AFRRI 93-1

TECHNICAL REPORT

Assessment of the

Risks from

Imbedded Fragments

of Depleted Uranium

LTC Eric G . Daxon, MS, USA

CPT Jeffery H . Musk, OD, USA

AFRRI TR 93-1

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Armed Forces Radiobiology Research Institute

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Bethesda, Maryland 20889-5603

March 1993

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DEFENSE NUCLEAR AGENCY

ARMED FORCES RADIOBIOLOGY RESEARCH INSTITUTE

BETHESDA, MARYLAND 20889-5145

27 March 1992

MEMORANDUM FOR DIRECTOR, PROFESSIONAL SERVICES, OFFICE OF THE

SURGEON GENERAL (SGPS-PSP)

SUBJECT : Research Request ; Health Effects of Depleted Uranium Imbedded in Tissue

Reference : Brigadier General Ronald R . Blanck (SGPS-PSP) letter of 26 February 1992

In response to your letter of 26 February 1992, subject as above, AFRRI has conducted a

detailed review of the pertinent scientific literature regarding the health effects of depleted

uranium (DU) fragments which are imbedded in tissue . In addition, we have consulted with a

wide range of scientists with expertise in this area . A summary of our findings is attached .

It is clear from our analysis that there are several areas in which there is little or no

scientific data which would enable more definitive risk assessments to be made .

Nevertheless, in order to meet your operational requirements, attachment (1) addresses each of

the issues raised in your letter . To address areas in which there remains substantial scientific

uncertainty, attachment (1) also identifies specific research needs .

Based on available data, in almost all cases, we recommend that standard medical criteria

should be used to determine the advisability of the removal of imbedded DU fragments

without regard to the radiological characteristics of the fragment . More specific guidance is

provided in attachment (1) .

Point of contact is Lieutenant Colonel Eric G . Daxon, Chief, Operational Dosimetry

Division, Radiation Biophysics Department, 301-295-2299 .

Attachment:ROBERT L. BUMGARNER

as statedCaptain, MC, USN

Director
Y4
AFRRI Technical Report 93-1

ASSESSMENT OF THE RISKS

FROM IMBEDDED DEPLETED URANIUM

FRAGMENTS

Prepared by :

Eric G . Daxon, LTC, MS, USA

and

Jeffery H . Musk, CPT, OD, USA

March 1993

Radiation Biophysics Department

Armed Forces Radiobiology Research Institute

8901 Wisconsin Avenue

Bethesda, Maryland 20889-5603

CLEARED FOR PUBLIC RELEASE

Distribution Unlimited

Assessment of the Risks

From Imbedded Depleted Uranium Fragments

1 . General

a. Authority

Letter, Office of The Army Surgeon General, (SGPS-PSP), Subject : Research

Request; Health Effects of Depleted Uranium Imbedded in Tissue, 26 February 1992 .

b. Mission

Assess the health risks associated with implanted DU fragments in the body to

provide medical guidance for current and future patients with these fragments, and

provide recommendations for future research .

2. Background

The primary conclusion of the review of the uranium literature' - '' and discussions with

others17-26 in the field is that this situation is radiologically and toxicologically unique . The

health risks of allowing depleted uranium (DU) fragments or any other radioactive heavy

metal to remain imbedded in an organ have not been studied . The uranium literature

reviewed is focused on inhaled or ingested uranium compounds . There is only one

reported instance of a DU fragment accidentally injected subcutaneously in a patient .

This case, as reported by Cole

'22 .21 provides little information for long-term effects

because the fragment was surgically removed after 8 months .

22,27

3. Chemical Toxicity

The toxicological effects of uranium are well known . The target organ for uranium heavy

metal toxicity is the kidney . The literature concerning the acute effects of uranium heavymetal poisoning on the kidney is extensive and is summarized in recent articles by

Leggett12 , Diamond13 and Kocher. 14 While the generally accepted threshold level for

kidney toxicity is from 1-3 μg of uranium per gram of kidney mass,"

13'14 there is

considerable discussion in recent literature concerning this limit .'

2,13,14

1
A review of uranium toxicology conducted by USAEHA" concluded that, while there was

substantial toxicologic data for inhaled and ingested uranium compounds, there was little

or no data for the metabolic behavior of implanted DU fragments . Key uncertainties

include organ specific solubilities ; organ specific retention functions; the metabolic impact

of a source term other than the lung or GI tract ; the potential for chronic kidney toxicity ;

the impact of fibrotic encapsulation, if it occurs ; and the chemical form of the imbedded

fragment .

The potential for wound contamination (the injection of small sub-millimeter fragments)

and for spallation of small fragments from large fragments introduces two additional

dispersal mechanisms - macrophage transport and the physical movement of intact

particles by the blood stream . The impact of both is an increase in the rate at which

uranium is deposited in the kidney and other organs . De Rey et al .' found insoluble U0 2

particles in the kidney 6 to 48 hours after injection of 4 to 40 micrometer diameter U0 2

micro-spheres into the subcutaneous tissue of the dorsal skin of female rats . This is

significantly quicker than predicted by standard metabolic transfer models for insoluble

compounds of uranium.

These limitations and uncertainties preclude a definitive assessment of the toxicologic

risks of allowing DU fragments to remain in the body for extended periods of time .

4. Radiological Effects

The literature is extensive concerning the deterministic and stochastic effects of acute and

chronic exposure to inhaled and ingested uranium compounds

.', 21-32 The lack of data for

imbedded uranium fragments precluded a direct determination of the potential long-term

radiological effects of these fragments . An estimate of the potential effects was obtained

by reviewing the literature available for plutonium, Thorotrast, and hot-particles .

The plutonium (Pu) literature 33-44 reviewed also focused on inhalation and ingestion, but

there were several studies that dealt with injected plutonium compounds .

Lushbaugh19,34.42 and Langham et al . 42 summarize the findings of studies of eight patients

with injected plutonium . Lagerquist et al . 43 and Carbaugh et al . 44 discuss patients with

plutonium contamination of puncture wounds . While these studies are somewhat useful,

their usefulness is limited because the exposure duration was relatively short (the longest

was 5-8 years), the particle sizes were small, and in each case the wounds were

debrided to removed the injected plutonium . For both the animal and human studies, the

plutonium injected was in the form of the fine particulates expected from injection wounds

caused by contaminated, sharp tools .

2
The Thorotrast literature is extensive'

34,47-62 and important because of the radiological

similarities with the situation under study . Thorotrast is a colloidal suspension of thorium

dioxide (ThO2) that was used as an intravenously-injected contrast agent for radiographic

imaging from the late 1920's until the late 1950's when its long-term radiologic health

effects became apparent

.11,4' The Thorotrast literature provides the most definitive

evidence that both clinically-significant deterministic and stochastic effects are possible

from long-term irradiation of low dose-rate a and (3 emitting radionuclides .

However, the differences in particle size and chemical properties between Thorotrast and

DU are significant enough to preclude a direct application of the data . The ThO2 particles

in Thorotrast were small enough (nanometers in size) to be engulfed by both the mobile

and fixed macrophages in the reticuloendothelial (RE) system which led to a time

dependent, selective concentration in the liver and spleen . This time dependence makes

dose-dependent extrapolations from Thorotrast data to a DU fragment difficult . In

addition, the selective retention by the RE system limited the exposure to the organs in

this system.

Although directed specifically at the radiation effects on the skin of a highly radioactive,

beta-emitting particle, the hot-particle research literature" -" provides valuable information

concerning the differences between the highly nonuniform irradiation that results from an

imbedded fragment and the results of the uniform organ irradiation upon which

assessments of radiation risk are based . Specifically, the hot particle research sheds light

on the relationship between the fraction of an organ system irradiated and the dose

required to produce both deterministic and stochastic effects. The primary conclusion of

this work is that the radiation risk of both endpoints is dependent upon dose and the

number of cells irradiated .

Based upon this review, the following radiobiological effects are possible from imbedded

DU fragments.

a. Granuloma Production

Cole's", " experience and Lushbaugh's

19,34,42 work indicate that granuloma

production in the muscle and fatty tissue will probably occur and will occur in all other

tissue types that elicit similar cellular responses to foreign bodies . It is still questionable

whether this encapsulation is permanent or will undergo the degradation-regeneration

cycle suggested by Lushbaugh for the plutonium cases he studied .

The data to date are insufficient to allow a determination of whether Thorotrastoma-like

growths are possible . A Thorotrastoma is a large growth that appears at the sites of

extravascular Thorotrast with a latent period of from 5-35 years postinjection17,47,48,53,60

These granulomas grow to large sizes ; in a few cases, clinically significant blood vessels

and/or nerves were enveloped, resulting in fatal conditions . 24 While a strictly chemical

causation cannot be dismissed, there is sufficient evidence to suggest a radiogenic

mechanism .

3
b. Local Tissue Necrosis

The results of the Thorotrast, lung inhalation studies, and animal studies showed

that local tissue necrosis followed by fibrosis was possible from the long-term irradiation

of tissues by a low dose-rate, a and (3 emitting radionuclide .

Dose estimates made at AFRRI based upon published data

71,71,71,71 indicated that the

probability of deterministic effects at distances greater than 1-3 mm from the surface of

any fragment is negligibly small . Depth-dose calculations indicated that at the distances

from the surface of all particle sizes studied (1-4 mm in diameter) the dose-rates were

less than the repopulation dose-rate for non-proliferative cells provided by the ICRP 28 (1-5

mGy/d) . The assumption in this analysis is that at distances greater than this,

deterministic effects will not occur because cell repopulation will compensate for cell

death for most tissue types . The most notable exception to this assumption is mature

neural tissue, the neurons of which do not usually have a proliferative potential .

The clinical significance of necrosis at distances closer to the fragment is dependent upon

the location of the fragment and the body's response to the fragment . Lushbaugh,34 in

his analysis of cases of injected plutonium, found that " . . .metallic plutonium implanted in

the skin in minute amounts elicits a foreign-body reaction of the granulomatous type,

which after subsiding in cellular activity becomes fibromatous ." As time progressed, the

collagen in the vicinity of the fragment liquified .

Lushbaugh speculated that the "pointed" nature of the granulomas he found and the fact

that the granulomas became more superficial, suggested that the altered collagen might

induce a cycle of inflammatory reaction followed by a reorganization and re-liquefaction

of the collagen .

c . Whole-Organ Deterministic Effects

The potential for multiple fragments in a single organ led to the examination of the

potential for whole-organ deterministic effects . A whole-organ deterministic effect is

defined as one in which there is a clinically significant compromise of organ function due

to the ionizing radiations emitted by one or more DU fragments .

The appearance of whole-organ deterministic effects from acute, high dose rate exposure

is well documented . Mettler and Mosely, 75 Conklin and Walker ' 76 and ICRP 41 28 provide

excellent summaries with extensive bibliographies for whole-organ deterministic effects

based primarily on examination of the Japanese atomic bomb survivors, radiation accident

victims, and radiation therapy patients . Direct extrapolation from high dose rate, acute

exposure to low dose rate protracted exposure is difficult because of the dose rate

dependence of the threshold dose required to produce a deterministic effect .

28

4
The results of inhalation studies with uranium and plutonium summarized in ICRP 31

30

and in other references'

1,33,11 show that whole organ deterministic effects are possible

from inhaled particulates . The Thorotrast studies',","-" provide the clearest evidence that

deterministic effects are possible from protracted exposures to low dose rate internal

alpha emitting isotopes . These studies showed that both fibrosis of the spleen and

cirrhosis of the liver could be related to the radiation emitted by the thorium dioxide

(ThO2) in the Thorotrast . The latent period for the onset of clinically significant liver

cirrhosis was on the order of 20 years after Thorotrast administration . 57 The latent period

for significant spleen fibrosis was not reported but is assumed to be comparable .

A dose calculation, made using similar methodology as described above, showed that the

risk of whole-organ stochastic effects do not become significant until the fragment density

in the organ exceeds one fragment per cm 3 of organ volume for the fragment sizes

considered (1-4 mm diameter) . At particle densities greater than this, the average dose

rate in the organ will exceed the repopulation dose rate for non-proliferative cells .

d . Stochastic Effects

The standard ICRP stochastic-risk-estimation methodology77 is directly applicable

for systemic DU but can be used only with caution when assessing the risks of imbedded

DU fragments . There are several unknowns that could cause this and similar procedures

to either overestimate or underestimate the stochastic risks . Included are these specifics :

(1) The hot-particle research indicates that the risk from an imbedded

fragment could be significantly less because fewer cells are irradiated . ICRP

methodology assumes that the dose is uniformly distributed over all of the cells in the

organ while a DU fragment will irradiate only the cells within a finite range of the

fragment.

(2) The Thorotrast experience showed evidence that the constant irradiation

of the same cell population could increase the risk by adding necrosis-regeneration as an

additional cancer induction mechanism . This mechanism is not considered in the ICRP

models or cancer risk estimates .

An estimate of the stochastic risk posed by an implanted, insoluble fragment was made

by calculating the effective dose equivalent (HE ) for a range of fragments (1-4 mm) for

each organ listed in ICRP 60 . 31 The actual organ weights were used to calculate the

dose as were the actual weighting factors (WT) . The calculation was performed assuming

that alpha dose could be ignored because the energy of these particles will be expended

producing lethal damage to the cells adjacent to the fragment and thus contribute nothing

to the stochastic risk .

5
For the largest fragment size evaluated (4 mm), the highest HE 'Sin

the thyroid because

of its relatively small mass . In this case, H E is 1 mSv/y (100 mRem/y) . Using current risk

estimates, 32 these values represent an increase in lifetime risk of fatal cancer of 0 .3%.

The value for other organs will be substantially lower because of their larger masses .

At this point in the discussion, it is important to recognize that this risk estimate is based

upon a single, insoluble fragment imbedded in an organ and does not include the risk

from systemic DU .

5 . Conclusions

a. Chronic kidney toxicity is a potentially clinically significant health effect from

imbedded DU fragments . While the toxicology of uranium in the kidney is well known,

little is known about the toxico-kinetic behavior of imbedded uranium . This information

is required to make definitive estimates of both the toxicological and radiological risk .

b. Based upon the literature reviewed, the potential exists for both stochastic and

deterministic radiation effects from the long-term exposure to imbedded DU fragments .

(1) The most clinically significant, radiogenic effect is the potential for a

Thorotrastoma-like growth to form at the site of single or multiple imbedded-fragments .

The risk, if any, of this growth formation cannot be estimated . It is still uncertain whether

this is a radiation effect or an effect due to the chemical nature of the Thorotrast colloid .

(2) The risks of fragments near neural tissues should be carefully assessed

because of the nonproliferative nature of these cells .

(3) The potential does exist for whole-organ deterministic effects but only

for organs with a large number of imbedded fragments . The point at which this effect is

likely to occur requires a detailed estimate of the dose to the organ from all sources of

DU . First order, dose estimates indicate that particle densities greater than one fragment

per cm3 of organ volume are required as long as the fragments are insoluble and there

are no other sources of DU in the body . Fragment sizes considered in this calculation

range in diameter from 1-4 mm .

(4) Using the best risk estimation procedures available, the estimated

increased lifetime risk of fatal cancer from a single, insoluble, DU fragment in any organ

is at most 0 .3% . Scaling this risk for multiple fragments or fragments with systemic DU

is difficult and should be done on a case-by-case basis after assessing the total DU

content in the patient .

6
c . The toxicological and radiological unknowns are significant enough to warrant

both follow-up of current patients and research to more clearly define the long-term risks

associated with these fragments . This is especially important in light of the latent periods

noted for both deterministic and stochastic radiogenic effects .

6. Clinical Recommendations

a. The primary clinical recommendation is to continue to use standard medical

criteria for fragment removal . Include consideration of the potential impact of a

granuloma or a Thorotrastoma-like growth as a part of the decision making process for

fragment removal as well as the potential for tissue necrosis for fragments lodged in or

within 1-3 mm of neural tissue .

b. Determine the total amount of DU in the patient and continue to monitor

patients with confirmed DU fragments for signs of kidney toxicity and any of the

radiological endpoints discussed . Monitoring is required primarily because of the

toxicological but also because of the radiological uncertainties .

c. If fragments are excised based upon accepted clinical criteria, save the

fragment and surrounding tissue for further analysis .

7. Research Recommendations

a . Epidemiology

Establish a registry that will allow for the efficient acquisition, cataloging, and

analysis of the results of patient monitoring . This effort should include

(1) periodic examinations to watch for and catalogue signs of chronic kidney

toxicity, granuloma induction, and cancer;

(2) periodic bioassay and whole-body counting to determine the metabolic

behavior of the internalized DU and to provide information concerning the solubility of the

DU ; and

(3) a program for tissue analysis if fragments are subsequently removed for

medical reasons.

7
b. Animal Model Experimentation

The primary objective of animal model experimentation is to allow a detailed

observation and study of the pathology of these fragments under controlled conditions .

The specific objectives of this experimentation should include the following steps :

(1) Accurately assess the toxico-kinetic properties of the various chemical

forms of DU that could be imbedded in patients .

(2) Investigate whether there are DU specific cancer induction mechanisms

similar those observed in Thorotrast-specific liver cancers .

(3) Determine whether the radiogenic deterministic effects noted above

occur and, if they do, at what fragment densities and latent periods .

(4) Assess the impact of long-term, low-dose-rate irradiation of specific

tissues such as those of the nervous system .

(5) Determine the potential for chronic nephrotoxicity as a function of organ

in which the DU is implanted

(6) Conduct pathological studies of the tissue surrounding the fragment .

c. Dosimetry

Perform definitive absorbed dose calculations using advanced techniques to

determine the significance of particle size and shape .

8
Acknowledgements

This document could not have been prepared in the time frame allotted without the expert

assistance the authors received from scientists at AFRRI and from the scientific

community at large . The expert critique and many fruitful discussions with CDR E .

Kearsley, AFRRI, are gratefully acknowledged and were keys to the successful

completion of this document . The keen radiobiological insights provided by Dr . E. J .

Ainsworth, AFRRI, and Dr . P . Durbin, Lawrence Berkeley Laboratory, showed the way

for many of the approaches taken in this work . A special note of thanks is due to Dr .

Durbin for her excellent discussion of the applicability of the Thorotrast data to this work .

The medical advice of Dr . R . Bumgarner, AFRRI, and Dr . D . Browne, AFRRI, was crucial

in forming the clinical recommendations of this work . The review and advice given by

CAPT W. Flor and Dr . R . Young, RARP, DNA, are gratefully appreciated . The experience

of Mr. L . Cole (Aerospace Ordnance) with imbedded DU fragments was instrumental in

the formation of one of the major conclusions of this report .

The efforts of Mr . M . Weeks, USAEHA, in reviewing the uranium toxicology literature were

superb . His expertise and keen insights in this area were indispensable . Mr. R . Swatski,

USAEHA, deserves a note of thanks for his assistance in bioassay techniques .

The insights and expertise of Dr . N . Wald and Mr . J . Rosen, University of Pittsburgh,

concerning the need and methodology for quantifying DU in the body contributed

significantly to the direction of this project .

As always, the personnel of REAC/TS were exceptionally helpful and shared both their

time and expertise . A special note of thanks is due to Dr . Fry, Dr . Lushbaugh, and Dr .

Ricks .

The scientists at the Inhalation Toxicology Research Institute (ITRI) and the Pacific

Northwest Laboratories (PNL) Hanford Laboratories were especially helpful in sharing

both their data and insights into this problem . A special note of thanks is due to Dr . B

Scott, ITRI, Dr . R. Guilmette, ITRI, Dr . E . H . Carbaugh, PNL, Dr . G . Dagle, PNL, and Dr .

M . Swint, PNL .

The contributions of the Army personnel from the Walter Reed Army Medical Center

(WRAMC) and Uniformed Services University of the Health Sciences (USUHS) are

gratefully acknowledged . The work of CPT M . Melanson, WRAMC, Dr . Philips, WRAMC,

and Dr. C . Ferguson, USUHS contributed to this effort .

9

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1 1
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