SOURCES, EFFECTS AND RISKSOF IONIZING RADIATION
United Nations Scientific Committee on the
Effects of Atomic Radiation
UNSCEAR 2016
Report to the General Assembly,
with Scientific Annexes

UNITED NATIONSNew York, 2017

NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Seventy-first Session, Supplement No. 46 and corrigendum (A/71/46 and Corr.1). The
report ­reproduced here includes the corrections of the corrigendum.
The designations employed and the presentation of material in this publication do not imply
the expression of any opinion whatsoever on the part of the Secretariat of the United Nations­
concerning the legal status of any country, territory, city or area, or of its authorities, or­concerning the delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those that were in use at the time thedata were collected or the text prepared. In other cases, however, the names have been updated,
where this was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
Sales No. E.17.IX.1
ISBN: 978-92-1-142316-7
eISBN: 978-92-1-060002-6© United Nations, January 2017. All rights reserved, worldwide.
This publication has not been formally edited.
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Corrigendum to Sales No. E.17.IX.1
18 May 2018

Sources, Effects and Risks of Ionizing Radiation:
UNSCEAR 2016 Report to the General Assembly,
Scientific Annexes A, B, C and D
Corrigendum
Annex D, page 438, paragraph 319, last line
should read
(18.6 mBq/d) and not (18.6 mBq/L)

V.18-03158*1803158*

ANNEX D
BIOLOGICAL EFFECTS OF SELECTED INTERNALEMITTERS—URANIUM

361

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM

363

CONTENTSI.

INTRODUCTION ................................................................................................................................. 365

II. SOURCES AND LEVELS .................................................................................................................... 367
A. Natural sources .......................................................................................................................... 367
B. Artificial sources ........................................................................................................................ 374
III. PHYSICAL, RADIOLOGICAL AND CHEMICAL CHARACTERISTICS ..................................... 378
A. Physical and radiological characteristics .......................................................................... 378
B. Chemical characteristics......................................................................................................... 379
IV. HUMAN EXPOSURE .......................................................................................................................... 380
A. Exposure of members of the public ................................................................................... 380
B. Occupational exposure .......................................................................................................... 382
C. Measurement of uranium ...................................................................................................... 382
V. BIOKINETICS........................................................................................................................................ 383
A. Inhalation..................................................................................................................................... 384
B. Ingestion ...................................................................................................................................... 385
C. Absorption .................................................................................................................................. 386
D. Systemic distribution, retention and excretion ............................................................. 386
E. Materno-fetal transfer ............................................................................................................. 387
VI. DOSIMETRY ......................................................................................................................................... 388
VII. BIOLOGICAL EFFECTS ...................................................................................................................... 390
A. Chemical versus radiological toxicity ................................................................................ 390
B. Kidneys ......................................................................................................................................... 391
C. Bone............................................................................................................................................... 397
D. Lungs ............................................................................................................................................. 399
E. Liver ............................................................................................................................................... 400
F. Brain............................................................................................................................................... 401
G. Reproduction and development ........................................................................................ 405
H. Other organs .............................................................................................................................. 408
I.

Relative biological effectiveness ......................................................................................... 414

J.

Lethal effects .............................................................................................................................. 414

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VIII. EPIDEMIOLOGICAL STUDIES......................................................................................................... 416
A. Studies of occupational exposure ...................................................................................... 416
B. Studies of Gulf War veterans ................................................................................................ 433
C. Studies of environmental exposure................................................................................... 434
IX. RESEARCH NEEDS ............................................................................................................................. 437
X. GENERAL CONCLUSION ................................................................................................................. 438
XI. ACKNOWLEDGEMENTS .................................................................................................................. 439
APPENDIX A. TABLES SUMMARIZING URANIUM LEVELS IN WATER, STUDIES OF
OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE TO URANIUM ...................................... 441
REFERENCES............................................................................................................................................... 467

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 365

I. INTRODUCTION
1.
This annex provides a review of the scientific literature on characteristics of uranium, its
biokinetics and dosimetry within the human body for various physical and chemical forms and routes ofintake into the body, radiobiological and toxicological effects of exposure to uranium, andepidemiological studies of nuclear workers and the public who have been exposed to uranium.
2.
Uranium was discovered by Martin Heinrich Klaproth in 1789 and its radioactive properties by
Antoine Henri Becquerel in 1896. Uranium, element 92 in the periodic table, is present naturally in allrock and soil. Levels of uranium content in soil depend on local geology and range widely from a
few mg/kg up to levels of several per cent in ore bodies. The Committee in its UNSCEAR 2008 Report[U10] reported a median activity concentration of around 30 Bq/kg (1.2 mg/kg) for uranium in rock andsoil. Uranium is released to the environment through natural events such as forest fires and volcanoes
and released from rock and soil through natural processes. It is distributed through mechanisms such asleaching to ground and surface water and through wind erosion of soil. In turn, uranium in water, soil
and air is taken up by plants and animals. People may be exposed to uranium by inhalation of airborne
particulates, through skin uptake and through ingestion of uranium in food and water.
There are three naturally-occurring, alpha-particle emitting, isotopes of uranium: 238U, 234U and235
U. Two of these, 238U and 235U, with radioactive half-lives of 4.47 × 109 and 7.04 × 108 years
respectively, are the parents of radioactive decay chains that are major contributors to the backgroundradiation exposure of the human population. Uranium-238 supports 14 decay products. The isotope
234
U, with a half-life of 2.45 × 105 years, is a member of the 238U decay chain. In natural uranium, 238U
is the most abundant isotope in terms of mass (99.2742%), while 234U and 235U constitute only 0.0054%
and 0.7204%, respectively [N8, S15]. Figure I shows a simplified radioactive decay chains for 238U.
Other isotopes, such as 232U, may be produced in thorium breeder reactors. Further, 236Uranium, with ahalf-life 2.35 × 107 years, is present in spent nuclear fuel and in reprocessed uranium [W24], and occurs
naturally as a very small component of natural uranium (<10−11% by mass).
3.

4.
Both 238U and 234U, when in secular equilibrium, contribute 48.9% of the total alpha particle
activity of natural uranium, while 235U contributes 2.2%. Some nuclear reactors require fuel that isenriched to the fissionable isotope 235U. Current technologies for enriching natural uranium are gaseous
diffusion and centrifugation. Enrichment increases the proportion of 235U from its natural levels(0.72%) to 2–5%, depending on the design requirements of nuclear power reactors. In addition, higher
enrichment levels (>90% of 235U) are achieved for use in weapons. The term depleted uranium (DU)
refers to isotopic mixtures that contain a lower percentage of 235U than is present in naturally occurring
uranium. It is recovered as a by-product of the enrichment process. The proportion of 235U in DU is
between 0.2 and 0.3%. Reprocessed uranium (especially from earlier military reprocessing) may also be
contaminated with traces of fission products and transuranic elements [W24].
5.
Uranium compounds exhibit differences in their chemical and physical properties and, as a result,also differ in their toxicological properties. For example, uranium compounds vary widely in theirsolubility and this can result in differences in bioavailability following intake (via inhalation oringestion) into the body [A31, L9, S37, U16]. The biological and health effects of uranium are due toits chemical and radiological toxicity. In general, this toxicity, as demonstrated in animal studies, iscaused by chemical rather than radiological components, excepting that effects induced by the isotopesof higher specific activity and by enriched uranium are more probably due to radiation exposure.

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6.
Since 1949, many animal studies have indicated that the toxicity of uranium is due mainly tochemical damage to the kidneys [A25]. Other systems or organs may also be affected by exposure touranium, such as the skeleton [A26], the lungs [L18], the gonads [A19] and the liver [P6].
Figure I. Radioactive decay chain for 238U [I17]
Half-life is expressed in a = year; d = day; h = hours; m = minutes; s = seconds

7.
Uranium concentrations in environmental media may be measured in terms of radioactivity(measured in Bq/L, e.g. by alpha spectrometry) or mass (measured in µg/L, e.g. by high-resolution
inductively coupled plasma mass spectrometry). Consequently, data on uranium levels in soil, air, waterand food are indicated in Bq/L and in µg/L.
8.
A general concept is the relation between radioactivity and mass. As mentioned above, theactivity of each member of a chain headed by a parent radionuclide would be the same under conditionsof secular equilibrium, but the mass of each member of the chain would be quite different. The
relationship between activity, A, and mass, M, of a radionuclide is given by:
2
/

where



A =
A0 =
AW
 =
T1/2
M =

activity of a radionuclide, Bq;
Avogadro’s constant, 6.023 × 1023 atoms/mole;=atomic weight of the radionuclide, kg/mole;decay constant, dis/(atom s);=
half-life of the radionuclide, s;mass of the radionuclide, kg.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 367

For natural uranium, the activity is 25,400 Bq/g (table 1). However, as shown in table 1, the natural
relative abundance of 234U, 235U and 238U can be expressed in terms of either numbers of atoms or
weight, giving slightly different values [K3, M31, M32].
Table 1. Mass activities of the three natural isotopes of uranium [K3]
Relative abundance
Natural uranium
238
235
234

atoms% (wt%)

mBq/μg U

U

99.274 (99.284)

12.40

U

0.720 (0.711)

0.60

U

0.0054 (0.0053)

12.40

II. SOURCES AND LEVELS
A. Natural sources
1.

Levels in soil

9.
Naturally occurring radionuclides in the environment affect the levels of background radiationencountered at different locations around the world [N2, U8]. As mentioned by Cuney [C38], three
types of deposits contain more than three quarters of the worldwide uranium resources: unconformityrelated deposits, iron oxide–copper–gold (IOCG) deposits, and sandstone-hosted deposits [L10].
10. The concentration of uranium in soil varies with location and local geology. Its concentration isrelatively low in basic rock, such as basalt, and higher in acid rock, such as the sedimentary rocksaturated with silica. The uranium content of granites is higher still [U10]. For example, the nominal
activity concentration of uranium in soil is about 15 Bq/kg of 238U (1.2 mg/kg) with a typical activity
range of 10–50 Bq/kg (0.4 to 2 mg/kg) [N2, U10]. Much higher concentrations are found in uranium
mining areas such as the Northern Saskatchewan in Canada, the Colorado Plateau and central Florida
where phosphate is mined. The uranium content of phosphate rock used for phosphate fertilizers ranges
from about 50 to 2,400 Bq/kg of 238U (4–190 mg/kg) [A31, N2, R20, U8]. One of the highest activity
concentrations worldwide is localized in the region of Recife in Brazil, with sedimentary rock that
contains 30–500 mg/kg with an average of 150 mg/kg (1,860 (range 372–6,200 Bq/kg of 238U)) [S18].
However, since uranium in soil may be more or less tightly bound depending on soil characteristics, theuranium speciation in soil has an impact on bioaccessibility in the gut.

2.

Levels in air

11. Soil particles containing uranium may be transferred into the atmosphere through natural
mechanisms. The natural uranium concentration in air is typically very low, varying from location tolocation according to local ground sources [H19]. Airborne uranium can deposit on soil, plants andopen water as dry or wet deposition [A31].

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12. Golchert et al. [G16] measured airborne concentrations of 238U of around 0.3 Bq/m3 at a site near
the Argonne National Laboratory (Illinois, United States). Average levels of natural uranium in ambient
air have been reported to be 0.25 µBq/m3 of 238U (0.02 ng/m3) in Tokyo [H19]. Tracy and Prantl [T17]found the average concentration of 238U in air in a southern Ontario rural environment to be about
1.25 µBq/m3 (0.1 ng/m3), on the basis of measurements of 226Ra in dust and an assumption ofequilibrium between 238U and 226Ra. Taken together, these different values indicate an average uranium
level in air of around 1 µBq/m3.
13. The World Health Organization (WHO) [W14] estimates that an adult of average size inhales
20 m3 of air per day with a nominal natural uranium concentration of 0.6 µBq/m3 of 238U (0.05 ng/m3),
corresponding to 12.4 µBq (1 ng) of 238U. These values lead to a calculated annual intake throughinhalation by adults of approximately 0.0045 Bq of 238U. For comparison, tobacco smoke (from two
packages of cigarettes per day) contributes to 0.11 Bq of 238U (corresponding to 9 µg) of inhaled naturaluranium per year [L49].

3.

Levels in water

14. As long as uranium is inside undisturbed crystalline rock in secular equilibrium with its progeny,
the ratio of 234U to 238U is expected to be one. Nevertheless, disequilibrium can be observed when rockis disturbed by chemical or physical processes involving water. As a result, water from any source may
contain 234U/238U ratios greater than unity because of the greater mobility and increased availability of
234
U, generally due to a reducing environment [D1]. Two isotopes in the decay series, 234Th and 234mPa,
separate the two uranium isotopes and their different solubilities in the source rock, permitting 234U to
be released preferentially and leading to variations in the ratio 234U/238U [O9]. In addition, the total
uranium activity present in water may influence the 234U/238U ratio. Indeed, Ortega et al. found that
~80% of samples with a high ratio of disequilibrium (>1.6) were linked to the lowest uranium activities<50 mBq/L, when the samples with a low activity ratio (<1.5) corresponded to samples with highconcentrations of uranium (>200 mBq/L) [O8].
15. Uranium is present in different water sources (surface water, groundwater and drilled water) at
variable levels [W16]. In oxygenated surface water, uranium levels were found at around 0.02 to 6 µg/L
(0.25–76 mBq/L of 238U). In sea water, its average content is 3.3 µg/L (42 mBq/L of 238U), often boundby ligands or associated with suspended particles [B42]. Natural uranium levels were found to behigher in Precambrian rock aquifers (average, 115.6 µg/L (1.45 Bq/L of 238U)) than in Palaeozoic
sedimentary rock aquifers (average, 3.5 µg/L (0.045 Bq/L of 238U)). Cothern and Lappenbusch [C34]reviewed the available data on the occurrence of uranium in surface and groundwater supplies in the
United States and reported that surface water samples derived from about 35,000 sources had an
average uranium concentration of 18 mBq/L of 238U (1.45 µg/L) (range from 0.18 to about
12,500 mBq/L of 238U (0.014–982 µg/L) and that about 55,000 samples of groundwater supplies had an
average uranium concentration of 55 mBq/L of 238U (4.4 µg/L) (range −0.018–12,000 mBq/L of 238U
(0.0014–942 µg/L)).
16. The WHO indicated values for uranium levels in water generally less than 12.4 mBq/L of 238U(<1 µg/L) [W15, W18]. The Agency for Toxic Substances and Disease Registry (ATSDR) reported anaverage concentration of 14.4 mBq/L of 238U (1.16 µg/L) [A31]. This was much higher than thepreviously reported value by the Committee in its UNSCEAR 1977 Report 0.54 mBq/L of 238U
(0.044 µg/L) [U7]. Thus, it might be more appropriate to report median rather than mean values
because of the large variation of uranium concentration in water. The Committee reported a variation ofnatural uranium concentrations measured in drinking water samples in 16 countries of about eightANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 369

orders of magnitude [U10]. A global overview of uranium concentration (µg/L) and activity (mBq/L) is
given in appendix A, in table A1 for the values measured in groundwater, in table A2 for the values
measured in surface water, in table A3 for the values measured in public water supplies and in table A4
for the values measured in bottled mineral water.
17. In Canada, different surveys aimed to measure uranium levels in drinking water in different
provinces. The mean natural uranium concentration in surface water and groundwater (some treated)
supplies was about 50 mBq/L of 238U (4 µg/L) in southern-central British Colombia [P32], 124 mBq/Lof 238U (10 µg/L) in south-eastern Manitoba [B21], 65 mBq/L of 238U (5.2 µg/L in the Kitigan Zibi First
Nation community in Quebec) [M58], and 5 mBq/L of 238U (0.40 µg/L) in Ontario [O3]. In summary,the analysis of the different values measured in these surveys indicates that mean uranium levels in
drinking water were extremely variable in the different Canadian counties/provinces, from 5 to
750 mBq/L of 238U (0.4–58.3 µg/L), including great internal variations depending on the precise
location. Furthermore, behind these average uranium levels in drinking water, more extreme values
were measured in some Canadian provinces or some counties in the United States as indicated inappendix A, table A1. In fact, natural uranium concentrations as high as 8,680 mBq/L of 238U
(700 µg/L) were found in private groundwater supplies [M64, M65]. A value of 25,048 mBq/L of 238U
(2,020 µg/L) was measured in groundwater in south-eastern Manitoba [B21].
18. Concerning water in the United States, official reports indicated an average natural uranium
concentration of 31.6 mBq/L of 238U (2.55 µg/L) in drinking water from 978 sites in the 1980s [U14].
These values are higher than those mentioned in a study by Fisenne et al. with mean activity of naturaluranium in drinking water in New York City ranging from 0.62 to 1.25 mBq/L of 238U (0.05 to
0.09 µg/L) [F5]. In this study, New York city tap water had 234U, 235U and 238U activities of 1.040.19,
0.0350.010 and 0.870.18 mBq/L, respectively [F5]. Maximum values were measured in Connecticut
86.472 mBq/L of 238U (7,780 µg/L). As for Canada, differences may relate to geographical variations
and local geology (appendix A, table A1).
19. In Finland, national and local surveys of uranium content in water distributed by Finnish
waterworks have been conducted. The median value was of 1.9 mBq/L of 238U (0.15 µg/L) [T22](appendix A, table A1). An extreme value of 114,100 mBq/L of 238U (9,200 µg/L) was measured in theSouth of Finland [M66]. It is noteworthy that although the uranium concentrations in Finnish wells
drilled in bedrock are among the highest in the world [K26, M66, M67, P28], the uranium
concentration in water distributed by the waterworks is generally low [M67, T22].
20. In France, periodic reports address the levels of the radiological quality of drinking water [I21].
Measurements performed during 2008 and 2009 indicate that 226Ra and uranium isotopes constitute themain contributors to a total alpha activity above 0.1 Bq/L; in this case, the mean value of uranium
concentration was 2.22 µg/L (27.5 mBq/L of 238U) with a range from 0.14 to 114 µg/L
(1.8-1,450 mBq/L of 238U) [I21].
21. Activity concentrations of natural radionuclides in soil, food, natural and drinking water were alsomeasured in China [P2]. However, measurements of uranium were not reported for food and drinking
water. Except for salt water lakes that presented higher uranium levels (22 µg/L or 272.5 mBq/L of
238U), the values for uranium in freshwater lakes, reservoirs, rivers, hot and cold springs, well water andsea water were similar (2.2 µg/L with a range from 0.87 to 3.82 (27.3 mBq/L of 238U with a range from10.78 to 47.3 mBq/L of 238U).
22. The guidance levels of radionuclide concentration provided in the WHO Guidelines for DrinkingWater Quality are based on an individual dose criterion (IDC) of 0.1 mSv committed effective dosefrom one year’s consumption of drinking water. They are expressed as activity concentration for a

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UNSCEAR 2016 REPORT

given isotope (Bq/L) and were calculated by dividing the IDC of 0.1 mSv per year by the product of theisotope dose conversion factor (Sv/Bq) and an assumed water consumption of 2 L per day (i.e. 730 L
per year). The guidance levels of radioactivity concentration for 238U and 234U have been rounded to
10 Bq/L and 1 Bq/L, respectively [W18].
23. Due to the fact that the uranium chemical toxicity is generally of greater importance thanradiological effects, several national and international guidelines refer to concentrations of uranium indrinking water, as indicated in table 2. Guideline values (in mg/L or µg/L) were derived from the total
tolerable daily intake (TDI) expressed in mg/kg or µg/kg of body weight (e.g. 60 kg for an adult usedby WHO), itself based on the no observed adverse effect level (NOAEL)1 or lowest observed adverse
effect level (LOAEL) for kidney toxicity, divided by an uncertainty factor of 100 (for intra- andinterspecies variation), and taking the daily drinking water consumption into account (~2 litres) [W16].
Table 2. National and international guidelines for uranium content in drinking water
Only chemical aspects of uranium toxicity are addressed in these guidelines

Organizations/countries

Uranium in drinking water (μg/L)

Reference

Australia

17

[N5]

Bulgaria

60[E2]

Canada20[H16]

Finland100[E2]

Germany

10[B27]

Slovenia

6.8

[E2]

USA

30

[U17]

WHO

30

[W18]

24. The WHO chemical guideline value for uranium in drinking water significantly increased from
2 µg/L in 1998 up to 15 µg/L in 2004 and then to 30 µg/L in 2011 [W18]. The current WHO chemical
guideline of 30 µg/L is still designated as provisional because of scientific uncertainties regarding
uranium toxicity, notably with regard to possible carcinogenic effects of uranium [A17] and specificsensitivity of some groups, such as children or people with hypertension or osteoporosis [F15].
25. Tables A1–A4 in appendix A show that uranium concentrations may exceed guideline values inseveral countries, including those of water from public supplies. In a study of 476 Norwegiangroundwater samples, 18% had natural uranium concentrations in excess of 20 μg/L (0.25 Bq/L of 238U)[F12]. Natural uranium concentrations in groundwater in excess of 20 μg/L (0.25 Bq/L) have also beenreported in parts of New Mexico, the United States [H5], central Australia [F9] and France [I21]. Some
Finnish studies noted a median uranium concentration of 28 μg/L (0.35 Bq/L of 238U) and 285 μg/L
(3.5 Bq/L of 238U) in drinking water [K26, P28], respectively. In Canada, one study also reported highlevels of uranium concentration up to 845 µg/L (10.5 Bq/L of 238U) in private wells [Z8].
26. In a Canadian study, Zamora et al. [Z6] found that water contributed 31–98% of the total daily
intake of uranium from food and water for individuals whose drinking water contained uranium atconcentrations ranging from 2 to 780 µg/L (25 to 10,000 mBq/L of 238U). This was similar to values
1
NOAEL: the greatest concentration or amount of a substance that causes no detectable adverse alteration in morphology,functional capacity, growth, or life span of the target organism under defined conditions of exposure [W13].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 371

obtained in studies by the United States Environmental Protection Agency, which reported that uranium
in drinking water contributed about 31% [U13, U14] of the total daily uranium intake.
27. In summary, uranium average levels in water worldwide are: 2 µg/L (15 mBq/L of 238U) for
groundwater (appendix A, table A1), 1 µg/L (12.4 mBq/L of 238U) for surface water (appendix A,
table A2), 1 µg/L (12.4 mBq/L of 238U) for public water supplies (appendix A, table A3), 0.5 µg/L
(6.5 mBq/L of 238U) for bottled mineral water (appendix A, table A4) (for natural uranium of
25,400 Bq/g). These median values hide great variability, notably for groundwater (0.0005–7.780 µg/L
(0.0063–96,472 mBq/L of 238U)). However, overall only a small proportion of few drinking water
samples (generally <3%) exceed the national or international guidelines. As expected, the values foruranium content in bottled mineral water are not so scattered.

4.

Levels in food

28. The measurement of the bioaccumulation of uranium in animals and plants shows thatconcentration factors are dependent on organism characteristics (e.g. species, life stage, physiology),
exposure pathways, and the chemical and physical characteristics of the environment [G4, Q2]. Various
publications have reported that the most available forms of uranium in plants were phosphate,
carbonate, sulphate or citrate forms [L14, L15].
29. Most available data relate to transfer through plants from their roots and the direct contamination of
aquatic organisms. Within plants, uranium concentrates mainly in the roots. Uranium found in meat anddairy products results from livestock feeding on plants and on food supplement made from natural
phosphates and supplied to dairy cows. Ingestion of soil particles, either directly or through consumptionof grass contaminated with soil, is likely to be a significant component of the total intake by livestock.
Transfer parameters of natural uranium are known for the main meat-producing species (cattle, sheep andpigs) and also for cow’s milk [I1]. They vary between 3.9 × 10−4 and 7.5 × 10−1 day/L in bovine meat andpoultry, respectively.
30. Uranium has been detected in a variety of foodstuffs, with great variability. The 238U activity has
been estimated to be 100-fold higher in root vegetables than in fruit or leafy vegetables as shown, forexample, by measurements for beets and tomatoes (100 vs. 1.13 mBq/kg, respectively) [I2]. A synopsis
of the activity of 238U measured by different authors in several types of foodstuffs is contained in theCommittee’s 1977 Report and in its 2000 Report [U7, U8]. Meat products have the lowest uranium
activity (between 0.08 and 20 of 238U mBq/kg). A recent report indicated activities of 238U between
1 and 49 mBq/kg for meat products [R11].
31. An estimate of daily uranium ingestion of food was made in Japan for urban residents [K30].
Concentration of 238U varied between 9.9 × 10−5 and 5.9 Bq/kg depending on food types: grain vinegar
and boiled and dried hijiki (a brown sea vegetable), respectively. When prepared diets were analysed,
the uranium concentrations observed were, on average, about four times higher than those seen in raw
foodstuffs. Hamilton explained this to the possible addition of uranium in seasonings and to transferfrom the cookware [H8]. It was unclear whether these dietary intakes included those from drinking
water and it was emphasized that the latter had sometimes been found to be equal to that from the diet
[H8]. Wrenn et al. have suggested that in regions where treated surface water was used for cooking anddrinking, food appeared to be the major source of uranium intake [W26].
32. In aquatic animals (crustaceans, molluscs and fish), the bioconcentration factor from water is very
low [I3]. Concentration factors for fish vary from 0.01 to 20. The values depend on the behaviour of theorganisms (pelagic species accumulate approximately 10 times less than benthic species) and the372

UNSCEAR 2016 REPORT

tissues considered (bone 200–8,000 and kidneys > liver and gills > muscles 1.5–24 > digestive system> gonads). A study was performed in Japan to determine uranium concentrations in marine organisms(soft tissues) [M15]. This study showed large differences in uranium levels depending on the marine
species, with a minimum value of 0.077 µg/kg (0.97 mBq/kg of 238U) measured in rockfish (kichiji) anda value of 5,040 µg/kg (63.8 Bq/kg of 238U) found in octopus. The values reported by Belles et al. also
indicated that fish and seafood showed the highest uranium concentrations (90 µg/kg, 1.1 Bq/kg of
238U), followed by dairy products (40 µg/kg, 0.5 Bq/kg of 238U) [B12].
33. The concentrations of uranium in fish are also dependent on uranium levels in water. The uranium
concentrations in the muscle (dry weight) of fish caught in a Canadian lake receiving effluents from auranium mill were 7–11 times higher than those from fish caught in uncontaminated lakes [S50].
Uranium mines and mills operating between the 1940s and the late 1970s have left behind legacy
contamination due to historic mining and milling practices and incomplete site remediation duringdecommissioning. In Beaverlodge Lake, Northern Saskatchewan, Canada, elevated concentrations ofuranium are still present with a mean concentration for the period 2013–2015 of approximately
135 µg/L (range 130–142) corresponding to 1.69 Bq/L of 238U (range 1.63–1.78) [C2, C3, C4].
34. Human health risk assessments for environmental contaminants take soil ingestion rates into
consideration. The value recommended by Richardson and Stantec Consulting Ltd. [R13] of 20–40 mg/d
for children is based on mechanistic assessments made by Wilson et al. [W21] and Ozkaynak et al. [O10].
Another report suggested assessing health risk for children with the value of 100 mg of soil per day [U15].
However, uranium bound to soils is not completely bioavailable. Reported bioaccessibility (in vitro
estimate of bioavailability) values are quite variable ranging from 2112% in the gastric phase and4817% in the gastric and intestinal phase [J4] to less than 5% in the gastro-intestinal phase [T16].
35. The urinary concentrations of several metals, including uranium, were found to be higher thaninternational reference values in a study of schoolchildren and working children in Lahore, Pakistan[S44]. The measured urinary concentrations of uranium corresponded well with uranium concentrations
in drinking water.
36. A study of 19 categories of food was performed by Fisenne et al. [F5, F6]. Potatoes, meat, fresh
fish and bakery products were found to contribute more than 70% of the average uranium intake(1.2 µg/d or 14.9 mBq/d of 238U). Dietary levels of uranium in the United Kingdom were reported in astudy of typical diets using both raw and prepared foodstuffs. Analysis of the raw foodstuffs indicatedthat 83% of the daily intake of uranium derived from starchy roots, vegetables and fruit, and cereals.
37. The Committee in its 1977 Report [U7] included a summary of 238U concentrations in foodstuffs
in France, Japan and the former Soviet Union along with the results given above for the United States
and the United Kingdom. In areas with typical uranium concentrations in soils, the daily dietary intake
fell within a relatively small range, ~0.9 to 1.5 μg natural uranium (11.5 to 19 mBq of 238U). This range
is consistent with values given in several publications calculated from the mass activity of naturaluranium (25,400 Bq/g): 1.32 µg/day corresponding to 16.4 mBq/day of 238U for typical diets of adults
in New York City, Chicago and San Francisco in the United States [W11], 1.14 µg/day (14.5 mBq/dayof 238U) [K30] and 1.46 µg (18.6 mBq/day of 238U) in different cities in Japan [N9]. In the UnitedStates, the average daily per capita intake of natural uranium in foodstuffs was estimated to range fromabout 1 to 33 µg (i.e. from about 12 mBq 238U/day to 405 mBq 238U/day) determined from excretionmeasurements [S26]. The values given by ATSDR indicated that the daily intake of uranium from foodsources ranged from 0.9 to 1.5 μg/day [A31, W11]. Similar values were given for European countries[W15]: intakes ranged from 6 to 22 mBq/day of 238U corresponding to 0.47 and 1.77 µg/day,
respectively. This daily intake contributed to a body burden of around 50 µg (0.62 Bq of 238U) in
humans [F6].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 373

38. The Codex Alimentarius gives guideline levels applied to radionuclides contained in food,destined for human consumption and traded internationally, which has been contaminated following a
nuclear or radiological emergency [C29]. These guideline levels apply to food after reconstitution or as
prepared for consumption, i.e. not to dried or concentrated foods, and are based on an intervention
exemption level of 1 mSv in a year. A value of 100 Bq/kg is given for 235U. However, these guideline
levels exclude radionuclides of natural origin such as 238U.
39. In summary, uranium is present in a variety of foodstuffs, with great variability. Potatoes, meat,
fresh fish and bakery products were found to contribute more than 70% of the average uranium daily
intake. The total daily intake in food was found to be around 1.5 μg (18.6 mBq of 238U), about twicethat via drinking water, recognizing that levels in diet and drinking water can vary greatly.

5.

Levels in milk

40. Some publications report uranium levels in milk, notably from cattle. The uranium concentrations
measured in milk were in a wide range, from 0.012 to 0.41 µg/L (0.15–5.2 mBq/L of 238U), dependingon the species and the technical methodology (table 3). A mean value of 0.26 µg/L is given,corresponding to 3.3 mBq/L of 238U (range 0.001–1.20 µg/L; 0.012–15 mBq/L of 238U), if the highest
values of Santos et al. [S3] are excluded. This mean value is above the reference value of 1 mBq/L of238
U given in the Committee’s UNSCEAR 2000 Report [U8]. Furthermore, transfer coefficients ofuranium into milk are also available in the literature [A5, K1, T8, W9, W28] and presented for different
species in table 4.
Table 3. Uranium content (mass and activity) in milk (animals)
Values are expressed in kg of fresh matter, the numbers in italics correspond to calculated data obtained from the mass
activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium of 48.3%[U] in μg/L

238

U in mBq/L

Reference

0.14–0.24

1.74–2.98

[A14]

1.20

14.8

[S43]

0.10 (0.03–0.24)

1.24 (0.38–3.0)[F16, M34]

0.72±0.35

8.9±4.3[A5]

0.001–0.01

0.01–0.12[R11]

0.21±0.02

2.56±0.25[P19]

0.25±0.06

3.07±0.74[P20]

3.09 (0.18–9.6)

38 (2.2–118)

[S3]

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UNSCEAR 2016 REPORT

Table 4. Transfer coefficients of uranium into milk (animals)
n.i.: not indicatedSpecies

Transfer factor (d/L)

Range (d/L)

Reference

Cattle2.0 × 10−4

6.0 × 10−5–6.0 × 10−4

[T8]

Cow

2.9 × 10−3

5.0 × 10−4–6.1 × 10−3

[K1]

1.0 × 10−3

3.0 × 10 –3.0 × 10

Goat

1.4 × 10

−3

n.i.

[K1]

Camel

4.2 × 10−3

1.1 × 10−3–1.5 × 10−2

[A5]

Sheep and goat

−4

−3

[T8]

B. Artificial sources
41. The main application of uranium is for energy production and military use. Uranium-235 isnaturally a fissile isotope. Uranium is used primarily in most nuclear power plants. Its utilization inmost reactors requires enrichment of natural uranium containing 0.72% by weight of 235U to a 235U
content of 2–5%. Weapons use high enriched uranium with over 90% 235U. Some research reactors andnaval reactors also use high enriched uranium. Depleted uranium is used as a metal in kinetic energy
penetrators and tank armour.
42. The nuclear fuel cycle leading to the production of electricity from uranium in nuclear powerreactors includes mining, milling, conversion, enrichment, fabrication of nuclear fuel and reprocessing[G18]. Mining for the extraction of uranium involves both conventional open pit (where deposits areclose to the surface) and underground mining (used for deeper deposits). Currently, most uranium
mining worldwide uses the in situ leach mining process [S4]. The milling process produces a uraniumoxide concentrate, named Yellowcake, which contains more than 80% uranium. This uranium oxide isthen converted to uranium hexafluoride (UF6). It contains only natural uranium, which is enriched via
one of the two major types of enrichment technologies, gaseous diffusion or gas centrifuge. The
enriched uranium hexafluoride is then converted to uranium dioxide (UO2) powder and processed into
ceramic pellets. Finally, these pellets are inserted into tubes of corrosion-resistant metal alloy, called
fuel rods, which are grouped in fuel assemblies for the nuclear fuel core of a power reactor.
43. The uranium remaining after removal of the enriched fraction is DU, containing 0.3% 235U or less
[B22, B26]. This uranium has various civilian applications, such as in counterweights or ballast in
aircraft or counterweights for rudders and flaps [B22], for X-ray radiation shielding in medical
equipment and also for containers for the transport of radioactive material. Moreover, DU has also beenused in glassware, ceramics and dentistry.
44. In addition to exposure to natural uranium in the environment, anthropogenic activities have led toincreasing uranium exposure for humans. For instance, uranium was found to leach into water fromuranium-bearing glass items (maximum uranium in water, 30 µg/L (0.38 Bq/L of 238U) and from ceramicglazed items in which natural uranium is used as a colouring agent (300 µg/L; 3.7 Bq/L of 238U) [L6].
45. Uranium is present in water as a result of leaching from natural deposits and waste from themining of uranium and other minerals, releases from the nuclear fuel cycle and the combustion of coaland other fuel [D22, E6, S26, T1]. Phosphate fertilizers, which may contain uranium at concentrations
as high as 150 mg/kg, may also contribute to the uranium content of groundwater [S26].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 375

46. Contamination of surface water and groundwater by effluents from uranium mining, milling, andproduction operations due to in situ leaching methods has been documented [A31, E1, H14, S50].
Table 5 shows some recent data. Except for some specific locations, i.e. at the pit, the values ofuranium concentrations in surface water or groundwater are usually below the WHO guideline of
30 µg/L (372 mBq/L of 238U).
47. Since the 1970s, DU is used for kinetic energy penetrators and tank armour, because of its
pyrophoricity [B22]. The military applications of DU led to the significant release of this radionuclide
into the environment during the conflicts in Iraq and Kuwait (321 tons of DU), in Bosnia-Herzegovina(3 tons of DU), and in the Kosovo (10 tons of DU). More details are given in reports by the United
Nations Environment Programme (UNEP) and the National Defence Research Institute (NDRI) [H13,U3, U4, U5, U6].
48. The use of reprocessed DU in mixed oxide (MOX) fuels (constituted by 8–9% of plutonium and~90% of DU) has been used as a recycling strategy by countries including France and Japan as an
option to reduce the necessity for storage of spent fuel [R6].
49. In a study in Tajikistan, uranium concentrations were shown to vary from more than 1,600 µg/L(>20 Bq/L of 238U) at the pit lake to 90 µg/L (1 mBq/L of 238U) in tube supplies and 6.3 µg/L
(80 mBq/L of 238U) in drinking water from the neighbouring village [S28]. Another study documented
uranium contamination of groundwater in Arizona, the United States after uranium mining [D13].
Approximately 20% of total uranium concentrations in the water samples exceeded the maximum
concentration level for drinking water of 0.37 Bq/L of 238U [U17]. In another study, the uranium
content was measured in drinking water samples from locations near the uranium mining site at
Jaduguda, India [P8] with uranium concentrations between 0.03±0.01 and 11.6±1.3 µg/L – values
below the WHO guidelines of 30 µg/L for uranium level in drinking water [W18].
50. Uranium conversion, uranium enrichment and fuel fabrication facilities are other steps in the
nuclear fuel cycle, which also release small amounts of uranium to the environment [A31]. Tracy andMeyerhof showed that concentrations of uranium in the air near a uranium refinery were 200 times
higher than background concentrations [T18]. For monitoring stations in Port Hope, Canada, where auranium refinery is operating, the annual average concentration varied between 0.001 and 0.0158 µg/m3
in 1988 and 1989. Uranium concentrations subsequently decreased and varied between 0.005 and
0.00028 µg/m3 in the early 2000s [C27]. In 2009, elevated levels of uranium were registered in storage
reservoirs of liquid radioactive waste at the Mayak facility, Russian Federation: the concentration was
370 mBq/L to 520 Bq/L for 234U, and 260 mBq/L to 520 Bq/L for 238U [T21].
51. Concentrations of uranium in surface waters downstream from currently operating uranium mines
and mills are relatively low and decrease with distance from the point of effluent discharge. For
example, between 2000 and 2012 in the vicinity of Canadian uranium mines and mills within 1 km
from the discharge points the mean concentration values ranged from 17 to 0.92 µg/L and decreased tomean values in the range of 1.44 to 0.096 µg/L at distances greater than approximately 10 km fromdischarge points [C28].
52. Environmental contamination by uranium caused by DU in ammunition used in military conflicts
was reported in several studies and in UNEP reports [U3, U4, U5, U6]. Uranium in agriculture soil in
Kosovo and Bosnia–Herzegovina averaged 1.8 and 3 mg/kg, while concentrations in public drinking
water averaged 0.5 μg/L (16.3 mBq/L of 238U) and 0.4 μg/L (5.1 mBq/L of 238U), respectively [C12].
The average uranium concentrations in soil and water were consistent with natural levels, although
localized areas of greater concentration were measured in the immediate surroundings of the DU

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UNSCEAR 2016 REPORT

penetrators [D4, E5, S2]. In the UNEP report on Kosovo, a great variability was observed in uranium
concentrations in water samples, with a range between 0.006 and 2.15 µg/L [U4].
53. Carvalho and Oliveira [C12] found high, localized contamination of soil with DU at Djakovica(4,662 Bq/kg of 238U; 376 mg/kg). The water samples collected from public water distribution networks
and river water ranged from 0.2 to 0.76 µg/L (2.5–9.7 mBq/L of 238U) and the air samples ranged from
0.8 to 7.2 µBq/m3. Consistent results from a number of studies indicate that environmental
contamination by DU has been very localized and confined to the areas of ammunition impact.
54. Concentrations of uranium were measured in surface and groundwater at the Semipalatinsk
nuclear test site, where more than 400 nuclear tests were conducted [L28]. The measurements showedthat 238U concentrations in well water within the study area were in the range of 74–213 mBq/L. The
results of these studies suggest that diverse human activities involving uranium (from extraction toapplication) have led to some localized increase of the concentration in the environment.

Table 5. Overview of uranium content in water close to nuclear fuel facilities worldwide
The numbers in italics correspond to calculated data obtained from the mass activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium (48.3%); * mean
value

Country

Location

Type of plants

Samplenumber238
U(mBq/L)

Total uranium(μg/L)

Reference

Lagoa Real

Mining and ore processing

26

5.45 (0.1–259)

67.6 (1.2–3 212)

[C13]

CanadaSaskatchewan, Beaverloke Lake

Mining

22

100.8

1 250

[Y1]

India

Jaduguda

Mining and ore processing

33

3.2 (0.03–11.6)

39.7 (0.37–144)

[P8]

India

Jharkhand, Narwapahar

Mining103

0.63 (0.10–3.75)

7.8 (1.24–46.5)

[R7]

India

Jharkhand, Bagjata

Mining10

3.22* (<0.5–11.2)

40* (<6.2–139)

[G12]

India

Jharkhand, Banduhurang

Mining10

2.15* (<0.5–27.5)

26.7* (<6.2–341)

[G12]

India

Jharkhand, Bagjata

Mining40(<61–55.9)(<12.6–693)[G13]

Kazakhstan andKyrgyzstan

Kurdai (Kazakhstan) and
Shekaftar, Kavak and Kadji-say (Kyrgyzstan)

Mining1028.2 (1.9–35.9)

350 (23.6–445)[U12](1 525 in lake at mining pit)

(18 910)

Kyrgyzstan

Mailuu Suu

Mining and milling

0.28 (0.27–0.34)

3.47 (3.35–4.2)

[C32]

25

(6 820 for tailings)
Nigeria

Jos plateau

Abandoned mining

5

0.10 (0.03–0.27)

1.24

[A22]

Nigeria

Abakaliki

Mining20

2 (0–7)24.6 (0–87)[O2]

Portugal

Viseu, Quinta do Bispo & Cunha Baixa

Mining1217.7 (1 km)

220 (1 km)[C11]

0.5 (7 km)

6.2 (7 km)

Tajikistan

Taboshar & Digmai

Mining and milling66.95 (3.4–92)

86.2 (42.2–1 138)

[S28]

USA

Karnes County, Texas Pana Maria

Mining and milling6

19.7 (14.8–95)

244 (183–1 178)

[M18]

USA

California Juniper

93.35 (0.02–52.37)

42.2 (0.25–649)[K8]

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 377

Brazil378

UNSCEAR 2016 REPORTIII. PHYSICAL, RADIOLOGICAL AND CHEMICAL CHARACTERISTICS
A. Physical and radiological characteristics
55. Uranium is an actinide and has one of the highest atomic numbers (92) of any naturally occurring
element. It is a silvery-white metal that is malleable, ductile, slightly paramagnetic, with a very highdensity. In its natural state, crustal uranium occurs as a component of several minerals, including
carnotite, uraninite (pitchblende) and brannerite, but is not found in the metallic state in nature. In
addition, uranium metal is pyrophoric. Due to its pyrophoricity, it is used in military applications,particularly in armor-piercing projectiles.
56. The three naturally occurring isotopes of uranium (234U, 235U and 238U) behave the same way
chemically but have different radiological properties (table 6). Uranium-238 has the longest half-lifeand consequently the lowest specific activity. It is the most abundant naturally occurring uranium
isotope. Among the natural isotopes of uranium, 234U has the highest specific activity and the shortest
half-life [L35, S15]. However, other isotopes of uranium may be produced, such as 233U that has a very
high specific activity (3.57 × 108 Bq/g) [L43].
57. Natural uranium is made of a mixture of the three isotopes described above with about 0.72% of
U in mass (table 7). Depleted uranium refers to isotope mixtures that contain a lower percentage of235
U (from about 0.2–0.3%) while enriched uranium contains typically 3–5% 235U in mass and may
contain up to 90% 235U for military applications (table 7) [L35, S15].
235

Table 6. Radiological properties of uranium isotopes [N8]nt: nuclear transformation

Half-life(years)Isotope234

Emitted energy (MeV/nt)

Daughter
nuclideAlpha

Electron

PhotonTotal

Th

4.84300.01370.00204.8587231

Th

4.46930.05300.16694.6891234

Th

4.25840.00920.00144.2691U

5

2.46 × 10

230

235

U

7.04 × 108

238

U

4.47 × 109

Table 7. Typical isotopic composition in mass and activity of different types of uranium [L35, S15]
Mass (%)
Type of uranium
NaturalDepleted
Enriched (3.5%

235

U)

238

U

235

U

Activity (%)
234

U

238

U

235

U

Activity (Bq) for 1 g
234

U

238

U

235

U

234

U

99.2840.711

0.0053

48.2

2.3

49.5

12 400580

12 47499.8070.0.1990.0008

86.1

1.1

12.8

12 400158

1 843

96.481

3.46

0.02831

14.7

3.4

81.8

12 0052 800

66 703

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 379

58. Uranium in rock and soil is in secular equilibrium with the daughters of the decay chain.
Uranium-238 decays to 234Th and 234mPa reaching secular equilibrium within about one year. The 238U
decay chain ends with the stable isotope 206Pb. However, disequilibrium between the uranium isotopes
can occur through physical and chemical changes involving water. For example, combinations ofphysical and chemical processes can lead to a separation of 238U and 234U in groundwater [N2].
Uranium-235 and 238U decays contribute to subsequent formation of 10 or more emitters of , and (figure I). Due to their short half-life, 234Th and 234mPa (24.1 days and 1.17 min, respectively) are
generally present together with 238U.

B. Chemical characteristics
59. Uranium has four valencies, which represent the number of valence bonds that uranium can form
with other atoms. The most common valencies of uranium in ores are IV and VI. The conditions oftransition from valency IV to VI depend on the redox potential of the medium. Compounds containing
hexavalent uranium are much more soluble than those containing tetravalent uranium. Hexavalenturanium forms complexes such as uranyl carbonates (UO2CO3) and uranyl sulphates (UO2SO4).
60. Uranium can take many other chemical forms. In nature, it is generally found as uranium dioxide(UO2) with other compounds, such as in pitchblende. Uranium dioxide (UO2) is the final product in the
manufacture of nuclear fuel pellets used in most reactors, and is also present as DU in MOX. Uranium
metal is generally alloyed with other elements (Si, Cr, Al, Fe, Mo, Sn, Al).
61. Uranium metal is pyrophoric and extremely reactive. It oxidizes readily to form triuranium
octaoxide (U3O8) and uranium dioxide (UO2). Uranium trioxide (UO3.xH2O) and uranium peroxide(UO4.2H2O) also exist. Triuranium octaoxide (U3O8) is the most stable oxide of uranium and is the form
most commonly found in nature. Both triuranium octaoxide (U3O8) and uranium dioxide (UO2) are solids
that have low solubility in water and are relatively stable over a wide range of environmental conditions.
Through reactions with acids, bases or chelating agents, compounds such as uranyl nitrate, uranyl
carbonate, uranyl chloride, uranyl sulphate and uranyl acetate may also be formed. Ammonium diuranate(NH4)2U2O7 is a basic product in the uranium fuel cycle, a component of Yellowcake, which is produced
during milling and consists of magnesia or ammonium diuranate (respectively MgU2O7 and (NH4)2U2O7).
These compounds are converted to uranium hexafluoride (UF6) prior to enrichment. During conversion,diuranate is converted to uranium trioxide (UO3), then UF4, and finally UF6 is then enriched from 235U
~0.7% to 235U at ~4%. This enriched UF6 is then converted into UO2 [D6].
62. As indicated above, different chemical forms of uranium are produced throughout the nuclear fuelcycle [G18]. Uranium-fluorine compounds are encountered in uranium processing, with uranium
hexafluoride (UF6) and uranium tetrafluoride (UF4) being the two most common. The compound UF6 isused in the enrichment process of uranium to increase the proportion of 235U, either by gaseous diffusion
or by gas centrifuge. It is prepared industrially by the reaction of UF4 powder with fluorine gas. Uranium
tetrafluoride is obtained by treating UO2 with gaseous fluorhydric acid. It is a non-hygroscopic, nonvolatile compound and very soluble in water. In the presence of water vapour, it undergoes pyrohydrolysis
and becomes UO2. When gaseous UF6 is released into air or as it enters the respiratory tract, it hydrolizes
with moisture in air to produce hydrofluoric gas and particulate UO2F2. The oxidation states andcrystallographic forms of uranium in DU particles have been determined from selected samples collected
at different sites in Kosovo and Kuwait contaminated by DU ammunition during conflicts [L39]. Oxidized
uranium (+6) was found in large, fragile and bright yellow DU particles released during a fire at DU
ammunition storage facilities in Kosovo and Kuwait and crystalline phases such as schoepite

380

UNSCEAR 2016 REPORT(UO3.2.25H2O), dehydrated schoepite (UO3.0.75H2O) and metaschoepite (UO3.2.0H2O) were identified[L39]. These DU particles were rapidly dissolved indicating a high degree of potential mobility andbioavailability. Crystalline phases such as UO2 and metallic uranium or U–Ti alloy were also determined
in impacted DU particles from Kosovo and Kuwait.

IV. HUMAN EXPOSURE

A. Exposure of members of the public
63. Natural uranium exposure of humans occurs through food, water and inhalation. Reviews of
autopsy data show that the skeleton is the main site of accumulation of uranium (~80% of total) [B53,
K6, S25, U18]. This result, observed in a United States population, was corroborated by measurements
made in the United Kingdom [H7, H8] and Japan [I18]. Publications differ about whether the
distribution of uranium in the skeleton appears to be uniform [H12] or not [S24]. The age dependenceof uranium concentration in the skeleton was also investigated in humans (from six months to 65 years)
from vertebrae bones collected in Canada from population exposed to high uranium levels in drinking
water [L11]. The data indicated higher uranium accumulation at six months.
64. Fisenne et al. [F6] summarized numerous publications from 12 countries concerning uranium
concentration in human tissues, including blood, soft tissue and bone. This analysis demonstrated small
differences in uranium concentration in soft tissue and bone. The authors calculated an average of 30 µg
for the skeletal burden. The body burden of uranium in humans was estimated between 50 and 60 µg, with
57% in the skeleton, 20% in muscles, 16% in fat, 4% in blood, 2% in the lungs, 1% in the liver and 0.36%
in kidneys as presented in figure II [F6]. One publication mentioned uranium levels in the human brain[K6] with values between 0.18 and 0.77 µg of uranium/kg (n=3), corresponding to 0.4 to 0.99%.
65. The Committee in its UNSCEAR 1977 Report [U7] provides further reference concentrations of
238
U in various human tissues expressed in mBq/kg: 20 mBq/kg in the lungs, 3 mBq/kg in the liver,
30 mBq/kg in the kidneys, 5 mBq/kg in muscles and 100 mBq/kg in the bones. Despite somedifferences, these values and those reported by [F6] are similar. High uranium concentrations were alsomeasured in the kidneys in humans [A2, D20, S25]. Calculations made for four age groups (infant, oneyear-old, ten-year-old, adult) indicated that long-term chronic uranium ingestion would result in akidney burden of 6.6% of daily uranium intake for all age groups [C21].
66. Fisenne and Welford [F4] measured an average kidney content of 0.13 g 238U from 12 New York
City dwellers, aged 20–60. An average daily New York City diet of 1.3 g yields a blood uptake of
0.026 μg. The kidney-to-blood uptake ratio was estimated at 4 and the bone-to-blood uptake ratio at
3.3. Figure III shows the average daily dietary intake of 238U measured in 16 cities in 12 countries [F7].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 381

Figure II. Distribution of 238U in human body [F6]

Figure III.

Average daily 238U dietary intake measured in 12 countries [F7]

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UNSCEAR 2016 REPORT

B. Occupational exposure
67. Exposure to uranium may also be relevant to occupational exposure, notably for workers involvedin electricity production in nuclear power reactors or at any stage of the nuclear fuel cycle. Each stageof the nuclear fuel cycle is associated with distinct exposure characteristics [D6, D7]. During mining,
workers may be exposed to various uranium compounds exhibiting different solubility such as
Yellowcake. Further, workers in metal mines, such as underground gold mines, may also be exposed touranium.
68. Several tissues were collected at the autopsy of workers by the United States Transuranium andUranium Registries (USTUR) [F3]. Some cases have been analysed following uranium exposure [A34,
R31]. Accidental exposure to uranium hexafluoride (UF6) led to long-term (65 years) retention of
uranium in the deep lungs and in thoracic lymph nodes [A34]. High concentration of uranium intracheobronchial lymph node was also found in other cases without accidental exposure [R31].
69. Often, data on worker exposure are restricted to measurements of external radiation exposure. For
instance, Anderson et al. reported that only 16% of the Oak Ridge Gaseous Diffusion Plant (ORGDP)
workers were monitored between 1948 and 1988 for internal exposure to uranium by urinalysis [A12].
The difficulty is that monitoring programmes for internal exposure need a combination of bioassay
techniques, e.g. urine and faecal analysis, especially in workplaces where compounds of different
solubility are handled and also in cases of accidental intakes [J6].
70. Following inhalation of insoluble forms of uranium, the lungs may retain the highest
concentrations of uranium [A2, I19]. Adams et al. reported measurements of uranium in kidney andbone following lifetime occupational exposure to uranium aerosols [A2], showing greater retention inbone than kidneys, as seen in data for natural uranium in tissue samples from members of the public.

C. Measurement of uranium
71. The amount of uranium taken into the body can be assessed from external radiation measurements
or by bioassay sampling (urine or faeces). The choice and efficacy of each procedure is dictated by theroute of intake, the pattern of exposure, the physical and chemical form of the uranium, the time between
intake and measurement, and the detection limit of the analytical procedure used [A31, L9, S30].
72. Exposure to uranium can be assessed through the detection of uranium in the urine [B4, C18,
C31, D21, L18, L21, M62, S37, S39, W12, W23]. After absorption through oral, dermal and inhalationroutes, uranium is excreted in urine mostly as uranyl ions. Uranium urinalysis data have been shown tocorrelate with airborne uranium exposure when averaged over time and the contribution from ingested
uranium is insignificant. Thus, urinalysis can be used to verify the adequacy of air sampling and as a
non-invasive method for the estimation of exposure [C18, D9, T7].
73. In vivo external radiation measurements can be used to determine the amount of uranium in the
respiratory tract or whole body. The energy of the main gamma emission from 235U is 186 keV.
Specialized counting systems (e.g. using germanium semiconductor detectors) are required. The
minimum detectable activity (MDA) of uranium in the chest depends on the isotopic mix of 235U and
238
U and also on the total amount of uranium in the chest or in the whole body. However, it is of theorder of 4 Bq of 235U and 100 Bq of 238U [L25]. When 234Th has reached secular equilibrium with 238U,
photon emissions from 234Th may be used in addition to those from 235U to further reduce the detection

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 383

limit, by summing the 234Th and 235U photopeaks. Kramer et al. have reported an MDA of 4 mg (i.e.
49 Bq of 238U) [K13]. The detection limit is a function of the chest wall thickness of the measured
individual. This parameter must be measured in order to interpret in vivo measurements of uranium inthe respiratory tract.
74. Measurement of uranium excreted in urine after exposure is potentially a more sensitive methodthan chest monitoring to determine the amount of inhaled uranium. The limit of detection by alpha
spectrometry is approximately 0.1 mBq of 234U, 235U or 238U in a 24-hour urine sample. Counting times ofapproximately one week are required to achieve this sensitivity. For natural uranium, a measurement of
0.1 mBq of either 234U or 238U would correspond to about 8 ng of total uranium. Specialized mass
spectrometric techniques (such as multicollector inductively coupled plasma mass spectrometry; highresolution inductively coupled plasma mass spectrometry; or thermal-ionization mass spectrometry) can
provide isotopic analysis at levels lower than can be achieved by alpha spectrometry [K12, L20].
Synchrotron-based X-ray techniques (e.g. X-ray fluorescence microscopy, X-ray absorption fine structure,
X-ray diffraction may be also used for uranium measurements [C15, P5].
75. The use of faecal assay is confined to intakes by inhalation of relatively insoluble forms ofuranium, and dose assessments using these data are subject to substantial uncertainties [D8, J6].
Measurement of uranium in hair could be used as an indicator of body burden in contaminated subjects[B16, I23, J3].
76. Many studies have reported urinary excretion of uranium in humans. The National Report on
Human Exposure to Environmental Chemicals [C16] gives uranium concentrations in both µg/L and µg/g
creatinine. Expressed in µg/L, mean levels of uranium in the general United States population range from0.005–0.009 μg/L according to surveys conducted from 1999 to 2012 on 18,266 individuals. Oeh et al.
[O1] measured uranium content in 113 urine samples from 63 occupationally unexposed persons inGermany. The urinary excretion of uranium per day was in the range of 1.4 to 77.5 ng with a geometricmean of 13.9 ng and median of 14.4 ng. Höllriegl et al. [H21] measured the uranium content in urine in
the general public of Nigeria with creatinine normalized values from <10.4 to 150 ng/L (median
13.8 ng/L) and from 2.52 to 252.7 ng/g creatinine (median 33.4 ng/g). Malátová et al. [M8] measured
daily excretion of 238U in urine in the general population (mean 0.311 mBq, range 0.011–2.88 mBq). The
measured urinary excretion per day among 40 active uranium miners indicate a mean value of 0.56 mBq
with a range of 0.08–2.77 mBq of 238U normalized to 1.7 g daily creatinine excretion [M7]. A study
performed in Italy indicated that the daily excretion for the Italian volunteers ranges from 8.2 ng to 59 ng
uranium [B1]. The lowest daily excretion was observed for the youngest volunteer (seven years old).

V. BIOKINETICS
77. The main routes of intake of uranium into the human body are ingestion and inhalation. Transfer
through intact skin is a minor route. Wounds require consideration in occupational exposure. In general,
occupational exposure arises primarily through inhalation of dust containing uranium or following
injury. Exposure of the general public arises mainly through ingestion of water or foodstuffs containing
uranium. The extent of transfer of ingested or inhaled uranium to blood depends on its chemical form
[I10, N2].

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A. Inhalation
78. The intake of radionuclides is determined by the air concentration and by the respiratory
characteristics of the subjects, particularly the ventilation rate, which changes according to the level of
exercise and determines the volume of air inhaled and the deposition of inhaled radionuclides in the
airways of the lungs.
79. For radionuclides inhaled in particulate form, regional deposition in the respiratory tract isgoverned mainly by the size distribution of the aerosol particles [I9]. Deposition fractions of gases andvapours are determined by their chemical form. After deposition in the respiratory tract, absorption andtransport of radionuclides involve three general processes. Material deposited in the anterior nasal
passage is removed by extrinsic means such as nose blowing. In other regions, clearance is competitive
between upward particle transport out of the lungs and dissolution and absorption to blood from thelungs. Particles escalated out of the lungs are subsequently swallowed and pass through the alimentarytract where absorption can occur.
80. The ICRP human respiratory tract model describes the biokinetics and dosimetry of inhaledmaterial and is used to calculate the inhalation dose coefficients that are in general use for radiologicalprotection and scientific purposes [I8]. This model represents the deposition of inhaled radionuclides inthe different regions of the respiratory tract, and the clearance of the deposited activity by mechanicaltransport and absorption to blood. Mechanical particle transport rates are taken to be the same for allmaterial, but are altered by factors such as smoking and disease. Absorption into body fluids depends
on the physical and chemical form of the deposited material [I7]. Absorption is modelled as a two-stage
process: dissolution (dissociation of material into body fluids) and uptake of soluble material. Uptake
into blood is usually treated as instantaneous while dissolution is time dependant and modelled by threeparameters: a fraction (fr) of the activity is rapidly dissolved at a rate (sr), the remaining fraction (1 – fr)
is dissolved at a slower rate (ss).
81. The absorption rate of a given compound may vary greatly depending on its method of production
and history. The ICRP recommends that the absorption rate of any material should be determined fromthe study of the material itself. In the absence of data, ICRP recommends default parameters for threereference absorption types: Type F (fast), corresponding to rapid and complete absorption of theradionuclide with a half-time of about 10 min; Type M (moderate), corresponding to the absorption of
20% of the activity with a half-time of 10 min; Type S (slow), corresponding to the absorption of 1%
with a half-time of 10 min [P4].
82. Hodgson et al. [H20] and Ansoborlo et al. [A15] reviewed the absorption kinetics of uranium
compounds handled in the British and French nuclear industry. In vivo experiments in rats and in vitro
dissolution studies led to the classification of UO2 and U3O8 as Type S; mixed oxides, UF4, UO3 and(NH4)2U2O7 as Type M; and UO4, UO2(NO3)2 and UO2F2 as Type F. In addition, these studies provided
specific absorption parameter values for each of these compounds. Duport et al. [D32] studied thesolubility of radioactive dust present in the workplace atmosphere from three types of Canadianuranium ores—Yellowcake, UO2 and UO3—using simulated lung fluid and determined their solubility
classification. Solubility studies were conducted in Canada on material from various uranium mining
and production facilities [R17]. Bečková and Malátová [B10] studied the solubility of dust samples
from the underground uranium mine, Rožná, using simulated lung fluid and calculated specificabsorption parameter values for 238U, 234U and 230Th. The dissolution parameters calculated for UF6
mixture were higher than the current ICRP dose coefficient for Type F uranium (factor 2–7) [A34].
83. Models allow dose calculation from the inhalation of uranium particles in different chemical forms
and in several sizes. However, specific data might be needed for remediation and decommissioningANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 385

activities potentially generating uranium nanoparticles [T20]. A study of inhaled nanoparticles of uranium
in rats [P18] showed that 97% of inhaled particles were deposited in the deep lung and partly translocatedto the pulmonary interstitium. Approximately 22% of these deposited particles were rapidly cleared (lungretention half-life of 2.4 h) and for the 78% remaining, the lung retention half-time was estimated at 1,412
days. The ICRP is currently developing material specific absorption parameter values for compounds ofuranium and is revising the default parameter values for Type F, M and S compounds.

B. Ingestion
84. Material may reach the alimentary tract either directly by ingestion or indirectly by transfer fromthe respiratory tract or from the systemic circulation. Absorption takes place largely in the specialized
absorptive region of the small intestine [L2]. The extent of absorption of individual radionuclides isdependent on the chemical properties of the element, and also the specific form of the intake. It isquantified by the fraction of element reaching blood following entry in the alimentary tract. The
absorption and retention of radionuclides in the human alimentary tract are described in the human
alimentary tract model produced by ICRP [I14]. This model depicts transfer of ingested material
between alimentary tract regions, faecal elimination and absorption into blood [I14]. In the ICRP
model, the fraction f1 represents the small intestinal absorption, and the symbol fA refers to the total
absorption from the different sectors of the human alimentary tract, including the walls [I14].
85. Soluble uranium is absorbed throughout the small intestine [D25, K9]. Comparative data between
species (rabbit, rat, hamster, dog, baboon, pig and human) have been provided by several authors [F11,T19, W26]. Tracy et al. reported a gastrointestinal absorption factor of 0.06% in rats and rabbits [T19]
while Frelon et al. reported a value of 0.4% in rats [F11] for uranyl nitrate administrated in drinking water.
Leggett and Harrison [L23], Zamora et al. [Z5, Z7] and Wrenn et al. [W27] reviewed the uptake ofingested uranium from the alimentary tract in environmentally exposed human subjects and in volunteer
studies. The distribution of fA values was in a range of 0.001 to 0.063, with daily uranium intake varying
from 0.37 to 573 µg. The authors estimated that the best estimate for fA was 0.009, with no correlation
with age, sex, duration of exposure, and total uranium intake. These values are in accordance with those ofanother study that found fractional absorption (fA) values in a range from less than 0.1% to about 6% forindividual subjects, with the central values from the different studies falling in the range 1–2% and 4%
from water for both 234U and 238U [S30]. On the basis of available data, the ICRP Publication 69 [I10]takes the fractional absorption of uranium from diet to be 2% in adults.
86. In newborn infants, fractional absorption may increase by a factor of about two due to the higher
intestinal permeability [I14]. This higher absorption in newborns was measured in different species(rats, guinea pigs, pigs, dogs) [S45, S47]. On the basis of animal data, ICRP recommended an f1 valueof 0.04 for infants and 0.02 for anyone more than one year of age [I10]. Chen et al. measured uranium
concentrations in 73 bone ash samples of young children residing in a Canadian community known tohave an elevated level of uranium in its drinking water supply [C22] and estimated fractional
absorption with confidence intervals as wide as 0.0930.113 for infants and 0.0500.032 for children of
1–7 years. In another extended study by Chen et al. [C23], the absorption fractions were estimated to be
0.0300.022 for children and youths of 7–18, and 0.0210.015 for adults of 18–25 years of age.
87. Experimental studies have shown that fractional absorption depends strongly on the ingested
chemical forms. The ICRP is currently revising its Publication 69 [I10] and will adopt an fA value of
0.002 for relatively insoluble compounds (e.g. UO2, U3O8) and an fA value of 0.02 for all other moresoluble chemical forms [P4]. A biokinetic model was recently developed to describe uptake andretention in hair following ingestion [L34].

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C. Absorption
88. Few human data are available on uranium transfer through skin in a report of the National Council
on Radiation Protection and Measurements [N3] and in a review of the Armed Forces Radiobiology
Research Institute [M17]. Accidents involving workers with extensive skin exposure to uranium havebeen reported in the other reviews. Lu and Zhao indicated a rapid increase in the uranium level in urine
followed by severe kidney dysfunction [L48] with a return to normal values at post-accident day 30.
These results were similar to the clinical follow-up made on workers with acute uranium compound
intoxication [S16]. Acute renal failure occurred for several days post-accident with recovery one month
later. The result of a 33-year follow-up showed that kidney and liver functions were normal [S49].
89. In the use of DU munition, small particles originating from DU dust can contaminate open
wounds, and embedded DU fragments may be implanted in muscles. Uranium urine concentrations
following accidental intramuscular implantation of metal DU fragments were measured in United States
service members exposed to DU through incidents involving DU munition and vehicles protected by
DU armour [M25]. Uranium values were from 0.001 to 39.955 µg/g creatinine.
90. Several in vivo studies of rodents with uranium exposure of intact skin [D10, O4, T23] demonstratethat very soluble forms of uranium such as uranyl nitrate and ammonium uranyl tricarbonate are able todiffuse through the skin layer [L47]. The LD50 of uranium depended on the species as follows: rabbits>rats >guinea pigs >mice. This toxicity increased with the time and the area of exposure. In vitro Franz
diffusion chamber model [T23] and in vivo hairless rat model may be used for evaluation of uranium
passage through intact skin [P16, P17]. An in vivo study showed that a significant uptake of uranium froma uranyl nitrate solution could occur within the first six hours of exposure after skin contact. Furthermore,as high uranium concentration remained present at the deposit site for up to 24 hours after contamination,skin provided a reservoir for uranium that remained bioavailable [P17].
91. Percutaneous diffusion of uranium was also studied on damaged skin from hairless rats, following
an abrasion (stratum corneum removal) [P15, P17]. In vitro study of biopsies showed that thepercutaneous absorption of uranium increased with the impairment of the stratum corneum. Ex vivo
studies with biopsies showed an increase in the diffusion of uranium through skin after abrasioncompared with that through intact skin. These results have been confirmed in vivo in hairless rats [P16].
92. The NCRP’s biokinetic model describes the mobilization of radionuclides, including uranium,
entering the body through a wound to blood [N3]. Three wound retention categories were described,
corresponding to contamination with soluble forms, colloids, particles or fragments. The uranyl ion(UO22+) was classified as a weakly-retained radionuclide, and UO2 oxide particles behaved rather asstrongly-retained radionuclides.

D. Systemic distribution, retention and excretion
93. The translocation of uranium to blood strongly depends on the physical and chemical form of theinitial compound [A15]. After its absorption to blood, uranium is present mainly as uranyl ionscomplexed to proteins (e.g. transferrin, albumin) or bicarbonate anions [A16]. The main sites ofdeposition of uranium from the circulation are the skeleton, kidneys and general soft tissues. Humanand animal data show that urinary excretion is rapid with about two thirds of uranium reaching blood
excreted in the first 24 hours and a further 10% over the next 5 days. Most of the remaining uranium is
excreted over a period of a few months, but a small percentage of the amount injected may be retained
for a period of years [L22].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 387

94. The work of Leggett [L22] was used by ICRP [I11] to propose a reference model for uranium
biokinetics. This model is constructed within a physiologically-based framework that is also applied tothe alkaline earth elements. Rates of uranium transfer between plasma, red blood cells, skeleton, liver,kidneys, other soft tissue and excretion pathways are based on measurement of uranium in humans andanimals and consideration of the physiological processes. The model considers age-related changes inorgan and tissue uptake and retention of uranium. The ICRP will use the same model in ongoing
revisions of dose coefficients [P4].
95. The United Kingdom Royal Society [R28] used the ICRP’s biokinetic models to estimate theconcentrations of uranium in the kidneys following chronic exposure over one year at a constant daily
uptake of 1 µg of uranium to blood. The estimated uranium concentration in the kidneys was
0.0056 µg/g kidney after one year and 0.011 µg/g kidney after 50 years of contamination. This result is
not in accordance with the result of other studies. For instance, a study measured 238U in diet andkidney tissue in residents of New York and showed that a daily intake of 1.27±0.03 µg resulted in auranium concentration in the kidneys of 0.00043±0.26 µg/g that was constant over ages <20 years to>60 years old [F4].
96. Several studies have found that uranium can be incorporated into brain tissues [B11, G10, L30,
O7]. It has been demonstrated by an in situ rat brain perfusion method that uranium is able to cross the
blood-brain barrier [L27] but the mechanism by which uranium is transferred to the brain is unknown.
After acute, subchronic or chronic exposure, low uranium concentrations are found in the various
structures of the brain [B6, F8, H24, L38, P11, P12]. The level of uranium in the brain, notably inolfactory bulbs, was greatest after inhalation [H26, T15]. Such uranium concentration in olfactory bulbs
as compared to other cerebral structures is attributable to the direct transfer of uranium via olfactory
receptor neurons [I6, T15].
97. Mean values of uranium concentrations in human breast milk were reported as 0.03 µg/L
(0.76 mBq/L) [W9] and 0.30 µg/L (7.6 mBq/L) [C1]. The daily intake of uranium of mothers is
0.030.019 µg/kg (meanSD) [W9]. These values are in accordance with values measured in several
animal studies, which suggest similar transfer processes (see also table 3).

E. Materno-fetal transfer
98. Few data are available on materno-fetal transfer in humans and in animals. Some publications
have reported uranium concentrations in fetal samples [B46, B47, L26, S17, W10], in placenta [B47,
S17, W10], in amniotic fluid [C14, S17] and in cord blood [G22].
99. Ham et al. [H7] reported uranium concentrations measured in human fetus and Bradley andProsser in placenta samples [B47]. The activities of 238U ranged from 0.1 to 9 mBq/kg in the fetal
samples of human fetus and from <1 to 11 mBq/kg in placenta samples. Uranium concentrations ranged
from 0 to 0.2 µg/L (mean=0.024 and median=0.005) in human amniotic fluid [C14] and from 0.003 to
0.834 µg/L (mean=0.104 and median=0.057) in cord blood [G22].
100. An experimental study performed by Legrand et al. on pregnant rats exposed to uranium via
drinking water (40 and 120 mg/L) indicated no elevated uranium concentration in exposed fetuses ascompared to control animals [L26]. Another study performed by Sikov and Mahlum on pregnant rats
after injection indicated that only a small fraction of the injected nuclide (148 kBq of 233U) entered thefetus and the distribution within the fetus was dissimilar from that observed in the dam [S17]. Only
0.06% of injected dose/g body weight was measured in fetal kidneys at 20 days as compared to 5.18 in

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UNSCEAR 2016 REPORT

the dam. The authors also reported 0.03% injected dose/g body weight in fetus, 0.05% in placenta and0.001% in the amniotic fluid [S17].
101. The ICRP [I12] has provided biokinetic and dosimetric models and dose coefficients for theembryo, fetus and newborn as a result of intake of radionuclides by the mother. The term fetus refers to
the developing human offspring after the eighth week of pregnancy. The equivalent dose to the embryo
is assumed to be the same as that to the uterus wall and proportional to the concentration of uranium inmaternal soft tissue. The ICRP uses a simple approach for the calculation of fetal doses for the majorityof elements and their radioisotopes, including uranium, considering data collected from studies ofanimals and humans [I12, I13]. Thus, fetal doses from uranium are calculated on the basis of relative
concentrations of uranium averaged over the whole body of the fetus (CF) and that of the mother (CM).
A conservative CF:CM ratio of 1 is used for intakes of uranium during pregnancy. The distribution of
uranium in the fetus is assumed to be 80% to skeleton, 2% to kidneys, and 18% to other tissues [I12].

VI. DOSIMETRY
102. Absorbed doses in tissues are calculated using dosimetric models such as those of ICRP (e.g. [I7,I10, I11]) and of the Medical Internal Radiation Dose (MIRD) committee [B39]. The absorbed dose is
the fundamental quantity that is estimated and averaged over particular tissues and organs. The
distribution of absorbed dose from internally deposited radionuclides, here the uranium isotopes,
depends on a number of factors, including the distribution of the radionuclides within organs andtissues, and the penetration and range of radiation emitted from the radionuclides. Dosimetric models
have been developed for this purpose.
103. Absorbed doses from photons and electrons are calculated by applying Monte-Carlo codes ofradiation transport to anthropomorphic computational phantoms representing a reference person [I15].
Alpha particles are considered to be absorbed in the region where they are emitted, except for theskeleton, lung, urinary bladder and alimentary tract where the respective positions of the alpha-emitting
radionuclides and of the sensitive target cells are taken into account to assess the dose absorbed by thetarget cells. In most organs and tissues, local activity and also the radiosensitive target cells are
assumed to be uniformly distributed. However, in these few specific tissues, the identification of theputative radiosensitive cells allows a more precise definition of the source and target geometry ofirradiation, which is of concern for the short-range alpha particles emitted by uranium isotopes. The
target cells identified in the thoracic airways include basal and secretory cells in the bronchial
epithelium, endothelial cells such as those of capillary walls, and type II epithelial cells in the alveolarinterstitial region [I8].
104. Following the ICRP, the equivalent dose in a region T, HT, is defined as:

w D
R

T ,R

R

where DT,R is the average absorbed dose in region T, due to radiation of type R; wR is the radiation
weighting factor for radiation R and is equal to 1 for photons and beta particles and 20 for alphaparticles [I10, I15].
The effective dose E is defined as a weighted average of equivalent doses to radiosensitive tissues ofthe body:

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 389

E   wT H T   wT  wR DT , R
tTR

where wT is the tissue weighting factor for tissue T, with the sum of wT being 1. The committed
effective dose ET(τ) is defined as the effective dose delivered over the time τ following intake of aradionuclide. The τ is usually set to 50 years for adults and for children up to the age of 70 years so as
to cover life-long irradiation [I10].
105. Doses from the inhalation or ingestion of unit mass of uranium can be determined by multiplying
the corresponding dose coefficient (i.e. for 238U, 235U and 234U) by the isotopic activity for each level ofenrichment [I7, I11].
106. The ICRP provides reference dose coefficients per intake of uranium isotopes for workers [I7]and members of the public [I10] in accordance with the international safety standards of the IAEA [I4].
The values for inhalation by workers and ingestion by members of the public are given in tables 8 and
9, respectively. The f1 values of the ICRP model depend on age, and the model for the systemic
behaviour of uranium is also age-dependent, and so the committed effective dose per unit intake
calculated for ingestion of soluble uranium by members of public exhibits age-dependence (table 9).
Table 8. Committed effective dose per intake (Sv/Bq) for inhalation by workers (for 5 μm AMAD
particulates) [I7]
Solubility group of uranium compound: F (fast soluble), M (moderately soluble) and S (slowly soluble)

Absorption type

Isotope
F
234

U

235
238

M
–7

S

6.4 × 10−6

2.1 × 10

6.8 × 10−6U

6.0 × 10−7

1.8 × 10−6

6.1 × 10−6U

5.8 × 10−7

1.6 × 10−6

5.7 × 10−6

Table 9. Committed effective dose per unit intake (Sv/Bq) for ingestion of soluble uranium bymembers of public [I10]Age at intake
Isotope3 months

1 year

5 years

10 years

15 years

−7

−7

−8

−8

7.4 × 10−8

7.5 × 10

5.0 × 10−8

8.5 × 10−8

7.1 × 10−8

7.0 × 10−8

4.7 × 10−8

8.0 × 10−8

6.8 × 10−8

6.7 × 10−8

4.5 × 10−8234

U

3.7 × 10

1.3 × 10

8.8 × 10235

U

3.5 × 10−7

1.3 × 10−7

238

U

3.3 × 10−7

1.2 × 10−7

Adult

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UNSCEAR 2016 REPORTVII. BIOLOGICAL EFFECTS

A. Chemical versus radiological toxicity
107. Uranium represents a particularly difficult problem for internal emitter studies because of its
chemical and radiological toxicities. It is a radioactive heavy metal, and it is difficult to characterizedifferences in responses to the metal component alone, the radioactivity alone, or the possible combined
effects of both. Some studies on DU have attempted to define the metal component, however these arelimited by the presence of radioactivity.
108. Despite the dual toxicity of uranium, few studies investigate the respective parts of its chemical
and radiological toxicities. As with all chemicals, the chemical toxicity of uranium is linked to its
ability to interfere with compounds and biochemical processes in living organisms. The chemical actionof all isotopes and isotopic mixtures of uranium is independent from the specific activity because
chemical action depends only on chemical properties [W13]. However, it is dependent on its physicaland chemical forms. For instance, the NOAEL values measured for uranium effects vary depending on
the absorption type of uranium compound, i.e. F (fast soluble), M (moderately soluble) and S (slowly
soluble). Different reports gave NOAEL values as a function of the administration mode and theexposure duration [A31, W14].
109. Concerning the radiological hazard of uranium, alpha particles do not penetrate beyond the outerlayer of skin, except in regions of thinner skin (the depth varies typically in the range 20–100 µm). The
impact on health of alpha particles of uranium is expected mainly after internal contamination anddepends partly on the route of exposure (inhalation or ingestion) [W14].
110. Both natural uranium and DU pose primarily chemical rather than radiological hazards in the
short term. The toxicity of uranium depends on its chemical form and the route of exposure [A31]. The
potential health effects arising from uranium exposure are discussed below. Some effects are related tothe chemical toxicity of uranium, notably renal effects, while other effects are mainly due to theradiological toxicity of uranium, such as tumorigenic effects.
111. The relative importance of chemical and radiological toxicities of uranium thus depends on the
degree of enrichment of 235U (and 234U), the compound solubility, the chemical speciation and the modeof incorporation [A31, S46, T9]. Chemical toxicity from uranium exposure appears mainly in thekidneys and is assumed not to occur below a threshold concentration. The thresholds given in theliterature are most often derived from a NOAEL in animal experiments with the application of an
appropriate safety factor for transposition to humans [A31]. Human autopsy data are used to confirm
these observations [A31, S43].
112. Stradling et al. discussed anomalies between radiological and chemical limits for uranium after
inhalation by workers [S41]. As a consequence of the different procedures used in their calculation,
they are incompatible and adherence to one limit may result in a breach of the other. They concluded
that for chronic intake by members of the public, it can be deduced that a unified exposure level of
0.5 µg/kg per day or a daily intake of 35 µg would be acceptable in most cases. More recently, Thorne
and Wilson proposed higher limits corresponding to 2 µg/kg per day or a daily intake of 140 µg [T9].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 391

B. Kidneys
113. The limited human studies suggest that damage to the kidneys can be detected following chronic
exposure that results in uranium concentrations as low as 0.1 µg per gram kidney [R28]. Human studies
also suggest that acute intake which leads to a peak uranium level of about 1 µg per gram kidney canlead to detectable kidney dysfunction [R28]. Some authors have aimed to predict renal concentrations
in human populations exposed to uranium for dose assessments [C21, S31]. In the epidemiologicalsection some human data are presented of populations exposed to high uranium concentrations indrinking water.

1.

Acute exposure

114. Morphological renal modifications induced by uranium (from 0.1 mg/kg after injection) werereported in rodents in several experimental studies, suggesting that the kidneys are the major target
organ of acute uranium toxicity independent from the route and duration of exposure [B25, D17, G27].
Histopathological changes, including degenerative changes or necrosis of the proximal tubularepithelium and glomeruli, were reported after acute exposure in rats [D12, M16]. Further, somehistological alterations were noted in renal tubules of rats following chronic exposure with elevatedconcentration of uranium [G10, O7]. Thus, acute exposure may lead to alteration of glomerules andtubules, whereas chronic exposure to uranium seems to affect only tubular functions. Following
intramuscular injection of DU, rats undergo dose-related tubular necrosis and glomerulonephritis. After30 days, glomerular damage is reversible in rats at all doses (0.1–1 mg/kg) but there is a dose dependent
delay in the initiation of the regeneration, seen first in the low-dose group (0.1 mg/kg) [Z17].
115. An experimental study performed by Shiquan et al. on rats considered a wide range in uranium
concentrations of 5, 2.5, 1.0, 0.5, 0.25, 0.1, 0.05, 0.025, 0.01, 0.0075, 0.005, 0.0025 and 0.001 mg/kg,
administered by intraperitoneal injection as uranyl nitrate [S14]. Doses from 0.01 to 0.05 mg/kg
induced slight renal damage. The lowest dose that induced renal damage in all rats of one group was
0.1 mg/kg. At the highest dose (5 mg/kg), necrosis of the proximal tubular epithelium was observed
after 6–12 hours, and half the rats died after 6–8 days. Primary damage to the kidneys was necrosis of
the proximal tubular epithelium. After repair with regeneration, different degrees of fibrous scarring
were found in the kidneys.
116. The third segment of the proximal convoluted tubule is the most affected site in the kidneys ofrats [G11] and humans [M9]. Experimental studies performed on dogs [M63] demonstrated that thecomplexed uranium (VI) is filtered from blood via the glomeruli. In the proximal tubule, water isreabsorbed and uranium is concentrated. As urinary flow acidifies, uranium (VI) complexes are
dissociated and uranium can bind epithelial membrane proteins. Uranium kidney retention thusincreases with urinary acidity and decreases with uranium complexation.
117. Table 10 summarizes studies of the toxic effects of uranium on the kidneys of rats following acuteexposure. Biological effects indicating toxicity of uranium to the kidney were noticed starting from
0.1 mg/kg [Z17] to 126 mg/kg of body weight [F18]. Most of the studies were done on rats and showeda decreased creatinine clearance and an increased electrolyte or protein excretion, indicating tubular
alterations of the kidneys [B5, F18] that can also be associated with liver alteration as shown by
increased transaminase level [G29].
118. Shude and Suquin et al. reported dose evaluation and medical follow-up of a case of acuteuranium compound intoxication [S16, S49]. A nuclear worker received both thermal and acid burns. A

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UNSCEAR 2016 REPORT

solution of uranyl nitrate hexahydrate was spurted on his body, and uranium was absorbed through theskin to blood. Acute renal failure and toxic hepatitis occurred during several days post-accident andrecovery occurred one month later. The amount of uranium taken into the body as a result of thisincident was calculated to be 116 mg [S16, S49]. The result of 33 years’ follow-up showed that thefunction of kidney and liver were normal. Chromosome aberrations of peripheral lymphocytes wereobserved, including ring, fragment and dicentric. The results of other examinations were at normal
levels, including peripheral blood, bone marrow, immune system, cardiovascular and respiratory
function, endocrine and metabolism [S49].
Table 10. Summary of studies of toxicity of acute exposure in kidneys of adult rats
ip: intraperitoneal; im: intramuscular; iv: intravenous; BUN: blood urea nitrogen; GFR: glomerular filtration rate; LDH: lactate
dehydrogenase; AST: aspartate aminotransferase; ALT: alkaline phosphatise; BW: body weight

UraniumcompoundUranylnitrateExposureconditions
ip 0.001–5 mg/kg

Postexposure
follow-up
8 daysSex
Biological effects
Male

Necrosis of the proximal tubularepitheliumStudyreferences[S14]

Damage repair with renal fibrous scar
Half died after 6–8 days in the highestdose group
Uranylacetate

ip 0.1–1 mg/kg

30 daysMale

Increased creatinine, BUN and albuminat high dose in serum[Z17]

Uranylnitrate

ip 0.5 mg/kg

5 daysMale

Increased creatinine, urea, cholesterol,phospholipids in plasma[B5]

Uranylfluoride

ip 0.66 mg/kg

110 days

Male

Decreased kidney weights[D12]

Uranylnitrateim 0.2–2 mg/kg

28 daysMale

Decreased plasma ALT, AST, protein
and increased urea, creatinine, ALP[F18]

Uranylnitrateip 10 mg/kg

28 daysMale

Increased concentrations of sodium
and protein in urine[H6]

Increased LDH, AST in plasma andprotein, albumin in urine

Decreased GFRUranylnitrateip 11.5 mg/kg

3 daysMale

Increased creatinine, urea, ALT, AST
plasma levels[G25]

Uranylnitrateim 7.9–126 mg/kg

28 daysMale

Decreased BW and died after 3–7 days

[F18]

Uranylnitrateip 5/10/20 mg/kg

2 daysMale

Histopathological lesions[A18]

Uranylnitrate

ip 50–500 μg/kg

21 daysFemaleRenal morphological alterations (at thefirst dose, becoming increasingly
prominent with higher doses)[B17]

Uranylnitrateiv 15/25 mg/kg

17 hours

FemaleChanges in endothelial cellmorphology for the higher dose

[A33]

Increased plasma creatinine and urea
plasma levels

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 393

119. Other high human exposure—accidental or deliberate—were reported. Roszell et al. reported
27 cases of human exposure to uranium and the resulting kidney effects [R24]. The uranium burden
estimated in the kidneys ranged between 10 µg/g kidney after accidental inhalation of UF4 powder[L48] and 100 µg/g kidney after deliberate ingestion of 15 g uranium acetate [P9]. Early symptoms ofrenal failure were noted in the first weeks after exposure, with renal dysfunction observed in somecases until 6 [P9] or 18 months [L48] after exposure. Kathren and Moore re-evaluated the intake anddeposition of soluble natural uranium compounds in three men accidentally exposed in an explosion in
1944. One of the three exposed individuals showed an altered clearance pattern for uranium shortly
after the accident, possibly from pulmonary oedema associated with concomitant exposure to acidfumes. However, medical examinations of two of the men 38 years after the accident revealed no
detectable deposition of uranium [K4].
120. Table 11 provides a summary of the effects of chronic uranium exposure on the kidneys ofexperimental animals. Conversely, chronic exposure did not clearly induce a toxic effect on the kidneysof mammals, with duration of exposure from three to twelve months and exposure level from 0.02 to
200 mg/kg. Tissue alteration of the tubules or glomerules was observed only for uranium doses above
400 mg/kg [G10, Z13]. After a nine-month chronic exposure to uranium via ingestion of uraniumcontaminated drinking water, the kidneys of rats did not show signs of histological lesions for uranium
renal levels >3 µg/g (3 µg/g for 120 mg/L [D29] and 6 µg/L for 600 mg/L [P23]).
121. Gilman et al. [G10] noted that effects on the kidneys could be seen at uranium levels of 0.06 mg ofuranium per kilogram of body weight per day for male rats. Nevertheless, no rise in histopathologicalseverity with increasing dose was reported: histological lesions starting from the lowest concentration(0.96 mg/L, 0.09 mg/kg body weight) were not significantly different from the kidney lesions observed forthe highest concentration (600 mg/L) [G10, G11]. No clear dose-dependent effect was observed after
chronic exposure. Indicators of kidney function after acute exposure (0.1–10 mg/kg) included theconcentrations of blood urea nitrogen (BUN), creatinine in blood or protein in urine [B5, F18, G23, H6,
O7]. Conversely, only limited changes were identified for chronic exposure to uranium in drinking water(2–16 mg/kg) [G11, O7] or from implanted DU pellets (200 mg/kg) [P12, Z13, Z14].
122. Various urinary parameters—including levels of urea, glucose, creatinine, total protein, and albumin
and also activities of LDH and N-acetyl-beta-D-glucosaminidase (NAG), and glucose excretion—had themost persistent effect after chronic exposure [G10]. Complementary studies showed that chronic low doseuranium exposure did not modify the nephrotoxic effects of gentamicin renal response as evidenced by therenal tissue levels of kidney injury molecule (KIM-1), osteopontin, and kallikrein [R27]. The results
observed with osteopontin were different from those found in clinical studies, which indicated a decreased
osteopontin level in urine [P30]. Gentamicin-induced increase in renal levels of KIM-1 was augmented inrats previously exposed to uranium as compared to uncontaminated animals.
123. In a dose-response study (0.27–40 mg/kg) of chronic oral exposure of rats, nephrotoxic andpro/anti-oxidant effects were analysed after three- and nine-month exposure [P23]. The uranium
content of the kidneys was proportional to uranium intake after three and 9 months of contamination. It
reached 6 µg/g of kidneys for the highest uranium exposed group, a nephrotoxic level for acute intake.
Uranium microdistribution analyses showed that it was found mainly in the nucleus of renal proximal
tubular cells and to a lesser extent in other renal structures. Nevertheless, no renal impairment wasobserved according to histological analysis or measurements of sensitive kidney biomarkers such as
KIM-1, 2-microglobuline or retinol binding protein. Uranium contamination appeared to reinforce theantioxidant system in the kidneys as the glutathione pool increased dose-dependently up to tenfold.

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UNSCEAR 2016 REPORT

Table 11. Summary of studies of biological effect of chronic exposure to uranyl nitrate on kidneysof male adult animals
PCT: proximal convoluted tubule

Follow-up

Biological effects

Studyreferences

Species

Exposure conditions

Rat

Oral
100 mg/kg

27 days

Histopathological lesions (increased when
exposure duration increased)

[G15]

Rat

Oral
0.02–40 mg/kg

91 days

Decreased haemoglobin, erythrocytes,
glucose not correlated to the concentrationin drinking water[G11]

Histopathological lesions in the lowest group
Rat

Oral
2.7 mg/kg

275 days

Decreased plasma vitamin D and vitamin D
target genes in the kidney tissue

[T11]

Rat

Oral
2.7 mg/kg

275 days

Following single exposure toacetaminophen (paracetamol), increased
PCT necrosis of the kidney

[G26]

Rat

Oral
2–16 mg/kg

28 days

Increased glycaemia whatever the dose inplasma

[O7]

Mouse

Oral
13–26 mg/kg

122 days

Decreased urea and increased creatinine inplasma[T4]

RabbitOral
0.02–400 mg/kg

91 daysNo biochemical changes

[G10]

Rat

Muscle implantation
200–600 mg/kg

91 and 360 days

Increased plasma urea, creatinine andurinary beta-2 microglobulin and albumin

[Z14]

Rat

Oral
0.014-8 mg/kg

275 days

No biochemical changes

[D29]

Oral
0.27–40 mg/kg

91 and 275 days

Rat

Kidney histopathological lesions in thehighest group

No renal histopathological lesions
Glutathion increase dose-dependently andlipid peroxidation decrease in kidney[P23]

No nephrotoxity (biomarkers and histology)

124. A study by Silver et al. provided information regarding non-malignant chronic kidney disease[S19], which proved to be non-significant. There was a trend in chronic renal failure deaths in the
Colorado uranium miller cohort with duration of uranium milling employment (SMRs of 1.27, 1.33 and1.53 for 1–2, 3–9 and ≥10 years of employment, respectively) [P21]. However, when treated end-stage
renal disease for those receiving renal dialysis or kidney transplants, the incidence was evaluated using
the ESRD program (End Stage Renal Disease) date, there was no excess (SIR=0.71, 95% CI:
0.26-1.65). In the Fernald cohort, mortality from chronic renal disease was not related to uranium
exposure [S19] (see also table 18). Other studies of uranium worker cohorts indicated no significant
overall excesses of chronic kidney disease death [B38, C20, D33, M26, M27, P24]. Some renal effects
were studied in humans following chronic exposure to uranium via drinking water. These data areshown in appendix A, table A11, which summarizes the published literature on the health effects ofhuman exposure to uranium through ingestion of surface or groundwater.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 395

2.

Influence of age

125. Few studies have investigated the influence of age at exposure on renal toxicity. The first results
considering this issue were published before 1920 for studies using dogs [M3]. The author
demonstrated that older animals developed more severe uranium poisoning than young animals,
associated with more marked histological alterations, leading to an impaired functional capacity [M3].
This result was corroborated by a more recent experiment, also performed on dogs [P10]. Uranium
effects on renal function (glomerular filtration rate) were more severe in older (3/4 weeks) than inyounger dogs (1/2 weeks). Recent publication of an experiment performed on rats with 0.1–2 mg/kg ofuranium acetate indicated a higher uranium concentration in the kidneys of neonatal animals than in
prepubertal or adult animals [H22].
126. Magdo et al. studied the effects of the high uranium concentration in drinking water of a private
wells used by a family (two adults and five children). The authors measured concentrations of up to(1,160 µg/L) in the groundwater [M5]. The authors evidenced a nephrotoxicity in the youngest family
member (a three-year-old child), demonstrating the highest sensitivity to uranium exposure. This caseshows potential for significant residential exposure to naturally occurring uranium in well water. It
highlights the special sensitivity of young children to residential environmental exposures, a reflectionof the large amount of time they spend in their homes, the developmental immaturity of their kidneys
and other organ systems, and the large volume of water they consume relative to body mass [M5].
However, this result appears inconsistent with observations made in young rodents.

3.

Biological mechanisms

127. According to Leggett [L21], uranium binds to the luminal brush-border membrane of tubules.
This binding decreases reabsorption of sodium and other compounds, resulting in an increased urinary
excretion of proteins, glucose, catalase, phosphate, citrate and sodium without causing cellular damage[B25]. Uranium can then separate from the luminal membranes by a number of mechanisms including
association with complexing ligands from the urinary tubular flow, detachment of uranium-boundmicrovillosities, and elimination of dead cells. The mechanism by which uranium then enters tubularcells has been investigated. Once in the cytoplasm, uranium accumulates in lysosomes, where it
precipitates with phosphate, forming microcrystals at high concentrations [M47]. This process induced
destruction of the lysosome.
128. The mechanisms of uranium effects on the kidneys have not been fully elucidated. The relations
between uranium penetration into and distribution within cells and its toxicity was analysed in kidney
proximal tubular cells. Some authors posited that uranium did not need to penetrate cells to exert its
toxic effect [L21, M68] while others posited that it did [L1, M47]. Rouas et al. have suggested that thephysical form of uranium (soluble or precipitate) and its intracellular localization play a role in cell
toxicity [R26]. They suggested that uranium may be visualized in the nuclei in kidney cultured cells
exposed to uranyl nitrate. Experimental studies have indicated that uranium exposure of animals (rats ormice) at 5–25 mg/kg may induce changes in solute transport [G11, T5], protein biosynthesis-related
genes [T4, T5] or cell signalling [P26, T5].
129. Several studies reported effects of uranium on renal transporters, Na+,K+-ATPase [B48], sugartransporters [G17, N4, R19], sodium-dependent phosphate cotransporters [M68, M69] and organic
cation transporters [M4, S13] but these effects were studied only in vitro using relatively high uranium
concentrations.

396

UNSCEAR 2016 REPORT130. Mitochondrial dysfunctions have recently been demonstrated in rats after injection at 0.5, 1 and
2 mg/kg per intraperitoneal injection [S9]. Isolated mitochondria from the uranyl acetate-treated rat kidney
showed a marked elevation in oxidative stress accompanied by mitochondrial membrane potential
collapse as compared to the control group. In addition, direct incubation of isolated kidney mitochondria
with uranyl acetate (50, 100 and 200 µM) suggested that uranyl acetate can disrupt the electron transfer
chain at complex II and III.
131. To investigate the influence of uranium speciation on its toxicity, cells representative of rat kidney
proximal epithelium (NRK-52E) have been exposed to uranyl-carbonate and -citrate complexes,
because they are the major complexes transiting through renal tubules after acute in vivo
contamination. When citrate is added to the exposure medium, the predominant species is uranium(VI)-bicarbonate. Nonetheless, citrate increases uranium (VI) toxicity and accelerates its intracellularaccumulation kinetics without inducing precipitation [C10].
132. Uranium can induce cell death but the exact mechanisms are still unclear. Some proposedmechanisms include apoptosis or genotoxicity [M54, T6, V5]. The mechanisms of acute toxicity ofuranium (from 50 to 500 µM) have been studied in renal cell lines and have shown a specific uranium
signature characterized by the downregulation of tubulin and actin [P27]. The most investigatedmechanism to explain uranium toxicity is the oxidative stress response, investigated both in vitro on
cell cultures and in vivo following acute or chronic exposure in rats and mice [B5, S9, T4, T5, T6]. The
results of these studies suggested uranium-induced oxidative stress imbalance with an increased
reactive oxygen species production associated with a depletion of endogenous cellular antioxidants forelevated concentrations administrated to cells (>400 µM) or to animals (>0.5 mg/kg).
133. Several studies have focused on the interaction between iron metabolism and uranium, in
conjunction with the affinity of these two elements for some proteins such as transferrin, ceruloplasmin
and ferritin [V8]. These studies revealed changes in gene expression and protein carriers of iron, DMT1
(Divalent Metal Transporter Type 1) and Fpn (ferroportin), in the liver and kidneys [B19]. A similar
study [D19] performed on rats chronically exposed to uranium in drinking water (2.7 mg/kg/day)showed the appearance of iron granules (aggregates) in the kidneys, indicating that chronic
contamination by uranium could cause long-term changes in the regulation of iron metabolism. A
recent study using surface plasmon resonance techniques has shown a strong affinity of fetuin-A
protein for uranyl ions even though this protein is present in a very small amount [B7].

4.

Conclusion

134. The kidneys are known as the most sensitive target organ after acute exposure, on the basis ofwell-documented studies. Studies on rodents (mice and rats) indicated that injury to the kidneys occurs
from 0.1 mg/kg whole body and renal concentrations of >3 µg/g, targeting the third segment of theproximal convulated tubule. Conversely, data on chronic exposure to low uranium doses are more
recent and have not shown clear nephrotoxic effect at 2–20 mg/kg and no specific biomarkers havebeen identified to date. New blood plasma or urinary biomarkers of the renal function or integrity havebeen investigated in experimental or clinical studies, with a view to allowing a precise diagnosis of thekidney function [G27]. Mitochondrial dysfunction seems to be involved in toxic mechanisms ofuranium, but the mechanisms of its toxicity are not fully elucidated to date, especially after chronic
exposure to low and high doses. Further experimental studies are necessary for a better comprehensionof the renal alteration process and the identification of more specific biomarkers of kidney alteration.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 397

135. Chemical effects on the kidneys are usually assumed not to occur below certain thresholdconcentrations of uranium; most often, these findings have been derived from animal experiments withthe appropriate safety factors applied to human exposure [A31]. Maximum concentrations over 3 μg of
uranium per gram of kidney have been used as the basis for occupational exposure limits (e.g. [H20,
L21]). Leggett [L21] suggested that the occupational limit based on 3 μg of uranium per gram of kidney
is about tenfold too high for non-occupational exposure. Indeed, some human studies suggest thatdamage to the kidneys can be detected following chronic exposure that results in uranium
concentrations as low as 0.1 µg per gram kidney [R28]. Thorne and Wilson [T9] suggested 30 µg U/kg
kidney as a level below which effects will not be observed. Further, following a review of the existing
literature, Leggett et al. have recommended that “the concentration of uranium in the kidney should notexceed 1 μg U/g kidney at any time” [L25].

C. Bone1.

Acute exposure136. Several animal experiments demonstrated a high uranium accumulation in bones of rats and dogs
[A23, A24, P31]. Several studies performed on rats have investigated the effects of uranium on bone
physiology. These studies found an impairment of bone growth and bone formation [P33, U1, U2].
These effects were associated with inhibition of endochondral ossification in mice [B45] and in rats
[D15]. Other rat experiments indicated that uranium induced ultra-structural alterations in osteoblasts[T3]. An acute high dose of uranyl nitrate also delayed both tooth eruption and development in rats
[P33]. However, the retardation observed seven days after acute uranyl nitrate exposure was reversed
completely after 27 days [P34].
137. The in vivo results were confirmed by in vitro studies that showed that human osteoblasts weresensitive to uranium effects (increased reactive oxygen species production, decreased alkaline
phosphatase activity, modified osteoblast phenotypes, genomic instability) [M38, M39, M42, T3]. An
increase in oxidant stress shown by an increased lipid peroxidation was also observed in vivo in rat
bone at high doses [G8].

2.

Chronic exposure138. On the basis of measured tissue concentrations and organ weights [F4, F8, L22, W26], bone tissue
may contain up to 66–75% of the body burden of uranium following chronic exposure to uranium.
139. Several rat studies were designed to determine the uranium content of bones following chronic
contamination [A24, P3, R18]. Rodrigues et al. showed that accumulation of uranium in the rat skeleton
following intake via food increased to reach a plateau after one month [R18]. A long-term study ofPaquet et al. demonstrated that uranium accumulation in bones increased until 18 months [P3].
140. Some experiments investigated the long-term accumulation in bones of young male rats (between
the weaning and the post-puberty periods) [A23, R18]. Experiments performed on females during thegrowing period indicate that concentration of uranium in the animals’ femora increased faster in theearly stages of the animal life, then saturating in adult animals.

398

UNSCEAR 2016 REPORT141. Contamination of growing rats with uranium in food led to accumulation in bones (0.1–1.1 µg
U/g bone) that exhibited the same pattern as the skeleton growing curve. Despite this accumulation,
there was no change in the bone mineral density (BMD) [R18]. However, uranium exposure of adults
led to a decrease in the BMD.
142. In contrast, a study of chronic exposure of growing rats to natural uranium for nine months via
daily oral ingestion (uranium-contaminated drinking water at 40 mg/L) affected the skeleton by
decreasing messenger RNA (mRNA) expression of genes involved in bone metabolism and decreasing
femoral cortical bone area, while no changes were observed in adult rats [W1]. Chronic contamination
by subcutaneous implantation of powdered uranium dioxide (125 mg/kg) in rats resulted in an
inhibition of bone formation as has also been described for acute poisoning with uranium [D15].
143. Bone metabolism was investigated in human populations receiving high levels of uranium via
drinking water by measurements of biochemical indicators of bone formation (osteocalcin and amino
terminal propeptide of type I procollagen) and a marker for bone resorption (serum type I collagencarboxy-terminal telopeptide (CTx)) [K27]. The authors showed an elevation of CTx and osteocalcin
that could be associated with increased uranium exposure.

3.

In vitro studies: mechanisms

144. The cytotoxic effect of uranium on rat and human osteoblasts is highly dependent on its
speciation. Exposure to non-toxic doses or non-toxic species of uranium induces the activation of twomarkers of bone formation and mineralization (osteocalcin and bone sialoprotein), while their inhibition
is observed after toxic exposure [M37, M38]. This study highlights the importance of a controlled
speciation of uranium in toxicological studies.
145. In vitro transcriptomic studies performed on several human cell lines taken from kidneys or lungs
as representative targets have highlighted the involvement of osteopontin in the uranyl toxicity
mechanisms [P29]. This major non-collagenous protein involved in the organo-mineral homeostasis of
the bone presents a specific composition in acidic clusters associated with numerous phosphorylations,and also a relative plasticity. Qi et al. showed with in vitro models that native phosphorylated
osteopontin binds uranyl with a nanomolar affinity and that this binding induces conformationalchanges enabling the formation of a very stable complex of uranium [Q1].

4.

Conclusion

146. In conclusion, acute and chronic exposure to uranium-induced biological effects on bonemetabolism such as the impairment of bone growth and of bone formation and the inhibition of
endochondral ossification or the delay of development. Most effects were observed in experimental
models (rodents or isolated humans cells). One study performed on humans exposed to high levels of
uranium in drinking water showed an elevation of type 1 collagen carboxy-terminal telopeptide (CTx),a plasma marker for bone resorption, and of osteocalcin, indicator of bone formation [K27]. All thesestudies—in animals and humans—suggest that uranium affects bone turnover. Osteoblasts appeared tobe the main cell targets of uranium. Some effects were also observed in humans, indicating that bone
may be a target of uranium chemical toxicity in humans.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 399

D. Lungs
1.

Acute exposure147. In general, the more soluble compounds (uranyl fluoride, uranium tetrachloride, uranyl nitrate) areless toxic to the lungs but more toxic to distal organs due to easier absorption of the uranium from thelungs into the blood and systemic transport [G1].
148. The behaviour of uranium in the lungs following inhalation has been studied in animal
experiments from various industrial settings [A31, C30, C31, D3, E3, S35, S38, S39, S40, W19, W20].
These studies demonstrated that the behaviour of uranium, its distribution, and its clearance in lungs isdependent on the solubility of uranium compounds. Results of these experiments were used to confirm
or improve the ICRP models as described in chapter V on biokinetics.
149. Concerning the clinical effects of uranium in the respiratory system, authors reported alveolar
fibrosis in rats [M60], congestion and haemorrhage in rats and guinea pigs [L19] and bronchopneumonia
in rats and rabbits [D36] for uranium levels of between 10 and 100 mg/m3. The comparison of repeated
and acute uranium exposure via inhalation was performed in rats [M55] with aerosols varying from 116 to
375 mg/m3. The results showed that UO2 repeated pre-exposure by inhalation increased the genotoxic
effects of UO4 inhalation, when UO4 exposure alone had no effect. However, it is not clear if these effects
were due to a potentiation of the effect of UO4 by pre-treatment with UO2 or to a cumulative effect of thetwo types of exposure.

2.

Chronic exposure150. Experimental studies performed on dogs, monkeys and rats with uranium show that inhalation ofnatural uranium dioxide (UO2) at a mean concentration of 5 mg U/m3 for periods as long as five years led
to pulmonary neoplasia and fibrosis [L18]. Pulmonary neoplasia developed in a high percentage of thedogs examined two–six years after exposure. Pulmonary and tracheobronchial lymph node fibrosis,
consistent with radiation effects, was dose dependent and more marked in monkeys than in dogs.
151. Nose only inhalation in rats showed that chronic inhalation of natural uranium ore dust (without
significant radon content) created a risk of primary malignant and non-malignant lung tumour
formation [M49]. The frequency of primary malignant lung tumours was 0.016, 0.175 and 0.328 andprimary non-malignant lung tumours 0.016, 0.135 and 0.131 in the control, low (19 mg/m3 leading toan absorbed dose of 0.87 Gy) and high (50 mg/m3 leading to an absorbed dose of 1.64 Gy) aerosol
exposed groups, respectively, without difference in tumour latency between the groups. Despite lymph
node specific burdens ranging from 1 to 60-fold greater than the specific lung burden in the same
animal, no lymph node tumours were observed.

3.

In vitro studies: mechanisms

152. Inhalation of soluble uranyl nitrate led to uranium uptake in the lysosomes of alveolar
macrophages and precipitation in the form of insoluble phosphate [B20]. A study by Lizon and Fritschon alveolar macrophages with uranium concentrations from 5 × 10−5 to 10−3 M showed that the toxicity
of uranium was concomitant with the presence of insoluble forms in the culture medium [L40].

400

UNSCEAR 2016 REPORT153. Orona and Tasat analysed rat alveolar macrophages to better understand the pathological effects
associated with DU inhalation, metabolic activity, phagocytosis, genotoxicity and inflammation [O6].
The effects of 12.5–200 μM DU seemed to be dose-dependent, most observed from 100 µM. At low
doses, DU induced phagocytosis and at high doses, provoked the secretion of TNFα. Apoptosis was
induced through the whole range of doses tested. The uranium-induced TNFα secretion bymacrophages was consistent with results from previous studies [G5, Z11]. Lung fibrosis was correlatedwith abnormal expression of TNFα and IL−6, which could be antagonized by antibodies against TNFα[Z11, Z12].
154. Orona and Tasat suggested that at low doses (12.5 µM), DU induced O2−, which may act as theprincipal mediator of DNA damage, while at higher doses (200 μM), the signalling pathway mediatedby O2− may be blocked, and the prevailing DNA damage would be by TNFα [O6]. A study by Monleau
et al. indicated that exposure to DU by inhalation resulted in DNA strand breaks in broncho-alveolar
lavage cells and in an increase in inflammatory cytokine expression and production of hydroperoxides
in lung tissue [M56].
155. In addition to effects on pulmonary macrophages, a study showed that uranium (from 0.25 to1 mM) induced significant oxidative stress in rat lung epithelial cells followed by a concomitantdecrease in the antioxidant potential (glutathione and superoxide dismutase) of the cells [P13]. Further,some publications indicated that not only soluble (uranium acetate) but also particulate (uranium
trioxide) uranium induced concentration-dependent cytotoxicity in human epithelial cells [W22].
156. Depleted uranium was clastogenic and induced chromosomal aberrations after 48 hours [L4]. Xie
et al. [X1] found a loss of contact inhibition of these cells after particulate DU exposure, withchromosome instability and a change of cell phenotype, suggesting a neoplastic process.

4.

Conclusion

157. Experimental acute and chronic studies demonstrated possible effects of uranium on fibrosis andtumour formation in lungs. Data obtained in vitro indicated the induction of genotoxic lesions (DNAstrand breaks) and activation of inflammatory pathways on alveolar macrophages with high uranium
concentrations. However, these underlying mechanisms were not investigated in vivo, limiting therelevance of these molecular effects to understand the link between uranium exposure and observed
pathologies (fibrosis and tumour formation).

E. Liver158. Accumulation of uranium was observed in the liver of rats after injection, implantation or oral
administration (uranyl nitrate) but at a lower concentration than in the kidneys for the same level of
exposure [C35, P3, P11]. Acute exposure led to decreased liver weight and increased plasmatransaminase levels, both indicators of liver hepatotoxicity in rats [G24, M57, O7] and in mice [O11].
159. More recently, some results were published on hepatic effects of uranium following in vivo
exposure of rats [D29, G29], which demonstrated that some enzymes of xenobiotic metabolism, notably
the cytochrome P450 of type 3A (CYP3A), were modified by chronic contamination with DU. The
time-course study performed at 1, 3, 6, 9 and 18 months after exposure indicated that significant
changes were observed at six and nine months [G29], with a 50% decrease in the mRNA level ofANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 401

CYP2C11 at six months and an increase in gene expression of CYP3A at nine months. Concerning thedose–response study, the most substantial effects were observed in the liver of rats after nine months of
exposure to 120 mg/L: CYP3A gene and protein expression and enzyme activity all decreased by morethan 40% [D29, G29].
160. Several studies investigated the functional consequences of a co-exposure to uranium (uranyl
nitrate) and the drugs chlorzoxazone [C26, M57], ipriflavone [C25], theophylline [Y4] or paracetamol[G27, R25] in rats. Altered drug pharmacokinetics was observed with high dose and chronic low dose
exposure to uranium, which could be due to liver dysfunction. Functional toxicity of uranium was also
estimated by measuring xenobiotic detoxification enzymes and their gene expression levels, protein
levels or enzyme activities. Some studies reported altered levels of xenobiotic detoxification enzymes[G27, P6] while others reported altered pharmacokinetic metabolism of certain drugs after acute [C25,
C26, M57] and chronic exposure to uranium [G27]. Oxidative stress may also occur in hepatocytes
exposed to uranium, as demonstrated by mitochondrial or lysosomal alterations [P26] ormetallothionein involvement [M47].
161. Chronic contamination with DU (uranyl nitrate, 1 mg/rat/day for 9 months) affected cholesterol
metabolism in the rat liver [R2]. Relative mRNA levels of the enzyme cholesterol storage weremodified, and also the proteins involved in the transport and the regulation of cholesterol homeostasis.
One accident involving workers with extensive skin exposure to uranium has been reported in theliterature [L48, S16, S49]. These results were similar to observations from the clinical follow-up of
workers with acute uranium compound intoxication. Toxic hepatitis occurred for several days postaccident with recovery one month later [S16]. The result of 33-year follow-up showed that liverfunctions were normal [S49]. In conclusion, experimental studies performed in rats indicated thaturanium exposure induced some biological effects on the liver, without a high uranium accumulation inthis organ. These biological effects did not lead to the appearance of pathologies in animals. However,in humans, one study reported a transient toxic hepatitis.

F. Brain1.

Behavioural effects

162. Adult rats exposed to uranium showed subtle but significant behavioural changes. Increases inlocomotor activity, in line crossing and in rearing behaviour were observed after exposure of rats to DU
in drinking water at 2 or 4 mg/kg per day or after inhalation [B52, M54]. Females seemed to be moreresistant: unlike males, they did not show locomotor symptoms [B51]. Exposure to uranium to 0.1, 0.3
or 1 mg uranium/kg also affected working memory with poorer performance (decreased latency) in alight–dark passive avoidance response system [B6]. The spatial working memory measured by thepercentage of spontaneous alternation was significantly lower after exposure to DU by inhalation andafter ingestion of 1 mg per day of 4% enriched uranium [H24, H25, M54]. Lastly, exposure at this doseof enriched uranium had a deleterious effect on anxiety and increased the amount of rapid eye
movement in sleep [H24, H25, H26]. However, DU had no significant effect in the same experimental
conditions [H24, H26, L30]. A recent review summarized the different effects of uranium on behaviour.
It can lead to neurobehavioural impairments, including increased locomotor activity, perturbation of thesleep-wake cycle, decreased memory, and increased anxiety. The mechanisms underlying theseneurobehavioural disturbances are not clearly understood [D16].

402

UNSCEAR 2016 REPORT163. Mouse experiments were conducted on ApoE−/− mice that had been genetically knocked out for
the apolipoprotein E gene, the product of which regulated cholesterol metabolism. These mice had
hypercholesterolemia and expressed biochemical markers of Alzheimer’s disease. Administration of
DU to these mice resulted in impaired memory compared to unexposed ApoE−/− mice [L33]. This
cognitive effect was associated with a trend toward higher total cholesterol content in the cerebral
cortex (+15%). This study demonstrated that some pathological conditions may increase sensitivity touranium. Table 12 summarizes the main studies on animal behaviour after uranium exposure.
Table 12. Summary of studies of uranium exposure on rodent behaviour
im: intramuscular; DU: depleted uranium; EU: enriched uranium

UraniumcompoundSpecies

Exposure conditions

Main biological effects

Reference

UranylacetateAdult rat

2 and 4 mg/kg/day (water) DU
during 2 weeks and 6 months

Increased locomotor activity[B52]

UranylnitrateAdult rat

2.5, 5 and 10 mg/kg/day (water)
DU during 3 months

Increased locomotor activity,
decreased spatial memory[B11]

UranyldioxideAdult rat

Inhalation DU 30 min at
197 mg/m3, 4 days a week for
3 weeks

Increased locomotor activity anddecreased spatial memory one
day post-exposure[M54]

UranylacetateAdult rat

im. 0.1, 0.3 and 1 mg/kg DU

Decreased locomotor activity,
decreased grip strength,
decreased working memory at 6,
13, 20 and 27 days post-dosing[B6]

UranylnitrateAdult rat

1 mg/kg/day (water) 4% enricheduranium (EU) during 1.5 months

Decreased spatial memory,increased of anxiety[H25]

UranylnitrateAdult rat

1 mg/kg/day (water) 4% EU during
1.5 months

Increased paradoxical sleep[L29]

UranylnitrateAdult rati.p. 144 μg /kg

No change in sleep-wake cycle[L30]

UranylnitrateAdult rat

1 mg/kg/day (water) 4% EU during
3 or 9 months

Decreased spatial memory[H24]

Uranylacetate

Fetal
mouse

1, 2 and 4 mg/kg/day DU during
gestation and lactation

Accelerated appearance righting
reflex, forelimb placing, grasping,swimming and weight gain

[B50]

Uranylacetate

Young
mouse

1, 2 and 4 mg/kg/day (water) DU
during 21 days since the birth

Decreased locomotor activity,
decreased working memory[B51]

UranylacetateFetal rat

10, 20 and 40 mg/kg/day (water)
DU during 3 months (male)

Decreased learning in pups

[A10]

UranylnitrateAdult rat

1 mg/kg/day (water) DU during
2 months since the birth

Decreased spatial memory[B15]

Uranylnitrate

Adult
mouse

4 mg/kg/day (water) DU during 3.5
monthsImpaired memory[L33]

1 and 3 days

(ApoE−/−)

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 403

2.

Neurotransmitters164. Several experimental studies suggest that uranium can induce changes in neurotransmitter levels:
acetylcholine levels were unchanged in the hippocampus after exposure to 1 mg DU per kg and day but
were decreased in the cortex [B14]. Chronic DU contamination induced a fall in the rate ofacetylcholine (ACh) and AChE activity in the entorhinal cortex and cerebellum [B15, B55]. This
disturbance of cholinergic function was associated with a decrease in gene expression of several
proteins [B14]. These studies suggest that the modifications of neurobehavioural tasks following
uranium exposure could be linked with a change of AChE activity in the cerebral cortex [B52].
165. A study performed in Sprague-Dawley rats (following 1.5, 6, or 9 months with 2.7 mg U/kg perday) reported that AChE activity was not significantly affected in the striatum, hippocampus, or frontal
cortex at any time point, but it was significantly decreased in the cerebellum at six months [B55].
Depleted uranium exposure at 2.7 mg/kg per day also induced a significant decrease in AChE activity
in the striatum and cerebral cortex [B14, B55]. A dose–response study performed at nine months
following chronic contamination indicated that uranium effects (15% decrease in AChE activity) wereindependent of uranium content in drinking water (from 0.2 to 120 mg/L).
166. A 1.5-month ingestion of 1 mg U/kg per day increased the dopamine level in the hypothalamus[B55]. Chronic exposure produced a significant decrease in the serotonin (5HIAA) level and theserotoninergic (5HT-ergic) turnover ratio in the frontal cortex and also a decrease in the dopamine(DOPAC) level and dopaminergic (DA-ergic) turnover ratio in the striatum [B55]. It appeared that
disruption of these systems differed depending on the brain structure considered, the time of exposureand the degree of uranium enrichment [A1, B14, B55, L29].

3.

Oxidative stress167. One specific mechanism by which uranium leads to neuro-effects could be oxidative stress. The
behavioural changes correlated with lipid peroxidation in the brain induced by uranium [B52, G8]. The
gene expression or enzymatic activity of the main antioxidant enzymes, i.e. superoxide dismutase,catalase and glutathione peroxidase, increased significantly in the hippocampus and the cerebral cortex
after exposure to DU and decreased after exposure to 1 mg of 4% enriched uranium per kg per day[L31, L38]. The cell response to DU could be interpreted as a defensive mechanism towards free
radical damage to cerebral tissue (increase of several antioxidant agents in order to counteract theoxidative stress). The oxidative stress induced by the enriched uranium is possibly too high to be
counteracted by the cell defences.
168. A dose–response study performed nine months after chronic contamination with DU from 0.2 to
120 mg/L indicated that uranium affected the activity of these enzymes differently (diminution for SOD
and increase for GPx or Catalase). The gene expression of inducible nitric oxide synthase, the enzymethat synthesizes nitric oxide, increased significantly after chronic exposure to 1 mg DU per kg and day[L38]. Repeated administration of DU as uranyl acetate during seven days also increased the nitrite
levels in the brains of rats [A1].

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4.

Exposure of developing animals

169. In rodents, exposures at 1, 2 or 4 mg DU/kg per day during development accelerated theappearance of several types of behaviour: righting reflex (for example, when the rat is put on its back, itturns over immediately), placing reactions (for example, the rat is held by the tail over a table until its
whiskers get near, when it puts its paws on the table), grasping (the rat is picked up and the palm istouched with a wire and the response is to grip the wire), swimming and weight gain [B50].
170. Animals exposed to uranium at 1, 2 or 4 mg U/kg per day during development had a decreased
locomotor activity [B51] and their performance was worse on a test of working memory [B15]. The
spatial learning of the offspring of uranium-exposed male rats at 1, 2 or 4 mg U/kg per day for learning
was also affected [A10]. A dose–response study (0, 10 or 40 mg/L of uranium in drinking water)
indicated no significant uranium effect on behaviour at 10 mg /L, and an impairment of object
recognition memory (−20%) at 40 mg/L [L32].
171. Neurogenesis processes during pre- and postnatal brain development were studied in rats byinvestigating the structural morphology of brain, cell death and cell proliferation after chronic exposure
to drinking water contaminated with uranium (40 and 120 mg/L) [L26]. Major changes were observed
at 120 mg/L, both during prenatal and postnatal periods. At the highest dose, DU caused opposite
effects during brain development on cell proliferation and cell death processes, mainly between prenatal
and postnatal development. These modifications did not have a major impact on brain morphology but
they could affect the next steps of neurogenesis and disrupt the organization of the neuronal network.
172. Some studies were published on the comparative effects of depleted and enriched uranium in rats
[H24, L31]. Chronic exposure to 4% enriched uranium for 1.5 months through drinking water increased
the amount of paradoxical sleep, reduced the spatial working memory capacity and increased anxiety
while no effect was observed following exposure to DU [H24]. These cognitive effects were associatedwith imbalance of oxidative stress [L31]. Indeed, lipid peroxidation was increased in brain after
enriched uranium exposure but not after DU exposure. Enriched uranium induced a decrease of antioxidative enzymes, and DU induced an increase of these anti-oxidative enzymes.

5.

Conclusion

173. Animal studies suggest that uranium can have some negative effects on the behaviour of mature
animals that could be explained at a neurochemical level (neurotransmitters, oxidative stress) for
highest doses. In addition, some results obtained in rats and mice demonstrate differential effects
between depleted and enriched uranium, suggesting the importance of the radiological toxicity ofuranium. The data also suggest that the developing animal may acquire a specific sensitivity to uranium
effects. In humans (workers or public), the correlation between behavioural symptoms and exposure touranium was not demonstrated. Thus, data obtained in animals are only suggestive until they can be tied
to meaningful human research.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 405

G. Reproduction and development
1.

Female reproductive function

174. Results for measurements of uranium concentrations in gonads were contradictory depending on
the study (species, administration pathway, uranium dose and exposure time). In fact, high uranium
accumulation is found in some fish and birds. For instance, significant uranium accumulation wasmeasured in female fish gonads (Danio rerio), corresponding to >20% of the relative burden [S20].
175. A dose-dependence of uranium concentration in ovaries was measured in rats and their offspring
after chronic oral exposure via food [H9, H10]. The accumulation of uranium was higher in the second
exposed generation. Other experimental studies performed on mice failed to report uranium
accumulation in the ovary after contamination by nitrate uranyl with doses up to 400 mg/L for uranium
content in drinking water [A21, F2, R9].
176. Some studies found that uranium affected oocyte quality in vivo with a 50% reduction in the
proportion of healthy oocytes from 20 mg/L [F2] and germinal vesicle oocytes cultured in vitro in thepresence of 1 mM uranyl acetate and observed for 72 hours [A21]. In vivo, these morphological effects
were observed from uranium content in drinking water above 5 mg/L [F2]. A study with similar
approaches (uranium ingestion via drinking water in mice) indicated similar results, with increased
dysmorphism of oocytes in contaminated groups (from 2.5, 5 and 10 mg U/kg per day chronicallyadministered in drinking water for 40 days) in a dose independent manner [K24]. In addition, a study
on mice contaminated in utero by uranium levels in drinking water from 0.5 to 60 µg/L, showed anincrease in uterine weight and a decrease in primary follicles [R9].
177. Reproductive effects following chronic oral uranium exposure were observed in rats exposed
during the first and the second generation [H10]. No effect were observed in F0 rats, but pregnancy rate,normal labour rate, and survival rate were decreased in offspring [H10]. In vitro organ culture system
was used to investigate the effects of uranium on human gonads during the first trimester of gestation(7–12 weeks) [A13]. Uranium at 0.05 mM increased the apoptosis rate, decreasing the germ cell densityof human fetal ovaries. The authors also demonstrated that human fetal germ cells were more sensitive
to uranium than mouse germ cells.

2.

Male reproductive function

178. Some animal studies indicated accumulation of uranium in testes with 0, 5, 10, and 25 mg/kg/dayof uranyl acetate dehydrate before mating and up to 21 days post birth [P7]. A linear dose-dependence
was found in testes of Japanese quail, with a ratio of accumulation similar in testes and in kidney [K25].
A dose-dependence of uranium concentration in testes was measured in rats and their offspring after
chronic oral exposure via food [H10]. The accumulation of uranium was higher in the second
generation.
179. Concerning the effects of DU on sex hormone levels, experimental studies performed in male rats
showed differing results. One experiment performed in male rats indicated an increase in testosterone
and luteinizing hormone levels and a decrease in follicle stimulating hormone level after a four-monthcontaminated food ingestion [H10], while a nine-month contaminated drinking water ingestion did notlead to changes in testosterone and 17β-estradiol levels [G20]. The different uranium doses 4 and
40 mg/kg per day in the studies of Hao et al. [H10], and 2.7 mg/kg per day in the study of Grignard etal. [G20] were used to explain the different levels. However, changes in testosterone levels were not

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UNSCEAR 2016 REPORT

observed in depleted-uranium Gulf War veterans [M19, M20]. A nine-month chronic oral exposure toenriched uranium produced a significant increase in the blood levels of testosterone at 40 mg/L in
drinking water, while no effect was observed with DU [G20].
180. Some reports on rodents highlighted a negative impact of uranium on male reproductive function,
including a decrease in male fertility and in the spermatid number per testis with a few
histopathological effects on the seminiferous tubules and interstitium after chronic exposure [L37,
L41]. Although some abnormal morphological forms and sperm parameters measured were affected byuranium exposure, these changes were independent of the uranium dose levels from 10 to 40 mg/kg per
day corresponding to ~200 to 800 mg/L in drinking water, respectively [L37]. Further, a doseindependent decrease in the pregnancy rate was observed in untreated females mated with male mice
exposed to between 10 and 80 mg/kg per day of uranium [L41].
181. Implantation of DU pellets did not change the concentration, motion and velocity of sperm, andthere is no evidence of detrimental effects of uranium on mating success, suggesting that implantationof up to 20 DU pellets of 1×2 mm (760 mg) in rats did not have an adverse impact on male
reproductive success, sperm concentration, or sperm velocity [A19]. Testicular histopathologicalabnormalities with deformations of seminiferous tubules (marked reduction in the seminiferous tubule
diameter) were observed in mice after high acute exposure [J1]. A seven-day daily intraperitoneal
administration of uranyl nitrate (0.5 mM/kg) induced a marked reduction in the seminiferous tubule
diameter and gametogenic count, with signs of testicular necrosis and exfoliation of germ cells,
including karyolysis and karyorrhexis figures.
182. The contribution of new in vitro models, such as organotypic culture systems, helps theunderstanding of the underlying action mechanism of chemicals. This approach was used as a
toxicological test to evaluate the effects of various compounds, including uranium, on gametogenesis
and steroidogenesis in rat, mouse and human testes [H1]. Some effects on germ cell development(reduction of the number of germ cells) or Leydig cell function were observed for uranium
concentrations above 5 × 10−5 M in human testis cells and above 5 × 10−4 M in rat testis cells [A13].
183. Uranyl fluoride injected in vivo into mouse testes led to an increase in the frequency ofchromosomal aberrations in spermatogonia and primary spermatocytes [H27]. These results wereconfirmed in another study that indicated the highest effects when doses of UO2F2 increased up to
6 mg/kg at 12 days post-exposure [H28]. A study performed with enriched uranium demonstrated
chromosome aberrations in spermatogonia [Z15]. Chromosome fragmentation, translocation,
polyvalence in primary spermatocyte and DNA strand breakage were observed in sperm. Effects ofuranium on human male reproduction studied in Gulf War I veterans did not evidence deleterious
effects on sperm quality, including volume, concentration, total sperm count, and functional parametersof sperm motility [M20, M21, M22].

3.

Effects on embryos and development

184. The effects of uranium on embryotoxicity were studied in rats and mice after acute exposure[D17]. Subcutaneous injections of uranyl acetate dihydrate (0.5, 1 and 2 mg/kg/day) in mice from day
6 to day 15 of gestation induced various effects [B44]. Although it was not dose-related, embryotoxicity also occurred in all uranium-treated groups (significant increases in the number of non-viable
implantations and in the percentage of postimplantation loss). Both the maternal NOAEL and the
NOAEL for embryotoxicity of uranyl acetate dihydrate were below 0.5 mg/kg/day, whereas the
NOAEL for teratogenicity was equal to 0.5 mg/kg/day.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 407

185. Few animal studies investigated the effects of uranium exposure on development and results wereconflicting, depending on the quantity of administrated uranium and the exposure duration.
Subcutaneous injections of uranyl acetate dihydrate from day 6 to day 15 of gestation induced
malformations detected at 1 and 2 mg/kg/day in mice [B44], while no effect was observed at
0.5 mg/kg/day.
186. Paternain et al. demonstrated that embryo lethality could be observed in mice contaminated at
25 mg/kg/day [P7]. Significant increases in the number of dead young per litter were seen at birth andat day 4 of lactation in the 25 mg/kg/day group. The growth of the offspring was always significantly
lower for the uranium-treated animals. Since no effect was observed at lower doses (5 and
10 mg/kg/day), the results suggest that uranium does not cause adverse effects on fertility, general
reproductive parameters, or offspring survival at the concentrations usually ingested by man.
187. In vitro studies were also conducted on one-cell mouse embryos in culture medium with uranyl
nitrate at concentrations of 26, 52, 104 and 208 µg/mL [K23]. The results obtained showed thatconcentrations from 26 µg U/mL induced the delay of embryo development and the impairment of
blastomere proliferation. A study of acute toxicity was performed in mice receiving 4 mg/kg of DU per
intraperitoneal injections (i.p.) at day 11 of gestation and observations were made 4 days later.
Paradoxically, the authors found an increase in the fetus length and weight [M46].
188. Subcutaneous injections of uranyl acetate (0.415 and 0.830 mg/kg/day) were given to pregnant
rats on days 6 to 15 of gestation [A9]. Maternal toxicity and embryotoxicity were noted at the higher
dose, while fetotoxicity was evidenced at both doses. The fetotoxicity was evidenced by significant
reductions in fetal body weight and increases in the total number of skeletal abnormalities [A9].
189. Some studies indicated developmental toxicity of uranium, including teratogenicity, following anacute subcutaneous administration of 1 or 2 mg/kg/day [B44, D18]. A study by Zhu et al. [Z15] wasperformed with enriched uranium injected in rat testes, causing skeletal abnormalities in fetal rats witha positive correlation to the injected dose.
190. Hereditary effects of uranium were investigated in rats following the implantation of uranium
pellets in muscle (up to 12 DU pellets corresponding to 360 mg) [A20]. This study indicated nochanges in sperm motility and ribcage malformations, suggesting that uranium was not a significant
reproductive or developmental hazard. This study is in accordance with another study that indicatedthat uranium did not cause any adverse effects on fertility, general reproductive parameters, or offspringsurvival at the concentrations usually ingested by humans [P7]. One study performed on miceinvestigated the transmission of genetic damage to offspring of fathers contaminated with uranium via
depleted-uranium-implanted pellets [M45]. The authors demonstrated a dose-dependent increase in
mutation frequency in the offspring. Congenital malformations [A6, A7, S48] or birth defects [A3, B54,
F1] were reported in some human populations, but these effects were not correlated to a quantificationof uranium exposure.

4.

Conclusion

191. Some publications focused on reproduction and development issues after exposure to uranium inanimals (rats and mice). These studies indicated that both male and female reproductive functions(quality of oocytes and sperm parameters, embryo viability, and the development processes) may beaffected by acute and chronic exposure. However, these effects were observed for exposure levels
greater than either typical occupational or environmental levels of exposure.

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UNSCEAR 2016 REPORT

H. Other organs
1.

Skin

192. A study of acute exposure of rabbits was conducted using different administrations of uraniumoxide: subcutaneous deposit of ~30 mg U3O8; cutaneous deposit of 70 mg of U3O8 or 5 µg of uranium
acetate (1.9 kBq of 233U) [W3]. Uranyl nitrate, in ethereal or aqueous solution, produced a superficial
coagulation necrosis within a few hours [O4]. A similar but delayed effect was seen seven–nine days
following the application of powdered hygroscopic uranium pentachloride to the skin. Uranium
tetrachloride in suspension in lanolin caused a moderate local erythema of the skin at the site ofapplication, which disappeared in one–two days.
193. In vitro studies on primary cultures of rat skin keratinocytes and fibroblasts [P15] showed agreater decrease in proliferation rate associated with a greater mortality rate in rat skin keratinocytes
than in rat skin fibroblasts after uranium exposure. This can be explained by the three times higher
ability of keratinocytes to incorporate uranium compared to fibroblasts. This greater capacity of
epidermal cells than dermal cells to incorporate uranium was confirmed in vivo in hairless rats
following topical contamination with uranyl nitrate.
194. The consequences of protracted exposure to uranium were investigated using guinea pigs andrabbits [O4]. Guinea pigs that were repeatedly exposed to uranyl nitrate exhibited a superficial
coagulation necrosis and an inflammation of the epidermis. Their skin was in a constant state of
encrustation and desquamation accompanied by rapid regeneration from beneath. Rabbits that wererepeatedly exposed at multiple dermal sites exhibited an effect similar to that seen after single acuteexposure, but those rabbits that were repeatedly exposed at the same site developed severe dermal
ulcers after five to ten applications of the compound. Another in vivo study in rats revealed that longterm exposure of the dermis to uranium (U3O8 at 0.012 g/d for 30 daily topical applications) led to an
epidermal atrophy which, in turn, resulted in an increased permeability of the skin [U2].

2.

Endocrine system and metabolism

195. Vitamin D is essential for the homeostasis of calcium and phosphorus in the body. A few studies
have determined the effects of acute or chronic uranium contamination on the metabolism of vitamin D
in rats. Contamination by DU via drinking water at 40 mg/L [T11] induced a decrease in the bloodlevels of vitamin D in rats following a nine-month chronic exposure. Moreover, uranium targeted key
transcription factors (PPARα, PPARγ, HNF-1α, HNF-4α, LXRr, RXRα, and VDR) involved in thismetabolism [T11, T12]. However, these molecular changes did not lead to the emergence of diseaseassociated with vitamin D metabolism.
196. Chronic contamination by DU (uranyl nitrate, 2.7 mg/kg/day for 9 months) affected cholesterol
metabolism in the liver and brain [R1, R2], mRNA levels of the enzymes involved in the cholesterol
storage were modified in the liver and brain, and mRNA levels of enzyme involved in the cholesterolsynthesis were modified in the brain. Uranium also affected the proteins involved in the transport ofcholesterol and the regulation of cholesterol homeostasis. Thus, a chronic ingestion of uranium

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 409(40 mg/L in drinking water) caused subtle molecular effects on metabolism in the liver and brain ofrats. However, overall cholesterol levels were unaltered in this study using 40 mg/L uranium indrinking water.
197. Studies of rats exposed to uranium showed both disruptive effects on the reproductive system andestrogenic effects. Chronic contamination with DU (560 Bq/L) in drinking water produced no change inthe blood levels of the two principal steroid hormones—oestradiol and 17-testosterone (synthesized by
the testis), whereas contamination with enriched uranium (1,680 Bq/L; 40 mg/L) produced a significant
increase in the blood levels of testosterone [G20]. Consistent with the absence of hormonal changes
with DU, chronic contamination with DU did not induce a change of gene expression. However, theexpression of enzymes involved in the metabolism of hormones was amplified following a nine-month
exposure to enriched uranium. In addition, enriched uranium increased the gene expression oftranscription factors (RXR, LXR, FXR, SHP, SF-1, DAX-1) that positively regulate steroid
metabolism. These results show a differential effect of depleted and enriched uranium contamination on
testicular steroidogenesis [G20].
198. The human body is frequently exposed to potentially toxic compounds and is able to metabolize
them in order to protect itself. Xenobiotic-metabolizing enzymes, including cytochrome P450
(CYP450), play a central role [G25]. The kidneys and liver can metabolize many drugs or otherxenobiotics. Disturbances of this system have been demonstrated in vitro [M43] and in rats exposed tonephrotoxic [M57] or non-nephrotoxic uranium concentrations [P6, S29]. These studies showed that theexpression and activity of CYP450 can be modified by uranium exposure. The consequences of suchmodifications on xenobiotic metabolism were investigated using acetaminophen [G26]. Rats
contaminated with DU presented slower plasma acetaminophen elimination and also more marked renal
histological changes and an increase in blood markers of liver damage (at 40 mg/L during 9 months).
However, only slight effects of uranium were reported on enzymes of xenobiotic metabolism when
acetaminophen was administrated to rats as a single therapeutic treatment [R25].
199. In conclusion, studies performed on animal models (rat and mouse) chronically exposed toradionuclides showed that the chronic ingestion of uranium resulted in subtle biological effects on
various metabolic systems. These modifications did not lead to the appearance of pathologies, even for
uranium levels in drinking water up to 40 mg/L. The observed biological effects probably resulted froman adaptive response to the internal contamination.

3.

Immune and haematopoietic systems

200. Very few studies have investigated the effects of uranium exposure on the haematological system.
Reduced erythropoiesis might be expected owing to accumulation of uranium in bone in proximity tobone marrow and renal damage might result in a decrease in the number of red blood cells. A study
using rats found that chronic ingestion of uranium at 40 mg/L in drinking water for nine months led tokidney deterioration which may have been responsible for an observed decrease in the red blood cellcount; there was an associated modification of spleen erythropoiesis and levels of molecules involvedin erythrocyte degradation [B19].
201. A study by Giglio et al. was performed to assess the effect of uranium (uranyl nitrate) on the rateof erythropoiesis in rats [G9]. The authors showed that a single injection of uranium at 1 mg/kg induced
a transient depression of the red cell volume between 7 and 14 days. These effects were associated witha decreased Epo production and direct or indirect damage of erythroid progenitor cells.

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202. An experimental study using mice fed uranium-contaminated food [H11] compared the effect ofconcentrations of DU of 0, 3, 30 and 300 mg/kg feed for a duration of four months. The mostsignificant effects were observed in the 300 mg/kg group while the effects were either minor orindiscernible in the other groups. At high dose, the authors observed decreased immune function,
manifesting as decreased secretion of inflammatory mediators in the peritoneal macrophages, and also
reduced cytotoxicity of the splenic natural killer cells. Moreover, the cellular and humoral immune
functions were abnormal (decreased proliferation of the splenic T cells, proportion of the cluster ofdifferentiation (CD) 3+ cells, ratio of CD4+/CD8+ cells and delayed-type hypersensitivity, and increased
proliferation of the splenic B cells, total serum immunoglobin (Ig) G and IgE, and proportion of splenicmIgM+mIgD+ cells). The authors concluded that chronic intake of high doses of DU (300 mg/kg) had asignificant impact on the immune function, most likely due to an imbalance in T helper Th1 andTh2 cytokines.
203. Studies on rats have addressed the effects of uranium exposure on the mucosal immune system of
the intestine following ingestion of uranium-contaminated drinking water [D26, D27, D28]) and inlungs following inhalation [M54, M56, P6]. Studies performed on the rat intestine found that Peyer’s
patches (aggregated structures of gut-associated lymphoid tissue) were a site of retention of uranium
following chronic ingestion (with uranium content in drinking water of 40 mg/L) after 9 months,
without inducing any biological effects on the function of Peyer’s patches [D26]. However, chronic
ingestion of uranium (nine months at 40 mg/L in drinking water) led, in the long term, to some changes
in the immune cell populations in lamina propria, diffuse gut-associated lymphoid tissue, notably
increase in neutrophil number (+300%) and decrease in macrophage (−50%), and mast cell number(−30%) in rats [D28].
204. Dublineau et al. indicated that immune cell populations in the intestine (neutrophils, mast cells,
macrophages) did not vary after 9 months of uranium exposure in rats, at any exposure level (from0.2 to 120 mg/L in drinking water) [D29]. The authors observed an increase in mRNA levels ofcytokines (IFN-gamma, IL-10, and CCL-2), at uranium levels in drinking water >20 mg/L, and adecreased protein expression of cytokines (IFN-gamma, IL-10, and TNFα). Such effects may be
explained by uranium interaction with proteasome [M6]. Changes in immune cell populations of theintestinal wall were not reported in the short term following acute contamination with a sublethal doseof uranium in rats (204 mg/kg of DU per os) [D27].
205. Immunological changes of long-term uranium exposure were investigated in mice fed withvarious DU doses (0, 3, 30 and 300 mg/kg food) [H11]. A four-month contamination of animals with
300 mg U/kg food led to a decreased secretion of nitric oxide, interleukin (IL)-1β, IL-18, and tumour
necrosis factor (TNF)-α by the peritoneal macrophages, a decreased proliferation of the splenic T cells
and increased proliferation of the splenic B cells associated with an increase in total serum
immunoglobin (Ig) G and IgE, and proportion of splenic mIgM(+)mIgD(+) cells. Such effects were notobserved for the lowest groups (3 and 30 mg U/kg food).
206. Some studies reported effects of uranium exposure on pulmonary immune cells following
inhalation in rats [M54, M56, P6]. An uptake of uranium by pulmonary macrophages was found(phagocytosis), followed by an accumulation of uranium in lysosomes [B20, M61]. This accumulation
was associated with release of pro- and anti-inflammatory cytokines in vivo [M54, M56] or in vitro[G5, W8, Z12]. Inflammatory cells were observed in proximity to aggregates of uranium particulates[L9]. This inflammatory cell response may lead to oedema and bronchial inflammation [B8, M59]. An
induction of apoptosis was observed in vitro in macrophages and T lymphocytes (CD4+) [W8].
207. In the follow-up of United States veterans of the first Gulf War published by McDiarmid et al.
[M25], the authors reported for the first time on the analysis of immune function in Gulf War I veterans

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 411

exposed to DU, investigating the lymphocyte response to stimulation by two T-cell mitogens. The
results on released cytokines (IFN, IL-10 and IL-2) in the high- and low-uranium exposure groups did
not provide evidence of an effect of uranium on the immune cells.
208. Haematological parameters were recorded in some human populations exposed to uranium.
Haematocrit, haemoglobin and RBC content from uranium processing site workers remained within thenormal ranges [S10]. Haemoglobin concentrations, erythrocyte counts, haematocrit values, and mean
corpuscular volumes were determined on a group of miners in a uranium mine [V6]. There were small
differences of mean values from those of controls, such as diminution of haemoglobin concentrations
and erythrocyte counts when uranium exposure time increased, but the mean values remained within
normal limits. A clinical study of Gulf War veterans showed that soldiers exposed to uranium had areduction in haemoglobin and haematocrit levels [S32].
209. In conclusion, it appears that slight modifications of the immune system, either systemic or
mucosal (including intestines and lungs), were induced following uranium exposure only at high doses,
at concentrations usually not incorporated by humans.

4.

Cardiovascular system

210. Few human data are available concerning uranium effects on the cardiovascular system. A study
was performed on people who had used drinking water from drilled wells containing high levels of
uranium (up to 1,500 µg/L) for several years. This study suggested that uranium exposure wasassociated with greater diastolic and systolic blood pressure [K28]. Two other studies were performed
among residents living near the Fernald Feed Materials Production Center, which functioned as auranium processing facility from 1951 to 1989 [P22, W2]. The systolic and diastolic mean bloodpressure levels were higher for population groups living near this uranium plant than those found in thegeneral population, and for most age- and sex-specific groups. However, neither distance nor direction
from the site influenced the blood pressure measurement results, suggesting that these findings are notexposure-related [P22]. Another study showed similar results: women with higher uranium exposure
had elevated systolic blood pressure compared to women with lower exposure, but the changes
observed in diastolic blood pressure or hypertension were not related to exposure level [W2].
211. Concerning experimental studies, there is a lack of literature on the effect of uranium exposure on
the development of cardiovascular diseases. One of the consequences of uranium-induced kidneydisease could be adverse effects on the cardiovascular systems by a number of mechanisms, includingchanges to the renin-angiotensin pathway. Several publications have focused on the relationshipbetween kidney and cardiovascular systems in humans [P1, R21, T2]. Consequently, the absence of
relevant publications precludes demonstration of an obvious link between uranium exposure andinduction of cardiovascular pathologies.

5.

Effects on DNA

212. Uranyl acetate staining of DNA has been used for staining fixed cells for more than forty years[H27]. In vitro studies performed with purified DNA showed the presence of a tight binding site for theuranyl ion (UO22+) in a four-way DNA junction [M53], demonstrating that uranium can be bound to
DNA in vitro. Exposure to uranium may lead to inhibition of DNA-binding proteins [H15, V7]. In vitro
studies demonstrated that uranium can displace transcription factor binding to DNA and that it can bindto serum proteins accumulation in the nucleus of human cells [H15, V7]. Experimental studies have

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UNSCEAR 2016 REPORT

shown accumulation of uranium in the nucleus of human cells (renal, hepatic, neuronal cells) treated invitro [G30, R26] and in kidney cells of rats treated in vivo [H23].
213. Depleted uranium can induce oxidative DNA damage [B3, K2, M40]. These studies suggested
that DU could induce DNA lesions through interaction with cellular oxygen species. These results were
corroborated by an in vivo study that showed that inhalation of DU resulted in a production ofhydroperoxides in lung tissue of rats [M56]. A recent in vitro experimental study reported the formationof uranium–DNA adducts and mutations in mammalian cells after direct exposure to a compound of
DU [S34]. The data suggest that uranium could be chemically genotoxic and mutagenic. The uniquemutation spectrum in hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus elicited byexposure to DU suggests that uranium-generated mutations in ways that are different from spontaneous,
free radical and radiological mechanisms [C33].
214. Another study on rats demonstrated that UO2 repeated pre-exposure by inhalation increased DNA
single-strand breaks induced by a single UO4 inhalation exposure in epithelial nasal cells, bronchoalveolar lavage cells and kidney cells, whereas a single inhalation exposure to UO4 alone had no such
effect [M55]. In vitro studies indicated that uranium-induced DNA single-strand breaks were catalysedin the presence of ultraviolet light or ascorbate [M53, N7, Y2]. In vivo [M54, M55] and in vitro [D5,T6] studies showed that uranium induced DNA double-strand breaks. An in vitro study demonstrated
that DU was a weak clastogen2 and induced aneugenic3 effects while enriched uranium is a more potent
clastogen [D5].
215. In summary, experimental studies performed in vivo in rodents or in vitro in cell cultures
suggested that uranium could be chemically genotoxic and mutagenic through the formation of strand
breaks and covalent uranium-DNA adducts.

6.

Cytogenetic damage

216. Uranyl fluoride injected in vivo into mouse testes led to an increase in the frequency ofchromosomal aberrations in spermatogonia (breaks and polyploids) and primary spermatocytes(fragments, chromatid exchanges, reciprocal translocations) [H27]. An in vitro study performed onhuman bronchial fibroblasts indicated no significant increase in chromosomal damage following
chronic exposure to uranyl acetate and a slight increase following exposure to uranium trioxide [W22].
An increase in the frequency of sister chromatid exchange and in the frequency of chromosomal
aberrations was also observed in cell lines [L36] and in human osteosarcoma cells [M41].
217. A study by Hao et al. using rats showed that chronic oral exposure to DU in food led to anincreased frequency of micronuclei in bone marrow cells at 4 and 40 mg U/kg/day in weaning rats
[H9]. Miller et al. investigated the transmission of genetic damage to offspring of males micecontaminated with uranium via depleted-uranium-implanted pellets. The authors demonstrated a dosedependent increase in mutation frequency in the offspring [M45].
218. Chromosome aberrations in Gulf War I veterans following DU exposure were evaluated in several
studies [A8, B2, M24, N6]. Four biomarkers of genotoxicity (micronuclei, chromosome aberrations,mutant frequencies of HPRT and PigA4) were examined. There were no statistically significant
2

A clastogen is a mutagenic agent that induces disruption of chromosomes.
An aneugenic agent promotes aneuploidy in cells during mitosis or meiosis leading to the presence of abnormal number ofchromosomes in cells.
4
PigA gene mutation assay is used to assess genomic instability through the measurement of fluorescently labelled antibodies tospecific membrane proteins by flow-cytometric methodology.
3

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 413

differences in any outcome measure when results were compared between the low- and the highuranium groups. However, modelling suggests a possible threshold effect for mutant frequencies
occurring in the highest uranium exposed cohort members [M24]. This study demonstrates a relatively
weak genotoxic effect of the DU exposure. In the second study [B2], the results indicate that ongoing
systemic exposure to DU occurring in Gulf War I veterans with DU embedded fragments does not
induce significant increases in micronuclei in peripheral blood lymphocytes compared to micronuclei
frequencies in veterans with normal uranium body burdens.
219. Some studies investigated the possible effects of uranium exposure on chromosomal damage inworkers and reported an increase in chromosomal aberrations in miners [P25, Z3, Z4] whereas otherssuggested no significant effects [B49, K21, L42, M33, M70, W25]. Martin et al. performed a study forworkers from fuel production and fuel enrichment plants to analyse asymmetrical chromosome
aberrations and sister chromatid exchanges [M13]. Both worker groups had higher levels ofchromosome aberrations than the studied controls. This effect appeared not to be linked to externalradiation. Smoking increased the frequency of dicentrics but not the sister chromatid exchanges in theworkers exposed to soluble uranium, suggesting some interaction between the two clastogens.
220. In conclusion, some experimental studies performed on animals or on culture cells at high dosesof uranium demonstrate an increase in the frequency of chromosomal aberrations (fragments, chromatid
exchanges, reciprocal translocations). Human data are inconclusive but consistent with effects at higher
levels of exposure.

7.

Tumorigenic potential

221. Information about the carcinogenesis processes induced by uranium in experimental models andhumans was provided by the WHO [I5]. Publications on experimental models are detailed below.
222. Chronic inhalation of natural uranium ore dust alone created a risk of primary malignant and nonmalignant lung tumour formation in rats [M49]. The risk of the induction of malignant tumours was notdirectly proportional to dose but was directly proportional to dose rate. A study performed on micereported an increase in osteosarcoma and acute myeloid leukaemia with 239Pu and 241Am but nosignificant difference between results for 233U exposed animals and controls [E4]. The authors
considered that the observed differences between the radionuclides were due to differences in
irradiation of peripheral and central regions of the bone marrow, with lowest doses from 233U. No renal
and liver carcinomas were noted [E4].
223. A study by Hahn et al. conducted in vivo showed that intramuscular DU fragments induced soft
tissue sarcomas (fibrous histiocytoma, fibrosarcoma and osteosarcoma) at the site of implantation [H3].
However, no direct dose-dependent relationship could be drawn due to the presence of varying
corrosion products. Intravenous injection of murine haematopoietic cells into depleted-uraniumimplanted mice was followed by the development of leukaemia in 76% of mice implanted with DU
pellets in contrast to 12% of control mice [M44].
224. Miller et al. reported the ability of DU-uranyl chloride (10–250 µM) to transform immortalized
human osteoblastic cells to the tumorigenic phenotype [M39]. The changes in phenotype arecharacterized by anchorage-independent growth, tumour formation in nude mice, expression of highlevels of the k-ras oncogene, reduced production of the Rb tumour-suppressor protein, and elevatedlevels of sister chromatid exchanges per cell.

414

UNSCEAR 2016 REPORT225. Some sparse studies have been performed on DU clean-up workers and on populations fromdepleted-uranium-contaminated regions [K20, M35, M36]. In clean-up workers, the total number of
DNA alterations was higher immediately after decontamination than before decontamination, buttumours did not develop in the group of DU clean-up workers during the investigation period of four
years [M36]. This point is not surprising, since four years would be a short latency period for thedevelopment of any tumour. In summary, some publications reported tumorigenic effects of uranium inanimals (mice or rats) or tumorigenic potential in in vitro models.

I.

Relative biological effectiveness226. Relative biological effectiveness is an empirical value that measures the capacity of a specific
type of ionizing radiation to produce a biological effect in a particular biological system (for instancesurviving fraction of irradiated cells). It is the ratio of biological effectiveness of one type of ionizing
radiation relative to a reference radiation (gamma- or X-rays), given the same amount of absorbed
energy. Thus, in the case of uranium isotopes, these values refer exclusively to radiobiological effectsof alpha particles compared to the reference radiation. The chemical toxicity of uranium may influenceobserved RBE values. RBE values are used in experimental radiobiology and are also used by ICRP to
derive radiation weighting factors for the calculation of effective dose, which allows the summation ofradiation doses for all radiation types for the control of exposure. The value of the weighting factor
used by ICRP for alpha particles is 20 compared with a value of 1 for all low-LET radiation [I15].
While there are no direct determinations of alpha particle RBE for uranium isotopes, and such studies
would require the use of high specific activity isotopes such as 233U to avoid chemical effects, there is
no reason to consider that alpha particles from uranium will have different relative effectiveness fromalpha particles of similar energy emitted by other radionuclides (e.g. 222Rn and 239Pu [M12]).

J. Lethal effects
227. The lesion that can cause animal death after acute contamination is tubular nephritis, which, as
described above, results from the metallotoxic properties of uranium at high doses. Following
intravenous injection of a soluble form of uranium, the lethal dose (LD50) over a period of three weeks
after injection was measured as 0.1 mg/kg for rabbits and 20 mg/kg for mice [B20]. In rats, deathoccurred from 3 to 7 days for doses 8 mg/kg [F17]. Following oral ingestion of uranium acetate, theLD50 after two weeks was more than 100 mg/kg in rats and mice [D17].
228. One publication reported the deliberate ingestion of uranium (15 g of uranium acetate) [P9]. This
ingestion resulted in an acute renal failure, with persistent renal impairment six months after the initial
exposure. However, no death was reported despite the high uranium level ingested. This suggested thatseveral grams of uranium for ingestion intakes are necessary for inducing death in humans [K5].
229. As indicated in the recent review of Pernot et al. [P14], the definition and classification of thedifferent types of biomarkers have varied slightly, depending on the biomedical field considered. A
biomarker has been defined as “any measurement reflecting an interaction between a biological system
and an environmental agent, which may be chemical, physical or biological”. No real bioindicator is
specific for uranium exposure. Concerning uranium exposure, the analysis of uranium content (total

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 415

concentration or radiological activity in 238U, 234U and 235U) in urine [C18, L21, S37] may provide
information on uranium exposure. More indications are given in the uranium measurements section.
230. Since the kidneys are sensitive to damage by uranium, renal molecules were studied to describe
potential health consequences [G27, G28]. However, standard potential bioindicators have not yet
proven to be sufficiently specific and reproducible. The development and validation of bioindicatorsthat link uranium exposure to renal damage would be valuable [G27].
231. Currently, urinary levels of albumin, glucose, β2-microglobulin and N-acetyl-β-Dglucosaminidase activity are used to evaluate possible renal effects of uranium in humans [K26, K28]
or in animals [G27]. The use of osteopontin as a potential bioindicator of uranium effects was recently
investigated in a combined experiment and human study [P30]. A decreased osteopontin level in urine
was found when the concentration of uranium in urine, after acute exposure, exceeded 30 µg/L. Such a
decrease may suggest renal damage induced by uranium exposure. However, no clear relationshipbetween exposure level, duration of exposure and observed renal effect can be drawn from the available
studies on humans. One experimental study performed on rats at 40 mg/L of uranium in drinking water
failed to demonstrate variations in renal osteopontin mRNA level in the kidneys [R27].
232. Zamora et al. [Z6] studied the effects of chronic ingestion of uranium via drinking water onhuman populations. They found statistically significant subtle changes in two of the biologicalindicators measured, namely ratios of glucose and LDH to creatinine excreted (table 13) that did nottranslate to any observed health effects. In addition, LDH excretion decreased with higher exposure.
The excretion of β−2 microglobulin increased but the increase was not statistically significant.
233. Some biochemical parameters were measured in the urine of Gulf War veterans [M20, M22, M23,
M24, M25, S32]. Table 14 summarizes some of the results obtained. None of the levels measured were
statistically significantly different from control values. Glucose concentrations were lower for the highexposed veterans whereas the concentrations of -2 microglobulin and retinol binding protein werehigher. The results of the study indicated that there were a few subtle trends in changes of biochemicalparameter levels of exposure.
234. The use of omic techniques (genomics, proteomics and metabolomics) to screen unknown
biological or toxicological effects is expanding to develop new bioindicators. Omic methodology has
recently been used to screen mRNA, proteins or metabolome involved in the response to uranium
exposure in various cell lines or in animals [G21, M6, P27, P29, T4, T5]. A recent study has
demonstrated the relevance of metabolomics in cases of uranium exposure [G21]. The aim of this study
was to assess the biological changes in rats caused by ingestion of natural uranium in drinking waterover 9 months and to identify potential biomarkers related to such contamination. LC-MS
metabolomics identified urine as an appropriate biofluid for discriminating the experimental groups. Of
the 1,376 features detected in urine, the most discriminant molecules were metabolites involved intryptophan, nicotinate, and nicotinamide metabolic pathways, in particular N-methylnicotinamide.
These results are in accordance with a previous study that showed the role of N-methylnicotinamide inrats with experimental renal failure induced by uranium [S12]. The study of Grison et al. thus
establishes the validity of using metabolomics to address chronic low-dose uranium contamination[G21]. These studies show that while reliable biomarkers of tissue damage are not yet available,
modern techniques have the potential to identify such molecules.

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UNSCEAR 2016 REPORT

Table 13. Inter-subject variability in bioindicator data (adapted from [Z6])Low exposurea(<1 μg U/L (n=20))

High exposurea(2–781 μg/L (n=30))

55.9 (20.2–111)

82.4 (32.7–427)

Mass of LDH per unit mass ofcreatinine excreted (U/g)

25 (7.6–66)

17 (0–410)

Mass of -2 microglobulin per unit
mass of creatinine excreted (μg/g)

43 (11–270)

56 (15–340)

Urinary parameter
Mass of glucose excreted (mg/d)aMedian value with range provided in brackets. The group ‘Low exposure’ is considered as the control group.

Table 14. Bioindicator data for Gulf War veterans (adapted from [M23])
Normalrange

Low exposurea(<0.1 μg uranium per gramof creatinine (n=25))

High exposurea(≥0.1μg uranium per gramof creatinine (n=10))

Glucose g/day

0.0–0.5

6.3±4.38

0.12±0.01

-2 microglobulin μg/g creatinine

0–160

59.08±7.48

81.72±13.28

Urine retinol binding protein μg/g
creatinine<610

31.00±4.73

48.11±9.73

Urinary parameteramean ± standard error.

VIII. EPIDEMIOLOGICAL STUDIES
235. Several population groups have been considered for epidemiological studies on the health effects ofuranium due to occupational (uranium mines, milling and processing plants, facilities involved in the
nuclear fuel cycle) or to environmental exposure (elevated uranium levels in drinking water, vicinity ofuranium processing facilities or areas affected by depleted-uranium-munition use). Clear and comparative
epidemiological information is limited. Nonetheless, in appendix A, tables A1–A4 summarize theprincipal studies and characterize their value in assessing uranium risks for occupational exposure, andtables A5 to A7 for environmental exposure.

A. Studies of occupational exposure236. The preparation of the fuel used in nuclear power plants relies on a complex cycle, including thesteps of mining, crushing of the ore and preparation of Yellowcake (uranium mills and processing
plants), conversion of uranium oxide to UF6, enrichment, and fuel manufacturing. Other activities
include research and reprocessing of the nuclear fuel. These activities involve different types of jobs
and different patterns of uranium exposure. Also, historical methods of individual exposure monitoringvary (measurement of ambient exposure, bioassay of excreted uranium, personal film dosimeters, invivo measurements).

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 417

237. Studies of workers involved in the nuclear fuel cycle present a good potential to investigate cancer
and other health effects of internal uranium exposure on the basis of long-term follow-ups, insofar as
they have individual estimates of exposure levels. These studies have been identified as among the most
pertinent ones to quantify a potential exposure-risk relationship [L16].

1.

Uranium miners

238. Miners are exposed to internal contamination due to inhalation of long-lived radionuclides (LLR)
from uranium ore dust, but also to external gamma radiation and radon and its progeny. The main
source of radiological exposure of uranium miners is radon and its decay products. Many
epidemiological studies of uranium miners have been performed that demonstrated an association of
accumulated exposure to radon and its decay products with lung cancer risk [I16, L17, N1, U9, W17].
239. A concerted European effort (Alpha risk project) [T10] has furthered the assessment of healthrisks associated with uranium exposure based on the Czech, French CEA-COGEMA and German
Wismut cohorts. Individual exposure to uranium was estimated from measurement of ambientconcentration (in Bq/m3). The assessment of uranium contamination in miners was based on thereconstruction of individual accumulated ore dust exposure over time. The development of dedicateddosimetric software enabled the estimation of cumulative organ doses due to radon and its progeny,
LLR arising from uranium ore dust, and external gamma ray exposure [M10, M11]. This approachallowed the estimation of the contribution of uranium exposure to the total organ dose, and the initiative
has resulted in a number of cohort and nested case-control studies of uranium exposure and mortality
by cancers, leukaemia or cardiovascular diseases [D23, D31, K15, K17, M50, M51, M52, R4, R5, T13,
V2]. A difficulty with the uranium miner studies is that the lung doses from short-lived radon decay
products are much larger than and often correlated with the LLR exposure from uranium, whichhampers the assessment of exposure effects for lung cancer.

2.

Uranium millers

240. The first steps after uranium extraction are crushing of the ore and preparation of the Yellowcake
by uranium millers or as part of uranium processing. Like the miners, millers are subjected to inhalationof radon and radon decay products, external gamma radiation and inhalation of LLR from uranium ore
dust. One potential constraint of uranium miller studies is that, despite uranium LLR exposure being ahigher percentage of total radiation dose, uranium miller exposure is typically much lower thanuranium miner total exposure. Individual exposure to uranium among millers has been estimated solely
from measurement of ambient concentration (in Bq/m3).
241. Only a few cohort studies have specifically considered health risks among uranium millers[B36, K17, P21, Z1]. These studies reported mortality results, but only the German miller study
estimated individual LLR exposure from uranium ore dust and potential health risk [K18]. They
studied 4,054 millers who had never worked in underground or open pit mines and assessed mortality
from various diseases in relation to their exposure to radon, external gamma ray, LLR and silica dust
exposure [K18].

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3.

Nuclear fuel cycle workers

242. A variety of epidemiological studies enabled the estimation of health risks among workers
involved in the fuel nuclear cycle: in the United States (Fernald; Rocketdyne; Oak Ridge TEC, Y-12
and K-25; Paducah; Linde; Mallinckrodt), in the United Kingdom (UKAEA and AWE composite
cohorts, Sellafield), and in France (CEA; AREVA NC; Eurodif) [C5, Z9, Z10].
243. After milling, the nuclear fuel cycle entails different successive steps, including conversion,enrichment, fuel manufacturing, reprocessing and research. These steps involve diverse radiologicaland chemical exposure to different forms of uranium compounds. However, as these steps are notdistinguished in most of the epidemiological studies, they are considered together in this section.
Individual exposure to uranium has often been estimated solely from measurement of ambientconcentrations. Uranium exposure is preferably estimated from bioassays of individuals’ excreted
uranium or by other personal measurement (in vivo counting). In most studies exposure estimates forworkers could be based only on ambient measurements at job locations or even extrapolations for timeand location with no available ambient measurements.

4.

Results of occupational exposure studies

244. The exposure situations may influence cancer risk in occupational settings, especially for lungcancers. For miners, the main exposures are from radon (internal exposure), external gamma radiation,and exposure to uranium dust. Typically, workers in the nuclear fuel production are subjected to lessradon exposure but additional potentially toxic chemical exposure. In addition, for lung cancer,
confounding factors may occur due to variations in smoking habits, about which most studies containlittle or no information. Exposure levels have been assessed differently in various studies depending on
the occupational exposure setting and the historical exposure information available.
245. Characteristics and results of uranium miner, miller and processor studies are summarized inappendix A, tables A1–A4, with the studies in tables A3 and A4 having more quantitative analyses. The
health outcomes are described below by organ systems. Since well-conducted nested case-control
studies provide risk estimates that in principle are comparable to those from the full cohort, the resultsof both types of studies are provided together without distinction.
246. Studies that have identified uranium-exposed cohorts have varied in the amount of data theypresented to adduce uranium health effects. Studies that contain a subset of uranium-exposed workers
who are not actually identified as exposed provide essentially no information on uranium effects; moststudies in appendix A, table A1 fall into this category. Others have identified uranium workers but haveno individual exposure levels and therefore provide only standardized mortality ratios (SMRs) or otheroverall statistics which yield little valid information on uranium effects because they consider thosewith appreciable exposure and little or no exposure as a composite group. Also, SMRs are subject to“healthy worker bias”; such studies are shown mainly in appendix A, table A2. Analyses by duration of
employment can also be subject to “healthy worker survivor bias” and therefore should be viewed
circumspectly. Analyses that show SMRs or relative risks (RRs), including hazard ratios (HRs) andodds ratios (ORs) by cumulative dose groups are somewhat informative, but difficult to interpret since
the common problem of small numbers within groups leads to inconsistencies in risk estimates acrossgroups; trend analysis summaries are helpful but fail to provide quantitative overall risk estimates(appendix A, table A3). Studies that provide quantitative risk estimates per unit of exposure arepresented in appendix A, table A4.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 419

247. Studies that explicitly estimate individual uranium exposure and use those data to calculatequantitative dose-response associations with specific health end points are valuable for assessing risk.
Typically, dosimetric estimates are made for detailed types of jobs at particular work locations for
specific periods based on ambient monitoring data, and this job exposure matrix (JEM) is applied toindividual work records. Better individual dosimetry is achieved when individual urinalyses of uranium
excretion or other personalized measurements are available, supplemented by ambient monitoring.
However, some quantitative studies had limited ability to distinguish effects from LLR exposure fromuranium from those associated with external irradiation or radon decay products because those doses
were much larger than the LLR doses to organs. That problem applies especially to lung cancer amongminers, since radon decay products usually contribute much more lung dose than LLR, so that in minerstudies the LLR lung dose was often only 1–2% as great as the radon decay product dose and the twodoses are typically correlated. In that situation, estimates of LLR-associated risk may be inaccurate toan unknown degree.
248. The following overview of associations of LLR exposure from uranium with diseases thought tobe induced by uranium will concentrate on the most informative studies that have presented quantitative
dose-response data. The most recent reports of study cohorts are shown in preference to older reports toavoid redundancy of information, since the most recent data with longer follow-up and sometimes
improved dose information provide better risk estimates.
249. The study results will be considered by organ systems. Essentially, all the informative studies ofoccupational populations exposed to uranium have been conducted since 1980, some with exposure
dating back to the mid-1940s. These studies considered a large range of potential health effects. Amongthe most frequently considered ones are respiratory cancers (lung, laryngeal), urological cancers(kidney, bladder, prostate), digestive cancers (stomach, intestine, liver, pancreas), cancers of brain andcentral nervous system, lympho-haematopoietic malignancies (leukaemia, lymphoma, multiple
myeloma). Non-cancer diseases have also been considered, especially respiratory, circulatory and renal
system diseases. Further details about these studies are presented in appendix A, table A4.

(a) Lung cancer and other respiratory diseases
250. Lung cancer. Studies with quantitative risk estimates for respiratory diseases from LLR exposure
from uranium are presented in table 15. Ten reports were found that had dose-response estimates forlung cancer risk based on individualized estimates of uranium exposure. The study of CEA-COGEMA
miners in France reported a positive risk coefficient for LLR exposure from uranium, though the radonand external-radiation co-exposure make the result difficult to interpret. Other miner studies have notcharacterized and analysed LLR exposure from uranium and lung cancer. The German study ofuranium millers [K18] reported a dose-response analysis of LRR exposure from uranium and lungcancer risk. The association was non-significant and in the negative direction. Two other studies ofuranium millers reported no significant elevation in lung cancer mortality [B36, P21].
251. The remaining eight reports of LLR dose-related lung cancer mortality were based on workers innuclear processing industries. The nature of the workplaces and the types of measurements andprocedures that generated the individual exposure estimates are given in appendix A, table A4, for thevarious studies. The large study of Fernald workers, with 269 lung cancer deaths, showed a positive,
but non-significant, association and most other studies had negative or non-significant coefficients ofrisk. Additional uranium worker cohorts showed no significant elevation in overall lung cancer SMRs
[C36, D33, D34, M26, M27]. However, the relatively small French study of the AREVA NC Pierrelatte
plant showed significant positive dose responses [G31]. This is the only study that conducted separate
analyses for exposure to uranium compounds that differ in solubility (Types: F, M and S). They found420

UNSCEAR 2016 REPORT

the Type M and Type S exposure conferred lung cancer risk (table 15). In a further analysis [G32] that
distinguished exposure to natural uranium from the reprocessed uranium which has a different isotope
composition, they found that risks were especially dose related for reprocessed uranium of the Type M
and Type S. This suggests that insoluble uranium particles with a longer residence time in the lungconfer more risk than the more soluble particles with a shorter residence time. However, theseinteresting results were based less than 55 lung cancer deaths and require confirmation in larger studies.
Table 15. Dose-response studies of uranium exposure and risk of respiratory system diseases
Study references

No. ofdeathsNature ofuranium work

Unit of uranium (LLR)
exposure

Risk estimate per unit
LLR exposurea

LUNG CANCER
France, CEACOGEMA [R5]
(Also [R4, V2])

94

MiningkBqh/m3

ERR=0.32 (95% CI: 0.09, 0.73)

Germany, milling
[K18]

159

Milling

100 kBqh/m3

ERR=−0.61 (95% CI: −1.42, 1.9)

France, AREVA NC
[C6]

48

Processing

Years of Types F, M,
and S uranium
exposure

HR=1.01 (95% CI: 0.96, 1.01) [F]
1.07 (1.01, 1.13) [M]
1.07 (1.01, 1.14) [S]France, AREVA NC
[G32]

53

Processing

Years of exposure to
Types F, M and S
reprocessed uranium

HR=1.07 (95% CI: 0.96, 1.19) [F]
1.13 (1.03, 1.25) [M]
1.13 (1.01, 1.25) [S]

USA, TEC/Y-12/
Mallinckrodt/
Fernald [D35]b

787

Processing

0.5, 2.5, 5, 25, 50,≥250 mGy LLR

USA, Rocketdyne
[B38]

94

Processing

100 mSv LLR

USA, Fernald [S19]269

ProcessingmGy LLR

ERR=0.022 (95% CI: −0.009, 0.06)

USA, Paducah
gaseousdiffusion [C17]129

Processing

μg.y

RR=0.91 (95% CI: 0.5, 1.6) (21–50 μg.y)
0.95 (0.6, 1.6) (51–125 μg.y)
0.51 (0.3, 0.9) (>125 μg.y)

USA, Y-12 [R12]111

Processing

10 mSv LLRFrance, Gaseous
diffusion [Z10]100

Processing

Low, medium, high

OR=1.03, 0.57, 0.85, 0.82, 0.64, 2.05
(95% CI: 0.20, 21), respectivelyc
RR=1.01 (95% CI: 0.89, 1.16)

ERR=–0.77 (95% CI: –2.5, 1.0)
Exposure to natural soluble uranium
compounds (with 90% CI):
Medium: RR=0.92 (CI: 0.54, 1.6)
High: RR=0.74 (CI: 0.42, 1.3)
Enriched uranium (n=23):
Medium RR=1.8 (CI: 0.64, 4.6)
High RR=0.69 (CI: 0.21, 1.9)
Depleted uranium (n=23):
Medium RR=1.2 (CI: 0.33, 3.7)
High RR=1.5 (CI: 0.61, 3.9)

EXTRATHORACIC RESPIRATORY CANCERS
Germany, Wismut
[M51]

554

Miners

10 kBqh/m3

ERR=0.098 (95% CI: –0.11, 0.31)(Laryngeal cancer)

Germany, Wismut
[K17]

234

Miners

100 kBqh/m3

ERR=−0.17 (95% CI: −2.50, 2.16)(All extra-thoracic airway cancers)

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 421

Study references

No. ofdeathsNature ofuranium work

Unit of uranium (LLR)
exposure

Risk estimate per unit
LLR exposurea

NON-MALIGNANT RESPIRATORY DISEASEFrance, CEACOGEMA [R5]37

MinerskBqh/m3

ERR=−0.086 (95% CI: n.e.)dUSA, Y-12 [R12]50

Processing

100 mSv

ERR=−0.085 (90% CI: −0.32, 0.15)

USA, Fernald [S19]e102

Processing

100 μGy LLR

ERR=−0.0062 (95% CI: −0.007, 0.0006)a

Risk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio) and RR(relative risk or rate ratio) are expressed as a multiple of the rate in the baseline (lowest/no exposure) group. (ERR = RR – 1).
bThis study [D35] was partially repeated later on [R12, S19] but included two cohorts that were not reported elsewhere.

c

The risk estimate of 2.05 for the ≥250 mGy group became 0.36 in an analysis with adjustment for smoking.

d

Not estimable from the likelihood profile.

eAnalysis of chronic obstructive pulmonary disease.

252. In summary, there is mixed evidence for the lung carcinogenicity of uranium. The inconsistency
may relate to variations in the amount and types of exposure data available (e.g. extrapolated dosereconstruction, ambient monitoring, uranium urinalyses or other personalized exposure measures) or tovariations in methods for calculating LLR doses from the raw data. The inconsistency can also relate toother radiation or chemical exposure that may not have been adequately accounted for in the LLR
analyses, or to dose-dependent variations in smoking behaviours. On the other hand, since the studies
have low statistical power to detect risks, given the relatively small numbers of lung cancers and fairly
low levels of LLR exposure from uranium for most workers, it is notable that two cohorts with doseresponse data showed a statistically significant association [C6, R5].
253. Other respiratory cancers. A study of all extrathoracic airway cancers, based on a well-definedcohort of the German uranium miners, showed a negative dose-response coefficient for LLR exposure
from uranium [K17]. Another study of German uranium miners had LLR dose-response data forlaryngeal cancer, which yielded a non-significantly positive risk coefficient [M51]. There was no
association of LLR exposure from uranium and laryngeal cancer among French uranium miners [R5].
Other studies have reported overall excess laryngeal or upper airway cancers in worker populations
potentially exposed to uranium [B18, B29, B33, D35, G31], but those are based on small numbers ofcancers, without individual uranium exposure estimates, and with limited information on the risk
factors of smoking and alcohol intake.
254. Non-malignant respiratory disease (NMRD). Four studies with dose-response analyses allreported negative dose-response coefficients for NMRD [B38, R5, R12, S19]. Pinkerton et al. [P21]reported an inverse relationship of NMRD with length of time working in uranium milling. SMRs in a
number of other cohorts with uranium exposure were not significantly elevated [C20, C36, D33, D34,
M26, M27, R14, Z10] so there is no evidence that NMRD is associated with uranium exposure.

(b) Lymphatic and haematopoietic cancer
255. Leukaemia. Since leukaemia shows a large excess relative risk from radiation exposure, it is astrong a priori candidate to investigate regarding uranium exposure effects. Table 16 shows uranium
dose-response related results for leukaemia. A nested case-control study of leukaemia mortality within
the large collection of German Wismut miners [M50] found a positive but non-significant associationof estimated LLR exposure with non-chronic lymphocytic leukaemia (non-CLL) risk. The positive risk
coefficient was driven entirely by the highest dose group (≥20 kBqh/m3, ERR=1.26, 90% CI: 0.7, 2.2,

422

UNSCEAR 2016 REPORTn=14). A smaller miner study in Czechia found a statistically significant dose-response association ofleukaemia mortality with total red bone marrow dose, of which the majority was from LLR exposure[T13]. Three smaller dose-response studies of leukaemia risk in the uranium processing industries did
not support excess risk (table 16). In summary, there is limited dose-response evidence for an
association of uranium exposure with subsequent leukaemia. Atkinson et al. [A29] reported a nonsignificant SMR (SMR=1.10; 95% CI: 0.89, 1.33; n=103) in nuclear workers, particularly among
workers monitored for internal radiation exposure. Others likewise have reported non-significant
overall SMRs in uranium worker cohorts [C36, D30, D33, D34, L44, M26, M27, P24, S5, Z2, Z10], but
did not estimate worker uranium doses or conduct LLR dose-related analyses.
256. Other lympho-haematopoietic malignancies. Lymphoma is a biologically plausible outcome of
inhalation exposure to uranium, since uranium deposited in the lung tends to migrate to the thoracic
lymph nodes. However, there are few studies providing dose-dependent analyses of uranium exposureand lympho-haematopoietic malignancies other than leukaemia (table 16). The cohort of German
uranium millers [K18] showed a non-significant negative risk coefficient for all lympho-haematopoietic
malignancies. In the Rocketdyne cohort there was a non-significant positive dose-response [B38],
though the specifics were not reported. A French study of gaseous diffusion plant workers reported a
non-significant excess risk for all lympho-haematopoietic malignancies other than leukaemia among
those with medium or high exposure to soluble uranium [Z10]. A study in the United States showed for
uranium miners an elevated risk of lympho-haematopoietic malignancies (SMR=1.38, 95% CI: 1.03,
1.82) [S5]. Pinkerton et al [P21] showed a suggestive excess of lymphatic and haematopoietic
malignancies, excluding leukaemia, (SMR=1.44, 95% CI: 0.83, 2.35, n=16) with no dose response.
257. A study of non-Hodgkin’s lymphoma (NHL) at the Paducah gaseous diffusion plant [C17]produced high relative risks, but the fact that there was no dose response suggests that the high values
are likely attributable to a deficit of NHL in the baseline comparison group rather than large excesses in
the other dose groups. NHL mortality was non-significantly elevated for exposure to uranium in the
Fernald cohort [S19]. The Czech uranium miner study [T13] indicated a non-significantly elevated
SMR of 1.4 (95% CI: 0.9, 5.1, n=16) for NHL but did not provide a dose-response analysis. Other
uranium worker cohorts reported null overall SMRs for lymphomas or all lympho-haematopoietic
cancers [B38, C9, C36, D30, D33, D34, G31, L44, M27, P21, P24, S5, Z2].
258. In the study at the Oak Ridge K-25 gaseous diffusion plant by Yiin et al. [Y3] with a doseresponse analysis of multiple myeloma and uranium exposure, a significant association was not found.
A significant overall excess of multiple myeloma was found among United States miners (SMR=1.97,
95% CI: 1.05, 3.37, n=13), and an excess based on two cases (SMR=8.38; 90% CI: 1.44, 26.20) was
reported among French CEA-COGEMA uranium processing workers [B9]. A non-significant excess ofmultiple myeloma was observed among Mallinckrodt uranium processing workers [D33] (SMR=1.30,
95% CI: 0.42, 3.0, n=5). The SMRs for multiple myeloma were not significantly elevated in otheruranium worker groups [C17, Z2].

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 423

Table 16. Dose-response studies of uranium exposure and risk of lympho-haematopoietic
malignancy mortality
Study references

No. of deaths

Germany, Wismut
[M50]

b

Nature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate per unit LLR
exposure a

LEUKAEMIA
218 (non-CLL)

Mining100 kBqh/m3

Czechia [T13]30

Mining

Svc

USA, Paducah[C17]

21 (all types)

Processing#1 (0–20 μg.y)#2 (21–50 μg.y)#3 (51–125 μg.y)#4 (>125 μg.y)

Baseline#2: RR=0.73 (95% CI: 0.2, 3.0)
#3: RR=0.49 (CI: 0.2, 2.3)
#4: RR=0.77 (CI: 0.2, 2.5)

USA, Rocketdyne[B38]

10 (non-CLL)

Processing

100 mSv LLR

RR=1.06 (95% CI: 0.50, 2.23)

USA, Fernald [S19]28 (non-CLL)

Processing

100 μGy LLR

HR=0.18 (95% CI: 0.012, 0.80)

ERR=0.76 (90% CI: –1.26, 2.78)
ERR=2.5 (90% CI: 0.3, 9.3)

OTHER LYMPHO-HAEMATOPOIETIC MALIGNANCIES
Germany [K18]23 (all lymphohaematopoietic)

Millers

Zhivin, Gaseous
diffusion [Z10]28 (all lymphohaematopoietic)

Processing

100 kBqh/m3

ERR= –0.65 (95% CI: –2.78, 1.47)

Medium and highexposure

Natural soluble uranium
compounds (with 90% CI):
Medium RR=1.4 (CI: 0.52, 3.9)
High RR=1.08 (CI: 0.37, 3.3)

USA, Paducah[C17]

26 (non-Hodgkin’s
lymphoma)

Processing#1 (0–20 μg.y)#2 (21–50 μg.y)#3 (51–125 μg.y)#4 (>125 μg.y)

USA, Fernald [S19]12 (non-Hodgkin’s
lymphoma)

Processing

100 μGy

HR=1.2 (95% CI: 0.88, 1.5)

98 (multiple
myeloma)

Processing

10 μSv

OR, 1.04 (95% CI: 1.00, 1.09)

USA, K-25 [Y3]

Baseline#2: RR=9.95 (95% CI: 1.2, 81)#3: RR=8.85 (CI: 1.1, 71)#4: RR=5.74 (CI: 0.7, 45)aRisk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio) and RR(relative risk or rate ratio) are expressed as a multiple of the rate in the baseline (lowest/no exposure) group. (ERR = RR – 1).
b

Non-CLL, all leukaemias except chronic lymphocytic leukaemia.

cAnalysis was for total red bone marrow dose, of which 52–64% was estimated to be due to LLR from uranium dust inhalation.

(c) Digestive system cancer
259. Stomach cancer. Only a few studies have conducted dose-dependent analyses of uranium
exposure and digestive system cancers (table 17). Studies of German uranium millers [K18], theFernald uranium processors [S19], and Rocketdyne workers with internal exposure monitoring [B38]
all showed weakly positive but non-significant dose-response risk estimates for stomach cancer. The
risk of mortality from stomach cancer was increased with the alpha absorbed stomach dose among
German uranium miners (ERR per Gy=37.3; 95% CI: 3.4, 71.1, n=592), but the contribution of LLR to424

UNSCEAR 2016 REPORT

the absorbed stomach dose was less than 1% [K15]. Other uranium worker cohorts reported null overall
SMRs for stomach cancer [B38, C9, C17, D34, L44, M26, R5, S5, Z1, Z10].
260. Intestinal cancer. The study of German uranium millers showed non-significant ERR coefficientsfor both colon and rectal cancers [K18], and both the French uranium miners study [R5] and theRocketdyne study [B38] reported non-significant LRR dose coefficients for colorectal cancers. On theother hand, a dose-response analysis of combined small intestine and colon (but not rectum) cancer at
the United States Fernald uranium processing plant yielded a statistically significant excess risk [S19].
Since this result was based on relatively small numbers, it is in need of confirmation by larger studies.
Other uranium worker cohorts reported null overall SMRs for colon or colorectal cancers [C9, D33,
D34, G31, L44, M26, P21, Z1, Z10] but did not conduct LLR dose-related analyses.
261. Pancreatic cancer. The United States Paducah [C17] and Fernald [S19] studies provided doseresponse analyses of pancreatic cancer after LLR exposure (table 17). Neither study provided anindication of an association with uranium exposure, nor did the studies of French uranium miners [R5]or Rocketdyne workers [B38]. However, the studies had relatively small numbers of pancreatic cancers
and thus limited statistical power. Other reports have indicated non-significant SMRs for pancreaticcancer in uranium processing workers [C36, D33, D35, L44, M26, Z1, Z10] but did not estimate
worker uranium doses or conduct LLR dose-related analyses.
Table 17. Dose-response studies of uranium exposure and risk of digestive system disease mortality
Study references

No. of deaths

Nature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate per unit LLR
exposure a

STOMACH CANCER
Germany, [K18]49

Milling

USA, Fernald [S19]29

Processing

100 kBqh/m3

ERR=1.5 (95% CI: −2.9, 5.9)b100 μGy

ERR=0.041 (95% CI: −0.20, 5.6)

INTESTINAL CANCER
Germany, [K18]22 (colon)

Milling

100 kBqh/m3

ERR=–0.07 (95% CI: –3.3, 3.2)

Germany, [K18]26 (rectum)

Milling

100 kBqh/m3

ERR=0.56 (95% CI: –3.1, 4.2)

USA, Fernald [S19]48 (colon &small intestine)

Processing

100 μGy

ERR=1.5 (95% CI: 0.12, 4.1)

PANCREATIC CANCER

a

USA, Paducah [C17]30

Processing#1 (0–20 μg.y)#2 (21–50 μg.y)#3 (51–125 μg.y)#4 (>125 μg.y)

Baseline#2: RR=1.42 (95% CI: 0.4, 4.7)
#3: RR=0.49 (95% CI: 0.1, 1.9)
#4: RR=0.97 (95% CI: 0.3, 3.0)

USA, Fernald [S19]41

Processing

100 μGy

HR= 0.61 (95% CI: 0.015, 3.5)

Risk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio), RR(relative risk or rate ratio) and OR (odds ratio for case-control studies) are expressed as a multiple of the rate in the baseline(lowest/no exposure) group. (ERR = RR – 1).
b

Estimate is adjusted for radon exposure levels.

262. Liver cancer. Dufey et al. [D31] observed a non-significant increase in liver cancer mortality risk
associated with high-LET absorbed liver dose among German uranium miners (ERR per Gy=48.3; 95%
CI: −32.0, 128.6 (n=159) after adjustment for low-LET dose). However, the contribution of LLR to theabsorbed liver dose was less than 2%, so the association is not informative regarding uranium risk.
Among French uranium miners there was also a non-significant association of LLR exposure and liverANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 425

cancer risk [R5]. Other uranium worker cohorts reported non-significant SMRs for liver cancer [B38,
C9, M26, M27, P24, R5, Z10] but had no uranium dose-response analyses.
263. In summary, there is no persuasive evidence of an association between uranium exposure anddigestive cancers. The effect, if any, is likely small. However, the relatively small numbers of digestivecancer cases and consequent limited statistical power to detect effects make any conclusion uncertain.

(d) Kidney and other urological cancers
264. Kidney cancer. The toxicological data suggest that uranium exposure may be related to urologicalcancers, especially to the kidney because of the potential for both adverse radiological and metal effects
upon that organ. The available epidemiological studies with dose-response results are shown intable 18. Dose-response analyses of kidney cancer in relation to LLR exposure have been conducted forthe cohorts of miners in France and Germany [D23]. Neither cohort showed a significant association
with kidney cancer even though the large German miner cohort had a substantial number of renal
cancers. In the French CEA-COGEMA cohort, the overall SMR was elevated for kidney cancer(SMR=2.0, 95% CI: 1.2, 3.1, n=20), but LLR analyses were not reported [V1].
Table 18. Dose-response studies of uranium exposure and risk of urological system disease mortality
Study references

No. of deaths

Nature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate per unit LLR
exposure a

KIDNEY CANCER
France, CEACOGEMA [D23]11

MiningkBqh/m3

HR=0.89 (95% CI: 0.55, 1.42)

Germany, Wismut
[D23]

174

MiningkBqh/m3

HR=1.009 (95% CI: 0.991, 1.027)

Germany [K18]11

Milling

100 kBqh/m3

USA, Fernald [S19]15

Processing

100 μGy

ERR=7.36 (95% CI: –11, 26)
ERR=0.039 (95% CI: −0.021, 0.55)

OTHER UROLOGICAL DISEASES
Germany [K18]30 (Prostatecancer)Milling

USA, Fernald [S19]19 (chronic
kidney disease)

Processing

100 kBqh/m3

ERR=0.21 (95% CI: –2.8, 2.4)

100 μGy

HR=0.98 (95% CI: 0.78, 1.1)aRisk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio) and RR(relative risk or rate ratio) are expressed as a multiple of the rate in the baseline (lowest/no exposure) group. (ERR = RR – 1).

265. The study of German uranium millers [K18] had a large risk coefficient for kidney cancer but theassociation was non-significant because the number of cases was small (n=11) and consequently theconfidence interval of the estimate was very wide. The dose-response coefficients for the Fernald
uranium processing workers [S19], the Rocketdyne workers [B38] and the French uranium miners [R5]were all non-significant. Overall SMRs for kidney cancer were found to be increased in two uraniumprocessing facilities: Y-12 [C20, L44] and Capenhurst [M26]. But at Capenhurst, the increase waslimited to unexposed workers. The UK Nuclear research workers also experienced elevated mortality
from kidney cancer [B18, C8]. However, none of these studies included an investigation of the relation
with internal exposure to uranium. Other uranium worker studies did not report significantly elevatedoverall SMRs for kidney cancer [C9, C17, L44, S5, Z10] but had no uranium dose-response analyses.

426

UNSCEAR 2016 REPORT266. Bladder cancer. French uranium miner studies reported a non-significant LLR dose-response
association with bladder cancer [R5]. An increase in mortality (an elevated overall SMR) from bladdercancer was reported among Fernald workers [D35]. It was potentially associated with a high exposure
to the cutting fluids used during uranium metal production but not with internal exposure to uranium
compounds [R14]. In a more recent study of the Fernald workers [S19], elevated mortality wasobserved only among salaried female workers; for cancer of the bladder and other urinary organs, theSMR was 5.13 (95% CI: 1.06, 15.0; n=3). However, the small number of cases, no increase in bladdercancer mortality among males (n=21) or hourly paid female workers (n=0), and no dose-response
information argue against a meaningful excess [S19]. Other reports have indicated non-significant risks(usually SMRs) for bladder cancer in uranium processing workers [B38, Z1, Z10], but did not estimate
worker uranium doses or conduct LLR dose-related analyses.
267. Prostate cancer. The recent study of German uranium millers analysed uranium dose and prostatecancer risk and found no evidence of an association [K18], albeit the number of prostate cancer deaths
was small (table 18). The study of United States Rocketdyne workers reported a non-significant doseresponse trend in the negative direction for prostate cancer (n=63), but did not provide a risk coefficient[B38]. The LLR dose-response trend among French uranium miners was likewise non-significant [R5].
268. Radiation-exposed worker cohorts with excess prostate cancer have been investigated for internal
radionuclide exposure in the UK Atomic Energy Authority cohorts [A28, B18, R22] but with only alimited examination of uranium exposure. Rooney et al. [R22] conducted a nested case-control
examination of the relation between prostate cancer and occupational exposure in those cohorts,
including 136 prostate cancer cases and 404 controls and examination of 29 radionuclides. Three cases
and twelve controls had an indication of potential uranium exposure, and zero cases and six controls
had documented uranium exposure (RR=0, 95% CI: 0, 2.55), so no effect on prostate cancer mortality
was observed. Other studies have reported non-significant overall SMRs for prostate cancer among
uranium workers [D33, L44, M26, Z1, Z10] but had no uranium dose-response analyses.
269. In summary, except for the German Wismut cohort, the number of kidney cancers was very small,thus constraining the ability to detect small-to-moderate effects. Since the studies of kidney cancer andchronic kidney disease are uniformly negative, the risk of uranium exposure for kidney cancer is weakor absent. The data do not generally support an increase in bladder cancer associated with uranium
exposure; in fact, the only dose-response report regarding bladder cancer risk had a negative coefficient[B38]. The two studies that have evaluated dose-response data for prostate cancer did not show asignificant association.

(e) Brain and central nervous system cancers
270. Experimental evidence indicates that uranium compounds, particularly more soluble ones, crossthe blood-brain barrier, thereby potentially putting the brain at risk. There have been only a small
number of studies with dose-response analyses of brain and central nervous system (brain/CNS)
tumours (table 19). An analysis of brain/CNS tumours by LLR dose groups was conducted among
Paducah gaseous diffusion uranium enrichment workers [C17], but no trend by dose was seen. A studyof French uranium miners reported a non-significantly positive brain/CNS tumour dose-response risk
for LLR exposure, accompanied by an overall excess (SMR=1.71, 95% CI: 1.00, 2.74) [R5]. Similarly,
three United States studies of uranium processing workers did not find a dose-related excess ofbrain/CNS tumours [B38, C17, C20].
271. Carpenter et al. [C7] investigated the possible association between brain/CNS cancers andexposure to external and internal radiation among Oak Ridge Y-12 workers. The internal dose to theANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 427

lung, calculated as in the study by Checkoway et al. [C20], was used as a surrogate for the internal doseto the brain for the 47 cases and 120 matched controls. Odds ratios (ORs) were non-significantly
elevated for categories of cumulative lung dose: ≥150 to 290 mSv (OR=2.8; 95% CI: 0.7, 11.9; n=5);≥300 to 450 mSv (OR=2.7; 95% CI: 0.8, 9.3; n=5); and among workers with mean annual lung dose>150 mSv (OR=1.7; 95% CI: 0.7, 4.2; n=16). No dose–response trend was observed after adjustment
for possible confounding factors (26 different chemicals, socio-economic status, duration of
employment), using either a 5- or 10-year dose lag. Other studies of uranium worker cohorts indicatedno significant overall excess of brain/CNS tumour deaths [C9, D33, L44, M26, M27, P24, R14, Z10]
but did not estimate worker uranium doses or conduct LLR dose-related analyses.
272. A limiting factor in all of these studies was the very small numbers of tumours, so only quite alarge excess risk would be detectable. Clearly more data are needed to make a better judgment aboutbrain/CNS tumour risk from uranium exposure.
Table 19. Dose-response studies of uranium exposure and risk of brain and central nervous system(CNS) tumour mortality
Study references

No. ofdeathsNature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate per unit LLR
exposure a

BRAIN/CNS TUMOURS
kBqh/m3

ERR=0.28 (95% CI: n.e. <0, 1.87)b

Processing#1 (0–20 μg.y)#2 (21–50 μg.y)#3 (51–125 μg.y)#4 (>125 μg.y)

Baseline#2: RR=0.66 (95% CI: 0.1, 4.2)
#3: RR=1.07 (95% CI: 0.2, 4.8)
#4: RR=0.45 (95% CI: 0.1, 2.2)

Processing#1 (0–9 mSv)
#2 (10–49 mSv)
#3 (≥50 mSv LLR)

Baseline#2: RR=1.10 (95% CI: 0.2, 6.5)
#3: RR=0.45 (95% CI: 0.1, 3.2)

France, CEACOGEMA [R5]
[Also [V2]]17

Mining

USA, Paducah [C17]14USA, Y-12 [C20]14aRisk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio) and RR(relative risk or rate ratio) are expressed as a multiple of the rate in the baseline (lowest/no exposure) group. (ERR = RR – 1).
bn.e. = not estimable from the likelihood profile.

(f) Circulatory diseases
273. Suggestive findings from external radiation studies over the past 15–20 years have prompted
examinations of circulatory disease risks as a potential radiation effect of internal radionuclides. The
available studies of uranium exposure have evaluated the risk for all circulatory system diseases (CSD)
and major subcategories of CSD, namely ischaemic heart diseases (IHD) and cerebrovascular diseases(CeVD) (table 20).
274. Circulatory system diseases. The German Wismut miner cohort is the largest to study uranium
associated CSD risk. They reported a negative CSD risk coefficient for internal LLR exposure on thebasis of 5,417 CSD deaths [K14]. Two reports of CSD in the French CEA-COGEMA miner cohort areof interest (table 20). A report of the entire cohort indicated a non-significantly positive risk coefficient[R5], while another report of the subset of the cohort for whom information on radon, external radiation
exposure, and medical risk factors for CSD also was available showed a nearly significant risk of CSD
from LLR exposure after accounting for the other factors [D24].

428

UNSCEAR 2016 REPORT275. A report of the French AREVA NC uranium processing cohort found that exposure to Type M
and Type S (less soluble) reprocessed uranium conferred statistically significant risk of CSD, as did
Type S natural uranium exposure [G33], but Type F exposure did not. The study found statisticallysignificant associations of CSD with the number of years exposed to Type S exposure to both
reprocessed and natural uranium, and a near-significant association for Type M reprocessed uranium(table 20) [G33]. Less quantitative but supportive findings were that CSD mortality was increased
overall among workers exposed to slowly soluble reprocessed (HR=2.13; 95% CI: 0.96, 4.70) andnatural uranium (HR=1.73; 95% CI: 1.11, 2.69). In the subgroup of smokers, the risk estimates werehigher but with larger CIs (HR=1.91; 95% CI: 0.92, 3.98 for natural uranium and HR=4.78; 95% CI:
1.38, 16.50 for reprocessed uranium). The AREVA NC findings suggested that types of uranium with along residence time in tissues may confer risk of CSD.
276. McGeoghegan et al. [M29] reported an association between mortality from CSD and radiation
exposure in males performing industrial work in the British Nuclear Fuels Limited cohort (BNFL). This
cohort consisted partially of uranium workers (37% of the cohort were workers employed at the
Springfields uranium processing plant and 6.7% at the Capenhurst uranium enrichment plant). Their
analysis of internal exposure to any radionuclide gave a dose-response ERR per Gy of 0.76 (90% CI:
0.37, 1.23; n=2,275), but a dose-response analysis was not available specifically for uranium exposure.
277. Ischaemic heart diseases. The large German Wismut study of uranium miners found a negativerisk coefficient for LLR exposure and the end point of all heart disease (table 20) [K14]. The otherstudies evaluated IHD as a cardiovascular end point. Studies of French uranium miners (CEACOGEMA) reported negative risk coefficients for IHD for the entire cohort [R5] and for the subset
where they could account for radon, external radiation, and medical heart disease risk factors [D24].
The German uranium miller study also reported a non-significantly negative risk coefficient for LLR
dose [K18]. McGeoghegan et al. [M29] reported an association between mortality from IHD andradiation exposure in males performing industrial work at BNFL. Their analysis of internal exposure to
any radionuclide gave a dose-response ERR per Gy of 0.52 (90% CI: 0.09, 1.06; n=1,494), but uranium
exposure was not analysed.
278. Cerebrovascular diseases. The same set of studies also provided risk estimates for CeVD
(table 20). The large German Wismut study of uranium miners found a negative risk coefficient for
LLR exposure and CeVD [K14]. Studies of French uranium miners (CEA-COGEMA) reported nonsignificant positive risk coefficients for CeVD for the entire cohort [R5] and for the subset withadjustment for radon, external radiation, and medical heart disease risk factors [D24]. The German
uranium miller study reported a non-significantly negative risk coefficient for LLR dose [K18]. In the
study of French AREVA NC uranium processing workers, there was a statistically significant risk forType S exposure to reprocessed uranium and a near-significant risk for Type M reprocessed uranium[G33], but little indication of risk from natural uranium exposure. Further, McGeoghegan et al. [M29]also reported an association between mortality from CeVD and radiation exposure in males performing
industrial work in the BNFL cohort. Their analysis of internal exposure to any radionuclide gave adose-response ERR per Gy of 1.47 (90% CI: 0.49, 3.00; n=456).

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 429

Table 20. Dose-response studies of uranium exposure and risk of circulatory system disease mortality
Study references

Nature ofuranium work

No. of deaths

Unit of uranium(LLR) exposure

Risk estimate
per unit LLR exposure a

ALL CIRCULATORY SYSTEM DISEASES
Germany, Wismut
[K14]

5 417

Mining100 kBqh/m3

ERR=−0.2 (95% CI: −0.5, 0.06)

France, CEACOGEMA [R5]185

MiningkBqh/m3

ERR=0.016 (95% CI: −0.06, 0.13)

France, CEACOGEMA [D24]76

MiningkBqh/m3

HR=1.13 (95% CI: 0.97, 1.31)

France, AREVA NC
[G33]

111

Processing

Reprocesseduranium,
absorption Types
M, S

HR (95% CI)
Cumulative exposure duration(per year):
1.09 (1.02, 1.18) [M]
1.11 (1.03, 1.20) [S]
1.04 (1.00, 1.07) for naturaluranium [S]High cumulative exposure:
3.40 (1.47, 7.85) [M]
8.79 (1.21, 28) [S]2.84 (1.38, 5.85) for naturaluranium [S]Cumulative exposure score:
1.14 (1.05, 1.24) [M]
1.17 (1.07, 1.27) [S]
1.07 (1.02, 1.13) for naturaluranium [S]France, Gaseous
diffusion [Z10]281

Processing

Medium and highvs. no exposure

Natural soluble uranium
compounds RR (95% CI):
Medium RR=0.98 (0.71, 1.3)
High RR=1.2 (0.85, 1.6)
Enriched uranium (n=45):
Medium RR=0.96 (0.32, 2.9)
High RR=0.84 (0.28, 2.8)
Depleted uranium (n=45):
Medium RR=0.64 (0.23, 1.7)
High RR=0.84 (0.32, 2.3)

HEART DISEASE
Germany, Wismut[K14]

3 719 (all heartdisease)Mining100 kBqh/m3

ERR=−0.3 (95% CI: −0.6, 0.02)

France, CEACOGEMA [R5]72 (Ischaemic
heart disease)

MiningkBqh/m3

ERR=−0.029 (95% n.e. (<0, 0.14)b

France, CEACOGEMA [D24]26 (Ischaemic
heart disease)

MiningkBqh/m3

HR=0.94 (95% CI: 0.73, 1.20)

Germany [K18]341 (Ischaemic
heart disease)

Milling

100 kBqh/m3

ERR=–0.09 (95% CI: –0.84, 0.65)

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UNSCEAR 2016 REPORT

Study references

No. of deaths

France, AREVA NC[G33]

48 (Ischaemic
heart disease)

Nature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate
per unit LLR exposure a

Processing

Reprocesseduranium,
absorption Types
M, S

HR (95% CI)
Cumulative exposure duration(per year)
1.08 (0.97, 1.21) [M]
1.14 (1.03, 1.26) [S]
1.04 (0.99, 1.10) for naturaluranium [S]High cumulative exposure:2.05 (0.53, 7.85) [M]
4.38 (0.47, 41) [S]2.57 (0.82, 8.07) for naturaluranium [S]Cumulative exposure score:
1.12 (0.99, 1.27) [M]
1.17 (1.03, 1.33) [S]
1.13 (1.05, 1.22) for naturaluranium [S]France, Gaseous
diffusion [Z10]95 (Ischaemic
heart disease)

Processing

Medium and highvs. no exposure

Natural soluble uranium
compounds (with 95% CI):
Medium RR=0.71 (0.39, 1.3)
High RR=0.91 (0.53, 1.5)

CEREBROVASCULAR DISEASE
Germany, Wismut
[K14]

1 297

Mining100 kBqh/m3

ERR=−0.05 (95% CI: −0.5, 0.6)

France, CEACOGEMA [R5]41

MiningkBqh/m3

ERR=0.125 (95% CI: −0.06, 0.50)

France, CEACOGEMA [D24]16cMiningkBqh/m3

HR=1.17 (95% CI: 0.90, 1.53)

Germany [K18]171

Milling

100 kBqh/m3

ERR=–0.17 (95% CI: –1.14, 0.80)

France, AREVA NC
[G33]

31

Processing

Reprocesseduranium,
absorption Types
M, S

HR (95% CI)
Cumulative exposure duration(per year)
1.09 (0.93, 1.27) [M]
1.11 (0.95, 1.29) [S]
1.04 (0.97, 1.11) for naturaluranium [S]High cumulative exposure:5.71 (1.48, 22) [M]
3.26 (0.97, 11.0) for naturaluranium [S]Cumulative exposure score:
1.13 (0.97, 1.31) [M]
1.16 (1.00, 1.35) [S]
1.01 (0.92, 1.12) for naturaluranium [S]ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 431

Study references

No. of deaths

France, Gaseous
diffusion [Z10]77

Nature ofuranium work

Unit of uranium(LLR) exposure

Risk estimate
per unit LLR exposure a

Processing

Medium and highNatural soluble uranium
compounds (with 95% CI):
Medium RR=1.2 (0.66, 2.3)
High RR=1.07 (CI: 0.6, 1.9)aRisk estimation metrics: ERR (excess relative risk) for which zero represents no excess or deficit; HR (hazard ratio) and RR(relative risk or rate ratio) are expressed as a multiple of the rate in the baseline (lowest/no exposure) group. (ERR = RR – 1).
bn.e. = not estimable from the likelihood profile.

c

A case-control subset of workers for whom information was available on radon and external gamma exposure and medical risk

factors. Risk estimates were adjusted for those factors.

279. Studies of CSD/IHD/CeVD end points typically had greater statistical power than those for mostcancer diseases because the numbers of CSD-related deaths were much larger than for most types ofcancer. Other considerations arise; one might expect lesser statistical power to detect CSD because theconsensus has been that the risk coefficients derived for external radiation of the circulatory system areseveral times smaller than for cancer induction. On the other hand, damage to the kidney, which isthought to be a primary target organ for uranium, affects the risk of heart disease, probably through therenin-angiotensin pathway. Results regarding CSD end points are also difficult to interpret because of
the numerous medical and lifestyle factors that affect cardiovascular risk. The results of the French
processing workers (AREVA NC) suggesting that uranium compounds with low solubility may induce
CSD more than soluble compounds are somewhat puzzling. While less soluble uranium compounds arethought to confer more risk to the lung because of longer residence times, it is believed that moresoluble compounds confer larger doses to most other organs than insoluble compounds do because ofdifferences in biokinetics. If so, the results of the French processing workers (AREVA NC) are contrary
to what one would expect for CSD, IHD and CeVD.

(g) Conclusion
280. From the occupational exposure studies, a weak association of lung cancer risk with uranium
exposure is concluded. However, currently available results are not consistent enough to demonstrate a
causal association with uranium exposure. The results for leukaemia, other lympho-haematopoietic
malignancies, digestive system cancers, kidney and other urological cancers and brain/CNS tumours
did not provide clear evidence of uranium exposure-related risks. The results for non-malignant
diseases—respiratory, cardiovascular and kidney diseases—also showed no relationship with uranium
exposure. A number of studies without dose-response analyses for LLR exposure have provided nulloverall risk estimates for every health end point considered; while the negative SMRs are not very
specific, at least they suggest the risks are likely to be small.

5.

Limitations of occupational exposure studies

281. For uranium miners studies, recent developments enabled the calculation of organ doses and,
therefore, estimation of the contribution of LLR from uranium ore. Studies published up to now havedemonstrated a very small contribution of uranium to miner dose. Organ doses appear to be dominatedby radon and radon decay products for lungs and by external gamma exposure for other organs.
Demonstrating a potential risk associated to uranium, therefore, appears difficult.

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UNSCEAR 2016 REPORT

282. Studies of uranium millers are limited in size, with the exception of the German Wismut miller
study, which allowed assessment of individual radiation doses from uranium exposure [K18].
Undertaking analysis of combined cohorts after further development of organ dose calculation should
improve results in the future.
283. Most studies of workers in the nuclear fuel cycle are limited by the difficulties in estimating thedoses due to uranium internal contamination. Recent studies are the most meaningful since they havebeen based on more accurate exposure assessment and for some of them internal organ-specificabsorbed doses were estimated by implementing the latest updates of the ICRP models and dosimetric
tools. Nevertheless, improvement of dosimetric estimation is still needed to provide pertinent estimatesof potential risks associated with uranium contamination. Segmentation between the different steps ofthe nuclear fuel cycle should enable improved assumptions regarding the solubility of the uranium
compounds. The combined use of individual urinalysis dosimetry and of job exposure matrices may
also allow improved characterization of radiation doses from uranium exposure and the quantificationof related risks.
284. Natural uranium is not very radioactive (238U decays very slowly) and its chemical properties areoften such that any inhaled or ingested uranium is excreted rather quickly from the human body. Thus,
studies of exposure to enriched or reprocessed uranium may be more informative. Some publications
indicated that—even when the uranium doses are known—external exposure can dominate [L24]. In
addition, most of these studies had major limitations (poor statistical power, no or imprecise estimatesof doses, insufficient accounting for other exposure influences). Moreover, other exposure is mostly nottaken into account, such as exposure to chemicals, heat and noise, which may also contribute to theincrease of certain diseases.
285. Uranium worker data have often been limited to studies of male Caucasians. Quantitative
generalization to women or other population groups is therefore uncertain. No occupational studies
have attempted to examine genetic, epigenetic or metabolic susceptibility factors for uranium relateddiseases. Worker studies also provide no information about children, who may be more susceptible tothe effects of uranium exposure than adults.
286. Continued follow-up of the principal uranium worker cohorts that have individualized worker
exposure data will be valuable. Many members of the cohorts were relatively young at their most recent
follow-up. Because mortality rates for many cancers increase as a power of age attained, these cohorts
will become increasingly informative with future follow-up, providing greater ability to detect smaller
effects and generate more precise risk estimates.
287. Since most studies have a limited number of uranium workers and relatively slight exposure formost of the workers, it is unlikely that epidemiological studies of individual nuclear facilities will havesufficient statistical power for a reasonable prospect to detect risks. Consequently, international pooled
studies with high-quality, harmonized individual exposure estimates are likely to be necessary to assessuranium risks with high precision. However, studies of workers have advantages over those on
environmental exposure of the public or of special groups (e.g. military personnel deployed in regionswith potential DU exposure). The advantages particularly centre around having measurements toestimate individual uranium exposure levels, along with other occupational radiological exposure sothey can potentially distinguish LLR exposure from other exposures. In addition, some of the studies
had data on various chemical exposure at workplaces.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 433

B. Studies of Gulf War veterans288. Depleted-uranium munition and armour were extensively used by the United States military in thefirst Gulf War in Iraq and Kuwait (Desert Storm) and again in the Balkans military action. Military
personnel were exposed to DU via inhalation or wounds, notably due to friendly-fire incidents burning
depleted-uranium-containing tanks and ammunition and clean-up operations [B26].
289. Several authors reported investigations on the Gulf war and the Balkan veterans, especially on
United States, United Kingdom, Canadian, Danish and Dutch veterans [B28, M1, M2, S36, U11],
which were reviewed by others [I20, L5, S6]. For example, the Institute of Medicine [I20] discussed
extensively the results of about 25 studies on health outcomes following exposure to natural uranium
and DU. The review integrated malignant (lung cancer, leukaemia, Hodgkin’s and non-Hodgkin’s
lymphoma, bone cancer, renal cancer, bladder cancer, brain and other nervous system cancers, stomach
cancer, prostatic cancer, testicular cancer) and non-malignant (renal disease, respiratory disease,neurological effects, reproductive and developmental effects, cardiovascular effects, genotoxicity,
haematological effects, immunological effects, and skeletal effects) pathologies. They concluded that
there was insufficient evidence to determine whether an association exists between exposure to uranium
and the health outcomes cited above. However, the two following major limitations of the veteranstudies were identified: (a) short period of follow-up and (b) poor assessment of uranium exposure.
290. The Royal Society comprehensively reviewed the use of DU, especially on the battlefield [R28].
The Royal Society concluded in its report that doses from DU were unlikely to be high, even in themost unfavourable (battlefield) conditions, so that lung cancer risks were unlikely to be more thandoubled. The report indicated a potential non-radiological risk associated with exposure to DU, in
particular with its nephrotoxicity. A summary of studies of the health status of veterans with potential
or known exposure to DU is given in appendix A, table A5.
291. A recent study by Strand et al. aimed to investigate cancer incidence and also all-cause mortality
in a cohort of Norwegian military present in Kosovo between 1999 and 2011 [S42]. Cancer incidence
and mortality were studied from 1999 to 2011 and compared to national rates. The authors found no
excess incidence of cancer except an elevated SIR for melanoma of the skin in men. All-cause mortality
was half the expected rate (SMR=0.49; 95% CI: 0.35, 0.67).
292. A biennial health surveillance programme established for the United States Gulf War veterans has
shown continuously elevated DU concentrations in urine among those with embedded fragments forover 20 years [M25]. No differences have been seen between the high- and low-exposure groups withregard to haematology, clinical chemistries, neuroendocrine parameters, bone metabolism,
neurocognitive function, immune function, pulmonary function or nodules. Regarding renal function
and injury, no high vs. low exposure differences were found for 16 clinical indicators of renal function,
six urine markers for kidney injury, or four urine measures of low molecular weight proteins, except for
two sensitive biomarkers of proximal tubule function that suggested subtle renal injury [M25].
293. In a study by Hines et al., some self-reported respiratory symptoms, mean pulmonary function
values and prevalence of low-dose chest computed tomography abnormalities were compared in two
populations of Gulf War veterans (high body burden group vs. low body burden) [H18]. The authors
found no significant differences between the two groups, suggesting that DU levels inhaled during the1991 fire incidents probably do not cause long-term adverse pulmonary health effects [H18].
294. In conclusion, several studies on the health pathologies among veterans with potential or no
exposure to DU were published. Up till now, no clinically significant pathology related to DU has beenfound in the veteran’s cohorts. The diversity of these studies in terms of topics has limited their

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UNSCEAR 2016 REPORT

reproducibility, except for the biennial examinations of a small group of United States veterans withretained DU shrapnel in whom comprehensive examinations have consistently found no clinically
adverse effects.

C. Studies of environmental exposure
1.

Living around uranium processing facilities

295. Numerous, mostly ecological, studies have been carried out to assess whether long-term residence
in the vicinity of nuclear fuel cycle facilities or nuclear power plants affects the health of the residents.
To focus on uranium effects, only studies carried out in population groups living around uranium
processing facilities (after uranium mining and prior to electricity production) were examined. Elevenpublished studies were identified over the past ten years, which are presented in appendix A, table A6.
296. Because of potential bias, inability to check the validity of ecological results, and the lack ofsufficient measurements of ambient uranium exposure levels, no firm conclusion could be drawn from
ecological studies. Further, caution is required in interpreting ecological studies in general as causal
inference is not warranted because of numerous limitations in their study design. The major limitationof ecological studies is the potential of ecological associations to misrepresent, sometimes greatly, thebiological effect at individual level. Thus, an association observed between variables on an aggregate
level does not necessarily mean that the same association will exist at individual level [G19].
297. Lane et al. reported a review of 13 epidemiological studies conducted in Port Hope, Canada in thepast 30 years, including residents and workers [L7]. These studies included environmental
measurements of the radiological and non-radiological contaminants, the estimation of the multipathway of exposure and also the health risks to the population, using environmental monitoring data or
dose reconstruction methods based on a variety of approaches. The authors concluded that, taken
together, the findings of these studies conducted on the Port Hope community indicated that observed
adverse health effects were unlikely to be the result of exposure to environmental contaminants fromradium and uranium processing. Other studies shown in appendix A, table A6 are also consonant withthat conclusion.

2.

Living in an environment affected by depleted uranium munition use

298. Some epidemiological studies attempted to determine if the health of populations living incountries or regions involved in the recent conflicts (i.e. Iraq, Kuwait, Bosnia and Herzegovina,
Kosovo, Serbia and Montenegro) was affected by the use of DU in shrapnel or tanks. Iraq is the moststudied country for investigation on possible effects of DU. Several publications aimed at describing
the incidence and types of congenital malformations [A6, A7, S48] or birth defects [A3, B54, F1].
However, these publications failed to demonstrate a link between the increase in these pathologies andthe environmental exposure to DU, notably due to the absence of evaluation of the exposure levels.
299. Few studies investigated cancer incidence in these populations. Al-Hashimi and Wang used intheir study three sub-periods (1980–1990, 1991–2000, and 2001–2010), corresponding to the three Iraq
wars, the Iran–Iraq war (1980–1988), the Gulf War I in 1991 and the Gulf War II in 2003 [A4]. The
authors reported increases in the total number of cancer cases. However, the in-depth analysis indicatedANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 435

a decrease in incidence rates in most cancer types when they were analysed statistically, considering
population growth in the Ninawa province in the northern part of Iraq.
300. Another study aimed to describe changes in haematological malignancies (leukaemia andHodgkin’s lymphoma) in Croatian counties potentially exposed to DU in comparison to the pre-war
period [L3]. This study did not find a significant difference in the incidence of these haematologicalmalignancies.
301. In parallel to these health studies, measurements were made of daily urinary uranium excretion inGerman peacekeeping personnel (n=1,228) and unexposed subjects coming from the South of Germany(n=113) to assess potential intakes of DU [O1]. A daily urinary excretion of uranium of
13.92.2 ng/day (3 to 23 ng/day) measured for German peacekeeping personnel was similar to that of
unexposed subjects (12.82.6 ng/day).

3.

Drinking water with elevated uranium levels

302. Possible health effects after long-term ingestion of uranium via drinking water was reviewed by
Guseva Canu et al. [G32]. The description and main results for selected studies of the possible impactof elevated levels of uranium in drinking water are summarized in appendix A, table A7. This table
notes potential uranium effects ascribable to its dual radiological and chemical toxicity. However, somestudies related the effects to chemical toxicity only [K26, K27, K28, M9, S8, Z6], while other studies
related to potential radiation effects [A32, K29, S7].
303. As shown in appendix A, table A7, most of the studies focused on the nephrotoxicity of uranium
using cross-sectional study designs. In total, five studies were carried out: in Canada [M9, Z6, Z8]; inFinland [K26]; and in Sweden [S8]. The uranium concentrations in water were fairly similar in all thestudies, with median concentrations in the range 20–30 µg/L among the exposed groups. All thesestudies, except the one from Mao et al. [M9], found no glomerular effect of chronic ingestion of
uranium. Among people drinking water from private drilled wells, uranium exposure caused damage tothe proximal tubule, shown by nephron reabsorption alteration [K26, S8, Z6] or tubular cytotoxicity[S8, Z1] was observed in four of the studies. Several biomarkers were measured in these studies (e.g.
creatinine for glomerular filtration function at the early stage of renal injury) but none was specific for
injury caused by uranium. Kurttio et al. [K29] carried out a case–cohort study in Finland of bladder andkidney cancer after long-term consumption of private well water containing uranium and its decay
products. No association between the prevalence of these cancers and the uranium concentration in well
water was found [K29].
304. Lymphatic and haematopoietic malignancies were considered in three studies [A32, S7, W23].
Seiler [S7] investigated whether 16 children with leukaemia in the City of Fallon, Nevada, UnitedStates, had higher levels of naturally occurring radioactive material in their well water compared toother inhabitants of the town. Water samples were collected in 2001 for the measurement of uranium,
radon and gross alpha concentrations, and leukaemia cases were identified for 1997–2000. To resolve
this potential time sequence problem, the authors also retrieved the 1989 citywide water analyses. The
natural origin of the uranium present was confirmed by the calculation of the isotopic ratio. No
difference was indicated in uranium concentration in the water drunk by the children compared to otherinhabitants.

436

UNSCEAR 2016 REPORT305. Witmans et al. [W23] compared the uranium concentrations in water between non-Hodgkin’s
lymphoma cases and their matched controls selected from the Saskatchewan (Canada) cancer registry.
The cases had been exposed to significantly higher uranium concentrations in drinking water than thecontrols. However, uranium was one of 63 inorganic constituents tested in the study.
306. A case–cohort study by Auvinen et al. [A32] of Finnish adults that enrolled 35 cases of leukaemia
also reported a negative result regarding exposure to naturally occurring uranium (and its decay
products) in drinking water and leukaemia [A32]. The statistical power of the study was limited and nodata on potential confounding factors were available. The risk of stomach cancer from exposure tonaturally occurring radionuclides in drinking water was investigated. However, no association was
found in this study.
307. Clinical studies in Nova Scotia, Canada performed on 324 persons exposed to variable amounts ofnaturally occurring uranium in drinking water (up to 0.7 mg/L) found no relationship with overt renal
disease. Though there was a trend towards increasing excretion of urinary -2 microglobulin withincreasing concentration of uranium in well water, this was not seen in the group with the highest
uranium well-water concentrations. This group had significantly reduced its consumption of well waterby the time the measurements were made, supporting the hypothesis that the suspected tubular defectmight well be rapidly reversible [M64, M65].
308. A pilot study by Mao et al. of three communities in Saskatchewan with mean uranium levels
ranging from 0.71 (control) to 19.6 g/L found a statistically significant association (p=0.03) between
increasing but normal levels of urine albumin and the uranium exposure [M9]. Another Canadian study
on two groups of subjects with chronic exposure to uranium in drinking water, the first group exposed
to <1 g/L and the other exposed to 2–781 g/L found no correlation with alkaline phosphatize and-2 microglobulin in urine. The authors concluded that the uranium concentrations observed in the
study affected the kidney function at the proximal tubule [Z6].
309. Another study by Zamora et al. [Z8] on chronic ingestion of uranium in drinking water
demonstrated subtle changes in two of the indicators measured that were statistically significant—namely, glucose and LDH excretion concentrations. However, this did not result in any observable
health effects (see also table 13). In addition, the change in LDH excretion was rather beneficial andwas seen only in males. Thus, these changes are not nephrotoxic effects.
310. In conclusion, epidemiological studies of public uranium exposure to drinking water indicate thatchemical toxicity of uranium may occur mainly in the kidneys and, in high concentrations, uranium
may affect the kidney function. However, the functional alterations found in the kidneys were small andwithin normal limits, so the clinical significance of the findings may be minimal. The available
literature focused on lymphatic and haematopoietic tissue malignancies is limited to three studies,
which do not support a causal association between uranium exposure and those malignancies.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 437

IX. RESEARCH NEEDS
311. The estimation of organ doses from incorporated uranium isotopes depends on the availability of
reliable biokinetic data and the construction of physiologically realistic biokinetic models. In general,
good human and animal data are available for the construction of models. However, limited information
is available on the age-dependence of organ retention and excretion rates, including information on the
cross-placental transfer of uranium. In addition, more information is required on the distribution of
uranium within tissues and cells, for example in CNS tissue and lungs.
312. Dosimetric models in general apply the same assumptions regarding source and target
distributions within tissues to all internal emitters. For example, uranium isotopes and otherradionuclides deposited in bone are assumed to accumulate on internal bone surfaces and/or in bonevolume and target cells for cancer induction are assumed to reside along bone surfaces (bone cancer)
and throughout red bone marrow (leukaemia). The validity of such assumptions requires further
investigation, with consideration of the inhomogeneity of uranium distribution within tissues and cells.
313. Toxicological studies of uranium exposure are required to distinguish the chemical andradiological components of damage caused to cells and tissues, including short-term damage to organfunction and longer-term effects including cancer. Comparisons of radionuclide toxicity and RBE
determinations would assist in quantifying the potential health effects of uranium isotopes. Studies of
the age-dependence of chemical and radiological toxicity would be valuable.
314. Future epidemiological studies require careful consideration of the acquisition of dosimetric datato assess individual organ and tissue doses for cohort subjects. A high priority would be a consortium
effort by investigators to develop pooled data on uranium risks. The result could be considerable gains
in the statistical power and precision of risk estimates that would potentially provide the best overallanswers achievable as to health effects from uranium exposure. Pilot studies to quantify the magnitudeof uncertainties in exposure assessment would ideally be part of this effort, so that sound estimates of
dosimetric uncertainties could be incorporated into the risk modelling [L13, S21].
315. Concerning (molecular) epidemiology, setting up prospective follow-up or case control studies inselected subgroups, including collection of information on biomarkers, has the potential to provide
more specific dose–response curves for defined subsets of cohorts and thereby improve knowledge ofhealth effects in humans, including cancer and non-cancer diseases. High-throughput technologies(especially the -omics) would be relevant to apply to this field. However, proposed biomarkers willneed to be rigorously evaluated as to their ability to improve exposure and risk assessment.
316. Mixed exposure should be taken into account when studying effects, such as other radionuclides(e.g. 239Pu, 222 Rn), other chemical carcinogens (e.g. solvents, smoking, dust, silica, asbestos) and also
the physical forms of uranium (solubility), e.g. through further development of exposure matrices in
epidemiological research, and through animal studies.
317. Understanding the molecular mechanism of action of uranium on cells in culture and animalmodels, both as a metal and as a radionuclide, would be important in (a) facilitating the identification of
bioindicators; (b) identifying portions of the molecular response that are attributable to the radiation
response, the heavy metal response or both; and (c) defining the possible development of mitigators,(few mitigators for uranium exposure).

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X. GENERAL CONCLUSION
318. This annex provides a detailed review of sources and levels of uranium in the environment,
exposure of the public and workers to uranium, biological effects of uranium, and epidemiologicalstudies of nuclear workers and the public exposed to uranium.
319. Uranium is a naturally occurring radionuclide and is ubiquitously distributed in the environment.
In daily life, people are exposed to uranium originating mainly from drinking water and foodstuffs.
Average uranium levels in water vary between countries and within countries, with typical values ofaround 2 µg/L (~25 mBq/L of 238U) in groundwater and 1 µg/L (~12.4 mBq/L of 238U) in public watersupplies. Some drinking water samples (<3%) may exceed the national or international guidelines set toprevent kidney toxicity. Concerning foodstuffs, potatoes, meat, fresh fish and bakery products are themain sources of uranium ingestion. The total daily intake from water and food consumption is around
1.5 μg/d (18.6 mBq/d of 238U).
320. The main routes of entry of uranium into the body are inhalation and ingestion. The absorption toblood in each case is highly dependent on the chemical form (speciation) of the intake. For example,
human data show that the absorption of ingested uranium is a few per cent of intake for soluble forms
in water compared with substantially less than 1% for insoluble oxides. Human and animal data havebeen used to model the behaviour of uranium absorbed to blood, showing that the main site of retention
is the skeleton, with lower amounts in soft tissues and rapid urinary excretion of a large proportion. The
ICRP models make appropriate use of the available data.
321. Uranium is both a radioelement and a metal, and biological effects may result from the combined
effects of the chemical element or species and the radiation. The radiological and chemicalconsequences of internal exposure to uranium depend partly on the route of intake (principally
inhalation or ingestion), and the chemical form of the intake. Some effects are likely to be related to thechemical toxicity of uranium species, namely the renal effects, whereas others are rather related toradiological toxicity of uranium, including tumorigenic effects such as soft tissue sarcomas in rats andosteosarcoma in mice. In general, chemical effects are observed with short lag-times after exposure
whereas radiological effects such as carcinogenesis have long lag-times.
322. Considering the chemical effects of uranium species, the kidneys are the most sensitive target
organ. At higher levels, chemical effects of uranium are also observed in bones, indicating that uranium
can induce effects on bone metabolism such as the impairment of bone growth and formation. Chemical
effects of uranium have also been observed, in rodent studies, in liver, gonads, central nervous system,and the immune system. These experimental studies indicate that uranium induces biological effects inthese organs, but the changes do not lead to the appearance of observable pathologies. While effects inthese tissues may be seen at higher doses, damage to kidneys (and skeleton) is likely to be critical.
Concerning the central nervous system, animal studies suggest that high doses of uranium may havesome negative effects on the behaviour of animals. With the exception of kidney damage, animalstudies showing toxicological effects have used concentrations of uranium substantially above those towhich humans are exposed. No clinically significant pathologies have been found in the veteran cohortspotentially exposed to DU. Moreover, the biennial examinations of a group of United States veteranswith retained DU shrapnel have found no clinically meaningful adverse effects.
323. Epidemiological studies of uranium miners and millers have included estimates of doses, showing
the small contribution of uranium to overall doses and the dominant contributions of radon and radon
decay products to lung dose and external gamma radiation for other organs. Most studies of nuclear
workers are limited by difficulties in estimating radiation doses due to uranium. A weak association oflung cancer risk with uranium exposure is suggested but the currently available results are notANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 439

consistent enough to demonstrate a causal association. Results for other malignancies and nonmalignant disease were also negative. The Committee concluded that epidemiological studies of public
exposure to uranium in drinking water have reported small functional alterations in the kidneys, within
normal limits and hence of minimal clinical significance.

XI. ACKNOWLEDGEMENTS
The Committee wishes to acknowledge with gratitude the help of the experts E. Ansoborlo (France),
Y. Gueguen (France), I. Guseva-Canu (France), D. Laurier (France), P. Lestaevel (France), F. Paquet(France), E. Rage (France), J. Harrison (United Kingdom) and R. Shore (United States), who weredirectly involved in preparing the evaluation, and S. Baatout (Belgium) for critically reviewing themanuscript. In particular, the Committee would like to thank I. Dublineau (consultant), who mainly
elaborated this scientific annex based on a first draft prepared by K. Bundy (Canada), D. Chambers(Canada), R. Lane (Canada) and B. Thériault (Canada). The views expressed in this scientific annex
remain those of the Committee and do not necessarily represent the views of individual experts, theUnited Nations or its Member States.

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 441

APPENDIX A. TABLES SUMMARIZING URANIUM LEVELS IN
WATER, STUDIES OF OCCUPATIONAL AND ENVIRONMENTALEXPOSURE TO URANIUM
Tables A1 to A4 present uranium levels in water.
Tables A5 to A8 present four groups of occupational studies that provide increasing levels of
information on uranium-specific risks.
Tables A9 to A11 present studies of risks from various sources of potential military and environmental
exposure to uranium.

Table A1.

Overview of uranium content in groundwater worldwide

The numbers in italics correspond to calculated data obtained from the mass activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium of 48.3%; * meanvalue (not median value); n.i: information not included in the study

Continent
EuropeSouth America

Location

Sample number

Total uranium (μg/L)

238

Reference

U (mBq/L)

Finlandn.i.

396

0.15 (<0.01–10)

1.84 (0.12–123)[T22]

FinlandSouth

13

285 (5.6–3 410)

3 504 (143–41 924)

[P28]

Finland

South

288

1.5 (0.3–800)

19 (4–9 990)

[V4]

Finland

South

194

28 (0.001–1 920)

344 (0.01–23 605)

[K26]

Finland

South

167

2 (<0.01–1 770)

24.6 (<0.12–21 761)

[M67]

SwedenVärmland153

6.7 (<0.20–470)

82.4 (<246–5 778)

[S8]

SwedenSouth

328

14.2 (<2–425)

177 (<27–5,293)[I22]

NorwaySouth476

2.5 (−750)

31 (−9 300)

[F12]PolandSwieradow51

1.26 (0.2–2.4)

15.55 (2.4–29.4)

[K10]

Spain

Catalonia

37

4.88 (<0.41–56.1)

60 (<5–690)[O8]

Switzerland

n.i.

5 548

0.77 (0.05–92.02)

9.5 (0.61–1 131)

[S33]

FranceVals les Bainsn.i.

1.85 (0.55–3.6)

22.7 (6.8–44.3)[M34]

GreeceNorth

10

2.02 (0.15–7.66)

25.06 (1.82–95.3)[S1]

Canadan.i.

n.i.

0.31 (0.16–6.23)

3.8 (2.0–76)[L12]CanadaKitigan Zibi, Quebec

32

39.25 (0.4–845.33)

470 (4.9–10 392)

[Z8]

CanadaSoutheastern Manitoba

287

10 (<0.02–2 020)

124 (<0.25–25 048)

[B21]

CanadaNova Scotia

20

0.39 (0.06–41.08)

4.8 (0.8–505)

[K19]

USA

Connecticut

11

16.3 (0.21–1 166)

200 (2.6–14 335)

[M5]

USA

Connecticut

35

157 (1.8–7 780)

1 930 (22.1–95 649)

[O5]

USA

Cities with the largest
average concentration

55 4331.04 (0.03–1 945)

12.95 (0.37–24 124)

[C34]

Brazil

Sao Paulo et Santa Catarina

78

0.28 (0.008–15.0)

3.4 (0.1–184.3)[B43]

Braziln.i.

358

1.2* (<0.01–7.5)

14.8 (0.12–92.2)[G14]

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 443

North America

Country

Country

Asia

Table A2.

Sample number

Total uranium (μg/L)

238

Reference

U (mBq/L)

Moroccon.i.

15

4.5 (0.37–25.1)

55 (4.5–309)[H4]

Ethiopia

Rift Valley138

0.55 (0.005–48)

6.8 (0.06–590)

[R10]

Egypt

Eastern desert

12

5.21 (1.19–519.4)

64.1 (14.6–6 386)

[D2]

Ghana

North and coast

195

0.114 (<0.001–1.99)

1.4 (<0.01–24.4)[R23, Z16]

Fujian Province

China

110 and 552

0.54 (0.03–13.4)

6.6 (0.4–164)

[Z16]

Iran

Caspian Sea

27

2.2 (0.24–5.4)

27 (3–66)[J5]

Jordann.i.

n.i.

1.3 (0.5–6.7)

16.0 (6.6–82.4)[V3]

Bangladesh

West

67

2.5 (0.2–10)

30.7 (2.5–25.8)

[F14]

Japan

Niigata

230.001 (0.0005–0.03)

0.018 (0.005–0.383)

[T14]

India

Hisar

38

33.9* (5.3–113.5)

417 (65.2–1 395)

[G3]

India

Kula area

15

0.83 (0.26–2.56)

10.2 (3.2–31.5)

[S27]

India

Punjab25

22 (2.65–74.98)

271 (32.6–922)[K22]

Overview of uranium content in surface water worldwide

The numbers in italics correspond to calculated data obtained from the mass activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium of 48.3%;
n.i: information not included in the study

Continent
EuropeCountry

Location

Sample number

Total uranium (μg/L)

238

U (mBq/L)

Reference

Finland

Southern Finland

184

0.18 (0.08–34)

2 (1.0–420)[V4]

Finlandn.i.

152

0.099 (<0.01–0.92)

1.2 (<0.12–11.3)[T22]

North America

USA

Cities with the largest average
concentration

34.5610.45 (0.03–1 737)5.55 (0.37–21 534)

[C34]South America

Argentina

n.i.

92

1.9 (<0.01–50)

23.4 (<0.12–615)

[B41]

Asia

India

Upper Siwaliks and Punjab

34

3.84 (1.08–19.68)

47.2 (13.3–242)

[S23]

Iran

Ardabil22

4.2 (2.1–13.6)

51.6 (25.8–167)[H2]

UNSCEAR 2016 REPORT

AfricaLocation

444

Continent

Table A3.

Overview of uranium content in public water supplies worldwide

The numbers in italics correspond to calculated data obtained from the mass activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium of 48.3%; * meanvalue (not median); n.i: information not included in the study

Continent
EuropeCountry

Location

Sample number

Total uranium (μg/L)

238

U (mBq/L)

Reference

Southern Finland951

1.25 (<0.01–1 770)

15.4 (<0.12–21 761)

[M67]

Germany

Bavaria461

0.9 (<0.01–39)

11.1 (<0.12–479)[R3]

Germany

National scale564

3.2 (<0.7–320)

39.3 (8.6–3 934)

[B23]

Germany

National scale

164

0.073 (0.00115–9.0)

0.90 (0.001–111)[B24]

Germany

National scale36

2.0 (<0.16–60.2)

24 (<2–740)[G2]

Austrian.i.

41

0.91 (0.06–79.2)

11.2 (0.72–975)[G6]

Austria

Waldviertel

48

1.1 (0.1–57.5)

14.05 (0.7–707)[W5]

GreeceAksios, Kalikratia

23

3.46 (0.061–10.02)

42.5 (0.75–123)[K7]

PolandCentre26

0.39 (0.03–1.94)

4.8 (0.4–23.9)

[P20]

Spain

Biscay40.07 (0.003–0.24)

0.8* (0.04–2.9)

[H17]

Italy

Rome

9

1.46 (0.02–8.37)

18 (0.3–103)[J2]

Norway, Sweden, Finland, Iceland

Several places22

0.107 (0.0049–56.2)

1.32 (0.06–691)[F13]North America

USA

Illinois, Minnesota, Texas, Wisconsin

24

0.25 (0.1–13.2)

3.1 (1.23–162)[L50]

South America

Argentina

12 provinces

145

0.4 (<0,01–21)

4.9 (<0.12–258)[B41]

AfricaMoroccoNational scale

6

0.75 (0.20–1.28)

9.25 (2.5–15.7)

[H4]

Asia

Islamic Rep. of IranArdabil3

7.6 (4.7–11.7)

93.4 (57.8–144)

[H2]

India

Punjab

3.84 (1.11–19.68)

47.2 (13.6–242)

[S22]

India

Punjab

10.4 (1.24–45.42)

260 (30–1 150)

[R8]

India

Punjab29 (2.5–313)

357 (30.7–3 848)

[S11]

India

Himachal Pradesh

46

1.34 (0.56–10.11)30 (10–260)

[R8]

India

Western Haryana

23

17.03 (6.37–43.31)

209.4 (78.3–532)[K1]

Australia

West

23

0.19 (0–1.16)

2.3* (0–14.3)[W7]

Australia

West

173

0.06* (<0.001–1.40)

0.74 (<0.01–17.2)[C1]

Oceania45

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 445

Finland

446

Overview of uranium content in bottled mineral water worldwide

The numbers in italics correspond to calculated data obtained from the mass activity of natural uranium of 25,400 Bq/g and from the relative proportion of 238U (12.4 mBq/μg) in natural uranium of 48.3%; * meanvalue (not median); n.i: information not included in the study

Continent
EuropeCountry

Sample number

Total uranium (μg/L)

238

U (mBq/L)

Reference

Germany908

0.17 (<0.0005–16.0)

2.09 (<0.006–197)[B24]

Germany

21

0.41 (<0.08–11.4)

5 (<1–140)

[G2]

Spain

32

0.48 (0.04–5.8)

5.9 (0.5–70.9)[D14]

Slovenia

11

0.42 (0.09–4.3)

5.2 (1.1–53)

[B13]

Italy

21

1.38 (0.20–9.92)

17 (2.5–122)

[R30]

Italy

51

0.73 (<0.01–7.2)

8.97* (<0.17–89)[D11]

Poland220.59 (0.06–0.86)

7.26 (0.75–10.54)[C19]

Croatia120.53 (0.17–1.19)

6.55 (2.1–14.6)[R29]

France, Portugal, Spain

14

3.58 (1.79–40.7)

44 (22–500)[M14]

France106

0.2 (<0.10–19)

2.25 (<1.3–230)[A27]

28 countries

132

0.23 (0.0002–27.5)

2.8 (0.002–338)[K11]

Austria100.16 (0.012–5.4)

2.0 (0.15–66.4)[W4]

Norway, Sweden, Finland, Icelandn.i.

0.102 (0.0055–32.4)

1.25 (0.07–698)[F13]South America

Argentina

62

1.9 (0.04–11)

23.4 (0.5–135)[B40]

AfricaTunisia10

1.01 (0.13–2.14)

12.36 (1.56–26.36)[G7]

Morocco100.54 (0.34–0.70)

6.6 (4.2–8.6)[M48]

Kuwait23

0.22 (0.05–2.04)

2.74 (0.63–25.07)

[A11]

Asia

UNSCEAR 2016 REPORT

Table A4.

Table A5.

Studies of workforces that include workers (potentially) exposed to uranium though not explicitly identified

Study references

Summary of study

Summary of findings relating to uranium

Relevance for this report

Atkinson et al.
[A29]

UKAEA employees, 1946–1996. 10,249 deaths. Dosimetry:
external radiation doses. Neutron and tritium doses included
when available. Internal doses noted but not quantitative

All cancer: external radiation exposure trend tests in
those monitored for any internal exposure. Trends
not significant for all cancer, stomach, colon, liver,pancreas, lung, bladder, kidney, brain

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Prostate cancer: dose-response trend before 1980, but
not 1980–1997 among those with internalmonitoring, but uranium not examined
Further analysis of an extended UKAEA dataset [A29], conducted bytime period to examine internal exposure for pre/post 1980 andprostate cancer. Excess associated with work with heavy-water
reactors. Radionuclides of concern: 3H, 59Fe, 51CR, 60Co, 65Zn. Casecontrol prostate cancer substudy conducted

Prostate cancer: exposure levels at heavy-water
reactors fairly constant over time, but no indicationof elevated risk after 1980. So earlier excess withinternal exposure probably not meaningful

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Carpenter et al.
[C8]Cancer mortality 1946–1988 among 75,006 UKAEA, AWE and
BNFL employees. Uranium exposure not assessed

All cancer: analyses of external radiation plus tritium
exposure

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Carpenter et al.
[C9]Cancer mortality 1946–1988 among 40,761 UKAEA, AWE or BNFL
employees who had radionuclide monitoring

All cancer: separate analyses conducted for tritium,
plutonium and other radionuclides. Insufficient detailabout other radionuclides, so no uranium analyses

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Cragle et al.
[C36]

Savannah River Plant (USA) conducted uranium processing,nuclear fuel fabrication and processing. Follow-up to 1980,
9,860 white male employees. 85% of exposure to externalradiation; exposure to numerous internal radionuclides

Analyses by time of first employment and years of
employment. Suggestion of elevated leukaemia riskin small subgroup of early workers, but uranium
exposure not reported

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Fraser et al. [F10]

Cancer mortality and morbidity in UKAEA cohort of 39,718 during
1946–1986. Internal exposure noted for tritium, plutonium orother unspecified radionuclides

Cancer analyses conducted for external exposure,tritium, plutonium and “monitored for any
radionuclide”

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

Loomis and Wolf
[L44]

Cancer mortality (1947–1990) among 6,591 white males at USA Oak
Ridge Y-12 nuclear material production plant. Plant converted UF6
to UF4 to uranium metal which was fabricated and milled. Other
exposure: beryllium, solvents, machine oils, mercury, lead

No measurements or estimates of uranium exposure,
so no relevant analyses

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

McGeoghegan
and Binks[M28]

Mortality and cancer morbidity in 2,209 radiation workers at UK
Chapelcross plant, 1955–1995. Main activity: operation of
450 MW Magnox gas cooled reactors

No measurements reported of internal exposure: only
external radiation analysed

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

McGeoghegan
et al. [M29]38,779 radiation and 15,040 non-radiation male workers at UK
BNFL
facilities(Sellafield,
Springfields,
Capenhurst,
Chapelcross). Some workers had exposure to uranium,
plutonium, tritium and other radionuclides

Investigated circulatory and other non-cancer
diseases. No measurements of internal exposure,analysed external radiation exposure only

Not possible to derive uranium-specific risks,because uranium workers not analysed
separately, and uranium-specific doses not used

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 447

Atkinson et al.
[A30]

448

Abbreviations: LLR, long lived radionuclide exposure, primarily from uranium

Study references
Baysson et al.
[B9]Boice et al. [B36]

Summary of study
Metallurgy department workers (N=356) of French CEA,
1950–1968 were studied for excess cancers (1950–1990),
since workers believed there was a cancer cluster.
Department research primarily on uranium metallurgy.
Reconstructed external radiation doses; internal
radionuclide and chemical exposure noted. Radionuclides:
thorium, natural uranium/enriched uranium, some
activation and fission products
Mortality in uranium miners and millers, Grants, New Mexico,
1979–2005: 1,735 underground uranium miners and 904
non-mining uranium millers. No measurements available
on either radon or uranium exposure levels

Summary of findings relating to uranium
255 handled radionuclides, principally
uranium, mean exposure duration 11 years

naturalAll cancer: suggestion of risk (p=0.13) per year
handling radionuclides, but stronger trend forhandling chemicals
Multiple myeloma: suggestive excess, but only 2 cases(0.2 expected, SMR=8.4, 90% CI: 1.4, 26). No evidenceof cancer cluster
Increased mortality in underground miners: lungcancer, non-malignant respiratory disease, livercirrhosis. No significant excess among non-mining
millers.Among uranium millers:

Relevance for this report
Study small, low statistical power. Analysis only for
exposure to any radionuclide. Potential confoundingby chemical exposure. Multiple myeloma results:
small numbers, maybe a chance finding frommultiple comparisons. Not possible to deriveuranium-specific risks, because uranium doses notused

One of few studies of uranium millers. Study suggests
uranium exposure effects are small or absent but notpossible to derive uranium-specific risks, because
uranium doses not used

Total cancer: SMR=0.89, n=65
Lung cancer: SMR=0.85, n=21
Cerebrovascular disease: SMR=1.06, n=14Heart disease: SMR=0.84, n=73
Non-malignant respiratory disease: SMR=1.07, n=25
No suggestive excesses of kidney cancer, liver cancer
or lymphoma, but small numbers
Dupree-Ellis etal. [D33]

Mortality (1942–1993) investigated among 2,514 white maleworkers at Mallinckrodt (USA) uranium processing plant.
Mean cumulative total dose, 47.8 mSv. For ~11 years plantalso processed pitchblende, which increased externalradiation exposure

All cancer: SMR=1.05 (95% CI: 0.93, 1.07). Some
evidence of excess kidney cancer (ERR per Sv=10.5,
90% CI: 0.6, 57; n=10) in relation to external radiation
exposure

Only total dose analysed, mainly external radiation.
Not possible to derive uranium-specific risks,because uranium doses not used

Kreuzer et al.
[K16]

Circulatory system disease (CSD) mortality (1946–2008,
n=9,039 CSD deaths) in 58,982 male German Wismut
uranium miners. External radiation estimated using a job
exposure matrix

Circulatory disease: ERR per Sv for external gamma
radiation: −0.13 for CSD, −0.03 for ischaemic heartdisease, and 0.44 (95% CI: −0.16, 0.44) for
cerebrovascular disease

Analysis for external radiation exposure only. Not
possible to derive uranium-specific risks, because
uranium doses not used

UNSCEAR 2016 REPORT

Table A6. Studies of groups of workers identified and investigated as uranium workers but not monitored specifically for potential exposure to uranium, so uraniumspecific doses were not available

Summary of study

Summary of findings relating to uranium

Relevance for this report

Lane et al. [L8]17,660 Canadian Eldorado uranium workers (Beaverlodge andPort Radium miners, Port Hope uranium refinery/processing).
Radon decay product exposure, mortality (1950–1999) andcancer incidence (1969–1999)

Significant associations of radon decay productexposure and lung cancer mortality (n=618) in eachsubcohort. No associations for any other cancers. No
estimates of LLR risk

Analysis for radon decay products only. Not possible
to derive uranium-specific risks, because uranium
doses not used

McGeoghegan
and Binks[M27]

Mortality and cancer incidence at UK Springfields uranium
production plant, 1946–1995. Main activities, uranium fuelfabrication and UF6 production. 13,960 radiation workers

No measurements of internal exposure; all analyses forexternal radiation exposure

No analyses of internal exposure. Not possible toderive uranium-specific risks, because uranium doses
not used

McGeoghegan
and Binks[M26]

Mortality and cancer incidence studied at UK Capenhurst
plant, 1946–1995. Main activities, uranium enrichment for
military or power plant purposes. 12,540 employees

No measurements of internal exposure; all analyses forexternal radiation exposure

No analyses of internal exposure. Not possible toderive uranium-specific risks, because uranium doses
not used

McGeoghegan
et al. [M30]407 workers involved in 1957 Windscale uranium pile fire.
Mortality and cancer incidence 1957–2007. Estimatedplutonium, but not uranium, doses

No measurements of internal exposure; only externalradiation analyses

No analyses of internal exposure. Not possible toderive uranium-specific risks, because uranium doses
not used

Pinkerton et al.
[P21]

Mortality of 1,484 men employed in 7 uranium mills inColorado Plateau, USA (1940–1998). Mortality (SMRs)
examined by duration of employment and time since first
employment

No individual estimates of radiation exposure weremadeNo data available on internal exposure. Not possible toderive uranium-specific risks, because uranium doses
not usedRooney et al.
[R22]

Nested case-control study in five UKAEA facilities of incident
and fatal prostate cancer and exposure to radionuclides.
136 prostate cancer cases diagnosed 1946–1986 and 404
matched controls. 28 (21%) prostate cancer cases and 46(11%) controls had potential exposure to 3H, 51Cr, 59Fe, 60Co
and/or 65Zn

Prostate cancer: risk increased with duration andconcentrations of exposure to the targetedradionuclides (possible exposure RR: 2.36, 95% CI:
1.26, 4.43; documented exposure RR: 5.32, 95% CI:
1.87, 17.2)

Negative association with uranium exposure (yes/no).
Not possible to derive uranium-specific risks,because uranium doses not used

Indicated prostate cancer not associated with uranium
exposure; but uranium exposure was rare. Found0 cases and 6 controls with documented uranium
exposure (RR=0, 95% CI: 0, 2.55)

Vacquier et al.
[V1]

French CEA-COGEMA uranium miners (1946–1990) followed
up through 1999, mean 30.1 years. Radon exposure
estimates from ambient monitoring and worker job,
location and year. LLR exposure not estimatedElevated SMRs for total cancer (SMR=1.19), lung cancer(SMR=1.43) and kidney cancer (SMR=2.00), but notleukaemia. Significant radon dose response for lungcancer, but not kidney cancer or leukaemia. No
analyses with regard to LLR exposure

Not possible to derive uranium-specific risks, because
uranium doses not used

Walsh et al. [W6]

Radiation dose and prostate cancer mortality examined in
the 1970–1990 subset (55,435 miners) of German Wismut
uranium mining cohort. Follow-up, 1970–2003, n=263
prostate cancer deaths. Only gamma dose analysed

External gamma dose response: ERR per Gy=−1.18(95% CI: –2.4, 0.02)

Study analysed external dose and prostate cancer
mortality. Not possible to derive uranium-specificrisks, because uranium doses not used

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 449

Study references

Studies of workers monitored for potential exposure to uranium, with occupational dose records, but uranium-specific doses not explicitly analysed
Summary of study

Summary of findings relating to uranium

Relevance for this report

Boice et al. andRitz et al.[B38,R16]46,970 employees, Rocketdyne, USA (1948–1999); 5 801
had radiation exposure, 2,232 monitored for internal
radionuclides. Mortality follow-up 1948–2008 (mean33.9 years). Activities: operating research nuclear
reactors, fabricating nuclear fuel, disassembling anddecontaminating reactor facilities, decladding spent
nuclear fuel and storing nuclear material. Intakes of 14
radionuclides calculated for 16 organs using ICRP
biokinetic models; >30,000 urinalyses. Most significant
internal exposue was from enriched uranium, especiallyfor lung and kidney. A few workers received high lungdoses (~0.3 Sv) but 87% of workers had committed
equivalent dose to all tissues well below 10 mSv

For those monitored for internal exposure, no SMR excesses
seen for any cause: all cancers (except leukaemia);
leukaemia; cancers of lung, kidney, stomach, liver,prostate, brain; heart disease and cerebrovascular disease

Sufficient data to estimate internal radionuclide
exposure on basis of urinalyses. Uranium was largest
contributor to internal dose but other radionuclides
also present. Study limitations: relatively low career
doses, incomplete information on smoking. Study does
not suggest any strong uranium risk but has
uncertainties regarding uranium doses and small
numbers of deaths

Dufey et al.
[D30]

Leukaemia nested case-control study in cohort of 58,987
German Wismut male uranium miners, 1946–2003; 128
leukaemia cases (40 CLL and 88 non-CLL) andunspecified number of controls. Mining performed
1946–1989. Cohort mean dose 48.8 mGy, of which
external gamma contributed 40.9 mGy

Leukaemia: analyses for total dose to red bone marrow.
For a 2-years lag, linear ERR per Gy was 1.39 (90% CI:−0.77, 3.56) for all leukaemia and 2.08 (−0.84, 4.99) for
non-CLL. Suggestion of increased non-CLL only for thehighest dose group: for 0.4, 5.0, 25.6 and ≥103.7 mGy
RRs were 0.53, 0.89, 0.67 and 1.25 (90% CI: 0.69, 2.20),
respectively

Strengths included large cohort, long and high quality
follow-up. However, no assessment of LLR uranium
exposure, so study uninformative regarding uranium
effects

Dufey et al.
[D31]

Liver cancer mortality (n=159) in cohort of 58,987 male
German Wismut uranium miners, 1946–2003. Mining
1946–1989. Average liver dose, 47.9 mGy low-LET and
2.4 mGy high-LET irradiation; mean high-LET liver dose:
2.1 mGy from radon/progeny and 0.8 from LLR. Arsenic
measurements available

Liver cancer: the analysis by high-LET dose categories
did not reveal any statistically significant elevations inrisk, and dose-response analysis, adjusting for low-LET
dose, age and calendar years, yielded ERR per Gy=48.3(95% CI: –32, 129). Examined confounding factors
including arsenic exposure and alcoholism

Analysis adjusted for low-LET radiation exposure, but did
not account for radon decay product exposure.
Contribution of LLR to total absorbed liver dose was<2%, so study provides little information regarding
uranium risk

Dupree et al.
[D34]

995 white male employees (1943–1949) of Linde, USAuranium processing company followed up 1943–1979.
Doses reconstructed from ambient monitoring data,
surface contamination, urinalysis and film badges.
Exposure mainly to uranium with low solubility. Job
exposure was categorized as <10, 10–100 and>100 mSv/y of internal exposure (which was greaterthan external exposure levels)

Elevated SMRs found for laryngeal cancer (SMR=4.47,
95% CI: 1.4, 10.4, n=5), arteriosclerotic heart disease(SMR=1.19, CI: 1.01, 1.39, n=159) and non-malignant
respiratory diseases (SMR=1.52, CI: 1.04, 2.14, n=32). No
excess risk seen for lung, colorectal or lymphohaematopoietic malignancies. No analyses by uranium
exposure levels

No quantitative analyses by uranium exposure levels, so
uninformative regarding uranium risk. Given the
exposure information developed, cohort has somepotential to contribute to future uranium risk
assessment

Uranium doses, RR at 100 mSv:
All cancer except leukaemia: 0.98 (95% CI: 0.82, 1.17, n=266)
Lung cancer: 1.01 (CI: 0.89, 1.16, n=94)
Non-CLL leukaemia: 1.06 (CI: 0.50, 2.23, n=10)
Other trends for internal (mainly uranium) exposure: nonsignificant increasing trends, cancers of stomach, kidney,
brain/CNS, lymphomas; Non-significant decreasing trends,
cancers of colorectum, pancreas, prostate, bladder, andnon-malignant respiratory disease

UNSCEAR 2016 REPORT

Study references

450

Table A7.

Study references

Summary of study

Summary of findings relating to uranium

Guseva Canu etal. [G31]

Cancer mortality (1968–2005) examined in 2,709 maleworkers at French AREVA NC Pierrelatte uranium
enrichment and conversion plant. 15 former uranium
miners excluded. Uranium assessments: individual
dosimetry badges; faecal/urine bioassays and in vivo
measurements performed but not available

All cancer: the SMR=0.70 (95% CI: 0.60, 0.81, n=193)

Kreuzer et al.
[K15]

Stomach cancer mortality (1946–2003; n=592) in 58,677
male German Wismut uranium miners and exposure toexternal radiation, alpha radiation, fine dust with silica
and arsenic. Mean estimated LLR exposure,
4.1 kBqh/m3 (<0.05 mGy), was substantially correlatedwith arsenic exposure

Stomach cancer: for alpha irradiation, ERR per Gy=22.5(95% CI: −27, 72) with statistical adjustment for otherexposure variables. RR in highest alpha dose category(10–26 mGy) not significant: 1.59 (CI: 0.69, 2.49)

Not analysed for LLR exposure. Only <1% of the alphadose to the stomach due to LLR, so uninformative
regarding a uranium risk

Mohner et al.
[M52]

Nested case-control study of leukaemia mortality (1953–
1998) among ~360,000 male German Wismut uranium
miners. 377 leukaemia deaths and 980 controls
matched on age. Cumulative red bone marrow (RBM)
doses from external radiation, radon decay products,
LLR and occupational medical diagnostic radiation(including 17,578 X-ray examinations), using a detailed
job exposure matrix. Mean cumulative LLR RBM dose
estimated to be <0.05 mGy

Added analysis of medical X-ray exposure tooccupational radiation sources. Analyses wereconducted only for total occupational RBM radiation
exposure, both internal and external and for medical
X-rays. Case-control analyses for LLR already reported
in [M50]

Report is uninformative for assessing uranium risk since
analyses were of all radiation exposure combined

Polednak andFrome [P24]18,869 white males worked at the Oak Ridge TEC
uranium conversion and enrichment plant (operated
1943–1947) but not at the Y-12 plant which succeeded
it. Workers in some departments (e.g. chemical dept.)
exposed to high ambient uranium dust. In 1945
average levels of uranium in air in various departments
ranged from 25 to 300 μg/m3. Among 226 men withurine samples, 72% had >0.01 μg/ml and 33% >0.05.
Mortality 1943–1977

Elevation in lung cancer (SMR=1.22, 95% CI: 1.10, 1.36)
but not higher among those working in areas withmore uranium dust or those with longer employment.
Mortality not elevated for stomach cancer (SMR=0.73),
kidney cancer (SMR=0.75), bone cancer (SMR=0.90) or
leukaemia (SMR=0.92)

Individual measurements of uranium exposure levels
available for only an undefined subsample of workers,
so dose-response analyses not conducted. Smoking
information not available

Lymphoma and rectal cancer: non-significant increases
in rectal cancer (SMR=1.48, n=10) and non-Hodgkin’s
lymphoma (SMR=1.32, n=8). Trend analyses by timefirst employment and length of employment notsignificant for all cancer, lung cancer, upper aerodigestive tract cancer, and lympho-haematopoitic
malignancy

Relevance for this reportMortality in relation to internal radiation dose notreported, so study uninformative regarding uranium
risk

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 451

Summary of findings relating to uranium

Relevance for this report

Rage et al. [R4]Lung cancer mortality (1956–1999) studied among 3,377
French uranium miners hired ≥1955 when LLR andgamma ray measurements became available. Among
2,745 with exposure to uranium, mean was
1.63 kBqh/m3 (maximum 10.36). LLR contributed only
1.3% of total alpha-particle lung dose. Annual lungdose due to LLR significantly correlated with doses
from low-LET radiation (r=0.49), radon gas (r=0.53), andradon decay products (r=0.50)

Lung cancer: significant risk lung cancer mortality
associated with total absorbed lung dose (ERR per
Gy=2.94, 95% CI: 0.80, 7.53, n=66) and the alphaparticle absorbed dose (ERR per Gy=4.48, CI: 1.27, 10.9).
Assuming RBE=20 alpha-particles, ERR per Gy for total
weighted lung dose was 0.22 (CI: 0.06, 0.53). LLR ERR
was 5.0 (CI: 1.2, 12.3) per 10 mGy

Statistical analysis of LLR provided only weak
information; since LLR were correlated with and a small
percentage of total exposure the LLR risk estimate may
be inaccurate. No information on smoking habits.
Therefore study provides little information regarding
uranium risk

Zablotska et al.
[Z1]

Mortality (1950–1999) and cancer incidence (1969–1999)
of Port Hope, Canada radium and uranium process
workers. 2,472 (87% males) worked only with uranium.
Gamma was predominant radiation exposure, so
analyses were of gamma and radon decay products(RDP), not of LLR. Urinalysis for uranium begun in early
1960s; alpha counting of urine samples for workers
exposed to enriched uranium conducted on a limited
basis, so not used in dose assessment

No significant elevations in various cancer SMRs. No
excess cancer incidence seen for a number of cancer
types or all cancer. Dose-response analyses reported
for RDP and external gamma. In uranium workers, lungcancer RDP risk estimate non-significantly elevated.
Other malignancies and circulatory diseases: no
significant dose related elevations in risk for either RDP
or external exposure

Study of uranium workers was negative, other than aweak association of RDP exposure and lung cancer
incidence (but not mortality). Had no LLR exposure
estimates, so analyses of uranium effects could not bepresented. Substantial uncertainties: limited or no
exposure information for early workers, lack ofsmoking information. Study uninformative regarding
uranium exposure risk

UNSCEAR 2016 REPORT

Summary of study

452

Study references

Table A8. Studies of workers monitored for potential exposure to uranium for whom uranium-specific doses have been used in analyses so that uranium risks can be
explicitly examined
Abbreviations: LLR, long lived radionuclides; n.e., not estimable

Summary of study

Summary of findings relating to uranium

Relevance for this report

Carpenter et al.
[C7]

Case-control study of brain/central nervous system (CNS)
cancer deaths in workers (1943–1977) at 2 nuclear
facilities at Oak Ridge (ORNL and TEC/Y-12):
enrichment of 235U and conversion to UF4 (TEC, 1943–
1947); fabrication and testing of components fornuclear weapons (Y-12); nuclear energy technology
R&D (ORNL). 72 male and 17 female brain/CNS cancer
deaths (1943–1979). 4 matched controls per case. Work
locations/years rated by industrial hygienist for levelsof 26 agents, including uranium compounds

CNS cancer: 63% of brain/CNS tumours were malignant
glial tumours. Ever exposed to uranium, odds ratio(OR)=1.06 (95% CI: 0.5, 2.3, p=0.88) with no exposurelag, or 0.94 with a 10 years lag. Lagged levels of gradeduranium exposure (grades 1, 2 and 3, with 0=no
exposure as referent) had non-significant ORs of 0.88,
1.01 and 0.70, respectively. Analysis by duration ofheavier uranium exposure (grades 2–3, 10 years lag)showed: OR=0.86 for 1–3 years; 0.79, 3–10 years; 0.99,
10–20 years; 1.63, >20 years (n=3), not significant

Only semi-quantitative imputation of amount of
exposure. No elevated risk was apparent, but thereliability of dose categories unclear. Limited
information regarding uranium risk for brain/CNS
tumours

Chan et al. (andsupplement)[C17]

Mortality among 6,759 workers at Paducah Gaseous
Diffusion Plant, USA studied for 1952–2003. Workers
had potential exposure to external and internalradiation,uranium,
severalothermetals,trichloroethylene and other chemicals. Urinalyses ofuranium used to characterize the cumulative dose ofinternally deposited radionuclides as μg.years

RRs for different uranium exposure quartiles compared
to exposure quartile (<21 μg.years) are provided intable 15 (lung cancer); table 17 (leukaemia and nonHodgkin’s lymphoma); table 18 (pancreatic cancer);
table 20 (brain/CNS cancer)

Provides grouped quantitative information about thehealth effects of uranium exposure, though LLR linear
dose-response risk coefficients were not given.
Possible confounding by chemicals and smoking.
Provides semi-quantitative information regarding
uranium risk for several cancer sites

Checkoway et al.
[C20]

Mortality (1947–1979) investigated among 6,781 whitemale workers at Y-12 uranium fabrication plant (OakRidge, USA). 3,490 monitored for internal exposure.
Internal dosimetry: urine analyses begun in 1950, fully
implemented by 1953, and in vivo measurements
added in 1961. Internal lung doses calculated using
metabolic models. For monitored workers, mean lungdose 82.1 mSv. Mean external dose, 9.6 mSv. Other
exposure: beryllium, solvents, machine oils, mercury,lead. 45 lung cancer deaths in those monitored for
uranium exposure

Lung cancer: (n=45) Analysis with 10-years dose lag foralpha irradiation, compared to 0–<10 mSv group,

Provides some information on lung cancer among thosewith measured uranium exposure; showed little
apparent risk. Small numbers of lung and other cancers
limit the quantitative estimates. Smoking information
not available. Provides semi-quantitative information
regarding uranium risk for lung and brain/CNS cancers

0–49 mSv, RR=0.93 (95% CI: 0.41, 2.12)
50–99, RR=0.66 (CI: 0.23, 1.90)≥100, RR=1.12 (CI: 0.47, 2.65, n=11)
Brain/CNS cancer: (n=14) with no lag,
10–49 mSv, RR=1.10 (0.19, 6.5)
≥50 mSv, RR=0.45 (0.06, 3.2)
Other cancers: no bone cancers observed. Trend
analyses for kidney cancer (n=6) or other a priori
cancers not reported for uranium monitored cohort

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 453

Study referencesSummary of findings relating to uranium

Relevance for this report

A case-control study of circulatory system disease (CSD,
n=442) mortality, particularly ischaemic heart disease(IHD, n=167) and cerebrovascular disease (CeVD,
n=105), and 237 matched controls, nested among
5,086 French CEA-COGEMA uranium miners who werefirst employed after 1955, followed up through 2007,
mean 35.4 years. Individual exposure estimated fromambient
monitoring,
1959–1982
anddosereconstruction for 1956–1958. Since 1983, individual
LLR exposure estimated with film dosimeters. Mean
cumulative LLR was 1.2 kBqh/m3 (max=7.6)

Circulatory disease: statistically significant association ofradon exposure with both CSD (hazard ratio(HR)=1.11/100 WLM) and CeVD (HR=1.25/100 WLM) risk.
Records contained information on a number of medical
CSD risk factors for a subset of cases and controls. After
adjusting for radon and external gamma exposure andfor empirically the main medical risk factors, found LLR
HRs per kBqh/m3 of:

Had a substantial set of individual measurements of LLR
exposure. After adjusting for radon and externalradiation, detected no significant LLR risk for CSD, IHD
or CeVD. Confounding by medical CSD risk factors
proved to be small. Uncertainties: exposure prior to1983 estimated from ambient measurements or withno measurements may have had appreciablemeasurement error. Relevant for uranium risk
assessment of CSD

CSD: 1.13 (95% CI: 0.97, 1.31, n=76)
IHD: 0.94 (CI: 0.73, 1.20, n=26)
CeVD: 1.17 (CI: 0.90, 1.53, n=16)
LLR risks in entire nested case-control sample, but without
being able to adjust for medical risk factors, nearly identical

Drubay et al.
[D23]

Kidney cancer mortality in 3,377 French uranium miners
1956–2007, and 58,986 German uranium miners 1946–
2007. For respective French and German cohorts,
median durations of follow-up were 30.0 and 34.8
years; respective median kidney doses were 26.7 mSv(range 0, 498) and 34.4 mSv (range 0, 2 905)

Kidney cancer: SMRs were 1.49 (95% CI: 0.73, 2.67, n=11)
for French cohort and 0.91 (CI: 0.77, 1.06, n=174) for
German cohort. A 10-years lagged LLR dose-response
analysis showed hazard ratio (HR) per kBqh/m3 with
10-years lagged cumulative dose of 0.89 (CI: 0.55, 1.42)
for the French and 1.009 (CI: 0.991, 1.027) for the GermancohortLack of association with estimated LLR exposuresuggests kidney cancer effect is likely small.
Uncertainties: no information about smoking; Frenchcohort was small; workers also had radon and external
gamma exposure

Dupree et al.
[D35]

Nested case-control study of lung cancer mortality (787cases with 787 matched controls) in cohorts at 4 USA
uranium processing facilites: TEC (operated 1943–1947
only) and Y-12 (1947–1982), Mallinckrodt (MCW, 1942–1966) and Fernald (FMPC, 1947–1982). Maximum
follow-up period, 1943–1983. Primary radiation hazard
was from airborne dust of mainly insoluble naturaluranium compounds. For FMPC, MCW and TEC,
ambient uranium monitoring to estimate internalradiation doses. Y-12 also had whole body counting
and urinalysis. Conversion to doses assumed Type S
uranium exposure. Smoking status available for 48% ofcases and 39% of controls

Lung cancer: analysis of internal radiation (primarily fromambient uranium), using 10-years lagged dose with
<0.5 mGy as baseline, showed no increased risk forworkers exposed below 250 mGy. Lung cancer odds
ratios (ORs) for 0.5, 2.5, 5, 25, 50, >250 mGy were 1.03,
0.57, 0.85, 0.82, 0.64 and 2.05 (95% CI: 0.20, 21),respectively for LLR. However, for the 166 case-control
pairs with smoking data, no elevation in risk (odds ratioof 0.36 in the highest internal dose group)

Analysis had large number of lung cancer deaths, afraction had urinalyses and/or whole body counting in
addition to ambient monitoring data. Suggests that
effect of uranium exposure must be small. Estimate of
ERR per Gy not reported, but the grouped dose data do
not suggest a statistically significant elevated lungcancer risk. Limitations: uncertain dose estimates forearly workers, concomitant exposure to radon andexternal radiation, and limited smoking information.
Provides semi-quantitative information regarding
uranium risk for lung cancer

UNSCEAR 2016 REPORT

Drubay et al.
[D24]

Summary of study

454

Study referencesSummary of study

Summary of findings relating to uranium

Relevance for this report

Guseva Canu etal. [G31]

Lung cancer mortality in 2,709 workers at the French
AREVA NC Pierrelatte uranium reprocessing plant
during 1960–2005. The plant enriched uranium via
gaseous diffusion caused uranium chemical
conversion. Uranium was only radioactive material
used at the plant. Semi-quantitative JEM tocharacterize uranium exposure (duration and intensity
specific for each job and calendar year, on a 4 point
ordinal scale). Smoking data on 6% of cohort

Lung cancer: (n=48) for durations of exposure >1 year to
Type F, M and S uranium compounds found hazard
ratios (HRs) of 1.05 (95% CI: 0.43, 2.52), 2.61 (0.87, 7.8),
2.58 (0.76, 8.8), respectively. For duration of exposure
as a continuous variable, HRs of 1.01 (0.96, 1.01), 1.07
(1.01, 1.13) and 1.07 (1.01, 1.14) per year exposure,respectively

Suggestions of elevated lung cancer risk after exposure
to slowly soluble (Types M and S) uranium compounds.
However, substantial uncertainties: small number oflung cancer cases, only an ordinal scale of exposure
intensity,
limitedsmoking
information,noindividualized information on chemical exposure.
Provides semi-quantitative information on uranium risk
for lung cancer, with analyses by uranium solubility,
but uncertainty due to small numbers

Guseva Canu etal. [G32]

Quantified uranium exposure using a job exposure
matrix for 2,897 workers at French AREVA NC
Pierrelatte uranium reprocessing plant. Classified
exposure by natural vs. reprocessed uranium, and bysolubility Types F, M and S. To model cumulative
exposure for individuals, estimated duration andintensity of exposure to Types F, M and S

Lung cancer: (n=53) For natural uranium exposure, nosignificant associations for Type F, M or S. For
reprocessed uranium, significant hazard ratios (HRs) inthe highest cumulative exposure group of 4.35 (95% CI:
1.25, 15) for Type M and 10.5 (CI: 2.3, 48) for Type S.
Dose-response analysis for reprocessed uranium
exposure duration gave HRs of 1.13 (1.03, 1.25) and1.13 (1.01, 1.25) for Types M and S, respectively.
Analysis in subgroup of 345 workers with smoking
information suggested no confounding by smoking

This exploration of chemical types and radioactivity levelof various forms of uranium suggests that naturaluranium has little or no lung carcinogenic effect.
However, the less soluble forms of reprocesseduranium dust, with their greater radioactivity andrelatively long residence time, may induce lung cancer
Limitations: study size was small. Only limited smoking
data available. Results require confirmation in larger
independent study

Lympho-haematopoietic malignancies: (n=21) Found
association with insoluble reprocessed uranium, but on
the basis of only 3 exposed cases
Guseva Canu etal. [G33]

Mortality from ischaemic heart disease (IHD, n=48),
cerebrovascular disease (CeVD, n=31) and total
circulatory system diseases (CSD, n=111) after chronic
exposure to uranium among 2,897 workers at the
French AREVA NC Pierrelatte uranium processing plant(1960–2006). Cumulative exposure to various uranium
compounds was classified by isotopic composition andsolubility type and quantified for individual job
histories via a job-exposure matrix (natural vs.
reprocessed uranium (RPU), and absorption Types F, M
and S)

Circulatory disease: CSD mortality was increased among
workers exposed to Type S RPU (HR=2.13, 95% CI: 0.96,4.70) and Type S natural uranium (HR=1.73, CI: 1.11,
2.69). Additional information on risk by duration andintensity of exposure for CSD, IHD and CeVD is given in
the text of table 20
For the subset of workers with available smoking data
they found nominally higher CSD HRs for RPU Type M
and S exposure among smokers than non-smokers, but
numbers of cases were small

Job exposure matrix was carefully done, but provides only
an approximate quantitation of uranium exposure.
Concerns with study are: small study size, limited
smoking data. Possible confounding: heat andtrichloroethylene exposure were correlated withuranium exposure. The analyses of Types M and S RPU
exposure did not adjust for the common exposure to
Type F and natural uranium. Provides semi-quantitative
information regarding uranium risk for CSD, including
analyses by uranium solubility and isotopic composition,
but with uncertainty due to small numbers

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 455

Study references

Kreuzer et al.
[K17]

Kreuzer et al.
[K18]

Mohner et al.
[M50]

Summary of findings relating to uranium

Relevance for this report

Circulatory system disease (CSD) mortality (1946–1998),
German Wismut male uranium miner cohort in relation
to external radiation, radon and LLR exposure.
Exposure estimated via a job exposure matrix JEM foreach radiation type,1946–1989. 5,417 deaths from CSD(1946–1998), including 3,719 from heart disease and1,297 from cerebrovascular disease. Mean LLR
exposure, 3.5 kBqh/m3 (maximum 132)

Circulatory disease: analyses for cumulative LLR
exposure lagged by 5 years. The LLR risk estimates (ERR
per 100 kBqh/m3) were

The largest systematically defined cohort of uranium
workers available. Uncertainties: no confirmation of
JEM by urinalyses, correlation of LLR exposure withexternal radiation and radon exposure not accounted
for, lack of dosimetric models to estimate LLR exposureof the heart and major arteries

Mortality from cancer of the extra-thoracic airways
among 58,690 male German Wismut uranium miners(1946–2008) in relation to radon and cumulative LLR
exposure. LLR exposure estimates derived by a job
exposure matrix based on ambient measurements as
described in Kreuzer et al. [K14]

Cancer of extra-thoracic airways (n=234): non-significant
increase with radon exposure: ERR/100WLM=0.036,
95% CI: −0.009, 0.08

Mortality in 4,054 male German uranium millers (1946–
2008) who had never worked as uranium miners, so
radon exposure was low, mean 8 WLM. Estimatedexposure to radon, external gamma radiation, LLR andsilica. Exposure estimates derived via a job exposure
matrix of intensity (from ambient monitoring) by
location, job, calendar year. Mean LLR: 3.9 kBqh/m3.
Preliminary organ dose calculations for alpha-emitting
LLR averaged 3 mGy for lung, and 1 mGy for liver andred bone marrow

All cancer: LRR ERR per 100 kBqh/m3 = −0.43 (95% CI:−1.31, 0.44, n=457), adjusted for radon exposure

Nested case-control study of leukaemia mortality (1953–
1989) among ~360,000 German Wismut male uranium
miners: 377 leukaemia deaths and 980 controls
matched on age. Job exposure matrix JEM by location,
job and year used to estimate red bone marrow (RBM)
exposure. JEM for radon and decay products (RDP),
external radiation and LLR exposure estimates for >500
different workplaces, 750 job titles, 44 calendar years.
Mean cumulative RBM dose was 23.6 mGy; only 2%
from inhalation of LLR

Leukaemia: non-chronic lymphocytic leukaemia (nonCLL) risk not associated with RDP, but showedsuggestive association with LLR exposure. ERR per
100 kBqh/m3 for LLR was 1.04 (90% CI: –0.64, 2.73,
n=377) for all leukaemia, 0.76 (CI: –1.26, 2.78, n=218)
for non-CLL and 1.35 (CI: –1.54, 4.24, n=159) for CLL.
Suggestion that the highest/longest LRR doses may
increase risk: for ≥20 kBqh/m3, (OR=1.26, 90% CI: 0.71,
2.22) for non-CLL. For acute myelogenous leukaemia,
the LRR ERR per 100 kBqh/m3 was 0.83 (CI: –1.9, 3.6)

CSD: −0.2 (95% CI: −0.5, 0.06)
Heart disease: −0.3 (CI: −0.6, 0.02)
Cerebrovascular disease: −0.05 (CI: −0.5, 0.6)
In no case did the highest dose category show significantly
elevated risk. Ischaemic heart disease (n=2,690) also did
not show a statistically significant elevation

No increase with LLR exposure: ERR per 100 kBqh/m3=−0.17, 95% CI: −2.50, 2.16 (adjusted for radon
exposure)

Lung cancer: LRR ERR=−0.61 (CI: −1.42, 1.9, n=159), (notadjusted for radon)

Estimate of risk for uranium exposure had potential
confounding by external radiation levels, arsenic andsilica dust exposure and smoking habit. Quantitativerisk estimate is relevant for uranium risk assessment:suggests little risk for extra-thoracic airways

Well conducted study, suggesting little/no association of
uranium exposure with various health outcomes. Study
size was small and no smoking information available.
Quantitative risk estimates are relevant for uranium risk
assessment

Additional LLR risk coefficients given in text of table 16(lympho-haematopoietic), table 17 (colon and rectal),
table 18 (kidney and prostate), table 20 (circulatory)

Provides evidence that LLR exposure has little
association with leukaemia risk. Limitations: prior to1955 little data on exposure levels so dose
uncertainties.
Mortality
may
have
been
underascertained because inadequate identifiers inearly years limited mortality linkage. Underlying cohortand numbers in it rather loosely defined, though it is
the largest uranium worker cohort. Quantitative risk
estimates are relevant for uranium risk assessment

UNSCEAR 2016 REPORT

Kreuzer et al.
[K14]

Summary of study

456

Study references

Study references

Summary of study

Summary of findings relating to uranium

Relevance for this report

Mohner et al.
[M51]

Nested case-control study of laryngeal cancer among~360,000 German Wismut male uranium miners ever
employed, 1950–1989. Tumour registry follow-up,
1961–1989. Two matched controls per case. Crude
information on smoking habits available for many
workers and anecdotal information on alcohol
consumption from medical records. Included 554
laryngeal cancer cases and 929 controls

Laryngeal cancer: elevated risk in highest cumulative LLR
exposure category (≥10 kBqh/m3), OR=1.63 (95% CI:
1.03, 2.59, n=56), adjusted for smoking and alcohol
intake. For continuous LLR cumulative exposure:
ERR=0.098 (CI: –0.11, 0.31) per 10 kBqh/m3, unadjusted,
or ERR=0.156 (CI: –0.11, 0.41) adjusted for smoking andalcohol intake

The same limitations for this study as for Mohner et al.
[M50]. Follow-up successful for only 72.8% of potential
controls. Quantitative risk estimate for laryngeal cancer
is relevant for uranium risk assessment

Rage et al. [R5]5,086 uranium miners employed by CEA-COGEMA in
France; followed up 1946–2007 (mean 32.8 years).
Cohort included 3,377 miners first employed after
1955, for whom radon, LLR and external γ-ray exposure
was recorded. Assessment of LLR exposure based on
ambient measurements 1959–1982 and individual
measurements thereafter. Doses retrospectively
reconstructed for the period 1956–1958 [R4]. Post-1955
workers had mean of 1.64 kBqh/m3 of LLR (range 0.01–
10.4)

Internal LLR dose-response analyses were conducted,
doses lagged 5 years. LRR results expressed as
ERR/kBqh/m3:
All cancer, 0.022 (95% CI: −0.049, 0.12, n=315);

LLR exposure related to various mortality end points.
Limitations: LLR correlated with and a small percentage
of total radiation exposure; smoking information
unavailable; lung cancer analyses did not adjust forsilica exposure. Quantitative risk estimates are relevant
for uranium risk assessment

Nested case-control study of lung cancer among 3,864
Y-12 (Oak Ridge, USA) workers hired 1947–1974. Y-12
was a nuclear material fabrication plant. Internal
exposure primarily LLR from ambient uranium dust.
Individual monitoring for external radiation exposure
began in 1948 and became plant-wide in 1961.
Urinalysis monitoring increased in coverage throughthe 1950s and in vivo monitoring begun in 1961. Mean
external lung dose (10.1 mSv) was fourfold lower than
mean cumulative internal dose (44.7 mSv). Other
exposure: beryllium, solvents, machine oils, mercury,
lead

Nested case-control analyses were conducted, withmatched controls. Exposure lagged by 5 years

All cancers except lung, −0.065 (n.e. 0.019, n=221);
Other LLR risk coefficients given in text of table 15(respiratory), 19 (kidney), 20 (brain/CNS) and 21(circulatory). In summary, only lung cancer showed asignificant positive association with LLR exposure

Lung cancer: LLR dose-response negative (ERR per
100 mSv=–0.077, 90% CI: –0.23, 0.07)
Smoking-related diseases other than lung cancer: LRR(ERR per 100 mSv=(–0.089) was negative, as was nonmalignant respiratory disease (–0.085), but with wide
confidence intervals

Provides evidence that uranium risk for lung cancer islikely small. Strength: measured exposure (both urine
assays and in vivo monitoring) and the fact that radon
exposure did not overshadow the LLR exposure of thelung. LLR exposure had substantial uncertainties, inpart because 58% of exposure person-years had
imputed rather than measured doses. Limitations: dose
uncertainties, inadequate information on smoking andworkplace chemicals, statistical power limited.
Quantitative risk estimate for lung cancer is relevant for
uranium risk assessment

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 457

Richardson andWing [R12]Lung, 0.32 (0.09, 0.73, n=94);

Summary of findings relating to uranium

Relevance for this report

Silver et al. [S19]

Cohort of 6,409 uranium workers at Fernald (USA)employed (1951–1985), and followed through 2004
(mean follow-up 37 years). Used urine uranium
concentration data (>250,000 urine samples) from1952 forward to estimate exposure to internallydeposited uranium compounds. Mean cumulative
doses to the lung for hourly and salaried workers were1,552 μGy and 388 μGy for LLR, respectively. Mean LLR
cumulative organ dose ranged from 1.1 mGy (lung) to
6.7 mGy (pancreas)

Analyses took into account pay code, birth year,
trichloroethylene exposure, radon and externalradiation. Overall: hourly males showed excess lungcancer (SMR=1.25, 95% CI: 1.09, 1.42, n=297). LRR ERRs
calculated for Caucasian males per organ-specific
100 μGy:
Intestinal cancer (small intestine and colon, notrectum): had a significant elevation in the highest dosegroup (>36 μGy, ERR=1.7, CI: 0.17, 5.7) and a significant
dose response (ERR 100 per μGy=1.5, CI: 0.12, 4.1,n=48). Other dose-response estimates at 100 μGy forinternal doses were null. Additional LLR risk coefficients
given in text of table 15 (lung, respiratory), table 16(leukaemia, lymphoma), table 17 (stomach, pancreas),table 18 (kidney)

This study has longer follow-up and better exposure
assessment than previous ones. Uranium internal
doses estimated for several different organs and linear
ERR estimates adjusted for other radiation exposure.
Sole positive finding related to intestinal cancer, which
is not a very high a priori suspect, so requires
confirmation. Limitations: no smoking data, limited
data on exposure to chemicals and other hazardous
substances, limited statistical power. Quantitative risk
estimates are relevant for uranium risk assessment

9,973 Czech uranium miners studied for leukaemia andnon-Hodgkin’s lymphoma risk. Two cohorts: S, 4,348
exposed 1948–1963; N, 5,625 exposed 1968–1986.
Though had limited exposure measurements, derived
location-job-year estimates of dose rates for hewers
and then proportionately scaled for other jobs todevelop a job exposure matrix JEM. Estimated 52–64%
of the red bone marrow (RBM) dose was from LLR.
Mean LLR RBM dose of 160 mSv for cohort S and
37 mSv for cohort N

Leukaemia: using 2 years dose lag, for 1−19 years since
1st exposure leukaemia SMR=1.0 (95% CI: 0.4, 2.1, n=7).
For >19 years since 1st exposure SMR=1.8 (CI: 1.2, 2.7,n=23). For total follow-up period, SMR=1.5 (CI: 1.1, 2.2,
n=30, mean RBM LLR dose 145 mSv). Due to small
numbers, did not separate out non-CLL leukaemias.
Leukaemia risk slope for total RBM dose (external,radon progeny and LLR), ERR per Sv=2.5 (90% CI: 0.3,
9.3)

Dose uncertainties were probably large, especially forearlier years (that contributed the highest exposure)and the number of malignancies was small. Analyses of
LLR exposure were by average SMRs and not dose
responses. Study suggestive of leukaemia risk fromuranium exposure, but study limitations weaken the
conclusions

French cohort of 3,377 uranium miners first employed
1955–1990 when exposure to external radiation, radon
and uranium dust (LLR) could be estimated. 3,240 had
internal exposure. Follow-up through 1999, a mean of
26.5 years; mean LLR exposure, 1,632 kBqh/m3. LLR
exposure estimates: reconstructed before 1959;
ambient measurements 1959–1982; since 1983
personal film dosimeters. Since external radiation, LLR
and radon exposure instances were correlated,
determined which were associated with cancer risks

LLR exposure was correlated r=0.52 with cumulative
radon exposure, 0.47 with external exposure.
Combined cumulative radiation exposure showedsignificant dose response only for lung cancer. Linear
ERR risk coefficients per (kBqh.m-3) for LLR exposure,lagged 5 years:(Prior reports:[D33, R14,
R15])

Tomasek andMalatova [T13]

Vacquier et al.
[V2]

Non-Hodgkin’s lymphoma (NHL): dose response notsignificant (p=0.16), though a nominal overall excess(SMR=1.5, CI: 0.9, 2.2)

All cancer: 0.001 (95% CI: –0.08, 0.11);
Lung cancer: 0.25 (CI: 0.02, 0.70);
Brain/CNS cancer: 0.17 (CI: n.e., 2.0)

LLR dose-responses could not be calculated withadjustment for radon or external exposure. Substantial
correlation of LLR with radon and gamma exposure, so
LLR risk estimates not well defined but suggestive
small association with lung cancer. Limitations:
uncertainties in exposure assessments, correlated
exposure, lack of smoking data. Quantitative risk
estimates are relevant for uranium risk assessment

UNSCEAR 2016 REPORT

Summary of study

458

Study references

Study references

Summary of findings relating to uranium

Relevance for this report

Yiin et al. [Y3]

Nested case-control study of multiple myeloma among
47,941 workers at the K-25 Oak Ridge, USA gaseous
diffusion uranium enrichment plant (operated 1945–1985). Five matched controls per case. Exposure tosoluble and insoluble uranium compounds. Individual
uranium dose estimates based on ambient
measurements and urinalysis. Formed groups
according to the strength of the dosimetry: grouping I,
multiple urinanalyses and extensive ambient
measurements; groupings II also included those withfewer measurements; grouping III, all cases andcontrols. External radiation doses and medical
radiation exposure also compiled

Multiple myeloma: 98 multiple myeloma death cases
and 490 controls. Analyses adjusted for birth cohort,
external and medical irradiation, mercury, nickel andtrichloroethylene exposure. For those with the best
estimated uranium doses to the bone marrow(Group I), the odds ratio (OR) at 10 μGy was 1.04 (95%
CI: 1.00, 1.09). For total case-control group (Group III),
OR was identical: 1.04 (CI: 1.00, 1.09). Indicated a weakassociation of bone marrow dose from uranium withmultiple myeloma risk

High quality study. Included detailed uranium exposure
assessment and analyses adjusted for external andmedical radiation doses and prevalent chemicals. Weakassociation found between uranium bone marrowdose and multiple myeloma risk; requires confirmation
by other studies. Limitations: less measurement data
were available for workers in the earlier days.
Quantitative multiple myeloma risk estimate is relevant
for uranium risk assessment

Zhivin et al.
[Z10]Studied 4,688 French gaseous diffusion uranium
enrichment workers (AREVA NC, CEA and Eurodif) with
exposure to mainly soluble uranium compounds(Type F). Used plant-specific job exposure matrices
JEMs to estimate cumulative exposure. The AREVA NC
job exposure matrices showed 64% sensitivity and 80%
specificity in validation against bioassay data. Medianfollow-up, 30.2 years, 1968–2008. Had estimates ofpotential
confounding
exposuresituations:trichloroethylene, heat, noise

From job exposure matrices, grouped workers into no,low, medium, high exposure for analysis. Analysed
external radiation, and natural, enriched and DU.
Analysed all cancer, lung cancer, lymphohaematopoietic malignancies, and circulatory diseases.
Results by exposure group presented in text of table 15(lung), table 16 (lympho-haematopoietic), table 20(circulatory)

Study developed quantitative estimates of uranium
exposure, but analysed only low, medium and highgrouped uranium exposure. Valuable because it
considered mainly highly soluble uranium andcompared natural, enriched and depleted isotopic
forms.
Providessemi-quantitative
information
regarding uranium risk for CSD, including analyses ofisotopic composition

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 459

Summary of study

460

Table A9.

Studies of groups with potential military uranium exposure
Summary of study

Summary of findings related to uranium

Relevance for this report

Following lay-press reports of alleged excess leukaemia
among Dutch Balkan veterans, study examined cancer
incidence, comparing 18,175 Balkan-deployed military
male personnel with 135,355 non-Balkan deployed
military males and with general population rates.
Maximum follow-up was for nearly 15 years. Some
differences between the Balkan and non-Balkan
cohorts’ military status, e.g. conscripted soldiers (15%vs. 81%, respectively)

All cancer: total cancer incidence 17% lower among
Balkan than non-Balkan personnel (hazard ratio (HR)0.83, 95% CI: 0.69, 1.00)

No information about exposure to DU available, so study
non-informative about uranium effects

Hines et al. [H18]37 US Gulf War I veterans who had inhalation exposureto (and sometimes retained fragments of) DU fromfriendly fire incidents were examined. Compared thosewith high vs. low body burdens of DU, as measured byurine assay. DU remaining in the body is 40% lessradioactive but chemically similar to natural uranium.
Low and high exposure groups similar in age, race, BMI
and smoking

Non-malignant respiratory disease: no differences
between low and high exposure groups for any of a listof pulmonary symptoms or for history of steroid
prescriptions. No significant differences regarding DU
exposure levels in pulmonary function parameters or
chest CT findings

Study strengths: had clinical examinations, spirometrictesting, symptom reporting, and smoking information.
DU findings do not indicate any non-malignant
pulmonary effects. Provided limited information
regarding uranium effects due to small sample size andlikelihood that exposure levels were low

Labar et al. [L3]

Ecological study to examine childhood haematologicalcancers in Croatian counties with DU (10 counties),
chemical plant damage (2 counties) or "population
mixing" (4 counties). Compared disease rates forchildren ages 0–14 before (1986–1990), during (1991–
1995) or after (1996–1999) the Croatian war in thosecounties

Childhood haematological malignancies: in the 10
counties with DU exposure, no significant increases
during or after the War were found for lymphatic
leukaemia, myeloid leukaemia, Hodgkin’s lymphoma,
or non-Hodgkin’s lymphoma

No evidence for an effect of DU on childhood
haematological malignancies. Exposure very low, andecological data are susceptible to various unidentified
biases, so study provides no meaningful information
on uranium risk

Macfarlane et al.
[M2]

A 13 year follow-up was conducted of 51,753 UK
veterans deployed in the Gulf War and 50,808 otherveterans matched for age-group, sex, rank, service andlevel of fitness, who were not deployed to the Gulf.
57% responded to a questionnaire about deployment
experiences and morbidity

7% of those with questionnaires responded they hadreceived DU exposure, among whom there were 9
disease-related deaths. The DU exposed vs. unexposed
yielded a RR=1.00 (95% CI: 0.99, 4.04) after adjustment
for age, sex, smoking and alcohol intake

DU exposure was based on unverified self-reports andthe risk estimate was for overall disease deaths, not apriori causes. The small number of deaths (n=9) among
those reportedly exposed to DU is a very weak finding

McDiarmid et al.
[M22]

US Gulf War veterans with DU exposure were followedup (1991–2005) for clinical and laboratory end points.
On basis of repeated urine uranium measurements,
10 were designated as high DU exposure and 24 as low
exposure. Exposure resulted from inhalation, woundcontamination and/or embedded fragments (for~30%)

The extensive clinical examination did not show any
differences between the high and low exposed group.
Other high/low exposure comparisons: no difference inurine retinol binding protein, a biomarker of renal
proximal tubule function. No differences found on:other renal measures, a neurocognitive test battery,neuroendocrine parameters, semen parameters, or
HPRT mutations. A borderline increase in chromosome
aberrations in the high exposure group

Among the several dozen parameters measured, only
chromosome aberrations showed a (suggestive)
difference. The multiple comparisons and small sample
size limited the statistical power and meaningfulnessof the comparisons

Bogers et al.
[B28]

Miscellaneous cancers: rates of digestive, respiratory,urogenital and haematological cancers nonsignificantly lower in the Balkan vs. non-Balkan group
Leukaemia: HR could not be calculated for leukaemia
because of the small number of cases (Balkan n=5)

UNSCEAR 2016 REPORT

Study referencesSummary of study

Summary of findings related to uranium

Relevance for this report

McDiarmid et al.
[M23]

35 US Gulf War veterans with DU exposure in 1991 wereagain evaluated in 2007 with numerous clinical andlaboratory measures

Only two parameters showed marginal differences
between the high- and low exposure groups: β2
microglobulin (81.7 vs. 69 μg/g creatinine, respectively;
p=0.11) and retinol binding protein (48.1 vs. 31 μg/g
creatinine; p=0.07). No differences were seen in rates ofchromosome aberrations or HPRT mutations

Among the several dozen parameters measured, only
two showed a suggestive difference. The multiple
comparisons and small sample size limited thestatistical power and meaningfulness of thecomparisons

McDiarmid et al.
[M25]

37 US Gulf War veterans with DU exposure in 1991 wereagain evaluated 20 years after exposure (2011) for
numerous clinical and laboratory end points. Reportfocused on acute renal toxicity and included three newsensitive markers of kidney tubular injury

No differences between high- and low-exposure groups
for: haematology, clinical chemistries, neuroendocrine
parameters, bone metabolism, neurocognitive
function, immune function, pulmonary function or
nodules. Regarding renal function and injury, no highvs. low exposure differences were found for 16 clinicalindicators of renal function, 6 urine markers for kidney
injury, or 4 urine measures of low molecular weightproteins, although a re-analysis using a different
definition of high exposure showed elevations in two
kidney injury markers

Two sensitive markers of kidney tubular injury suggested
subtle renal injury, but this found only after the maincategories of high vs. low exposure showed nodifferences. Multiple comparisons and small sample
size limit the inferences that can be drawn from thestudy

Strand et al.
[S42]Cancer risk and all cause mortality studied among 6,076
Norwegian military UN peacekeepers in Kosovo, 1999–
2011. No information available on DU exposure. Mean
follow-up, 10.2 years; 4.4% women

69 cancer cases observed (SIR=1.04, 95% CI: 0.81, 1.33).
Suggestion of elevation in melanoma (SIR=1.90, CI:
0.95, 3.4, n=11). No elevation in stomach, liver, lung,
prostate, kidney, bladder, brain cancers or lymphohaematopoietic malignancies

With no data on DU exposure, study is uninformative
regarding uranium risk

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 461

Study references

462

Study references

Summary of study

Summary of findings related to uranium

Relevance for this report

Boice et al. [B31]

Study evaluated cancer incidence (1993–1997) amongresidents near Apollo (began operations 1957) andParks uranium-plutonium processing plants in
Pennsylvania, USA. Study population included about
17,000 individuals in 8 nearby municipalities

All cancer: found 581 incident cancers when 574 were
expected (SIR=1.01, 95% CI: 0.93, 1.10)

Earlier investigation had obtained soil measurements ofuranium, plutonium and other isotopes and air
measurements of gamma radiation; all levels well
below Nuclear Regulatory Commission releaseguidances. Those measurements too sparse to be used
to directly assess uranium effects associated with
exposure of individuals. Limited environmental
measurements and negligibly low exposure levels
mean study is not informative as to uranium effects

Boice et al. [B30]

Boice et al. [B32]

People in two counties proximal to the Apollo and Parks,
Pennsylvania, USA former uranium/plutonium material
processing plants were concerned regarding possible
elevated rates of cancer, especially childhood
leukaemia. Study compared cancer mortality rates inthose two counties (population ~443,000) with six
other counties (population ~864,000) matched on age,
race, urbanization and socioeconomic factors.
Comparisons made before, during and after operationsof the uranium-plutonium plants

Cancer mortality rates investigated in Karnes County,
Texas, USA, a county with uranium mining and milling
activities from 1959 to early 1990s, with 3 mills and >40
mines. No uranium enrichment activities. Karnes cancer
mortality rates before, during, after that period (1950–
2001) compared with four match control counties.
1,223 cancer deaths observed in Karnes County (1,392
expected) and 3,857 in control counties. Texas
Department of Health monitored Karnes radiationlevels, found no elevations in radioactive material
in/near homes

A priori tumour sites: for tumour sites with potentiallygreater exposure they found: lung (SIR=0.88), kidney(SIR=1.05), non-Hodgkin’s lymphoma (SIR=1.10), liver(SIR=0.61) and bone (2 observed, 1.19 expected), noneof which were statistically significant elevations. Also
thyroid and female breast cancer rates were notelevated, nor was leukaemia
All cancer: during 1950–1995, 39,287 cancer deaths
occurred in the proximal counties and 77,382 in thecontrol counties. Compared to control counties, RRs in
proximal counties for all cancer deaths before (1950–
1965), during (1965–1980) and after (1980–1995) werevirtually identical—0.95, 0.95 and 0.98, respectively—
indicating no effect of potential uranium/plutonium
exposureStrengths: the mortality ascertainment was high, sample
size was large. Most likely uranium-related cancer types
examinedA priori tumour sites: for childhood leukaemia (total n=119
proximal county cases and n=272 control cases) before,
during, after RRs=1.02, 0.81, 0.57, respectively. Lungcancer (RR=0.85, 0.99, 0.95), bone (RR=0.96, 1.00, 1.01),
liver (RR=0.98, 1.07, 1.01) and kidney (RR=1.00, 1.08, 1.02)
not significantly elevated in the proximal counties

Conclusion: because of low exposure levels andecological nature of the study, does not adequately
address the health risks of uranium

All cancer: Karnes County RRs of 1.0 in 1950–1964(before/beginning of mining-milling), 0.9 in 1965–1979(early operations), 1.1 in 1980-1989 (later operations
and latency period) and 1.0 in 1990–2001 (few/no
operations)

Strengths: mortality ascertainment was high. A priori
cancer types specifically examined

A priori tumour sites: for prime exposure periods (1965–
1979 and 1980–1989), Karnes county RRs were 1.0, 1.2,
respectively, for lung cancer, 0.8, 0.9 for kidney cancer,
1.0, 0.8 for liver cancer, and 1.3 (n=20) and 1.7 (n=17)
for leukaemia. no RRs significantly elevated. Childhood
cancer mortality 1965-2001, non-significant RR of 1.3(n=8 cases)

Relevance: because of low, unknown exposure levels
and ecological nature of the study, does notadequately address the health risks of uranium

Weaknesses: no individual or even county-level
estimates of uranium exposure levels. Proximal county
areas were rather broad, further diluting possible
exposure, though nearly all inhabitants lived within
20 miles of a processing plant

Weaknesses: limited uranium exposure measurements
available to use in analysis. Cancer mortality
misdiagnoses, especially for liver cancer

UNSCEAR 2016 REPORT

Table A10. Studies of general population groups with potential environmental exposure to uranium by inhalation

Summary of study

Summary of findings related to uranium

Relevance for this report

Boice et al. [B34]

Mortality evaluated during 1978–2004 for 1936–1984
residents of Uravan, Colorado USA, a uranium mill
town. Mining and milling activities during mid-1930s to
1984. The mean follow-up time since first Uravan
residence, 38.1 years

All cancer: no significant elevation in overall cancer
mortality or cancers of lung, kidney, breast; leukaemia;
non-malignant respiratory, renal or liver disease
among females or the 622 uranium mill workers, but
excess lung cancer found among undergrounduranium miners. Had no quantitative information on
exposure levels of mill workers

Study uninformative regarding uranium effects because
no uranium exposure data and has low statistical
power

Boice et al. [B35]

Comparison of 1950–2000 mortality in Montrose County,
Colorado, USA (Uravan and other mining/milling
operations) with five comparison counties

All cancer: no difference in total cancer

Since no information on who was exposed to uraniumand exposure levels, study uninformative regarding
uranium risk

Cancer incidence (1982–2004) and mortality (1950–
2004) in Grants, New Mexico, USA residents: Grants
mining during early 1950s to 1990; milling operations
1958–1990

Lung cancer: found increased mortality from lung cancer
among men (SMR=1.57, 95% CI: 1.21, 1.99)

Chen et al. [C24]

Ecological study of cancer incidence in Port Hope,
Ontario, Canada residents, 1992–2007. In 1981–1982,
air uranium concentrations averaged 0.02 μg m-3
leading to a committed effective dose of 0.16 mSv, but
by 1988–1989 were reduced to 0.00105 μg m-3. Larger
doses received from gamma and radon exposure.
Population ~16,500

Standardized incidence ratio (SIR) for leukaemia, 0.86
(95% CI: 0.60, 1.21), with no elevation of childhood
leukaemia rate SIRs were <1.0 for a number of othercancer sites. A significant elevation of lung cancer
incidence, perhaps related to smoking habits

Provides some information on average air uranium
levels, but analyses were ecological and not specific foruranium exposure. Study useful insofar as it rules outlarge uranium effects

Report of theConsejo deSeguridad
Nuclear [C37]

Ecological study of cancer mortality in municipalities
near seven nuclear power plants and five fuel cycle
facilities (chemical conversion of uranium concentrate)in Spain. Cancer mortality (1975–2003) ofmunicipalities within 30 km of facilities compared tosimilar municipalities 50–100 km distantWith reconstructed external doses, reported increasing
dose-response trends for kidney cancer around nuclear
power plants and for lung and bone cancers around
fuel cycle facilities, but had not estimates of uranium
exposure

Report is uninformative regarding uranium exposure
effects, as it is an ecological study and only estimatedexternal radiation exposure

Lopez-Abente etal. [L46]

Examined solid cancer mortality (1975–1993) in 283
towns in Spain within 30 km of one of four nuclear
power plants or four nuclear fuel facilities, compared to
275 towns 50–100 km away, matched on various
sociodemographic variables

They concluded that lung cancer and kidney cancer
mortality rates were higher in the 30 km area, but othertypes of cancer were not

Various inconsistencies in the results depending on how
the analyses were performed. They chose analyses thatshowed positive effects. No information presented onuranium exposure levels, so study is uninformative
regarding uranium risk

Boice et al. [B37]

A priori tumour sites: montrose elevation of lung cancer inmales (RR=1.19, 95% CI: 1.06, 1.33), thought to be due tounderground miner radon exposure and heavy smoking.
No excess of breast, kidney, bone, liver or childhood
cancer, leukaemia, non-Hodgkin’s lymphoma, renal
disease or non-malignant respiratory disease

Stomach cancer: stomach cancer mortality among
women was high (SMR=1.30, 95% CI: 1.03, 1.63), butelevated mainly in the early years before milling
operations began

Lung cancer excess was likely due to miner radon
exposure and smoking. Uranium exposed individuals
not identified, so it is uninformative

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 463

Study referencesSummary of findings related to uranium

Relevance for this report

Lopez-Abente etal. [L45]

Examined lympho-haematopoieticmalignancies (LHMs)
in 489 towns within 30 km of Spain’s seven nuclear
power plants and five nuclear fuel facilities (“exposed”),
compared to 477 towns 50–100 km away(“unexposed”). Exposed towns reported 610
leukaemias, 198 lymphomas and 122 multiple
myeloma deaths during 1975–1993

No excess LHM found in towns near nuclear power
plants. Reported excess leukaemia mortality near two
nuclear fuel facilities and excess myeloma mortality
near one nuclear fuel facility. No exposed town showedexcess leukaemia for the under age 25 group. Analysesof all nuclear fuel facilities combined did not yieldstatistically significant excess for any end point(leukaemia, leukaemia <25 years, myeloma, Hodgkin’s
lymphoma, non-Hodgkin’s lymphoma)

Selecting a few “significant” results from a large numberof statistical tests is questionable. The results for all
nuclear fuel facilities combined, or all nuclear power
plants, do not indicate elevated risks for lymphohaematological malignancies

Pinney et al.
[P22]

Examined prevalence ratios of diseases among 8,496
residing within 2 miles (3.2 km) from Fernald, USAuranium plant, or within 5 miles (8 km) and ingroundwater runoff direction, or with well/cistern.
Medical conditions obtained by questionnaire andscreening examination. Prevalences were compared to
NHIS/NHANES data (national standardized surveys)

Reported a number of elevated prevalences of kidney
and bladder diseases/conditions compared to NHIS
data, but screening questions or coding sometimes
differed between the two datasets. Found nodifferences for diabetes, thyroid diseases or respiratory
diseases. Several clinical laboratory variables showedsmall but significant differences between those within
2 miles or more distant, and a different set of variables
were significant for those using wells/cisterns

Distance from the plant and/or possible exposure toplant runoff used as surrogates for uranium doses.
Actual measured exposure levels very low. Since
perceived residential risks from Fernald were current in
the population, results based on self reports may havebeen biased. Inconsistencies among comparisons oflaboratory findings create uncertainty in theinterpretation

Table A11. Summary of literature review on health effects of human exposure to uranium through ingestion of surface or groundwater
Study

Study design

Country

Mao et al. [M9]Cross-sectional

CanadaChemical toxicity
urinary system

Zamora et al.
[Z6]

Cross-sectional

CanadaKurttio et al.
[K26]

Cross-sectional

FinlandKurttio et al.
[K28]

Cross-sectional

Finland

EffectEffect measurement

Relevance for this reportofComparison of biomarker levels in urine (microalbuminuria)
and serum (creatinine)

Positive association between uranium cumulative
exposure index and albumin level

Chemical toxicity
urinary systemofComparison of biomarker (glucose, creatinine, protein, beta2microglobulin, alkaline phosphatase, γ-glutamyl transferase,lactate dehydrogenase, N-acetyl-β-D-glucosaminidase) levels

Alkaline phosphatase, beta2-microglobulin levels
correlated with uranium level in water

Chemical toxicity
urinary systemofComparison of biomarker (calcium, phosphate, glucose,
albumin, creatinine, beta2-microglobulin) levels

Significantly increased calcium, fractional excretion

Chemical toxicity
urinary systemofComparison of renal damage indicators (glucose, creatinine,alkaline phosphatase, γ-glutamyl transferase, lactate
dehydrogenase, N-acetyl-β-D-glucosaminidase, calcium,
phosphate, cystatin C, glutathione-S-transferase) in urine

No statistically significant association between
uranium concentrations in urine and any of therenal damage indicators, except glucose excretionin urine and diastolic blood pressure

No association between uranium exposure andother parameters

UNSCEAR 2016 REPORT

Summary of study

464

Study references

StudyStudy design

Country

EffectEffect measurement

Relevance for this report

Selden et al.
[S8]Cross-sectional

SwedenChemical toxicity
urinary systemofComparison of biomarker (albumin, beta2-microglobulin,
protein HC, kappa and lambda chains, N-acetyl-β-Dglucosaminidase) levels in urine

Significant increase in urinary excretion of β-2
microglobuline, kappa and lambda chains, and HC
protein with medium to high uranium
concentrations
inurine.
Dose–response
relationships observed after exclusion of subjects
with diabetes

Kurttio et al.
[K29]

Case-cohort

FinlandUrinary system as targetof radio-toxicity

Comparison of risk of bladder cancer by uranium level andradiation doseNo excess of bladder cancer with increased level ofuranium or radiation dose

Kurttio et al.
[K27]

Cross-sectional

FinlandBone as target
chemical toxicity

Correlation between uranium exposure and biomarkers
associated with bone (osteocalcin, aminoterminal
propeptide of type I procollagen, serum type I collagencarboxy-terminal telopeptide)

Marginal positive association of uranium
concentrations in drinking water with serum type I
collagen and carboxy-terminal telopeptide only inmen (p=0.05)

of

No significant association between uranium
exposure and bone turnover indicators in women
Seiler [S7]Ecological

USA

Comparison of uranium concentration in wells used by casefamilies and other wells

No significant difference between uranium
concentrations in wells used by families ofleukaemia cases (median=3.4 μg/L) and theuranium concentrations in other wells (1.6 μg/L)
No differences in concentrations of gross α activity
or of Rn (617 vs. 563 pCi/L)

Auvinen et al.
[A32]

Case-cohort

Finland

Lympho-haematopoietic
systemComparison of risk of leukaemia according to uranium level

No excess of leukaemia according to uranium levelof drinking water

Witmans et al.
[W23]

Case-control

CanadaLympho-haematopoietic
systemComparison of Uw and Thw exposure between cases andcontrols

Cases had higher uranium concentrations indrinking water than controls (p=0.001)
No significance difference in Th w (p=0.22)

Auvinen et al.
[A32]

Case-cohort

Finland

Digestive system

Stomach cancer risk according to uranium level

No excess of stomach cancer by uranium level

ANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 465

Lympho-haematopoietic
systemANNEX D: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—URANIUM 467

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