Radiation Chemistry

Ionizing ra diation produces abundant secondary electrons that rapidly sl ow down (thermali z e) to energ i es below 7.4 eV , the threshold to produce electronic transitions in liquid water.

For bot h t h e primary charged particle a nd the secondary electrons, this sl owing down proc ess is accom p lished by transfer of energy to the m e dium in a sequence of discrete ev ents .

Stopping power (-dE/dx) treats the slowing down process as a c ontinuous function, sometim e s referred to as the continuous slowing down approximation.

Depending on the am ount of energy transferre d to the electron, the m o lecule can undergo:

 Ionization (threshol d in water ~ 13 eV)

 excitation (threshol d in water ~ 7.4 eV)

 thermal transfer

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The example shown is for 20 keV electrons.

[Thermal transfers (vibration, rotation, tran slation) a r e largely inconsequential. A dose of 10 4 Gy would be necessary before the thermal effects (a few degrees centigrade) became large enough to affect cellular biochem i stry.]

Initial Physical Events

The initial event is the transfer of ~ 7 - 100 e V, an am ount of energy sufficient to cause (m ultiple) ioniz a tions or exc itations in water molecules.

Transfer of energy to the medium in biological syste m s usually involves i onization of a wa t e r molecule, but can al so involve th e cellular macro m olecules (e.g., DNA) directly.

Through i onizations and excitations the passage of a charged particle through biological mediu m creat es three speci es i n the local vicinity of the particle track :

Direct ionization of water produces a rad i cal ion and a free subexcitation electron (E < 7.4 eV).

H 2 O

 r  ad 

H 2 O· + + e¯

Energy transfer can produce a water molecule in an excited st ate.

H 2 O

 r  ad 

H 2 O*

The ti me s cal e for the cr eation of these speci es is on the order of 10 -16 seconds .

Prechemical Reactions

The three initial species begin to diffuse and react with each other or ot her m o lecules in the m e d i um .

Som e of these reactions produce radicals.

 Radical refers to an atom or molecule that contains an unpaired electron.

 Radicals are highly reactive.

 Radicals can be neutral or charged.

The electron is captured by water through dipolar interactions, becom i ng solvated, and referred to as an aqueous electron or a solvated electron:

e¯ + H 2 O 

 surrounde d by a “cage” of water;

e¯ + H +  H· or it can react with H + to form a radical.

 The radical ion of water can dissociat e to produce a hydroxyl radical and a hydrogen i on.

H 2 O· +  H + + HO·

 The exci ted wat e r mol ecule can dissipate excess energy by bond breakage to produce hydroxyl and hydrogen radicals.

H 2 O*  HO· + H·

It takes ~ 5 eV to break the O-H bond.

Exam ple of the dissociation of excited water to form hydroxyl and hydrogen radicals (from Tubiana, 1990).

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The actual concentrations of the radicals are very s m all, especially when co mpared to the concentrations of ions pres ent from the dissociation of wat e r.

Thus, the three initial species :

H 2 O * , H 2 O· + and e¯,

react further to produce chemi c ally reactive species :

HO·, H · , and 

Water radiolysis produces highly reactive HO· and H· radicals.

These r a dicals are m u ch m o re reactive than HO¯ or H + from ionic dissociation. HO· is a powerful oxidizing ag ent, very reactive ch em ically.

Oxidation: the loss of electrons. The el ectrons are transferred to the oxidizing agent, whi c h beco mes reduced.

Reduction: the addition of electrons. May involve the addition of electron only, or the addition of hydroge n together with an electron.

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Chemical Stage

After ~10 -12 sec, the chem ically r eactive species are still locat ed in the vicinity of the origina l H 2 O * , H 2 O· + and e¯ species t h at caus e d their creation.

Three of t h e new speci es creat e d are radicals: HO·, H·, 

These species now begin to migrate randomly about their initial positions. As this diffusion proceeds, individual pa irs may co m e close enough together to react with each other.

A variety of reactions are possible in the track of the charged p a rticle.

HO· + HO·  H 2 O 2

HO· +

  OH 

HO· + H·  H 2 O

H + +

  H·

e  + e 

+ 2 H O  H

+ 2 OH 

aq aq 2 2

e  + H· + H O  H + OH 

aq 2 2

H· + H·  H 2

Most of these reactions remove chemi c ally reactive sp ecies from the system.

With time (by ~ 10 -6 sec) all of the reactive speci es have diffused sufficiently far that further reactions are unlikely.

The chemi c al development of the track is over by 10 -6 sec.

Radical Diffusion

If the m easured diffusion constant for a gi ven species is D, then, on average, it will move a s m all distance, λ , in a time, τ , such that

 2

6  D

The reacti on radius, R, is a measure of the reactivity of the individual species. If a reactive speci es diffuses closer to a “target” than the reactive r a dius. It will react.

Simulati ons of Charged-Particle Tracks

The diffusion form ula and the recom b inat ion reactions described above allow Monte Carlo sim u lation of th e charged-particle tracks.

Monte Carlo codes are used to m odel:

 passage of the charged particle,

 generation of secondary electrons,

 generation of chemi c ally reactive speci es,

 diffusion of the reactive species through a series of “random walk” jum p s,

 reco m b ination events in any pairs that come closer than the reactive r a dius.

Exampl es of T r ack Simulations

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When the electron st ops, in the upper left re gion of t h e figure, the track density is higher.

This illustrates the hi gh-LET nature of the electron track end.

Exampl es of t r ack simulations

High-LET particle (prot on) produces a straight tr ack , in contrast to the torturous tracks of electrons .

High LET particles have a dense form ation of react ants along the particle track.

In the simulation, clusters and spurs are also generated along the track.

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Examples of Simulated Particle Tracks

Expanded view of the high-L ET proton track.

Expanded scales show a close-up view of track developm ent as a function of tim e.

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Radiochemical Yield: G values

In sim u lations, the num b ers of the various chemi c al species can be tabulated as a function of time.

G value : the num ber of a particular species produced per 100 ev of energy loss by the charged particle and its seconda ries when it stops in water.

 Som e species will decrease with time, oth e rs will increase with time.

 By about 10 -6 sec, al l chemi cal development of the track is over. G values will not change m u ch after that.

 The alpha particle has 4 times higher LET.

 LET decreases at higher energies, th e init ial density of react ants is lower, m o re survive without reco m b ining (lines 1-4), less produced (lines 4+5).

 The alpha track is denser, the G values ar e lower, because more reco mbine.

 Electrons, protons and alpha particles all produce t h e same s p ecies in t r ack regions (at 10 -15 sec), H 2 O * , H 2 O· + and e¯.

 The chem ical (and biological) diffe rences later ar e d u e to the different spatial patterns of energy deposition along the track, ie., track density.

Effect of LET on G values

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The F r icke Dosi meter

Originally developed as a dose-measur ing device. Strong LET dependence li m its this application.

Most useful as a method to di rectly m e asure the numbers of reactive species in solution.

 The standard solution: 1 m M FeSO 4 in 0.8 N H 2 SO 4

 When irradiated, the Fe 2+ is oxidiz e d to Fe 3+ .

 Fe 3+ generates a blue color that can be quantified with a spectrophot ometer.

 The colori metric dose response is linear up to 400 Gy.

 The oxidation is complete at ~ 700 Gy.

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[Tubiana, 1990]

Fricke Dosimeters

The chemi cal r e actions involv ed in Fricke dosimetry are: H· + O 2  HO 2 ·

HO 2 · + Fe 2+  HO 2 ¯ + F e 3+

HO 2 ¯ + H +  H 2 O 2

HO· + F e 2+  HO¯ + Fe 3+

H 2 O 2 + Fe 2+  HO¯ + Fe 3+ + HO·

H· + H 2 O  HO· + H 2 (only in the absence of oxygen)

 Each H· will produce 3 Fe 3+

 Each H 2 O 2 (radiolytic) will produce 2 Fe 3+

 Each HO· (radiolytic) will produce 1 Fe 3+ Overall, when O 2 is present,

G(Fe 3+ ) = 2 G(H 2 O 2 ) + 3 G(H·) + G(HO·)

What is the use of a Fricke Do simeter?

 Dem onstrates that scave nger m o lecules will react, cell com ponents should react si milarly.

 Can be used to test other com p eting scavengers.

 Demonstrates that n o t all ener gy depos ition translates into scavengable species, i . e., at high LET ther e i s consid erable intratrack reco mbination.

Direct Acti on, I ndirect Acti on and the Oxygen Ef fect

 So far, the radiation chem istry of water h a s been co nsidered.

 It is possi ble that energy can be deposite d directly in the biologi cal m o lecule of interest (e.g., DNA).

 The result would still be ionization a nd/or excitation leading to radical form ation in the biol ogical m o lecule.

 Biological radicals can undergo reactions sim i l a r to those described for water.

Direct act i on : energy depositi on directly in the biological molecule ( e .g., the DNA as shown here). The dose response relationshi p shoul d be linear.

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Indirect a c tion: Relies on the ionization of the solvent m o lecules as interm ediaries. Indirect action is di ffusion lim ited, the dose response relationship can be com p lex.

Water radiolysis produces many reactive species.

Experiments with scavengers specific for individual reactive species have shown that it is prim arily the hydroxyl radical (HO · ) that is responsible for radiation dam a ge to DNA.

[Hall,2000]

For high-LET radiation , direct action is the pre domin ant mechanis m o f DNA dam a ge.

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Radiation dam a ge in DNA can be repaired by several processes.

 Recombination: reaction of nearby radical with the DNA radical to regenerate the original DNA. Tim e scale is < 10 -11 sec.

 Restitution: chem ical restoration of the DNA; no enzy m e involved. There are a nu mber of intracellular reducing ag ents that can react with radicals, the m o st im portant of which is glutathi one (GSH). The sulfhydryl group on GSH can donate H· to the DNA, produc ing the restored DNA and a more stable (and less reactive ) sulfur radical. The ti me scale is < ~ 10 -3 sec.

DNA· + GSH  DNA + GS·

 Repair: there are many cellula r enzymes that recognize and repair DNA dam a ge. Tim e scale is m i nutes to hours.

“Fixation” of damage by oxygen

 O 2 is a powerful oxi dizing agent. O 2 has two unpaired electrons: a stable biradical.

 O 2 reacts r eadily wit h organic radicals:

DNA· + O 2  DNA-O-O· (DNA hydroperoxy radical) DNA - O-O· H·  DNA- O-OH (DNA hydrope roxide)

 If oxygen reacts with the DNA radical bef o re it is repaired, the damage

becom e s harder, if not im possible, to re pair. Cann o t be repai r ed by chemi cal restitution.

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[Hall, 2000]

Scavengers

Chem icals that can react with reac tive speci es, like HO· , can b l ock the indirect

effects of radiation.

 Scavengers provi de a way to estim ate relative contributi ons of direct and indirect effects.

 Scavenger s for specific reactive speci es can help define the radiation chem istry.

 Scavenger experim e nts suggest that 60 - 70% of the damage in cells exposed to low-LET radiation is caused by HO · radicals.

Radical Scavenging

In order to sim p lify com p lex chem istry in soluti ons or cells, scavengers can be added to selectively react with one or mo re types of radicals.