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* The University of New Mexico THE UNNERSITY OF NEW MEXICO COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO Correspondence Continuing Education Courses for Nuclear Pharmacists VOLUME I, NUMBER 4 Low Level Exposure to Ionizing Radiation: Current Concepts and Concerns for Nuclear Pharmacists by: Stanley M. Shaw, Ph.D. William R. Widmerj DVM, M.S. Co-sponsored by: mpi phwmacy services inc an mesnam company @ ~c UnivccsiV of New Mexico College of Pharmacy is aPPrOVd by the titan Cooncil on Phannacautid Education u a ptwidm of co~~ing p~tical education. Program No. 180-039-92-. 2.5 Co-t HOUmor .2S ~U’s @

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Page 1: Correspondence Continuing Education Courses for Nuclear … · 2018. 12. 3. · RADIATION INJURY OF GENETIC (HERITABLE) EFFECTS OF RADIATION A. Introduction B. Mutagenesis c. Assessing

*

The University of New Mexico

THE UNNERSITY OF NEW MEXICOCOLLEGE OF PHARMACY

ALBUQUERQUE, NEW MEXICO

Correspondence Continuing Education Coursesfor

Nuclear Pharmacists

VOLUME I, NUMBER 4

Low Level Exposure to Ionizing Radiation:Current Concepts and Concerns for Nuclear Pharmacists

by:

Stanley M. Shaw, Ph.D.

William R. Widmerj DVM, M.S.

Co-sponsored by: mpi

phwmacy services incanmesnam company

@

~c UnivccsiV of New Mexico College of Pharmacy is aPPrOVd by the titanCooncil on Phannacautid Education u a ptwidm of co~~ing p~ticaleducation. Program No. 180-039-92-. 2.5 Co-t HOUmor .2S ~U’s

@

Page 2: Correspondence Continuing Education Courses for Nuclear … · 2018. 12. 3. · RADIATION INJURY OF GENETIC (HERITABLE) EFFECTS OF RADIATION A. Introduction B. Mutagenesis c. Assessing

William B. Hladik III, M. S., R.Ph., University of New Mexico

Director of Ptim Continuing Wucm”on

Hugh F. Kabat, Ph. D., University of New Mexim

me UNM P- Cotiuing Educalion tiff and the -r WOU W to gratefi@ achowtigeSharon 1. Ramirez for her technkal suppoti ad asstice ti the produhn of thk pubh&u.

copyright 1992University of New Mexice

Pharmacy Contiuing WucationAlbuqwrque, New Mexim

Page 3: Correspondence Continuing Education Courses for Nuclear … · 2018. 12. 3. · RADIATION INJURY OF GENETIC (HERITABLE) EFFECTS OF RADIATION A. Introduction B. Mutagenesis c. Assessing

LOW-LEVEL EXPOSURE TO IONIZING MIATTONCURRENT CONCEPTS AND CONCERNS ~R NUCL- ~-S

The objective of this review is to

exposure to ionizing radiation.

STATEMENT OF OBJECTIVES

provide an overview of some of the current concepts and concerns about low-levelTopics considered are mechanisms of radiation injury, ass-sing risk, genetic

(heritable) effects, radiation carcinogen~is, and effects upon the embryo/fetus. The review is not all-inclusive as thematerial available is voluminous. However, upon successful completion of the course the reader should be able ~:

1.

2.

3.

4.

5.

a

6,

7.

8.

9.

10.

11.

12.

13.

14.

15,

16.

17.

e

18.

19.

20.

Describe the ititial chang= in DNA brought about by radiation.

Discuss the concepts of repair of DNA following irradiation.

Understand the concept of target theory and resultant terminology.

Describe cell survival vs. dose relationships for single-hit, multi-hit systems.

Compare the concept of the “Q” thwry to target theory.

Describe the difference between a gene (point) mutation and a chromosome mutation.

Understand radiation-induced injury to chromosomes.

Discuss the controversy regarding the shape of the dose response curve for radiation-induced genetic effects.

Discuss the importance of speciw, dose rate and dose as relevant to induction of mutations.

Describe two methods for ass=sment of the risk of genetic effects caused by ionking radiation.

Understand the concept of the genetically significant dose.

Define the term radiogenic cancer.

List and explain three possible mechanisms regarding the induction of cancer by radiation.

Define the terms absolute risk and relative risk of radiogenic cancer,

Describe dose response models for cancer induction and relate the fundamental different= between models.

Explain the consequences of employing one dose response modeI for cancer induction vs. another.

Compare the risk of death from cancer from an acute dose to that from a fractionat~ dose.

List the potential effects of in utero exposure of the embryo/fetus to ionizing radiation.

Describe the risk of mental retardation from in utero exposure to radiation.

Discuss the concept of radiation induced life-span shortening vs. the concept of hormesis.

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I.

II.

III.

Xv.

v.

VI.

vu.

COURSE OUTLINE

INTRODUCTION

OVERVIEW: MECHANISM

RADIATION INJURY

OF

GENETIC (HERITABLE) EFFECTS OF

RADIATION

A. Introduction

B. Mutagenesis

c. Assessing the Risk

RADIATION CARCINOGENESIS

A. Introduction

B. Mechanisms of Can~r Induction

c. Assessing the Risk

D. The BEIR V Report

EFFECTS OF IONIZING ~IATION

ON THE EM13RY0 AND THE FETUS

OTHER LATE EFFECTS DUE TO LOW-

LEVEL IONZING RADIATION

SUMMARY

LOW-LEVEL EXPOSURE TO IONIZING~DIATION: CURRENT CONCEPTS AND

CONCERNS FOR NUCLEAR PHARMACISTS

By

Stanley M. Shaw, Ph.D.Professor and Head

Division of Nuclear PharmacyDepartment of Medicinal Chemis~

and PharrnacognosySchool of Pharmacy and Pharmacal Sciences

Purdue UniversityWest Lafayette, Indiana 47907-1248

William R. Widmer, DVM, M.S.Diplomate ACVR

Associate Professor, Diagnostic ImagingDepartment of Veterinary Clinical Sciences

School of Veterinary MedicinePurdue University

West Lafayette, Indiana 47907-1248

INTRODUCTION

Understanding the current concepts and concernsabout low-level exposure to ionizing radiation is ofthe utmost importance to the nuclear pharmacist. Itis the responsibility of the nuclear pharmacist toinform ancillary personnel about the potentiallyharmful effects of radiation. As new knowledge isgenerated, the nuclear pharmacist must be aware ofchanges in concepts and the implications for allpersonnel employed in the pharmacy.

Because of the ex~llent radiation protectionprocedures utilized in a nuclear pharmacy, thebiological effects of low-level chronic exposureoccurring over years of employment is tie mainconcern for personnel in nuclear pharmacy practice.Concerns regarding low-level chronic exposureinclude Carcinogenesis, life-span shortening,cataractogenesis, and genetic dysfunction. Of theseeffects, radiation carcinogenesis is considered as thesingle most impotit consequence of low levelexposure to ionizing radiation (1). .

Although there is an abundance of literatureregarding the deleterious effects of low-level chronicexposure, considerable controversy and uncertainty

2

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mutations within a human population increases withuny increase in radiation dose. The Committee onBiological Effects of ionizing Radiation (BEIR Iv(11) reported that aIthough there is evidence ofrepair of genetic damage at the molecular level, themajori~ of present data suggest frequency ofdamage induced by low-level ionizing radiation bestfits the linear, no threshold dose responsehypothesis.

Fgure 5.

10 ‘remDOSE

&se response model de~ed from the resti of lhe“~egamo~eft apetiem. ~ec~x mutationswre ~udiedand mwwn ~quen~ w higher No!e ti smmg qausdmiicfunction d higher doses. me dotied linee represetiexbuptin from high-dose &in.

Assessing the RiskTwo methods are generally used to assess the risk

for genetic effects caused by ionizing radiation:absolute risk and doubling dose. A third method,the genetically significant dose, is used to chart theimpact of ionizing radiation on the humanpopulation, particularly regarding medical exposure.The absolute risk of genetic effects is expressed asthe number of mutations per rem or rad of ionizingradiation. With absolute risk, the incidence ofspontaneous mutation is ignored and the incidence ofmutation is quoted as a function of dose. Estimatesin man, based on animal experimentation suggestthat the absolute risk of mutation is approximately10-7per rem per gene (8). Because the spontaneousmutation rate in man is 105 per gene per generation,detection of absolute changes in radiation-inducedmutations is problematic and requires largepopulations ~d long-term study. Therefore, it isoften easier to use the doubling dose method toassess the relative genetic risk.

The doubling dose is the dose of radiationrequired to cause twice the number of spontaneous

mutations (2,8). Because this method takes intoaccount the natural, or spontaneous mutation rate, itis known as the “relative” mutation risk. Al~oughextremely controversial, early evidence from atomicbomb survivors set the acute doubling dose forhuman beings at 156 rem (13). By calculation, thedoubling dose for chronic low-level exposure wasestimated to be 468 rem. ~ese doses werecalculated from three genetic effects studied in thechildren of the survivors. In contrast, the BEIR Vreport states that the results of atomic bomb datasuggest the median doubling dose is 100 rem. Thisis in agreement with the results of animal studiesusing various genetic endpoints, where the mediandoubling dose for low-level, low LET radiation wasfound to be approximately 100 rem (11). Theseestimates fall within the 50-250 range originallysuggested by the megamouse project.

The genetically significant dose (GSD) is anindex used to assess the presumed impact of gonadalexposure to ionizing radiation on whole populations,T’he GSD is expressed in reins and relates to apopulation and not the individual or the number ofmutations produced. Only radiation doses to thegonads of the members of tie population that willreproduce are considered genetically significant. Ino~er words, the GSD mer;ly determines the gonadaldose that is received by those that will likely bearchildren md averages it over the entire population(gene pool). Therelore, people that receive gonadalradiation, but are not considered likely to havechildren, do not contribute a genetically significantdose. Similarly, a gonada.1dose absorbed by young,healthy individuals contributes to the GSD. Finally,the GSD attempts to average the impact of presumedgenetic effects for the entire population. Thus, theGSD is the dose that if given to each member of thepopulation would result in the same genetic impact(effect on total gene pool) that actually results fromdoses received by those producing offspring.

In summary, current evidence implies that myincrease in the amount of radiation exposure isexpected to cause a proportional increase in thefrequency of mutations and there is some “risk” foroccupational workers (9, 11). It has been suggestedthat a dose of 1 rem per generation might raise thespontaneous mutation rate by 1% (10). Thus, forchronic low-level, low LET exposure, the increasein mutation frequency may be undetectable in thehuman population (8). Although human data issparse, it appears that human beings are no moresensitive to heritable effects of radiation than

7

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animals; possibly, human beings are less sensitive(10). Ionizing radiation is known to cause mutation,but a statistically significant increase in heritableeffects has not bmn documented when occpationdexposure has remained within dose limitsrewmmended by the NCRP.

a ll~e~O~e Hrefers to thefact that over 7 Won mice

wem used, aot giant mice from mum-on.

RADIATION CARCINOGENESIS

IntroductionThe potential for cancer induction is considered

the most important concern resulting from chronic,low-level exposure to ionizing radiation (8,9).Although smdied extensively, the mechanism, thedose-response curve and the absolute risk ofradiation carcinogenesis remain poorly understood.Because carcinogenesis is a late effect that occursyears after exposure to radiation and becauseradiation-induced cancers are no different thancanwr caused by other agents, the epidemiologica.1investigation of radiogenic cancer has progressedslowly. Perhaps the most practical approach to thestudy of radiogenic mcer involves the assessmentof absolute risk of cancer from medical andbackground radiation sources. Quantization of therisk of chronic low-level radiation exposure is amajor endeavor of organizations such as theInternational Commission on Radiation Protection(IRCP) and the National Commission on RadiationRotection (NCRP).

Unlike heritable effects, there is ample data onradiation-induced cancer in-human beings. Many ofthe early workers in the field of radiation, includingMine. Curie and her daughter, suffered fromradiogenic ~cer. Historically, high doses ofionizing radiation have been associated with skin,lung, thyroid, breast, bone and lymphatic tumors(1,8). In addition, radiation is known to induceleukemia and other hematopoietic neoplasms.Various cancers have been documented in peopleexposed to large doses of gamma radiation atChernobyl and atom bomb explosions. Scientistsgenerally concede that exposure to any dose ofionizing radiation carries some risk (probability) ofcancer induction, although it may be imperceptibleat low doses (8,10,11). Unfortunately, few data areavailable for assessing the risk of human cancer inthe low dose range (<10 rem). The majority ofrisk assessments for low-dose, low-level exposurehave been extrapolated from- high dose data. Risk

for cancer at many sites including leukemia, breastand thyroid cancers associated with low-levelexposure have been estimated (11). Regardingradiogenic cancer, the bone marrow, thyroid gland,breast, and to a lesser extent, bone are mnsideredthe more sensitive organs of the human body.

Mechanisms of Can= InductionWhile the exact mechanism of radiogenic cancer

is unknown, there is an unequivocal association ofradiation exposure and cancer. Several theories havebeen proposed; thr~ will be described here. Thefirst is the two-step initiation-promotiontheory. Itisbelieved that most cancers are a two step process(8). First, the genome of the &ll is injured in someway by a, carcinogen (initiation). This injury,followed by a latent period, is usually unapparent andcannot be measured by routine medical tests.However, cell injury can be enhanced by anadditional insult (promotion) which results intumorigenesis, Ionizing radiation is thought to bea carcinogen that causes tiltiation. Chemicals,viruses, mutation and free radicals are otherexamples of initiators. Promoters include hormonesand some carcinogens as well as the event of celldivision.

A second theory regarding the mechanism ofradiogenic cancer is the mutational theory. Thewtationul theo~ is supported by evidence thatradiation alone may cause somatic mutations whichresult in cancer induction. While the exact geneticchange associated with mutation is unknown, thealtered genome results in malignant transformationthat establishes a clone of cancer cells, Potions ofthe cells genome that down-regulate cell division arepossibly altered by mutagenesis. Chromosomalaberrations are frequently obsemed in cancer cells (8).

The oncogene theory proposes that all ceilscontain oncogenes that are normally suppressed bya regulator gene. If chromosomes are broken byradiation and rejoined, rearrangement (translocation)may result so that the oncogene is no longer locatednear a regulator gene. Thus, the onmgene can bemrned-on, expressing a malignancy. However, thereis no direct evidence that oncogenes are activated byionizing radiation (2).

Ass=sing the RiskAs with genetic effects, the risk of radiogenic

cancer can be expressed in absolute and relativeterms (8, 10). Ahsolwe risk is the number of excesscancers per unit of time in a specific population per

8

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unitof dose.comparingpopulations.

Absolu& risk is usually derived byirradiated versus nonirradiatedRela”ve risk is the ratio between the

risk of cancer induction for a population receiving agiven mean dose and m unexposed population(similm to the doubling dose concept). The relativerisk may be expressed as a multiple or fraction ofthe spontaneous cancer rate for a population.Because the spontaneous rate of cancer is low,expressing risk in this way may be quite misleading.For instance, if the spontaneous cancer rate is 2%,doubling the risk would give a cancer rate of 4%,only representing a few cases, Therefore. risk isbest expressed ii absolute terms.

The dose-response relationships for induction ofradiogenic cancer is very complex and wntroversia.1(1,8,1 1,12,14,15). In most animal and ceil culturemodels there is a dose-dependent increase intumorigenesis (steep) portion followed by adose-dependent decrease when there is “saturation”at higher doses (> 300 rem). Data from humancancer resulting from high doses (atomic bombdetonations and nuclear accidents) of radiation alsofit a similar dose-response curve. Establishing theexact shape of the curve below 100 rem is

●problematic because extrapolation from high dosedata is needed (limited human or animal data isavailable for Iowdose exposure. ) It is even moredifficult to set the 0-10 rem region of the curve, therange of low-level exposures. Compounding theissue, most high-dose data was associated with ahigh dose rate, Therefore, extrapolation of highdose animal data and the available human data is oneOf the mOSt controversial issues in the field ofradiobiology. Because of the complexity of the issueat hand, only the dose response for low-level,low-LET radiation will be presented.

The BEIR V ReportThe subject of dose-response and assessment of

risk for radiogenic cancer was addressed in theBEIR V report in 1990. The Committee used threegeneral methods of extrapolation from the high doseregion of the dose-response curve (Fig. 6 ). Thelinear model, used for the MPD concept, assumes nothreshold and that the effectiveness of radiation perunit of dose is the same at high and low doses.This, again, is consistent with the concept that anyradiation exposure is harmful. Animal data su~~est

● �✍otherwise; that the low part of the dose-effect curvebends downward, hence the “below linear model”(Fig 6). With this model, the risk per dose unit is

less at low, doses and some degree of repair orthreshold effect is implied. An “above linear model”was proposed, which has a rapidly rising doseresponse rate (slope) at low-levels. The above linearassumption was used to fit data from occupatiomdlyexposed workers at nuclear power plants and thePortsmouth Naval shipyard and from soldiersexposed to nuclear weapons tests (8,15). The modelhas been debated, and was refuted by the 1980 BEIR111report. Many scientists question the above linearmodel because the population sample W= too smalland may have been at a higher risk for cancerinduction in the first plain, The possibility that thismodel is correct is alarming; the increased sensitivityto low-level radiation would imply that 50-70% ofall human cancer would be due to naturalbackground radiation**, rather than the presentestimate of 1% (8).

linear - quadratic

/

P“ ,

I10 rem

DOSE

figure 6. Gene- dose response madd for Muetiw of tiiageniecancer, & doses greater tin 10 mm h inctience of saucerk wdy a mh functin of dose. Below 10 rem, &sbpe of h curve b unknown. fire h k h suggw lhatIhe low dose region maybe (a) bar, P) above linear or (c)below hear. The BI~ V repoti comtiem ihe below 10 rempohn of tie curve to be kr. me respoase c~es forspec~ &geaic cancem are av&ble (11).

For doses below 10 rem, the BEIR V Committeeconcluded that the frequency of canwr induction,like heritable effects, is best represented by thelinear-quadratic model with no threshold. The BEIRV Committee adopted this position after carefulreview of tie life-span study of Japanese atomicbomb survivors, people that received therapeuticx-rays for ankylosing spondylosis, tuberculosis,dermatophytosis (tinea capitis) and cancer of thecervix. The Committee determined that the risk ofradiogenic cancer w= 3 times higher for solid

9

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tumors and 45 timesgiven in the BEIR

higher for leukemia than was111 Report. The estimated

absolute lifetime risk of death from cancer followinga 10 rem acute whole body dose was stated to be0.8%. For chronic (fractionated) exposure the riskdecreased by a factor of 2, implying repair mayoccur. Compared to previous reports, the committeestated that the risk for leukemia was also increasedfor those subjected to in Wero irradiation.

The principal conclusion of the BEIR VCommittee is that if 100,000 paple of all agesreceive a whole-body dose of 0.1 Gy low LETradiation in a single brief exposure, 800 extra canmrdeaths are expected over their remaining lifetimes inaddition to the nearly 20,000 cancer deaths in theabsence of the radiation. The BEIR V Report alsolists the expected types of cancer and differences inrisks due to sex and age at time of exposure.Furthermore, it provides estimates of risk forchronic continuous low dose rate exposures to allradiation qualities. For example, estimates oflifetime excess wcer mortality per 100,000 exposedpersons are listed below:

a. continuous Iif*e expo8ure to lII18v/y (1W mrem/y)

b. continuous exposure to 0.01 Svly from age 18y to 6Sy

27@ II

As stated pwviously, the mtuml cancer death mte in theUSA is 20,000 per 100,000 persons (given in terms of riskover a lifetime).

A linear dose-response model was preferred bythe BEIR V Committee. The Committee stated thatdeparture from linearity could not be excluded atlow doses beyond the range of observation. Theyalso reasoned that the departures could be in eitherdirection, i,c, increased or decreased risk.Moreover, the Committee noted that epidemiologic

fdata cannot rigorously exclude the existence of athreshold in the millisievert dose range.

While these findings indicate that the risk of ~radiogenic cancer is greater than previously thought,the BEIR V Report has been questioned by leading ●radiobiologists and physicians (16). Much of thecontroversy stems from the use of data gleaned fromthe atomic bomb survivors, who received acute(microsecond) doses. No adjustment was made bythe BEIR V Committee for the differenw in doserate effect when extrapolating the data m representthe response to low-level irradiation. Because repairis known to occur at lower dose rates, the frequencyof dose related effects is usually considered to bereduced by a factor of 2-3 (16).

What practical conclusions can be drawn fromthese studies? First, risk assessments for low-levelexposure are really estimates, extrapolated from highdose data. High-dose data are available to healthscientists for studying dose-response. Data onlow-level exposures, suitable for epidemiologicanalysis, are not available. This includes the 0.1-0.5rem range used in nuclear medicine patients. Thisis because the difference between the incidence ofspontaneous and radiogenic cancers is so small thata-sample population of millions would be needed toconduct a meaningful study (16). Semnd. the entire ●issue of risk due ti low-level exposur~ must beplaced into perspective when people residing in areasof high natural background radiation do not have ahigher rate of solid tumors or leukemia whencompared to other populations. Third, if therecommended MPD were to be reduced by one-half,nuclear medicine workers would likely be unaffectedbecause most exposures are <2.5 rem per year (16).

**~e e-ted hse from ~tuml baekgmund -n isapproximately8@250 mdyear depending on geogmphicLocation. ~is is wefl below the 10 md mnge that isco&& to be low-level.

EF~~S OF IONIZING RADIATION ON THEEMBRYO AND THE FETUS

Excessive exposure of the embryo or the fetus toionizing radiation may cause a classic triad ofembryonic death, congenital malformation or growthretardation in mammals (8,17). Exposure of thedeveloping embryo to ionizing radiation may causemajor congenital defects, embryonic death orperinatal death. During the period of 9preirnplantation (O-9 days in man), the conceptus isparticularly sensitive to radiation. Based on

10

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.

extrapolation from experimental animals, h uterodoses of 10-25 r+ may be lethal duringpreimplantation. However, suniving embryos areat a low risk for congenital abnormalities andperinatal death.

Ionizing radiation is teratogenic and may causemajor congenital malformations, includingmicrocephaly, microphthaLmia, cerebral hypoplasia,and skeletal and dental defects. Thesemalformations are most common when exposureoccurs during the period of organogenesis (10-50days). Irradiation at this time has been associatedwith a high incidence of growth retardation andperinatal death (8,11).

With in utero exposure to ionizing radiationduring the period of the fetus (51 days-term), themost likely deleterious effects are fetal growth andmental retardation, and maldevelopment of thecentral nervous system. Although differentiation ofmost human tissues has ceased by 51 dayspost-conception, the central nervous systemcontinues to develop, even postnatally. Thedeveloping embryo/fetus is sensitive toradiation-induced mental retardation, and there islittle if any threshold for this effect between 48 and112 days of gestation. This unique sensitivity can beexplained by intense neurond stem cell proliferationduring organogenesis. Analysis of data from atomicbomb survivors implies that the risk of severe mentalretardation at 48-112 days is 40-45% per seivert(100 rem) (9,11). Exposure after 112 days ofgestation may also cause mental retardation, but therisk is reduced by a factor of 4 because neuronalproliferation has peaked, The occurrence ofradiation-induced mental retardation often correlateswith microcephaly (17).

The incidence of childhood leukemia might beincreased by in wero exposure to ionizing radiationat anytime during gestation (8,9,17). There is databoth for and against this concept. Studies in the

USA and England claim arI association betweenchildhood malignancy and in utero irradiation, whileresults from animal experiments and data fromatomic bomb survivors do not (8).

OTHER LATE EFFECTS DUE TOLOW-LEVEL IONIZING RADIATION

Life-span shortening, and cataractogenesis areother effects that may be linked to chronic exposureto low doses of ionizing radiation. While there isabundant literature reg-mding these effects, their

importance is considered less than those effectspreviously described in this paper.

Although studies have suggested that low-levelexposure to radiation causes life-span shortening,this issue remains in doubt. In many of thesestudies, the decrease in life span was actually asecondary effect resulting from cancer induction(1,18). Life span shortening attributed solely tochronic radiation exposure in people has not beenconclusively demonstrated.

The lens of the eye is sensitive to ionizingradiation. In atomic bomb survivors, single doses inthe range of 60-150 rad of gamma radiation waaconsidered the threshold for ca~actogenesis. Withhighly fractionated exposure, the threshold was 5000rad (11). These doses are clearly beyond theoccupational limit.

The mammalian gonads are also sensitive to theeffects of ionizing radiation (11). In the humantestis, an acute dose of 15 rad is sufficient to causetemporary infertility. The human ovary is lessradiosensitive than the testis, where the threshold foracute exposure is approximawly 65 rad.Fractionation increases the tolerance to infertility(11). It should be stressed that the major risk to thegonads for low-level exposure to ionizing radiationis mutation, as described under “Genetic Effects ofRadiation. ”

Paradoxically, there is scientific evidence that insome instances, chronic low-level exposure toionizing radiation causes a beneficial effect. Thesebeneficial effects include enhanced resistance todisease, improved viability, and increased life-span.Studies have shown that laboratory animals exposedto chronic low doses of ionizing radiation mayoutlive control animals. At the cellular level, it hasbeen suggested that beneficial radiation-inducedmutations may result in hormesis. Mechanisms areunclear, but may include enhanced repair of DNAdamage, improved scavenging of free radicals,stimulation of the immune response, and improvedmaintenance of cell populations (19,20). Althoughthe concept of radiation hormesis is fascinating, ithas not gained widespread acceptance in thescientific community. However the issue cannot beavoided and merits further investigative efforts.

CONCLUSION

Knowledge of the biological effects of ionizingradiation is of contemporary importance to nuclearpharmacists for three main reasons. First, it is

11

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necessary for nuclear pharmacy practitioners to ntainadequate radiation safety practices in the work place.Semnd, nuclear pharmacists are often the mainsource of expertise regarding biological effects ofradiation in laboratories where radiopharmaceuticalsare used. Lastly, those occupationally exposed tochronic low doses of ionizing radiation should bekept abreast of new theories and concepts generatedby research in radiobiology,

As expeti, the jury is still out in regard to thetrue risk from low-level chronic exposure to ionizingradiation. The data included herein are not intendedto bring forth fear for personnel employed in anuclear pharmacy, but to reinforce tie attitude of ahealthy respect for the potential harm fromoverexposure to radiation. However, the nuclearpharmacist must maintain a proper perspective. Forexample, the author of an article in a health physicsnewsletter (21) presented comparisons of risk tonuclear power plant workers to other occupationsand situations. He cited an overall radiation riskinefficient of 3xl& per rem for nucleu power plantworkers as compared to an annual risk for crewmembers being involved in a aircraft accident witha fatality as 4.5xl@ for scheduled commercialcarriers and 7.7x10-3 for scheduled commutercarriers. Also, we accept a per capita annual riskgreater than 2X104 for the privilege, convenienceand advantages of automobiles and trucks.

In summary, there is a risk from radiation ofwhich occupational workers must be aware.However, the h~ful effects attributed to ionizingradiation at doses below the maximum permissibledose level (5 rem/yr) may never be truly resolvedeven by statistical methodology with largepopulations. Utilization of a good practice techniqueand adherence to safety guidelines remain theapproach to assuring a safe environmentattaining conformity to the ALARA concept.

bestand

1. Hall EJ. kte Effects of Radiation: carcinogenesis andlife span shortening. In: Radiobio[o~for /he Radwlogist.3rd d. Haggemtnwn, MD: Harper & Row;1988:3S~89.

2. Hall H. Cell survival curves. In: Idiobiology for theRadiologist. 2nd ed. Haggerstown, MD: Harper& Row;1978:18-37.

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Sutherland RM, Mulcahy RT. Basic principlm of tradmtion biology. In: Cfinical Oncology for MedicalSttie~ and Physicians: A MuWisc@inay Approach.

Rochester, NY: American Can-r Society; 1983:057. i

Coggle J. The effect of mdiation at tbe molccti and ●subcelIular levels. In: BwLogicul ~ects ofRadiatwn. 2nd.- .ed. New York, NY: International Publications SemiCc;1983:29-31.

Alper T, Cmmp WA. The role of repair in radiobiology.fiperentti 19S9;45:21-33.

Fra&enburg-SchwagerM. Review of repair kinetics forDNA damage induced in eukaryotic ~-lls in vitro byionizing radiation. Radiother and Oncol1989:14:307-320.

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Coggle JE. MdIcal effects of low doses of iotigradiation. Radiat Prot Dosim 1989;30:5-12.

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Health effects of exposure to low Icvels of ionizingradiation. (B131RV report). &netie E#ec& of Radtin. ●Washington DC; National Research Council; NationalAcademic Press; 199065-125.

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b19. Wolff S. ~ mdiation-indud cffti hermetic? Science

1989;245:574.

* 20. SaganLA. On tiiation, paradigms and horrnesis.

● tiience 1989;245:574.

21. Alexander W. A=ptable mdiation risks for nuclearpowqlant workers. 271e Health P@sics Sociely ’s

Newslener 1986; 14:1+.

QUEmONS

1.

2.

In regard to low-level chronic exposure, the single moatimportant consequence is:

a. radiation carcinogen-isb. lifespan shorteningc. oataractogeneaisd. organ fibrosis

In determining the true risk of low-level exposure thegreatest controversy mntinues over

a. the length of time necm to developcataracts

b. the risk of high dosesc. the d-~nse relationship for low dosesd. the lack of high dose data to aid in drawing

inclusions

● 3. With low L~ radiation, initial damage to the DNA ismd]ated by:

a. the direct hit on a single strandb. ionization on purine basesc. e~me mediated reactionsd. mdiolysis of intraoelh.da.r water (indirect

effect)

4, For the single-hit dose-response model the Do for a cellpopulation is the dose that:

a. will give an average of one hit per target inthe population

b. will result in the da of eaoh cellc. oan be tolemted and repairedd. will result in the death of 37% of the cells in

the popuhdion

5. For a twotarget dose -rise mdel for a cellpopulation, the shoulder on the dose-~nse curveindieatea:

●6.

a. cells oannot be repairedb. that bth targeta have been hit oncec. a region of sub-lethal damaged. nothing regarding effeots upon targets within

the cell

Prior to the Chernobyl dlasater the beat souroe of humandata for determining genetic (heritable) effects ofradiation has been:

a. patients exposed to diagnostic x-raysb. survivora of the fihima and Nagasaki

atomic bombsc. radiologists from the 1920S ~d. radium dial painters

7. Gene mutations from early work with Droaoph@ (fruitfly) indicatd that gamma tilatim:

a. eaud genetic effeota that wem not cumulativefrom doses received over time

b. ~uaed gene mutati-s that were dependentupon dose rate

c. oaused gme mutations directly proportiomd todose

d. W@ a non-linear, tihold response

8. The mults of the megamouae projeet mg~lngradtilon indu~ mutations indi=ted ~

a. the degree of low ~ Alation damage wasnot influen~ by dose rate

b, genetic damage wuld be repaidc. there was little difference in mutadms

produced by high ~ compared to low LETdtation

d. the doubling dose for mice was the same asfor fruit flies

9. Absolute risk is a method used to assess the risk for

genetic effects oaused by radiation. In absolute risk

a. the incidenoe of spontaneous mutation is-sidered

b. the risk of mutation is approximately lU1 pergene

c. the determination of radiation-inducedmutations can be aooomplished in a fewmonths

d. the genetic effects are expressed as thenumbr of mutitions per rem

10. The doubling dose of radiation is stated as the dose tocause twice tbe number of spontaneous mu~tions. Theacute doubling dose for humans based upon atomicbomb survivors is rema.

a. 6b. 156c. 256d. 456

11. The ealculati doubting dose for humans based upon theatomic bomb sumivom for chronic low-level expureis estiti to be reins .

a. 68b. 168c. 368d. 468

12. In tbe dculation of genetically significant dose,radiation doses arewnsidered.

13

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a. to the enk populationb. to child=c. to members of the population that will

reproduced. to nucl= mdlcinelnucl- pharmacy

Pe-nel only

13. Radiation-inducedcanc-

a. are -men in low-level exposure situationsb. -ur rather quickly after acute exposure

differ from cancers pduced by other agents: cannot be clearly identified as

dlation-induced

14. Regd~ng tiiatim-induced cancers, theare -sidered as more dcaensitive.

a. skin and liver

b. ey~ and skin

c. colon and eyeSd. b=t and thyroid

15. in the **step initiation-promotion theory for cancerinductim

a. radiation is conaidercd as an ititiatorb. d:ation is consided to be a promoterc. the genomc of the cell is not injured initially

by the diationd. the initial mdiation injury to the cell can be

measured by routine mdlcal tests

16. In the oncogene theury for cancer induction it is

- ~fi

17.

a. cells have regulator genes normally suppressedby an oncogene

b. radiation acts by activating the regulator genesc. chromosom= are broken by tilationd. WISis tie main method of canGer induction by

radiation

Relative risk for expressing the risk of radiogeniccancer:

a.

b.

c.

d.

is the number of excess cancers per unit oftime in a specXc population per unit of d-may provide rather misleading risk numberswhen compared to the spontaneous cancer mteis the ratio between the risk to medidexposure and reactor personnelis the beat way to exp- radiation-inducedcancer risk

18. The d~response relationship for induction ofradiogenic cancer in humans is:

a. well established and acceptedb, the same for low dose snd high done datac, d upon animal datad. very complex and wntroversial

19. The MPD~cept is based upona4

-~nae mdel.

a. linear at all d- 4

b. blow linear at low dosesc. above Iin- at low doses ed. a tinmr-quadratic

20. For doses below 10 rem, the B~ V Commi~cmcluded that tie frequency of ~cer induction is ktrepresented by:

a. a lin~ modelb. a below lin- mdel at low doriesc, an above linear model at low d-d. a lin= quadratic mdel

21. The B= V Committee determined that the risk of#logenic cancer was times higher for solidtumors than given in the B~ III report.

a. oneb.c. Ld. four

22. In the R~ V Gmmittee * the absolute lifetimerisk of d~th from cancer following a 10 rem acutiwhol~wy dose W= stated as -t.

a. 0.1b. 0.5c. 0.8d. 1.0

23. Imixing dtation is a temtogenic agenk

a. producing congenital malformations that differtim other teratogenic agents

b. when applied to the mothers armwhen given betweendays 1-9 of gestation

: when sufficient expure is given to theembryo dutig organogeneais

24. Suficient raddon exposure to the fetus may resdt in:

a. skeletal defectsb. small eyeac, mental retardationd. denti defects

2s. Radiition hormeaiw

a. is proposed as a Poaaibllity for higher dosesgiven over a long period

b. is an accepted concept by dlation scientistsc. is a ~cqt that indlcatea the exceptional

danger from titationd. indi-atea a potential beneficial &ect from

diation@

14