Damage Propagation in Complex Biological Systems Following Exposure to Low Doses of Ionizing...

7/29/2019 Damage Propagation in Complex Biological Systems Following Exposure to Low Doses of Ionizing Radiation

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Damage Propagation in Complex Biological Systems FollowingExposure to Low Doses of Ionizing Radiation

Ludwig E. Feinendegen1, Herwig Paretzke2 and Ronald D. Neumann3

1. Department of Nuclear Medicine, Heinrich-Heine University, Dsseldorf,Germany; and Medical Department, Brookhaven National Laboratory, Upton, NY,USA

2. Institute of Radioprotection, Research Center for Health and EnvironmentalSciences (GSF), Neuherberg, Munich, Germany

3. Department of Nuclear Medicine, Clinical Center, The National Institutes ofHealth, Bethesda, MD, USA.

Abstract : Biological organisms contain hierarchical organization, from atoms to molecules, cells,tissues, organs, and the whole organism. Complex signaling by molecules within and betweencells controls homeostasis and adaptation of the whole organism against perturbations. Energydepositions from ionizing radiation in tissue micro-masses trigger stochastically local molecularevents that may result in structural damage with consequent short or long term changes infunction. Damage to DNA in a tissue element increases over a certain dose range linearly withthe energy deposited. This is a defined risk of DNA damage production by the energy

deposition events. A second risk describes the probability of damage propagation from theprimary site at the basic level of molecular organization to higher levels of the organism. Thissecond risk depends on both quality and quantity of perturbations received at the basic level,and on the resistance by homeostatic controls against transfer of such damage. The homeostaticsignaling that controls the second risk at different levels does not respond to small perturbationsin a linear fashion. Moreover, protective responses under homeostatic control at the variouslevels of biological organization may become up-regulated temporarily and specifically by lowlevel perturbations. These adaptive responses reflect the tolerance of homeostatic control, and,thus, also depend on "dose". The low-dose induced temporary up-regulations of protectionmay operate also against non-radiogenic perturbations; for instance against those from metabolicproducts, such as reactive oxygen species (ROS). At single cell exposures below 0.1 Gy,adaptive protections against propagation of non-radiogenic damage often tend to outweighpermanent manifestations of radiogenic damage. The quality and extent of homeostatic responsesare under genetic control. Thus, complex systems responses encompass both damage and

prevention of further damage and its propagation to higher levels; they are expected to varyamong individuals. The balance between health risk and benefit of low-level radiation exposureof any given individual may become predictable by gene-expression profiles in un-irradiatedand irradiated tissue cells of this individual at some future time.

Key word : Damage Propagation, Biological Systems, Low Doses, Ionizing Radiation

Asian J. Exp. Sci., Vol. 22, No. 2, 2008, 7-24

Introduction

Assessment of biological effects, be theyexpressing risk or benefit, in radiologicalexposures at low level exposure is currentlyfaced with great uncertainties that derivefrom the basic sciences in radiation biology

and molecular biology, as well as fromepidemiology. A major uncertainty lies in thehigh prevalence of malignant diseases

especially in older populations whereasionizing radiation is a comparatively veryweak carcinogen even at higher doses, theeffect of which is most difficult toquantify in necessarily limited numbers ofexposed people (Mosmann, 2007).

Epidemiology will hardly ever contributeto solve this uncertainty for statisticalreasons. On the other hand, research in cells,


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tissues, and animals over the past fewdecades increasingly provide evidence thatlow doses of ionizing radiation initiatebiological responses that were unexpected

and often different from previously knownresponses at higher exposure and exposurerate levels. In fact, entirely new phenomenahave been uncovered such as low-doseinduced delayed appearing, and temporarilylasting cellular signaling changes affectingintracellular enzymes activities, reactions toreactive oxygen species, DNA synthesis andrepair, apoptosis, cell differentiation, andimmune responses (Feinendegen et al.,2007). These responses occur in conjunctionwith altered gene expression patterns andalso express the capacity of the biologicalsystem to adaptively protect itself againstrenewed potentially damaging toxins. Theselow-dose specific cell responses aredescribed in the context of other newlyrecognized phenomena which may also ariseafter high dose irradiation. These secondcategory responses predominantlyencompass both the so-called bystandereffects (Mothersill and Seymour, 2006), aswell as genomic instability that may befall

cellular progeny over many cell generations(Kadhim et al., 2006).

All these relatively new experimentalfindings appear to embrace a commonpattern, despite the broad variation of theirnature and of the biological systems in whichthey were observed. The plethora of data onlow-dose effects clearly challenges the claimthat the dose-risk function most likelyadheres to the linear-no-thresholdhypothesis. This hypothesis has its origin inthe seminal discoveries by Mller beginningin 1927 (Mller, 1927), with the subsequentobservation that radiation may cause gene

mutations proportionally to the absorbeddose over the full dose range studied.

The present contribution continues theefforts published previously (Feinendegen et

al ., 1995; Feinendegen et al., 1999;Feinendegen et al., 2000; Feinendegen etal., 2004; Feinendegen et al., 2005) topresent a conceptual frame that allows toaccommodate coherently the various data inthe light of system radiation biology.

Principal components of radiation-response systems and their interactionsin homeostasis

Low level exposure of biologicalsystems to ionizing radiation nearly always

affects multiple sites at the molecular levelrandomly in the irradiated cells and tissues.In order to understand responses to lowdoses the principle structure and function ofthe exposed system needs consideration.

The evolution of biological organismsbrings increasing complexity towardsstructurally defined levels of organization ina hierarchical manner, as schematically seenin Figure 1: At the basic level are the atoms(99 % of them are C, H, O, N, S, and P).

These constitute also metabolically relevantmolecules that consist of 2 to some ~ 104

atoms. The molecules are structurally highlydefined to serve both as architectural buildingblocks as well as metabolic functional units,and ca. 80 % of them by weight constitutewater. There are about 1011 such moleculesper individual cell each complete with a fullset of genes. With their particular functionscells operate as a whole and are fundamentalunits of life. About 109 cells are on averagein 1 gram of tissue and organ, each oneserving in specific ways to guarantee theproper structural and functional integrity of

Feinendegen L. E. et al. (2008) Asian J. Exp. Sci., 22(2), 7-24


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the tissue and organs and, thus, the entireorganism. The organism operates as a wholeusing multiple intricate nets of signaling thatprovide for homeostasis at all levels of

organization even in a potentially lifethreatening environment (Feinendegen et al.,2005).

The predominant signaling tools areelectrons as well as molecules that canrecognize each other because of theirchemical and physical properties. One may,in principle, discern three types of signalingloops within a whole body. There is thesignaling between molecules within cells,between cells of a given tissue or organ, and

between different tissues and/or organs. Allsignaling, wherever it occurs, involves cellsthat have receptors, usually highly specializedfor uniquely interacting with, and to produce,molecular ligands as signals.

Figure 1 schematically conveys the factthat signaling between and at eachhierarchical level of organization tends tokeep the whole organism in a state ofadaptive homeostasis, i.e., at steady state ofall metabolic reactions and operations in theface of unavoidable perturbations thatchallenge all levels of organization from bothexternal and internal sources. If a perturbationat a given level of organization is relativelysmall, the system mostly returns to steadystate in nearly an immediate response byintertwined feed-back controls to protectsystem integrity. With increasing gravity of aperturbation at a given level the organismsuffers stress, often with the consequentgeneration of delayed secondary reactionsgenerally referred to as adaptive responses.

These equip the organism - usuallytemporarily - with an improved capacity fordefending against, and reconstituting itself inthe face of, a renewed attack of a similar

quality, and for even more efficiently returningto its steady state operation. In case ofseverely disruptive perturbations at a lowhierarchical level of organization, the local

damage produces challenges for the higherlevels of organism responses designed torestore an organisms homeostasis bydamage removal, architectural remodelingand functional reconstruction. An example isthe common experience of wound healingafter a macroscopic tissue injury. Diseaseevolves when the protective barriers againstdamage propagation through ascendinghierarchical levels are overwhelmed bydamage and, thus, loose their capability toregain homeostasis.

Homeostatic perturbations byionizing radiation

Ionizing radiation primarily interacts withatoms at the initiation of, and along, chargedparticle tracks, caused by deposition ofenergy along the track passage in cell-tissuemicroscopic regions, thus creating eventpackages, according to the radiation quality(ICRU, 1983; Paretzke, 1987). Such eventsencompass molecular modifications on site bydirect action and secondarily mainly byreactive oxygen species (ROS) fromradiogenic hydrolysis (Hall, 2000). A specialcase worth mentioning here is that of the so-called Auger effect. This effect elicits grosslymixed types of radiation quality that arise onthe one hand from multiple electron tracksand also from a charged atom. For instance,each decay of 125-iodine within the confinesof the DNA molecule causes at least onesevere double strand break at the molecularsite of the decay from charge transfer

processes and, thus, acts as a tool ofmolecular surgery; in addition, numerousother DNA damages occur aweay from thedecay site in the affected cell from the

Damage Propagation Biological Systems Following Low Doses of Ionizing Radiation


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multitude of electron tracks associated withAuger effects.(Feinendegen and Neumann,2004).

Any of these stochastically distributed

events triggers biological responses byaffected cells, be they hit directly, or activatedindirectly by signaling through the tissuematrix from hit cells, i.e. through bystandereffects (Mothersill and Seymour, 2006). Withincreasing total energy deposited by a givenradiation quality, and, thus, with increasingnumbers of initial triggering particle tracksbiological responses eventually may affect awhole organ or even the whole organism atevery level of its biological organization.

Nevertheless, the generation of responseswherever they occur appears to alwaysoriginate in cells. In other words, homeostaticperturbations may be triggered by energydeposition events anywhere in the system andwith their numbers increasing may becomeobservable to engulf successive higherorganizational levels such as tissues, organsand even the whole body (Fliedner et al.,2005). The probability of such anobservation, obviously, largely depends onthe type, quality, and extent of initial

homeostatic perturbations at the molecularlevel, and on the tolerance of homeostaticcontrols operating at subsequent higher levelsvia signaling within and between cells, andbetween cells of different tissues and/ororgans, all under homeostatic control (Arthuret al., 2000).

Principal physiological barriersagainst radiation-induced diseases

Normal organisms command an array ofimmediately operative physiological barriers

that protect against immediate and lateconsequences of potentially life-threateningimpacts. Such impacts may occur at any level

of biological organization. An example ofbarrier at the tissue level is the skin thatprotects against manifold mechanical stressesand if injured, will initiate protective

responses leading, for instance, to woundhealing through signal-induced cellproliferation and differentiation. Operating atvarious ascending levels of the organism, thebarriers actually form a sequence of defensesagainst the propagation of any exo- orendogenous damage sufficient to evolve intoclinical disease, as shown schematically inFigure 2. Otherwise, a human organismmade up by more than 1013 complicatedcellular entities would never have a chanceof living up to 100 years. Thus, with aholistic view of systemic function one maydiscern (Feinendegen et al., 2007;Feinendegen et al., 1995; Feinendegen etal., 1999; Feinendegen et al., 2000;Feinendegen et al., 2004; Feinendegen etal., 2005) :

a) defenses via scavenging mechanisms atthe atomic-molecular level;

b) molecular repair especially of DNA, withreconstitution of essential cellconstituents and functions;

c) removal of damaged cells from tissueeither by induced cell death, i.e.,apoptosis, or by stem cell differentiation,or by a stimulated immune response.Depending on the degree of disturbancerepair often is associated by replacementof damaged and/or lost cells formaintenance of tissue function.

These immediate responses againstpotentially damaging events are quite wellunderstood especially regarding DNAdamage from exposure to ionizing radiation(Hall, 2000). Within minutes after irradiation


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Biological Systems are Complex and Adapting

Cellular Molecules

Respond

Organism

Tissues

CellsIntercellular

+ Matrix Signaling

Intracellular

Signal ing

Neuro-Hormonal

Signal ing

Degree of PerturbationStress

of Homeostasisof homeostasis

they respond to perturbations

Ad ap t ive Pro tec t ion Damag e

Fig. 2

Atoms

Death

Cancer

Pathology

Molecules

Cells

Tissues

Organism

Complex Adaptive Systems,

Protec t at Var ious Levels

Immune Response

Cell Differentiation

Apoptosis

DNA Repair

Defense, Scavenging

Ioniz ing

Radiat ion

Physiological

Bar r ierrs agains t Disease

Disease

Fig. 1


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there is a plethora of DNA modificationsincluding a broad distribution of number andquality of DNA double strand breaks percell, which can be visualized and counted per

individual cell by immuno-histochemicalmethods. (Rothkamm and Lbrich,. 2003).Usually well within 24 hours, the fluorescentfoci, supposedly indicative of double strandbreaks, decrease to a lower number, closerto that of the background spontaneous, i.e.pre-irradiation, number. The capacity ofnormal cells to repair DNA and other cellulardamage is genetically determined inaccordance with the individuals genome.Today, more than 150 genes have beendescribed to be involved in DNA repair athigh doses; other genes in a similar numberare active in low-dose stress response. Eachgene has the potential to vary amongindividuals through polymorphisms,mutations, and even deletions from theindividuals genome. In general, then, initialnon-lethal radiation damage is answeredreadily by immediate attempts at structuralreconstitution with regained functionalhomeostasis.

One should note that the various

barriers are, in a way, twofold. On the onehand, there is a preexisting physical orchemical protection preventing an impactfrom disrupting a biological structure with theconcomitant disturbance of homeostasis. Onthe other hand, there is also an immediatebiochemical-cellular response with rapidsignaling for gene activation required forreconstitution of structure and function. Bothof these types of immediate protections areknown to operate not linearly with the degreeof energy impact and its ensuing primarydamage. In fact, immediate protectiveresponses appear as deterministic types ofresponses. This means, an energy impact of

a given level must be large enough toovercome a threshold of neutralization beforestructure and/or function are perturbedsufficiently to elicit the organisms response

to restore homeostasis. Such principaldeterministic response patterns areobservable at any level of biologicalorganization, even at the basic molecular levelsuch as DNA (Bond and Varma, 1995).

There are many common dailyexperiences with this principle responsepattern. Thus, for tissue damage to occur andtrigger a biological response, an objectcausing a contusion, for instance, must havea certain force before cells are disrupted to

cause local bleeding or an open wound whichthen generates local healing. Below this levelof force there will be no harm from aninteraction of a blunt object with tissue suchas skin. Another common example relates toinfectious disease. In the presence ofantibodies, infectious disease develops onlyabove a given minimal inoculation of micro-organisms that depends on the degree oftoxicity of the microorganism and on thestatus of the bodys immune system. Belowthis level, local cellular reactions and

protective antibodies, if present, operateimmediately and effectively. A third exampleis the extent and duration of sun-bathing thatmay damage DNA and cells. A certainintensity and duration of exposure is neededbefore the skin reacts and turns red or eveninto a sun burn.

In general then, only when damagecausing homeostatic perturbationsoverwhelms structural and functional barriersat successive levels, from the molecular tocellular to tissue level, disease can developsometimes with a potentially severe or evenlethal outcome. Since increasing doses ofionizing radiation eventually paralyze barriers



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at all hierarchical levels, higher radiationdoses in large target volumes may allowdamage at basic levels of organization topropagate with minimal or no inhibition and

thus to evolve into clinically evident disease.As a consequence, many, but definitely notall, dose-response functions expectedly tendto be linear at higher doses, but not so at lowdoses. Because the above-mentionedphysiological barriers at all levels are undergenetic control, certain defects in theinvolved genes, which control thesephysiological protections, may changeindividual radiation sensitivity drastically(Cleaver, 1968).However, one should keepin mind that in most cases diseases arecontrolled by a set of at least several genes.

The physiological barriers sketched outabove may also operate against thedevelopment of some types of clinical cancer.Even if the protective mechanisms againstcancer are still not fully understood, theireffects are obvious. An illustrative exampleis the relationship between the extent ofDNA damage caused by radiation and theprobability of cancer induction in the exposedindividual. Thus, the ratio of radiation

induced DNA double strand breaks includingthose of the multi-damage site-type in apotentially oncogenic blood-forming stem celland of lethal leukemia has been estimated tobe close to 1012 (Feinendegen et al., 1995),or even higher;this datahas its source inexperimental and epidemiologicalobservations. The claim that even a singleDNA double strand break, however grave,in a stem cell may cause cancer isscientifically unjustified. Low-dose inducedcancer is, nevertheless, believed by many forpractical and applicable reasons to increaseproportionally with dose under theassumption that a certain, however small,

fraction of radiogenically transformed cellscould escape barriers and expands intoclinical cancer:

Adaptive protection at ascending

levels of biological organization

Adaptive protections need considerationespecially in those instances whenhomeostatic perturbation at a given level isrelatively large but below the level of barrierbreak-through, i.e. in stress situations.Adaptive responses are well known, forinstance, following so-called oxygen stress(Finkel and Holbrook 2000; Chandra et al.,2000). Also, low level exposure to ionizingradiation can change cellular signaling with

temporary changes in enzyme activities thatare involved in protecting against reactiveoxygen species (ROS) and in DNA synthesis(Zamboglou et al., 1981; Feinendegen etal., 1984), DNA repair (Olivieri et al.,1984; Wolff et al., 1988), and DNAdamage removal by various routes(Feinendegen et al., 2007; Feinendegen etal ., 1995; Feinendegen et al., 1999;Feinendegen et al., 2000;Feinendegen etal., 2004; Feinendegen et al., 2005; Kondo1988; James and Makinodan 1990; Tubianaet al., 2006). These and other well-documented cell and tissue responses to lowlevel radiation exposure are currentlyunderstood to be the consequences ofdelayed and mostly temporary up-regulationof physiological barriers against thepropagation of damage from the lower to thehigher levels of biological organization. Theseresponses summarily here referred to asadaptive protections generally begin tooperate within a few hours after toxic

exposure, and may last from hours to monthsdepending on the type of protection. Itappears that adaptive protection againstROS lasts a shorter period of time than the



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protective up-regulation of DNA repair,which in turn seems to last shorter than thelow-dose induced stimulation of the immunesystem lasting at least for several months or

longer, as schematically illustrated in Figure3 (Feinendegen et al., 2007; Feinendegen etal ., 1995; Feinendegen et al., 1999;Feinendegen et al., 2000;Feinendegen etal ., 2004; Feinendegen et al., 2005;Feinendegen, 2005).

These delayed appearing and mostlytemporary up-regulations of existingbarriers can be observed at very low dosesin the range of mGy and show on averagea maximum effectiveness at an acute dose

of about 0.1 Gy. They disappear as dosesincrease beyond 0.2 Gy of low-LETradiation and are hardly, or not at all, seenanymore beyond about 0.5 Gy(Feinendegen et al., 2007; Feinendegen,2005; Feinendegen et al., 1996). However,the probability of apoptosis, if one classifiesit as an expression of adaptive protection,apparently increases linearly beyond 0.5 Gyover a certain dose region. Figure 4 is, likeFigure 3, a schematic presentation ofaverage values from many available

observations (for review Feinendegen et al.,2007; Feinendegen et al., 1995;Feinendegen et al., 1999; Feinendegen etal ., 2000; Feinendegen et al., 2004;Feinendegen et al., 2005; Tubiana et al.,2006).

The low-dose specific responsepattern in terms of adaptive protection isin agreement with data on gene activitymodulation after low- and high-doseirradiation (Tubiana et al., 2006;Franco et

al., 2005). Low-level radiation exposuremodulates the activities of a set of genes,mostly involved in stress responses. These

genes do not respond to high-level exposure,and vice versa. But a large number of genesrespond to both low- and high-levelirradiation. Thus, in one recent study, out of

10500 genes in human keratinocytes a totalof 853 genes were modulated between 3 to74 hours after irradiation, and of these 214only appeared changed with an irradiation by1 cGy, mainly stress response genes. Thehigh dose of 2 Gy modulated the activitiesof 639 genes. Both doses changed theexpression in 269 genes. This set of datashows statistically a highly significantdifference between gene activityresponses at low and high doses (Francoet al., 2005).

Adaptive protection, again, is acommon physiological phenomenon,understood in every days life. Bodybuilding through properly dosed trainingstress is a well known experience.Immunization by small amounts ofmicroorganisms against outbreak ofdisease caused by larger amounts of thismicroorganism is again commonknowledge and basis of vaccination.Examples at the cellular level are

responses to increasing concentrations ofROS (Sen et al., 2000).

In a normal cell about 109 ROSmolecules arise in the cytoplasm outsidemitochondria on average per day, mainlyfrom metabolic reactions; and additionalsmall ROS bursts come from variousresponses to external cell signaling (Sen etal., 2000; Pollycove and Feinendegen,2003). When an average electron, forinstance produced by 100 kV x-rays, hits a

cell, about 150 ROS occur in that cell withina fraction of a millisecond. Supra-basalbursts of ROS either from metabolic



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Fig. 4

Detoxification (ROS Scavenging); Apoptosis

DNA R epair; Cell Proliferation

Immune Response

Norm

alized

DegreeofResponse

Log Time after Single Irradiation

H o ur s Days W eeks Mo n th s 00

Acu te R epa ir

Low-Dose (Low-LET) Induced Adaptive ProtectionSimple scheme of durations of protection (tp)

ProtectionagainstDamage

Single Dos e (Gy)

Ad apt ive p ro tectio n in vo lves

gene expression and boosts:

DNA Dam age Prevention

D NA D a mage R ep air Immune Response

max. S protect.

? 0.6 - 1

Damage Removal (Apoptosis)

Low-Dose (Low-LET) Induced Adaptive ProtectionSimple scheme of dose-response functions

Dose-response funct ions are mostly not linear

Fig. 3


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reactions or from normal backgroundradiation can trigger reactions commonlyaddressed as cellular oxidative stressresponses. These involve cell signaling of

many kinds some with consequences ofcellular damage or benefit. They includedefense mechanisms, repair of DNA and cellstructures, changes of cell cycle times,induction of apoptosis and immunogenicalterations leading, for instance, to immunestimulation (Finkel and Holbrook, 2000;Feinendegen and Neumann, 2000). To whatdegree low-dose initiated damage or benefitfrom non-destructive homeostaticperturbations with subsequent adaptiveprotection prevails depends on species,tissues and cells (Finkel and Holbrook,2000;Feinendegen and Neumann, 2000;Feinendegen, 2002), determined by theunique genetic make-up of the individual. Inthis context, normal background irradiationshould be seen also participating in keepingtissue homeostasis (Feinendegen, 2002).

Adaptive protection at low-levelradiation exposure in risk assessment

The various mechanisms of adaptiveprotection need to be considered when itcomes to assessing risk especially of cancerinduction from low-level exposure. To do thiscoherently and effectively, one should try toadopt a model into which all the phenomenathat modulate low-dose responses can beaccommodated. Various types of modelsoffer inputs regarding probabilities of celltransformation, clonal expansion, cell removalby different routes; and, thus, serve asinsights into mechanisms of radiation inducedoncogenesis. Such models are the two-stage

clonal expansion model and its modifications(Moolgavkar and Knudson 1981;Schllnberger et al., 2005). However, most

health-physics models pay insufficientattention to the broad range of biologicalresponse phenomena predominant in theprocess of damage propagation from the

basic molecular level to increasingly complexand hierarchical levels of biologicalorganization. Other types of modelapproaches embrace a broader range ofbiological protection by low doses andappear to come closer to this aspect ofbiological reality (Feinendegen et al.,1995; Feinendegen et al. , 1999;Feinendegen et al., 2000;Feinendegen etal., 2004; Heidenreich and Hoogenweem,2001; Scott 2004; Leonard 2007).

One current model presentation adheresto an approach that was initially introducedby the first author and his collaboratorsbriefly and schematically in 1995(Feinendegen et al., 1995) It has becomemore sophisticated over the years but retainsits broad appeal to include all aspects andnewer findings by fully incorporating the dualeffect of low doses and dose rates in bothcausing damage and in providing for and up-regulating damage prevention by way ofadaptive protection against damage

propagation to higher levels of biologicalorganization towards clinical disease(Feinendegen et al., 2007; Feinendegen etal ., 1995; Feinendegen et al., 1999;Feinendegen et al., 2000;Feinendegen etal., 2004).

The basis of this more recent approachis schematically illustrated in Figure. 5.There appear to be two types of risks thatare essential in the assessment of a lethaloutcome of radiation- induced cancer, or any

other late radiogenic disease. First, there isthe risk of introducing dangerous damage atthe DNA level. This first step largely depends



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Fig. 5

Damage Propagation and Homeostasis

Damage propagation Pprop f (dam age severity;homeo. response)

Damage induction P ind per unit D (?z1? N H)

There are two risks:

? R1

= Risk of defined initial dam age per unit D (Pind

)

? R 2 = Risk of damage propagation (Pprop)

Risk of disease to arise from a given damage, R1,

equa ls the probability, Pprop, that this damage porpagates

through successive highe r levels of biological organization.

System

DN A

Fig. 6

Induction

ofProtection In

duction

ofDam

age

Single Dose (Gy)

Induction of protection . Induction of damage

Dual Effect of Low-Dose (Low-LET) Radiation

Apop tos is

Pprot f (D; tp) Pi nd


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on stochastic generation, and primary andsecondary interactions of energy depositionsat sensitive cell sites, such as the DNA-histone complex. The probability of

incidence of a radiogenic damage in theDNA of a given cell rises proportionally todose over a certain dose range. If one ormore of particular types of DNA damageswould lead one or more cells to acquiring thepotential of causing severe consequences fortheir host organ/tissue and whole organism,then the question of protective reactionseventually at any organizational level arises.If no protective mechanisms existed or ifsuch mechanisms would operate at aconstant rate in the organism, the degree orextent of the initial damage could by simpleprobabilities of damage incidences linearlydetermine the degree or extent of resultantdisease. This is, as stated above, indeed theinherent, but unproven, assumption usedcurrently by radiation epidemiologists inderiving cancer risk from data as a functionof absorbed dose.

However, the second risk is that theprimary damage will propagate to higherlevels of biological organization. Both the

immediate barriers and their adaptive up-regulations at the various organizational levelsin response to non-disruptive homeostaticperturbations often operate in a non-linearmanner. They involve defined mechanismsthroughout their effective responses. Thissecond risk depends, thus, on complexcellular responses at the various levels of theorganism and is largely controlled byresponding gene expression and many otherparameters such as the immune status.

In this context, it is crucial to note thatonce adaptive protection reactions havebegun to function at and between the various

levels of biological organization, they mayoperate also against damages of similar typesbut of different origins, be they radiogenic ornon-radiogenic (Feinendegen et al., 1995;

Wolffet al., 1988). Therefore, quantities andqualities of various types of DNA and otherdamage from radiation exposure and of non-radiogenic origin need to be compared andbe related to the corresponding incidence ofcancer induction (Pollycove, andFeinendegen, 2003). If one considers theinduction of DNA double-strand-breaks asa relevant initial step towards carcinogenesis,which is not proven yet, it is worth tocompare the different sources of suchdouble-strand-breaks in human cells. Anattempt to quantify DNA damage fromnormal background radiation and of non-radiogenic, mainly metabolic origin has cometo predict that at the level of single cells thereare per day on average about a thousandtimes more metabolically caused DNAdouble-strand-breaks than double-strand-breaks caused by background radiation(Pollycove, and Feinendegen, 2003). Asimilar relatively high ratio of double-strand-breaks from the two sources was confirmed

subsequently by experimental observationsfrom various laboratories (Rothkamm andLbrich, 2003;Sedelnikova et al., 2004).Considering the relatively large number ofmore severe types of radiogenic DNAdouble-strand-breaks compared to thatcaused by normal metabolism (Ward, 1988;Hada and Sutherland, 2006), it is notsurprising in this working hypothesis andirrespective of defined oncogenic mechanismsthat human cancer induction from metabolicsources is not about a thousand times but

only about 30 to 50 times more frequent thanthe calculated radiogenic cancer at normalradiation background levels, provided the



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assumed linear dose-risk relationship appliesto the calculation of both incidences. Theundisputed relatively large incidence of non-radiogenic metabolic or spontaneous

cancer lets it appear justified to assume thatthe low-dose induced up-regulations ofprotection operate mainly against the earlysteps of spontaneous cancer risk(Feinendegen et al., 1995;Feinendegen etal., 2005; Pollycove, and Feinendegen,2003; Feinendegen, 2003). Here again,experimental evidence agrees with thisassumption (Tubiana et al., 2006;Azzamet al., 1996; Redpath and Antoniono,1998; Mitchel et al., 2003; Tapio andJacob 2007).

The simple model used in thispresentation to demonstrate the effect ofprotection induction includes the two risksmentioned above, that of R

1relating to

damage induction, with the riskcoefficient, P

ind, and that of R

2relating to

damage propagation ascending throughthe consecutive higher levels of biologicalorganization towards causing finallyclinical disease

Risk coefficient Pind

is taken to be theprobability of radiation induced seriousDNA damage per unit dose D ofradiation, which hypothetically wouldevolve to clinical cancer assuming no or someconstant rate of protection irrespective of thevalue of D. This probability is assumed to beconstant per unit D over a certain doserange. Coefficient P

indthus conforms in this

simple model to the conventionalproportionality constant in the wellknown expression of the linear dose-risk

function: R = D.The coefficient of the second risk R

2is

here expressed by the term Pprot

f

(D, tp). It gives the fractional cumulative

probability of the protection up-regulation perunit D inhibiting damage propagation, as afunction of D and of the duration of

protection effectiveness tp:as illustrated inFigures 3 and 4. An f (D, t

p) value here

of 0 means no adaptive protection, and avalue of 1 means full protection ofdamage propagation by adaptiveresponses in the system. Hence, R

2describes the diminution of damagepropagation.

As outlined above, the low-doseinduced protections at the various levels areseen to operate against propagation of

damager, especially that of DNA, of anyorigin, be it non-radiogenic or radiogenic, thatthreatens to develop into clinical cancer.Introducing the variable P

spoto describe the

prevalence of spontaneous, i.e., non-radiogenic, serious cell damage causingcancer per individual at the time ofobservation, and adding the term P

indD

to

indicate that Pprot

f (D, tp), of course, also

affects Pind

D, the value of Pprot

f (D, tp)

(Pspo

+ Pind

D) describes the total, beyondthe immediate protection remaining

probabilities of dose dependent inductions ofprotection against propagation of any cell andDNA damage to cause cancer. Thisemphasis on the dual effect of low-doseradiation is consistent with experimentalobservations on mechanisms leading to theindividual responses, see Figure 6.

The following mathematical expressionsimplifies the approach published elsewherein microdosimetry terms (Feinendegen et al.,1995; Feinendegen et al. , 2000;

Feinendegen et al., 2004; Feinendegen,2003). The net risk of cancer, R, at a givenlevel of D is then in this model the sum of



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the two separate risks R1and R

2, as defined

above:

R= P

indD - P

prot f (D, t

p) (P

spo+ P

indD)

Note that with increasing D, the termPprot

f (D, tp) (P

spo+ P

indD) tends

towards zero notwithstanding theprotective contribution by apoptosis (seeFigure 4). Moreover, the term alsoreaches zero with t

pbecoming too short

for Pprot

f (D, tp) to develop or operate

(see Figure 3). Thus, as discussed below,in case of protracted exposure at low doserates individual energy deposition eventsoccur at certain time intervals per exposedmicro-mass depending on dose rate per

radiation quality. In such situations, thetime t

pmay be too short not only for P

prot

f (D, tp) to develop and act, but also P

indD

may be augmented through interference withacute repair of the primary damage(Feinendegen and Graessle, 2002).

The graphic display of the model inFigure 7 in principlecombines data fromexperimental observations, referred toabove. The straight line expresses R

1and

shows the linear increase of radiation-

induced DNA damage causing clinical cancerassuming no or a constant rate of protectionirrespective of D. This display negates here,for ease of reading, the possibility ofcontributions of secondary DNA damage, beit from bystander effects or through genomicinstability. This plotting adheres to the linear-no threshold-hypothesis conventionallyexpressed as R = D. - The lower curvedline illustrates the inverse expression ofthe second dose-risk function R

2= P

prot

f (D, tp) (P

spo+ P

indD), showing damage

propagation being inhibited by the overalleffect of low-dose induced protection againstP

spoand P

indD, with P

spobeing here the

predominant term in normal individuals. Thedifference between these two dose-riskfunctions, R

1- R

2, yields the net dose-risk

function R which the solid middle line

illustrates. For individual application, thismodel needs amendment with individuallymeasured data, which are expected to varybetween species, individuals, and cell typesbecause of individual genetic control. Theresult of this model approach, nevertheless,conforms to a large set of experimental andepidemiological data, and is in line with theconcept of hormesis (Tubiana et al., 2006;Azzam et al., 1996; Redpath andAntoniono, 1998; Mitchel et al., 2003;Tapio and Jacob 2007; Pollycove andFeinendegen 2001).

Low dose rate exposure

The present short treatise on theconsequences of the dual effects of low-levelexposure to ionizing radiation at the basicmolecular level, and on damage propagationin complex biological organisms would beincomplete without reference to low dose rateexposure. As alluded to above, dose ratesmay be described in terms of mean timeintervals t

x

between consecutive energydeposition events per exposed micro-mass,i.e., between consecutive micro-dose events,for a given radiation quality (Feinendegen andGraessle, 2002;Feinendegen et al., 1985;Feinendegen et al., 1994).An example isgiven here from studies (Yamamoto et al.,1998) in which mice were chronicallyexposed to tritiated water throughout life. Asshown in Figure 8, thymic lymphomainduction and life shortening only appearedat dose rates above 1 mGy per day. This

dose rate at chronic tritium exposurecorresponds to about 1 micro-dose event of1mGy occurring per micro-mass within less



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Fig. 7

Fig. 8

Adapted from Yamamoto O. et al., 1998

Dose R ate Effectschronic e xposure to tritiated water in mice

Thymic Lymphoma Induct ion

and

Life Shor tening

only appeared when dose rate was above 1 mG y / day

( x 1 mGy-hits ; tx < 1 d ay )

z1 = 5.7 keV / ng ? 1 mGy

R=

RiskofCancer

Bkgd

Dual Effect of Low-Dose (Low-LET) Radiation

0 0.2 0.4 0.6

Cancer with constant

protection probability Net Risk

of CancerRn

Adaptive protection

against cancer

Metabol. Cancer Risk

Single Dose (Gy)

Rn = Pind D - Pprot f (D; tp) (Pspo + Pind D)

Simple scheme


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than 1 day, i.e., at a tx

shorter than 1 day(Feinendegen et al., 2007)There was nothymic lymphoma and no life shortening whentx

was longer than 1 day. Such assessment

complements other reports on the effects ofchronic low dose rate exposures to a givenradiation quality (Pollycove andFeinendegen, (2003; Scott, 2004;Feinendegen and Graessle, 2002).

Occupational exposures in humans, forinstance, usually deliver much lower doserates as discussed above, and thus providefor relatively long t

x. Other examples are in

many epidemiological data on accidental ormedically directed chronic irradiations of

humans. At an optimally long tx immediateand adaptive protections are expected tofully operate within the cells capacities(Feinendegen and Graessle, 2002). This islikely the reason for the repeatedepidemiology observation of a reducedcancer incidence below the backgroundincidence at chronic low dose rate exposures(Tubiana et al., 2006; Pollycove andFeinendegen, 2001;Luckey, 1980).Onerecent reference relates to the analysis of themortality of 45 468 Canadian nuclear power

industry workers after chronic low-doseexposure to ionizing radiation (Zablotska etal., 2004). This paper quotes: For all solidcancers combined, the categorial analysisshows a significant reduction in risk in the 1-49 mSv category compared to the lowestcategory (


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Note: Presented also at the 4. Biophysikalische Arbeitstagung in Bad Schlema, Germany, Sept. 26 29, 2006, andsimilarly at the International Workshop on System Radiation Biology GSF- Neuherberg, Munich, Germany,February 14 16, 2007 as published by Atoms for Peace, an International Journal 1: 336-354, 2007."

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