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OCR for page 276
6
Uranium
INTRODUCTION
Minerals containing uranium are widely distributed in the sur-
face areas of the earth's crust. Some are of commercial value and
contain various oxides of uranium, including uraninite, pitchblende,
carnotite, and brannerite. Uranium ~ also found in phosphate rock,
lignite, and monazite sands. The potential health effects of uranium
in mining or in refining operations are complicated by the presence of
other alpha-emitters in the ore, such as radium and radon. Natural
uranium contains about 99.283% Of 238 U by weight, 0.711~o 235U,
and 0.0054~o 234u. 238U has a very long half-life of 4.5 x 109 yr so
that this isotope, although accounting for the largest fraction, by
weight, of natural uranium in the soil, accounts for only half of the
radioactivity. The remainder is derived from 235U and 234U.
Uranium is a dense metal (19.07 g/cm3 at 25°C) that is chem-
ically reactive and combines with most elements. Its chemistry has
been studied in great detail. In the crystalline state it can have va-
lences ranging from +3 to +6. Only the uranic compounds, U(IV),
and the hexavalent urany} compounds, UO22+, are sufficiently stable,
both thermodynamically and kinetically, in aqueous solution to be
of biological importance.
Uranium forms a highly complex series of oxides, including UO2,
U3Os, and UO3. Uranates are obtained when uranium is fused
with alkaline earth carbonates. Uranium hexafluoride, UFO, is an
276
OCR for page 277
URANIUM
277
important industrial compound since it is readily volatile (melting
point, 64.1°C).
Uranium has assumed enormous importance as a result of its use
in nuclear fuel. Previously, however, its industrial use was limited,
and most uranium that was recovered as a by-product of vanadium
mining was discarded. It has some utility as an intensifier in photog-
raphy, in dry copying ink, as a colorant in ceramics or glass, in the
production of armor-piercing- projectiles, and for use as ballast.
ABSORPTION AND DISTRIBUTION OF NATURAL URANIUM
Uranium is ubiquitous in soil and, following uptake into crops, is
a trace constituent of food, particularly cereals. Food is the principal
origin of the natural uranium content of the body for most popula-
tions, although water may be an important source in certain areas.
Gastrointestinal uptake is generally low about loo of soluble salts
and less than 1% of insoluble compounds.65 Absorption is reasonably
independent of the mass of uranium ingested. As expected, there
appears to be no preferential biological uptake Of 234 U compared to
238U, and their ratio in the body is similar to that ingested. There
are considerable regional variations, particularly in the concentra-
tions in water supplies, and these are reflected in variations in the
body content of uranium of populations in those areas.~3
The distribution of uranium found in human postmortem studies
has been reviewer] by Wrenn et al,65 who noted a range in total body
content of 2 to 62 fig. The skeleton ~ a major storage depot, and
the differences between the concentrations observed in various pop-
ulations is considerable. The concentrations of uranium in skeletal
tissue from Nepal was about six times that observed in the United
States.~3 There appears to be no increase in skeletal content with
increasing age, and this has been interpreted as suggesting that
equilibrium ~ established between intake and excretion during life
and that the biological half-life of uranium in bone is fairly short.
However, the natural uranium content of lung, liver, kidney, and ver-
tebra was found to be age dependent.~i Cayenne and Welfordii also
noted that the skeletal content in their material was only one-tenth
of that predicted by the International Commission on Radiological
Protection (ICRP).25
OCR for page 278
278 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
PHARMACOKINETICS AND TOXICOLOGY
The uranyl ion, UO22+, is central to an understanding of the
toxicology of uranium, because it forms stable complexes with car-
bonate and phosphate ligands in biological fluids and, to a smaller
degree, with carboxyl and hydroxyl ligands. The stability of the
UO2HCO3+ complex depends on the pH of the solution, and the pH
at different anatomic sites affects its distribution in the body.
Early toxicological studies were reviewed by Hodge,20 who noted
that the toxic effects of uranium were first examined after uranium
was extracted from pitchblende, followed by the preparation of urany!
nitrate, sulfate, and chloride. In 1853 Leconte (cited by Hodge20) dis-
covered that uranium acetate could induce glycosuria in dogs. This
discovery resulted in its widespread use as a homeopathic remedy in
the treatment of diabetes mellitus because of the mistaken conclu-
sion that the effect was an abnormality of carbohydrate metabolism.
However, extensive research soon showed that it was the result of
renal damage, and uranium compounds became the agent of choice
in the production of chronic renal lesions in experimental animals.
Chronic nephritis was an important and widespread disease at the
time, and the discovery of an experimental model that appeared
to anemic the human disease attracted much interest. The renal le-
sion was found to be unique, and was later assumed to be the only
toxic effect of uranium important to man, in that uranium was not
thought to accumulate in bone or to constitute a radiation hazard.
However, the enrichment of natural uranium and the production
of artificial isotopes with high specific activities stimulated inten-
sive research, which has been reviewed by various authors who used
data drawn largely from the original Manhattan Engineering District
StUdies.20948,5l,55
A classic handbook of experimental pharmacology comprehen-
sively treating uranium, plutonium, and transplutonic elements was
edited by Hodge et al.22 It contained seven chapters devoted solely
to uranium and uranium mining. Chapter 122 summarized the early
history of uranium poisoning (1824-1942), Chapter 366 the results
of toxicologic experiments in animals since 1942, and Chapter 423
the direct information on the metabolism of uranium in humans.
Chapter 546 described the development of criteria for the protection
of humans against uranium intoxication. This book was followed by
a conference62 on occupational health experience with uranium up
to 1975. The proceedings included a comprehensive review of the
metabolism and effects of uranium in animals.9 in 1975, a Brazilian
OCR for page 279
URANIUM
279
symposium reviewed the environmental transport and accumulation
of all naturally occurring alpha-emitters in areas of high natural
background radiation.64 A 1979 symposium on actinides in humans
and animals63 brought together researchers working on environmen-
tal transport, occupational exposure, and metabolism and effects.
More recently, a colloquium on biokinetics and analysis of uranium
in man,34 sponsored by the U.S. Uranium Registry, brought infor-
mation and progress in several fields up to date. It reviewed the
biokinetics and toxicology of uranium in animals; updated metabolic
models of uranium with special attention to circulatory transport,
deposition, and retention in kidney and bone; and evaluated bioki-
netic models and internal radiation dosimetry. It also included a
historical review of uranium in humans, a discussion of human epi-
demiology, and sessions on analytical methods. The implication of
recent findings regarding toxicity, radiation effects, and extrapolation
of results to humans were summarized.
As previously described, the uptake of uranium from food is the
principal source of natural uranium in the general population. In the
industrial environment, the respiratory tract is the most important
route of entry. Soluble salts of uranium can be absorbed through
the skin, but there are no data on the rate of such absorption in
humans.57
The disposition of inhaled uranium aerosols in the body is de-
termined by the size of the inhaled particles and their solubility. In-
soluble particles with an aerodynamic diameter (ADD) smaller than
about 5 ,um may be deposited in the alveoli. After some months they
are removed from the alveoli to the cilia lining the upper airways and
are swallowed so that they are excreted through the gastrointestinal
tract. A proportion of the deposited particles remains permanently
in the Jung tissue or is stored in the hilar lymph nodes. Larger aerosol
particles (> 5 ,um ADD) are deposited on the upper airways and can-
not penetrate as far as the alveoli. These particles are removed by
the cilia within a few hours or days. They are swallowed and excreted
by the gastrointestinal tract. The retention of an insoluble uranium
aerosol in the lung is thus dependent on whether it is of a size such
that it is deposited mainly in the alveoli or on the ciliated airways.
In addition to the site of deposition in the lung, the solubility of
the aerosol is also an important determinant of the biological half-life.
In fact, ICRP25 classified the biological half-life of uranium aerosols
according only to their estimated solubility and took no account of
particle size. The stable complexes formed between the urany} ion
OCR for page 280
280 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
and bicarbonate anions emphasize the importance of distinguishing
between solubility in water and solubility in biological fluids.
Results of animal studies60 have suggested that uranium in the
tetravalent state, U(IV), is oxidized to U(VI) before absorption,
unless given intravenously; the metabolism of U(IV) is therefore
less relevant to occupational or environmental exposure of man and
will not be reviewed here. After absorption from the lungs or af-
ter intravenous injection in experimental animals, soluble salts of
U(VI) are partitioned in the bloodstream approximately 60%0 in
a form generally accepted to be the bicarbonate complex and the
remaining 40% bound to plasma proteins, primarily transferrin.~5 47
The {ow-molecular-weight bicarbonate complex Is filtered out of the
bloodstream in the renal gIomeruTi and passed into the tubules. The
fraction bound to plasma protein cannot penetrate the giomerular
lining, but because equilibrium between the two fractions in the
bloodstream Is maintained, in due course all plasma uranium passes
to the renal tubules, except for that which is diverted to the skeletal
tissue. Between 10 and 30% is reversibly bound to the surface of
the bony structures. During gIomerular excretion of uranium, the
stores of uranium in the extracellular fluid and skeletal system are
mobilized, and the renal tubules continue to excrete uranium; over
60~o of a single intravenous dose is excreted in the first 24 h.~5 23 46 47
Within the renal tubules, water and bicarbonate are absorbed.
The resulting decrease in pH causes the uranyI-bicarbonate complex
to dissociate and release the highly reactive urany! ion. This forms
complexes with phosphate ligands on the luminal surface of cells
lining the tubules. The complexing probably suppresses cellular
respiration due to enzyme inhibition and results in slow cell death.20
The accumulation of uranium in the kidneys accounts for about
20~o of an intravenous dose during the first 24 h.47 The rate of
excretion depends on the urinary bicarbonate content and acidity.
Very alkaline urine limits dissociation of the urany! complex and
increases uranium excretion.
The deposition of uranium in bone was originally considered not
to be important, because of the low specific radioactivity of natural
uranium and in view of the obvious severity of the renal effects.
However, uranium behaves chemically like calcium, and the skeletal
system might be the target organ in the case of enriched uranium.
The use of autoradiography with isotopes with high specific activities
has provided much experimental information on the mechanism of
deposition of uranium in bone. It has shown that uranium shares
OCR for page 281
URANIUM
281
characteristics with radium, which Is distributes] throughout bone (a
volume seeker), and with plutonium, which remains on the surface of
the bone.39 42 The initial deposition is nonuniform and is at the sites
of active calcification.37 5t Subsequently, there is a slow relocation
throughout the volume of the bone. The mechanisms are uncertain.
Many inhalation experiments using uranium have been carried
out in animals. In general, soluble salts, such as UFO, UO2F2, and
UO2(NO3~2 6H2O, are rapidly cleared to the kidneys and bones, with
none remaining in the lungs after 30 days. In contrast, less soluble
compounds such as UO2 are largely cleared from the pulmonary
tissue to the ciliated airways and eliminated by the gastrointesti-
nal tract. A fraction is retained in the Jung tissue or hilar lymph
nodes, and lit tie accumulates in tissues outside the thorax. Recent
studies have shown that the distinction between compounds which
are soluble in water and those which are insoluble is not a reliable
indicator of clearance rates because of the rapidity of formation of
the bicarbonate-urany} complex in biological fluids. For example,
using UO3 which was classified by ICRP26 as a class W compound
on the basis of solubility, Stradiey et al.49 exposed rats to an aerosol
and by direct injection of an aqueous suspension of the dust into
the pulmonary region of the lung. The aerosol had an activity mean
diameter of 1.4 ,um (~ 4.0~. Retention of uranium in the lung was
represented as the sum of two exponential terms with half-times of
0.9 (96%o) and 60 (by) days. This unexpectedly rapid clearance
of uranium from the lungs resulted from its solubility in biological
fluids with transiocation in the bloodstream and later excretion in
urine. The size of the aerosol particles was such that they had a high
probability of deposition in the alveoli where clearance to the ciliated
airways would take months in the case of insoluble particles.
Data derived from human experience are sparse. Human in-
travenous exposures for experimental purposes were carried out
in six hospital patients (Rochester, N.Y.), in eight terminally ill
brain tumor patients (Boston, Mass.), in studies to investigate bone
metabolism in seven patients with different bone diseases, and in
healthy control subjects.2t These experiments provided information
on the distribution and renal effects of acute exposures, but are of
less value in predicting the effects of chronic Tow-level exposure. In
an inhalation experiment reported by Harris and Davies, a subject
inhaled approximately 30 mg of UO3 or UF4 over a period of 24 clays.
The particle size of the aerosol was not stated. Retention was esti-
mated by measuring total excretion of uranium from the body. The
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282 HEALTH RISKS OF RADON ANrD OTHER ALPHA-EMITTERS
TABLE 6-1 Distribution of Uranium in Postmortem Tissues of a Single
Uranium Worker
Uranium Uranium Uranium Normal Content of
Wet Concentration Weight in Weight in Whole Organ in
Weight (,ug/g wet Sample Whole Organ Reference Man
Tissue (g) weight) (,ug) (fig) (fig)
Lung 17041 1.2 1~249 1~250 1.1
Lymph nodes 12 1.8 22 35 0.4
Bone 114 0.09 10.3 1,000 25.0
Kidney 217 0.15 32.6 30 0.14
Liver 177 0.02 3.5 35 0.4
Other — — — — 12.5
SOURCE: Data from Donoghue et al.8 (occupational) and Wrenn et al.65 (general public).
results showed that 60~o of the material that had been inhaled was
still present after 32 days, with a period of rapid urinary elimination
during the first 20 h after inhalation and slower excretion during the
next 2~200 h.
In an alternative approach for obtaining data on the kinetics of
uranium in human subjects, Donoghue et al.8 examined, for uranium
content, postmortem tissues of workers who had been exposed when
alive. They reported autopsy data on a worker who had been em-
ployed in a uranium workshop for 10 yr and who died suddenly from
natural causes. Dust exposure had been to uranium mostly in the
form of U3Os (85~o), with the remainder being in the form of UO2.
Those estimates were based on analysis of settled dust and might not
have reflected the composition of inhaled dust. The distribution of
uranium In the postmortem tissues is shown in Table ~1.
Extensive information is available on the content and distribu-
tion of uranium in the human body under different circumstances.
The purpose of Table ~1 is to contrast the distribution associated
with the inhalation of U3Oe derived from occupational sources with
that typically found in the body of nonoccupationally exposed indi-
viduals. The total amounts present in the latter would depend on
the uranium content of food and water during life and thus on the
geographical area from which the specimens were obtained.
Donoghue et al.8 compared the body content of uranium in
the case that they reported with that calculated from estimates of
occupational exposure during life and the retention values predicted
from ICRP models.25 Uranium in the lungs and thoracic lymph nodes
were less than 1% of the predicted values. These discrepancies could
be due to errors in the exposure estimates or in the assumptions
OCR for page 283
URANIUM
283
contained in the mode! and emphasize the large uncertainties in
estimating risks.
NEPHROTOXIC EFFECTS
In the case of natural uranium, the toxicological data identify the
kidney as the target organ, although specific acute toxic effects are
associated with the inhalation of certain compounds such as UF4 and
UC}4. Studies done after the acute administration of soluble uranium
to animals2355 indicated that substantial renal damage occurred
when the concentration of uranium in the kidney exceeded 3 Agog
of renal tissue. If the same concentrations were relevant to human
experience and renal tissue of a standard man24 of 310 g is used, this
corresponds to a total uranium content in the two kidneys of 930 ,ug.
Wrenn et al.65 have recently reviewed metabolic models of the
accumulation of uranium in the human kidney under conditions of
equilibrium where the intake rate equals the excretion rate. The
several models used26 46 65 similar equilibrium values of uranium in
kidney if the same daily input to blood is assumed for each. The
ICRP model25 uses a two-component exponential retention function
in kidney with half-times of 6 days associates] with 12% of the dose
to blood and 1,500 days associated with 0.05~o of the dose to blood.
The model of kidney retention adopted by Wrenn et al.65 is that of
Spoor and Hursh.46 Spoor and Hursh used a Today half-time in the
kidney with 1 loo transfer from blood to kidney. Durbin34 has recently
evaluated the information on retention of uranium in the kidney in
seven mammalian species and concluded that the rate of elimination
of uranium deposited in kidney has two phases, with the first (95~o
of the dosage) having a half-time from 2 to 6 days and the second
having a half-time from 30 to 340 days. Under equilibrium conditions
of intake and excretion, the daily urinary excretion predicted by these
models associated with the buildup of 3 Agog in human kidney would
be about 400 to 500 ,ug of uranium, of which only a part is contributed
from the release of uranium deposited in kidney. In man about 70%0
of injected urany] nitrate was excreted in urine in 24 h.46 For a rapid
acute exposure of man to soluble uranium compounds, if ll% were
deposited in kidney, an acute intake of uranium to blood of 8,400
,ug would be required to produce an initial concentration of 3 Agog
kidney, and about 70~o (5,900 ,ug) would be excreted in urine during
the subsequent 24 h.
OCR for page 284
284 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
The mechanism of the renal lesions has been extensively investi-
gated.~4 i~ The kidney responds to toxic levels of uranium within
the first ~ to 2 days after a single injection35 but, unlike mercury
poisoning, the changes are progressively severe over the first 5 days;
whether this is due to the continuous release of further uranium by
mobilization from the skeleton or the progression of the initial lesion
is not known. The renal deposits formed after a single administration
are also excreted rapidly, either because of reversal of the phosphate-
binding sites in the tubular cells or because of the sloughing and
excretion of dead cells that contain uranium. This acute phase of
damage can be followed by repair with modified epithelium consist-
ing of flattened, imperfectly differentiated cells that are remarkably
resistant to the toxic effects of further injections of uranium. Young
animals have considerably more resistance than older animals, and
there are important species differences in sensitivity, possible owing
to differences in urinary pH.~9 Rats are much more resistant than
dogs. Humans are probably close to dogs in sensitivity (P. Mor-
row, personal communication, 1986~; this is considered below in the
discussion of thresholds of toxicity.
The lesions in the proximal convoluted tubules result in the
appearance of glucose, low-molecular-weight proteins, and amino
acids in the urine. These substances are normally reabsorbed from
the tubular fluid, and their appearance in urine ~ due mainly to
malabsorption by the damaged tubular cells and partly to tubular
excretion, but not to increased gIomerular permeability. They are
of practical relevance, because they make it possible to detect early
renal damage in industrial workers through routine monitoring of
urine for abnormal proteins.
The work of Morrow et al.36 has cast some doubt on the validity
of the conclusion that 3 ,ug/g is the threshold level of nephrotoxicity.
In the dog kidney, they concluded that <1 ~g/g was associated
with histological and transient biochemical abnormalities for injected
doses of 0.01 mg/kg UO2F2. In the female Wistar rat, Bentley et
al.5 showed that renal concentrations were 10 ~g/g at 0.05 mg/kg of
injected urany] nitrate at 24 h postinjection, and that 0.01 mg/kg
produced a transient proteinuria.
Morrow et al.36 report half-times of 16 days in rat kidney after
single exposures to UO2F2, whereas Bentley et al.5 report on a twos
phase retention, with the first component having a half-time of 2.2
days and the second a half-time of 13 days, consistent with the
general mammalian metabolic model of Durbin.34 Morrow et al.36
OCR for page 285
URANIUM
285
find a rapid (unspecified rate) and slower (half-life, 9.3 days) release
rate from dog kidney.
Whether the rat or dog is more sensitive is not clear. Morrow
et al.36 believe the rat is more resistant than the dog, but exper-
iments In which the 50% lethal dose (LD50) is determined suggest
that the dog is more resistant based on lethality.9 The question of
which animal is a better mode} for uranium effects in man deserves
further investigation, as does the pharmacokinetics of early uranium
deposition in kidney up to 10 days postinjection and its relationship
to biochemical and histological indicators of response and damage.
In the absence of reliable epidemiological evidence, the interpre-
tation of animal toxicological data has assumed considerable impor-
tance as a source of inference about the likely effects of human ex-
posure. However, it is clear from the preceding discussion that there
are important species differences in sensitivity and in the effects of
single versus chronic exposure. Both single and chronic exposures are
relevant to human populations. The laboratory experiment of single
acute exposure mimics accidental exposures, but chronic exposure
experiments are more important in estimating environmental effects
or those In working populations. The major difficulty is in choos-
ing the animal species that is the best mode} for predicting human
toxicity.
The literature contains a sufficient number of investigations in
which injected UO2(NO3~2 was used to compare relative species
sensitivity. Durbin and Wrenn,9 in their review of toxicity in the
rabbit, guinea pig, dog, cat, and mouse noted a variation in sensitivity
of 2 orders of magnitude, from 0.1 mg/kg in rabbit to 20-25 mg/kg
in C3H mice. The greater sensitivity of the rabbit and guinea pig
may be due to the greater acidity of urine in herbivores. Information
on humans is inadequate to estimate an accurate LDso for man,
but there is information on levels that are not acutely toxic, and
systemic doses of 0.1 to 0.3 mg/kg of soluble uranium have not
produced mortality due to kidney lesions in man.6 30 46 The LD50 for
man is probably similar to that in the rat or dog. Generally one-tenth
the LD50 produces no or few acute deaths in experimental animate.
Thus, the LDso in man should be no lower than that for the rat or
dog, about 1 to 2 mg/kg. Parentally administered UO2(NO3~2 and
UO2F2 are equally toxic in mice and rats and twice as toxic as less
soluble UCi4.~7
OCR for page 286
286 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
In the adult male Wistar rat, there is a gender sensitivity, with
the LD50 for the male being about 2.5 mg/kg and that for the female
being about ~ mg/kg, for intraperitoneal injection of UO2F2.~7
Thirty-day feeding experiments in rats with compounds of ura-
nium that are insoluble in water (UO2, U3Os, and UF4) were found
to be nontoxic, whereas water-soluble compounds were relatively
more toxic. For the toxic compounds, 2 to logo in the diet produced
lOO~o mortality, and at 0.1 to loo it produced growth depression.
The relative species susceptibility in oral 30-day feeding studies is
rabbit > dog > rat. For interspecies scaling for nephrotoxicity, the
relative absorption from the gastrointestinal tract is important. The
recent article by Wrenn et al.65 summarizes what is known about
mammalian metabolism of uranium, including gastrointestinal am
sorption.
Tolerance has sometimes been used in the literature to mean the
ability of animals to resist the toxic action of uranium more effectively
when a dose is given repeatedly rather than acutely. Although the
experiments of Haveni7 in the rat showed that survival to an LD50
could be increased two- to fourfold by administering conditioning
doses up to one-third that of an LD50, the tolerance induced was
temporary; it was accompanied by histological alterations in the
kidney, with some cells excreting atypical amounts of citric acid;
and there were gross alterations of kidney appearance at autopsy.
Tolerance does not develop at lower doses. Therefore, it seems to be
a laboratory phenomenon of little practical importance, especially as
applied to occupational protection of workers.
There is some evidence in mice and dogs that the combination of
alpha radiation and chemical toxicity produces a greater nephrotoxic
eject than either does seperately.~9 The relevance of this to human
risk estimates is difficult to determine.
In one of the few studies to show an effect of uranium on humans,
Thun et a}.53 evaluated kidney function among uranium mill workers
and found a statistically significant excretion of beta-2-microgiobulin
and five amino acids. Although the levels of tubular proteinuria
were low, a correlation existed between the clearance of beta-2-
microgiobulin, relative to that of creatinine, and the length of time
that the uranium workers had spent in work areas with the high-
est exposures to soluble uranium. Thun et al.53 believe that these
data suggest reduced renal proximal tubular reabsorption, which is
consistent with uranium nephrotoxicity.
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292 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
of 238u, 234U, and 230Th. But animal exposure experiments50 have
shown that, after exposures to uranium ore dusts, the radioactivity
in tracheobronchial lymph nodes due to 230Th was 20-50 times that
due to 234 U or 238U. This difference led Archer et al.2 to conclude
that the excess mortality observed in uranium workers was a mani-
festation of 230 Th exposure. It should be noted that they observed
no excess mortality due to tumors of bone or liver, and there was
no excess of renal lesions. However, the epidemiological power of
the study indicates that it constitutes fairly weak evidence against
a specific toxic effect of uranium. For example, malignant disease of
the digestive system (ICD 6th revision codes 15~159) was associated
with an expected number of deaths of 5. The power to detect a 50~o
increase in cause-specific mortality was only about Who. In the case
of other cardiovascular and renal diseases (ICD codes 330-334, 444-
468, and 592-594), the expected number of deaths was 9.15, and the
corresponding power was about Who.
A direct approach to the question of specific uranium toxicity is
provided by surveys of workers exposed to enriched uranium. Such
an investigation was published by Polednak and Frome38 in connec-
tion with a cohort of 18,869 white men employed between 1943 and
1947 at a uranium conversion and enrichment plant in Oak Ridge,
Tennessee. The plant was engaged in the enrichment of uranium
with an electromagnetic separation process. Workers were exposed
to uranium dust, including uranium oxide and uranium tetrachIo-
ride. Airborne uranium concentrations decreased over a number of
years, but this was probably not associated with a concomitant de-
crease in the radiation hazard, because the product was more highly
enriched in 234 U and 235U, which have much higher specific activities
(radioactivity per unit mass) than 238U. The type and solubility of
the uranium compounds also changed over time. In the earlier years,
insoluble oxides were present with the more soluble chloride (ACID.
Later, UFO was received directly from another facility, so that insol-
uble oxides were partly replaced by more soluble compounds (UFO
and UF2O2~. However, the UFO gas was immediately converted to
oxides and then to green salt (USA. Even though the process was
mostly enclosed, exposures to oxides and UF4 could have occurred.
Radium (the source of radon gas) had been largely removed from
the uranium before it entered the plant. As a result, the pulmonary
radiation hazard to these workers was related only to the inhalation
of dust containing the various uranium isotopes and compounds.
Ascertainment of deaths was obtained through the Social Security
OCR for page 293
URANIUM
293
TABLE 6-2 Causes of Death after Uranium Dust
Exposure
Length of Employment
< 1 yr (n = 4.337) 21 yr (n = 4.008)
Cause of Death Observed SMR Observed SMR
Cancer of lung 50 0.92 66 1.06
Cancer of bone 1 0.82 1 0.74
Leukemia 2 0.25 9 1.02
Diseases of respiratory
system 61 1.19
Chronic nephritis 5 0.69
~1
57 0.93
0.51
Administration, and causes of death were determined from death
certificates. Duration of follow up extended to 25 or 30 yr after first
employment. Average air concentrations of uranium, according to
surveys carried out by industrial hygienists employed by the com-
pany, ranged from 25 to 500 ~g/m3. It should be noted that this
method of expressing the concentration of uranium in the air may
not be appropriate in the case of enriched uranium. In general, the
mortality experience of the cohort did not show increased SMRs for
Jung or bone cancer or for renal disorders, such as chronic nephritis.
The summary results for selected causes of death among white men
who worked in departments involving uranium dust exposure are
shown in Table ~2.
Although there was no overall increase in lung-cancer deaths,
a more detailed analysis provided evidence of a greater risk among
those who were first exposed when older. Among workers first hired
(and thus assumed first exposed) over the age of 45, the odds ratio
was 1.51 (95%0 confidence interval, 1.01-2.31~.
A weakness of this study is that the duration of exposure was
only 1 or 2 yr in most instances. This limits any inferences regarding
effects of long-term uranium exposure.
In a further analysis of the same cohort, Cookfair et al.7 under-
took a case-control study nested within the cohort to examine the
risk of lung-cancer death among men who received radiation expo-
sure to the lungs as a result of inhaling uranium dust or the dust of
uranium compounds.
Cases consisted of the 330 cohort members who died of lung
cancer. They were matched on year of birth with two sets of controls,
one consisting of men who died of diseases other than cancer and the
other of men known to be alive. The cumulative lung radiation dose
OCR for page 294
294 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
TABLE 6-3 Cumulative Lung Dose Odds Ratios (OR)
Cases versus Deceased
Exposures
Cases versus Deceased Controls
OR (95% confidence interval;
p= 0.05)
Cases versus Controls
OR (95~o confidence interval)
Hire age c 45 yr
Low
Medium
High
Hire age 2 45 yr
Low
Medium
High
0.84 (0.50-1.41)
0.49 (0.26-0.92)
0.65 (0.36-1.17)
2.27 (0.85-6.07)
2.86 (0.70-11.54)
4.48 (1.20-16.85)
0.5 (0.34-0.92)
0.31 (0.17-0.56)
0.54 (0.31-0.97)
1.03 (0.44-2.42)
1.81 (0.510-6.50)
3.79 (1.01-134.3)
aLow, 0.001-5 reds; medium, 5.001-20 reds; high, 20.001-75 reds.
resulting from the inhalation of uranium compound dust and other
potential carcinogenic agents was calculated for each member of the
study population. Data were subjected to Mantel-Haensze] stratified
analysis and logistic regression. The results of the logistic mode} are
shown in Table ~3.
The data show that, among the older group, the relative risk
increased with exposure. The pattern was reflected in subgroups of
known smoking status. The data support the hypothesis that radia-
tion exposure of the lungs resulting from the inhalation of uranium
dust and the dust of uranium compounds is a risk factor for lung
cancer among white men who were 45 yr old or older when first
exposed. No increased risk was noted in those who received less
than 5 red to the lungs. Two hypotheses might help to explain this
apparent interaction between age of hire and cumulative Jung close:
Either older workers are more susceptible to uranium-induced lung
cancer or the latent period is longer for younger workers than for
older workers. Increased susceptibility in older workers could have
many explanations, including delayed clearance of uranium dust and
previous tissue damage.
Another retrospective study of mortality patterns among a co-
hort of uranium mill workers was reported by Waxweiler et al.58
Records from seven uranium mills throughout the Colorado Plateau
were obtained, and 2,002 men who had worked for at least 1 yr in
the mills were selected for study. Only those who stated on their job
applications that they had never worked in uranium mining were in-
cluded; the purpose of this restriction was to examine the health risks
of uranium exposure in the absence of uranium mining. The cohort
OCR for page 295
URANIUM
295
was traced with standard mechanisms. Risk of mortality was ana-
{yzed with a modified life-table system, with expected deaths based
on U.S. death rates specific for cause, age, race, sex, and calendar
period. Follow-up was 98~o complete, and 533 deaths were observed,
compared with 605 expected. Labor turnover was high: Only a small
fraction worked for more than 5 yr. Mortality from all causes com-
bined, and particularly from stroke and cardiovascular disease, was
well below expected. This was interpreted as representing a healthy
worker effect. A prior hypothesis included an excess of lung cancer
(SMR, 83; 95~o confidence interval, 54-121), malignancies due to
lymphatic and hematopoietic tissue other than leukemia (7th revi-
sion ICD, 20~203, 205; 7 deaths observed versus 5.6 expected), and
chronic renal disease (7th revision ICD, 592-594; SMR, 167; 95~o
confidence interval, 60-353~. Detailed analysis of the small excess
of deaths due to lymphatic malignancies (other than leukemia) indi-
cated that the excess risk was limited to the induction latency period
beyond 20 yr (6 observed verses 2.6 expected). This corroborated the
excess of deaths due to the same malignancies reported in another
cohort of uranium rn~lers.2
An occupational etiology was considered plausible toxicologi-
cally, because yellow-cake dust and insoluble yellow-cake uranium
compounds accumulate in the tracheobronchial lymphatic system
after inhalation,828 52 so they constitute a potential source of ra-
diation to the lymphatic glands. However, the findings should be
treated with caution since there was a paucity of observed and ex-
pected deaths beyond 5 yr of employment, and the findings were not
statistically significant. There appeared to be no increase in Jung-
cancer deaths even when latency and the low regional rate of death
due to malignant lung disease was allowed for. Of the six deaths
associated with chronic renal diseases, three were probably due to
prostatic obstruction, and the three due to giomerulonephritis were
all in men who were exposed only briefly. A clear relationship to
occupation was not established.
The previous studies identified in this section referred to mortal-
ity. Morbidity due to nonmalignant respiratory disease in uranium
miners has been cIanned to result from radiation exposure.) Archer et
ai.3 discussed the implications of their earlier findings of pulmonary
impairment in working miners. Their mortality data indicated that
death due to pulmonary insufficiency was as common in miners with
radiologic evidence of pneumoconiosis as in those with no x-ray ev-
idence of pneumoconiosis. The dominant causative factor in both
OCR for page 296
296 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
groups was presumed to be radiation exposure or cigarette smoking.
However, these exposures are not related to the specific question of
uranium inhalation but rather to radon-gas inhalation and exposure
to mixed mine dust.
Wilson6t investigated this problem in a cohort of white men
hired between 1952 and 1972 in a uranium mill. A few of the workers
had worked elsewhere in the company before the uranium mill began
operating. The study population consisted of 4,101 workers who had
worked for at least 3 months. Respiratory morbidity events were
abstracted from medical insurance claims In which a diagnosis was
given by a physician. Cohort and Mantel-Haensze! stratified analy-
ses were used after estimated cumulative radiation exposures were
categorized into low, moderate, and high. These exposure estimates
were made on the basis of the toxicity, frequency of use, and amounts
of substances used in the various departments. They were not based
on measurement of airborne radioactivity. An increased relative risk
of respiratory disease was found with increasing cumulative uranium
exposure, even when age at diagnosis, duration of employment, and,
to some extent, smoking habits were controlled for. Smoking histories
were available only for workers employed after 1968. The smoking
data included 17.4% of the study population, both current and for-
mer workers. Because of these limitations, it was possible only to
examine the distribution of smoking in the various uranium-exposure
categories, rather than to make detailed adjustments. The assump-
tion was made that the estimates correctly indicated the smoking
habits of other members of each category. Wilson noted that 80%
of the employees had no respiratory symptoms but that estimated
uranium exposure appeared to be the principal occupational expo-
sure that contributed to the development of nonmalignant respira-
tory disorders. It was not possible to determine whether the effect
of exposure was due to some chemical attribute of the uranium or
to its radioactivity. A critical review of the validity of this study
must take account of the inherent weakness of morbidity data based
on diagnoses obtained from insurance claims, even when given by
a physician. There were no hard data on the extent of exposure
to chemical agents or uranium or on smoking histories. In view of
these limitations, the study results cannot be accepted as convinc-
ing evidence of an excess of nonmalignant respiratory disease due to
uranium exposure.
Indirect evidence of uranium exposure and mortality was oh
tained in a geographic survey by Wilkinson,59 who found higher
OCR for page 297
URANIUM
297
rates of mortality from gastric cancer in several northern New Mex-
ico counties with substantial deposits of uranium, compared with
counties without such deposits. The differences persisted after so-
cioeconomic status or ethnic group was accounted for. A number of
etiologic possibilities were considered, including exposure to radon
or radon daughters and trace elements, such as arsenic, cadmium,
selenium, and lead. These are all commonly found in areas with ura-
nium deposits, and the study did not provide evidence of an effect of
uranium itself.
In summary, these investigations have provided suggestive but
not convincing evidence of deleterious human effects of chronic ex-
posure to uranium dust. There has not yet been any clear indication
of renal disease in man due to low-specific-activity uranium, and
the only positive finding involved the relative risk of Jung cancer in
the case-control study of Cookfair et al.7 Caution is required in the
interpretation of these results as an indication of the absence of any
effect. The surveys generally included a large number of workers
who were exposed for only a short time, and environmental exposure
estimates were poor. Clearly, long-term follow-up of workers with
adequate documentation is required.
RISK ESTIMATES
Uranium presents two separate potential risks due to its nephro-
toxic action and as a result of alpha radiation. At present there is
little convincing epidemiological evidence that serious renal disease
has occurred in human populations as a result of chronic low-level
exposure nor of increased rates of malignant tumors. However, this
does not constitute reliable evidence of the absence of important
health effects in occupationally exposed groups since the available
epidern~ological studies had limited power to detect increased rates
of disease if these were present. It is for this reason that much weight
has been given to inferences drawn from the results of animal stud-
ies and from tumor rates in human populations exposed to other
alpha-emitting elements.
The renal threshold concentration of uranium that results in sig-
nificant damage is a matter of controversy, and estimates range from
3 to < 1 Agog. The appropriate level depends, to an extent, on the
choice of animal species and metabolic model. Adoption of a specific
toxic threshold level and its relation to an airborne concentration for
control purposes in the occupational environment requires further
OCR for page 298
298 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
assumptions which are being reevaluated by the International Com-
mission on Radiological Protection. At present it is premature to
attempt a risk estimate for the probability of developing renal dam-
age, and there is an evident need for weD-controlled epidemiological
studies. The importance of such information ~ emphasized by the
likelihood that control levels in industry may need to be guided more
by the potential for nephrotoxic effects than by the effects of alpha
radiation. Quantification of the risks associated with alpha emis-
sion during chronic exposure to uranium cannot be determined from
published epidemiological studies because of confounding factors and
because of the limited power of the surveys to detect increased rates
of tumor incidence or mortality. For this reason estimates have been
based, by analogy, on the effects of other alpha-emitting elements in
human populations and from experiments using uranium in animals.
The most probable effect, if any, of exposure to uranium would be ex-
pected to be an increase in bone sarcomas. It ~ certainly reasonable
to believe that this can result from high-specific-activity uranium.
The likelihood of sarcomas resulting from population exposure to
natural exposure is exceedingly low and is only demonstrable if a
linear dose-response relationship ~ assumed.32 If the dose-response
relationship is quadratic, then virtually no effect would be expected
as a result of exposure to natural uranium. Assuming a linear rela-
tionship and a constant nonoccupational intake of 5 psi/day, Mays
et al.32 estimate that the risk of bone-sarcoma induction over a life-
tune Is 1.5 bone sarcomas/million persons. In the United States this
may be contrasted with the naturally occurring incidence of bone
sarcomas of about 750.
This evidence suggests that exposure to natural uranium ~ un-
likely to be a significant health risk In the population and may well
have no measurable eEect.
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61.
62.
63.
64.
65.
66.
Representative terms from entire chapter:
uranium compounds
