ML20003F869
| ML20003F869 | |
| Person / Time | |
|---|---|
| Issue date: | 01/26/1981 |
| From: | Minogue R NRC OFFICE OF NUCLEAR REGULATORY RESEARCH (RES) |
| To: | Rich Smith NRC OFFICE OF STANDARDS DEVELOPMENT |
| References | |
| RIL-111, NUDOCS 8104230787 | |
| Download: ML20003F869 (5) | |
Text
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UNITED STATES f
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W ASHINGTON, D. C.
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a JAN 2 61981 MEMORANDUM FOR: Ray G. Smith, Acting Director
,t Office of Standards Development 2'
FROM:
Robert B. Minogue, Director L
Office of Nuclear Regulatory Research
SUBJECT:
RESEARCH INFORMATION LETTER # 111 - ACUTE EFFECTS OF INHALATION EXPOSURE TO URANIUM HEXAFLUORIDE AND PATTERNS OF DEPOSITION Introduction and Summary This memorandum transmits the results of completed research on evaluation of the biological effects of inhalation exposure to uranium hexafluoride.
t The work was performed by the Department of Radiation Biology and Biophysics
_i at the University of Rochester under the direction of the Environmental Effects Research Branch of RES.
Research Request SD-77-4 stated that studies were needed on the biological effects of uranyl fluoride (UO F ) in order to include a bioassay program I
for uranium hexafluoride (UFs)2 2in Regulatory Guide 8.11, " Applications of 2 2 P us HF.
l 3foassay for Uranium." Gaseous UF hydro?yzes in air to form UO F 6
The rates of deposition, retention and excretion of uranium were determined and indicators of acute uranium toxicity were evaluated for UFs and UO F -
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Methodology
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The experimental plan was designed to examine primarily the relationship of inhaled UO F2 2 or UFs to the resulting uranium burden in the lungs, kidneys, and whole body and to the subsequent uranium elimination pattern.
Two animal species, dogs and rats, were selected to reveal or v'erify any
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species differences. A range of uranium doses was used to establish the approximate level for renal injury. Other experiments were conducted
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to examine possibly more sensitive indicators of reaal injury and to
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determine if the combination of HF + U0 F2 2 produces a greater effect than f.
U0 F2 2 alone.
9 b
Dog Studies Young adult female Beagle dogs were anesthetized with pentobarbital and intubated with an intratracheal tube for administration of U0 F. Immediately after exposure, the animals were gama counted 22 to establish their individual initial body (lung) burdens.
Catheterized i
urine specimens were obtained during the first day post-exposure. A
- e limited number of intravenous administrations were performed to assist it in the interpretation of the retention and elimination data.
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Ray G. Smith Rodent Inhalation Studies Young adult male rats were given nose-only exposures to UO F2 2 while unanesthetized in a special restraining tube connected to a Lovelace exposure unit.
Immediately after exposure, the heads of the rats were washed with aqueous detergent and each animal was whole-body counted. The rats were returned to their individual metabolism cages for the duration of the study (6-14 days). Selected experiments were conducted involving administration of UO F intravenously, intra-i, tracheally, or by gavage (stomach tubes)2 2 Rodent Intratracheal Instillation Studies Young adult male rats were anesthetized with pentobarbital and a small area of the trachea around the larynx was exposed surgically. The solutions of UO F2 2 and/or HF were delivered to the lungs by hypodermic syringe. The surgical opening was closed with autoclips and the animals M
placed into individual metabolism cages.
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In the deposition pattern studies, urine and feces were collected daily and assayed for uranium content. Blood and urine samples taken from selected animals were examined for plasma urea nitrogen and urinary protein and glucose, respectively.
At death or sacrifice, each animal was necropsied and' major organs 3
were assayed for radioactivity.
Samples of lungs and kidneys from selected s
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animals were fixed and stained for histopathologic examination.
In the dose-response studies, additional measurements of body weight, water intake, food consumption, and urine volume were made daily.
Sections of lung, kidney, spleen, heart, liver and trachca were fixed
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and stained for histopatholcgic examination.
Results and Discussion The results of each experiment are given in the tables and figures of NUREG/CR-1045, which has been provided to you. The following conclusions
,,.i have been drawn:
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is renal and the
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The principal route of excretion of absorbed UO F22
.C urinary excretion rate in the dog can be correlated with U+6 absorbed J.
dose (uptake) as a power function relationship wherein t (time) has the exponent - 1.45.
This agrees quite well with the available human data from uranyl nitrate administration and the ICRP excretion model.
2.
The urinary excretion of uranium is not easily related to total intake l
as differences in upper respiratory tract deposition directly determine the t,
unabsorbed fraction, which approximates that eliminated in the feces.
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Ray G. Smith effect is clearly evident whn the rat and dog data are compared, where, as the result of both species and exposure-method distinctions, the intake which is absorbed (after inhalation) is fraction of the UO;F2 around 33 percent in the rat and virtually 100 percent in the dog. Man is expected to fall into an intermediate position depending on the particle size of the U0 F, and the respiratory performance of the 22 individual, among other things.
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Even i' the intake of U0 F is restricted to the lower airways and 22 5
pulmonary parenchyma, as it was in the dogs, and the resulting intake is tantamount to uptake, the possibility of relating lung (thoracic) levels to excretion is tenuous because the absorption of U0 F22 is so rapid. The dog data suggest at least 70 percent of the UO F2 2 will be
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absorbed with a half time of s 15 minutes. While the clearance kinetics of the remainder of the U0 F in the lungs cannot be described precisely, 22
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the uranium appears to follow kinetics similar to those exhibited by
'c other soft tissues, e.g., skeletal muscle and liver, suggesting the blood-borne U'6 levels and the urinary elimination rates are probably more important than specific pulmonary translocation processes in j
determining the final phase of pulmonary retention.
4.
In the dog, approximately 75 percent of the absorbed dose was excreted in I,
the urine during the first post-exposure day. There is some indication for greater urinary elimination of uranium at lower absorbed doses, i.
although the evidence is far from substantial. This suggests occupational exposures would result in somewhat higher 24 hour2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> values, and this view is
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consistent with the ICRP excretion model for U+6 which predicts 80 percent urinary elimination during the first day. All of the available studies, both human and animal, provide excretion data at slightly or definitely nephrotoxic dose levels of U+6 5.
Retention data from UO F studies are somewhat variable and must be 22 l
considered tentative. On the basis of the first study, the dog and rat
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retention data for uranium in the kidney are quite harmonious. The dog l
7 experiments (inhalation and intravenous) suggest 5 to 10 percent of the absorbed dose is present in the kidneys at 6 days post-exposure, and the
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kidney levels exhibit a fairly protracted retention time. Consequently, the 5 to 10 percent retention level in rodent kidneys from 6 to 14 days
, 'Jh is in general agreement with the dog data.
6.
The bone and kidneys are the two major retention sites for U+6, but more data are needed on both before more definitive retention functions are available.
7.
Absorbed doses of UO F down to 0.05 mg kg-1 give clear evidence of 22 uranium-induced nephrotoxicity. Whereas previously reported human and animal studies suggest 0.1 mg kg-1 as an approximate threshold dose s^
for renal injury, the current study suggests the threshold is nearer 0.01 mg 1:
kg-1 in the previously-unexposed (novice) subject.
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The indicators of renal injury initially tested were urinary protein and glucose, and plasma urea nitrogen (PUN). Of these, urinary glucose appeared to be the most sensitive early indicator, i.e., when comparing pre-exposure and post-exposure values.
PUN's were typically slower to change; consequently, they peaked several days after the glucosuria and albuminuria.
9.
Possible synergism of U0 F2 2 aerosol and stoichiometric amounts of HF gas, which would typify a UFs release, was investigated.
Findings to date are inconclusive.
Future Work The first year of this experimental study did not address sufficiently the f
possibility of synergistic effects when the hydrolysis croducts of UF; (viz, UO F2 2 + 4HF) were present together in the exposure. This will be investigated in the second year of the project, especially in relation to
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U+5 retention, urinary excretion and renal toxicity.
The available data on UO F2 2 excretion and that en other 'M c: counds has been acquired from subjects, both man and laboratory animals, at dose levels i
> 0.01 mg kg-1, i.e., at certainly nephrotoxic levels. Also, tnere i: an important information gap on the behavior of the kidney which has :een exposed to U+3 previously. This could range from tests for possible pre-dispositional effects from subliminal doses, up to tests on the response
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of severely injured and " recovered" kidneys to further uranium exposure.
This
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i research area has important implications in plant experience and for potential bioassay and injury assessment procedures.
Currently, limited numbers of evaluations of previously-exposed animals are being undertaken insofar as nephrotoxic indicators are concerned and in relation to renal injury thresholds and retention functions.
Associated with the foregoing is need for further work on renal injury I
indicators. Since the first year's study, the scope has been broadened to
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include inulin clearance and urinary phosphate, a-amino acid nitrogen and h
N-acetyl s-glucosaminadase.
t h-Distinctions between the normal and exposed kidneys should ultimately be A
expressed in terms of the dose modification producing nephrotoxicity.
It is conceivable, for example, that the so-called regenerated nephron (" tolerant" y
kidney) does return to normal insofar as proteinuria is concerned, but there
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may be more persistent renal effects and indicators of renal dysfunction, and t
these should be assessed in terms of minimally effective doses or thresholds.
b Retention functions for bone and kidney are needed for at least 8 weeks post-exposure so that current estimations regarding the return of exposed persons to work can be verified. The distribution and retention data from the first year's study were limited to 1 week in the dog and 3 weeks in the rat. These t
data provided an excellent basis for some current exposure protocols which are designed to produce 3 ug U g-1 kidney levels at 60 days post-exposure.
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Conclusions and Recommendations a
Results to date support the relation between absorbed dose and urinary elimination rate proposed by the ICRP for U+6 compounds. The completed studies indicate pulmonary retention of UO F22 is extremely short and suggest that the threshold absorbed dose for producing renal injury is
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of the order of 10 ug kg-1 body weight.
' I However, we suggest revision of Regulatory Guide 8.11 be delayed until
,[i the additional studies discussed above are completed. The final report 4
is expected by the end of this fiscal year.
- v For further information on this study, please contact Dr. Judith D. Foulke
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(427-4358).
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Robert B. Minogue, Director
- j Office of Nuclear Regulatory Research i
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