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Transcript of Illinois Institute of Technology
04/20/23 Stochastic Damage; High-LET p. 1 of 75
Illinois Institute of Technology
Physics 561 Radiation Biophysics
Lecture 9:Cancer, Genetics, and
High LET radiation30 June 2014
Andrew Howard
04/20/23 Stochastic Damage; High-LET p. 2 of 75
Plan for this lecture Cancer, concluded
– Mutagenesis– Animals & humans– Dose-response– Latency
Genetics–Chromosomal damage–Recombination–Frameshifts–Genes and Introns–Structural components
Genetics, concluded– RNA vs. DNA– The genetic code– Relative sensitivities– Organismal differences
High-LET radiation– Energy deposition– Impact on DNA– Resistance to repair– The Ullrich experiment– Damage to chromosomes– Cataracts
Is an Ames Test a Good Substitute for These Complex Systems?
No! 1,8-dinitropyrene is the
most mutagenic substance known in the Ames test; yet it is only weakly tumorigenic in rats.
04/20/23 Stochastic Damage; High-LET p. 3 of 89
Why might we care about dinitropyrene?
Most mutagenic substance known in Salmonella strain TA98: 72900 revertants/nanomole
Nitroarenes like this one were found to be present in used toner, i.e., combustion waste from Xerox toner
When this appeared, Xerox chemists reformulated their toner to drastically reduce the nitroarene content in the used toner.
Mermelstein (1981) Mutation Research 89:187-196. Löfroth et al(1980) Science 209:1037-1039 and
Mermelstein et al (1980) Science 209:1039-1043. So: all’s well that ends well!
04/20/23 Stochastic Damage; High-LET p. 4 of 89
This is also a story about enzyme induction
Nitroarenes like dinitropyrene and other polynuclear aromatic hydrocarbons, (e.g. benzo(a)pyrene) are known to be inducers of enzyme activities
Some of these enzyme activities actually activate toxicants rather than detoxifying them
Most of the activity of these enzymes will detoxify; But if 1% makes things worse, we want to understand that
1% activation So we found that pretreatment with these compounds
could induce subsequent binding of other compounds to mouse DNA:Howard et al (1986), Biochem. Pharm. 35: 2129-2134.
04/20/23 Stochastic Damage; High-LET p. 5 of 89
Animal Cell-Line Cancer Studies How similar are these rodent cell systems
(CHO, mouse) to human cells? Answer: Human cells:
– Are more resistant to spontaneous immortalization
– Tend to give more nearly linear responses to dose
– Radical scavengers and cold don’t protect as much:That suggests that direct mechanisms prevail in humans and indirect mechanisms are more important in rodents
04/20/23 Stochastic Damage; High-LET p. 6 of 89
More on humans vs. rodents
High-LET studies indicate that repair is less effective in human cell systems than in animal cell systems
Is the timescale a factor in that? Humans live a lot longer than rodents.
Promotion can be studied in animal cells, along with initiation
04/20/23 Stochastic Damage; High-LET p. 7 of 89
Radiation Carcinogenesisin Human Populations
Occupational: radiologists, miners, dial painters Medical exposures:
– Ankylosing spondylitis– Nonmalignant disease in pelvis and breast– Multiple fluoroscopies in to chest (e.g. in TB patients)– Infants & children with enlarged thymus and ringworm– Children exposed in utero to diagnostic X-rays
Nuclear accidents and weapon detonations Environmental background (see last chapter)
04/20/23 Stochastic Damage; High-LET p. 8 of 89
Dose-Incidence in Cancer Studies We seek a relationship relating post-exposure
incidence ID to dose D and normal incidence In
Model might be: Linear: ID = In + 1D
Quadratic: ID = In + 2D2
LQ: ID = In + 1D + 2D2
Corrected for loss of clonogenic potential: ID = (In + 1D + 2D2)exp(-1D+2D2)
04/20/23 Stochastic Damage; High-LET p. 9 of 89
Linear, Quadratic, LQ Models
We try to devise low-dose models based on high-dose data, where the three models are close together. It’s often difficult:
04/20/23 Stochastic Damage; High-LET p. 10 of 89
Latency Definition (in the cancer context):
Time between the mutational events that began cellular transformation and the appearance of a medically observable malignancy
How long in humans?– A few years (blood or lymphatic cancers)– 15-30 years for solid tumors– Animals: scale these numbers to animal’s lifespan– These numbers are minima:
leukemia can take > 15 yrs
04/20/23 Stochastic Damage; High-LET p. 11 of 89
04/20/23 Stochastic Damage; High-LET p. 12 of 75
Macroscopic Damage to Chromosomes
First half of chapter 13 Structural changes in chromosomes
– Inversions of fragments– Multiple hits– Isochromatid breaks– Dicentrics– Minutes– Cross over
04/20/23 Rad Bio: Genetics p. 13 of 75
Generalizations about Genetics Main focus here is on ways that ionizing
radiation can damage the physical and replicative properties of DNA
We’ll look at three length scales:– The individual base-pair (~0.5 nm)– The gene (1000 bp - many nm)– The entire chromosome (200 nm or more)
Focusing only on single-base mutations (substitutions, deletions, insertions) does not tell the whole story
04/20/23 Rad Bio: Genetics p. 14 of 75
Early studies
T.H. Morgan studiedchromosomes in Drosophila
Tradescantia (spiderwort)microspores: Sax, 1938-1950
More Tradescantia: Lea et al, 1946:Provided quantitative data on chromosomal aberrations during first mitotic cycle
04/20/23 Rad Bio: Genetics p. 15 of 75
1960’s-1970’s:chromosomes
Metaphase chromosomes readily studied
Human lymphocytes extensively studied that way
“Premature chromosome condensation” used to study interphase chromosomal organization
Courtesy HelmholtzZentrum München
04/20/23 Rad Bio: Genetics p. 16 of 75
Chromosome Breakage Quite common result of radiation exposure Can happen before replication:
then the structural defect will be replicated(if the cell survives)
Can happen afterward:then one of the two chromatidswill differ from the other one.
Types of damage:Subchromatid, Chromatid, Chromosome
Repair tends to be rapid
Wheat chromosomesCourtesy USDA
04/20/23 Rad Bio: Genetics p. 17 of 75
Single-Hit Breaks
Cartoons show * as centromere and ^ as break Single-Hit:
A B C * D E F^ G H I
A B C * D E F + G H I This can recombine in a number of ways:
A B C * D E F I H GI H G A B C * D E FG H I A B C * D E F
… or a circle plus a fragment without a centromere, which won’t be able to use the spindle machinery to get sorted.
04/20/23 Rad Bio: Genetics p. 18 of 75
Double Hits
A B C * D^ E F^ G H I A B C * D + E F + G H I
Numerous ugly combinations can arise, e.g.E F A B C * D I H G
Acentrics can readily arise
04/20/23 Rad Bio: Genetics p. 19 of 75
Multiple Hits in Replicated Chromosomes
See figs. 13.1 and 13.2 Major losses of genetic
information possible Balanced
translocations: no harm done!
Dicentrics--two centromeres in one pair of chromosomes.
04/20/23 Rad Bio: Genetics p. 20 of 75
SCE: another form of multiple-hit damage
Sister chromatid exchange: exchange of DNA fragments from one chromatid to another between the two chromatids of a single chromosome
– Important for chemical mutagens– Not common with radiation
Cartoon courtesy madsci.org
04/20/23 Rad Bio: Genetics p. 21 of 75
Double-stranded breaks
04/20/23 Rad Bio: Genetics p. 22 of 75
Recombination
+
04/20/23 Rad Bio: Genetics p. 23 of 75
Breakage and Exchange Hypotheses Breakage hypothesis (Sax, 1940’s onward):
Types of aberrations that require one break follow linear dose-response; those requiring two or three follow quadratic or cubic dose-response.
Exchange hypothesis (Revell, 1950’s onward):emphasizes reciprocal exchanges among chromosomal materials: rate D1.7
Alpen says the data don’t support this one much.
04/20/23 Rad Bio: Genetics p. 24 of 75
Using FISH to sort this out
Fluorescence in situ hybridization: available before modern genetic tools
Probe segments bind to DNA regions of high homology
Used to sort out differences between breakage hypothesis and exchange hypothesis
From Wikipedia
04/20/23 Rad Bio: Genetics p. 25 of 75
Gene Mutations
We’ve discussed these in detail previously Types:
– Deletions (frameshift)– Additions (slightly less likely) (frameshift)– Substitutions (e.g. C for T; no frameshift)
Remember that three bases code for an amino acid! If we skip a single base, we can throw off every single
amino acid that is coded for downstream of the error. Mutation frequencies are often linear with dose
04/20/23 Rad Bio: Genetics p. 26 of 75
Effect of Frameshift
Suppose the DNA duplex looks like this:5’- A - T - C - G - C - A - A - 3’ (template strand)3’- T - A - G - C - G - T - T - 5’ (coding strand)
Now we delete one base, so that the coding strand is3’- T - A - G - G - T - T - 5’
Now the amino acids coded for will be different.
04/20/23 Rad Bio: Genetics p. 27 of 75
Frameshifts (continued)
• Most common form of (local) DNA damage• Defined as any form of DNA damage that leads
to a loss of one base during replication or transcription.
• Chemistry• Deletion of bases• Fragmentation of sugar-phosphate
backbone• Distortion of base-base hydrogen bonds
and other 3-D elements
04/20/23 Rad Bio: Genetics p. 28 of 75
Consequences of frameshifts
• Result in complete misreading of remainder of message
• Obviously they’re less dangerous near the end of a gene!
• Frameshift in an intron near the end of a gene might mean the mRNA will be correct
04/20/23 Rad Bio: Genetics p. 29 of 75
Genes A gene is a unit within a chromosome (i.e., a
stretch of DNA) that gets transcribed and thereby codes for a specific function.
Most genes ultimately code for proteins; but Some code for transfer RNAs, rRNA, sRNA Eukaryotic genes often have exons and introns:
– Exons are segments of a gene that are ultimately turned into proteins
– Introns are segments of a gene that are removed from the message before translation
04/20/23 Rad Bio: Genetics p. 30 of 75
How Introns are Removed Suppose we begin with a
2000-base-pair gene. It will be transcribed to
make a 2000-base messenger RNA molecule
That gets chopped up to make up a ~960 base ultimate message
This will produce a 320-amino acid protein (960/3 = 320)
2000 base-pairs of DNA
transcription2000 bases of RNA
exon exon exon exon exonintron intron intron intron
960 bases
320-amino-acidprotein
translation
splicing
04/20/23 Rad Bio: Genetics p. 31 of 75
Structural components of genes
Bases– Adenine– Cytosine– Guanine– Thymine
Phosphate-deoxyribose backbone Double helix enables the replication and transcription
processes and offers physical stabilization
A C
G T
04/20/23 Rad Bio: Genetics p. 32 of 75
Review of DNA backbone
Sugar-phosphate backbone on each strand has a nitrogenous acid base attached at the 1’ position of the ribose ring
The lack of an -OH group on the 2’ position prevents formation of a reactive intermediate; this makes DNA more stable than RNA
DNA’s double-helical structure also helps its stability.
ON
OCH2
PO O-
O
PO O-
O
ONext sugar
(Base)
2’
04/20/23 Stochastic Damage; High-LET p. 33 of 75
Differences between DNA and RNA
RNA has a hydroxyl at the 2’ position on the ribose ring RNA is made up of A, C, G, U
rather than dA, dC, dG, dT DNA is replicated using a molecular machine called
DNA polymerase DNA codes for RNA (tRNA, mRNA, rRNA, or sRNA)
using a molecular machine called RNA polymerase DNA is more chemically stable than RNA
04/20/23 Stochastic Damage; High-LET p. 34 of 75
Types of RNA
Our focus on central dogma sometimes makes us forget about RNA types other than mRNA
Type # bases % of synthesis
% of RNA
DS? Role in translation
mRNA 150-104 25 3 no Protein template
tRNA 55-91 21 15 part Amino acid activation
rRNA 100-104 50 80 part Scaffolding, catalysis
sRNA 15-1000 4 2 hybrid various
04/20/23 Stochastic Damage; High-LET p. 35 of 75
RNA hairpins
DNA is almost always double helical;Watson-Crick base pairing contributes to stability
RNA sometimes has complementary bases that allow for bases to pair up around a (hairpin) loop
5’-A-U-G-G-C-C-G-A-A-U-G-C-C-A-U-3’
5’-A-U-G-G-C-C-G3’-U-A-C-C-G
U
A
A
04/20/23 Stochastic Damage; High-LET p. 36 of 75
Special features Code is redundant 43 = 64 codons Only 20 amino acids plus a few control codes;
most amino acids have more than one codon each associated with them(minimum=1, maximum=6).
Middle base is generally conserved; all the codons for any given amino acid generally have the same middle base.
First RNA base may be sloppy
04/20/23 Stochastic Damage; High-LET p. 37 of 75
Genetic code: mRNA version
Determined by hard work in ~1958-1965
Slight variations in a few organisms
04/20/23 Stochastic Damage; High-LET p. 38 of 75
Errors in Fidelity and Their Consequences
How do chemicals & radiation affect fidelity(rate of mutation)?
Increase likelihood of replication error Radiation: bond disruption in bases
(or sugars)– Direct (radiation breaks bonds in DNA)– Indirect (radiation causes free radicals;
free radicals break bonds in DNA)
04/20/23 Stochastic Damage; High-LET p. 39 of 75
Chromosomal Instability The observation is that cell death continues for
several cellular generations after the initial exposure
The explanation is that the chromosome becomes unstable, i.e. it loses some of its ability to remain structurally sound.
This instability is heritable and therefore accounts for some of these long time-scale effects
Little (1990): decreases in cloning efficiency lasts for 20-30 population doubling times in mammalian cells
04/20/23 Stochastic Damage; High-LET p. 40 of 75
Results in intact eukaryotes Not as easy to study as in culture Most work historically has been done in Drosophila
– Rate of production of lethal mutations is linear with dose
– Dose rate is irrelevant– Male gamete’s sensitivity varies greatly with the stage
of development at which irradiation occurs– Rate of mutations ~
1.5*10-8 - 8*10-8 per locus per cGy. n.b.: a locus is a testable genetic element; it’s
typically one gene, although it could be a group of genes controlled by a single promoter
04/20/23 Stochastic Damage; High-LET p. 41 of 75
Results in Mammals
Concern was raised in the 1960’s that we shouldn’t base mammalian exposure risks on Drosophila data
Mouse specific locus test: suggests– 2.2*10-7 mutations/locus/cGy (~5x higher).– Dose-rate matters: fewer observed mutations
at lower dose rate. Difficult to extrapolate these mouse results to
humans Rates around1 - 5*10-7 is typical.
04/20/23 Stochastic Damage; High-LET p. 42 of 75
Repair
Cell has mechanisms to recognize & replace faulty bases before they have a chance to be replicated
Some injury may disrupt a large enough segment of DNA that repair either fails or is error-prone
04/20/23 Stochastic Damage; High-LET p. 43 of 75
High LET Radiation
Review definition of LET:Rate of change of energy with distance along a track
Caveat I: Local Deposition, i.e.,depositions far from track don’t count
Caveat II: LET only associated with charged particles
04/20/23 Stochastic Damage; High-LET p. 44 of 75
LET Equation: Bethe-Block Formulation
If we let:– z* = Effective charge of projectile particle– Z = Atomic number of atoms in medium– A = Atomic weight of atoms in medium– C = sum of electron shell corrections– /2 = condensed medium correction– = v/c for particle– I = <ionization potential for absorbing medium>
-dE/dx = [0.307z*2Z/(A2)]•{[ln((2m0c22)/(1-2)I)] - 2 - C/Z - /2}
04/20/23 Stochastic Damage; High-LET p. 45 of 75
What does this mean?
It’s a messy equation, but we can derive several pieces of wisdom from it.
-dE/dx is inversely proportional to 2, so slow particles dump more energy per unit length
-dE/dx is proportional to z*2, so highly charged particles deposit more
Chemistry of target doesn’t matter too much, because Z/A is almost constant
The term inside the curly brackets is a correction
04/20/23 Stochastic Damage; High-LET p. 46 of 75
Where is Energy Deposited?
Most of the energy is deposited just before the particle stops moving
We’re interested in average LET over a region or track
04/20/23 Stochastic Damage; High-LET p. 47 of 75
Depositions with heavy particles “Bragg peak”: most of the energy is
deposited over a narrow linear track. W.H. Bragg (father of W.L. Bragg)
characterized this
Rel
ativ
e io
niza
tion
Range, cm0 10
1
4
425 MeVa neutrons in water
04/20/23 Stochastic Damage; High-LET p. 48 of 75
Calculating Averages of Continuous Variables
We wish to calculate the mean of a continuous function f(x) over a range of x from a to b,Then <f(x)>a,b = [∫a
b f(x)dx ] / (b-a)
f(x)
xa b
f(x)
a b
Area under curve =
∫ab f(x)dx
<f(x)> = (f(a)+f(b))/2
(a+b)/2
04/20/23 Stochastic Damage; High-LET p. 49 of 75
Applying this to LET
Average LET over energies:
(LETav)S = { ∫E1E2 [LET(E)]dE } / (E2-E1)
So for a slowly varying LET function we assume that it is close to linear, i.e.(LETav)S = [(LET)1 + (LET)2] / 2
These are instances of track segment averages, (LETav)TS;they’re somewhat different from energy averages, for which we average over energy deposited.
04/20/23 Stochastic Damage; High-LET p. 50 of 75
Alternative averages
Energy-averaged LET(see previous slide; energy range from E1 to E2):
<LET>E = { ∫E1E2 LET(E) dE } / (E2-E1)
where E is the energy that we’re averaging over. Track-averaged LET
(track from position a to position b):
<LET>TS = { ∫ab LET(x)dx } / (b-a)
where x is the linear dimension through which the energy is being deposited a
b
04/20/23 Stochastic Damage; High-LET p. 51 of 75
Average LET, keV µm-1
Table 14.1:
Radiation type (LETav)TS (LETav)E
60Co -rays 0.27 19.6250 kVp x-rays 2.6 25.83 MeV neutrons 31 44Radon rays 118 8314 MeV neutrons 11.8 125Recoil protons 8.5 25Heavy recoils 142 362•Looks like the (LETav)TS is more in accord with our intuitive notion of what constitutes LET!
04/20/23 Stochastic Damage; High-LET p. 52 of 75
Direct & Indirect Effects
High LET means that many ionizations occur in a small neighborhood LET Spur energy Events/µm Spacing KeV/µm eV nm
60Co 0.25 60 4 250Radon 118 60 2000 0.5
This fact by itself accounts for much of the difference in biological consequence of high LET radiation
04/20/23 Stochastic Damage; High-LET p. 53 of 75
Biological Effects of High-LET Radiation
RBE = relative biological effectiveness analogous to OER in its definitional form:
RBE = (dose for given end point for reference radiation) /(dose for given end point for test radiation)
Problem with this formulation:– assumes that dose-response curves are described
by identical functions, i.e.– RBE is independent of the response level at which
it is estimated. Often not true!
04/20/23 Stochastic Damage; High-LET p. 54 of 75
MTSH comparisons Cf. fig. 14.3: Xrays and fast neutrons
Results from hamster fibroblasts
04/20/23 Stochastic Damage; High-LET p. 55 of 75
Can we define a single RBE?
Not really, unless our survival curves are really just rescalings of one another (“dose-modifying effect”)
For MTSH data RBE will be close to constant if the extrapolation numbers aren’t too high
For LQ we’re definitely going to have to pick a survival ratio
04/20/23 Stochastic Damage; High-LET p. 56 of 75
Survival Level Matters!
04/20/23 Stochastic Damage; High-LET p. 57 of 75
LQ case
RBE varies significantly between S=0.1 and S=0.001:
04/20/23 Stochastic Damage; High-LET p. 58 of 75
Relationship between RBE and LET
RBE vs LET: Generally higher LET radiations have higher RBE, up to a certain
point. With some systems the curve turns over.
LET, keV/µm
RB
E
100 101 102 103
Two hamster cell lines (from fig.14.5)
1
23
45
04/20/23 Stochastic Damage; High-LET p. 59 of 75
Cell-Cycle Dependence for RBE
Low LET radiations exert much more effect in late G2 & M than elsewhere
High LET radiation exerts approximately equal effects throughout the cell cycle
Reason: irreparable damage early in the cycle will persist through mitosis, so it’s just as bad!
04/20/23 Stochastic Damage; High-LET p. 60 of 75
OER vs LET
OER for High-LET Radiation is generally smaller than for low-LET radiation because the damage is less dependent on oxygen fixation of radical species.
This plot shows OER going not to 1 but to ~1.5--because water-derived radicals are still produced at high LET; cf. Fig. 14.6.
OE
R
LET, keV/µm1 100010 100
1
2
1.5
04/20/23 Stochastic Damage; High-LET p. 61 of 75
LET vs Fractionation
Recall that repair-competent systems respond less to fractionated doses than to single doses whereas repair-deficient systems are fractionation-independent
For high-LET radiation, fractionation does not decrease biological effects
04/20/23 Stochastic Damage; High-LET p. 62 of 75
Contrarian results for fractionation Sometimes in tumors fractionation increases the
undesirable biological effect, i.e. more healthy cells die per 100 tumor cells killed!
– Why? - no explanation in Alpen– 2-stage model for cancer: (Ullrich)– Also: high dose rate (equivalent to fewer fractions)
is more likely to simply kill the cell rather than producing clonogenically competent but mutated cells(remember the concept of correcting for mortality in epidemiology)
04/20/23 Stochastic Damage; High-LET p. 63 of 75
Late Effects of High LET Radiation
You can induce cancer with neutrons Ignores fractionation or (!) damage is
more likely with fractionation Tumors also arise from heavy-ion
irradiation
04/20/23 Stochastic Damage; High-LET p. 64 of 75
LET vs. Cross Section Alpen looked at particle fluence as a dose parameter--
requires constant LET over volume Result: power-law relationship between cross section for
tumor induction and LET (fig.14.7)
Cro
ss S
ect
ion
, µm
2
LET, keV/µm0.1 1 10 100
.1
10
0.001
04/20/23 Stochastic Damage; High-LET p. 65 of 75
General note re linearity
Ordinary linear relationship:– Both axes on linear scales.– y = ax + b,– a = slope, b = Y intercept
Semi-log linear relationship:– X linear scale, Y logarithmic– ln y = ax + b– exp(ln y) = exp(ax+b)– y = exp(b) exp(ax) = keax
– for k = exp(b)
x
y
b
x
ln y
b
04/20/23 Stochastic Damage; High-LET p. 66 of 75
Third possibility: power law
Here we have linearityon a log-log plot:
ln(y) = alnx + b exp(ln(y)) = exp(alnx)exp(b) y = k exp(a ln x) for k=exp(b) But aln x = ln(xa), so y = kexp(ln(xa)) = k xa
So this is a power law.
ln x
ln y
b
04/20/23 Stochastic Damage; High-LET p. 67 of 75
Probability of TraversalsTable 14.2 shows that multiple traversals of the nucleus are very rare even at high dosesIt also shows a close correspondence between cross section for tumor production and cross section for traversalDose, <fluence/ Probability of traversalsGy cell> 0 1 2 >= 10.01 0.006 0.993 0.006 2.1*10-5 0.0060.02 0.013 0.987 0.013 6.8*10-5 0.0130.05 0.032 0.968 0.031 5.0*10-4 0.0320.15 0.097 0.907 0.088 4.0*10-3 0.0920.20 0.129 0.878 0.114 7.0*10-3 0.1210.30 0.193 0.823 0.159 1.5*10-2 0.1760.40 0.258 0.772 0.199 2.5*10-2 0.227
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Number of Traversals
04/20/23 Stochastic Damage; High-LET p. 69 of 75
Cell Transformation in High-LET Irradiation
Assertion: non-local effects on DNA predominate over point mutation events
Certain assay systems suggest this assertion: Kronenberg et al, human TK6 lymphoblasts--
entire hprt gene is missing after irradiation This gene codes for hypoxanthine phosphoribosyl transferase,
an important enzyme in DNA synthesis “If large genomic changes are brought about by heavy ion
radiation, then a multistep process may be short- circuited to a single event.”
04/20/23 Stochastic Damage; High-LET p. 70 of 75
Cataracts
The vertebrate eye is a remarkable organ
All the living components must be completely transparent for maximum fidelity of light transmission.
Even the lens is made up of living cells!
A loss of transparency is a cataract,either evanescent or permanent.
A variety of insults can give rise to a loss of transparency.
04/20/23 Stochastic Damage; High-LET p. 71 of 75
Cataracts
Cataracts are common with high-LET radiation Reminder: cataracts involve loss of transparency in the
lens because problems with differentiation will lead to failure of alignment of the fibers
Cataracts happened with workers in early accelerator facilities
RBE values are high, and tend to be higher for lower doses (i.e. low doses cause almost as many cataracts as higher doses)
04/20/23 Stochastic Damage; High-LET p. 72 of 75
Cataracts from high-LET radiation
It’s long been known that high-LET radiation can give rise to cataracts, even at low doses.
Relative biological effectiveness of high-LET radiation (neutrons) is 30 or more for low doses
RBE goes down for higher doses Beams of ions (Z > 20) produce similar
effects, again including lowered RBE for higher doses.
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Cataracts from specific types of radiation
Neutrons:– In animals: cause cataracts with RBE~2 to 100– But with humans: cataracts become rare up to 2 Gy,
almost universal at D > 11 Gy. Argon and iron ions: RBE ~12-40 for low doses (below
0.25 Gy), more like 2-5 for higher doses Why does the RBE depend on dose?
– Can’t kill a cell more than once?– Mechanistic explanations (see Ullrich discussion)?
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The Ullrich Tumor Experiments
Ullrich found that with low doses of neutrons, fractionation never diminished incidence of tumors
With certain types (lung, mammary) there was an enhancement in tumor rate with fractionation
Dose-response was nonlinear Saturation and fall-off of incidence with high
doses
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Ullrich Experiment: Why? Mechanisms of Genetic Damage Low vs High LET
– Low-LET radiation exerts many of its effects at the level of point mutations(single-base substitutions, deletions, or additions)
– High-LET exerts most of its effects on a more macroscopic scale