cern course – lecture 2 october 27, 2005 – l. pinsky dosimetry and the effects of the exposure...

CERN Course – Lecture 2October 27, 2005 – L. Pinsky

Dosimetry and the Effects of the Exposure of Humans to Heavily

Ionizing Radiation 1

Surviving in space: the challenges Surviving in space: the challenges of a manned mission to of a manned mission to MarsMars

Lecture 2Dosimetry and the Effects of the Exposure of Humans to Heavily

Ionizing Radiation




What Are the Problems Associatedwith Human Radiation Exposure?

• AcuteAcute (High Intensity-Short Duration—DeterministicDeterministic EffectsEffects)– Serious Debilitation and Death (within Hours to Months)– NOT GENERALLY THE BIGGEST PROBLEM FACED in Long Term

Human Space Travel (Because the potential sources of this kind of threat are easier to mitigate).

• ChronicChronic (Low Intensity-Long Duration— Stochastic EffectsStochastic Effects)– Increased Risk of Cancer in the Future (Acceptable = <3% Increase)– Potential Increased Risk of Other Diseases (Coronary, Brain Cell Loss)– Increased Risk of Debilitations Like Cataracts…– THE REAL HURDLE (Due to “Bureaucratic” Career Dose Limits)




Contrasting Acute v. Chronic

• Imagine having to set limits on bloodblood-loss– For AcuteAcute loss situations over a few hours, the amount

of loss (without replacement) before serious health effects may occur is perhaps as much as a few liters…

– …On the other hand, for ChronicChronic loss situations like blood-donors, one might safely donate one liter every 6 weeks, or almost 350 liters over a 40 year “career.”

• The reason for the difference is the human body’s ability to replace (blood-loss) and repair (radiation damage) in cases of such “insults”…




The General Problem

• NASA needs to be able to PREDICT DOSESPREDICT DOSES or at least estimate conservative maximums– GCRGCR—Solar Modulation Fluctuations

• (OR— + any Interstellar Spectral fluctuations???)

– Solar Particle EventsSolar Particle Events• CME’s + lower flux events

– In LEO, Trapped RadiationTrapped Radiation fluxes are significant in low shielding situations…




A Short Primer on Dose

• Radiation Dose:Radiation Dose:– EnergyEnergy deposited per gm (~cm3) of tissue by

Ionizing Radiation– For Dose D D, the Rad (100 ergs/gm) has been

replaced by:– …the Gray (Gy) = J/kg = 100 RadGray (Gy) = J/kg = 100 Rad,– …or more commonly: 1 cGy = 1 Rad




Acute v. Chronic Equivalent Dose

• Equivalent DoseEquivalent Dose — Dose Modified by Effect in “Generic” Human Tissue– Quality Factor Modifiers, WWRR (RBE) with

respect to gamma radiation’s effect for each kind of radiation RR, summed over all tissues, TT…

HTR = R WR DRT

– For CHRONICCHRONIC Doses, the Rem has been replaced by the Sievert (Sv) = 100 RemSievert (Sv) = 100 Rem

– For For ACUTEACUTE Doses, the Dose is given in Doses, the Dose is given in Gray-Gray-Equivalent (Gy-Eq) = 100 Rads of X-RaysEquivalent (Gy-Eq) = 100 Rads of X-Rays




“Effective Dose Equivalent”

• Effective Dose EquivalentEffective Dose Equivalent — Uses a Different Weighting Factor for EACHEACH kind of tissue, WWTT , summed over EACH “Organ” and , summed over EACH “Organ” and

then over the whole body…then over the whole body…– Also quoted in Sieverts (for Chronic—Stochastic Sieverts (for Chronic—Stochastic

Effects)Effects)…

– E = WT HT = WT [ R WR DRT dT]




Effects of Dose• ACCUTE DOSESACCUTE DOSES (High Short Time Exposures)

– 4.5 Gy = LD 50/60 (50% Lethal in 60 Days) [without medical intervention…]

– 1.0 Gy = “Radiation Sickness” (Nausea, Diarrhea)– No Macroscopically Observable effects < 0.1 Gy…

• CHRONIC DOSESCHRONIC DOSES (Low Continual Exposure)– Increased Cancer and other risks (Coronary, Eye…)– No Observable Short-Term effects…– Long-Term Effects from Long-Term Effects from High LETHigh LET (Linear Energy Transfer (Linear Energy Transfer

—Energy deposited per unit track-length by ionizing —Energy deposited per unit track-length by ionizing radiation) exposure such as Heavy Ions are radiation) exposure such as Heavy Ions are UNKNOWNUNKNOWN……

• Acute Dose Limits are Acute Dose Limits are NOTNOT related to Chronic Limits related to Chronic Limits




Where do we get Data on the Effects of Doses?

• Actual Human Exposures– Hiroshima Survivors represent the best extant cohort for

long term effects…– Accidents—Sporadic and low statistics….– Clinical Exposures—Low Doses or in Radiation Therapy

exposures, localized high doses… No Controls…– Existing Astronaut “cohort”…

• Animal Exposures– Inter-species extrapolation uncertainties…

• Isolated Cell Culture Exposures– In Vitro cells do not behave like there conterparts In Vivo




From NASA SPP

Energy Loss by Heavy Ions in Tissue




On The Baseline Mars Mission~ 1 Fe Traversal PER CELL

• The “Deep Space” GCR Fe ~ 1 per m2 Ster Sec…• Human Body ~ 1 m2 * 4 Ster or ~10 Fe/sec• Baseline Mission = 3 Years ~ 108 sec• So, there will be 109 Fe traversals per mission• 1 m2 = 1012 m2 & each human cell ~ 103 m2

• …Or, ~109 cells in a typical cross section view• …Thus, ~ 1 Fe traversal PER CELLThus, ~ 1 Fe traversal PER CELL !!!• The Mission Volunteer Sign-Up Sheet will be The Mission Volunteer Sign-Up Sheet will be

Available After My Talk…Available After My Talk…




DNA-Double Strand Breaks“Complex Lesions” & “Biological Dose

• The latest idea is that multiple breaks within 30 base pairs on a DNA strand is a better measure of the likelihood of causing a cancer to form than other measures of dose.

• We cannot yet calculate that liklihood from “first principles.”

• We can estimate it from empirical radiation exposure data…




Current Cancer Risk Model (NCRP-132)

1) Estimates of radiation induced cancer mortality are based on the atomic-bomb death certificate data for 1950 through 1990. Other human data (reactor workers, patients) used as checks for consistency

2) A minimum latency period following exposure for radiation induced cancers of 10-years for solid cancers is assumed. For leukemia, minimum latency of 2-years, however risks are multiplied by 0.1, 0.25, 0.5, 0.75, 0.9, and 1 for years 3, 4, 5, 7, and 8 or more years after exposure, respectively.

3) The excess relative risk for solid cancer is assumed to be constant over time following exposure. For leukemia a decline in excess risk with time after exposure is assumed.

4) The baseline survival and cancer rates for astronauts are assumed as those of the US population (SEER, 2000).

Slide Courtesy of F. Cucinotta, NASA/JSC




Current Cancer Risk Model (NCRP-132)(Continued)

5) The transfer of risk from the Japanese to the US population for solid cancers is made using the average of the multiplicative and additive transfer models, and for leukemia’s using the additive transfer model.

6) The dose response for the acute exposures of the Japanese survivors is assumed to be a linear function of dose. For leukemia a linear-quadratic dose response function is used.

7) For chronic exposures a dose and dose-rate reduction factors of two is assumed. The quadratic term in the leukemia response model is set to zero.

8) For high-LET radiation, an LET dependent radiation quality factor, Q(L) recommended by the ICRP is used to scale the doses (No other factors in the model are assumed to depend on radiation quality).





Current Model- continued• q(a) = probability to die for age a and a+1 based on US mortality rate, M (all

causes) and exposure dependent cancer rate, m

• Probability to survive to age ‘a’

• Mortality rate for ion fluence F, of LET, L (transfer model weight)

• Excess Lifetime Risk (ELRELR)

• Risk of Exposure Induced-Death (REIDREID)

LLFDDREF

LQaaEARvaMavERRaaEm EcEE )(

)()],()1()()([),,(

E Eaa aa

EEE aaSaMaaESaaEmaMELR ),,0()(),,()],,()([

Eaa

EE aaESaaEmREID ),,(),,(

)],,()([21

1

),,()(),,(

aaEmaM

aaEmaMaaEq

E

EE

1a

auEE

E

a)],aq(E,[1a),aS(E,





Transfer ModelsAvailable data Populations Individuals*

• Cohort baseline BJ (unexposed group)

• US Baseline BA

A linear coefficient fit to exposed cohort

Additive Transfer:

RiskA = BA + Jx Dose

Multiplicative Transfer:

RiskM = BA/ BJ x Jx Dose

• Accuracy?

– large variations for specific tissue sites

– healthy workers or individuals

• genetic background

• dietary/environmental

– untested for space radiation non-cancer risks

Mult. Additive Ratio Mult. Additive RatioIncidence 13.5 6.73 2.01 6.18 5.01 1.23

Stomach 0.25 2.27 0.11 0.15 1.36 0.11Colon 1.29 0.56 2.29 1.15 0.36 3.19Liver 0.06 0.21 0.28 0.11 0.4 0.28Lung 5.53 1.33 4.15 0.94 0.36 2.58Skin 0.8 0.13 6.31 1.09 0.11 10.2Breast 8.96 2.14 4.19 * * *Ovary 0.81 0.26 3.13 * * *Bladder 1.3 0.35 3.71 0.77 0.23 3.35Thyroid 0.05 0.04 1.34 0.02 0.01 2

Mortality 5.26 3.94 1.34 2.64 2.46 1.07

Females Males

(%) Excess Lifetime Cancer Risks for 1 Gy kerma at Age 30 y

LSS Transfer to US (NCRP Report 126)

Additive Transfer: radiation acts independent ofspontaneous cancer risksMultiplicative Transfer: radiation risk depends onspontaneous cancer risks





• Method: Monte Carlo sampling over each factor in model based on current knowledge to form Probability Distribution Function (PDF)Probability Distribution Function (PDF)

• PDF defined to bound values of each factor (quantile) x:

• Cancer mortality rate for ions

• Physics PDF based on comparisons to flight data

• Use of REID corrects for competing risks (important for Mars mission)

Methods for Uncertainty Estimates

Dr

PTSD

x

xxxxsexagemsexagem ),(),( 0

LQion xxLLQLFsexagemEsexagem )()(),(),,( Factors (NCRP 126):xD = DS86 (dosimetry of A-bombs)xS = Statistical errorsxT = pop. transferxP = Bias xDr = Dose-rate effectsxQ = Quality factorsxL = physics (transport/dosimetry)

DDREF

0 1 2 3 4 5 6 7 8 9 10

Pro

bab

ility

0.0

0.2

0.4

0.6

0.8

1.0

Differential (Model 1) CumulativeDifferential (Model 2)Cumulative





Radiation Quality Effects Tradition- Effects increase to about 100-200 keV/m

and then decline due to “overkill” Mechanisms:

– Energy deposition in Biomolecules Cluster DNA damage site Gene deletion/mutation Chromosomal aberrations

– Sterilization term in dose-response– Genomic instability– LET or dose thresholds in activating molecular

pathways (epigenetic effects)

LET, keV/m1 10 100 1000

RB

Em

ax

1

10

100

Cell transformation HPRT MutationDicentricsCentric ringsInitial Isochromatid BreaksComplex ExchangesH. Gland TumorsSkin Cancer in RatsQuality Factor

Approximate LET where maximum RBE was found in biological experiments. Biological system Endpoint LET at peak

RBE, keV/m LET range (No. of ions studied)

Reference

Human TK6 lymphoblasts cells

TK mutants 60 32-190 (6) Kronenberg (1994)

Human TK6 lymphoblasts cells

HPRT mutants 60 32-190 (6) Kronenberg (1994)

Human lung fibroblasts

HPRT mutants 90 20-470 (9) Cox and Masson (1979)

Human Skin fibroblasts

HPRT mutants 150 25-920 (7) Tsuoboi et al. (1992)

V79 Chinese hamster cells

HPRT mutants 90 10-2000 (16) Kiefer et al. (1994); Belli et al. (1993)

Caenorhabditis elegans

Recessive lethal mutations

190 0.55-1110 (14) Nelson et al. (1989)

Human lymphocyte cells

Chromosomal exchanges

147 0.4-1000 (10) George et al. (2003)

Human fibroblast cells

Chromatid breaks

80-185 13-440 (6) Kawata et al. (2001)

C3H10T1/2 mouse cells

Transformation 140 10-2000 (10) Yang et al. (1989)

C3H10T1/2 mouse cells

Transformation 90 20-200 (10) Miller et al. (1995)

Syrian hamster embryo (SHE) cells

Transformation 90 20-200 (8) Martin et al. (1995)

Mouse (B6CF1) H. gland tumors

185* 2-650 (6) Fry et al. (1985)

Mouse (B6CF1) H. gland Tumors

193 0.4-1000 (7) Alpen et al. (1993)

Mouse (CB6F1) Days life lost 52* 50-500 (6) Ainsworth (1986) *Track-segment or spread-out Bragg peak (SOBP) irradiations. Slide Courtesy of F. Cucinotta, NASA/JSC

Cell Death is good




Uncertainties in Biological Effectiveness

LET, keV/m

1 10 100 1000

Qtr

ial(L

)

0

20

40

60

80

100

LET, keV/m1 10 100 1000

Q(L

)

0

20

40

60

80

100

• Trial Function, Q(L)

– Sampling:

• L0 [1, 15] (flat 5 to 10)

• Lm [50, 250] (flat 80 to 150)

• Declining slope, p [0,2]

• Qp = 30 log-normal with GSD=1.8

m

mp

trial

LL

LLL

LL

LC

BALLQ

0

0

/

1

)( • Space missions-trial Q convoluted with trial LET spectra to form sample rate

JLJtrialElJEJ xLLQdL

dFdLaaEmaaEm )(),,(),,(





Accuracy of Physics Models: + 20%(environments, transport, shielding)

ISS Mission





PDF for Physics Uncertainties- GCR

Effective Dose, Sv

0.50 0.75 1.00 1.25 1.50

PD

F(E

)0.000

0.003

0.006

0.009

0.012

0.015

0.018

Monte-Carlo results

L, keV/m1 10 100 1000

F(>

L), 1

/(cm

2 yr)

10-2

10-1

100

101

102

103

104

105

106

107

108

109

HZETRN Model90% CI bounds





Fatal Cancer Risk per Rad vs. LET95% Confidence Intervals-All Uncertainties Combined

LET, keV/m

1 10 100 1000

%R

EID

per

rad

0

1

2

3

4

5

6Fold uncertainty

(REID(97.5)/REID(50))

Dose, Gy

0.0 0.1 0.2 0.3 0.4 0.5 0.6

%R

EID

0

20

40

60

80

Expected50th percentile2.5th percentile97.5 percentile

1 GeV/u Iron Ions

US Males (1 Sv Acute at age 35-yr)

Age, yr

40 50 60 70 80 90 100

Fa

tal C

an

cer

Ris

k (%

)

0

5

10

15

20

25

30

35

Background no radiationBackground competing with IRELR (Solid Cancer)REID (Solid Cancer)

Average Life-loss from radiation cancer death(40-yr at exposure) low LET:Leukemia 20 yrSolid Cancers

Multiplicative Transfer 12-yr Additive Transfer 20-yr

HIGH LET???Slide Courtesy of F. Cucinotta, NASA/JSC




Uncertainties not Included• Deviation from linear-additivity models• Radiation quality and latency or progression

– Models assume a constant ERR (Equivalent Relative Risk) for solid cancers with no time-dependence on radiation quality

– Animal and cellular models suggest decreased latency with increasing LET and ERR declines after saturation

– Possible uncertainties for mixed fields and progression not modeled

• Radiation quality and susceptibility– Population averaged values do not account for dispersion due to genetic factors (familial,

high and low penetrance genes, SNP’s-Single Nucleotide Polymorphisms)– Neutron carcinogenesis studies show RBE variations across mouse strains for same tissue

• Non-cancer mortality– Dose limits need to consider life-loss per death across each cause– For Mars mission non-cancer risks may be a significant competing risk to radiation

carcinogenesis





High LET- Protraction Effects

Age, days250 450 650 850 1050 1250

Mo

rta

lity

Ra

te/ 1

0,0

00

Mic

e/ D

ay

0.1

1

10

100

Controls

80 rad(3.3x24 fract.)

240 rad(10x24 fract.)

80 rad(acute)

Pulmonary Tumors - fission neutrons in B6CF1 mice (Fry et al., Env. Int. 1, (1972))

Slide Courtesy ofF. Cucinotta, NASA/JSC




Radiation “Risqué”- transgender estimates*(M(a) = Net Mortality & MC(a) = Cancer Mortality)

*Differences between males and females are approximate level of change for calendar year changes





Summary of Issues• Acute effects are more predictable than

Chronic effects for Space Radiation Exposures…

• Cancer Risk is the Primary Chronic Effect.– Big uncertainties exist in estimating risks

because:• Effects from high LET radiation are poorly known

• Cancer causes themselves are not well understood.

• Current Policies Require Limiting Risks to the same values as for Earth-based workers.




Possible Strategies• Classical Solutions: Time, Shielding &

Distance…– Distance—we can do nothing about…– Time—More powerful rockets to reduce

mission durations and thus exposure time…– Shielding—Doable from the physics

standpoint… but Expensive from the standpoint of weight (& $$$)

• Long Surface Stays—Use local soil overburden as shielding material…

cern course – lecture 2 october 27, 2005 – l. pinsky dosimetry and the effects of the exposure...

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