inhalation of radon and its short-lived
decay products, cancer risks in humans from exposure to alpha particles (a) emitted by
radionuclides are estimated using the following equations:

Solid tumors —

R
St, = REF, x EF, x —#TM~ xD 9
a ‘aL a DDREF, a (9)
Leukemias —
R, = a x REF,, x EF, x D, (10)

where REF,,, is the radiation effectiveness factor at low doses and low dose rates of high-energy
gamma rays, EF, is the enhancement factor representing an inverse dose-rate effect under
conditions of chronic exposure, R,,, is the risk coefficient (ERR per Gy) at high acute doses of
high-energy gamma rays for the solid tumor of concern, a is the coefficient of the linear term in
the linear-quadratic dose-response relationship for leukemias at high acute doses of high-energy
gamma rays, DDREF, is the dose and dose-rate effectiveness factor for gamma rays and other
low-LET radiations, and D, is the absorbed dose of alpha particles in the organ or tissue of
concern. Since exposures to alpha-emitting radionuclides are assumed to be chronic, the
enhancement factor, EF,, is applied in all cases.

The assumed probability distributions of REFs for alpha particles and the enhancement
factor representing an inverse dose-rate effect are summarized in Table 9.

The point values wz = 20 and Q =25 in Table 1 are at about the 55" and 65" percentiles,
respectively, of the probability distribution of REF,, for solid tumors, and lie between the 90" and 95"
percentiles of the probability distribution of REF, for leukemias. We also note that a best estimate of
RBEy for inhaled alpha-emitting radionuclides of 30 derived by the ICRP (1980) from studies in animals
(see Table 8) is at about the 70" percentile of the distribution for solid tumors.

38


DRAFT June 17, 2002

REF for Leukemias

In contrast to the case of alpha particles and solid tumors discussed above, there are data
in humans that can be used to infer an REF for alpha particles and leukemias. As discussed
below, the data seem to indicate that the REF for leukemias is substantially less than the REF for
solid tumors. However, interpretation of the available data is problematic, owing to difficulties
in separating the issue of estimating absorbed doses of alpha particles in bone marrow from the
issue of biological effectiveness. These issues are related to the question of where radiosensitive
cells in bone marrow are located relative to the locations of alpha-emitting radionuclides on bone
surfaces or within bone marrow.

Studies of medical patients who were administered Thorotrast'” and experienced an
excess of leukemias are a potentially important source of information on the REF for alpha
particles. An REF can be inferred by comparing estimated risks of leukemia in Thorotrast
patients with an estimated risk at low doses and low dose rates of gamma rays, as derived from
data in the Japanese atomic-bomb survivors and an assumed DDREF. Based on an estimated
lifetime risk of leukemia of (5-6) x 10TM> Gy”! in Thorotrast patients (National Research Council,
1988) compared with an estimated risk of 5 x 10°? Gy”! at low doses and dose rates of gamma
rays, the EPA initially concluded that the “effective RBE” for alpha particles and leukemia is
essentially unity (EPA, 1994; Eckerman et al., 1999). The EPA also noted, however, that the
lower than expected leukemia risk in Thorotrast patients may result from a nonuniform
distribution of dose within bone marrow such that average doses to sensitive target cells are
substantially lower than calculated average doses to bone marrow (EPA, 1994). That is, the low
leukemia risk in the Thorotrast patients may reflect the use of models that overestimate dose to
radiosensitive cells, rather than a low biological effectiveness of alpha particles.

Subsequent to the EPA’s initial estimate of an “effective RBE” of unity for alpha
particles and leukemia in Thorotrast patients, Hunacek and Kathren (1995) evaluated the data
from several studies and noted that reported doses to bone marrow per unit activity of ’Th
administered vary by a factor of about 10. As a result, the estimated risk of leukemia in
Thorotrast patients obtained from the various studies ranges from 5 x 10° to 6 x 10°? Gy"!; the
best estimate adopted by Hunacek and Kathren is 3 x 10°? Gy”'. These risks, when compared
with an estimated risk of 5 x 10° Gy”! at low doses and dose rates of gamma rays, indicate that
the REF for alpha particles and leukemia is likely to be substantially greater than unity; a central
estimate of REF obtained from these risk estimates ranges from 1 to 12. Based on the analysis
by Hunacek and Kathren, a subsequent uncertainty analysis of risk estimates in Thorotrast
patients by Grogan et al. (2000; 2001), and taking into account data on RBE for fission neutrons
and leukemias in mice (Ullrich and Preston, 1987), the EPA concluded that an RBE for alpha
particles and leukemia in Thorotrast patients could be described by a lognormal probability
distribution having a 95% confidence interval between 1 and 10 (EPA, 1999).

‘"Thorotrast is a colloidal form of thorium oxide. Doses from administered Thorotrast are due
mainly to alpha particles emitted by 7’Th and its decay products *Th and Ra.

34


DRAFT June 17, 2002

compared with the results of a study of mutations in Chinese hamster cells (Thacker et al.,
1979) summarized in Table 8.

* — Several inferences can be made from studies of the biological effectiveness of beta
particles from *H decay summarized by Straume and Carsten (1993) and discussed in the
following section. Studies of carcinogenesis endpoints in mammals and mammalian cells
indicated that the RBE of X rays was less than 2 (see Table 13). Studies of genetic
endpoints in mammalian systems and fish lymphocytes indicated that the RBE of X rays
was about 1.6 on average and did not exceed about 3.5 (see Table 14). A study of
chromosome aberrations in human lymphocytes indicated that the 68% confidence
interval of the RBE for X rays was (2.3, 3.9) (see Table 15); this estimate applies to the
same endpoint as the results summarized in Table 11. Results of studies of reproductive
effects in small mammals and fish summarized in Table 7 of Straume and Carsten (1993)
are not considered, because these endpoints are deterministic and, thus, are not considered.
to be relevant in estimating cancer risks in humans.

*  Astudy of tumor induction in rats (Wolf et al., 2000), in which the radiation under study
was fission neutrons, indicated that the RBE of X rays at a dose of 2 Gy was about 3.
This RBE should be especially relevant to estimating cancer risks in humans.

The indirect estimates of RBE for X rays suggest that a lognormal probability distribution
of RBE,, for lower-energy photons having a 95% confidence interval between 1.0 and 6.5 gives
too much weight to relatively high values. We believe this conclusion is reasonable even though
uncertainties in the indirect estimates undoubtedly are substantial. We also note that the highest
values of RBEy, in Table 11 have the largest uncertainties, which indicates that these values
should be given less weight compared with the lower, and less uncertain, estimates of RBEy for
the same endpoint. Based on this information, we reduce the upper confidence limit of the
lognormal probability distribution of RBE,, obtained from studies of dicentric chromosomes in
human lymphocytes from 6.5 to 5.0.

Thus, the lognormal probability distribution of RBE,, that is assumed to describe all the
radiobiological data discussed above has a 95% confidence interval between 1.0 and 5.0. The
geometric mean (median) and geometric standard deviation of this distribution are 2.2 and 1.5,
respectively. The assumed distribution assigns a small weight (2.5%) to an assumption that the
biological effectiveness of X rays and other lower-energy photons is the same as, or lower than,
that of high-energy gamma rays, and to an assumption that values greater than 5 are possible.
Neither of these assumptions can be ruled out by the available radiobiological data.

We then investigated whether useful information on the biological effectiveness of X rays
relative to high-energy gamma rays can be obtained from epidemiological studies of human
populations. We compared estimated risks of thyroid cancer in children exposed to X rays with
estimated risks of thyroid cancer in Japanese atomic-bomb survivors who were exposed in
childhood mainly to high-energy gamma rays. In the atomic-bomb survivors, the following

45


DRAFT June 17, 2002

Table 8. Estimates of RBE,, for alpha particles obtained from reviews and analyses
of selected studies by the NCRP (1990) and Muirhead et al, (1993)

Endpoint RBE,, Reference
Lung tumors (various species) 30 (6-40) ICRP (1980)?
Bone tumors (dogs) 26 NCRP (1990)°
Bone tumors (mice) 25 NCRP.(1990)°
Lung tumors (dogs) 30-60 NCRP (1990)?
Bone tumors (dogs) 4-6 Griffith et al. (1991)
Lung tumors (rats) 25 Hahn et al. (1991)
Lung tumors (dogs) 36 Hahn et al. (1991)°
Cell transformation (C3H10T% mouse cells) 10-25 Brenner (1990)
Cell mutation (Chinese hamster cells, V79) Up to 18 Thacker et al. (1979)
Chromosome aberrations (liver cells of Chinese 15-20 Brooks et al. (1972);
hamster) Brooks (1975)
Chromosome aberrations (human lymphocytes) 5-35 Edwards et al. (1980);

Purrott et al. (1980)

Germ cell mutations (chromosome fragments, 22-24 Searle et al. (1976)
chromosome translocations, dominant lethals)

“Adapted from data presented in Section 7 of NCRP (1990) and Table 7.3 of Muirhead et al.
(1993). RBEy is RBE at low doses and low dose rates of the reference radiation obtained by
extrapolation of data on dose-response for alpha particles and the reference radiation at high doses. The
reference radiation in all studies was either beta particles from decay of radionuclides, including *°Sr/”Y
and '“Ce, or high-energy gamma rays from decay of Co.

‘Range is based on analyses of dose-response at 10% and 40% lung tumor incidence for
inhalation of soluble and insoluble alpha-emitting radionuclides combined; estimates based on analyses
for inhalation of insoluble °Pu oxide only range from about 10 to about 60-100.

“Estimate based on re-analysis of preliminary data given in Mays and Finkel (1980).

4Range based on preliminary estimates given by Boecker et al. (1988) and Griffith et al. (1987);
value toward upper end of range is not supported by subsequent analysis by Hahn et al. (1991), and value
from Boecker et al. (1988) could be as low as 10.

‘Estimate based on subsequent analysis of data given in Boecker et al. (1988) and Griffith et al.
(1987).

33


DRAFT June 17, 2002

ranges in tissue. For example, *°Pu appears to be about 15 times more effective than Ra in
inducing bone tumors in mice and dogs when toxicity is estimated based on the average skeletal
dose (NCRP, 1990). However, this difference is due mainly to the deposition of radium and
strontium throughout the volume of bone, in contrast to plutonium which remains on bone
surfaces. Similar effects are shown in studies of the toxicity of other alpha-emitting
radionuclides in bone including, for example, “!Am and “°*Cm (NCRP, 1990).

Estimates of RBE,, for alpha particles obtained from reviews and analyses by the NCRP
(1990) and the NRPB (Muirhead et al., 1993) are summarized in Table 8. This summary also
includes estimates obtained in an earlier analysis by the ICRP (1980). The RBEs in Table 8 are
central estimates, and they vary from about 5 to nearly 100 (see footnote b). Based on these data,
and taking into account that there is uncertainty in the central estimates, we assume a lognormal
distribution of REF, for alpha particles and solid tumors having a 95% confidence interval
between 3 and 80. This distribution has a geometric mean (median) of about 15 and a geometric
standard deviation of 2.3. A lognormal distribution was selected based mainly on the variability
in estimates of RBEy, and the difficulty in judging a credible upper bound of possible values.

In a previous analysis of selected data, including consideration of estimated risks of lung
cancer in underground miners who were exposed to alpha-emitting radon decay products
(National Research Council, 1988) compared with estimated risks of lung cancer in Japanese
atomic-bomb survivors who were exposed mainly to high-energy gamma rays (Shimizu et al.,
1990), the EPA (1999) adopted a lognormal probability distribution of REF, for alpha particles
and solid tumors (referred to as an “RBE” by the EPA) having a 90% confidence interval
between 5 and 40. The geometric mean of the EPA’s distribution is 14 and the 95% confidence
interval lies between 4.1 and 49. The lower confidence limit in our probability distribution is
similar to the EPA’s, except we have assumed a slightly lower value to account for uncertainties
in the lowest estimates of RBE,,. The upper confidence limit in our probability distribution is
substantially higher than in the EPA’s; our assumption is based on the considerations that several
estimates of RBEy in Table 8 are in the range of about 20-40 and the early estimates for
insoluble plutonium and lung cancer in mammals by the ICRP (1980) included values in the
range of about 60-100. However, since the high estimates of RBE,, for insoluble plutonium and
lung cancer have not been seen in more recent studies, only a small weight is given to values
greater than 80 in our distribution.

With the exception of exposure of the lung to radon and its short-lived decay products
noted in the Introduction, the assumed probability distribution of REF, described above is used
to estimate risks of solid tumors in humans at low doses and low dose rates of alpha particles in
accordance with eq. (2). Since alpha-emitting radionuclides of concern in exposures of workers
and the public, excluding radon, have half-lives of at least 0.5 years and are tenaciously retained
in the body, acute exposure to alpha particles emitted by inhaled or ingested radionuclides should
not be of concern. External exposure generally is not a concern for alpha particles emitted by
radionuclides, due to the short range of these radiations in matter.

32


DRAFT June 17, 2002

Table 10. Dose-response relationships of X rays and reference high-energy gamma
rays for induction of dicentric chromosomes in human lymphocytes*

Dose range” a+ SE’ B+SE°
Reference Radiation (Gy) (x 10? cy) (x10? Gy”)

Bauchinger 220 kVp X rays 0.5-4 40+03 5.98 £0.17
(1984) Co y rays 0.5-4 1.1404 5,55 + 0.28
Fabry et al. 250 kVp X rays 0.05-2 4421.0 6.0+ 1.1
as) “Co ¥ rays 0.05-2 3.0+0.8 4341.0
Lloyd et al. 250 kVp X rays 0.05-6 3,640.5 6.67 + 0.22
989) Co y rays 0.05-6 14204 7.59 £0.27
Littlefield et al, 220 KVP X rays 0.25-3.75 4.3208 6.604
(1989) “Co y rays 0.25-4 1.6+0.7 5.7203
Brewen and 250 kVp X rays 0.5-4 9140.2 6.0+0.7
Luippold (1971)"
Brewen et al. Co y rays 0.5-4 3.9411 8.2+0.4
(1972)!
Lloyd et al. 250 kVp X rays 0.05-8 48+0.5 6.2403
(979) “Co y rays 0.25-8 1.6203 5.0 £0.2

“See Tables 2.6 and 2.7 of NCRP (1990).

’Doses were delivered acutely or over time period of about 10 minutes or less.

“a and B are coefficients of linear and quadratic terms in linear-quadratic dose-response
relationship, respectively, and SE is the standard error.

Results for X rays and gamma rays were reported separately.

* — Studies of mutations in human diploid fibroplasts (Cox et al., 1977; Hei et al., 1988)
summarized in Fig. 3.13 of NCRP (1990), in which the radiations under study included
protons, deuterons, and heavy ions, indicated that the RBE of X rays was about 3 or less.

¢ A study of dominant lethal mutations in cells of mice (Pomerantseva, 1964) discussed in

Section 4.1.1.1 of NCRP (1990), in which the radiation under study was high-energy
protons, indicated that the RBE of X rays was about 1.5.

43