radiobiology in cardiovascular...

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STATE-OF-THE-ART PAPER

Radiobiology in Cardiovascular Imaging
Pat Zanzonico, PHD, Lawrence Dauer, PHD, H. William Strauss, MD
ABSTRACT

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The introduction of ionizing radiation in medicine revolutionized the diagnosis and treatment of disease and dramatically

improved and continues to improve the quality of health care. Cardiovascular imaging and medical imaging in general,

however, are associated with a range of radiobiologic effects, including, in rare instances, moderate to severe skin

damage resulting from cardiac fluoroscopy. For the dose range associated with diagnostic imaging (corresponding to

effective doses on the order of 10 mSv [1 rem]), the possible effects are stochastic in nature and largely theoretical. The

most notable of these effects, of course, is the possible increase in cancer risk. The current review addresses radiobiology

relevant to cardiovascular imaging, with particular emphasis on radiation induction of cancer, including consideration of

the linear nonthreshold dose-response model and of alternative models such as radiation hormesis.

(J Am Coll Cardiol Img 2016;9:1446–61) © 2016 by the American College of Cardiology Foundation.

T he use of ionizing radiation in medicine hasrevolutionized the diagnosis and treatmentof disease. Radiation-based imaging tech-

niques continue to improve the quality of healthcare. As a result of the documented value of diagnosticimaging, the use of these techniques has growndramatically over the last several decades (1). A recentAmerican College of Radiology white paper (2) re-ported that the annual number of nuclear medicineprocedures saw a 3-fold increase (from 7 million to 20million) and that the annual number of computed to-mography (CT) procedures was increased 20-fold(from 3 million to 60 million) between 1985 and 2005in the United States. This increase has led to an in-crease in exposure of the population to radiation,which in turn, raises concern over the radiogenic risksassociated with medical imaging. Reports of suchrisks, some alarmist in tone (3), in both the scientificand the lay media have led to thoughtful criticalevaluation of imaging procedures, with technicaloptimization, justification (i.e., elimination of trulyunnecessary procedures), and minimization ofimaging doses without compromising the diagnostic

m the Memorial Sloan Kettering Cancer Center, New York, New Yor

ationships relevant to the contents of this paper to disclose.

nuscript received April 21, 2016; revised manuscript received September

information being sought. However, the excessiveemphasis on radiogenic cancer risk can create themisconception that not only is radiation the only riskto be considered in medical imaging but also that thebenefit of imaging procedures may be outweighed bythe risk. It is in this context that the current reviewaddresses radiobiology relevant to cardiovascular im-aging, with particular emphasis on radiation inductionof cancer, including consideration of the linear non-threshold dose-response model and of alternativemodels such as radiation hormesis. Additional recentarticles on the radiobiologic effects of cardiovascularimaging are included in the references (4–6).

STOCHASTIC AND DETERMINISTIC EFFECTS

OF RADIATION

The radiobiologic effects of radiation are oftendistinguished as either stochastic (i.e., statistical) ornonstochastic (i.e., deterministic). The distinctionbetween stochastic and deterministic effects isperhaps best understood in terms of their respectiveprobability-dose and severity-dose relationships, as

k. The authors have reported that they have no

21, 2016, accepted September 22, 2016.

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcmg.2016.09.012&domain=pdf

http://dx.doi.org/10.1016/j.jcmg.2016.09.012

AB BR E V I A T I O N S

AND ACRONYM S

ICRP = International

Commission on Radiological

Protection

NCRP = National Council on

Radiation Protection and

Measurements

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 9 , N O . 1 2 , 2 0 1 6 Zanzonico et al.D E C E M B E R 2 0 1 6 : 1 4 4 6 – 6 1 Radiobiology in Cardiovascular Imaging

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illustrated in Figure 1. A stochastic effect is charac-terized by the absence of a threshold, meaning thatany radiation dose above background is associatedwith a corresponding finite (or non-zero) increase inthe probability above background of the effectoccurring. As the dose increases above background,this excess probability also increases. However, theseverity of the effect does not increase with dose; thatis, the severity of a stochastic effect is independent ofdose. Stochastic effects include radiation-inducedcarcinogenesis and germ cell mutagenesis and aregenerally associated with low-level (e.g., diagnostic)exposures. A deterministic effect is characterized by awell-defined threshold dose, meaning that the prob-ability of the effect occurring does not increase abovethe background probability until the threshold isexceeded. However, once the threshold dose isexceeded, the severity as well as the excess proba-bility of the effect increase with dose, with essentiallyall irradiated individuals exhibiting the effect (i.e.,the probability reaches 100%) at sufficiently highdoses; the dose-dependent probability increases in asigmoidal fashion typical of pharmacological dose-response curves. The range of effects of radiation onskin typifies deterministic effects, as discussedbelow. Deterministic effects are generally associated

FIGURE 1 Radiation Effects

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Stylized probability-dose and severity-dose relationships for stochastic

with high-level (e.g., therapeutic) radiationexposures.

At the cellular level, stochastic effectspresumably result from nonlethal geneticmutations, and in principle, the clonogenicproliferation of a single mutated cell mayprogress to a tumor. Although it is a grossoversimplification (and one which ignores
immunosurveillance and other homeostatic func-tions), this effect is mechanistically consistent withthe presumed absence of a threshold dose for a sto-chastic effect such as cancer induction. Induction of adeterministic effect, on the other hand, requireselimination by apoptosis or other cell-killing mecha-nisms of a critical mass of cells within 1 or morefunctional cell compartments in order to induce ademonstrable clinical effect. This is consistent with anon-zero threshold for such an effect and with thedose dependency of the severity as well as the prob-ability of deterministic effects.
For cardiovascular imaging, the radiation doses,expressed in terms of effective dose, are typically<10 mSv (1 rem); organ absorbed doses range from 10to 50 mGy (1 to 5 radiation dose [rad]), with mostorgan doses at the lower end of this range (6)(Figure 2). For cardiovascular imaging, as for

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Threshold

and deterministic effects.

FIGURE 2 Radiation Doses in Cardiovascular Imaging

0 5 10 15 20 25

Effective Dose (mSv)

Annual BackgroundRadiation (U.S.)

Chest X-Ray

Diagnostic CardiacCatheterization

Percutaneous CoronaryIntervention

Cardiac CT, RetrospectiveECG-Gating

Cardiac CT, ProspectiveECG-Triggering

CT Pulmonary Angiography

CT Thoracoabdominal Aorta

Dual Isotope 201TI/ 99mTc

Rest-Stress 99mTc

Rest 201TI

Low-Dose 99mTc Stress

18F-FDG-PET

InvasiveProcedures

CT

NuclearCardiacImaging

3

0.02

7

17

12

3

4

9

22

11

11

3

5

Effective doses for common cardiovascular imaging procedures with current instruments

and techniques. For comparison, the average annual effective dose per capita from natural

background radiation in the Unites States is also shown (6). Reproduced with permission

from Meinel et al. (6). 18F-FDG-PET ¼ 18F-labeled-fluorodeoxyglucose positron

emission tomography; 99mTc ¼ Technetium isotope; CT ¼ computed tomography;

ECG ¼ echocardiography.

Zanzonico et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 9 , N O . 1 2 , 2 0 1 6

Radiobiology in Cardiovascular Imaging D E C E M B E R 2 0 1 6 : 1 4 4 6 – 6 1

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diagnostic imaging generally, the radiation effects ofpractical concern are therefore largely low-level sto-chastic effects, most notably, possible carcinogenesis.As discussed below, however, there are also potentialrisks of noncarcinogenic effects and even of deter-ministic effects associated with cardiovascularimaging.

RADIATION EFFECTS OF CARDIOVASCULAR

IMAGING: NONCARCINOGENIC

REPRODUCTIVE EFFECTS INCLUDING GERM CELL

MUTAGENESIS. Sex, or germ, cells (i.e., sperm andeggs) are among the most radiosensitive cells in thebody. As reviewed by Hall and Giaccia (7), gonadalirradiation can result in adverse effects on reproduc-tive function, ranging from heritable mutations insperm and eggs to impaired fertility and even per-manent sterility at sufficiently high doses. Testiculardoses as low as 0.15 Gy (15 rad) result in oligospermiaand doses >0.5 Gy (50 rad) in azoospermia andtherefore temporary sterility (with latent periods ofseveral months after exposure). The duration of ste-rility is dose-dependent, ranging from <1 year atdoses up to 1 Gy (100 rad) to several years at doses of2 to 3 Gy (200 to 300 rad); sterility may be permanent

at gonadal doses of 5 to 6 Gy (500 to 600 rad) orgreater. Ovarian doses required to induce permanentsterility range from 12 Gy (1,200 rad) in pre-pubescentfemales to 2 Gy (200 rad) in sexually mature,pre-menopausal females. Because eggs are non-proliferating (in contrast to spermatozoa), there is nosignificant latent period associated with radiogenicinfertility in females.

Aside from the issue of radiogenic impairment offertility and as early as the 1920s, Hermann Muller, inhis Nobel Prize-winning work, reported that exposureto X-rays could cause demonstrable germ cell muta-tions resulting in heritable effects (ranging fromchange in eye color to recessive lethal mutations) inthe offspring of irradiated fruit flies (Drosophilamelanogaster) (8). A “doubling dose” (i.e., the gonadalradiation dose which increases the overall rate ofmutations in a defined set of genes to twice thespontaneous rate) as low as 5 roentgen (R) (equivalentto 5 cGy or 5 rad) was estimated from these data; thisfinding was largely the original basis for establishinga maximum permissible dose limit of 5 cGy (5 rad) peryear for occupationally exposed individuals in the1950s (9–11). At about the same time, the husband andwife team of W.L. and L.B. Russell at the Oak RidgeNational Laboratory initiated what came to be knownas the “megamouse project,” to determine locus-specific mutation rates in mice under various irradi-ation conditions (including widely varying doses anddose rates) (12,13). This seminal work demonstrated awide (w30-fold) variation in the sensitivity of specificgenes to radiogenic mutations; a pronounced dose-rate effect; and the maximal elimination (i.e., repair)of radiogenic mutations in germ cells if conceptionwere delayed at least 2 months post-irradiation (cor-responding to w6 months in humans). In addition tothe Russells’ non-human studies, germ cell muta-genesis and its possible effects have been extensivelystudied among subsequently conceived offspring (atotal of >30,000 children) of A-bomb survivors whoreceived significant but nonlethal doses of radiation(mean gonadal dose: 0.3 to 0.4 Gy [30 to 40 rad]).There was no significant increase among these chil-dren in the incidence of genetic abnormalitiescompared to that in a matched population born tounexposed Japanese parents (a total of >40,000control children) (14–16). Despite the absence of anydemonstrable genetic effects, statistical analysis hasbeen used to derive estimates of the mutation rate inhuman populations exposed to low-linear energytransfer, chronic, or low-dose-rate irradiation, withthe risk per million live-born progeny in the first (F1)generation as follows (17): autosomal dominant andX-linked diseases: 750 to 1,500 cases/Gy (7.5 to 15.0

FIGURE 3 Congenital Abnormalities and Perinatal Death From In Utero Irradiation

100

80

60

40

20

00 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Mouse

1 2 4 6 9 12 16 20 25 29 32 37 41 45 54 70Human

(%)

Inci

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Pre-implantation Organogenesis Fetus

Days of Post-Conception

Pre-natalDeath

CongenitalAbnormalities

NeonatalDeath

Incidence (percentage) of congenital abnormalities and of pre-natal and neonatal death

in mice receiving an x-ray absorbed dose of 2 Gy in utero as a function of gestational age

(23,26). Adapted with permission from Hall and Giaccia (23).


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cases/rad); autosomal recessive: w0 cases/Gy(0 cases/rad); chronic multifactorial diseases: 250 to1,200 cases/Gy (2.5 to 12.0 cases/rad); and congenitalabnormalities: w2,000 cases/Gy (20 cases/rad). Thetotal risk is therefore on the order of 3,000 to 4,700cases/Gy (30 to 47 cases/rad), which represents 11 to17 %/Gy (0.11 to 0.17 %/rad) of the baseline frequency(28,000 per million for Mendelian and chromosomaldiseases). This corresponds to an overall doublingdose of the order of 1 Gy (100 rad).

Patient gonadal doses in cardiovascular imagingare generally quite low, ranging from well under 1 cGy(1 rad) for cardiovascular fluoroscopy and cardiac CTto w1 cGy (1 rad) for nuclear cardiology (18–20); thevery low doses associated with radiographic imagingprocedures, of course, are due to the fact that thegonads are distant from the heart and receive only ascattered radiation dose. Even for interventional ra-diologists performing cardiovascular fluoroscopy,occupational gonadal (i.e., under-apron) doses are onthe order of only 10 mGy (1 mrad), or roughly 10 mGy(1 rad) per year (21,22). Thus, for patients undergoingcardiovascular imaging procedures and for personnelinvolved in performing such procedures, it is unlikelythat there is any practically demonstrable risk ofeither radiogenic impairment of fertility or of germcell mutagenesis.

TERATOGENESIS. The embryo and fetus are highlyradiosensitive, and radiation effects on the conceptusinclude lethality, congenital abnormalities, growthretardation, and childhood cancer (23). The proba-bility these effects will occur depends on the dose(Figure 3), gestational age at the time of irradiation(Figures 3 and 4), and dose rate (Table 1) (24–26). Theteratogenic effects of lethality, congenital abnormal-ities, and growth retardation are deterministic effectsand thus characterized by a well-defined thresholddose. As illustrated, for example, in Figure 4, for theincreased incidence of severe mental retardationamong children irradiated in utero at the time of theatomic bombings of Hiroshima and Nagasaki, thethreshold dose appears to be at least 0.23 Gy (23 rad)and possibly as high as 0.64 Gy (64 rad), with themaximal risk resulting when fetal irradiation isdelivered at 8 to 15 weeks post-conception (24).Importantly, radiation doses to the embryo or fetusassociated with cardiovascular imaging (includingfluoroscopy) are only 1 to several cGy (1 to several rad)(18,27,28) and thus at least 1 order of magnitude lowerthan the threshold dose for deterministic effects onthe conceptus. These effects, therefore, are not ofpractical concern in the context of cardiovascularimaging.

CARDIOVASCULAR EFFECTS. Although high (i.e.,therapeutic) doses of ionizing radiation have longbeen associated with cardiovascular disease andcirculatory disease in general (29,30), a causativerelationship between such diseases and lower(i.e., diagnostic or occupational) exposures remainssomewhat less apparent (31–34). In addition to thatprovided by the LSS (Life-Span Study) of atomic bombsurvivors (31–34), a recent meta-analysis by Littleet al. (35) appears to have found evidence for sucha relationship. Using peer-reviewed publicationsreporting the incidence of circulatory disease(including ischemic heart disease) following cumula-tive mean whole-body doses <0.5 Sv (50 rem) andcurrent mortality rates for 9 developed countries,excess relative risks of circulatory disease were esti-mated. Excess population risks for all circulatorydiseases combined ranged from 2.5%/Sv (95% confi-dence interval [CI]: 0.8%/Sv to 4.2%/Sv) for France to8.5%/Sv (95% CI: 4.0%/Sv to 13.0%/Sv) for Russia.There are still concerns with occupational studiesbecause of confounding background risk factors forcardiovascular disease. Although much uncertaintystill exists, whether such associations between low-level radiation exposure and circulatory diseasesactually reflect an underlying causal dose-responserelationship that remains linear at low doses, the

FIGURE 4 Mental Retardation in Children Irradiated In Utero

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Control(0.00)

0.01-0.09(0.05)

0.10-0.49(0.23)

0.50-0.99(0.64)

1.00+(1.38)

Fetal Dose (Gy)

All Ages 8-15 Weeks 9-25 Weeks >26 Weeks

Incidence (percentage) of severe mental retardation in children irradiated in utero at the time of the atomic bombings of Hiroshima and

Nagasaki (combined data) as a function of absorbed dose, stratified according to gestational age at the time of the bombings (24).

Reproduced with permission from the National Academies Press (24).

TABLE 1 Dose Rate Effect in Radiation Teratogenesis

Abnormality

Dose Rate, Gy/min (rad/min)*

1 (100) 0.3 (30) 0.01 (1) 0.005 (0.5)

Microcephaly 9.1 41 20 0

Anencephaly 30 14 3 0

Absent kidney 21 6 2.6 0

Cleft palate 52 38 18 12

Limb malformation 44 16 3.1 1.3

*The percentage of rat pups with severe congenital abnormalities following a1.5-Gy (150-rad) dose in utero decreases sharply, for some effects to 0, as thedose rate decreases from 1 to 0.005 Gy/min (100 to 0.5 rad/min) (25).



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overall excess risk of mortality after low-dose expo-sure may be approximately twice that currentlyassumed based on estimated risks of mortality due toradiation-induced cancers alone. However, it shouldbe noted that the current state of relevant epidemi-ological evidence has led some (e.g., Akiba [36]) toconclude that the currently available findings “do notconstitute convincing evidence for an excess risk ofcirculatory disease in relation to low-level radiationexposure” (36). One of the difficulties is that there isan absence of a broadly accepted radiobiologicalmechanism that plausibly explains the apparentepidemiological associations between low-dose radi-ation and cardiovascular diseases. There is clearly aneed for additional epidemiological and mechanisticstudies in this area.

CATARACTOGENESIS. The lens of the eye has longbeen recognized as one of the most radiosensitivetissues in the body, with cataracts induced bydoses <2 Gy (200 rad) and protracted doses <5 Gy(500 rad) (37). The exact mechanism of radiationcataractogenesis remains unclear, however. Althoughcataractogenesis has historically been considereda deterministic effect with a threshold of w2 Gy(200 rad), recent studies, including those of A-bombsurvivors, American astronauts, and Chernobylclean-up workers, suggest a much lower thresholddose, perhaps on the order of 0.5 Gy (50 rad) or less

(37–39). Such studies further suggest that the dose-response relationship for radiation cataractogenesismay actually follow a linear, no-threshold model.Cataractogenesis is unique among radiation risksassociated with medical imaging procedures in thatthere is a potentially significant risk to imagingpersonnel directly involved in some such procedures,specifically, fluoroscopy (40–44). Combined with therelatively high patient doses delivered by the pri-mary x-ray beam and the close proximity of thefluoroscopist to the patient during the actual beam-ontime, radiation scattered from the patient may deliversignificant doses to the fluoroscopist’s eyes and thuspose a significant risk of radiation cataractogenesis.The results of several recent studies of interventional

TABLE 2 Lens Exposure While Operating at Patient’s Upper Abdomen During Low-Dose Posterior-Anterior, Left Anterior Oblique, and

Right Anterior Oblique Fluoroscopy and the Impact of Various Shielding Strategies (51)

Shielding Strategy

Posterior-Anterior 15� Left Anterior Oblique 15� Right Anterior Oblique

Lens-Dose RateLens Dose

Reduction Factor

Lens Dose RateLens Dose

Reduction Factor

Lens Dose RateLens Dose

Reduction FactormSv/h mR/h mSv/h mR/h mSv/h mR/h

Image intensifier at 3 cm (close) 0.32 37.0 – 0.946 108.0 – 0.171 19.5 –

Plus leaded table skirt 0.217 24.8 RM 0.79 90.0 RM 0.156 17.8 RM

Plus unleaded eyeglasses 0.205 23.5 1.0 0.74 85.0 1.1 0.153 17.5 1.0

Plus leaded eyeglasses 0.04 4.6 5.4 0.101 11.5 7.8 0.024 2.7 6.6

Plus scatter-shielding drape 0.033 3.8 6.5 0.087 10 9.0 0.035 4.0 7.2

Plus leaded eyeglasses andscatter-shielding drape

0.007 0.77 32.2 0.014 1.6 56.3 LLD LLD >1,000

Plus ceiling-suspended shield LLD LLD >1,000 LLD LLD >1,000 LLD LLD >1,000

LLD ¼ below the lower limit of detection; RM ¼ reference measurement.


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radiologists and other staff performing fluoroscopiccardiovascular imaging, in fact, suggest a causalrelationship between cataracts (or at least lens opa-cifications) and occupational radiation exposure(37,41,43,45). In the 2010 study by Ciraj-Bjelac et al.(43), for example, interventional radiologists andnurses and age- and sex-matched unexposed controlswere screened for lens opacities according to dilatedslit-lamp examination and posterior lens changesgraded using a modified Merriam-Focht technique.Individual cumulative lens x-ray exposure wascalculated from responses to a questionnaire andpersonal interview. The prevalence of radiation-associated posterior lens opacities was 52% (29 of 56participants; 95% CI: 35% to 73%) for interventionalradiologists, 45% (5 of 11 participants; 95% CI: 15% to100%) for nurses, and 9% (2 of 22 participants; 95% CI:1% to 33%) for controls. The relative risks of lensopacity, therefore, were 5.7 (95% CI: 1.5 to 22) forinterventional radiologists and 5.0 (95% CI: 1.2 to 21)for nurses. The estimated cumulative eye dosesranged from 0.01 to 43 Gy (1 to 4,300 rad) with meanand median values of 3.4 and 1.0 Gy (340 and 100rad), respectively. Importantly, in addition to therelatively small number of study subjects, individualcumulative lens doses were derived by calculationbased on responses to a questionnaire and personalinterview rather than by direct measurement. Theseand other data nonetheless suggest a significant dose-response relationship between occupational exposureand the incidence of posterior lens changes.

Based on the foregoing and other such data, theInternational Commission on Radiological Protection(ICRP) recently recommended reducing the annualdose limit to the lens of the eye for occupationallyexposed individuals from its current value of 150 mSv(15 rem) to 20 mSv (2 rem) (46). Although this

recommended lens-of-eye dose limit has not yet beenimplemented in the United States, the Electric PowerResearch Institute recently reviewed the availableepidemiologic research (47), and the National Councilon Radiation Protection and Measurement (NCRP) ispreparing an updated commentary addressing theissues of risk and dose limitation in radiation pro-tection and including guidance on the lens of the eye(48). At the same time, various shielding strategieshave been investigated to evaluate their impact inreducing eye dose in fluoroscopy (48–53). Forexample, using an anthropomorphic phantom and aminiature solid-state dosimeter positioned at thephantom’s eye, Thornton et al. (51) evaluated theimpact of common shielding strategies used aloneand in combination on the scattered dose to thefluoroscopy operator’s eye. The dose rate was recor-ded with and without a leaded table skirt, nonleadedand leaded (0.75-mm lead equivalent) eyeglasses,disposable tungsten-antimony drapes (0.25-mm leadequivalent), and suspended and rolling (0.5-mm leadequivalent) transparent leaded shields. Each strat-egy’s shielding efficacy was expressed as a reductionfactor equal to the ratio of dose rate without eyeshielding to that with shielding. The results for anoperator positioned at the patient’s upper abdomenand for posterior-anterior and left and right anterioroblique views are presented in Table 2. Use of leadedglasses alone reduced the lens dose rate by a factor of5 to 10; scatter-shielding drapes alone reduced thedose rate by a factor of 5 to 25. Use of both togetherwas always more protective than either used alone,reducing dose rate by a factor of 25 or more. Lens dosewas routinely undetectably low when a suspendedshield was the only barrier used during low-dosefluoroscopy. Clearly, such practical shielding strate-gies, especially when used in combination, can

TABLE 3 Dose- and Time-Dependent Deterministic Effects of Radiation on Human Skin (55,56)

Absorbed Dose,Gy (rad)

National CancerInstitute Grade

Approximate Time of Onset of Effects Post-Irradiation

Prompt: <2 Weeks Early: 2–8 Weeks Mid-Term: 6–52 Weeks Long-Term: >40 Weeks

0–2 (0–200) Not applicable No observable effects expected No observable effectsexpected

No observable effectsexpected

No observable effects expected

2–5 (200–500) 1 Transient erythema Epilation Recovery from hair loss No observable effects expected

5–10 (500–1,000) 1 Transient erythema Erythema and epilation Recovery; after higher doses,prolonged erythema andpermanent partialepilation expected

Recovery; after higher doses,dermal atrophy andinduration expected

10–15 (1,000–1,500) 1–2 Transient erythema Erythema and epilation;possible dry or moistdesquamation; recoveryfrom desquamation

Prolonged erythema;permanent epilation

Telangiectasia; dermal atrophyand induration expected;skin expected to be weak

>15 (1,500) 3–4 Transient erythema; after veryhigh doses, edema and acuteulceration expected, withsurgical intervention mostlikely required longer term

Erythema and epilation;moist desquamation

Dermal atrophy; secondaryulceration due to failure ofmoist desquamation toheal, with surgicalintervention most likelyrequired

Possible late skin breakdown;wound might persist andprogress to deeper lesion,with surgical interventionmost likely required

Reproduced with permission from Balter et al. (56).



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dramatically reduce the eye dose and thus the risk ofcataractogenesis (54).

SKIN DAMAGE. In cardiovascular fluoroscopy andinterventional imaging generally, skin absorbed dosescan be up to several Gy (several hundred rad) (54–58).The acute threshold absorbed dose for skin effects (w2Gy [200 rad]) (Table 3) may therefore be exceeded(55,56). In rare instances, skin doses may be consid-erably higher than 2 Gy (200 rad) and result in necroticdamage so severe as to necessitate surgical interven-tion (Table 3, Figure 5) (55,56), particularly as fluoro-scopically guided procedures have become morecomplex and beam-on times have increased. Largelyfor this reason, in 1994, the U.S. Food and DrugAdministration issued a health advisory entitled“Avoidance of Serious X-ray Skin Injuries to Patientsduring Fluoroscopically Guided Procedures” (59) andestablished regulatory limits for the entrance doserate, specifically for the air kinetic energy released perunit mass (KERMA) rate (AKR). With certain excep-tions, the AKR shall not exceed 88mGy/min (10 R/min)at the measurement point. (The foregoing regulatorylimit applies specifically to fluoroscopic equipmentmanufactured on or after May 19, 1995. If the x-raysource is below the patient table, the AKR shall bemeasured at 1 cm above the tabletop. If the source isabove the table, the AKR shall be measured at 30 cmabove the tabletop with the end of the beam-limitingdevice or spacer positioned as closely as possible tothe point of measurement. In a C-arm type of fluoro-scope, the AKR shall be measured at 30 cm from theinput surface of the fluoroscopic imager.) The Food

and Drug Administration subsequently amended itsregulation entitled “Performance Standards forIonizing Radiation Emitting Products. FluoroscopicEquipment” (60). The additions required that fluoro-scopic equipment manufactured after June 10, 2006display both AKR and cumulative air KERMA in orderto provide the fluoroscopist with real-time patient ra-diation dose data, with the intent that such informa-tion would result in reduced radiation doses.

RADIATION EFFECTS OF

CARDIOVASCULAR IMAGING:

CARCINOGENESIS

Despite the various noncarcinogenic risks associatedwith cardiovascular imaging and medical imaging ingeneral, the principal radiation risk of practicalconcern remains the possibility of cancer induction.The scale of this risk appears to differ sharply be-tween pre- and post-natal irradiation. The actual risk,if any, of radiation carcinogenesis at diagnostic andother comparably low doses remains highly contro-versial, and some have argued that there is, in fact, ahormetic (or protective) effect against the develop-ment of cancer at doses at or below w0.1 Sv (10 rem).The findings on radiation carcinogenesis and on ra-diation hormesis are extensive and continue to grow,and even a cursory review of these reports is beyondthe scope of the current article. However, a brief re-view of pre- and post-natal radiation carcinogenesisand of radiation hormesis is provided.

PRE-NATAL IRRADIATION. In contrast to the deter-ministic, high-dose effects of irradiation of the embryo

FIGURE 5 Skin Reactions From Excessive Fluoroscopic Irradiation

Photographs of representative skin reaction grades resulting from excessive fluoroscopic irradiation and corresponding to those described in

Table 3. (A) Grade 1; (B) grade 2; (C) grade 3; (D) grade 4 (55,56). Reproduced with permission from Balter et al. (55) and Granel F, Barbaud

A, Gillet-Terver MN, et al. Chronic radiodermatitis after interventional cardiac catheterization: four cases [in French]. Ann Dermatol Venereol

1998;125:405–7.


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and fetus (discussed above), the increased risk ofchildhood cancer, a stochastic effect, associated within utero irradiation is worrisome even at diagnosticradiation doses. The NCRP recently published adetailed review and evaluation of pre-conception andpre-natal radiation exposure health effects (61). Orig-inally, the Oxford Survey of Childhood Cancers in the1950s suggested an association between an increasedrisk of childhood cancer, principally leukemia, andexposure in utero to diagnostic x-rays (62). In thatretrospective case-control study, of 7,649 childrenwho died of cancer, 1,141 had been x-rayed in utero;among the controls (i.e., children who did not developcancer), only 774 had been irradiated in utero. Thisyields a crude hazard ratio of 1,141:774 ¼ 1.47 (i.e., a47% increase) for childhood cancer per obstetric x-rayexamination. The children underwent irradiation for 1to 5 films, with a fetal dose per film ofw3mGy (0.3 rad);

the estimated doses have a large uncertainty, however.The apparent carcinogenicity of in utero irradiation atdiagnostic levels remains controversial. For example,in a more recent population-based study (63) inOntario, Canada, from 1991 to 2008, 5,590 mothersunderwent diagnostic imaging studies (73% were CTscans and 27% were nuclear medicine scans), and1,829,927 mothers did not. After a median follow-up of8.9 years, 4 childhood cancers developed in theexposed group (1.13 per 10,000 person-years) and 2,539in the unexposed group (1.56 per 10,000 person-years),yielding a hazard ratio of 0.68 (95% CI: 0.26 to 1.8),suggesting therefore that diagnostic imaging in preg-nancy is not carcinogenic. Although the associationbetween in utero irradiation and childhood cancerappears to be incontrovertible, the question remainswhether this is a causative relationship or an exampleof “reverse causation” (64): because pregnant women



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were referred for imaging for some medical problem,their childrenmight have been at a naturally increasedrisk for cancer due to their mother’s underlying med-ical condition rather than as a result of any diagnosticirradiation. The preponderance of evidence, however,suggests a causative relationship between diagnosticirradiation in utero and an increased risk of childhoodcancer. The relevant studieswere reviewed in detail byDoll and Wakeford (65), who concluded that a typicalobstetric x-ray examination (corresponding to a fetalradiation doses of w10 mGy [1 rad]) results in an in-crease in the incidence of childhood cancer ofapproximately 40%, with an excess absolute risk ofw5%/Gy (0.05%/rad). In light of such a significant riskof childhood cancer associated with (and possiblycausatively related to) diagnostic imaging studies,prudence dictates that proceeding with such a study ina pregnant (or possibly pregnant) female should bebased on a considered and documented decision as toits medical necessity despite the foregoing risk. Thisdecision should include consideration not only ofalternative procedures not involving irradiation of theconceptus but also of the timeliness (or not) of theavailability of such procedures relative to the urgencyof obtaining the diagnostic information being sought.For fluoroscopic and CT examinations of the heart, thedose (i.e., the scattered-radiation dose) to the embryoor fetusmay be so low, well below 1 cGy (1 rad), that thedecision to proceed with the examination will bejustified in almost all cases; for nuclear cardiologystudies, however, where doses to the conceptus maybe as high as 1 to several cGy (1 to several rad), the de-cision to proceedmay be less clear-cut but nonethelessgenerally justified.

POST-NATAL IRRADIATION. Although the possibilityof induction of a subsequent cancer in an unborn childfrom in utero diagnostic irradiation is understandablyworrisome, a concern more frequently encountered isthe risk of radiation carcinogenesis resulting fromimaging studies in pediatric and adult patients. Thechallenge in assessing this risk is that there are fewreliable data in humans that quantify an increasedcancer incidence, if any, following diagnostic radia-tion doses (i.e., <w100 mSv [10 rem]). Unfortunately,no prospective epidemiologic studies with appro-priate nonirradiated controls have definitely demon-strated either the adverse (or hormetic, i.e., beneficial)effects of radiation doses <100 mSv (10 rem), andcurrent estimates of the risks of low-dose radiationsuggest that large-scale epidemiological studies withlong-term follow-up would be needed to actuallyquantify any such risk or benefit; such studies may belogistically and financially prohibitive.

The most creditable dose-response data for radi-ation carcinogenesis in humans involve mainlydoses 1 to 2 orders of magnitude greater than thoseencountered in diagnostic imaging studies, on theorder of 1 Sv (100 rem) and greater, including mostnotably, A-bomb survivor follow-up data. A handfulof high-profile studies, however, have reportedcancer risks derived from relatively low-dose expo-sures. Pierce and Preston (66), for example, pub-lished an analysis of A-bomb Radiation EffectsResearch Foundation data for cancer risks amongsurvivors receiving doses <0.5 Sv (50 rem), withw7,000 cancer cases among w50,000 low-dose sur-vivors. They concluded that cancer risks are notoverestimated by linear risk estimates computedover the dose range 0.05 to 0.1 Sv% [10 rem]), with astatistically significant risk in the range of 0 to 0.1 Sv(0 to 10 rem) and an upper confidence limit on anypossible threshold of 0.06 Sv (6 rem). The UnitedKingdom CT study (67,68), a record-linkage study ofleukemia and myelodysplastic syndrome and ofbrain cancer incidence following CT scans of 178,000pediatric patients (0 to 21 years of age), reportedexcess relative risks (see below) of 36/Gy (0.36/rad)for leukemia and myelodysplastic syndrome and of23/Gy (0.23/rem) for brain cancer. These values arehigh, and critical evaluation of this study citedabsence of individual scan parameters and thereforeorgan doses for individual patients and, again, thepossible confounding effect of reverse causation(64,69). In the INWORKS (Ionising Radiation andRisk of Death from Leukaemia and Lymphoma inRadiation-monitored Workers) study (70–73), an in-ternational cohort study of more than 300,000workers (more than 8.2 million person-years) in thenuclear industry with detailed external dose data(mean dose: 21 mGy [2.1 rad]), the reported excessrelative risk for all cancers was 0.51/Gy (95% CI: 0.23to 0.82/Gy [0.0051/rad; 95% CI: 0.0023 to 0.0082/rad]). In addition to possible uncertainty inpersonnel dose estimates, smoking and occupationalasbestos exposure were identified as potential con-founding factors; however, exclusion of deaths fromlung cancer and pleural cancer did not affect theassociation of cancer risk and occupational radiationexposure.

Estimation of the excess cancer risk from imagingstudies and other low-dose exposures requiresmathematical extrapolation of high-dose dose-response data to the lower diagnosis-dose range.There are at least several distinct dose-responsemodels for radiation carcinogenesis which can beused for this extrapolation: the supralinear model,the linear no-threshold (LNT) model, the sublinear (or

CENTRAL ILLUSTRATION Dose-Response Curves for Radiation Carcinogenesis

Zanzonico, P. et al. J Am Coll Cardiol Img. 2016;9(12):1446–61.

Stylized dose-response curves for radiation carcinogenesis for the supralinear, linear no-threshold (LNT), sublinear (or linear-quadratic), and

hormetic models. Note that for the hormetic model the excess incidence becomes negative at low radiation doses, indicating a cancer

incidence less than the naturally occurring incidence and thus a radioprotective effect.


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linear-quadratic [LQ]) model, and the hormesis model(Central Illustration).

The supralinear model implies that the cancer riskper unit dose (i.e., the risk per Sv or per rem) isgreater at lower than at higher doses. There are nodata or mechanistic considerations which supportsuch a model, and thus, it is not a creditable optionfor extrapolation of high-dose cancer risk estimates todiagnostic doses.

The LNT model, which implies a uniform cancerrisk per unit dose from higher to lower doses, is themodel currently recommended by authoritativeadvisory bodies such as the ICRP (74), the NCRP(75,76), and the United Nations Scientific Committeeon the Effects of Atomic Radiation (77) and adoptedby regulatory agencies such as the Nuclear RegulatoryCommission (78). As the name LNT indicates, alsoimplicit in this model is the fact that there is no

threshold dose for radiation carcinogenesis; that is,there is no radiation dose above background belowwhich there is not a finite increase in cancer risk. Theexcess absolute risk is the number of excess fatalcancers per number of irradiated individuals (excessabove the naturally occurring incidence) predicted bythe model in a large (and therefore sex- and age-averaged) population exposed to a uniform whole-body dose (or effective dose) of radiation. Theexcess relative risk (ERR) is the excess absolute riskdivided by the naturally occurring incidence of fatalcancer and may be expressed as either a fraction or apercentage per unit of effective dose. The excessnumber of fatal cancers in an irradiated populationusing the LNT model can then be calculated as [thenumber of persons exposed � effective dose (rem ormSv) per person � ERR (/rem or/mSv)]. A widely citedERR value is that recommended by the NCRP Report

FIGURE 6 Radiation Hormesis in Preclinical Models

100

80

60

40

20

0

-20

100 200 300 400 500 600

Dose (mGy)

Per

cen

t Pro

tect

ion

18 Studies

Dose dependence of the radioprotective, or hormetic, adaptive response of acute low-dose irradiation in preclinical models. Each observation

point of protection per study was plotted individually as a function of dose, yielding a total of 54 observation points. The categories of

response included molecular-level, cellular-level, and cancer-level responses and included enzyme inactivation, DNA repair changes, and

chromosomal changes such as micronuclei formation, cell death, immune response, experimental cancer, and metastasis induction, and by-

stander protection. Reprinted with permission from Feinendegen (83).



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115 (79), 5 � 10�5 per person per mSv (or 5 � 10�4 perperson per rem). Thus, if a population of a millionpeople each received an effective dose of 10 mSv(1 rem), the expected number of excess fatal cancersobserved in this population over the balance of thelifetimes of the individuals in this population wouldbe 1 � 106 persons � 10 mSv � 5 � 10�5 person/mSv ¼500. This compares to the spontaneous, or back-ground, lifetime incidence of w300,000 (or 30%)otherwise occurring in such a population; this corre-sponds to an increase in overall incidence ofonly 0.17% (¼ [500/300,000] � 100%). Importantly,even if one concedes the accuracy of the LNT model,it cannot be applied reliably to individuals but only tolarge populations (74); that is, populations suffi-ciently large that differences in radiation sensitivityrelated to sex, age, diet, and other lifestyle effectsand intrinsic biology are effectively averaged out.

The sublinear, or LQ, model implies that the excesscancer risk per unit dose is lower at lower than athigher does and further implies the possibility of atleast a practical threshold dose for radiation carcino-genesis, that is, a non-zero dose below which there isno demonstrable increase in cancer incidence.

According to the hormesis model, individualsexposed to low radiation doses actually have a

lower subsequent risk of cancer than unexposedindividuals (Central Illustration), presumably as aresult of radiogenic upregulation of cellular repairmechanisms or other adaptive response(s) (80,81).Although radiation hormesis had been largelydismissed for many years, there are mounting cred-itable data in peer-reviewed studies supportingthis phenomenon (82). Feinendegen (83), for ex-ample, recently reviewed a number of preclinicalstudies demonstrating radiation hormesis and, inparticular, radioprotective adaptive responses to low-dose irradiation (Figure 6) and concluded that radia-tion doses <w600 mGy (60 cGy) induced a pro-nounced (w50%) protective effect against a variety ofmolecular, cellular, and whole-animal radiation ef-fects (83).

Some argue that the data and associated analysessupporting the LNT model are further refuted byepidemiologic and experimental studies and that thismodel overstates the risk of radiation carcinogenesisat doses on the order of 100 mSv (10 rem) and less anddoes not account for creditable evidence for athreshold for cancer induction, that is, a non-zeroradiation dose below which there is no increasedrisk of cancer (84–87). Others argue that the prepon-derance of data, especially epidemiology data,

FIGURE 7 Risk of Cancer Among A-Bomb Survivors

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

-0.2

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Weighted Colon Dose (Gy)

ER

R

LQ (< 2 Gy) LQ

L

Excess relative risk for all solid cancers as a function of colon absorbed dose (as a surrogate for effective dose) in the A-bomb LSS. Black

circles represent ERR and 95% CI for the dose categories, and the solid lines represent the fits of the L (with 95% CI [dotted lines]) and LQ

models to these data. The fit of the LQ model for the data restricted to doses <2 Gy (LQ < 2 Gy) is also shown (32). Reprinted with permission

from Ozasa et al. (32). ERR ¼ excess relative risk; L ¼ linear; LQ ¼ linear-quadratic; LSS ¼ life-span study.


1457

support or at least are consistent with an LNT dose-response model down to the low-dose range (76,88).The validity, applicability, and utility of the LNTmodel and of alternative models thus remainscontroversial and subject to often contentious debate(86,89–92). As John Boice, president of the NCRP, hasaptly stated, “LNT is not TNT, but differences inopinions sometimes appear explosive!” (93). Forexample, the attitude of a number of investigatorswith respect to the LNT model was recently expressedby Calabrese (94).

“[T]he evidence used by the US NationalAcademy of Sciences (NAS) Biological Effects ofAtomic Radiation (BEAR) I Committee, GeneticsPanel, in 1956 to usher LNT into its dominantposition in cancer risk assessment is highlyproblematic. The Genetics Panel did not baseits assessment on appropriate studies, and theresearch record was falsified and fabricated toenhance acceptance of its LNT recommenda-tion. The Genetics Panel also failed to providea justification for the switch from the thres-hold to the linear model. However, as a regu-latory tool, LNT had two attractive features:namely, ease of application and likelihood to

consistently overestimate risk (U.S. Inter-agency Staff Group 1986). Therefore, once theNAS recommendation for LNT was accepted,risk estimates became highly sensitive to theLNT model, making the latter a regulatory goldstandard without adequate validation.” (94)

The dilemma over the LNT model and alternativemodels in deducing reliable low-dose factors forradiation carcinogenesis from high-dose data isillustrated in Figure 7, summarizing the dose-response data and different model fits to these datafor solid-cancer incidence in the A-bomb Life SpanStudy (LSS) trial (32). Several points are apparentupon examining these data. First, even for anexposed cohort as thoroughly well-characterized asthe LSS cohort, the uncertainties (in terms of the 95%CIs) of the dose-dependent ERRs and of the models fitto these data are rather large (on the order of 50%).This suggests, at least to some, that risk factorsderived from such data may be unreliable. Second,statistical rigor aside, one is challenged to discern anysort of practically meaningful distinction between thefits of the linear and the LQ models to these dose-response data, especially in the low-dose range.Third, one is likewise challenged to confirm or refute



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a non-zero threshold. Based on a rigorously derivedlinear model fit to these data, the sex-averaged ERRper Gy was 0.42 (95% CI: 0.32 to 0.53 [ERR per rad:0.0042; 95% CI: 0.0032 to 0.0053]) for all solid can-cers at 70 years of age after exposure at 30 years ofage. The estimated lowest dose range with a signifi-cant non-zero ERR for all solid cancer was 0 to 0.20Gy (0 to 20 rad), and a formal dose-threshold analysisindicated no threshold (i.e., zero dose) was the bestestimate of the threshold. However, an alternativeanalysis of the LSS data showed that an LQ model wasthe best fit for dose-response data restricted to doses<2 Gy, as the risk estimates for doses up to w0.5 Gywere lower than those predicted by the linear model(95). Using a nonparametric statistical procedure, thisre-analysis derived a threshold of 200 mSv (20 rem)with a negative ERR, suggesting a radiation hormesiseffect.

BENEFIT-RISK ANALYSIS IN

CARDIOVASCULAR IMAGING

Application with certitude of the LNT dose-responsemodel for radiation carcinogenesis has led some toderive alarming estimates of excess numbers of can-cers as a result of medical imaging, for example, inthe thousands annually among the U.S. population(3). Such exercises largely ignore the considerableuncertainties (including the possibility of zero excessrisk and even a hormetic effect) in deriving suchestimates at diagnostic doses. Noncritical applicationof the LNT model in the context of medical imagingthus undermines a reasonable benefit-risk calculusand may thus adversely impact patients’ medicalmanagement. Furthermore, although the point isoften made that the benefits of the uses of radiationin medicine are much greater than any theoreticalrisks, quantitative estimates of the benefits are notcited alongside any quantitative estimates of risk.This alone—the expression of benefit in purely qual-itative terms versus expression of risk in quantitative,and therefore seemingly more certain, terms—maywell contribute to a skewed sense of the relativebenefits and risks of diagnostic imaging among healthcare providers as well as patients. One benefit of adiagnostic imaging procedure may be expressed asthe lives saved, that is, the number of lives lost by notperforming the procedure or by performing an alter-native, invasive procedure. (There may be, of course,other metrics of benefit such as improvements in thequality of life, shortening of hospital stays, andreduction of medical care costs.)

One example of such a quantitative benefit-riskanalysis is use of scintigraphic myocardial perfusion

imaging to predict and thereby avoid perioperativecardiac events and associated mortality in noncardiacsurgery (96,97). The most important cause of peri-operative cardiac mortality and morbidity ismyocardial infarction due to occult coronary arterydisease. In a Veterans Administration (VA) series(98), the incidence and mortality of such eventsassociated with vascular surgery (most commonly,carotid endarterectomy) was 13% and 40% to 70%,respectively. Based on pre-operative dipyridamolethallium-201 (201Tl) imaging, the incidence of peri-operative cardiac events was 2% for a severity leveland an extent of 0 and 100% for a severity level of 3and extent of 5 to 6, with 22% of patients havingreversible perfusion defects. Thus, perfusion imagingwas highly accurate for prediction of perioperativecardiac events. The number of vascular surgeries(from the VA database) was w9,500 per year, and thenumber of perioperative cardiac deaths (i.e., fatalmyocardial infarctions) was, thus, estimated as9,500 � 0.13 � 0.40 ¼ 494 deaths per year. Of these494 perioperative cardiac deaths annually, 0.22 �494 ¼ 109 were detectable pre-operatively andtherefore avoidable; that is, the gross benefit of pre-operative perfusion imaging with 201Tl is 109 livessaved per year in the VA system. The effective dosefrom the 201Tl study is 24 mSv (0.024 Sv [2.4 rem])(6,20). Using the LNT-based lifetime risk factor (i.e.,ERR) of 0.05/Sv, a total of 9,500 � 0.05/Sv � 0.024Sv ¼ 11 excess cancer deaths per year is predicted,yielding a net benefit of pre-operative myocardialperfusion imaging of 109 � 11 ¼ 98 lives saved peryear. If one considers a rest/stress myocardialperfusion study using technetium 99m-labeled ses-tamibi (99mTc-MIBI), the ED is w12 mSv (1.2 rem)(6,20), leading to only 6 excess cancer deaths per yearand possible greater clinical benefit. Performing car-diac positron emission tomography (PET) withrubidium-82 (82Rb) chloride would result in an evenlower ED of w7.5 mSv (0.75 rem) (6,20), thus result-ing in a theoretical risk of only 3 cancer deaths and anet savings of 106 lives per year.

The foregoing analysis and similar benefit-riskanalyses demonstrate that cardiovascular imagingand diagnostic imaging in general saves many thou-sands of lives every year, although the theoretical andpossibly overestimated cancer risks predicted by theLNT model are typically much lower.

CONCLUSIONS

Cardiovascular imaging and medical imaging in gen-eral are associated with a range of radiobiologiceffects, including, in rare instances, moderate to


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severe skin damage resulting from cardiac fluoros-copy. However, for the dose range associated withdiagnostic imaging (corresponding to effective doseson the order of 10 mSv [1 rem]), the possible effectsare stochastic in nature and appear to be largelytheoretical. The most notable of these effects, ofcourse, is a possible increase in cancer risk. The actualrisk, if any, of radiation carcinogenesis at diagnosticand other comparably low doses remains highlycontroversial. Although the LNT model is the pre-vailing dose-response model, some have argued thatthere is a non-zero threshold dose for cancer induc-tion and, in fact, a hormetic (or protective) effectagainst the development of cancer at doses at orbelow w0.1 Sv (10 rem). In any case, application withcertitude of the LNT or any alternative dose-responsemodel is unjustified and has led some to derivealarming and possibly misleading estimates of excessnumbers of cancers as a result of medical imaging.Application of the LNT or alternative dose responsemodel to estimate radiogenic risks of medical imagingindividual patients or to defined cohorts of patients,in particular, is inadvisable.

The International Organization for Medical Physicsissued a policy statement highlighting the substantialuncertainties in estimating population cancer riskand noting the dangers of extrapolating risk estimatesfor radiation doses <100 mSv (10 rem) (99). The use ofrisk factors to estimate public health consequencesfrom individual or population exposures must beconsidered in the context of the attendant un-certainties. These include uncertainties relatedto dosimetry, epidemiology, low statistical power,

modeling radiation risk data, and generalization ofrisk estimates across different populations and doserates (100). Uncertainties in such risk estimates havebeen suggested as being up to a factor of 3 lower orhigher than the estimate value itself (101). Such largeuncertainties render projections of radiation-inducedcancers or other detriment highly susceptible tobiases and confounding influences that may beunidentifiable.

Several other professional societies and scientificbodies have provided guidance on the assessment ofrisk at diagnostic and other comparably low doses.The ICRP states, “There is.general agreement thatepidemiological methods used for the estimation ofcancer risk do not have the power to directly revealcancer risks in the dose range up to around 100 mSv”(74). The Health Physics Society advises against esti-mation of health risks below an individual dose of50 mSv in 1 year or a lifetime dose of 100 mSv abovethat received from natural sources (102), noting that“below this level, only dose is credible and statementof associated risks are more speculative than cred-ible” (102). Finally, the American Association ofPhysicists in Medicine has stated that, “risks ofmedical imaging at effective doses below 50 mSv forsingle procedures or 100 mSv for multiple proceduresover short time periods are too low to be detectableand may be non-existent” (103).

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Pat Zanzonico, Memorial Sloan Kettering CancerCenter, 1275 York Avenue, New York, New York 10021.E-mail: [email protected].

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KEY WORDS cancer risks, deterministiceffects, hormesis, linear nonthresholdmodel, linear-quadratic model, radiationdosimetry, radiation effects, radiationgenetic effects, radiobiology, reversecausation, stochastic effects

APPENDIX For supplemental material andtables, please see the online version ofthis article.

























































































































































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