Microsoft word - busby&schnug.doc

Chris Busby1 and Ewald Schnug2

1Department of Human Anatomy and Cell Biology, University of Liverpool, Green Audit, Castle Cottage, Sea View Place, Aberystwyth SY231DZ, Wales, U.K.; 2Institute of Plant Nutrition and Soil Science, Federal Agricultural Research Centre
(FAL), Bundesallee 50, D-38116 Braunschweig, Germany


Uranium (U) is a natural, radioactive and toxic heavy metal, which is unavoidably
taken up with solid and liquid food. Mammals have a particular high sensitivity to
uranium (Fellows et al., 1998). Once the uranium is in the organism, it is transferred
to the extracellular fluids and transported through the blood to other organs. Uranyl
(UO 2+
2 ) is the soluble form transported and it forms complexes with protein and anions. The risks related to exposure to uranium can be both chemical and radiological. The first is related to the binding of U to biological molecules. This risk is particularly high for kidneys because of peak concentrations during the excretion process. With solid food the daily intake of U to humans amounts to 2 - 4 µg U (Schnug et al. 2005). The height of the total uranium intake, however, is governed mainly by the uranium concentration of the drinking water consumed by an individual. A case study in Northern Germany showed that, in 20 % of all cases, the intake doubled when certain mineral waters where consumed. In worst cases this figure could even increase ten-fold (Schnug et al. 2005). Thus increasing rates of kidney failure in humans over the last twenty years have been already suspected to contribute at least partially to the chronic increase of mineral water consumption, which causes a considerably higher uranium uptake (Schnug et al. 2005). Schnug and Lindemann (2006) found that between 1986 and 2004 with a certainty of 97 % both the mineral water consumption, and the frequency of kidney replacement therapy in Austria, Germany and the USA increased by the same extent (approximately 5 % per annum). Historically, uranium has been considered both a radiological and also a ‘heavy metal’ poison, following calcium in its distribution within the body, i.e. building up in bone, and with the principle target for toxicity being the lung and the kidney (RS 2001). More recently, it has been shown that uranium also targets the brain (ENVIRHOM 2006). The dangers arising from the biochemical toxicity of uranium are generally considered to overweigh the risks from its radioactivity (Milvy and Cothern 1990). As a basis to assess the chemical toxicity of uranium, occupational Loads and Fate of Fertilizer Derived Uranium, pp. xx-xx Edited by L.J. De Kok & E. Schnug 2007 Backhuys Publishers, Leiden, The Netherlands limits of a selection of heavy metals and other toxic substances are listed in Table 1.
The heavy metals listed, apart from uranium (!), are those which are regulated in the
“German ordinance for soil protection” (BbodSchV). It is worth mentioning here,
that uranium concentrations in soils are not covered by any legal regulation in the
great majority of countries in the world.

Table 1. Occupational limits for heavy metals and their species with some selected toxic
substances (Source: TRGS 900).
*NIOSH/OSHA (National Institute for Occupational Safety and Health): Recommended Exposure Limit
(REL) and Permissible Exposure Limit (PEL): 0.05 mg m-³ for uranium dust; NRC (Nuclear Regulatory
Commission) reports an “occupational limit” of 0.2 mg m-³; Agency for Toxic Substances and Disease
Registry (ATSDR;
Despite the common sense of the scientific community about the superiority of
chemical over radiological toxicity, the most recent releases of the German
ordinance for hazardous substances (TRGS 900) no longer cover uranium, because
its editors consider uranium to be regulated more effectively by radiological aspects.
The puzzling genotoxicity of uranium
Following renewed interest in uranium toxicity generated by the military use of
uranium weapons, it is found that the element exhibits genomic and other harmful
effects not predicted by its radioactivity (e.g. Abu Quare and Abou Donia 2002;
Craft et al. 2004; IRSN 2005; Bertell 2006). This has resulted in two schools of
thought: those based on the conventional radiobiological risk assessments (e.g.
Royal Society 2001; Wakeford 2001) and those pointing out that there are real
genomic effects which cannot be explained or predicted (Baverstock 2005; Bertell
2006). There certainly seem to be experiments which show anomalous genomic or
genetic effects (including Bosque et al. 1993; Miller et al. 1998, 2002, 2002, 2003,
2003, 2004, 2005; Coryell and Stearns 2006), but these are usually interpreted as
implying some unelaborated ‘heavy metal’ effect for uranium.
Uranium has three common isotopes, U-238, U-235 and U-234. The natural
U238/U235 isotopic ratio is about 138 : 1. With specific activity of about 14 MBq
kg-1 uranium has been considered to be a low cancer risk. U-238, the main isotope
has specific activity of about 12.4 MBq kg-1 so a concentration of 20mg/l represents
0.25 Bq l-1, but even counting the two beta-emitting daughter isotopes which are in
equilibrium, the overall activity is still less than 1 Bq l-1. Uranium can have fast,
medium and slow biokinetic clearance depending on the form: the slow components
can remain in the body for a considerable time. ICRP68 gives dose coefficients for inhalation of fast-, medium- and slow-dissolving forms of uranium at 4.4 x 10-7; M: 2.6 x 10-6; S: 7.3 x 10-6 Sieverts per Becquerel respectively and for ingestion, the ICRP68 dose coefficients are generally 4.4 x 10-8 and for the insoluble oxide UO2, 7.6 x 10-9. On the basis of these figures, and because of a low transfer coefficient, routine ingestion of water at the high end of the EPA limit should not result in doses greater than some tens of µSieverts. The Royal Society (2001) calculated that that a continuous daily contamination by 1 mg will eventually result in a steady-state kidney concentration of 12 mg l-1. Since this would result in microSieverts, the Royal Society and World Health Organisation (WHO) dismissed the concerns of the Gulf War veterans who suffered from Gulf War Syndrome. There are, of course, some fundamental problems with the IRCP radiological risk methods (see ECRR2003; CERRIE 2004; Fairlie 2005; IRSN 2006). The assumption that absorbed dose (energy per unit mass) is an accurate measure of risk is arguable. The decays from particulate uranium, the type resulting from weapons use, are short range and doses near micron-sized particles can be large for local tissue volumes within range of the decay. Nevertheless it is not only exposures to particles that seem to result in health problems: the uranyl ion also exhibits anomalous genotoxic effects at low concentrations causing genomic and genetic damage in cell cultures at concentrations where there are no significant alpha emissions (Miller et al. 2002; Smirnova et al. 2005). Uranium (and also tungsten) particles cause genetic changes in cell culture elements and cause cancer in laboratory animals (Miller et al. 2001). Uranium causes anomalous inflammation in lung, kidney, brain and other living tissue in rats and produces neurological effects in mice (ENVIRHOM 2006). Uranium causes chromosome damage in miners and Gulf War Veterans (e.g. Zaire et al. 1998; Schroeder et al. 2003). Since the ‘absorbed dose’ due to radioactive decay of uranium is very low in these studies, and in one experiment stochastically absent, these effects are puzzling on basis of conventional radiological risk models. They have been ascribed therefore variously to ‘heavy metal toxicity’ or ‘chemical effects’ or some unelaborated ‘synergy between radiation and chemistry’. But what are chemical ‘heavy metal’ effects in the cell? Some proposed mechanisms from the literature include: i) Enzyme poisoning by binding to S-H groups inhibits a critical reaction (e.g. Pb, Hg, Cd). ii) Binding to DNA phosphate (Mg2+, Ca2+, Sr2+, Ba2+, UO 2+ DNA tertiary conformation and alters folding or unfolding in some way. iii) Binding to some critical ‘receptors’ antagonize normal binding by agonists (e.g. zinc finger proteins and DNA replication). iv) Inflammatory responses at tissue level (brain, intestine, kidney, lung). This mechanism is often described as ‘oxidative stress’ or ‘genotoxicity’ since the effects are similar to effects with hydrogen peroxide and are alleviated by antioxidants and anti- free radical enzymes (e.g. superoxide dismutase) and/or various other markers and end points (e.g. ENVIRHOM 2005). In further examining this puzzle, let us consider what heavy metals have in common chemically. ‘Heavy metals’ have different valency states, affinity, redox equilibria, normal ionisation states, reactivity, Lewis acidity, ionic radii, energy levels, colour of compounds, work functions, solubility, melting points, boiling
points, etc. etc. No physical chemist would understand the concept of a ‘heavy

Secondary photoelectrons
This paper suggests an explanation for these anomalies involving the idea that
contamination by elements of high atomic number Z, which have significant affinity
for DNA will result in anomalously high absorption of natural background radiation
by the DNA and its re-emission as photoelectrons. This represents a kind of focusing
of natural background radiation (and any other external gamma or X-rays) into the
Chromosomal DNA is widely believed to be the target for ionising
radiobiological effects (e.g. see BEIR V 1990; ECRR 2003; CERRIE 2004a,
2004b). It has been known for some time that Uranium binds strongly to DNA
phosphate (DNAP) as uranyl ion UO 2+
2 (Zobel and Beer 1961; Huxley and Zubay 1961; Constaninescu et al. 1974; Nielsen et al. 1992). The affinity constant determined by Nielsen et al. (1992) was of the order of 1010 M-1 at pH values below 5 with binding of one uranyl ion to every two phosphate groups. This would give half saturation of DNAP at concentrations of uranyl of about 10-10 M, which represents a cell concentration of 23 ng l-1, at the lower end of urine concentrations that have been reported in those exposed to uranium weapons (Durakovic 2002; Busby and Hooper 2007). At higher pH's the amount of uranyl significantly increases to two ions per phosphate although the affinity constant decreased due to competition with polynuclear complexation reactions. Nielsen et al. (1992) showed that the uranyl binding to DNA was greater than that of the powerful bidentate chelating agent citrate. The authors employed their discovery that uranyl ion induces photochemical single strand breakage in the DNA following irradiation with visible light (> 420 nm), a photoelectron-produced DNA lesion like those we are drawing attention to here, though at lower photon energy. It is an interesting and well-known fact that the absorption of gamma and X-rays increases rapidly with atomic number. Uranium (Z = 92) and lead (Z = 82) are thus employed for shielding purposes. The relationship is often assumed to approximate a fourth power one, though the exponent varies in the range 4.0 to 4.8 depending on gamma energy and element (Krane 1988). One can therefore compare the absorption of external photon radiation by uranium with that of calcium ions, those displaced by the uranyl from the phosphate DNA backbone. For water (Zeff = 3.33) the fourth power ratio is greater than 500,000; for DNAP (Zeff = 5.5) it is greater than 50,000 the fourth power ratio is about 450. Thus uranium on DNA absorbs 450 times the background gamma and photon ionizing radiation than Calcium. But of course, Ca (Z = 20) already absorbs 1,000 times more gamma radiation than water and some 154 times more than the DNAP complex. It would thus seem that the Calcium ion associated with the DNAP is the dominant absorber in the genetic material of the cell. This effect is entirely absent from any microdosimetric assessment of risk. The Z4 enhancements of absorption for some tissue components is compared in Table 1 where the ratio to water has been normalised. Calcium, Strontium and Barium (included) all bind to DNA but their toxicity increases sharply in the sequence Ba2+ > Sr2+ > Ca2+ as we would expect from these considerations. The amount of energy deposited in different constituents of the DNA in a cell per Gray of radiation absorption has been calculated (Ward et al. 1988; BEIR V 1990). The cell was assumed to contain 6 pg of DNA of which 1.2 pg was phosphate. In Table 2, the BEIRV Table 1-1 (p. 14) is reproduced and these fundamental results are shown. The calculation takes no account of the atomic numbers (and hence the gamma absorption) of the DNA constituents: the fourth column, which was added, shows that Ward et al. (1988) calculate that the energy deposited per pg is the same whether we are dealing with water (Zeff = 3.3) or phosphate (Zeff = 9.4). If, at a cell concentration of about 10-10 M, the phosphate were half saturated with uranyl ions, at a stoichiometry of one UO 2+ phosphate groups we can easily calculate the mass of uranium on the DNA. It is 0.7 pg and this represents about 12 % of the DNA in the cell by mass. This soaking up of uranium by DNA was actually reported by Huxley and Zubay in 1961, who observed that purified DNA took up nearly its own dry weight of uranyl acetate from a 2 % fixing solution. They employed uranyl acetate as an electron microscope stain. Table 2. Fourth power of atomic number Z for some materials of interest compared with water. Material Z
The binding of uranium to DNA will produce a source of photoelectrons and recoil electrons inside what is conceded to be the target material for genotoxic effects. It is known from experiments with Auger emitters bound to DNA (e.g. radioactive 125I, experimentally bound to DNA precursors as a probe) that DNA is the target for the effects of ionising radiation (Baverstock and Charlton 1988). BEIR V (1990) state this clearly and tabulates results of calculations showing that the amount of energy deposited by one Gray of radiation in the DNAP of a cell is 36 keV, of which 7.3 keV were absorbed by the phosphate (see Table 2). This leads to 600 (60 eV) ionisation events in the DNAP (BEIRV 1990) per Gray. The total absorption of external gamma radiation by uranium-contaminated DNAP will therefore include the enhanced contribution from the uranium on the phosphate, which is simply 7.3 x 450 = 3285 keV per Gray resulting in an overall enhancement of deposition of energy by a factor of almost 100-fold. Thus, for an annual absorbed
dose of 1 mSv, the DNA of tissue containing quite modest and environmentally
common levels of uranium would be 100 mSv. For those who are occupationally
exposed, the enhancement would probably be greater both through the internal
uranium concentration term and also the external gamma radiation term. Perhaps it
is this overlooked phantom radiotoxicity resulting from photoelectron effects that
explains the various anomalous findings referred to earlier. The gamma radiation is
absorbed preferentially by the uranium atoms and the absorption cross section for
gamma photons is some 500,000 times greater than that of water. But this does not
mean that all the energy from the absorption is deposited in the DNA, since the
photoelectrons may have various energies, ranges and track directions. But it is not
only photoelectrons that are the ionizing agent near the DNA. Photoemissions
include electrons with a spread of ranges and velocities proportionate to the incident
photon energy. But there is also ionization of the uranium atom itself with ‘catalytic’
local effects. The loss of an electron will ionize the uranium and produce an excited
or ‘hot’ species, which may lose energy by abstracting an electron from local
hydration water or some other local molecule (see e.g. Gracheva and Korolev 1980).
Short-range electrons of lower energy may result from shell electron
rearrangements. This will lead to production of a different reactive hot radical or
ionic species at the uranium site. Note that the effect is catalytic and that the
uranium is regenerated.

Table 2.
Amount of energy deposited in DNA per cell per Gray according to Table 1-1 of
BEIRV 1990 and based on Ward et al.1988 with column showing that BEIRV made no
allowance for the gamma cross section of the various atoms.

Mass per cell (pg)
eV deposited
As far as the emitted photoelectrons electrons are concerned, for condensed phase DNAP in dividing cells, they will have a high probability of damaging DNAP along their track only where this track intercepts or lies near the DNAP. To assess the likelihood of DNA interception, that is the production of ion pairs close enough to the DNA for damage to occur, we need to examine the spectrum of ranges and thus energies. The energy dispersion of environmental gamma radiation at any point in tissue is a consequence of many energy splitting processes (Compton effect, pair production, Bremsstrahlung, etc.) with the result that the event number (ionization events, counts) increases rapidly with decreasing photon energy. This means that at the DNA, especially deep within the body of human beings (though not, perhaps to such an extent within small animals like mice and rats) there will be the highest density (counts, events) of photoelectrons of low energy and short path length. It
will be these that create the highest number of ionizations close to, or inside the
Respirable uranium particles

The analyses by the Royal Society were directed at respirable uranium oxide
particles. Uranium weapons produce large quantities of uranium oxide aerosol
particles of diameters less than 1 µm which are widely dispersed, long lived, and
respirable (RS 2001, 2002). Their effects remain in question (Busby and Hooper
2007). Research has shown that uranium particles can indeed cause anomalous
genotoxic and other harmful effects (Miller et al. 2001; Monleau et al. 2006) and
again, the conclusions have been that the material displays some ‘chemical heavy
metal ’ or ‘nanoparticle’ effect. What is overlooked is photoelectron enhancement.
Gamma photons induce photoelectrons in high Z particles, but since high Z
materials also have high stopping power for electrons, the range of the photoelectron
in the material now becomes a dominant consideration. The variation of photon
penetration into the particle with photon energy is also important. For example, the
penetration of a 20 keV photon into uranium oxide is 0.0015 cm but at 50 keV the
penetration is 0.12 cm (see Krane 1988). Approximate calculations based on the
photon and electron attenuation coefficients of uranium oxide particles of different
diameters (Busby 2006) suggested that the photoelectric enhancement of incident
gamma radiation is only significant for particles of diameter less than about 5 µ
diameter. For larger particles, photoelectrons excited within the mass of the particle
do not emerge. The result for small particles of high Z elements is that there will be
an enhanced short-range photoelectron ionization field close to the particle. The high
Z particles whether intrinsically radioactive or not will behave as ‘hot particles’ but
without any radiological decay. The effect will be largely irrelevant for large pieces
of shrapnel, for metal prostheses made of gold, gold tooth fillings and so forth, but
may be important for other exposures (e.g. platinum particles from catalyzers).

Supporting evidence, conclusions and speculations

These photoelectron enhancement effects have been reported (Herold et al. 2000),
and for gold nanoparticles have been employed (Hainfeld et al. 2005), and even
patented (US Patent 6955639B2 ), for enhancing radiotherapy. The enhancement of
ionization by elements of high atomic number was considered as early as 1949 when
Speirs showed that there would be a ten- fold enhancement in tissue near bone due
to the calcium in the bone. Since then a number of groups have looked at the effect
including Regulla et al. (1998), who actually measured photoelectron enhancements
of 100-fold near thin gold foils. The process has serious implications, for example
one other piece of supporting data may be the discovery of tungsten particles (Z =
74) in the atmosphere of Fallon, Nevada, where there is a much discussed childhood
leukaemia cluster (Sheppard et al. 2007). Kalinich et al. (2005) actually succeeded in inducing cancer in rats in which tungsten particles had been embedded. There are also large amounts of uranium (mainly particulate and sub micron oxides) in the Irish Sea sediments and these would be available by inhalation following sea to land transfer. The uranium contribution to analyses by the various UK committees examining child leukemia near Sellafield has not allowed for any photoelectron enhancement exposures and indeed treated the uranium exposures to the lymphatic system of children as some ‘natural’ exposure which could be used to assess the likelihood that the anthropogenic contribution was less (discussed in CERRIE 2004). Figure 1: Minimum concentrations of mineral elements essential for plants required for optimum growth as function of the fourth power of Z. (Y coordinate for uranium is fictive!). The idea that uranium particles (or uranium atoms bound to DNA) amplify effects from external irradiation is amenable to experiment. The extent of uranium binding to DNAP in vivo could be examined and also the range of photoelectrons arising from background radiation spectrum amplification determined. Finally this paper concentrates on uranium. But of course, this secondary photoelectron enhancement of background radiation has wider implications for exposures to other high Z elements both as molecular species and as particles. It is an interesting fact that living systems generally employ few elements of atomic number above calcium (Z = 20). The highest atomic number element existing in any quantity in mammals is zinc (Z = 30), and in general, no element above the first row transition metals is employed by living systems with the unusual exceptions of molybdenum (Z = 42) and iodine (Z = 53). Figure 1 demonstrates this for mineral elements essential for the life of higher plants. Here the logarithm of the minimum concentration of each element required for optimum growth (Schnug and Haneklaus 1992) of plants (Y) is plotted against the logarithm of the fourth power of Z. Of interest here is that members of the plant kingdom cannot move away, hide or escape from radiation. And so, if the effect represented a significant evolutionary stress, selection forces might be expected to bring about optimum processes for exclusion of high Z elements in proportion to some fourth power relation. The exponent may be greater than fourth power. If it is assumed that there is a threshold for radiation damage to the plant genome beyond which the evolutionary selection pressure is too great for species survival then it is possible to write for such stress: Stress = Concentration x Radiation Effect Radiobiological Dose-Response follows a well known linear-quadratic expression (BEIRV 1990) of the form Response = aD + bD2. Photoelectron Dose D is proportional to Z4. Thus it is possible to rearrange the relation in terms of concentration: where a,b,c, and d are arbitrary constants. In other words, a plot of log(concentration) against log(Z) should give a straight line with slope of -4 in the absence of quadratic terms, and a greater negative slope if they are present. These quadratic terms relate to double strand breaks, which occur when the ionization density is great. Figure 1 demonstrates startlingly that with increasing Z the amount required to maintain biological processes decreases linearly in proportion to slightly greater than the fourth power of the atomic number. The only exception among the elements plotted from this very close relation is boron. In the context of the hypothesis outlined here this might be due to the prominent feature of boron in capturing neutrons, which makes it potentially another source for radiation damage (Li et al. 2002; Zhang et al. 2003). The natural background dose at sea level from neutrons produced by cosmic ray interactions currently represents about 10 % of external dose (Weigel et al. 2002). The elements Lithium, Beryllium and Boron all have high neutron cross sections and might be expected to behave anomalously. Boron absorbs neutrons to produce an alpha particle in the reaction B (n, α; Krane 1988). Alpha particles (and neutrons) carry a radiobiological weighting of about 20 (BEIRV 1990) and so the displacement to greater toxicity of the boron point in Fig. 1 is at about the level that would be expected. For evolution to employ any of the many high Z elements available would carry a serious disadvantage on a planet with background gamma radiation as would the employment of the three neutron reaction elements. In mammals it is remarkable that the two most radiosensitive systems are the blood (leukemia) and the thyroid gland (cancer). These two systems are the main depots of iodine (Z = 53) in the body. The unusual jump over bromine to iodine in the thyroid leads to the hypothesis that the up-regulation of genes driven by thyroid hormones may involve radiation repair (Bedford and Dewey 2002), i.e. that one function of the thyroid is as a biological radiation detector. References

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UNPUBLISHED No. 07-4602 Appeal from the United States District Court for the EasternDistrict of North Carolina, at Raleigh. Malcolm J. Howard, SeniorDistrict Judge. (5:06-cr-00007-H)Before KING, Circuit Judge, HAMILTON, Senior Circuit Judge, andHenry F. FLOYD, United States District Judge for the District ofSouth Carolina, sitting by designation. Affirmed by unpublished per curiam opinion.

CURRICULUM VITAE Rajesh Kumar Goel EDUCATION Bachelor of Pharmacy (Amravati University, Amravati, (M.S.) India, 1993). Master of Pharmacy in Pharmacology (Panjab University, Chandigarh, India,1995). Ph.D. in Pharmacology (Panjab University, Chandigarh, India, 2004). APPOINTMENTS Associate Professor and Head, Department of Pharmaceutical Sciences and Drug Research

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