Low-dose radiation from 18 F-FDG PET does not increase cancer frequency or shorten latency but reduces kidney disease in cancer-prone Trp53+/ mice

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1 Mutgenesis vol. 29 no. 4 pp Advnce Access publiction 28 My 214 doi:1.193/mutge/geu17 Low-dose rdition from 18 F-FDG PET does not increse cncer frequency or shorten ltency but reduces kidney disese in cncer-prone Trp53+/ mice Kristin Tylor 1,2, Jennifer A. Lemon 1, *, Nghi Phn 1 nd Dougls R. Borehm 1 1 Deprtment of Medicl Physics nd Applied Rdition Sciences, McMster University, 128 Min Street West, Hmilton, Ontrio L8S 4K1, Cnd nd 2 Deprtment of Nucler Medicine, McMster University Medicl Centre, 12 Min Street West, Hmilton, Ontrio L8N 3Z5, Cnd *To whom correspondence should be ddressed. Tel: , ext ; Fx: ; Emil: lemonj@mcmster.c Received on Februry 2, 214; revised on Mrch 28, 214; ccepted on April 1, 214 There is considerble interest in the helth effects ssocited with low-level rdition exposure from medicl imging procedures. Concerns in the medicl community tht incresed rdition exposure from imging procedures my increse cncer risk mong ptients re confounded by reserch showing tht low-dose rdition exposure cn extend lifespn by incresing the ltency period of some types of cncer. The most commonly used rdiophrmceuticl for positron emission tomogrphy (PET) scns is 2-[ 18 F] fluoro-2-deoxyd-glucose ( 18 F-FDG), which exposes tissue to low-dose, mixed rdition qulity: 634 kev β+ nd 511 kev γ-rys. The gol of this reserch ws to investigte how modifiction of cncer risk ssocited with exposure to low-dose ionising rdition in cncer-prone Trp53+/ mice is influenced by rdition qulity from PET. At 7 8 weeks of ge, Trp53+/ femle mice were exposed to one of five tretments: Gy, 1 mgy γ-rys, 1 mgy 18 F-FDG, 4 Gy γ-rys, 1 mgy 18 F- FDG + 4 Gy γ-rys (n > 185 per group). The lrge 4-Gy rdition dose significntly reduced the lifespn by shortening the ltency period of cncer nd significntly incresing the number of mice with mlignncies, compred with unirrdited controls. The 1 mgy γ-rys nd 1 mgy PET doses did not significntly modify the frequency or ltency period of cncer reltive to unirrdited mice. Similrly, the PET scn dministered prior to lrge 4-Gy dose did not significntly modify the ltency or frequency of cncer reltive to mice receiving dose of only 4 Gy. The reltive biologicl effectiveness of rdition qulity from 18 F-FDG, with respect to mlignncy, is pproximtely 1. However; when non-cncer endpoints were studied, it ws found tht the 1-mGy PET group hd significnt reduction in kidney lesions (P <.21), indicting tht higher bsorbed dose (2 ±.13 mgy), reltive to the whole-body verge, which occurs in specific tissues, my not be detrimentl. Introduction It is estblished tht exposure to high doses of ionising rdition increses the risk of cncer in humns (1 5). The crcinogenic risk ssocited with low-level rdition exposures, however, hs not been estblished. Using humn epidemiologicl dt (tom bomb survivor cohort), regultory gencies linerly extrpolte high-dose responses into the low-dose rnge to offer conservtive pproch to rdition protection. This model is the liner no threshold (LNT) model of risk estimtion nd implies tht every dose cuses n increse in the risk of developing cncer bove bckground levels. In contrst, there is lrge body of both in vitro nd in vivo evidence, which shows tht low doses of rdition my not cuse detrimentl helth effects (6 9), or tht these exposures my be beneficil to the irrdited orgnism by incresing lifespn nd/or reducing crcinogenesis (1 12). It hs been demonstrted in vivo tht low doses of rdition cn induce n dptive response by modifying cellulr processes nd protecting ginst the effects of subsequent high, crcinogenic dose of rdition (13 15). As the use of dignostic imging continues to increse, positron emission tomogrphy (PET) plys progressively importnt role in medicl dignostics. The most commonly used PET rdiotrcer is the glucose nlog 2-[ 18 F] fluoro-2-deoxy-d-glucose ( 18 F-FDG). A typicl clinicl scn involving the dministrtion of 35-75MBq 18 F-FDG (16) exposes most tissues in n verge ptient to mximum bsorbed dose of pproximtely 1 mgy from positron emission (β+, E mx = 634 kev) nd nnihiltion photons (γ-rys, 511 kev). However, tissues with incresed uptke of the rdiophrmceuticl receive higher bsorbed doses thn the whole-body verge including the brin (1 36 mgy), hert (16 51 mgy), kidneys (7 23 mgy) nd bldder ( mgy) (17 21). Recently, clcultions bsed on using the LNT model hve emerged proposing tht rdition from dignostic imging procedures my cuse incresed cncer risk mong ptients due to ionising rdition exposure (22 24); however, there is little direct in vivo dt to support these estimtes. It hs been shown previously tht single 1-mGy γ-ry dose cn significntly extend the ltency period of lymphom nd spinl osteosrcom in cncer-prone Trp53+/ mice reltive to unirrdited controls (12). When 1-mGy γ-ry dose ws dministered 24 h before n cute 4-Gy γ-ry dose, the ltency period of lymphom ws significntly extended reltive to Trp53+/ mice receiving 4 Gy only (14). The gol of this reserch ws to investigte how modifiction of cncer risk ssocited with exposure to low-dose ionising rdition is influenced by rdition qulity from PET scns. Specificlly, to determine if single PET scn could lter cncer risk nd determine if single PET scn could lter cncer risk from subsequent cncer-inducing lrge-dose exposure. Cncer risk ws mesured in terms of the frequency nd ltency of cncers in Trp53+/ mice. Bsed on previous low energy trnsfer rdition studies, we postulted tht 1-mGy PET scn would replicte previous results in Trp53+/ mice nd significntly extend the ltency period of lymphom nd spinl osteosrcom nd protect ginst 4-Gy dose by extending lymphom ltency period (12,14). Despite n verge whole-body dose of 1 mgy, PET scns deliver doses 1 mgy in certin tissues nd consequently these tissues my hve different outcomes. Mterils nd methods Mice Mle mice with single defective copy of the Trp53 gene (B6.129S2- Trp53tm1Tyj/1) were bred with wild-type femle mice (129X1/SvJ) Downloded from by guest on 29 October 218 The Author 214. Published by Oxford University Press on behlf of the UK Environmentl Mutgen Society. All rights reserved. For permissions, plese e-mil: journls.permissions@oup.com. 289

2 K. Tylor et l. (Jckson Lbortory, Br Hrbour, MA, USA). The p53 knockout mouse strin crries muttion of the p53 coding region, eliminting p53 protein produced by tht llele (25). The F1 femle progeny were genotyped for Trp53 sttus t 4 5 weeks of ge by polymerse chin rection. Genotyped mice were subsequently ssigned to tretment groups. All mice were housed five to cge in specific pthogen-free conditions nd mintined on 12-h light/drk cycle, t 24 ± 1 C. Food nd wter were vilble d libitum. Protocols were pproved by the Animl Reserch Ethics Bord t McMster University nd crried out s per the Cndin Council on Animl Cre. Mouse tretments Trp53+/ mice (7 8 weeks old) were rndomly ssigned to one of five tretment groups throughout the durtion of the breeding progrm: Gy, 1 mgy γ-rys, 1 mgy PET, 4 Gy γ-rys, 1 mgy PET + 4 Gy γ-rys. A smple size of 18 mice per group ws determined to hve sufficient sttisticl power (.8) to detect differences of 3 dys between the 1 mgy exposed mice nd unirrdited controls (α =.5). Low-dose γ-ry nd PET tretments The 1-mGy γ-ry dose ws delivered using 137 Cs source (662 kev γ-rys) t the McMster Tylor Rdiobiology Source Fcility. Mice were plced in customised sectioned polycrbonte restrint tube for immobilistion during rdition exposure. The 1-mGy whole-body doses were delivered t dose rte of.18 Gy/min. In the low-dose PET group, the weight of ech mouse ws recorded prior to the injection (men = 2 ±.7 g). Mice were til vein injected with.75 ±.5 MBq (2. ±.13 μci) 18 F-FDG prepred t Hmilton Helth Sciences (Hmilton, Ontrio) to provide rdition exposure similr to tht ssocited with clinicl PET scn. This ctivity yielded whole-body dose of pproximtely 1 mgy in 2-g mouse (26). Absorbed doses in specific tissues rnged between 9 nd 4 mgy depending on the metbolic requirements of the orgn (Tble I). The 18 F ws produced by 18 O(p,n) 18 F rection using Siemens RDS112 11MeV Proton-Cyclotron nd the FDG ws prepred s published (28), meeting ll USP nd Helth Cnd regultory requirements. Mice were fsted overnight prior to isotope injection (12 14 h), wter ws vilble d libitum. Mice were housed individully for period of 24 h following the injection to minimise inter-mouse irrdition. Individul doses were mesured using CRC-12 rdioisotope clibrtor (Cpintec Inc., Rmsey, NJ, USA). The pre- nd post-injection ctivity of the syringe nd mesurement time ws recorded nd used to clculte the decy corrected ctivity dministered to ech mouse. 18 F-FDG in sline solution ws dministered by til vein injection. Food ws returned to the mice 2 h following injection to increse uptke of the 18 F-FDG nd simulte the conditions of clinicl PET procedure. Published bsorbed dose estimtes for 18 F-FDG for mice (29,3) were used to convert injected ctivity into whole-body doses nd structurespecific bsorbed doses (Tble I). High-dose γ-rdition tretment (4 Gy γ-rys) nd combined PET tretment The 4-Gy γ-ry dose ws delivered using the McMster 137 Cs source t dose rte of.35 Gy/min. Mice were immobilised s described previously during exposure. For the high dose with prior PET scn, mice were injected with 18 F- FDG s described, followed by 4-Gy γ-ry dose 24 h fter injection. Tble I. Absorbed dose estimtes for 2 ±.8 g mouse injected with.75 ±.5 MBq 18 F-FDG Structure Absorbed dose (mgy) Whole body ±.8 Whole body b 1.57 ±.7 Bldder wll b ± 2.64 Brin b 9.81 ±.6 Hert b 22.8 ±.15 Kidneys b ±.13 Reproductive orgns b,c ±.15 Dt re expressed s men ± stndrd error of the men. Obtined using n pproximte dose clcultion nd S vlue ( Gy/Bq s) (26). b Obtined using bsorbed dose vlues normlised to dministered ctivity (MBq) (27). c Averged vlue for reproductive orgns (27). 29 Cncer endpoints Following tretment, mice were returned to the housing room nd exmined dily for bnorml indictions. Objective criteri were set priori to determine endpoint for euthnsi, consistent with previous studies performed with Trp53+/ mice (1,13). Lymphom nd osteosrcom re the most frequent cncer types in Trp53+/ mice (25). Following euthnsi t endpoint, mice were subjected to complete necropsy nd histologicl ssessment. Stndrd tissues (sternum, thymus, hert, lungs, liver, spleen, kidneys, thorcic spine, lumbr spine, brin) nd ny bnormlities (tumours, enlrged orgns or lymph nodes etc.) were collected. All tissues were fixed in 1% buffered formlin. Vertebre nd other minerlised tissues were further deminerlised. Trimmed fixed tissue sections were embedded in prffin nd sectioned on Leic RM 2165 microtome t 3 μm thickness nd stined with hemtoxylin nd eosin for histologicl exmintion. The presence of ny pthology ws dignosed by n experienced niml pthologist bsed on slide exmintion nd necropsy reports. Blinded repet smples were resubmitted for qulity ssurnce with 1% demonstrted precision record. If two of the sme type of cncer were found in mouse, this ws counted s single cncer, s it ws not possible to distinguish n independent primry cncer from metstsis. If mouse hd multiple different cncer types, these were counted s individul independent cncers. Both survivl nd cncer ltency were defined s the time between tretment (7 8 weeks of ge) nd euthnsi t endpoint. Tissue-specific lesions Pthology reports provided informtion on the presence of lesions in ech tissue section submitted. A lesion ws defined s loclised pthologicl chnge in tissue relted to mlignnt or non-mlignnt disese. When lesion ws identified, the nture of the lesion ws identified for nlysis of disese processes. The rdition exposure ssocited with PET scn results in nonuniform bsorbed dose throughout the mouse following injection of the rdiophrmceuticl 18 F-FDG (Tble I). Most tissues received totl bsorbed dose of pproximtely 1 mgy; however, others received doses exceeding this vlue, bsed on metbolic or execrtory functions. The frequency of lesions were compred mong tretment groups in tissues receiving doses >1 mgy from the.74-mbq injection of 18 F-FDG. Sttisticl nlysis Sttisticl nlyses were performed using SigmPlot version 11. (Systt Softwre Inc., Germny). Dt is presented s medin ± stndrd error with two-sided P.5 considered sttisticlly significnt, unless otherwise specified. Differences in the frequencies of disese were tested for sttisticl significnce using Fisher s exct test or chi-squre test. Differences in overll lifespn nd cncer ltency (clculted s dys fter rdition exposure) were nlysed using the non-prmetric Mnn Whitney rnk sum test. Survivl curve probbilities were nlysed using Kpln Meier nlysis nd significnt differences in survivl were tested with log-rnk test. Survivl nlyses were corrected using competitive censoring. Results Overll survivl The survivl curves ssocited with the vrious tretment regimens re shown in Figure 1. The 4-Gy rdition exposure significntly decresed the medin lifespn in Trp53+/ mice reltive to unirrdited Trp53+/ mice by 252 ± 8 dys (P <.1; Tble II). The 1-mGy γ-ry exposure did not significntly chnge the lifespn of mice reltive to unirrdited controls (P >.861). Similrly, the 1-mGy PET scn did not significntly chnge lifespn reltive to the unirrdited controls (P >.71) or there ws no difference in survivl between mice receiving the 1-mGy γ-ry exposure nd the 1-mGy PET injection (P >.715). A PET 18 F-FDG injection dministered 24 h prior to 4-Gy dose did not significntly lter lifespn from mice receiving 4 Gy only (P >.513). Frequency nd ltency of mlignnt tumours The Trp53+/ mice in this study developed mlignnt tumours, benign tumours nd non-cncer diseses including chronic nephropthy nd dermtitis. Mlignncy ws the most common Downloded from by guest on 29 October 218

3 No incresed cncer risk for 18 F-FDG PET Fig. 1. Survivl probbility of Trp53+/ mice. The Kpln Meier method ws used to estimte the survivl curves nd differences between the curves were evluted with the log-rnk test. Time represents the number of dys following rdition exposure (dys t risk). All cuses of mortlity re included. The 4-Gy rdition exposures cused significnt decrese in lifespn (P <.1). Tble II. Medin Survivl for tretment groups Tretment No. of mice (n) Medin survivl (dys ± SEM) Gy ± 7 1 mgy γ-rys ± 8 1 mgy PET ± 8 4 Gy γ-rys ± 4 b 1 mgy PET + 4 Gy γ-rys ± 4 SEM, stndrd error of the men. Medin survivl post-tretment (t 7 8 weeks of ge). b P <.1 reltive to control mice. cuse of euthnsi with >84% of mice in ech tretment group developing t lest one mlignnt cncer, with mny dignosed with more thn one type of mlignncy following histologicl exmintion. The 4-Gy γ-ry exposure significntly incresed the number of mice with mlignnt tumours (94%) reltive to the Gy (P <.5; Tble III). The 18 F-FDG dministered 24 h before the 4-Gy exposure did not modify the frequency of mlignncy from 4 Gy only (97%; P >.233). Similrly, the 1-mGy dose (γ-rys or PET) did not significntly modify the frequency of mlignnt cncers from the Gy group (P >.83). In ddition, there ws no difference (P >.917) between the number of mlignnt tumours in the low-dose groups (1 mgy γ-rys or 1 mgy PET). The most frequent mlignncies observed were lymphoms, srcoms nd crcinoms (Tble III). Unirrdited mice developed srcoms most frequently (76%) followed by lymphoms (18%) nd crcinoms (1%). In contrst, mice irrdited with 4 Gy developed predominntly lymphoms (61%), followed by srcom (43%) nd crcinom (12%). The frequency of cncer types in the low-dose irrdited groups did not vry from the unirrdited controls (P >.286) or ech other (P >.258). The frequency of cncer types did not vry between the 1 mgy PET + 4 Gy γ-ry nd 4 Gy groups (P >.724). The ltency period for mlignnt tumours ws mesured from the time of rdition exposure to endpoint. The ltency period of mlignnt tumours in Trp53+/ mice significntly decresed following 4 Gy (194 ± 4 dys) reltive to unirrdited controls (451 ± 9 dys; P <.1). The ltency of mlignnt tumours in mice receiving PET 18 F-FDG injection prior to the 4-Gy exposure ws not significntly different from the 4 Gy group (P >.775). The ltency of mlignnt tumours in mice receiving 1 mgy γ-rys (46 ± 6 dys) or 1 mgy PET (453 ± 7 dys) ws not significntly different from the Gy group (P >.26). There ws lso no difference between the 1-mGy γ-ry nd 1-mGy PET rdition doses in terms of tumour ltency (P >.71). Frequency nd ltency of lymphom The 4-Gy γ-ry rdition dose significntly incresed the frequency of T-cell lymphom reltive to unirrdited controls (P <.1; Tble III). The frequency of B-cell lymphom did not vry with ny of the tretments (P >.5; Tble III). The 4-Gy γ-ry dose significntly reduced the ltency period of lymphom reltive to unirrdited controls (Figure 2). There ws no difference in the frequency or ltency of lymphom (T cell, B cell, totl) between the 1 mgy γ-ry (P >.286), 1 mgy PET (P >.52) nd Gy groups ( Figure 2) with competing cuses of deth censored. There ws lso no difference in the frequency nd ltency of lymphom (T cell, B cell, totl) between 1 mgy PET + 4 Gy γ-ry nd 4 Gy γ-ry groups (P >.738 nd P >.965, respectively; Figure 2). Frequency nd ltency of spinl osteosrcom Unirrdited mice hd higher frequency of spinl osteosrcom nd osteosrcom in generl compred with 4 Gy irrdited mice (P <.1; Tble III) with competing cuses of deth censored. There ws no difference in the frequency or ltency of spinl osteosrcom between the 1 mgy γ-ry (P >.412), 1 mgy PET (P >.59) nd Gy groups (Figure 3). There ws lso no difference in the frequency or ltency of spinl osteosrcom between the 1 mgy PET + 4 Gy γ-ry nd the 4 Gy groups (P >.889 nd P >.965 respectively; Figure 3). Tissue-specific lesions The frequency of tissue-specific lesions is summrised in Tble IV. There were no significnt differences for reproductive orgn lesions between ny tretment groups (P >.261). A significnt reduction in kidney lesions ws observed in mice receiving single PET injection reltive to unirrdited controls (P <.21). No significnt difference in kidney lesions existed between ny other groups of mice (P >.215). Lymphom nd chronic nephropthy (Figure 4) were the lrgest contributors to lesions in the kidneys of Trp53+/ mice. Discussion It hs been demonstrted previously tht low doses of rdition cn extend the lifespn or ltency period of tumour formtion in mice (11,12,31). The low-dose rdition exposure hs been shown to induce cellulr mechnisms including the up-regultion of ntioxidnts (32), incresed DNA repir cpcity (31), immune system up-regultion (11,33,34) nd 291 Downloded from by guest on 29 October 218

4 K. Tylor et l. poptosis of pre-mlignnt cells (35,36). This dption hs the cpcity to protect n orgnism when subsequently irrdited with high dose of rdition (13,14). Here, we investigted how modifiction of cncer risk ssocited with exposure to low-dose ionising rdition in Trp53+/ mice ws influenced by the rdition dose nd qulity from 18 F-FDG injections. An injection ctivity of.75 ±.5MBq 18 F-FDG ws used to simulte humn rdition exposure during clinicl PET scn (1 mgy). Humn scns involve the dministrtion of MBq 18 F-FDG (16) nd result in whole-body dose of pproximtely 1 mgy, wheres generl mouse-imging protocols require 18.5 MBq 18 F-FDG, with whole-body dose of pproximtely 26 mgy (27). This discrepncy stems from the difference in body size compounded by the higher sptil resolution requirements in smll-niml imging (37). The 1-mGy PET injection did not lter risk (ltency period or frequency of cncer) reltive to unirrdited controls. Moreover, the 1-mGy PET injection did not significntly modify the risk ssocited with the 4-Gy dose. We hd postulted tht 1-mGy PET scn would increse ltency nd/or lter tumour frequency, s previously demonstrted with single 1-mGy γ-rdition exposure (12,14). Our reserch did not replicte these results in Trp53+/ mice with respect to the extension of Tble III. Number of Trp53+/ mice with mlignnt tumours nd the frequencies of vrious subtypes Tretment No. of mice with mlignnt tumours the ltency period following the 18 F-FDG injection. It is likely tht the dose rte ssocited with the 1-mGy PET injection ws too low to induce n dptive response. The rte of dose delivery is n importnt fctor in the effectution of the dptive response nd lower dose rtes show higher dose threshold for induction of protective effects (13). An dditionl fctor impcting the lck of dpttion ws the inherent heterogeneity of 18 F-FDG tissue uptke. The mount of rdition bsorbed by the mjority of tissues my hve been below the threshold required to induce dpttion. The observtion tht single PET injection significntly reduced the incidence of kidney disese following 1-mGy PET scn reltive to unirrdited mice supports this postulte. An injection of.75 ±.5 MBq 18 F-FDG resulted in n pproximte bsorbed dose of 2 mgy to the kidneys, indicting tht higher doses t lower dose rte ws required to induce protection mechnisms. It ws observed tht the primry tumour type shifted from srcoms in unirrdited nd low-dose irrdited Trp53+/ mice to lymphom in high-dose irrdited Trp53+/ mice. The enhnced rdition sensitivity of lymphtic tissues (lymphom) reltive to mesenchyml tissues (srcom) in this mouse model nd relince on p53 function for the elimintion of pre-cncerous lesions is the likely explntion for this shift (38). It hs Totl lymphoms Totl srcoms Totl crcinoms T cell B cell Osteosrcom Other Gy mgy γ-rys mgy PET Gy γ-rys mgy PET + 4 Gy γ-rys P <.5 reltive to unirrdited controls. All Spinl Downloded from by guest on 29 October 218 Fig. 2. Survivl probbility of Trp53+/ mice with lymphom. Time represents the number of dys since rdition exposure (dys t risk). Fig. 3. Survivl probbility of Trp53+/ mice with spinl osteosrcom. Time represents the number of dys since rdition exposure (dys t risk). 292

5 No incresed cncer risk for 18F-FDG PET Tble IV. Number of Trp53+/ mice with tissue-specific lesions Tretment Kidneys Bldder Hert Reproductive orgns Control 1 mgy γ-rys 1 mgy PET 4 Gy γ-rys 1 mgy PET + 4 Gy γ-rys P <.21 reltive to unirrdited control mice. been shown tht the strongest expression of p53 mrna in wildtype mice occurs in the thymus nd spleen (sites of T-cell nd B-cell lymphoms) in response to ionising rdition exposure, leding to high levels of p53-dependent poptosis (38). A lck of significnt 18F-FDG uptke in these tissues would preclude the induction of n dptive response, preventing n observed increse in cncer ltency or decrese in tumour frequency. F-FDG ws not sufficient to induce n dptive response in our study. Overll, cncer risk ws not incresed due to dignostic 18FFDG irrdition. The reltive biologicl effectiveness of 18F-FDG is pproximtely 1. for cncer endpoints nd consequently the biologicl risk with this rdition qulity is not higher thn γ-rys. A p53 deficit cuses cncer proneness but does not seem to cuse ny predisposition towrds risk ssocited with 18F-FDG. Conclusion Funding Single 1-mGy γ-ry or 1-mGy PET doses did not significntly modify the frequency or ltency of cncers in Trp53+/ mice reltive to unirrdited Trp53+/ mice. When dministered 24 h prior to 4-Gy dose, the 1-mGy PET dose did not significntly modify the frequency or ltency of cncers in Trp53+/ mice from Trp53+/ mice irrdited with 4 Gy only. The risk of disese in tissues receiving higher doses following 18F-FDG injection, such s the kidney, ws reduced. This suggests tht the rdition dose provided by This reserch ws supported by the US Deprtment of Energy Low Dose Rdition Progrm (DE-FG2-7ER64343) nd the Ntionl Science nd Engineering Reserch Council of Cnd (238495). 18 Acknowledgements Expert technicl support ws provided by Mry Ellen Cybulski, Lis Lfrmboise, Nicole McFrlne nd Jckie Ferreir. Chntl Sb nd Rod 293 Downloded from by guest on 29 October 218 Fig. 4. Histologicl fetures of chronic nephropthy in Trp53+/ mice. (A) nd (C) re 2 nd 4 norml kidney (B) nd (D) re 2 nd 4 severe chronic nephropthy.

6 K. Tylor et l. Rhem from the McMster Center for Preclinicl nd Trnsltionl Imging provided technicl ssistnce with the 18 F-FDG injections, Dr Rmn Chirkl for support on the 18 F-FDG chemistry. Dr Den Percy provided expert histopthologicl nlysis of smples. Conflict of interest sttement: None declred. References 1. Preston, D. L., Shimizu, Y., Pierce, D. A., Suym, A. nd Mbuchi, K. (23) Studies of mortlity of tomic bomb survivors. Report 13: solid cncer nd noncncer disese mortlity: Rdit. Res., 16, Tubin, M., Aurengo, A., Averbeck, D. nd Msse, R. (26) Recent reports on the effect of low doses of ionizing rdition nd its dose-effect reltionship. Rdit. Environ. Biophys., 44, Ntionl Reserch Council. (26) Helth Risks from Exposure to Low Levels of Ionizing Rdition: BEIR VII Phse 2. The Ntionl Acdemies Press, Wshington, DC, USA. 4. Little, M. P. (29) Cncer nd non-cncer effects in Jpnese tomic bomb survivors. J. Rdiol. Prot., 29, A43 A Ullrich, R. L. nd Ponniy, B. 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