**8. Cisplatin**

*Use of Gamma Radiation Techniques in Peaceful Applications*

**6. High-Z elements and cancer radiotherapy**

mechanism of cisplatin is revisited below.

made the method the subject of a patent.

**and atomic high-Z elements**

Eakins et al. study was carried out by employees of the UK National Radiological Protection Board (NRPB) [27]. They used the computer code MCNP5 to model an arrangement consisting of concentric spheres with the particle at the centre and tissue shells surrounding the particle as had the Ulster modelling. However, like Pattison et al., Eakins et al. fixed the volume into which the photoelectron energy was converted into absorbed dose. The authors did, however, model a range of uranium particles, obtaining enhancements of 3-fold at 100 nm diameter and 20-fold for the 2.5 nm diameter particles. Like the Pattison et al. study, this was an absurd analysis since having a fixed volume for the dose absorption but increasing

The augmentation of dose due to secondary photoelectron emission from high-Z elements is not a new concept; it is just that it has been ignored for the purposes of radioprotection. The idea of employing high-Z elements and their photoelectron emission to augment radiotherapy doses was advanced by Matsudeira et al. who measured the radio-enhancing effect of iodine on cell cultures [28]. Nath et al. incorporated iodine into cellular DNA with iododeoxyuridine in vitro and found a radiation enhancement of about 3-fold [29]. Herold et al. injected gold particles directly into a tumour followed by irradiation and found that the excised cells had reduced plating efficiency [30]. Mello et al. found that direct tumour injection with iodine contrast medium followed by 100 kVp X-rays completely suppressed growth of 80% of tumours in mice [31]. Norman et al. modified a CT scanner to deliver X-rays to spontaneous brain tumours in dogs after iodine injection and found a 53% longer survival [32]. Synchrotron radiation was used in combination with the tumour injected drug cisplatin to treat brain tumours in rats [33]. The issue of the

The photoelectron enhancement by high-Z nanoparticles was exploited in cancer radiotherapy by Hainfeld et al. who attempted to increase the dose delivered to tumours by injecting 1.9 nm gold nanoparticles into mice [34]. The authors also

It is curious that historically photoelectron emission by internal high-Z elements

in living systems has received very little attention. The issue of enhanced doses near bones, due to the higher concentration of calcium in the bone, was addressed as long ago as 1949 by Spiers [35], and more recent work has also looked at photoelectron emission near the bone [36]. In 1988 Castillo reported burns and necrosis around reconstructive wires in mandibular cancer patients [37], and Regulla et al. employed a very sophisticated measuring apparatus to show a physical dose enhancement of about 100-fold and a biological enhancement into tissue of 50-fold within a range of 10μ from gold foil [38]. Despite work on enhancing radiotherapy which has been carried out, no authors appear to have related the question of photoelectron enhancement to health effects. One obvious question must be about the enhanced photoelectron doses near metal prosthetic structures containing zirconium (Z = 40). The element has a photoelectron cross section of 3.5E+3 at 150 keV compared with iron (Z = 26) at 5.4 and so would produce some 650 more

**7. Radiobiological dose enhancement effects from molecular** 

the particle size, the enhancement factor eventually becomes infinite.

**188**

photoelectrons.

There is further evidence from the anticancer agent cisplatin, cis-diaminedichloro-platinum (II). Cisplatin has been a chemotherapeutic agent of choice since 1978 and is given to more than half of all cancer patients. Its mode of action has been variously described as "damaging nuclear DNA and arresting cell division". A recent review states: "Almost 30 years after its clinical benefits were first recognised, studies still continue in an effort to understand exactly how cisplatin works" [39].

Cisplatin also augments radiotherapy, that is to say, the combination of cisplatin and radiotherapy results in much higher cancer therapeutic effects than either agent on its own. This is, of course, a pointer to the mechanism [33, 39]. It is suggested here, based on what has been written above, that cisplatin, a simple diaminedichloro-square planar complex of platinum (II), merely fixes the platinum atom (Z = 78) at the centre of the nuclear DNA where the secondary photoelectron doses are sufficient to fatally damage the DNA either from natural background radiation or in the case of the radiotherapy, from the induced photoelectrons. If this is the mechanism, then two suggestions are obvious: first, uranium as uranyl acetate, for example, also will act as a chemotherapeutic agent for cancer and will augment radiotherapy in the same way. Since it is suggested that it is the high-Z aspect of cisplatin that is the reason for its action, other high-Z molecular agents could be searched for or synthesised to act as DNA-seeking chemotherapeutic agents.

### **9. Evolution**

The question of the spectrum of elements utilised by evolution of life on earth has been generally approached from the point of view of physical chemistry and more specifically redox equilibria [40]. There may be a separate or additional explanation for the reason why elements of high atomic number (e.g. mercury, bismuth, lead, uranium) although often commonly available on earth are not used by living creatures. As has been shown, chemical elements absorb gamma and X-rays of energy below about 250 keV approximately in proportion to the fourth power of their atomic number Z, and the energy is converted mainly to photoelectrons and local Auger recoil electrons resulting from internal rearrangements in the case of high-Z elements. For elements immobilised inside living tissue, this results in higher doses to components near high-Z atoms or nanoparticles than would be experienced by the same tissue in the absence of the contaminant. Thus, high-Z elements, inside the body, act as devices for focusing and enhancing the doses from natural background radiation and should be seen as phantom radioactivity sources.

If the phenomenon is significant, then it would seem reasonable that the contemporary spectrum of chemical elements employed by living systems will have been produced by evolutionary selection forces responding to such potentially critical damage.

It is a well-known fact that the effects of ionising radiation on living systems are mediated by genotoxicity. The damage can be seen as a consequence of both singleand double-strand breaks in DNA; the dose (D) response (E) can be written as [41]

$$\mathbf{E} = \mathbf{a}\mathbf{D} + \mathbf{b}\mathbf{D}\mathbf{2} \tag{1}$$

But for the photoelectron effect being considered, dose (i.e. local dose at the DNA) can be written in terms of the atomic number Z or the elements:

$$\mathbf{D} = \mathbf{a}\mathbf{Z}\mathbf{4} \tag{2}$$

and thus

$$\mathbf{E} = \mathbf{c}\mathbf{Z}\mathbf{4} + \mathbf{d}\mathbf{Z}\mathbf{8} \tag{3}$$

(a, b, c, α and d being arbitrary constants). For evolution it can be assumed that any stress S which prevents an individual from reproducing will represent an inhibitory effect of the survival probability of the species. S can be written in terms of the concentration C of the element in the individual and the radiation effect on the DNA from the element:

$$\mathbf{S} = \mathbf{C} \mathbf{E} \tag{4}$$

**191**

from biological systems.

lium, Be(α, n); 4

**Figure 12.**

*−5.6 (R2*

an alpha particle (boron, 10B(n, α); i.e. 10B + n = 7

He + 9

elements (in Barns, 10Be = 3840, 6

has been measured at 46 cm<sup>−</sup><sup>2</sup>

these neutron radiations.

*The Secondary Photoelectron Effect: Gamma Ray Ionisation Enhancement in Tissues from High…*

biological processes: evolutionary niches are generally found to be occupied but clearly not ones that involve utilising elements of high atomic number. This is not because these elements are scarce. The crustal concentrations of uranium are quite high; there is a significant quantity of uranium in seawater, yet the transfer coefficient for the gut (in mammals) ensures that the element is excluded quite efficiently. The same is true for many other high-Z elements that have been excluded

 *= 0.514, F-statistic = 65.23 on 1 and 41 degrees of freedom; p < 10<sup>−</sup>10).*

*Plot of log(C) vs. log(Z); investigating the relationship between concentration of elements in humans and the atomic number Z. Note H, Li, Be and B are significant outliers from a relation for which the slope of log(Z) is* 

It is of interest that the elements lithium, beryllium and boron are significant outliers from the relation, and this needs addressing from within the general concept. One reasonable explanation is that all three elements are associated with neutron conversion effects, either the absorption of a neutron in a reaction that produces

absorption of an alpha particle in a reaction which produces a neutron (e.g. beryl-

ionising and carry weightings of between 5 and 20 for radiobiological effectiveness in models which assess risk [41]. The thermal neutron cross sections of these three

Li = 9400 and 7

overall background dose [43]. Thus, the displacement of the "radiotoxicity relation" to the left by about one order of magnitude corresponds to the mean relative biological effectiveness of neutrons and alpha particles. It is therefore unsurprising that these elements are outliers in the general linear correlation of the log terms and this may be interpreted as a consequence of the existence of a natural background of

So, in general high-Z elements are not employed by life. Why then is there the utilisation by mammals of the element iodine (Z = 53)? The iodine-containing

h<sup>−</sup><sup>1</sup>

higher than other higher Z elements (238U = 2.7). The neutron cross section of hydrogen is modest (0.2), but the atomic concentration of the element in water ensures significant neutron absorption and the production of energetic protons by recoil. The natural background neutron fluence at ground level, produced by cosmic rays,

Li + α; lithium, 6

equivalent to a dose of 10 nSv/h about 10% of the

Be = 39,000) are significantly

Be = 12C + n). Both alpha particles and neutrons are densely

Li(n, α)) or the

*DOI: http://dx.doi.org/10.5772/intechopen.86779*

$$\mathbf{S} = \mathbf{C} \text{ (cZ4 + dZ8)}\tag{5}$$

Thus,

$$\mathbf{C} = \mathbf{C} \mathbf{n} \mathbf{s} \mathbf{t} \text{ant} \mathbf{t} \left( \mathbf{c} \mathbf{Z}^4 \mathbf{+} \mathbf{d} \mathbf{Z}^8 \right) \tag{6}$$

If the log of the concentration of all elements found in living systems is plotted against the log of the atomic number Z, the theory predicts an approximately linear relation with slope of between −4 and −8 depending on the contributions of singleand double-strand breaks in DNA to the overall photoelectron and recoil genotoxicity. Of course, the proposed relation is for non-radioactive or weakly radioactive elements and assumes that only photoelectron and Auger effects contribute.

**Figure 12** shows a log-log plot of concentration of elements vs. atomic number Z for standard man. Data were from the International Commission on Radiological Protection [42].

Results (**Figure 12**) for elements of Z > 5 seem to support the idea that the photoelectric conversion of natural background radiation has been a significant effect in evolution. The slope of the log correlation is −5.6, between −4 and −8 as predicted, suggesting that a significant component of the effect involved double-strand breaks of DNA and thus ionisation which is very local to the elements. Indeed, it is curious how very few of the elements available to life have been employed by

*The Secondary Photoelectron Effect: Gamma Ray Ionisation Enhancement in Tissues from High… DOI: http://dx.doi.org/10.5772/intechopen.86779*

#### **Figure 12.**

*Use of Gamma Radiation Techniques in Peaceful Applications*

critical damage.

and thus

Thus,

Protection [42].

the DNA from the element:

by the same tissue in the absence of the contaminant. Thus, high-Z elements, inside the body, act as devices for focusing and enhancing the doses from natural back-

If the phenomenon is significant, then it would seem reasonable that the contemporary spectrum of chemical elements employed by living systems will have been produced by evolutionary selection forces responding to such potentially

It is a well-known fact that the effects of ionising radiation on living systems are mediated by genotoxicity. The damage can be seen as a consequence of both singleand double-strand breaks in DNA; the dose (D) response (E) can be written as [41]

E = aD + bD2 (1)

But for the photoelectron effect being considered, dose (i.e. local dose at the

D = αZ4 (2)

E = cZ4 + dZ8 (3)

(a, b, c, α and d being arbitrary constants). For evolution it can be assumed that any stress S which prevents an individual from reproducing will represent an inhibitory effect of the survival probability of the species. S can be written in terms of the concentration C of the element in the individual and the radiation effect on

S = CE (4)

S = C (cZ4 + dZ8) (5)

C = Constant/(cZ4 + dZ8) (6)

If the log of the concentration of all elements found in living systems is plotted against the log of the atomic number Z, the theory predicts an approximately linear relation with slope of between −4 and −8 depending on the contributions of singleand double-strand breaks in DNA to the overall photoelectron and recoil genotoxicity. Of course, the proposed relation is for non-radioactive or weakly radioactive elements and assumes that only photoelectron and Auger effects contribute.

**Figure 12** shows a log-log plot of concentration of elements vs. atomic number Z for standard man. Data were from the International Commission on Radiological

Results (**Figure 12**) for elements of Z > 5 seem to support the idea that the photoelectric conversion of natural background radiation has been a significant effect in evolution. The slope of the log correlation is −5.6, between −4 and −8 as predicted, suggesting that a significant component of the effect involved double-strand breaks of DNA and thus ionisation which is very local to the elements. Indeed, it is curious how very few of the elements available to life have been employed by

ground radiation and should be seen as phantom radioactivity sources.

DNA) can be written in terms of the atomic number Z or the elements:

**190**

*Plot of log(C) vs. log(Z); investigating the relationship between concentration of elements in humans and the atomic number Z. Note H, Li, Be and B are significant outliers from a relation for which the slope of log(Z) is −5.6 (R2 = 0.514, F-statistic = 65.23 on 1 and 41 degrees of freedom; p < 10<sup>−</sup>10).*

biological processes: evolutionary niches are generally found to be occupied but clearly not ones that involve utilising elements of high atomic number. This is not because these elements are scarce. The crustal concentrations of uranium are quite high; there is a significant quantity of uranium in seawater, yet the transfer coefficient for the gut (in mammals) ensures that the element is excluded quite efficiently. The same is true for many other high-Z elements that have been excluded from biological systems.

It is of interest that the elements lithium, beryllium and boron are significant outliers from the relation, and this needs addressing from within the general concept. One reasonable explanation is that all three elements are associated with neutron conversion effects, either the absorption of a neutron in a reaction that produces an alpha particle (boron, 10B(n, α); i.e. 10B + n = 7 Li + α; lithium, 6 Li(n, α)) or the absorption of an alpha particle in a reaction which produces a neutron (e.g. beryllium, Be(α, n); 4 He + 9 Be = 12C + n). Both alpha particles and neutrons are densely ionising and carry weightings of between 5 and 20 for radiobiological effectiveness in models which assess risk [41]. The thermal neutron cross sections of these three elements (in Barns, 10Be = 3840, 6 Li = 9400 and 7 Be = 39,000) are significantly higher than other higher Z elements (238U = 2.7). The neutron cross section of hydrogen is modest (0.2), but the atomic concentration of the element in water ensures significant neutron absorption and the production of energetic protons by recoil. The natural background neutron fluence at ground level, produced by cosmic rays, has been measured at 46 cm<sup>−</sup><sup>2</sup> h<sup>−</sup><sup>1</sup> equivalent to a dose of 10 nSv/h about 10% of the overall background dose [43]. Thus, the displacement of the "radiotoxicity relation" to the left by about one order of magnitude corresponds to the mean relative biological effectiveness of neutrons and alpha particles. It is therefore unsurprising that these elements are outliers in the general linear correlation of the log terms and this may be interpreted as a consequence of the existence of a natural background of these neutron radiations.

So, in general high-Z elements are not employed by life. Why then is there the utilisation by mammals of the element iodine (Z = 53)? The iodine-containing

**Figure 13.**

*Minimum concentrations of mineral elements essential for plants required for optimum growth as a function of the fourth power of the atomic number Z. The uranium data point is based upon detection of uranium in a wide range of plants [9].*

systems (blood, thyroid) are those which are clinically most sensitive to radiation exposure (for reasons which are clear from the discussions above). It was suggested that the reason why iodine was employed is that the element is being exploited for its radiation detection quality and that the thyroid mediates an induced radiation damage address system through upregulation of genes associated with cellular surveillance and repair [9].

Finally, the relationships discussed here also obtain for plants. Plants are unable to move to avoid radiation exposure and might be expected to reflect responses to evolutionary stresses. The relationship between atomic number and the optimum concentration of elements for plants to thrive has been shown to conform to the same relationship [9]. The correlation is given in **Figure 13**.
