Fachkommission Diabetes SLÄK Gemeinsamer Bundesausschuss Unterausschuss „Arzneimittel“ Auf dem Seidenberg 3a 53721 Siegburg Zustellung per E-mail an: nutzenbewertung@g-ba Stellungnahme zur Änderung der Arzneimittelrichtlinie in Anlage III: Glitazone zur Behandlung des Diabetes mellitus Typ 2 Scholz, GH, Schulze J, Hanefeld, M, Fischer S, Rothe U für die Fachkommission Di
Fmcs_a_357064 41.64 ++Medicine, Conﬂict and SurvivalVol. 25, No. 1, January–March 2009, 41–64 Depleted uranium: properties, military use and health risks Independent Consultant on Radioactivity in the Environment, London, UK This article describes uranium and depleted uranium (DU), their similarisotopic compositions, how DU arises, its use in munitions and armour-prooﬁng, and its pathways for human exposures. Particular attention ispaid to the evidence of DU’s health eﬀects from cell and animalexperiments and from epidemiology studies. It is concluded that aprecautionary approach should be adopted to DU and that there shouldbe a moratorium on its use by military forces. International eﬀorts tothis end are described.
Keywords: carcinogenic; depleted uranium; endocrine disruptor; Gulfwar; munitions; synergism; toxicity; United Nations; U-234, U-235,U-238 Depleted uranium (DU) is a matter of natural interest to Medicine, Conﬂictand Survival, as it lies at the intersection of several matters within thejournal’s remit, including nuclear weapons proliferation, the impact ofwarfare, adverse health eﬀects, international politics, toxic agents, radiationand radioactivity. In addition, the continued use of DU in munitions andarmour-prooﬁng by the United States and United Kingdom is a matter ofcontroversy – not unfamiliar territory for this journal.
DU is a waste product mainly from the production of enriched uranium for nuclear weapons. It has been, and continues to be, used by UK and USarmed forces in recent conﬂicts in the Middle East1 and the Balkan region2,3.
Many claims have been made of adverse health eﬀects, including the Gulf war syndrome, putatively arising from DU contamination during theseconﬂicts4. Uranium and its decay products have a unique combination oftoxic chemical and radiation properties which merit close scrutiny. In thepast, radiation protection authorities may have paid insuﬃcient attention tothe combination of DU’s properties, to the possible synergisms between ISSN 1362-3699 print/ISSN 1743-9396 onlineÓ 2009 Taylor & FrancisDOI: 10.1080/13623690802568962http://www.informaworld.com them which may result in multiplied adverse eﬀects, and to the existence ofDU’s decay daughters.
DU use is a controversial matter and a subject of current debate among international organizations including several United Nations agencies, suchas the General Assembly, United Nations Environment Programme, UnitedNations Human Settlements Programme and United Nations Institute forDisarmament Research5.
It is notable that most military forces do not use DU: it is thought that only the US and UK armed forces presently do so6. DU is obtainedas a waste product of nuclear power and of nuclear weapons manu-facturing. Uranium and DU are isotopically very similar and chemicallyidentical and for most practical purposes they may be considered the same.
Uranium is a radioactive heavy metal that is hazardous to humans in fourways: . as a toxic heavy metal.
. as a chemical carcinogen.
. as an endocrine disruptor, and. as a radiation carcinogen.
DU has about 75% of the radioactivity of natural uranium (U) (see below) and therefore a similar percentage of the radiation carcinogenicityof U. But it has the same chemical toxicity, endocrine disruptive propertyand chemical carcinogenicity as U.
Because of the controversy over DU, uranium is now one of the most studied radionuclides. In recent years, at least eight oﬃcial reports7–14 havebeen published on its toxicity and health eﬀects, together with at least ﬁvesizeable reviews15–19. Until the recent United States National ResearchCouncil report7, perhaps the most authoritative review was published in thetwo reports of the Royal Society in the United Kingdom on DU’schemical risks and radiation risks, respectively. The Royal Society reportsstated that there were legitimate concerns about the possible healthconsequences of using a radioactive and chemically toxic material formunitions but concluded that the risks of DU munitions to soldiers werevery low8. In particular, the Royal Society stated ‘Exposure to suﬃcientlyhigh levels might be expected to increase the incidence of some cancers,notably lung cancer, and possibly leukemia, and may damage the kidneys’.
Using a worst-case scenario, they estimated an extra 1.2 deaths per 1000from lung cancer amongst those most highly exposed (e.g. survivingpersonnel in a vehicle struck by a DU penetrator) (Ref. 9: p. 21, Vol. 2).
However, since the Royal Society’s reports, much new evidence fromradiation biology has emerged.
The two main sources of information on DU health risks are epidemiology studies, that is, studies of DU exposures and risks to human populations, and radiation biology studies in cells and animals. Althoughlay persons often feel that the former are more relevant, in fact muchmore information on the health eﬀects of DU is available from the lattersource.
U is a constituent of the earth’s crust with an average concentration of aboutthree parts per million. Some uranium ore regions of the world containmuch higher concentrations of uranium – typically about 1000 parts permillion.
In the nuclear power fuel cycle, uranium ore is mined, and uranium is leached from ore and reﬁned to almost pure uranium dioxide (UO2) for usein nuclear fuel6. (In passing, it is mentioned that uranium mining is highlydestructive of local environments and that uranium reﬁning creates verylarge quantities of radioactive tailings, which continue to release largequantities of the radioactive gases radon and thoron for millennia.) U consists of three main isotopes, U-238 (99.3%), U-235 (0.72%) and U- 234 (0.0054%). The isotopes U-238 and U-235 are primordial – that is, theywere created at the same time as the earth about 4.6 billion years ago. U-234is a decay product of U-238.
The vital consideration is that U-235 is ﬁssile, that is, it maintains nuclear ﬁssion in nuclear power reactors and is used in nuclear weapons. Most nuclearreactors are designed for uranium fuel that has been only slightly enriched inU-235, typically from 0.7% to between 2% and 4%. This is known as lowenriched uranium. This concentration is achieved by the process ofenrichment, whereby UO2 is converted to a gas (uranium hexaﬂuoride, UF6)and passed through gaseous diﬀusion or centrifuge facilities. U-235 is also avital ingredient of many nuclear weapons but here the enrichment required isto about 90% U-235. This is termed highly-enriched uranium.
DU is a waste product mainly from the manufacture of nuclear weapons. (It is also a waste product from nuclear fuel reprocessing, butsuch DU is not thought to be reused in signiﬁcant quantities.) Theenrichment processes for nuclear weapons create about seven metric tons ofDU waste for each metric ton of enriched uranium19. The result is that verylarge quantities of DU are produced as waste. In 1996, worldwideproduction of DU was estimated by the European Parliament’s Scienceand Technology Options Assessment (STOA) panel at about 35,000 metrictons per year7. As a result, it is estimated that over 1.2 million81 metric tonsof DU are currently stockpiled worldwide, mostly in the United States, andmostly in the unstable form of uranium hexaﬂuoride: this is a majorenvironmental waste problem to which insuﬃcient attention is given.
Uranium and DU can exist in a number of chemical forms as described inBox 1.
Chemical forms of uranium and depleted uranium.
Uranium oxidesUranium oxides include U3O8, UO2, and UO3. Both U3O8 and UO2 aresolids that are relatively stable over a wide range of environmentalconditions, with low solubility in water. DU is chemically more stable andsuitable for long-term storage or disposal in these forms. U3O8 is the moststable form and the form most commonly found in nature, and in ‘yellowcake’, a solid produced during mining and milling operations, named for itscharacteristic colour. UO2 is a solid ceramic material, and the form ofuranium used in nuclear reactor fuel. At room temperatures, UO2gradually converts to U3O8.
Uranium hexaﬂuorideUranium hexaﬂuoride (UF6) is an unstable form of uranium usedduring conversion and enrichment. It is a major chemical hazard. UF6can be a solid, liquid or gas within a range of temperatures andpressures. Solid UF6 is a white, dense, crystalline material, resemblingrock salt. While UF6 does not react with oxygen, nitrogen, carbondioxide or dry air, it does react rapidly with water or water vapour toform highly corrosive hydrogen ﬂuoride (HF) and uranyl ﬂuoride(UO2F2). Although very convenient for processing, UF6 is contra-indicated as a chemical form for long-term storage or disposal becauseof its instability.
Uranium metalUranium metal is among the densest materials known, with a densityof 19 g per cubic centimeter (g/cm3). The silvery white, malleable andductile metal is not as stable as uranium oxide and will undergo surfaceoxidation. It tarnishes in air, with the oxide ﬁlm preventing oxidationof the bulk material at room temperature. Uranium metal powder orchips will ignite spontaneously in air at ambient temperature.
Small amounts of DU are sometimes used in hospitals and laboratories as radiation shielding and, in the past, DU was used in counterweights in someaircraft wings; however these uses are small and declining in comparison withthe large amounts generated each year. The largest users of DU are militaryservices, but even they do not put much of a dent in DU stockpiles. Forexample, the STOA Panel19 estimated that the total quantity of DU inammunition used in Iraq and Kosovo corresponded to only 4 days’ DUproduction worldwide, that is, about 2% of annual DU production. DUstockpiles worldwide pose serious disposal problems to the governmentsinvolved – mainly the US, UK and Russia.
The US and UK military services use DU in ammunition and projectilemunitions, and in the armour-plating of vehicles for a number of reasons.
One is that DU is inexpensive and plentiful supplies are available. Another isuranium’s properties, as the chemical and physical properties of U metaland DU metal are almost identical. Uranium is a very dense metal with aspeciﬁc gravity approximately 70% greater than lead. This is useful in amilitary context because of the higher penetrative power and greatertrajectories of DU projectiles compared with tungsten-tipped munitions.
Also, DU alloys are very hard and pyrophoric, properties which make DUarmour-piercing munitions superior to conventional (tungsten) munitions.
DU armour-plating is also more resistant to penetration by conventionalanti-tank munitions. Probably another reason for DU’s use by US and UKmilitary forces is that it provides a partial solution to the mounting problemof DU wastes mentioned previously.
DU munitions were ﬁrst used extensively in the 1991 Gulf war, in Bosnia in 1995 and Kosovo in 1999. It has continued to be used in Iraq since 2003and perhaps in Afghanistan since 2002. Table 1 indicates the amounts ofDU used in recent wars by the US armed forces who are by far the largestuser of DU munitions.
Depleted uranium used by United States armed forces in recent wars On impact, DU in projectiles may be dispersed as aerosols which can be inhaled or ingested, or imbedded in tissue as shrapnel. Frequent continuingreports of illnesses suﬀered by combatants4 and civilians1 in these wars haveresulted in speculation that these may be because of DU exposures. SeeBox 2 for a discussion of the Gulf war syndrome.
Many soldiers and civilians from Gulf war areas have self-reported avariety of symptoms, usually collectively termed the Gulf war syndrome.
The syndrome appears to be a complex, progressive, incapacitating, multi-organ, system disorder whose symptoms can include fatigue, musculoske-letal and joint pains, headaches, neuropsychiatric disorders, confusion, visual problems, changes of gait, loss of memory, swollen or enlargedlymph nodes, respiratory impairment, impotence and urinary tractmorphological and functional alterations.
Whatever the causes, it is clear that the suﬀering is widespread, measurable and real to those aﬀected. Nearly 20% of all USpersonnel deployed to the 1991 Gulf war were receiving some formof disability compensation because of these eﬀects by 200175. Anumber of studies, summarized by Komaroﬀ, have found that armedforces from a number of countries deployed to the Persian Gulfregion were statistically signiﬁcantly more likely to report chronic,debilitating symptoms than military personnel deployed to otherareas76. Eisen et al. measured the prevalence of self-reported chronicillness among Gulf war combatants compared with a control groupof not deployed veterans. They found that deployed veteransreported dyspepsia, a group of common skin conditions (ﬁbromyal-gia), and chronic fatigue syndrome much more often than thecontrol group. The most striking association was with chronicfatigue syndrome77.
Some authors79,82 have alleged these symptoms may be because of, at least in part, DU exposures. There is some chromosomal evidence ofincreased radiation exposures in soldiers in the Middle East80. Inaddition, the UN Environmental Programme3 found over 300 DU-contaminated sites in Iraq. However, many soldiers and civiliansreporting these symptoms were unexposed to DU or were exposed tolow concentrations, so the single explanation of DU exposure for illhealth outcomes is considered unlikely. [There is one aspect whichcould result in greater (and more widespread) exposures to DUaerosols than those received from munitions use on tanks andbuildings, and these are ﬁres and explosions at DU weapons dumps.
Anecdotal reports indicate that there have been two such ﬁres in Iraq,with one ﬁre lasting 8 days. Clearly this is a matter which should beinvestigated, and consequent DU exposures estimated.] Many Gulf war personnel were exposed to many substances that in theory could have produced chronic tissue damage: solvents,insecticides, smoke and other combustion products, agents of chemicalwarfare (irreversible anti-cholinesterase inhibitors, such as sarin), andpyridostigmine bromide (a reversible anti-cholinesterase inhibitortaken to prevent the eﬀects of sarin). Also, they received an intensivebattery of simultaneously administered immunizations, which somebelieve75 could have produced chronic debility.
In conclusion, although our understanding of the etiologies of these symptoms remains poor to say the least, it is diﬃcult to ascribeanything more than a minor role to DU exposures, given the presentlevel of knowledge about DU exposures. More discussion on the Gulfwar syndrome is at Comparison of the radioactivity of DU and natural uranium Many reports state that DU has 60% of the radioactivity of U. However,the correct ﬁgure is closer to 75% for two reasons: enrichment facilitiessometimes use reprocessed (as opposed to 100% mined) uranium, and thepresence of U decay products.
The presence of reprocessed uranium in DU The DU used by the US military contains the isotope U-236 (at a concentrationof 0.0003%)8 which is not present in natural (i.e. mined) uranium. This man-made isotope arises only in nuclear reactors and its presence indicates that theDU batch used contained some uranium from the waste streams of reprocessingspent nuclear fuel, carried out mainly by France, the Russian Federation, theUnited Kingdom and the United States. Thus there are two types of DUdepending on its source; that is, from reprocessing or from mined uranium ore.
The important matter is that the former includes small amounts of reprocessed uranium from spent nuclear fuel. This is problematic becausereprocessed uranium is contaminated with the ﬁssion and activationproducts found in spent nuclear fuel. In particular, the ﬁssion product Tc-99 and the activation products Np-237, Pu-238, Pu-239, Pu-240 and Am-241are sometimes found in DU munitions20. DU made with some reprocesseduranium is therefore more radioactive than the DU derived solely frommined uranium ores20. Most reports state that the amounts of contaminantsin DU munitions from spent nuclear fuel are low. According to the USOﬃce of the Special Assistant for Gulf War Illnesses, the dose from thesecontaminants amounts to less than one 1% of the equivalent dose from DUexposures, and the authors have concluded that their risk impact was low12.
The Royal Society also stated that the concentrations found in the DUbatches it had examined were low, but it recommended continued vigilanceon the matter9.
Once DU has been made into munitions and placed in a warehouse, the U-238 and U-235 isotopes slowly decay and create various daughter products.
The main daughter products of U-238 are Th-234, Pa-234m, Pa-234 and U-234; the main daughter products of U-235 are Th-231 and Pa-231. Withinabout 6 months, these daughters are in secular equilibrium with theirparents: that is, the daughter amounts being created by the parent are equalto the daughter amounts disintegrating. Therefore the radiation from thesedecay products should be added when assessing the dangers of DU.
The key matter is that the decay products are mostly beta emitters, particularly Pa-234m, which emits very energetic beta particles. As explainedby the Royal Society9, these beta radiations may constitute as much as 40%of the absorbed dose (that is, 2% of the equivalent dose) to tissues nearembedded DU. It is important to realize that the additional risk from thebeta particles of decay products is currently not taken into account by theInternational Commission on Radiological Protection in its dose coeﬃcients(which estimate radiation doses from incorporated radioactive substances)for uranium isotopes. This should be corrected as soon as possible.
Bishop21 has estimated the total alpha, beta and gamma emissions per year from 1 g samples of U and DU. He concluded that DU together withits decay products in equilibrium are 75% as radioactive as U plus its decayproducts. The STOA report19 to the European Parliament using a crudermethod estimated that DU has 80% of the radioactivity of U. This meansthat the adjective ‘depleted’ in DU may give a misleading impression: a moreaccurate description would be the phrase ‘slightly less radioactive’. Foralmost all practical purposes, DU and U can be considered as the same.
DU exposures can occur via several pathways. One is external radiation,whereby beta radiation (and, to a much lesser degree, gamma radiation)from the decay products of DU irradiate the body, but in most cases suchexposures are very small. More important are the internal exposuresresulting from inhalation of DU aerosols and dusts, from ingestion of DUcontaminated water and food, and from wounds – in other words byinoculation of DU shrapnel.
When DU projectiles penetrate armoured vehicles, their occupants are often injured by DU shrapnel, which can remain in the body for lengthyperiods. When tanks are struck by DU projectiles, depending on the materialand thickness of their armour, about 10%13 is volatilized into an aerosol thatimmediately burns to form poorly-soluble uranium oxides that may remainin high concentrations in enclosed spaces, such as tanks and bunkers. Theseaerosols can contain very small particles of uranium oxide of between 0.1 and10 microns in diameter (1 m ¼ 1076 m or one millionth of a metre) which canbe inhaled and deposit in the lungs. White blood cells scavenge these particlesand transport them to tracheobronchial lymph nodes for lengthy periods.
These particles are usually insoluble, and are unlikely to be detected in urine samples. Therefore the routine practice of urine sampling of returningsoldiers is likely to be ineﬀectual at detecting uranium oxide exposures.
Uranium’s transport in soil depends very much on its solubility in water, butthis is highly complex and highly variable at diﬀerent pH values. Uraniumcan exist in the þ3, þ4, þ5 and þ6 oxidation states, with the þ4 and þ6states most common in the environment. These oxides are only sparinglysoluble, but will gradually form hydrated uranium oxides in moistconditions. The hydrated uranium oxides will then slowly dissolve and betransported into surrounding soil, pore water and eventually groundwater.
With metallic U particles, the oxidation rate depends on fragment size, pH,humidity, soil moisture content, soil chemistry, soil oxygen content and thepresence of other metals in the soil. Soil pH and dissolved carbonateconcentrations are the two most important factors inﬂuencing theadsorption behaviour of the common U6þ in soil22. However recent studiesof DU munitions buried in soils over for 3 years have shown acceleratedcorrosion and U leaching rates23.
Because of the increased awareness of the health hazards of uranium,there has been growing pressure to tighten drinking water standards foruranium in recent years. National standards vary considerably, partlybecause of diﬀerent assumptions about the daily consumption of water.
See Table 2.
National and international standards for uranium in drinking water.
Uranium standard mg (micrograms) per litre For example the US EPA’s maximum permissable concentration for U (i.e. and therefore for DU) in drinking water is 20 mg/l (micrograms ormillionths of a gram, per litre), but this is lax in comparison with the WHOguideline value (GV) of 2 mg/l. In Canada, the Government’s Federal –Provincial – Territorial Committee on Drinking Water calculated thehealth-based GV of uranium in drinking water to be 10 mg/l. In 1998, theWorld Health Organization proposed a ‘tolerable daily intake’ (TDI) of 0.6 mg per kg bodyweight24. This was derived by dividing the lowest Uconcentration in rats at which eﬀects were observed by an uncertainty factorof 100 (610 for interspecies variability and 610 for intra-speciesvariability). The TDI is an estimate of the amount that can be ingesteddaily over a lifetime without appreciable health risk. (See discussion atThe WHO alsoderived a GV of 2 mg/l for U drinking-water. According to the WHOreport, the GV ‘represents the U concentration . . . that does not result inany signiﬁcant risk to the health of the consumer over a lifetime ofconsumption’ (the reasoning was as follows: for an adult weighing 60 kg, theTDI corresponds to a daily U intake of 36 mg. Drinking-water is not theonly source of U intake, so assume that up to 90% of the TDI comes fromother sources (in practice, food). In other words, assume that food mightprovide as much as 32 mg daily. Then upto 4 mg may be allocated to thenormal consumption of 2 litres of drinking-water per day – hence the GV of2 mg/l. See .
Surprisingly there are currently no UK regulatory limits or oﬃcial guidance for uranium in mineral water, bottled drinking water or tap water(see Si-milarly, the European Commission has not introduced a drinking waterstandard for uranium because of pressure from some member states,although one is expected within a few years. In September 2008, the Germanfederal and state Ministers of consumer protection, responding to Germanconsumer concerns about uranium in domestic water supplies, agreed tointroduce a 10 mg/l drinking water standard for uranium25. It remainsunclear whether this value will be introduced in Germany before theEuropean Union introduces its own value. Earlier in 2006, the GermanParliament had approved regulations limiting the uranium concentration inbottled mineral waters to 2 mg/l for water designated for infants26.
The initial distribution of uranium compounds in humans strongly depends ontheir solubility and absorption route. On average, 1–2% of ingested uranium isabsorbed in the gastrointestinal tract in adults. The absorbed uranium rapidlyenters the bloodstream and forms a diﬀusible ionic uranyl hydrogen carbo-nate complex (UO 2HCO3 ) in equilibrium with a non-diﬀusible uranyl albumin complex. In skeleton, the uranyl ion replaces calcium in the hydroxy-apatite complex of the bone crystal. Once equilibrium is attained in theskeleton, uranium is excreted in urine and faeces. Under alkaline conditions,the uranyl hydrogen carbonate complex is stable and is excreted. In more acidicenvironments, the U complex dissociates and binds to the cellular proteins inthe tubular wall. The half-life of uranium in the rat kidney is about 15 days, andconsiderably longer (300–5000 days) in the rat skeleton27.
Large fractions of administered soluble uranium compounds can be absorbed. For example, 20–30% was found in the bones of male rats within2.5 hours of uranium administration, and 90% of the uranium remainingafter 40 days was found in bone28. Uranium compounds are distributed toall tissues, preferentially bone, kidneys, liver and testes10,29. Rats implantedwith DU pellets also show uranium concentrations in heart, lung tissue,ovaries and lymph nodes17. Like many heavy metals, uranium reacts withDNA, ions and blood proteins to form special compounds called complexes.
Uranium can cross the placenta and the blood-brain barrier and accumulatein the brain. Soluble uranium compounds are cleared more rapidly thaninsoluble compounds: two-thirds of uranium in blood is excreted in urineover the ﬁrst 24 hours. Elimination of soluble uranium is primarily by thekidneys and urine. The release of DU from embedded particles in shrapnel isslow: it takes 1.5 years for 80–90% of uranium in bone to be excreted17. Arecent study has revealed that U excretion is very slow and that urinaryexcretion of DU can be detected in people more than 20 years after theyinhaled U aerosols30.
Since at least the Second World War, it has been known that uranium, aradioactive heavy metal, was hazardous to humans. Like other heavymetals, such as chromium, lead, nickel and mercury, uranium is chemicallytoxic to kidneys, the cardiovascular system, liver, muscle and the nervoussystem. In kidneys, U is thought to interfere with proximal tubular functionat very low levels apparently without a threshold concentration31.
As all uranium isotopes are radioactive, they all also emit radiation.
This means that, in the United States (which perhaps has the mostdetailed regulations covering uranium) U exposures are regulated in twodiﬀerent ways – by radiation protection authorities and by chemicalregulation authorities. The former stipulates maximum doses fromuranium radiation exposures to the lung via insoluble uranium particles,as it was thought their long residence times in the lung could result inlung cancers. The latter stipulates maximum concentrations of solubleuranium chemicals, particularly in the kidney32. Uranium’s chemicaleﬀects were previously thought to occur at lower uranium concentrationsthan its radiation eﬀects33. However it is now known that this is incorrect,as both eﬀects can be stochastic, that is they can occur down to the verylowest levels.
Scientists are increasingly aware that uranium and DU are hazardous tohumans in a third way: they are chemically (as well as radiologically) carcinogenic. This considerably increases our perception of DU and Uhazards because low concentrations of soluble uranium throughout thebody – previously considered to be harmless (and therefore neglected) – arenow considered to be carcinogenic without threshold. In other words, nomatter how low the DU or uranium concentration, a small risk of chemicalcarcinogenesis remains. However, Taylor and Taylor have estimated thatthe risks of chemical carcinogenicity are low15.
The Royal Society’s 2001 report9 discussed the then emerging evidence of DU’s chemical carcinogenicity and it suggested that uranium’s chemicaland radiation eﬀects may act synergistically, that is, their eﬀects may need tobe multiplied rather than added together. More recently, the US NRCreport7 also examined uranium’s chemical carcinogenicity and expressedvariable views on the matter. For example, its Chapter 7 called for researchon ‘whether’ a chemical mechanism of uranium carcinogenesis existed.
However, Chapter 8 recommended that studies be conducted to determinethe relative contributions of ‘the’ chemical and radiological mechanisms ofuranium carcinogenesis. Unfortunately, since 2004 the US governmentappears not to have granted further funds to research DU carcinogenicity:for example, the lead agency on this research, the US Armed ForcesRadiobiology Research Institute, has signiﬁcantly reduced its pioneeringwork on this research.
Recent evidence34 suggests that DU may be hazardous to humans in a fourthway. It may act as an endocrine disruptor, that is, a substance which interfereswith hormones. A number of studies have indicated that heavy metals act asendocrine disruptors35. For example, cadmium stimulates the proliferation ofhuman breast cancer cells36, interacts with estrogen receptors36 and stimulatesestrogenic responses in vivo37. Raymond-Whish et al.34 tested whether DUadded to drinking water caused responses in the female mouse reproductivetract like those caused by the estrogen diethylstilbestrol. They concluded thaturanium is an endocrine-disrupting chemical and that populations exposed toenvironmental uranium (including indigenous populations in the UnitedStates living near uranium mine tailings) should be examined for increasedrisk of fertility problems and reproductive cancers.
Enhanced radiation from photoelectric eﬀect? A very recent article38 discussed a suggestion that DU and U atoms couldhave an enhanced radiation eﬀect because of interactions with backgroundgamma radiation. It is well known that such interactions occur because ofthe photoelectric eﬀects of gamma rays interacting with atoms of highatomic number (high Z). Such interactions result in a shower of secondaryemissions near the site of the relevant high Z atoms. However, the gamma ﬂux from background radiation is likely to be much too low for highexposures (that is, adverse health eﬀects) to occur. This is because each U orDU particle would have to be ‘hit’ by many background gamma rays toachieve this. If such large background ﬂuxes existed, background radiationdoses would have to be increased considerably for other reasons and thisseems very unlikely. If one were to switch a laboratory radiation detector toits highest sensitivity, one would get a few ‘clicks’ per second in a Geigertube with an area of about 4 cm2. Each ‘click’ represents a gamma photonfrom background radiation. One would need to observe a much higher rateof ‘clicks’ for the gamma ﬂuxes necessary for the above suggested eﬀects.
There are other matters which argue against this suggestion (for example, the preponderance of high energy over low energy gammas inbackground radiation, and the existence of Compton scattering which willdiminish the photoelectric eﬀect) but low gamma ﬂux is the main problem.
Further calculations are understood38 to be continuing to estimate theactual (very low) level of doses from the background photoelectric eﬀect onU particles, and what background gamma ﬂuxes would be needed toobserve adverse eﬀects.
Cell, animal, human and epidemiological studies A) Human cell evidence (in vitro studies) A comprehensive body of research indicates that DU exposures to humancells in vitro results in genotoxic eﬀects and induces cell phenomena closelyassociated with carcinogenesis. These cellular eﬀects and phenomena werereviewed by Professor Baverstock39 in 2006 for the Belgian Parliament.
. genomic instability – a process involved in carcinogenesis40.
. transformation to a tumorigenic state, whereby aﬀected cells grow as cancers when injected into mice41–45.
. induction of mutations whose presence characterizes most cancers46.
. DNA oxidative damage47.
. activation of gene expression pathways48.
. formation of DNA-U adducts49.
. induction of dicentrics in chromosomes – a radiation-speciﬁc change Long-term studies of insoluble uranium oxide inhalation in monkeysindicate the carcinogenicity to lung of this kind of exposure and possibly itsinvolvement in non-Hodgkin lymphoma54,55. Monleau et al. measured theinduction of DNA double strand breaks by inhaled DU in rats56. Hahn et al.
found an elevated risk of cancer in rats implanted with small DU foils. Theyconcluded that DU fragments embedded in muscle tissue were carcinogenicif large enough; however the mechanism was unclear57,58.
After mice were exposed to embedded DU for 3 months then injected with progenitor cells, Miller et al. found that 75% of mice developedleukemia compared with 10% in control mice42. In addition, mice showedchanges in the musculoskeletal system, such as bone formation andremodelling, after oral, intra-peritoneal, intra-venous and implantationuranium exposure41.
In vivo studies with embedded DU pellets in animals showed aberrant expression of oncogenes and tumour suppressor genes associated withcarcinogenesis52,59. Although these eﬀects may be caused by DU radiation,there are many reasons suggesting that its chemical eﬀects pre-dominate. Inthe in vitro transformation and sister chromatid exchange studies, inducedeﬀects were very much more frequent than expected from the very smallnumber of cells hit by an alpha particle (1 in 100,000 cells from a 10 mm-sized DU particle). In addition, similar transformation frequencies wereobserved with the non-radioactive heavy-metal carcinogens nickel and lead;it was speculated that genotoxicity of DU may be because of uranyl ionsacting to produce free radicals, particularly if the ions are eﬀectivelychelated to DNA like other metal ions52,59.
Uranium is a well-established nephrotoxin (that is, toxic to kidneys) in humans,the primary target being the proximal tubule. Damage occurs when uraniumforms complexes with phosphate ligands and proteins in tubular walls whichimpair kidney function. Biomarkers of these tubular eﬀects include enzymuriaand increased excretion of small proteins, amino acids and glucose. Uranium isalso a bone seeker and is incorporated into the bone matrix by displacingcalcium to form complexes with phosphate groups60.
McDiarmid et al.61 observed a statistically signiﬁcant increase in mutations in peripheral lymphocytes in three US Gulf war veterans withembedded DU fragments (from ‘friendly-ﬁre’ incidents) shown byuranium measurements in their urine. However, their continuing surveil-lance over 14 years has yielded no evidence of reproductive systemdysfunction, abnormalities in sperm or alterations in neuroendocrinefunction. Nevertheless, it should be recalled that soldiers are a healthysubset of the wider population, and the numbers of exposed soldiers in thesestudies are very small. Monleau et al. found that repeated uraniuminhalations tended to potentiate, that is increase uranium’s genotoxiceﬀects56. Zaire et al.62 observed the induction of chromosome aberrations inuranium mineworkers in Namibia. Such rearrangements of genetic materialin chromosomes are involved in the carcinogenic process.
Few, if any, epidemiology studies have shown convincing eﬀects speciﬁcallyfrom DU, as opposed to U, exposures. The Royal Society examined 14epidemiological studies of occupational uranium exposures to workersengaged in the extraction, milling and machining of uranium9. Theseshowed no sign of excess deaths because of cancer or kidney disease relatedto inhaling or ingesting uranium. However, the Royal Society reportstressed these studies should be interpreted with care. First, there were fewreliable data on uranium exposure levels to workers, particularly in the earlyyears of uranium processing when exposures because of inhalation ofuranium-containing dust were thought to be high.
In addition, smoking was a powerful confounder causing approximately 90% of lung cancers, and information on smoking habits was not availablefor any of the studies. Another problem was the healthy worker eﬀect, whichmeant that risk comparisons should be made with other workers and not thegeneral population. The report stressed that these types of epidemiologicalstudies were not able to detect small increases in risk, although a twofoldincrease in cancer might have been detectable. A cardinal rule inepidemiology is that the absence of evidence in studies should not be usedto allege evidence of absence63. In many cases, it may mean merely that thestudies were not powerful enough to detect an increased risk.
A number of studies have examined health eﬀects in small numbers of military personnel51 exposed to DU in ‘friendly-ﬁre’ incidents, but theirexposures to uranium dusts and aerosols were much lower than thoseexperienced during uranium mining and milling activities. Unfortunately,very few studies have been made of the many civilians exposed to DU invarious conﬂicts52. The two main exceptions are by Al Sadoon et al.64 in2002, and Fasy in 200365.
Those studies actually carried out raise as many questions as answers, particularly on the unusually low incidence rates of congenital malforma-tions in Iraq pre-1990 compared with Western rates. Hindin et al.66 carriedout an extensive literature review of congenital malformations following DUexposures in US military personnel. They concluded that the humanepidemiological evidence was consistent with increased risk of birth defectsin oﬀspring of persons exposed to DU.
Therefore, despite the existence of many reports on DU, it remains diﬃcult to assess whether (and to what degree) DU exposures have causedincreased ill health among exposed soldiers and others. This is because of theinconclusive ﬁndings of some of the reports; the large uncertainties in theassessed doses and risks from DU exposures; the possible presence ofconfounders; and the paucity of data from past battleﬁelds. In other words,the available epidemiological evidence on DU exposures in Iraq and otherbattle grounds is unreliable for establishing risks.
Possible synergism between radiation eﬀects and chemical eﬀects As discussed above, many studies clearly indicate that DU has bothchemically-induced and radiation-induced eﬀects. An important question iswhether synergism exists between these eﬀects, that is, whether theypotentiate one another. For example, synergistic responses occur whennickel exposure is combined with exposure to gamma radiation66. Andbystander (that is, un-irradiated) cells are vulnerable to both radiation-induced and chemical-induced eﬀects (Ref. 67:p. 277).
A signiﬁcant number of scientists have theorized that such synergism may occur. For example, Miller et al. speciﬁcally proposed that theradiological and chemical eﬀects of DU might play tumour-initiating andtumour-promoting roles (Ref. 48:p. 254). If this were the case, it would be aclear example of synergism. In addition, the Royal Society’s report stated: One could speculate . . . that the potential for synergistic eﬀects between theradiation and chemical actions of DU would be greatest in the vicinity ofparticles or fragments of DU, from which essentially all the surrounding cellsare chemically exposed and may thereby be sensitized to the occasionalradioactive decay particle9.
It concluded that further studies were required to examine the possibility of synergy between the chemical eﬀects and radiation eﬀects of DU9. TheUS NRC report7 also recommended that studies be conducted to determinethe relative contribution of chemical and radiological mechanisms ofuranium carcinogenesis. It added that if the chemical contribution werefound to be substantial, studies should then be undertaken to calculatecancer risks resulting from the combined chemical and radiological eﬀects ofDU.
Many articles in the scientiﬁc media have posed questions about theincidence of ill health and death in Iraq following alleged DUexposures in both wars. For example, see Ref. 1 and ¼ In addition, many private or unoﬃcial websites cite a great deal of anecdotal evidence of serious ill health among the Iraqi population. Forexample, among the many websites on this matter are the following: http://electronicdrum.wordpress.com/2004/07/13/more-articles-depleted-uranium-use-in-iraq-war/http://electronicdrum.wordpress.com/2004/07/13/us-forces-use-of-depleted-uranium-weapons-is-illegal/ Although clearly much public concern exists, the problem as stated above is the palpable lack of credible epidemiological evidence. This ispartly because of the many practical methodological83 problems withconducting epidemiology studies in Iraq, as mentioned above and recentlydiscussed by Hotopf and Wessely for example68.
But it is acknowledged that it is also partly because of political interference as well, particularly by the previous US administration. For example, in 2000,the UN General Assembly voted to recall a WHO team which had been sent toIraq to investigate the many claims of ill health from DU exposures. Manyobservers considered the vote was because of pressures by the US on non-aligned governments re-withdrawals of US aid to their countries. This is similarto the previous US administration’s reluctance to ﬁnd evidence of ill healthamong US war veterans69. In addition, in 2001, a draft WHO report on theradiological toxicity of DU was suppressed and not published, allegedly onorders from the then US government70.
An aspect rarely discussed is the apparent inability or reluctance of some observers to accept the overwhelming preponderance of evidence of DU illeﬀects at low concentrations from biological research, i.e. from animal andcell studies. It is argued here that these are more useful sources of data forderiving uranium’s risks than DU epidemiology studies. In fact, for safetyregulation purposes, uranium’s chemical risks are derived almost completelyfrom animal studies. This is not unusual as the risks of most chemicals arebased on the concentrations found not to be harmful in animals. Theseconcentrations are further divided by safety factors of 10–1000 then appliedto humans. That is, acceptable concentrations for humans are 10–1000 timessafer than those in animals. This simple system works well and is clearlyprecautionary.
With radionuclides, the precautionary approach for chemicals is unfortunately not used. Instead, radiation scientists insist that humandata (that is, from epidemiology studies) must be used to derive risks. Manymay instinctly think that these are a better source because humans are obviously diﬀerent from animals, and this is correct, in theory. But inpractice the matter is less clearcut, as many practical diﬃculties exist withepidemiology studies as indicated above. The greatest diﬃculty is that oneneeds very large, time-consuming and expensive studies involving thousandsof cases to obtain statistically signiﬁcant ﬁndings. Another diﬃculty is thatto estimate risks per unit exposure, one needs estimates of these exposuresand these are almost always lacking or highly uncertain. The result is thatepidemiological studies are a blunt tool for investigating risks and theexisting DU studies are highly unsatisfactory for deriving human risks.
Insisting on using such studies alone rather than relying on cell and animalstudies means that we might be underestimating DU’s risks. Sole reliance onepidemiological studies (which so far are all too statistically weak to pick upeﬀects) tends to downplay the substantial body of radiobiological evidencethat overwhelmingly points to DU being a chemical carcinogen, aradiological carcinogen, a heavy metal nephrotoxin and an endocrinedisruptor, all at relatively low levels of exposure71. Indeed, continuedreluctance to act on the many research ﬁndings from radiobiology could beconsidered a breach of the precautionary principle in law72.
There are other problems with continued DU use, apart from health concerns.
For example, its use acts to blur the distinctions between conventionalweapons, chemical weapons and (to a degree) nuclear weapons. In addition,DU use provides another indication of failed civilian control of the military. Itappears there was no prior civilian discussion of DU development, and the ﬁrstpublic knowledge of DU weapons apparently came via media reports from asoldier whistleblower. A moratorium on DU use could therefore be seen aspolitically as well as ethically desirable and health-wise sensible.
The legality of DU weapons use is a complex subject: a good review by Karen Parker is available at Itappears that no international laws directly govern the use of DU weapons.
At present, two schools of thought exist among anti-DU campaigners onhow to achieve a ban on DU use, one is via the anti-land mine legislationroute; the other is via the ‘DU is a humanitarian crime’ path: both appear tohave advantages and disadvantages which require a separate article tothemselves.
As reported by the UN6, many countries voluntarily do not use DU weapons and are not seeking to do so: in fact, in March 2007, the BelgianParliament voted unanimously to ban DU ammunition from June 2009.
Therefore DU does not appear to be seen as militarily necessary or decisiveby most countries.
International agencies have often debated whether DU should be banned from military weapons. In 2001, 2003 and 2005, the European Parliament called for a moratorium on the use of DU munitions. The 2005 Resolutionregarding DU was part of an 11-page document ‘Texts adopted byEuropean Parliament, on non-proliferation of weapons of mass destruction;A role for the European Parliament’. The Resolution reminded all EuropeanUnion Member States that they had signed the 1968 Nuclear Non-proliferation Treaty, the 1972 Biological and Toxin Weapons Convention,the 1993 Chemical Weapons Convention and the 1996 Comprehensive TestBan Treaty.
In December 2007, the UN General Assembly carried a Resolution (Number 62/30) by 136 votes to ﬁve, recognizing the health concerns overthe use of uranium weapons and requesting that states report to theSecretary-General on the matter73. Finally, in May 2008, the EuropeanParliament for the fourth time carried a DU motion that stronglyreiterated its previous calls on all European Union Member States andNorth Atlantic Treaty Organization countries to impose a moratorium onthe use of DU weapons with a view to the introduction of a total ban.
The resolution was adopted with 491 votes in favour, 18 against and 12abstentions74.
With the preponderance of cell and animal studies indicating that DU is avery hazardous substance, it is concluded that the safest, and precautionary,approach would be to seek an immediate moratorium on its use. In addition,the above political reasons argue for the adoption of a moratorium on itsuse.
Ian Fairlie is an independent consultant on radioactivity in the environment. He hasdegrees in chemistry and radiation biology, and his doctoral studies at ImperialCollege, London, examined the radiological impacts of reprocessing discharges atSellaﬁeld and Cap de la Hague. He has worked for various UK governmentdepartments and regulatory agencies, and advises environmental NGOs, theEuropean Parliament, and local authorities. Between 2001 and 2004 he was Secretariatto the UK government’s CERRIE Committee on the risks of internal radiation.
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DE SCHOLA LOQVAMVR – VOCABVLA ET SENTENTIAE 1. LA CLASE 2. LAS ASIGNATURAS graphis, -idis (graphium) m lápiz ars technica ( s. technologia) tecnología l. Catalana ( vel Valentiana) catalán ( o valenciano) l. Francogallica ( s. Gallica) francés l. Germanica ( s. Theodisca) alemán ātrulum gestābile, ī n ordenador portátil De schola loquamur . Germán González