Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate.

0.2 MB·English

by  Tanooka, Hiroshi

Int. J. Radiat. Biol., Vol. 87, No. 7, July 2011, pp. 645–652
Meta-analysis of non-tumour doses for radiation-induced cancer
on the basis of dose-rate
HIROSHI TANOOKA
Radiation Effects Association, 1-9-16 Kaji-cho, Chiyoda-ku, Tokyo, and National Institute of Radiological Sciences,
4-9-1 Anagawa, Inage-ku, Chiba, Japan
(Received 6 July 2010; Revised 26 November 2010; Accepted 2 December 2010)
Abstract
Purpose: Quantitative analysis ofcancer risk ofionising radiationas a functionof dose-rate.
Materialsandmethods: Non-tumourdose,D ,definedasthehighestdoseofradiationatwhichnostatisticallysignificant
nt
tumourincrease was observedabove thecontrol level, was analysed asa function ofdose-rate ofradiation.
Results: AninversecorrelationwasfoundbetweenD anddose-rateoftheradiation.D increased20-foldwithdecreasing
nt nt
dose-rate from 1–1078 Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body
radiationalsoshowedadose-ratedependencewitha5-to10-foldlargerD asdoseratedecreased.Thedose-rateeffectwas
nt
alsofound for highLETradiation but at10-fold lowerD levels.
nt
Conclusions: The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure
conditions. Thisanalysis explains thediscrepancy ofcancer risk between A-bomb survivorsand radium dial painters.
Keywords: radiation cancer risk, non-tumour dose, dose-rate
effectiveness factor (DDREF) for cancer risk was
Introduction
determined as 2–10 depending on the target organ
Thedose-rateofionisingradiationthathumanshave (NCRP 1980, International Commission on Radi-
been exposed to from natural to accidental radiation ological Protection [ICRP] 1991, UNSCEAR 1993,
sources varies over a wide range from 1079 to 107 NRPB 1995). The application of the linear non-
Gy/min.Radiationdose-rateaffectsthemagnitudeof threshold (LNT) model, based on the apparently
cancer risk even for the same total dose, and in linear dose-response relation of cancer mortality
addition changes the shape of the dose-response obtained from extremely high dose-rate cases of A-
curve. For assessment of cancer risks of ionising bombsurvivors,wasrecommendedfortheestimation
radiation resulting from different exposure condi- ofthecancerriskoflowdoseradiationforprotection
tions,ideally,asetofdoseresponsecurvesisneeded purposes (NCRP 2001, Brenner et al. 2003, BEIR
for each dose-rate. VII2005,ICRP2006);however,theLNTmodelwas
Currently, the estimation of human cancer risk questioned for its validity from experimental and
from low doses of radiation is an important problem epidemiological evidence (Kondo 1993, Acade´mie
anddatahavebeenextensivelyreviewed(Committee des Sciences 1997, Tanooka 2001, Tubiana et al.
on the Biological Effects of Ionizing Radiation 2006, Feinendegen et al. 2007). The history of the
[BEIR]/National Research Council [NRC], United LNTmodelexplainshowtheideaofatolerancedose
Nations Scientific Committee on the Effects of Ato- waschangedtothelinearityconceptbyincorporating
mic Radiation [UNSCEAR] 1986, 2000, National theviewofthegeneticist(Calabrese2009).However,
Council on Radiological Protection and Measure- arecentreviewofnewbiologicalandepidemiological
ments[NCRP]1980,BEIRV1990,BEIRVII2005, data still adopted the LNT model (Mullenders et al.
National Radiological Protection Board [NRPB] 2009). Whatever the model, there exists both linear
1995, Duport 2003). The dose and dose-rate and threshold type dose-response relations for
Correspondence:HiroshiTanooka,RadiationEffectsAssociation,1-9-16Kaji-cho,Chiyoda-ku,Tokyo,Japan.E-mail:[email protected]
ISSN0955-3002print/ISSN1362-3095online(cid:2)2011InformaUK,Ltd.
DOI:10.3109/09553002.2010.545862
646 H. Tanooka
radiation-induced cancers in experimental and epi- have resulted in a lower estimate of dose-rate and a
demiological data. For example, the shape of the higher estimate of D , provided that the radiation
nt
dose-response curve for cancer incidence may con- dose given only in the first half of the exposure time
formtoalineartypeforleukemiaandsolidcancersin waseffectivefortumourinduction.However,correc-
A-bombsurvivors(Chomentowskietal.2000),while tion for this gave little change in the plot of D
nt
it is non-linear, or even threshold-like, for bone versus dose-rate on a bi-logarithmic scale.
tumours in radium dial painters (Rowland et al.
1978) and liver tumours in thorotrast-injected
Results and discussion
patients (Anderson and Storm 1992). This discre-
pancy remained still to be explained. Numerical values for D and corresponding dose-
nt
In a previous study, non-tumour dose, D , was rates obtained from various tumour systems are
nt
defined as the highest dose at which no statistically listedinTableI.Thesevaluesweredividedintofour
significant tumour increase was observed above the groups, i.e., whole body irradiation with low LET
control level. It was proposed as a measure of the and high LET radiation and partial body irradiation
upper limit of radiation dose for non-detectable with low LET and high LET radiation, respectively.
cancer and D values were surveyed for in the Figure 1 shows a plot of D against dose-rate on a
nt nt
literature. The results showed that D depended on bi-logarithmic scale and regression lines fitted to the
nt
exposure conditions, i.e., acute, protracted, and datafordose-ratesbelow1Gy/min.Acleardose-rate
chronic exposures for whole body and partial body dependence of D is seen for the four exposure
nt
radiation for either low linear energy transfer (LET) patterns.
or high LET radiation, respectively, with an inverse For whole body irradiation with low LET radia-
correlation between D and dose-rate (Tanooka tion, D increased when lowering the dose-rate
nt nt
2001). The present study aimed to show the dose- below 1 Gy/min and became 20-fold higher at 1078
rate dependence of D more quantitatively as a Gy/min (Figure 1a). Only one point for humans was
nt
function of the dose-rate of radiation. availableforthehighdose-rate107Gy/min,basedon
the assumption that the A-bomb radiation was
delivered in 1 msec. It appeared that D is constant
Data base nt
for dose-rates between 1 and 107 Gy/min, as shown
Dose-response data covering ionising radiation ex- by the horizontal line in Figure 1a. For high LET
posuresfromnon-tumourtotumour-inducingdoses irradiation of the whole body, there were few data
were surveyed in the literature and are listed in available, but the dose-rate dependence of D was
nt
Table I. These include D values, and correspond- seenatalevelabout10-to20-foldlowerthanforlow
nt
ing dose-rates of radiation in mice, rats, dogs, and LET radiation, although high LET radiation has
humans with different tumour types obtained under been considered to have no dose-rate effect.
different exposure conditions. Data in the previous For partial body irradiation, the dose-rate depen-
study(Tanooka2001)andadditionaldatawereused dence of D was again seen for both low LET and
nt
for the present quantitative analysis. The data highLETradiation(Figure1b).Dose-response data
numbers in the previous study were unchanged for for dose-rates higher than 10 Gy/min were not
the convenience of comparison. available in the literature. The D level of partial
nt
bodyradiationwasabout5-to10-foldhigherforlow
LETradiationsand3-to5-foldhigherforhighLET
Estimation of dose-rate
radiations than those for whole body radiation.
Thevaluesforthedose-ratewereobtainedfromeach At an extremely high dose-rate for whole body
published paper. For external radiation, the dose- radiation,A-bombsurvivordata(Shimizuetal.1990)
rate was clearly presented in the literature either for gave a D of 0.2 Gy for leukemia mortality; while
nt
whole body or partial body exposures. However, for mouse data from nuclear detonation experiments at
internal radiation from radioactive nuclides, the similar dose-rates showed a significant increase in
estimation of dose-rate required assumptions and pituitary and Harderian gland tumours at the same
calculations depending on whether internal radio- dose, 0.2 Gy (Furth et al. 1954). Consequently,
activenuclidesweredistributedinthewholebodyor humans seem to be more tolerant to radiation than
depositedpartiallyinthetargetorgan.Moreover,the miceandtheregressionlinesdrawnfromanimaldata
radioactivity decayed with time and the radioactive may under-estimate D for humans. D values, for
nt nt
nuclide was cleared from the body. In the present partial body high-LET radiation to radium dial
analysis,anaveragedose-ratewasestimatedfromthe painters (Rowland et al. 1973, 1978) and thoro-
total dose divided by the exposure time or, when a trast-injected patients (Anderson and Storm 1992),
decay curve was available, an average dose-rate over weremuchlargerthanthoseforexperimentalanimals
the 70%decaytimewastaken. Thiscalculation may (Figure 1b), again indicating a higher radiation
Non-tumour dose and dose-rate 647
er d)
or ue
&St ontin
h h (c
c c
Reference Ullrichetal.(1976)00 00 00 Ullrich&Storer(1979a)Ullrichetal.(1976),Ullri&Storer(1979a)Ullrichetal.(1976),Ullri(1979b)00 00 Ullrich&Storer(1979c)00 00 Ullrichetal.(1979)00 Ullrich(1983)00 00 Ullrich(1984)Maisinetal.(1983)DiMajoetal.(1986)Covellietal.(1988) 00 Albertetal.(1972)Hulse&Mole(1969)Bartsraetal.(2000)Leeetal.(1982)Burnsetal.(1975,1993)Burnsetal.(1975)Burnsetal.(1978)Shimizuetal.(1990) Finkeletal.(1959)Yamamotoetal.(1998)Leeetal.(1982)Dudoignonetal.(1999)Morlieretal.(1994)
urGy
o 5
n-tumeD,nt 0.10.10.250.250.25*34 0.1 0.2520.10.50.52.50.10.10.10.020.0520.50.64 0.040.8601110200.75*0.2 200.713.310.19
Nodos * *
urdose,D.nt Dose-rate,Gy/min 0.450.450.450.450.450.45 0.45 0.450.450.45575.8106575.810642751060.40.427510657710641.3276106 571.71065.55.5,split4741062.555,split1.3881106 572106776.4106471.7106477106573106
o
m
u
n-t
e-rateofradiationandno Tumour thymiclymphomaHarderiantumouruterinetumourmammarytumourmyeloidluekemiareticulumcellsarcoma ovariantumour pituitarytumourlungadenomathymiclymphoma00 ovariantumourlungadenoma00 lungadenocarcinomaovariantumour00 00 thymiclymphomahepatocellularcarcinomasolidtumour,malignantlymphoma00 skintumour00 mammarycarcinomathyroidadenomaskintumour00 00 leukemia bonesarcomathymiclymphomathyroidadenomalungtumour00
s
o
D
I.
e dd
Tabl aRadiation WB-rayg00 00 00 00 00 00 00 00 00 WB-ray,protractedg00 PBX-rayPBneutronWB-rayg00 WBfissionneutron252WBCfneutronWB-raygWBX-ray00 WBneutronPBelectronPBrayfractionatedbWB-ray,fractionatedgPBX-rayPB-raybPBelectronPBprotonWBray,neutrong 90PBSr-ray,injectedb3WBH-ray,oralb131PBI-ray,injectedb237PBNp-ray,inhaleb222PBRn-ray,inhalea
D
C
wley vivor wley
RFM/Un00 00 00 00 00 00 00 00 00 00 00 00 00 BALB/c00 00 00 00 BC3F100 00 SwissCBA/HWAG/RijLong-EvansSprague-Da00 00 A-bombsur CF1BC3F1Long-EvansSprague-Da00
erSubject posureMouse00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 Rat00 00 00 00 HumanexposureradiationMouse00 Rat00 00
anumb cuteex Chronicnternal
Dat I.A123456 7 89101112131415161718192021 222324252627282930II.1)I3132333435
648 H. Tanooka
78) 2)
Reference Sandersetal.(1977)00 Sanders&Mahaffey(19Mays&Finkel(1980)Whiteetal.(1993)Hahnetal.(1999)Whiteetal.(1994)Rowlandetal.(1973)00 Anderson&Storm(199Rowlandetal.(1978) Uptonetal.(1970)00 Hulseetal.(1983)Ootsuyama&Tanooka(1991,1993)Thompson(1989) Nairetal.(1999) Chen&Wei(1990) Raabe(1984)Ishii-Ohbaetal.(2007)Inaetal.(2005)
e e
s s
a a
n-tumoureD,Gynt 0.250.050.18306.750.925*210 1.52.51640 8.6 ncerincre ncerincre 0.441*74
Nodos * * oca oca
n n
* *
s
h
nt
o
Dose-rate,Gy/min 472.5106773.4106571.9106376106373.2106571.3106775106777106772.8106771.1106774.9106 573106675106272106y/week,6m 672106 871.3106 975.7106 777106175106572106 971.8106
G
5
1.
Tumour 00 00 00 bonesarcoma00 lungtumourbonesarcoma00 00 livercancerbonesarcoma myeloidleukemia00 skintumour00 myeloproliferativedisease bonesarcomathymiclymphoma00
al
aRadiation 238PBPuO-ray,inhaleda2239PBPuO-ray,inhaleda2244PBCmO-ray,inhaleda290PBSr-ray,injectedb00 144PBSr-ray,inhaledb226PBRa-ray,injecteda00 228PBRa-ray,injectedb232PBThO-ray,injecteda2226228PBRaRa,orabþþ WB-rayg00 204PBTl-ray,skinb90907PBSrY-ray,skinb WB-ray,continuousg 00 00 226PBRa-rayaWB-rayg00 diation.ne.
ranli
ued). Subject 00Wister0000 0000 Dogbeagle0000 0000 0000 0000 0000 Humanthorotrastpatient00dialpainterationMouseRFM/Unmale00RFM/Unfemale00CBA/H00ICR Dogbeagle HumanhighradiationbackgroundareainIndia00highradiationbackgroundareainChina DogbeagleMouseC.B-1700C57BL/6j dyradiation.PB:Partialbodyncalculationfortheregressio
TableI.(Contin Datanumber 36373839404142434445462)Externalradi47484950 51 52 53 Dataadded545556Naturalbackgroundradiationlevel aWB:Wholebo*Notincludedi
Non-tumour dose and dose-rate 649
Figure1.Non-tumourdose,D ,plottedasafunctionofthedose-rateofradiation.(a)Wholebodyradiation.(b)Partialbodyradiation.
nt
Blocksymbols,lowLET;opensymbols,highLET.Mouse(.,(cid:2));rat(~,~);dog(&,¤);human,whole-bodylowLET(H);andhuman,
partialbodyhighLET(h).ArrowsindicateD higher.Numbersaffixedtoeachpointaredatanumbers(seeTableI).
nt
tolerance of humans. The other extreme case is the in space (Horneck et al. 2003) is also shown in
absence of thymic lymphoma induction in mice Figure 2, indicating a value close to D even with a
nt
irradiated at 261075 mGy/min with a total whole radiation shield. The cancer risk of medical exam-
bodydoseof7.2Gy;whereas,acuteradiationgivenin ination with computer tomography (CT) has been
fourfractionswiththesametotaldoseyieldeda90% analysedonthe basis ofwhole-bodydataofA-bomb
tumour incidence (Ina et al. 2005), as was originally survivors(BerringtondeGonzalezandDarby2004);
foundintheearlyexperimentsofKaplanandBrown however, this risk should have been analysed on the
(1952). basis of partial body data. The highest possible dose
Fractionationofradiationdoseatafixeddose-rate forCTwasstillfarlowerthanthecorrespondingD .
nt
within a defined time interval lowers cancer in- Recently, Tubiana et al. (in press) reported the dose
cidence, as shown in the induction of skin tumours response of second cancer incidence after radiation
by local irradiation in rats (Burns et al. 1973, 1975, therapy with a D of about 1 Gy based on a large
nt
1993). However, fractionation necessarily involves number of patients. This study provides important
repetitive irradiations, which results in a tumour- data on human exposure to partial body low LET
enhancing effect as seen for mouse thymic lympho- radiation.
ma induction (Kaplan and Brown 1952) and also in Therearedifferencesintheradiationsensitivityof
mouse skin tumour induction (Ootsuyama and tumour induction, depending on the type of tumour
Tanooka1991).Itshouldbenotedthattherepetitive and host sensitivity. D is much smaller in repair-
nt
treatment is efficient for chemical induction of deficient mice compared to wild-type mice (Ishii-
tumours. This contradictory effect should be con- Ohbaetal.2007),indicatingthattheregressionlines
sidered in analysing the dose-rate effect. represent the wild-type character of the hosts.
Figure 2 summarises the regression lines for the Currently, a large scale life-time exposure of mice
four exposure patterns. These four lines are thought toexternalgrays withgradeddose-rates from1–800
to cover all possible radiation exposure cases and mGy per 22 h a day (dose-rate: 7.561076 7
hopefullytoserveasameasureofcancerriskforany 661073 Gy/min, total dose for 3 years: 1.1 – 876
exposure situation inthe human environment. Total Gy) together with control mice is being conducted
whole body radiation doses received over 70 years andchromosomeaberrationdatahavebeenreported
from the natural environment high background (Tanaka et al. 2009). Such experiments will give
radiation areas in Kerala, India (Nair et al. 1999) more accurate data for the effect of dose-rate on
andYanjiang,China(ChenandWei1991)aremuch tumour induction. Further data will be needed to
smallerthanD fortherespectivedose-ratesineach cover the whole dose-rate range for tumour
nt
district (Figure 2). The radiation dose to astronauts induction.
650 H. Tanooka
Figure2.Summaryofregressionlinesfornon-tumourdose,D ,versusdose-rateofradiation.Regressionlinesfordose-raterangefrom
nt
1078to1Gy/min:wholebodylowLET,Y¼0.258X70.141,R2¼0.320;wholebodyhighLET,Y¼0.0207X70.0733,R2¼0.781;partial
bodylowLET,Y¼2.69X70.0857,R2¼0.147;partialbodyhighLET;Y¼0.0439X70.167,R2¼0.303.Bars:radiationdosesreceivedby
residentsinnatural(NB)andhighbackgroundareasinKerala,India,andYanjiang,China,over70years.CT:possiblehighestdoseto
patientsunderCTexamination.Space:possiblehighestdoseinspaceusinga10g/cm2shieldforsixmonths.Dottedverticallinesindicate
thedifferencebetweenexposuredoseandcorrespondingD value.
nt
University of Paris, France, for providing me with
Summary
valuable data prior to publishing.
Meta-analysisofthenon-tumourdose,D ,ofionising
nt
radiation showed a clear dependence on dose-rate Declaration of interest: The author reports no
over a wide range for four exposure conditions, i.e., conflicts of interest. The author alone is responsible
whole body irradiation with low LET or high LET for the content and writing of the paper.
radiationandpartialbodyirradiationwithlowLETor
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