Depleted Uranium and Human Health

Abstract

Depleted uranium (DU) is generally considered an emerging pollutant, first extensively introduced into environment in the early nineties in Iraq, during the military operation called "Desert Storm". DU has been hypothesized to represent a hazardous element both for soldiers exposed as well as for the inhabitants of the polluted areas in the war zones. In this review, the possible consequences on human health of DU released in the environment are critically analyzed. In the first part, the chemical properties of DU and the principal civil and military uses are summarized. A concise analysis of the mechanisms underlying absorption, blood transport, tissue distribution and excretion of DU in the human body is the subject of the second part of this article. The following sections deal with pathological condition putatively associated with overexposure to DU. Developmental and birth defects, the Persian Gulf syndrome, and kidney diseases that have been associated to DU are the arguments treated in the third section. Finally, data regarding DU exposure and cancer insurgence will be critically analyzed, including leukemia/lymphoma, lung cancer, uterine cervix cancer, breast cancer, bladder cancer and testicular cancer. The aim of the authors is to give a contribution to the debate on DU and its effects on human health and disease.

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Depleted Uranium and Human Health.
Armando Faaa*, Clara Gerosaa, Daniela Fannia, Giuseppe Florisb, Peter Van Eykenc, Joanna Izabela
Lachowiczd, Valeria Marina Nurchid
aIstituto di Anatomia Patologica, Dipartimento di Scienze Chirurgiche, University of Cagliari; AOU Cagliari, Cagliari,
Italy; bDepartment of Pathology, KU Leuven, Belgium; cDepartment of Pathology, Genk General Hospital, Genk,
Belgium; dDipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, I-09042
Monserrato-Cagliari, Italy
Abstract: Depleted uranium (DU) is generally considered an emerging pollutant, first extensively introduced into
environment in the early nineties in Iraq, during the military operation called “Desert Storm”. DU has been hypothesized
to represent a hazardous element both for soldiers exposed as well as for the inhabitants of the polluted areas in the war
zones. In this review, the possible consequences on human health of DU released in the environment are critically
analyzed. In the first part, the chemical properties of DU and the principal civil and military uses are summarized. A
concise analysis of the mechanisms underlying absorption, blood transport, tissue distribution and excretion of DU in the
human body is the subject of the second part of this article. The following sections deal with pathological condition
putatively associated with overexposure to DU. Developmental and birth defects, the Persian Gulf syndrome, and kidney
diseases that have been associated to DU are the arguments treated in the third section. Finally, data regarding DU
exposure and cancer insurgence will be critically analyzed, including leukemia/lymphoma, lung cancer, uterine cervix
cancer, breast cancer, bladder cancer and testicular cancer. The aim of the authors is to give a contribution to the debate on
DU and its effects on human health and disease.
Keywords: Depleted Uranium, uranium chemical properties, uranium metabolism, uranium toxicity, Persian Gulf syndrome
.
1. INTRODUCTION
A substantial public discussion on the health effects due
to the exposure to depleted uranium (DU) and on the use of
DU munitions has taken place during the last two decades
[1-9]. The concerns over health risk from DU weapons have
been recently reaffirmed by the UN general assembly with a
new resolution on December 2015, the sixth adopted on DU
since 2007.
The term Depleted Uranium, according with Durakovic, “is
a semantic attempt to reduce awareness of the significance
of its hazard to the biosphere” [2]. Even though DU is less
radioactive than natural uranium, it retains the chemical
toxicity associated with the original element, and it is now
considered an emerging environmental pollutant, introduced
into the environment primarily by military activity [7]. A
new clinical entity was described in soldiers invoiced in the
battlefield during the military operation called “Desert
Storm”, which took place in Iraq from August 1990 to July
1991, involving a coalition of 35 countries and a 700,000
contingent of mainly American men: the Gulf War
Syndrome [10]. Extremely fine dusty sand impregnated with
uranium was demonstrated to be able to travel tens of
kilometers in air, becoming hazardous to biological
organisms in a large geographic area [11].
*Address correspondence to Armando Faa, Dipartimento di Scienze
Chirurgiche, Anatomia Patologica, University of Cagliari, Via Ospedale 46,
I-09124 Cagliari, Italy, Email armando.faa@hotmail.it
In response to these concerns, many research projects have
investigated the health effects of DU munitions, both on
exposed soldiers as well as on inhabitants of the polluted
zones. However, in the war zones a number of other
chemical pollutants can confound the results of these studies,
as well as the disruption of the society. The most important
concerns regard the increased risks of radiation-induced
cancer from exposures to DU on the battlefield, the risks
from the chemical toxicity of uranium and the long-term
environmental consequences of the deployment of DU
munitions.
Here, data available from the literature regarding the possible
consequences of the release of enormous quantities of DU in
the environment will be reviewed and critically analyzed,
with the aim to give a contribution to the debate on DU and
its different effects of human health and disease.
2. PROPERTIES AND USES OF DEPLETED
URANIUM
2.1 Chemical properties
Before describing the chemical features of DU, we will
review the properties of the element uranium (U). The
knowledge of this element dates back to more than two
centuries ago, when Klaproth, a German chemist, in fact
recognized its presence in pitchblende in 1789. Only half

2 Journal Name, 2014, Vol. 0, No. 0 Principal Author Last Name et al.
century later (1841), Peligot was able to isolate uranium
[12], and in 1899 Becquerel published his notes on its
radioactive properties [13, 14].
Uranium (atomic weight 238.03 g mol-1) is a dense
silver-gray element (density 19.1 g/cm3, melting point
1132.2 °C, boiling point 4131 °C). Natural uranium is found
in rocks, soil and water, with an average concentration in the
earth crust of 2.7 mg/Kg-1 [9], or 0.0004% [15]. It occurs as a
mixture of three radioactive isotopes 238U (99.27%), 235U
(o.72%), and 234U (0.0055%) [8]. The radioactivity of natural
uranium, 25,280 Bq g-1, depends on the percentage and on
the specific activity of the three isotopes 238U (12,455 Bq g-
1), 235U (80,011 Bq g-1) and 234U (231 X 106).
Since the absorption of uranium compounds in the
organism strongly depends on their solubility, some
information on the uranium chemistry is necessary [16].
Uranium is present in the oxidation states 0, +2, +3, +4, +5
and +6, being the prevalent forms the tetravalent U (IV),
found in most minerals, and U (VI), which represents the
more suitable state [17]. Elemental uranium can be dissolved
in strong acids (slowly in H2SO4), while it is stable in strong
base solutions. Metallic uranium, divided in small particles,
is a pyrophoric material, and ignites spontaneously in air
[http://web.ead.anl.gov/uranium/pdf/earsum.pdf] [9].
Divalent uranium compounds (+2), as UO and US, exist only
in the solid state [18]. The trivalent compounds are readily
oxidized in water solution. Pentavalent uranium is oxidized
by oxygen in presence of air, and gives tetravalent and
hexavalent compounds by disproportionation in absence of
air. The tetravalent uranium compounds, stable in the
absence of air, comprise the oxide UO2, different salts and
basic salts as UO(NO3)2 and UOCL2. The chemistry of
uranyl (UO22+) cation is the most important for the
environmental and biological behavior of uranium. UO22+
has a linear configuration and can coordinate 4, 5 and 6
different donor atoms in the equatorial plane. Uranyl cation
is a “hard” cation that strongly interacts with inorganic
oxygen donor ligands and organic ligands like carboxylic
and amino carboxylic acids, phenols and humic substances.
It also reacts in some extent with nitrogen and sulfur ligands,
so presenting also a sort of “soft” character. More up-to-date
information on chemistry and speciation of uranyl and uranyl
compounds can be found in the reviews by Vandenhove et
al. (2011) [19], Maher et al. (2013) [20] and Berto et al
(2012) [21]. These last authors examine critically the
literature on the complex formation. equilibria involving
uranyl complexes and give clear picture on coordinating
ability of a number of inorganic and organic ligands,
determinant for environmental fate of UO22+, and its
absorption and bioavailability in animals and humans.
As for the analysis of uranium in environments and
biological samples is concerned, the determination of
uranium and the discrimination among natural, enriched or
depleted uranium can be performed with mass-spectrometric
techniques. In particular, inductively coupled plasma mass
spectrometry (ICP-MS) is well suited for these
measurements, thanks to its selectivity and low detection
limits. A minimum concentration of 235U of about 14 ngL-1 is
required to obtain measurements of this isotope reliable
enough for calculating accurate isotopic ratios [22].
2.2 Civil and military uses.
The demand of uranium fell down in the 90s of the last
century, at the end of the Cold War, but the request of
electricity, and of energy sources that do not produce CO2
emissions as fossil fuels, has given a new impulse in this
century to nuclear power generation, with a corresponding
increase in uranium demand. The total world production
passed from 41,282 tons of uranium in 2007 to the 60,496 in
2015, the major producer being Kazakhstan, Canada and
Australia, whose production nowadays amounts to the 71%
of the total world production [23]. The major use of uranium,
beside civil power generation, is in nuclear weapons.
Uranium, to be used as fuel in nuclear power plants needs to
be enriched in 235U, the fissionable isotope, from 0.7 percent
up to 3-5percent. The enrichment process gives as a
byproduct depleted uranium (DU), in which 235U is
decreased at a concentration of about 0.3%. The DU so
produced amounts at more than 90% of the total processed
uranium. DU is normally stored as UF6, the chemical form
more suitable for the enrichment process, in 14-ton steel
cylinders. In the U.S.A., these can be transferred to the U.S.
Department of Energy (DOE) or disposed as low level
radioactive wastes if converted into stable uranium oxides.
Currently, about 700,000 tons of depleted UF6 in about
57,000 steel cylinders are stored in DU deconversion
facilities. The potential contact of UF6 with moisture in air
constitutes the main hazard at these facilities. In fact, this
contact would produce the extremely dangerous HF and
gaseous uranyl fluoride. A tight control is necessary to
prevent the likelihood of such an event (U.S. Nuclear
Regulatory Commission [24]).
A certain amount of UF6 is treated to produce either
commercially valuable fluorine compounds, or metallic
uranium for the U.S. Army to be used as antitank rounds, or
for the other different applications. DU specific activity is
approximately 40% lower than that of naturally occurring
uranium. DU has several civilian and military applications,
and it has been utilized in a variety of civil and military
products. It has been used as a fluorescent additive in dental
porcelain crowns, as X-ray shielding in hospitals, as
counterweights for control surfaces (eg. flaps), in
commercial aircrafts, in the manufacture of keels for yachts,
and as the armor-piercing component of some munitions. In
the past, in the nineteen century, uranium has also been used
to color glasses and ceramic glazes and as a pharmaceutical
for the treatment of diabetes [25].
DU in the metallic form has high density and hardness as
well as pyrophoric properties, which makes it superior to the
classical tungsten armor-piercing munitions [26]. Due to
these properties, DU has been used during wartime in heavy
tank armor, armor-piercing bullets, and missiles, due to its
chemical properties coupled with its decreased radioactivity
as compared to natural uranium. In the review by Bleise et al
(2003) [9], a detailed description of the DU projectiles
(form, dimensions, weight of DU) is reported [5], and of
their fate when they impact on steel armor or on soft targets.

Short Running Title of the Article Journal Name, 2014, Vol. 0, No. 0 3
In particular, after the impact on armors, the DU munitions
fragment and catch on fire leading to explosion of a target,
producing aerosol containing uranium nanoparticles [27].
The way of entry of uranium-containing nanoparticles, their
chemical composition, chemistry, size, shape, morphology,
surface charge and area strongly affects their biological
activities and effects. Uranium nanoparticles, thanks to their
small size, can enter the body by crossing the intestinal
and/or the respiratory barriers, can pass into the blood stream
and lymphatic system, reaching organs and tissues,
eventually interacting with cell and biological structures,
thus damaging their normal function in different ways [28].
DU weapons are used unreservedly by the armed forces,
because of its high density and metallurgical properties, in
the manufacture of armor and armor piercing shells in
several countries [29]. The first intensive military use of DU
was in the Gulf war in 1991 [30]. In the south of Iraq, DU
was and still represents an environmental pollution problem,
because its levels raised after both Gulf wars I and II in 1991
and 2003 respectively [31].
3. METABOLISM OF URANIUM
3.1 Absorption
In the following sections, we will speak of uranium and not
of DU being the absorption, the toxicokinetics, the partition
in tissues and the chemo-toxicity independent of the isotopic
composition. These properties of uranium depend on the
chemical species present, and for inhaled particles, also on
the physical, aerodynamic, and thermodynamic features.
Uranium absorption is generally considered to be low by
inhalation, oral, and dermal exposures. As previously
indicated, it depends on the DU-containing nanoparticle size
[32]. The total content of uranium present in an adult human
body is about 100 micrograms, which is mostly derived from
uranium in food, uranium being especially derived from
vegetables, cereals and table salts. The mean daily intake of
uranium from food is estimated about 1-5 micrograms/day
[15]. There are different possible ways by which uranium
ions can enter into the human body: by inhaling uranium-
impregnated dust particles, by drinking water polluted by
uranium, or from the fertile soil layer via the food chain [33].
The major risk for DU over-exposition of soldiers in the war
theatre is DU dust generated when DU-containing
ammunitions hit hard targets, given that the primary route of
exposure of DU to humans is through inhalation and
ingestion [34]. The crews of military vehicles having been
hit by DU penetrators are considered the subjects at higher
risk of DU over-exposure: their body burdens have been
found to be above the range of values for natural uranium
[9]. Depending on aerosol speciation, inhalation may lead to
a protracted exposure of the lung and other organs.
Moreover, after deposition on the ground of the “dirty” sand
particles rich in DU, re-suspension can take place on the soil,
in particular when the DU containing particle size is
sufficiently small, ending with soil contamination. In
particular, DU nanoparticles < 100 nm are rapidly absorbed
and deposited in the respiratory tract after inhalation [35].
Transfer to drinking water and to locally produced food may
have potential to lead to significant exposures to DU of local
residents even after the end of the war [9]. The risk for DU
absorption and toxicity is increased in people living in
regions in the vicinity of former battlefields, where
munitions containing DU were deployed in large amounts.
Exposure, even in such cases, is by the inhalation route [36].
3.2 Blood transport.
Highly increased serum uranium concentrations have been
reported in populations in the warv theatre, when the army
utilized DU [37]. Uranyl ions are effectively transported in
the bloodstream through interactions with carbonate and
protein ligands. Under physiologic conditions, carboxylate
donors from biological ligands to uranyl are expected to
compete favorably against carbonate in the inner sphere of
the tris-carbonato uranyl complex [38]. A study carried out
with the aim of better clarifying the serum proteins involved
in uranium transport in human blood, involving a
combination of bidimensional chromatography with time-
resolved fluorescence, showed that about 20% of uranyl ions
in serum are associated with the protein pool. Transferrin,
ceruloplasmin and hemopexin displayed the capacity to bind
uranium ions with stoichiometry greater than 1 mole of
uranium per mole of protein. These findings taken together,
suggest that uranyl ions probably use a wide variety of
binding sites and coordination strategies in physiological
conditions, and provide additional insights into a better
understanding of uranium chemical toxicity [39].
3.3 Tissue distribution
After its entry into the bloodstream, uranium is co-deposited
on bone surfaces with calcium, where it may remain for
many years. DU crosses the blood brain barrier and
accumulates in the brain and preferentially in particular brain
regions. Specifically, the hippocampus and striatum
accumulate DU more readily than cerebellum and cortex, at
least with oral exposure [40]. In contrast, when using a dust
exposure protocol, the accumulation of DU in the CNS
occurs within the olfactory bulb, hippocampus, cortex and
cerebellum, demonstrating increasing concentrations of DU,
in that order [41].
3.4 Excretion
About 90% of ingested uranium is excreted in urine within
24 hours after ingestion, with most of the remainder being
excreted within the following weeks, only a few percent of
ingested uranium being retained in the skeleton. Normal
excretion levels of uranium lie in the range of 0.04-0.5 µg/L
of urine. Uranium does not deposit in any other tissue and,
like radium, it is absent in the bone marrow [15]. The
uranium concentration in urine samples are generally
utilized, in clinical practice, as an indication of the total
uranium body content as well as of the ability of the
organism to excrete the excess of DU stored in the different
organs and tissues. Recently, it has been shown that, in
subject who undergone long-term exposure from internalized
uranium, DU accumulation may be mitigated by increasing
its elimination with chelating agents. The use of chelating
agents might enhance the mobilization of DU deposited in
tissues and favor DU ions’ excretion through kidneys,
thereby reducing the risk of intoxication [36].

4 Journal Name, 2014, Vol. 0, No. 0 Principal Author Last Name et al.
4. DU TOXICITY
The complexity of the consequences on human health
following the over-exposure to Du has been highlighted by
several reports, indicating Du as an emerging environmental
pollutant, introduced into the environment primarily by
military activity in the absence of previous studies aimed at
verifying the possible toxic effects of DU on biological
systems [7]. Different consequences have been associated to
different types of DU overexposure. The toxic effects of DU
on human health are difficult to discern, since they derive by
both chemical and radiological properties. Therefore, the
distinction between uranium radiotoxicity, its chemical
toxicity and the radiotoxicity of its progeny should be better
defined [42]. DU exposure has been shown to be toxic to
many bodily systems, including brain, kidney, liver and
heart. Regarding the possible dermatologic lesions in DU-
exposed subjects, fragments of DU were documented in a
high percentage of veterans of Iraqi conflicts [43].
Concerning the dramatic health deterioration for Iraqi
citizens following the widespread depleted uranium use in
the 1991 Gulf War, a study on the environmental and health
consequences of depleted uranium use, found that uranium
concentration in the surface soil samples from the Kuwait
war theatre were not significantly different from DU
concentrations found in control soil samples [26]. Military
personnel wounded by DU shrapnel during military conflicts
are considered the typical target of DU-related toxicity,
given that internalized DU could represent a carcinogenic
risk factor, whereas concurrent alpha particle and heavy
metals might complicate this potential risk [44]. The use of
DU by the military in the war zone has been considered to
represent a source of controversy by Miller AC (2007) [45],
due to the numerous unanswered questions about the long-
term health effects of exposure to high quantities of DU. An
epidemiologic study carried out by the US Department of
Defense under a Congressional mandate in 2008 on veterans
exposed to DU, concluded that it would be difficult to
comprehensively assess DU-related health outcomes with
currently available data [46].
For a long period the vast majority of studies regarding
the possible toxicity of DU on human health were focused on
soldiers, and in particular on veterans of the Persian gulf war
and, subsequently, of the Balkan war. Only in recent years,
there has been widespread international concern about the
environmental contamination with DU from ammunitions
used in the Persian Gulf and Balkan conflicts. The first
studies focused on a possible damage to the local
populations due to contamination of soil, water and food by
DU, analyzed the potential relationship between DU
pollution and the increased insurgence of leukemia and
other lymphomas in the Kosovo and Bosnia-Herzegovina
region. These first studies did not show a significant increase
in DU concentrations in most of the environmental and food
samples analyzed, when compared to concentrations of
uranium measured in other European regions [47]. On the
contrary, astonishing data were obtained by a study on birth
defects and cancer incidence carried out in population of the
Iraqi town of Fallujah, where weapons containing DU were
extensively used in heavy fighting between US forces and
local soldiers in 2004. A sample of 4,843 persons was asked
to answer to a questionnaire, regarding the occurrence of
birth defects, infant mortality and cancer between January
2005 and 2010. Infant mortality rate in the age group 0-1
over the period 2006-2009 was 80 deaths per 1,000 births,
revealing a marked increase when compared to a rate of 19.8
in Egypt, 17 in Jordan and 9.7 in Kuwait in 2008. Moreover,
the mean birth sex-ratio in the post-war period was
anomalous: the ratio of boys to 1,000 girls in the 0-4 age
Fallujah cohort was 860, as compared to the constant sex
ratio in the normal human populations of 1,050 boys born to
1,000 girls. This finding indicates the existence of a genetic
damage stress, suggesting genetic damage to Fallujah
newborns.
Regarding cancer incidence, between Jan 2005 and the
survey end date there were 62 cases of cancer in the Fallujah
population, including 16 cases of childhood cancer in
children aged less than 14. When compared to cancer
incidence rates in the Middle East Cancer Registry (MECC,
Garbiah Egypt) for 1999 and rates in Jordan 1996-2001, the
overall incidence of cancer in the Fallujah population
appeared significantly increased. The Highest risk was found
for leukemia and lymphoma in the age group 0-34, for
female breast cancer in the age group 0-44, and for brain
tumors in all ages [48].
The complexity of the consequences on human health
following the over-exposure or the ingestion of DU has been
highlighted by several reports in recent years. Different
consequences have been associated to different types of
over-exposure. Acute exposure to large doses of DU may
have serious consequences for the kidney, which might
represent the target organ for the acute chemical toxicity of
this metal, ending with damage of the proximal tubular cells
and with potentially lethal tubular necrosis.
Uranyl acetate and uranyl nitrate have been shown to be
capable of inducing DNA strand breaks in the presence of
ascorbate, suggesting that uranium may be directly genotoxic
[49]. Moreover, uranium has been demonstrated to may
potentially induce oxidative stress through free radical
generation in lung epithelial cells, followed by concomitant
decrease in the antioxidant potential of the cells due to loss
of total glutathione and superoxide dismutase [50]. These
data taken together suggest that uranium may be directly
genotoxic and may, like chromium, react with DNA by more
than one pathway. Regarding the molecular pathway through
which uranium ions are toxic for human cells, a study
utilizing a combination of cytotoxicity assays, p53 activity
assays, western blotting and flow cytometry, demonstrated
that there is not a p53-mediated response to either uranium
ions, any cellular response to uranium exposure likely
occurring in a p53-independent fashion [51]. The role of
uranium ions in toxicity to renal epithelial cells has been
confirmed by an experimental study carried out in renal cells
in culture and in rats [52]. Treatment of uranium-treated
renal tubular cells with BPCBG, a uranium chelator,
significantly enhanced the cell survival, decreased the
formation of micronuclei and inhibited the production of
intracellular ROS.

Short Running Title of the Article Journal Name, 2014, Vol. 0, No. 0 5
A study based on a health surveillance project in a cohort
of Gulf War veterans 18 years after first exposure to DU,
evidenced the persistence of elevated concentration of
urinary uranium levels eighteen years after first exposure,
clearly indicating the need for continuous surveillance, due
to the ongoing mobilization of uranium from depots [53]. A
study based on a long-term medical surveillance aimed at
analyzing the markers of genotoxicity in a cohort of DU-
exposed Gulf War veterans followed since 1994
demonstrated a relatively weak genotoxic effect of DU
exposure [53]. A cancer surveillance study in 27361 Italian
soldiers deployed in Bosnia and 31,052 deployed in Kosovo,
carried out from 1996 to 2007, gave no sure indication,
regarding the hypothesis of an increased risk of cancer in
DU-exposed Italian military personnel and peacekeeping
troops. The increased incidence of Hodgkin’s lymphoma and
of thyroid cancer reported in this study, were considered
sporadic events unlikely related to DU exposure [54].
Even though limited data exist regarding the long-term
hazards of DU exposure on humans, however uranium is
suspected to be a major toxic and mutagenic agent. Reports
from the battlefield documented a rise of malignancies and
newborn malformations after war. In particular, leukemia
incidence was reported to be increased in the Balkans,
whereas congenital anomalies and Kaposi sarcoma showed a
higher incidence in Iraqi population. Moreover, Kaposi
sarcoma in Iraq in the after-war period was characterized by
a more aggressive behavior, when compared with the classic
Kaposi Sarcoma before, suggesting a potential relation with
DU, and possibly a different DU-related Kaposi Sarcoma
subtype. These data taken together lay stress on the
responsibility of the medical communities to thoroughly
check uranium for safety, and to ban DU use until proven
otherwise [55].
A study on cancer incidence in Iraqi population after the
gulf wars of 1991 and 2003 has opened a new divide
between researcher who think that Iraq is suffering from DU
pollution [56] and those convinced that the effects of the
1200 tons of ammunition dropped on Iraq during the Gulf
Wars may not harm public health [57]. In Fathi’s study, the
Iraqis were reported to face about 7,000 to 8,000 cancers per
year in the after-war period, with the overall incidence of
breast, lung cancer, leukemia and lymphoma being doubled
and even tripled in the after-war period. These data clearly
showed that the rate of cancer has significantly increased
since the Gulf Wars, and indicated DU as one of the main
factors responsible for this event. The comparison of the
toxicity of DU and lead evidenced that the main potential
hazard associated with exposure to DU is inhalation of the
aerosols created when a projectile hits an armored target,
whereas encountering uranium fragments is of minor
significance because of the low penetration depth of alpha
particles emitted by DU, which are unable to penetrate even
the superficial keratin layer of human skin [58]. A review of
studies carried out on civilian and military workers exposed
to DU, including veterans of the wars in the Persian Gulf and
the Balkans, in which lung, lymph hematopoietic, kidney
cancers, and circulatory diseases were examined, concluded
that existing epidemiological data on DU and associated
health outcomes are inconclusive [59]. A specific
consideration, regarding DU and human health and disease,
is deserved to those subjects living in the vicinity of former
battlefields, who undergo long-term exposure by inhalation
of DU. Subjects affected by internalized uranium are a
greater risk for the long-term implications on their health
status. Internalized uranium is generally considered a long-
term hazard, its toxicity depending upon multiple factors,
including the dose rate, the chemical form and site of
deposition of the uranium. The radiological toxicity and the
chemical toxicity of uranium and its compounds are
responsible for kidney damage and lung cancer. The most
vulnerable groups are children and older individuals
predisposed to hypertension or osteoporosis and individuals
with chronic kidney disease [36]. In spite of the multiple
reports of cases of leukemia and lymphoma insurgence in
Italian soldiers following their involvement in the war
theatre in the Balkans, a mortality study on the Italian cohort
of Bosnia and Kosovo veterans (71,144 persons) reported
that the Balkan cohort experienced a mortality rates lower
than the general population. Moreover, in the same study,
cancer mortality in the deployed Italian soldiers was half of
that from the general population rates [60]. The biological
monitoring of 35 Gulf War I US veterans wounded in DU
fire incidents, including a clinical surveillance program and
periodical control of uranium urinary concentrations, did not
report any DU-related health effects, in spite of the persisting
high uranium urinary levels 20 years after the first contact to
DU [61].
5. PATHOLOGIES FROM DU EXPOSURE
5.1 Development and birth defects
Although the chemical toxicity of uranium is well known,
little attention was paid to the potential toxic effects of
uranium on development in mammals. For many years, no
chemical mutagenesis has been demonstrated for this
element in mammals. Given that DU is about 3 million times
less radioactive than Ra-226, still found in many old
luminous docks and watches, and 10 million times less
radioactive than Am-241, that may be found in domestic fire
detectors, it has been hypothesized that DU-radiation
toxicity might be very low [15]. In recent years, fetal toxicity
including teratogenicity, has been reported in experimental
animals following uranium exposure during gestation [62].
An important contribution to a better knowledge of the
possible consequences of the paternal exposure to DU and of
the possible transmission of genetic damage to offspring
emerged by a very elegant study from Miller AC and
coworkers [63]. In this pivotal study, using a transgenic
mouse model and a lambda shuttle vector allowing mutations
to be analyzed in vitro, the authors investigated the
possibility that chronic pre-conception paternal DU exposure
could lead to trans-generational transmission of genomic
instability. As paternal DU-dose increased, there was a trend
towards higher mutation frequency in vector recovered from
the DNA obtained from bone marrow of the progeny,
resulting in a significant increase in mutation frequency.
Taken together, regardless of the question of DU-radiation
vs. DU-chemical effects, this study clearly indicated that
over-exposure of fathers to DU may cause trans-generational

6 Journal Name, 2014, Vol. 0, No. 0 Principal Author Last Name et al.
transmission of factor(s) leading to genomic instability in
the progeny, favoring the insurgence of cancer. Further
evidences on the possible relationship between
environmental characteristics, including exposure to DU, and
the prevalence of birth defects among children in the post-
war Iraq have been shown by a study carried out on more
than 10,000 Iraqi children and young adults in 2010 [64]. In
children living in the governorate of Basra, a higher number
of resident children having birth defects was found,
suggesting the existence of an association between reported
presence of potential sources of contamination in local
environments, including naturally occurring contaminants
and the detritus of warfare, and the insurgence of
developmental pathologies.
A study carried out in plasmid DNA aimed to
characterize how DU may cause DNA damage, revealed the
ability of uranyl acetate to promote the formation of DNA
which converted to single-strand breaks (SSB). Moreover,
radical scavengers did not affect the formation of uranium-
induced SSB, suggesting that SSB arose from the presence
of U-DNA adducts and not from the presence of free
radicals. These data clearly indicate that DU can act as a
chemical genotoxin and that DNA lesions formed by DU
may end with DU-induced mutations. A better understanding
of the mechanisms of formation of DU-induced mutations
might contribute to the identification of biomarkers of DU
exposure in humans [65]. The increased incidence in birth
defects observed in Iraqi population in the post-war period,
has been recently associated with the environmental
pollution regarding Iraq's land, air, water, and health
infrastructure caused by military actions. According with
these studies, the most important vector of toxic substances
released in the war theatres, including DU, might be
represented by the sand particles that reach Iraqi cities as
dust storms. The presence of DU in the Iraqi food chain is
documented by the increased concentrations of DU found in
animal organs that confirm the entrance of DU in the food
chain of Iraqi population. On the basis of these recent
findings, confirming the presence of a heavily contaminated
environment with DU and other pollutants related to war in
most of the Iraqi cities, the authors underlined the need for
actions focused on reducing pollution in the Iraqi
environment, in order to halt the related health problems
[66].
Recently, a molecular study performed to determine the
molecular mutational spectrum in 61 Veterans of the 1991
Gulf War, most of whom were exposed to DU, did not reveal
any significant differences in Veterans related to their DU
exposures, as compared to a control group [67]. A further
longitudinal study of HPRT mutations in Gulf War I
veterans exposed to DU, despite earlier reports of DU-
associated increases in HPRT mutations in some Veterans,
eventually confirmed previous studies indicating that HPRT
mutations are not increased by systemic DU exposure [67].
A recent study carried out by an Italian research group,
aimed to identify potential genotoxic risk associated with the
exposure to DU or other pollutants in the Italian Army
military personnel deployed in Iraq, did not detect any
toxicologically relevant variation of DNA-damage
biomarkers related to the deployment in the operational
theater [68].
5.2 The Persian Gulf syndrome
The insurgence of the Persian Gulf syndrome in Gulf War
veterans is characterized by the insurgence of dysfunctions
in at least three systems: psycho-physiological distress,
somatic distress, and arthro-neuromuscular distress [69].
Veterans of the Persian Gulf War of 1991 reported
symptoms of pain in a higher percentage, as compared to
other military comparison groups. Five main sites of pain
were identified, including muscle, joint, chest/heart, back
and abdominal. A greater proportion of Gulf veterans
reported symptoms at each site of pain when compared to a
non-Gulf military group. Gulf deployment was strongly
associated with abdominal pain, as well as with more general
symptoms such as fatigue, multiple chemical sensitivity and
post-traumatic stress disorder [70].
The hypothesis that DU might be related to the
insurgence of a syndrome affecting the veterans of the
Persian Gulf War, previously defined as Al-Eskan disease,
emerged in 1997. According with this hypothesis, the
prolonged exposition of soldiers to the fine sand dust of the
Arabian peninsula might trigger immunodeficiency, that
could be aggravated by opportunistic infections and other
non-microbial ailments, including DU. The hypothesis of a
major role of DU in the insurgence of this syndrome as a not
been completely demonstrated [71]. Al-Eskan disease was
subsequently defined as the Persian Gulf syndrome, or as the
Balkan syndrome [2], being mainly detected in soldiers
operating in the theater of operation of the Persian Gulf War.
The pathogenesis of the new syndrome was explained with
the exposition of soldiers to sand particles acting as vehicles
for low-intensity exposure to multiple chemical warfare
agents, including DU that could be able to deplete the
immune system [72]. The amount of DU utilized in the Gulf
and Balkan wars as an armor-penetrating ammunition is very
high. In the operation Desert Storm, over 350 metric tons of
DU were used in the war theatre, with an estimate of 3-6
million grams released in the atmosphere [2]. Among several
hundred thousand veterans deployed in the Operation Desert
Storm, 15-20% have reported to be affected by the Persian
Gulf syndrome, and about 25,000 died [2].
Initially, the consequences on human health of the release
in the environment of large quantities of DU in the Gulf War
theatre have been mainly described in United States and
European war veterans [73, 74]. Subsequently, studies on the
impact of the large amounts of DU on the residents of the
surrounding Gulf region were carried out, showing that DU
is hazardous to biological organisms, and that its impact on
the health of people in the area would be considerable [11].
The debate on the relationship between exposure to DU and
the insurgence of the gulf war syndrome was reinforced by
the article of Bertell [75], aimed to lay stress on the presence
of multiple un-answered questions regarding this important
topic. According with this author, the detrimental effects on
the health of veterans of the Gulf War of 1991, as well as on
the Iraqi people and military personnel participating to wars
in Kosovo, Afghanistan and Iraq during the second war, has

Short Running Title of the Article Journal Name, 2014, Vol. 0, No. 0 7
remained unresolved [75]. In the same article it is reported
that the number of Gulf War veterans who developed the
Gulf War syndrome following exposure to high quantities of
DU, has risen to about one-third of the 800,000 U.S. forces
deployed.
A study based on mathematical modeling to estimate
health risks from exposure to DU during the 1991 Gulf War
for US troops, revealed that veterans in vehicles accidentally
targeted by US tanks received significant DU exposure
levels, resulting in about a 1.4% lifetime risk of DU
radiation-induced fatal cancer [76]. In the same study, Iraqi
children playing for 500 h in or around DU-destroyed
vehicles were predicted to incur a cancer risk of about 0.4%.
Further studies clearly demonstrated the relationship
between the insurgence of neuropsychological changes and
the gulf war-zone exposure, with the presentation of
symptoms often occurring following Iraq deployment. One
of the main questions related to the gulf war syndrome, was
whether the posttraumatic stress disorder (PTSD) and
depression symptoms might endure in war-deployed
soldiers. A study carried out on 268 US army soldiers
deployed to the Iraq war, evidenced that only PTSD
symptoms, among soldiers back from deployment for 1 year,
were associated with a neuropsychological deficit, and in
particular with reduced attention [77].
A study carried out by the U.S. Department of Defense to
investigate undiagnosed Gulf War Illnesses in military
deployments produced new important data useful for a better
understanding and awareness of relevant psychosocial and
neurological interactions that probably represent a difficult
new frontier in biomedical research [78]. From this study,
the multi-factorial etiology of the disease emerged: the
effects of DU were associated with Leishmanial infection
and treatment, toxic pesticide exposition, multiple vaccines
and prophylactic drug interactions. The entity of the
diffusion of the gulf war illness has been better clarified by a
study aimed to analyze the prevalence of mental health
problems, particularly PTSD and depression, associated with
functional impairment among 18,000 US soldiers, 3 and 12
months after returning from combat in Iraq [79]. In this
study, the prevalence rates for PTSD or depression with
serious functional impairment ranged from 8.5% up to
14.0%, with some impairment between 23.2% and 31.1%.
The persistence of serious functional impairment at 12
months post-deployment, clearly indicate the persistent
effects of war zone damages, and provide important data to
guide post deployment care [79].
The frequent insurgence of cognitive disorders in Gulf
war veterans over-exposed to DU suggests that the central
nervous system may represent a target of DU. As for the
pathogenesis of neurotoxicity associated to DU exposure,
ending with the insurgence of the gulf war syndrome, several
evidences have suggested that DU could induce oxidative
stress and mitochondrial dysfunction in brain tissue. To shed
light on this hypothesis, brain mitochondria were incubated
with uranyl acetate. Exposure to uranium caused elevation of
mitochondrial ROS production, lipid peroxidation, GSH
oxidation, increase in mitochondrial permeability, decrease
in ATP production and increase in cytochrome c release
[80]. These data taken together suggest that oxidative stress
and impairment of oxidative phosphorylation in brain
mitochondria may play a fundamental role in DU
neurotoxicity as reported in Gulf War Syndrome. A recent
review on the gulf war syndrome more than 20 years after its
first description, confirms that this syndrome nowadays
appears as a new clinical entity, characterized by the
association of multiple functional symptoms regarding the
musculoskeletal, gastrointestinal, cutaneous, central and
peripheral neurological systems [10]. On the basis of the
multiple studies carried out on the pathogenesis of the gulf
war syndrome, the insurgence of the syndrome appears to be
related to the exposure to multiple risk factors, including
vaccines and their adjuvants, organophosphorous
compounds, pyridostigmine (given to the troops for the
preventive treatment of the former), impoverished uranium,
and the toxic emanations from oil well fires. Among the
soldiers and the civil population living in the war theatre
areas, the symptomatic subjects present with psychological
disorders that persist for many years, associating asthenia,
fatigability, mood decline, sleep disorders and cognitive
disorders. The clinical, psychological and laboratory
analyses carried out on people affected by the syndrome
evidenced the necessity to integrate the objective and
subjective dimensions as determinants of PTSD, for a better
comprehension of the pathogenesis of the gulf war
syndrome. The objective dimension should be related to the
external exposure to smoke from petrol wells, impoverished
uranium, biological agents, vaccines and adjuvants, and the
multiple chemicals released in the war theatre. The
subjective dimension should be related to the inner emotion
albeit reactive and characterized by a subjective stress.
Multiple stress factors were reported by the soldiers
deployed: repeated alerts of chemical attacks, hostility of the
environment characterized by frequent sandstorms, climatic
conditions making long hours static observation difficult,
collecting bodies, lack of knowledge of the precise
geography, and uncertainty of the duration of the war. All
these data taken together, the author concluded that rather
than toxic exposure to such and such a substance, the non-
specific syndrome called "Gulf War Syndrome" should be
considered the result of exposure to the eponymous peculiar
operational war theatre.
Interesting data emerged from a study focused on verifying
the prevalence of posttraumatic stress disorder among
different military subgroups operating in the war theatre in
Iraq and Afghanistan. In this study, the following subgroups
were considered: 1) the theatre of deployment (Iraq or
Afghanistan); 2) combat and noncombat; 3) enlistment type
(regular or reserve); 4) service branch (army, navy, and air
force). This study revealed that the prevalence rate of PTSD
was significantly higher among Iraq-deployed personnel
(mean 12.9%), compared with personnel deployed to
Afghanistan (7.1%). These data evidence and underline the
complexity of the pathogenesis of post-traumatic stress
disorders, and lay stress on the relevance of the deployment
location among the multiple factors that may favor the
development of the syndrome [81]. A recent study of post-
deployment military health of army personnel who had
deployed to Iraq during 2007-2008, including 1,560 US and

8 Journal Name, 2014, Vol. 0, No. 0 Principal Author Last Name et al.
313 UK soldiers, evidenced marked differences in mental
health outcomes between UK and US military personnel
[82]. According with this study, differences in combat
exposures might explain most of the differences in reported
prevalence of PTSD in soldiers of different nationality
participating to the same war.
5.3 Kidney disease
High levels of urinary excretion of uranium are frequently
associated with accumulation of uranium in the kidneys.
Renal storage occurs after high uranium intakes (more than
70-100 µg/Kg body weight) and may produce chemical
changes in the proximal renal tubules that is manifested as
protein loss through the urines. At very high levels of
uranium intake, experimental studies indicate that damage
may also occur in renal glomeruli. In human beings who
have had large acute intakes of uranium, these effects were
transitory and wholly reversible [15]. The potential risk for
uranium exposure to cause renal damage has been confirmed
by other studies, even though the risk of harm following DU
exposure in military settings was reported to be low [74].
Studies on populations chronically exposed to elevated
concentrations of uranium in drinking water provided some
evidence of adverse renal effects, as assessed by biomarkers
of proximal tubule damage. These preliminary data were
confirmed in a surveillance study of Gulf War veterans
exposed to DU, that evidenced increased urinary β(2)-
microglobulin and retinol binding protein levels, indicative
for an impaired proximal tubule function [83]. The kidney,
and in particular epithelial cells of the proximal tubules, have
been indicated as the principal target for the acute toxicity of
DU, tubular necrosis representing the most relevant clinical
consequence of acute toxicity in humans [7]. The precise
mechanism underlying DU-induced nephrotoxicity has not
been thoroughly recognized yet. To shed light on this topic,
mitochondria were obtained from rat kidneys, and
mitochondrial toxicity to uranyl acetate exposure was then
determined both in vivo and in vitro [84]. Incubation of
isolated renal mitochondria with uranium revealed the ability
of uranium ions to disrupt the electron transfer chain, leading
to induction of reactive oxygen species (ROS) formation,
followed by lipid peroxidation and glutathione oxidation,
ending with damage in the mitochondrial outer membrane.
Chronic ingestion of DU in rats has been shown to cause
kidney deterioration characterized by glomerular and tubular
changes, associated with anemia and splenic erythropoiesis
[85]. Taken together, these experimental data show that
uranium-induced nephrotoxicity is linked to the impairment
of electron transfer chain, and to the subsequent oxidative
cell stress. The hypothesis that mitochondrial dysfunction
might play a fundamental role in renal toxicity due to over-
exposure to DU, has been confirmed by the demonstration
that beta-glucan, a powerful antioxidant, prevents uranium-
induced mitochondrial dysfunction in rat kidney [80]. These
experimental data suggest that beta-glucan represents a
possible drug candidate for prophylaxis and treatment
against DU-induced nephrotoxicity.
6. DU AND CANCER
6.1 Lung cancer
Lung cancer incidence has been reported to be increased in
Uranium miners more then 50 years ago [86]. In recent
years, as a result of the inclusion of DU in the conventional
weapons arsenal, the potential for exposure to DU aerosols
and its associated radiological and/or chemical effects
became an important element of the USA commanders' risk
assessment. The Capstone DU Aerosol Study was
developed to measure the range of DU oxide aerosol
concentrations created inside a combat vehicle perforated
with a DU-enriched munitions, whereas the Capstone
Human Health Risk Assessment was developed to estimate
the associated doses, and to calculate the risk from DU dose
distribution within the body of each soldier [87]. Further
studies shed light on the physical-chemical characterization
of Capstone depleted uranium aerosols originated by the
impact of DU-enriched penetrators against an armored
target, followed by erosion and fragmentation of the
penetrators [88]. The application of X-ray diffraction
analysis revealed that the aerosol was a combination
primarily of U3O8 (insoluble) and UO3 (relatively more
soluble) phases. Moreover, scanning electron microscopy
analyses revealed a wide variability of DU particles: some of
the larger particles were spherical, occasionally with lobed
surface; other DU particles were characterized by fractures
that perhaps resulted from abrasion. Amorphous
conglomerates containing metals other than uranium were
also common in the aerosol, being especially associated with
the smallest particles.
In order to shed light on the possible toxic effect of DU on
the lung, uranium toxicity was evaluated in rat lung
epithelial cells [50]. This study revealed that uranium may
induce significant oxidative stress in rat lung epithelial cells,
followed by decreased cell proliferation due to loss of total
glutathione and superoxide dismutase in the presence of
uranium. An experimental in vitro study aimed to shed light
on the potential carcinogenicity of particulate DU in human
bronchial cells evidenced the loss of contact inhibition and
anchorage independent growth in cells exposed to DU after
24 h. Moreover, the majority of DU-transformed bronchial
cell lines acquired a hypo diploid phenotype and exhibited
significant chromosome instability, consistent with a
neoplastic phenotype [34]. A study aimed to better
understanding the pathological effects associated with DU
inhalation, first showed that macrophages present in alveolar
spaces are the main cell type involved in the internalization
of uranium particles [89]. In the same study, it was
demonstrated that uranium ions may impair cell metabolism
in different ways: at low doses, uranium induces both
phagocytosis and generation of superoxide anion (O₂⁻),
whereas at high doses it provokes the secretion of TNFα,
ending with pulmonary cell apoptosis.
In order to determine whether cancer incidence is greater
among Gulf War veterans compared with non-Gulf War
veterans, data from 28 state cancer registries and the
Department of Veterans Affairs Central Cancer Registry of
621,902 veterans who were deployed to the Persian Gulf
during the 1990 to 1991 Gulf War, were analyzed. The
overall proportion of cancers among Gulf War and non-Gulf
War veterans was reported to be similar (odds ratio, 0.99;

Short Running Title of the Article Journal Name, 2014, Vol. 0, No. 0 9
95% CI, 0.96-1.02). On the contrary, lung cancer showed a
statistically significant excess among Gulf War veterans
compared with non-Gulf War veterans (adjusted proportional
incidence ratios, 1.15; 95% confidence interval, 1.03-1.29)
[90]. An increased lung cancer risk among uranium-
processing workers has been reported by a multiple studies
published on veterans of the wars in the Persian Gulf and the
Balkans between 1991 and 2013 [59]. A recent study on
cancer incidence and all-cause mortality among 21,582
Norwegian military peacekeepers deployed to Lebanon
during 1978-1998, evidenced a higher risk of lung cancer in
soldiers with the highest conflict exposure time, as compared
with soldiers with a lower conflict exposure [91]. In the
same study, a decreased risk was found for cancer incidence
overall in Norwegian peacekeeper, as compared with the
national rates for cancer incidence. A study from a French
group focused on the detection of a possible relationship
between exposure to uranium compounds and mortality in a
cohort of 4,688 French uranium enrichment workers who
were employed between 1964 and 2006, revealed that the
standardized mortality rate for pleural cancer was
significantly increased as compared to general French
population. According with these data, exposure to soluble
uranium compounds should be considered as a potential risks
factor for the insurgence of mesothelioma [92].
6.2 Leukemia/Lymphoma
At the end of 2000, a higher incidence of leukemia was
reported among soldiers involved in the Balkan and in the
Gulf wars, DU used during these conflicts being considered
as a possible cause of leukemia insurgence. After these
initial alarming reports in the international press about the
increased risk for leukemia in war veterans returning from
the Balkans, due to their exposure to depleted uranium,
conflicting results have been published regarding this
hypothetical association. A study coordinated by the
Swedish National Board of Health and Welfare's cancer
register based on the follow-up conducted on the Swedish
personnel that had served in the Balkans, did not show any
correlation between service in the Balkans and leukemia
insurgence or other illnesses [93]. Another study on the
incidence of cancer among Swedish military and civil
personnel involved in the war theatre in the Balkans 1989-
99, gave no support for the hypothesis that service in the
Balkans could lead to hemato-lymphatic malignancies after
short latency, but the need for future follow up was
suggested for a better evaluation of long term risks of DU
exposure [94]. The authors analyzed the data reported by the
Cancer Registry of Croatia during the pre-war period (1986-
1990), war period (1991-1995) and post-war period (1996-
1999). A study aimed at defining the risk of developing
hematological malignancies in the population of Croatian
children aged 0-14 years who were potentially exposed to
DU intoxication during the war period (1991-1995), did not
show any significant difference in incidence of
hematological malignancies, in comparison to the pre-war
period [95]. In other studies, the retrospective assessment of
individual exposure has been considered insufficient for a
causal relationship between DU and leukemia insurgence
and, in general, for a better assessment of risks associated
with depleted uranium exposure [42]. A study aimed at
verifying the relationship between exposure to DU and
cancer insurgence in Danish Balkan veterans, did not
confirm previous data regarding an increased risk of
leukemia and testis cancer. In the same study, only the
incidence of bone cancer exceeded expectations [96].
The leukemogenic potential of DU has been verified in
an experimental model of leukemia, based on murine
hematopoietic cells (FDC-P1) that are injected into mice to
produce myeloid leukemia [44]. In this study, intravenous
injection of FDC-P1 cells into mice implanted with DU
pellets was followed by the development of leukemia in 76%
of all mice. In contrast, only 12% of control mice, not
implanted with DU, developed leukemia. This study first
demonstrated that a DU altered in vivo environment may be
involved in the pathogenesis of leukemia in an experimental
animal model. An experimental study aimed to determine the
involvement of DNA methylation in DU-induced leukemia
in mice, clearly showed that epigenetic mechanisms are
implicated in DU-induced leukemia, evidencing that
aberrant DNA hypomethylation is associated with DU
leukemogenesis [63].
A recent study carried out on Iraqi patients presenting with
leukemia after the Gulf war evidenced higher uranium
serum levels as compared to healthy Iraqi subjects. Serum
uranium concentrations in the leukemia patients group were
significantly different (P < 0.001) from those in the healthy
group [97]. A new contribution to the debate on DU
exposure in the war theatre and cancer insurgence came, in
recent years, from a study carried out on cancer incidence in
Dutch Balkan veterans [98]. In that study, cancer incidence
was examined in a cohort of 18,175 Dutch soldiers who had
been deployed to the Balkan region (1993-2001), with a
follow-up for 11 years. The cancer incidence rate, including
leukemia, among Balkan deployed military men was 17%
lower than among non-Balkan deployed military men,
suggesting that earlier suggestions of increased cancer risks
among Balkan veterans could not be supported by empirical
data.
6.3 Cervical cancer
An increase in the incidence of precancerous lesions of the
cervix has been reported in women from areas near the
borders with the former Yugoslavia after the Balkan war,
suggesting that cervical cancer insurgence might be
influenced by environmental factors such as exposure to DU,
due to the bombings of 1999. To verify this hypothesis, the
incidence rates of CIN and invasive cancer of the cervix
were calculated and compared in two periods: three years
before (1997-1999) and three years after (2000-2002) the
bombings [99]. In this study, a small but not statistically
significant increase in the incidence rates of CIN in the areas
near the borders with the former Yugoslavia were detected in
the post-war period, suggesting, but not certainly confirming,
a possible association between DU pollution and cervical
carcinogenesis.
6.4 Breast cancer

10 Journal Name, 2014, Vol. 0, No. 0 Principal Author Last Name et al.
A study carried out on breast cancer incidence in Iraqi
women in the post-Gulf War period, between 2000 and
2009, showed a significant and marked increase of the
overall incidence rate of female breast cancer in Iraq in the
post-war period. In particular, the incidence rate of breast
cancer ranged from 26.6 per 100,000 in 2000 up to 31.5 per
100,000 in 2009. Moreover, an intriguing finding was found
regarding the age of insurgence of breast cancer in Iraqi
women: 23,792 incident breast cancer cases, representing
33.8% of all breast cancers registered during 2000-2009,
were diagnosed in young girls aged less than 15 years,
revealing that breast cancer among Iraqi women affects
younger age groups than their counterparts in developed
countries [57]. These data taken together, suggest that
pollution due to the gulf war, including the release of high
amounts of DU on the soil and water, should be considered
as a possible etiological factor related to the insurgence of
breast cancer, particularly in very young Iraqi girls, and lays
stress on the necessity of further epidemiological research
studies aimed to examine possible causes and prevention
measures.
6.5 Bladder cancer
A study aimed to investigate cancer incidence and all-
cause mortality in a cohort of 6,076 Norwegian military UN
peacekeepers deployed to Kosovo between 1999 and 2011,
first evidenced a general cancer incidence in the cohort
similar to that in the general Norwegian population, with the
exception of a fivefold increased incidence of bladder cancer
among Norwegian soldiers who served in Kosovo for ≥ 1
year [100].
6.6 Testicular cancer
The incidence of testicular germ cell cancers in the
population of Eastern Croatia was analyzed in the 1969-2012
period, with the aim to investigate a possible association
between radioactive and toxic elements contamination,
mainly DU due to the Croatian War of Independence and
Bosnian War. To this end, 216 patients affected by testicular
cancer were subdivided into two subgroups: 1) distant pre-
war and war period 1969-1995; 2) the postwar period 1996-
2012. A significantly higher incidence for testicular germ
cell cancers emerged from this study, in Croatian population
in the postwar period. The incidence rate for non-seminomas
and for seminomas increased about 3.5 times (4.5 patients
yearly vs. 1.3 and 1.2 yearly, respectively), whereas the
incidence rate of testicular germ cell cancers overall
increased from 2.5 patients yearly up to 8.7 from the prewar
period to the postwar period [101]. Taken together, these
data suggest that the use of DU in armed conflicts is
associated with the insurgence of testicular germ cell
cancers, seminomas and non-seminomas, and lay stress on
the necessity of further studies in order to better characterize
the causative correlation between DU exposure and testicular
cancer insurgence.
CONCLUSION
The debate on the relationship between exposure to DU and
the insurgence of the multiple pathological entities, including
the gulf war syndrome and many tumors, appears to be
characterized by the presence of multiple un-answered
questions. The detrimental effects on the health status of
veterans of the Gulf War of 1991, of the wars in Kosovo,
Croatia, Afghanistan and the second war in Iraq, have remained
unresolved. The effects of DU contamination of water and soil
on people living in the proximity of the war theatre where huge
amounts of DU and other chemical pollutants were discharged
are only in part known. The number of people at risk of
developing severe consequences on their health status due to
over-exposure to DU are impressive: the number of Gulf War
veterans who developed the Gulf War syndrome following
exposure to high quantities of DU, has risen to about one-third
of the 800,000 U.S. forces deployed. But the most important
consequences of exposure to DU surely concerns people living
in the war regions. Some data reported in this review should be
stressed:
1. The 3.5 times increased incidence rate for testicular
tumors in Croatians from the prewar period to the
postwar period;
2. The fivefold increased incidence of bladder cancer
among Norwegian soldiers who served in Kosovo;
3. The increased incidence rate of breast cancer in Iraqi
women, from 26.6 in the pre-war period up to 31.5/
100,000 in 2009, 33.8% of all breast cancers being
diagnosed in young girls aged less than 15 years;
4. lung cancer showed a statistically significant excess
among Gulf War veterans compared with non-Gulf
War veterans;
5. Gulf War veterans exposed to DU show increased
urinary β(2)-microglobulin and retinol binding protein
levels, indicative for an impaired renal function;
6. The monitoring of Gulf War I US veterans wounded
in DU fire incidents, reported the persisting high
uranium urinary levels 20 years after the first contact
to DU;
7. Iraqi patients presenting with leukemia after the Gulf
war evidenced higher uranium serum levels compared
to healthy Iraqi subjects;
8. Among several hundred thousand veterans deployed in
the Operation Desert Storm, 15-20% have been
affected by the Persian Gulf syndrome, and about
25,000 died;
In spite of all these clinical evidences, and of all the
experimental data indicating potential genotoxic and
carcinogenic effects exerted by DU on human cells, it has been
claimed by a huge amounts of studies, here summarized, that
DU effects on human health should be considered minimal or
absent. In our opinion, this is the most important sensation,
emerging from the literature of the last twenty years: the

Short Running Title of the Article Journal Name, 2014, Vol. 0, No. 0 11
complete disagreement, among the different studies carried out
on DU, characterized by so strong contrasting results.
One question emerges from the DU story: how was it possible
the introduction of DU, a radioactive element, in the war zone in
the absence of any experimental and/or clinical evidence of its
safety both for soldiers and for the population interested by
bombing?
Since this and many other questions remain, at the best of our
knowledge, unanswered, given that studies conducted so far
have not provided a detailed account of the potential effects on
human health of the use of munitions containing DU, further
studies are needed in order to shed light on all the aspects of the
interaction between the large amounts of DU released in the
recent wars and the health status, with particular emphasis on
the consequences on civil populations living around the war
theatre, with the aim to band DU from weapons around the
world.
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Received: March 20, 2014 Revised: April 16, 2014 Accepted: April 20, 2014