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OCR for page 245
5
Thorium
INTRODUCTION
Thorium-232 is a primordial element that is distributed through-
out the environment. It has a very long physical half-life (1.41 x 10~°
yr) and decays by emission of an alpha particle creating a series
of radioactive daughters, many of which also emit alpha radiations.
One of these daughters is an isotope of radon, 220Rn, viz., thoron.
The high density and atomic number of thorium led to its use as
a contrast agent in medical radiography, as commercially prepared
Thorotrast, a 25~o colloidal solution of thorium dioxide (Thou. Un-
tiT after the end of World War lI, Thorotrast was used extensively
as an intravascular contrast agent for cerebral and limb angiography
in Europe, the United States, and Japan. It was also injected di-
rectly into the spleen for hepatolienography and into abcess cavities
in the brain and elsewhere. Direct instillation of Thorotrast into
the nasal cavity and paranasal sinuses was also practiced in the past
and resulted in a number of epithelial tumors.~3 Because of Thoro-
trast's colloidal characteristics, thorium and its decay products were
deposited in body tissues and organs, most frequently in the reticu-
loendothelial tissues and in bone. Deposition resulted in continuous
alpha-particle irradiation throughout life at a low dose rate.
Patients who received alpha-radiation exposure due to radiolog-
ically administered Thorotrast in the late 1920s through 1955 have
been followed in epidemiological surveys in Germany,5i Portugal,5
245
OCR for page 246
246 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
Denmark,ll and Japan.32 These studies, described below, demon-
strate primarily an excess of liver cancer, including hemangiosarco-
mas and cholangiosarcomas, and acute myeloid leukemia. This is
in contrast to the 224Ra-exposed patients, discussed in Chapter 4,
treated for tuberculosis and ankylosing spondylitis,4i in whom no
significant excess of liver cancer has occurred. The alpha-radiation
dosimetry in the liver and bone marrow is complex, and precise quan-
tification of risk in these patients is limited because of the nonuniform
distribution of thorium dioxide in these tissues and the possible ef-
fects of the colloidal material on cancer risk. Moreover, the dose
responsible for induction of neoplasia cannot be distinguished from
the wasted radiation after initiation has occurred. Therefore, dose-
response relationships are highly uncertain.
PROPERTIES AND DOSIMETRY
The long-lived isotope 232 Th is the parent of a naturally oc-
curring radioactive decay series. The thorium decay series can be
considered in two steps: (1) the formation of 224Ra by the successive
decays from 232Th, and (2) the decay of 224Ra and its daughters to
stable lead (Figure 5-1~. The isotope Ra (half-life, 3.62 days) is an
important member of the thorium decay chain; its decay results in
the ultimate emission of four alpha particles that release about 26.5
MeV. People with burdens of thorium administered for radiodiag-
nostic purposes are being irradiated by 224 Ra and its alpha-emitting
progeny as a result of its continuous production in viva from the
232Th.38 The radioisotopes in the thorium series and their physical
characteristics are listed in Table 5-1.39
ENVIRONMENTAL PATHWAYS4S
Thorium-232 is present in the soil at an average concentration
of about 25 Bq/kg (1 Bq = 27 psi). Because of its very low absorb
tion through the gastrointestinal tract, natural thorium is mainly
incorporated into the body by the inhalation of resuspended solid
particles at a rate of about 0.1 Bq/yr. The average body content
of thorium-232 is about 80 mBq, 60~o of which can be found in the
skeleton. Associated annual effective dose equivalent is estimated at
about 3 ,uSv (1 Sv = 100 rem). The decay product of 232Th, 228Ra, is
much more mobile environmentally, and unlike 232 Th, ingestion con-
stitutes the major pathway for intake. The annual level is about 15
OCR for page 247
THORIUM
228
224
MASS i
NUMBER
DECAY OF RADIUM-224 AND DAUGHTERS
224 (ThX) 3.62
1
220 RADON
(THORON) 55.6 ~
__
216 1 (ThA) 0~15 s
__
1
212 | LEAD
I (ThB) 10.6 h
208
247
MASS
NUMBER
232 1 1 41 x 101° y
to
RADIUM | (3_ | ACTINIUM L~;=
(MsThl) 5.75 y 1 | (MsTh2) 6.13 h I | (RdTh) 1~91 y I
~ .~
~ RADII M |
! (ThX) 3~62 d |
1a
1 ¢_ I BISMUTH _;;;
_~ L (ThC') 0.3 ,U~ I
36%' ,~
~ 1a
THALLIUM 13 ~ LEAD
(ThC") 3.1 m (ThD)
STABLE
FIGURE 5-1 Formation of 224Ra by successive decays from 232Th. Heavily
lined boxes have been drawn around the alpha-particle emitters important to
dosimetry. SOURCE: Rundo.38
OCR for page 248
248 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
TABLE 5-1 Radioisotopes in the Thorium Series
Radioisotope Particle Energya
(Historical Name) Element Half-Life (MeV)
Thorium 232Th 1.4 X 10~°yr a, 4.01 (76%)
cY, 3.95 (demo)
Mesothorium 1 228Ra 5.7yr ,B—, 0.02
Mesothorium 2 228Ac 6.13 h `S—, 0.45-2.18
Radiothorium 228Th 1.91 yr a, 5.42 (71%)
a, 5.34 (redo)
Thorium X 224Ra 3.64 days cz, 5.68 (955to)
cY, 5.44 (4.9~o)
Thoron 220Rn 55 s a, 6.28 (99.7%)
a, 5.75 (0.3~o)
Thorium A 2,6po 0.16 s ox, 6.78
Thorium B 2~2pb 10.6 h l]—, 0.58 (redo)
,B—, 0.34 (84(5o)
Thorium C 2~2Bi 60.5 min ,B—, 0.08-2.27 (redo)
~x, 6.09, 6.05 (36%)
Thorium C' (64870) 2,2po 0.30 As ~x, 8.78
Thorium C " (demo) 2o8Tl 3.1 min ,3, 1.0-2.38
Thorium D 208Pb Stable
aWhere the ,B- or cx-spectra contain many lines, only ranges of energy without abundances are
given.
SOURCE: Spiers45.
Bq by ingestion compared to approximately 0.01 Bq from inhalation
of the suspended soil particles. Radium-228, on the average, concen-
trates in bone at a level of about 90 mBq/kg and in soft tissues at
about 4 mBq/kg. The decay product of 228Th, as is true of 228Ra,
is concentrated in bone, with about 80~o of the body content of 300
mBq being found in the skeleton.
Ra(lon-220 and its decay products (hippo, 2~2Pb, nimbi, memo,
and 208 Th) are responsible for an additional annual effective dose
equivalent of about 0.22 mSv, 90~o of which is a result from indoor
exposure. Radon-220 and its decay products are generally present at
levels about 1() to 20-fold lower than that of 222 Ra (from the decay
of 226Ra'
BIOLOGICAL PROPERTIES OF THE THORIUM SERIES
Eight different chemical elements are represented in the thorium
series. Three of them (Th, Ra, Po) are represented by two isotopes
each (Figure 5-1 and Table 5-1~. As the chemical identity of a given
atom changes as a result of successive nuclear transformations, it
OCR for page 249
THORIUM
249
may find itself situated at a metabolically inappropriate site, and
there is the possibility that it may transIocate. The recoil energy
imparted to a nucleus on the emission of an alpha particle of several
megaelectronvolts of energy is on the order of 100 keV, far greater
than the strength of any chemical bond in the atom.38
Of the two isotopes of thorium in the precursors of 224Ra, the
parent of the series, 232 Th, is the only member of the chain that can
exist in viva in macroscopic quantities. The weight of 1 ,uCi of 232 Th
is 9.13 g, while the weight of 1 ,uCi of 228Th is 1.21 x 10-9 g. After
intravenous injections of such quantities, the concentration of 228Th
in the blood would be about 6 x 108 atoms/mI, but the concentration
of 232Th would be about 10~° times higher. Thorium appears to be
held tenaciously at either its site of formation in viva or its point
of entry into the body (other than the bloodstream), regardless of
the specific activity of the material. Following intravenous injection,
thorium of high specific activity deposits mainly on bone surfaces,
from which its release appears to be very slow. In the special case of
Thorotrast, in which macroquantities of 232Th in colloidal form are
injected, it is the physical form that controls its deposition in the cells
of the reticuloendothelial system rather than the chemical properties.
The colloid aggregates in viva into clumps as large as 100 ,um across,
and these aggregates are very stable. The 228 Th that is produced via
228 Ra and 228Ac in these aggregates does have some mobility, and
there is a small loss of activity from thorium deposits.38 39
ALPHA DOSIMETRY OF THORIUM IN HUMANS
Thorotrast was administered as a colloidal form of thorium diox-
ide; the colloidal particles agglomerate and pose a radiation risk
to the reticuloendothelial system in which they are ultimately se-
questered. The thorium is ultimately redistributed and produces a
nonuniform irradiation. The range of the emitted alpha particles in
unit density tissue is approximately 40 to 45 ,um, that is, about four
or five cell diameters. Microscopic and autoradiographic studies have
shown that the colloidal aggregates can range to about 100 ,um in
diameter, producing a highly nonuniform dose-distribution pattern.
Such a distribution is thought to be less biologically effective than
a more uniform distribution of the same amount of alpha-particle
energy33 for two reasons. First, some of the alpha-particle energy is
expended within the aggregate itself, and thus, that fraction of the
radiation dose is unavailable to surrounding cells at risk. Second, the
OCR for page 250
2s0 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
cells closest to the aggregates are subject to multiple alpha-particle
traversals of critical targets within the cells. Such over irradiation of
sensitive cells at risk increases the likelihood of cell killing or steril-
ization. To the extent that this occurs, it diminishes the opportunity
for the same cells to be transformed later and adds to the overall
oncogenic risk. This is illustrated in Figure 5-2, which shows a high-
resolution autoradiograph of a Thorotrast aggregate surrounded by
dense fibrotic tissue in the human liver.~3 Quantitative aspects of
this exposure situation are discussed in Appendix ~ and Chapter 4.
Radioactivity and, therefore, dose increase with the size of the
Thorotrast aggregation. However, this is offset to some extent
by alpha-energy absorption within the aggregate. With increasing
amounts of Thorotrast injected, an increase in the effective average
aggregate diameter and a corresponding decrease in the fraction of
alpha-energy emitted by the aggregate are found.50 Table 5-2 shows
the mean tissue doses in the liver and red bone marrow based on
measurements from the German Thorotrast study50 and indicates
the magnitude of dose modification to tissue afforded by the self-
absorption of the alpha particles in thorium dioxide aggregates. For
example, in the case of the liver, an increase in the injected quantity
of Thorotrast by a factor of 10 is associated with only a fourfold
increase in annual radiation dose. The lower uptake of Thorotrast
by the bone marrow and the consequent smaller mean aggregate size
produced less of an effect.
Following Thorotrast injection and deposition within the body, a
buildup of daughter products proceeds, but it never reaches equilibri-
um.38 The lack of equilibrium is indicated by the relative excretion
rates of 232Th and its daughters; thorium is excreted at a slow rate
relative to that of radium isotopes.38
Kaul and Noffz22 calculated absorbed doses to the liver, spleen,
red bone marrow, lungs, kidneys, and bone for long-term burdens of
intravascularly injected Thorotrast. The estimates were performed
for typical injection levels of 10, 30, 60, and 100 m} based on best
estimates of 232Th tissue distribution and steady-state activity ratios
between subsequent daughters. The typical tissue distribution of
232Th in patients was estimated in the German Thorotrast Study
to be as follows: liver, 59%; spleen, 29~o; red bone marrow, Who;
calcified bone, Who; lungs, 0.7~o; kidneys, 0.10~70.22 The thorium dioxide
concentration in regional lymph nodes of the liver and spleen was
high, but very low in other lymph nodes in the body.
OCR for page 251
THORIUM
251
FIGURE 5-2 High-resolution autoradiograph of liver autopsy specimen of a
60-yr-old male who died of hemangioendothelioma in the liver 15 yr after a
75-ml Thorotrast injection for hepatolienography. Magnification, X 1,250; oil
· ~
immersion.
OCR for page 252
252 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
TABLE 5-2 Mean Annual Alpha-Radiation Dose Following Thorotrast
Injection
Volume of
Thorotrast 232Th in Mean Tissue Dose/ml
Organ Injected (ml) Organ (Bq) FU Dose (Gy/yr) (Gy/yr)
Liver 10 4,850 0.85 0.13 0.0130
30 14,500 0.65 0.28 0.0093
50 24,200 0.52 0.38 0.0076
100 48,500 0.38 0.55 0.0055
Red bone marrow 10 740 0.97 0.04 0.0040
30 2,220 0.92 0.11 0.0037
50 3,700 0.87 0.17 0.0034
100 7,400 0.77 0.30 0.0030
aft is the fraction of alpha energy emitted by the aggregates.
SOURCE: Kaul and Noffz.22
Correcting for the alpha-particle self-absorption within Thoro-
trast aggregates, the mean radiation dose to a standard 70-kg man
at 30 yr after the intravascular injection of 25 m] of Thorotrast was
estimated to be 750 red to the liver, 2,100 red to the spleen, 270 red
to the red bone marrow, 6~620 red into various parts of the lung,
and 13 red to the kidney. Based on the tissue distribution of 232 Th in
Thorotrast-exposed patients and the mean concentration of 232 Th in
various organs of Thorotrast-exposed patients, Figure 5-3 ~ from the
study of Kaul and Noffz22) illustrates the mean steady-state alpha-
radiation dose rates in the liver, spleen, and red bone marrow. These
are plotted against the volume of Thorotrast injected to give values
of dose rate for any volume of intravascularly injected Thorotrast
between 10 and 100 mI. A typical injection of 25 m! of Thorotrast
administered for angiography would result in an estimated dose rate
of about 25 rad/yr in the liver and an average of about 16 rad/yr
to the endosteal cells of bone.50 Dose rates to various parts of bone
tissue (bone surface, compact and cancellous bone) were estimated
by applying the International Commission on Radiological Protec-
tion (ICRP) modeler on alkaline earth metabolism to the continuous
transIocation of thorium daughters to bone and to the formation of
thorium daughters by decay within bone tissue. The average dose to
calcified bone from transIocated 224 Ra with its daughters was esti-
mated to be 19 red at 30 yr after the injection of 25 m! of Thorotrast.
Both the steady-state activity ratio of thorium daughters to
232 Th and the self-absorption of alpha particles in 232 ThO2 aggre-
gates are important for estimating the absorbed dose in tissues due
OCR for page 253
THORIUM
253
200
1 60
~ 120
tar
Oh
to
~ 80
By
40
o
,'
-
-
/
/
/
/
/
/
!
Bonemarrow __-
~1 1 1 1 1 1 1 1 1
10 30 50 70 90 110
VOLUME OF INTRAVASCULARLY-
lNJECTED THOROTRAST, ml
FIGURE 5-3 Mean alpha-radiation dose rates to the liver, spleen, and red
bone marrow verses volume of intravascularly injected Thorotrast. SOURCE:
Kaul and Noffz.22
to Thorotrast. Gamma rays from 228Ac, 2~2Pb, and 208T! and alpha
rays from 232Th and 228Th emitted from autopsy samples make it
possible to estimate the steady-state activity ratio of thorium daugh-
ters to 232Th. The steady-state activity ratio of 228 Th to 232 Th can
be determined from an alpha~ray energy spectrum and that of 224 Ra
to 228Th and 228 Ra can be determined from a gamma-ray energy
spectrum.2i For estimation of average absorbed dose in an organ,
the distribution of Thorotrast aggregate sizes must be assumed. Ex-
amination of Thorotrast-exposed patients and results of laboratory
animal experiments demonstrate that the concentration of Thoro-
trast throughout the liver varies considerably, perhaps by a factor
OCR for page 254
254 HEALTH RISKS OF RADON AND OTHER ALPHA-~ITTERS
of 100 in Thorotrast-exposed patients. i3 Large paravascular in-
jections, together with the heterogeneous distribution in the liver,
may be sources of error for the calculation of the tissue dose to the
organs of the reticuloendothelial system. Moreover, the estimated
tissue dose is dependent on the tote] injected volume of Thorotrast,
the gross organ distribution of the 232Th and its daughter products,
the average size of the ThO2 aggregates, and the alpha-particle self-
absorption within the aggregates. At the cellular level, there may
be dose rate differences up to a factor of 10,000. Currently, only
estimates of the mean organ dose are available.
Kato et al.20 estimated the absorbed dose in the liver, spleen,
and bone marrow in 30 Japanese Thorotrast-exposed patients who
died of liver cancer, liver cirrhosis, and other Thorotrast-associated
conditions. In the liver, a mean dose rate of 36 rad/yr and a total
absorbed dose of 939 red was calculated; for the spleen the doses
were 200 rad/yr and 5,760 red, respectively; for the bone marrow the
doses were 99 rad/yr and 3,087 red, respectively. For the Japanese
patients with hepatic tumors,20 the mean latent period was 31 yr,
the mean absorbed dose in the liver was 939 red (range, 145-3,234
red), self-absorption was 0.5, body weight was 50-60 kg, and liver
weight was 1,200 g.
Kaul and Noffz22 estimated the mean dose rates in West German
patients based on a 25-mI intravascular injection of Thorotrast in a
70-kg person, to be as follows: liver, 25 rad/yr; spleen, 70 rad/yr;
bone marrow, 9 rad/yr; endosteal layer in bone, 16 rad/yr; main
pulmonary bronchi, 13 rad/yr, and kidneys, 0.4 rad/yr. The cal-
culations assume the 2~2Bi activity equals the 2~2Pb activity in all
tissues; if the kidney concentrates 2~2Bi from the blood plasma, then
the kidney dose rate could be much higher than 0.4 rad/yr. The
high dose rate to the endosteal layer in bone is due to the thorium
dioxide in adjacent bone marrow and transiocation of 224Ra from
deposits in the reticuloendothelial system to bone surfaces. For the
West German patients, the mean latent period was 30 yr, the mean
absorbed dose in the liver was 824 red (range, 384-1,391 red), the
self-absorption was 0.15~.48, the body weight was about 70 kg, and
the liver weight was about 1,800 g. The mean absorbed dose in the
liver in the Japanese data was 14~o higher than that in the Ger-
man data, in part, because of the less massive livers in the Japanese
patients.20
OCR for page 255
THORIUM
ANIMAL STUDIES
LIVER AND SPLEEN TUMORS
255
Several animal studies provide a better understanding of the car-
cinogenic potency of Thorotrast in humans. Early reports discussed
whether, in addition to radiation, a foreign bocly effect or the chem-
ical properties of Thorotrast should be taken into consideration as
potential causal factors in tumor induction. Bensted2 examined the
effects of zirconium dioxide aquaso} (Zirconotrast) and conventional
and 230Th-enriched Thorotrast in mice, and found no clear evidence
of an increased incidence of Thorotrast-specific tumors compared
with Zirconotrast. Faber6 injected rabbits with various amounts
of 230 Th-enriched Thorotrast and found a shortened latency pe-
riod for hemangioendotheliomas when compared with that caused
by commercial Thorotrast. Riede} et al.35.36 examined the distri-
bution of colloidal thorium, zirconium, and hafnium dioxides and
found that the organ distribution of Thorotrast and the kinetics of
thorium daughters demonstrated comparable biological behavior in
mice, rats, dogs, rabbits, and humans. The other colloids studied
failed to show any significantly different effects due to their distribu-
tion from those of the thorium dioxide sol.
The investigations by Wesch et al.54 55 are of particular interest
since their objectives were to test for a dose response for carcino-
genesis and to determine whether a foreign body effect was involved.
In these experiments, 232 Th was enriched with different fractions
of 230Th to allow variation in dose rate for constant volumes of
Thorotrast injected or varying volumes for a constant burden of ra-
dioactivity. They found that the frequency of liver and spleen tumors
following a single injection of Thorotrast followed a linear dependence
on radiation dose rate, but was not correlated with the volume of
Thorotrast injected. At a constant dose rate, an increase in the vol-
ume of Thorotrast did not increase the tumor risk but did decrease
the mean latent period. For a constant activity injected, a factor of
10 increase in the mass injected resulted in further life-shortening. A
linear dose-response relationship for liver cancer was found; I(D) =
3.3 + 0.79D, where I(D) is the crude incidence (~) of all liver tumors
and D is the dose rate. The correlation between dose and incidence
was 0.97. The value of ~ at D = 0 did not diner from the observed
control incidence of 2.7~o.
In later studies, Wesch et al.56 studied rats injected with Zir-
conotrast (colloidal ZrO2) in which 228Th was incorporated. The
OCR for page 265
THORIUM
15.0
no
on
I
O 10.0
At
C]
C'
At
-
t_ 5.0
:D
265
Malignant Hepatic Tumors
~ Cirrhosis
.h'
it'
O
J
0 - 1
0 10 20 30
Blood Diseases
1 1
40 50
DURATION FROM THOROTRAST ADMINISTRATION
TO DEATH (years)
FIGURE 5-6 The Japanese Thorotrast study. Duration from Thorotrast
administration to death due to hepatic malignant tumors, liver cirrhosis, and
blood diseases in the group exposed to Thorotrast intravascularly. SOURCE:
Mori et al.3i
In the patients exposed to Thorotrast intravascularly, the dose
rates to the liver estimated in 96 cases ranged from 2 to 69 rad/yr; the
mean absorbed dose was 919.6 red (standard deviation [SDi, 409.0
red) for 67 malignant hepatic tumors, 958.6 red (SD, 251.6 red) for
8 liver cirrhoses, and 757.3 red (SD, 334.5 red) for 21 other tumors
and diseases. The dose rates to the spleen, estimated in 82 cases,
ranged from 8 to 743 rad/yr. The dose rates to the bone marrow in
63 cases ranged from 1 to 157 rad/yr.
In a Japanese series of 120 autopsy cases of patients who died of
Thorotrast-associated conditions, there were reported23 36 cases of
OCR for page 266
266 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
cholangiocarcinoma, 25 cases of angiosarcoma, 10 cases of hepatocel-
lular carcinoma, and 4 cases of multiple hepatic malignancies. The
latent periods were as follows: cholangiocarcinoma, mean, 34.1 ~ 6.6
yr (range, 23-45 yr); angiosarcoma, mean, 36.4 it 5.4 yr (range, 27-49
yr); hepatocellular carcinoma, mean, 35.3 ~ 5.8 yr (range, 23-41 yr).
No unusual histological features were recorded in liver cancers in the
Thorotrast- and non-Thorotrast-exposed patients. The coexistence
of two or three different malignant neoplasms of the liver was found
in 4 (5.3~o) of the 75 Thorotrast-induced hepatic malignancies. In
55 Japanese patients who received Thorotrast intravascularly 29-50
yr previously, significant dose-dependent changes were found both
in the appearance of Howell-Jolly bodies in the erythrocytes, which
increased significantly with thorium body burden, as was an increase
in osmotic resistance of erythrocytes with an increase in thorium
deposition.42
THE DANISH THOROTRAST STUDY
A follow-up study of Danish neurosurgical patients injected with
Thorotrast during the years 1935-1946,- was begun a few years
after the cessation of the radiological use of Thorotrast. The control
population used is derived from the Danish Cancer Registry. The
malignant tumors found in excess in 1979 were as follows: cancers of
the digestive tract, 71 observed versus 21 expected; liver tumors, 50
versus 0.75; lung cancers, 14 versus 7.5; and leukemias 14 versus 1.6.
In the 1986 report of results to the end of 1983, 1,169 patients had
died and 150 were alive. Cancer types have shown little difference
over time, and only liver tumors and leukem~as show great divergence
from expected rates. Liver tumors were the largest single cause of
death from 1980 to 1983. There have been 93 liver cancers versus
0.89 expected, and 23 leukemias versus 3.12 expected. There also
appeared to be an excess of lung cancer (19 observed versus 9.1
expected). This apparent difference is unexplained.
THE AMERICAN THOROTRAST STUDY
Falk et ai.~4 carried out a preliminary epidemiological investiga-
tion of Thorotrast-exposed patients in the United States covering the
years 1964-1974 and found 26 cases of Thorotrast-induced hepatic
angiosarcoma. All patients had undergone either hepatolienography
or cerebral angiography. This hepatic tumor incidence was still in-
creasing in the early 1970s, and a larger proportion of the more recent
OCR for page 267
THORIUM
267
cases had undergone relatively low-dose Thorotrast radiological pro-
cedures and prolonged latent periods, ranging from 19.8 to 28.0 yr,
and 1 case was as long as 40 yr.
OTHER HUMAN STUDIES
Toohey et al.44 have measured the activity of thorium daughters
(228Ac, 2~2Pb, Rabbi) in viva in studies of the health effects of thorium
exposure on 133 former workers in a thorium refinery; in addition,
the exhalation rate of 220 Rn (from 224 Ra) was determined for each
subject. The values observed were elevated and appeared to be
representative of the given individual only. No correlation was made
concerning health outcomes.
Xing-an et al.57 have examined exhaled thoron activity and 228 Th
lung burden in 20 miners inhaling thorium dust in iron mines; the
228 Th lung burden was approximately four times higher than that
in nonexposed controls. The thoron concentrations in the breath of
miners were 3 to 4 times higher than those in controls. They also
found that the 228 Th body burden in 20 persons living in a high-
background area (Dong-anling region) was 3 times greater than that
in controls. No health ejects were examined.
ESTIMATION OF EXCESS RISK FOLLOWING
THOROTRAST ADMINISTRATION
The primary sources for determining the risks for tumor induc-
tion after exposure to thorium are the epidemiological studies of
Thorotrast-exposed patients. Although these can now provide esti-
mates for the risks of liver cancer and possibly leuke~rua, these risk
estimates are applicable only to intravascular Thorotrast exposure.
Animal studies indicate that it is primarily the alpha radiation from
232ThO2 that causes the tumors. Other forms of thorium would be
subject to different pharmacodynamics, and thus, the dose distribu-
tion and health ejects would be different.
In order to calculate the risk of dying by liver cancer after
Thorotrast injection, it is necessary to know the size of the Thorotrast
population cohort, the average dose to the liver per year, the number
of persons dead at time t, the number of liver cancers at time t, and
finally the number of liver cancers in the control group at time t. In
addition, it is necessary to assume a death rate at time t (to estimate
total liver cancers when the entire cohort is dead) and latent period.
OCR for page 268
268 HEALTH RISKS OF RADON AND OTHER ALPNA-EMITTERS
TABLE 5-5 Liver Cancer Data from Thorotrast Studies
No. of Years Average Total No. of Liver
Thorotrast Followed Liver Dose Cohort No. of Liver Cancers/
Study (date) (rad/yr) Size Deceased Cancers No. of Controls
German 40 (1984) 25 2,334 1,964 347 2/1,409
Japanese 40 (1984) 36 254a 180 50 6/446
Portuguese 30 (1976) 25 1,244 955 87 1/6S6
aOf 261 cases, 7 are untraced.
Both the German and the Japanese Thorotrast cases have been
followed for about 40 yr, and in the Portuguese study, results are
available as of 1976, at which time those cases had been followed for
about 30 yr. Table 5-5 lists the information from these three studies
needed to make approximate estimates of the liver-cancer risk.
The major assumptions in this calculation are (1) the rate at
which the study group is dying (which determines the total lifetime
of the study) and (2) the latency period. Figures 5-3 and ~5 appear
to provide evidence that the latent period is about 20 yr. Estimation
of the rate of dying is more difficult from the information available.
The rate is expected to increase with age, and the simple linear
mode] following liver-cancer deaths should be a rough approximation
to what wall actually occur. An example calculation of the risk is
given In the box entitled Example Risk Estimate for Liver Cancer
in the German Thorotrast Study."
Using these assumptions, excess lifetime risks have been cal-
culated for liver cancer for the three different Thorotrast studies,
namely, the German, the Japanese, and the Portuguese studies.
These risks are shown in Table 5-6.
An assumption of a shorter latent period, for example 10 yr as in
the Biological Effects of Ionizing Radiation (BEIR) Ill report,34 will
reduce these risk values because the effective dose will have increased
due to the longer time at risk. A 1() yr assumed latent period will
reduce the risk estimates by about one third. The 1980 BEIR ITI
report34 based its projections on an assumed minimal latent period of
10 yr and observed mortality to the end of life for the total population
in the three studies still alive and at risk; it estimated approximately
300 excess liver cancers/106 person-red of alpha radiation to the
liver.
It must be remembered that these estimates are for Thorotrast,
not thorium. The dosimetry of thorium in other forms will likely be
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THORIUM
269
EXAMPLE RISK ESTIMATE FOR LIVER CANCER
IN THE GERMAN THOROTRAST STUDY
Assumptions:
1. Total death rate after 20 yr parallels liver-cancer death
rate and is linear during the last 20 yr.
2. The latency period is 20 yr.
Assumed cohort average annual death rate = 1964/20 =
98.2 deaths/yr
Estimated remaining mean time to death of cohort = (2,334 -
1,964~/98,2 = 4 years
Total expected number of liver cancers = 347~20+434/20 =
416
Person-rad-wasted dose = 25~56,016 x 25) = 1,380,950
Total excess number of liver cancers = 416 - (2/1,409) x 2,334
= 413
Risk per 106 person-red = 413/1,380,950 = # 300/106 person-
rad
TABLE 5-6 Estimated Liver Cancer Risks
from Thorotrast
Thorotrast Expected Excess Person-Rad- Risk/106
Study Liver Cancers Wasted Dose Person-Rad
German 413 1.30 X 106 300
Japanese 67 0.256 X 106 260
Portuguese 111 0.40 X 106 280
quite different from the dose distributions associated with Thorotrast
aggregates, and the risk values will also be different.
Faber6 ~ 9 estimated the excess rate of liver cancer in adults as
4.2 cases/year/106 person-red. For a 4~yr follow-up, this would cor-
respond to about 170 cases/106 person-red. Such estimates, however,
are not based on modeling the pattern of risk over time and must be
considered provisional until more complete data are available.
Deaths from leukemia in the Thorotrast surveys in Germany,
Portugal, and Denmark are in excess of the national rates of death
from leukemia. Two categories of malignant disease exist, namely, (1)
malignant disease originating in the bone marrow, that is, leukemia
OCR for page 270
270 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
(including acute myeloid and chronic myeloid leukemia), multiple
myeloma, and hemangiosarcoma confined to the bone marrow; and
(2) malignant disease arising in the {ymphoid tissues, that is, ma-
lignant disease that includes thymoma, reticulosarcoma, and acute
lymphoid leukemia. By i978, the total of the former category in the
combined surveys exceeded 40 cases, which is a combined rate of
about 12 cases/1,000 persons.27 The expected number of cases would
depend on the age distribution of the population of Thorotrast-
exposed patients. If an expected value of 2/1,000 patients is as-
sumed, the excess due to Thorotrast would be 10/1,000.2728 The
average dose to bone marrow was about 150-200 rad.27 This would
result in an estimated lifetime linear risk coefficient of 50~0 excess
leukemia cases/106 person-rad.27
In the second category, a total of 11 cases have been recorded,27
which is a combined incidence rate of about 3/1,000 patients. If the
expected rate were 1.5/1,000, this excess would be significant. How-
ever, no risk coefficient can be estimated since diseases as uncommon
as those listed are difficult to distinguish in national registries, and
there are no reliable data on the dose to the lymphoid tissues in the
Thorotrast-exposed patients.27
Mole28 reported that by 1979, of 3,772 Thorotrast-exposed pa-
tients in the German, Danish, and Portuguese Thorotrast surveys,
26 died from bone marrow failure, that is, 6.9/1,000. If the expected
control value were approximately 1.6/1,000 and the bone marrow
dose is taken as 270 red over 30 yr for a 25-m! injection, then a
lifetime linear risk coefficient of 20 excess cases/106 person-red can
be estimated. However, the risk coefficient may be nearer to 30/106
person-red since the deaths in the Danish subjects occurred at 7-24
yr (mean, 16 yr)4 and in the Portuguese subjects at 8-37 yr (mean,
25 yr)5 after Thorotrast administration.
Mays and Spiess25 have estimated the risk of bone-tumor in-
duction In Thorotrast-exposed patients. In Germany, Portugal, and
Denmark, 3,000 patients followed for more than 10 yr had con-
tributed about 45,000 person-yr at risk beyond the first 10 yr by
1979; 3~ bone sarcomas had occurred, compared with 0.5 expected
cases. Rowland and Rundo37 have calculated that a typical intravas-
cular injection of 25 m! of Thorotrast gave an average dose rate
from transiocated 224 Ra of about 1 rad/yr to the marrow-free skele-
ton of an adult. Assuming that transiocated 224Ra is the source
of exposure, the risk coefficient estimated is 55-120 excess bone
sarcomas/106 person-red (average dose to the skeleton without bone
marrow). For comparison, the risk coefficient for protracted injec-
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THORIUM
271
tions of 224Ra is estimated to be about 200 excess bone sarcomas/106
person-red, based on 54 cases of bone sarcoma.25 The effect of age at
the time of Thorotrast administration on the induction of neoplasia
is poorly understood; patients receiving Thorotrast at younger ages
appear to have an excess of bone sarcomas, whereas patients receiving
Thorotrast at older ages do not.25
Liver tumors arising from hepatic parenchymal or bile duct cells,
or hemangioendotheliomas, have not been recorded in excess in hu-
mans exposed to external low linear energy transfer radiations, al-
though leukern~a is commonly induced from such exposures.34 This
is in contrast to the Thorotrast-exposed patients where the linear
risk coefficient for liver tumors is considerably higher than that for
leukemia.27 28 This may be due, in part, to the practice of averaging
the dose in the liver; local deposits of Thorotrast provide sufficiently
high local alpha-radiation doses to induce cycles of necrosis and re-
generation. While radiation plays an important role, it has been
suggested that it may be only the hepatocellular tumors and not
the hemangioendotheliomas that are associated with cycles of liver
necrosis and regeneration in the absence of radiation.6
The wide local variation of Thorotrast dose distribution in the
liver also occurs in the bone marrow, lymph nodes, and spleen;
Mole27 28 speculated that local radiation levels from Thorotrast de-
posits are much greater than dose averages throughout the tissue
and that this could be responsible for the high incidence of leukemias
in Thorotrast-exposed patients, and perhaps also for the apparent
excess of multiple myeloma and lymph node neoplasms. The inhomo-
geneous radiation produced by alpha-emitters and the nonuniform
and patchy anatomic distribution of Thorotrast complicate any at-
tempt to calculate radiation dosage to the tissues of these patients.
Correlation with histopathological findings based on terminal bur-
dens is difficult, since the uneven and irregular distribution with
increasing aggregation and flocculation of Thorotrast granules and
migration and redistribution of thorium constantly change the levels
of radiation dose. Further, some of the decay products of the compli-
cated thorium series are soluble, transIocate, and are bone seekers.
Thus, average dose to the tissues may be an inappropriate param-
eter, and calculations based on terminal burdens do not necessarily
represent the radiation dose that may be responsible for initiating
malignant processes.
In summary, the combined epidemiological studies of Thorotrast-
exposed patients provide estimates for the cancer risks and are listed
in Table 5-7.
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272 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
TABLE 5-7 Lifetime Excess Cancer Risks
from Thorotrast
Tissue
Risk Coefficient/ Latent Period (yr) for
106 Person-rad Colloidal 232ThO2
Bone
Liver 260-300
50-60
55-120
20
s
0
The extent to which these risk numbers apply to other thorium
adionuclides in other forms is unknown.
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Representative terms from entire chapter:
dose rate
