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Database of Radiogenic Cancer in Experimental AnimalsExposed to Low Doses of Ionizing RadiationPhilippe Duport a , Huixia Jiang b , Natalia S. Shilnikova b , Daniel Krewski b c & Jan M.Zielinski c da Institute of the Environment, University of Ottawa, Ottawa, Ontario, Canadab McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa,Ontario, Canadac Department of Epidemiology and Community Medicine, Faculty of Medicine, University ofOttawa, Ottawa, Ontario, Canadad Environment Health Science and Research Bureau, Health Canada, Ottawa, Ontario,Canada

Version of record first published: 29 Mar 2012.

To cite this article: Philippe Duport, Huixia Jiang, Natalia S. Shilnikova, Daniel Krewski & Jan M. Zielinski (2012): Databaseof Radiogenic Cancer in Experimental Animals Exposed to Low Doses of Ionizing Radiation, Journal of Toxicology andEnvironmental Health, Part B: Critical Reviews, 15:3, 186-209

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Journal of Toxicology and Environmental Health, Part B, 15:186–209, 2012Copyright © 2012 Crown copyrightISSN: 1093-7404 print / 1521-6950 onlineDOI: 10.1080/10937404.2012.659136

DATABASE OF RADIOGENIC CANCER IN EXPERIMENTAL ANIMALS EXPOSEDTO LOW DOSES OF IONIZING RADIATION

Philippe Duport1, Huixia Jiang2, Natalia S. Shilnikova2, Daniel Krewski2,3, Jan M. Zielinski3,4

1Institute of the Environment, University of Ottawa, Ottawa, Ontario, Canada2McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa,Ontario, Canada3Department of Epidemiology and Community Medicine, Faculty of Medicine, University ofOttawa, Ottawa, Ontario, Canada4Environment Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada

For decades, there have been debates regarding the nature of the relationship betweenexposure to low doses of ionizing radiation and cancer risk. Under the linear no-thresholdhypothesis, which serves as a theoretical basis for current radiation protection standards, therisk of cancer at low levels of exposure is presumed to be directly proportional to dose.Opponents of this hypothesis claim that there are threshold doses for radiation carcino-genesis, or even a reduction in cancer risk at low doses (a phenomenon referred to as“radiation hormesis”). Epidemiological, animal, molecular, and cellular studies were con-ducted to resolve this controversy, although each of these study types has its strengths andlimitations. Although the results of animal experiments are not directly applicable to humans,data can substantially add to our knowledge on the form of relationship between radiationdose and cancer risk in a wide range of doses. Laboratory animals are a homogeneous pop-ulation with little biological variability; animal experiments are conducted under controlledconditions with good estimates of radiation doses. In order to address the question of whetheror not the dose-response curve for radiation carcinogens is linear at low doses, a comprehen-sive database of animal carcinogenesis experiments was assembled involving exposure todifferent types of ionizing gradation. The database includes virtually all publicly accessibledata on the induction of radiogenic cancer in laboratory mammals. This review provides adescriptive overview of the experiments included in the database, along with a qualitativeassessment of the shape of the dose-response relationship for radiation carcinogenesis at lowdoses in experimental animals.

There has been, for many years, an intensedebate between proponents and opponents ofthe so-called linear no-threshold (LNT) hypoth-esis, under which the risk of radiation-inducedcancer is assumed to be directly proportionalto dose at low levels of exposure (Charles

Support for project was provided by Électricité de France, the Department of Energy (USA), the Central Research Institute of ElectricPower Industry (CREIPI, Japan), COGEMA Resources, Inc. (now AREVA, Canada), MDS Nordion, the Canadian Nuclear Society, and theCANDU Owners Group to the International Centre for Low Dose Radiation Research at the University of Ottawa. Additional supportwas provided by Health Canada to the McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa. D. Krewskiis the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa. We are grateful to BenaceurAssif, Dianne Murray, Jacques Deslauriers, and Russell Renaud for their assistance in the preparation of the database described in thisarticle.

Address correspondence to Jan M. Zielinski, Environment Health Science and Research Bureau, Health Canada, 50 ColombineDriveway, 1st Floor, Room 135, AL 0801A, Tunney’s Pasture, Ottawa, Ontario K1A 0K9, Canada. E-mail: jan_zielinski@hc-sc.gc.ca

2006). Under the LNT hypothesis, any amountof ionizing radiation, however small, increasesthe risk of cancer, with the excess cancer riskbeing directly proportional to radiation dose atlow dose levels. Brenner and colleagues (2003)reviewed the current scientific evidence in this

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regard, and biophysical evidence relating tolow-dose radiation cancer risks, and concludedthat the LNT hypothesis was consistent withcurrently available biological, epidemiological,and biophysical data. Skeptics of the LNThypothesis, Tubiana et al. (2006) argued thatthe LNT is not compatible with data obtainedat low doses.

A review of all the available informationprovides more nuanced indications. In general,dose-effect relationships at low doses appearto be compatible with the LNT, although wideconfidence intervals allow for a certain degreeof compatibility with either linear or nonlin-ear dose-response curves. A number of animalexperiments exhibit apparent negative dose-response relationships at the lowest dose levels,and sometimes at higher doses that are withinthe neighborhood of recommended or regula-tory dose limits for workers, and, a fortiori, forthe public; however, with some clear excep-tions, the wide confidence intervals surround-ing these dose-response relationships make itdifficult to interpret these apparent trends.In evaluating low-dose trends, it is importantto keep in mind that animal experiments wereconducted to quantify the adverse effects ofionizing radiation, rather than to explore low-dose effects.

The most direct evidence of radiation-related cancer risks in humans derives fromepidemiological studies of populations exposedto ionizing radiation, some of which provideinformation on cancer risks at low doses. Themost recent analysis of cancer incidence inatomic-bomb survivors (Preston et al. 2007)suggests that there is a significant linear dose-response for all solid cancers at doses in therange of 0–0.15 Gy. This dose-response rela-tionship could also be described by a thresholdmodel with a threshold at 0.04 Gy, althougha threshold model does not provide a signif-icantly better fit to these data than does alinear model.

The study of cancer risk in a large cohortof radiation workers (Cardis et al. 2005; 2007)reported a statistically significant rise in excessrelative risk (ERR) per unit cumulative dose(ERR/Sv) for solid cancers. However, a detailed

examination of observed versus expected num-ber of cancer cases (O vs. E) in the lowestdose intervals revealed a flat response to dosesin population subgroups whose total cumula-tive exposure was less than 50 and 100 mSv.In a pooled analysis of 7 epidemiological stud-ies of thyroid cancer involving a total of about120,000 people (58,000 exposed to externalionizing radiation and 61,000 unexposed) (Ronet al. 1995), a linear dose-response model pro-vided the best fit to the data for individualsexposed to radiation before 15 yr of age atdoses as low as 0.1 Gy. Studies of childhoodcancer following in utero exposure to diagnos-tic x-rays demonstrated an increased cancerrisk at doses as low as 10 mSv (Doll andWakeford 1997; Wakeford and Little 2002),although the causal nature of this associa-tion was questioned (Boice and Miller 1999).If the association between childhood cancerand intrauterine diagnostic x-ray exposure iscausal, the existence of a threshold for carcino-genic effects at doses above 10 mSv can beruled out (Wakeford and Little 2002).

Conversely, apparent thresholds wereobserved in some human populations inradium dial painters in whom no skeletalcancer was observed at doses lower than 1 Gy(Evans 1974), as well as in radiation workers atthe French utility company Électricité de France(Rogel et al. 2005), for cumulative dose rangesup to 200 mSv. Apparent thresholds were alsoobserved in some animal experiments (Sandersand Sanders 1993).

A number of international expert groupsconducted comprehensive reviews of the epi-demiological, radiobiological, and biophysicaldata in support of the use of the LNT modelfor radiation protection purposes (ICRP 2006;NRC 2006). It should be noted that the LNTis not universally regarded by its proponentsas immutable law, but rather as a workinghypothesis (Wall et al. 2006). It is acknowl-edged that mechanisms of intercellular interac-tion and interactions of cells with their extra-cellular matrix may lead to deviations fromlinearity at low doses; however, since neitherthe magnitude nor even the direction of thesedeviations is currently known, it is argued that

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it would be premature to replace the LNTmodel with a nonlinear radiation risk projec-tion model (Brenner et al. 2003; Brenner andSachs 2006; NRC 2006). In contrast to the con-clusions reached by the U.S. National ResearchCouncil (NRC 2006), the opinion of the FrenchAcademies of Sciences and Medicine (Tubianaet al. 2005; 2006) is that recent epidemio-logical and biological data are “incompatiblewith the postulate on which LNT is implicitlybased, namely the constancy of the carcino-genic effect per unit dose, irrespective of doseand dose rate.”

At present, there remains a degree of sci-entific uncertainty regarding the nature of therelationship between exposure to low doses ofionizing radiation and cancer risk. This uncer-tainty has important implications for the esti-mation of cancer risks associated with exposureto ionizing radiation, and the establishment ofhuman exposure guidelines for ionizing radia-tion, which might occur in a number of occu-pational, environmental, and medical contexts(NRC 2006). Resolution of this risk issue isimportant, but difficult. While epidemiologi-cal studies in humans are, and will remain,an important source of information on healthrisks associated with exposure to ionizing radi-ation, they lack statistical power to detectincreased cancer risks at doses below 100 mGy.Epidemiological studies may also be subjectto other limitations, including confounding byunmeasured covariates, such as socioeconomicfactors (Mao et al. 2001), exposure misclassifi-cation, and selection and/or recall bias (Wallet al. 2006). Cellular and molecular studiesare becoming increasingly important for ourunderstanding of biological mechanisms under-lying the adverse health effects of radiation inthe low dose range. However, biological end-points observed in cells may not be directlyindicative of radiation-induced carcinogenesisin living organisms (Wall et al. 2006).

Studies of radiation carcinogenesis inexperimental animals are valuable sourcesof information on radiation-induced cancers.Although it is acknowledged that the resultsof animal cancer experiments are not directlyapplicable to humans, these studies can

substantially add to our knowledge on the formof relationship between dose and cancer riskin a wide range of doses (UNSCEAR 2000).Laboratory animals within a given experimentrepresent a homogeneous population with rel-atively little biological variability, and the influ-ence of confounding factors can be eliminatedthrough randomization at the experimentaldesign stage (Gart et al. 1986). Further, animalexperiments are conducted under controlledconditions with reliable estimates of radiationdoses (UNSCEAR 2000).

In order to address the challenge of esti-mating cancer risks associated with exposureto low doses of ionizing radiation, a com-prehensive database of animal carcinogenesisexperiments was assembled involving exposureto different types of ionizing radiation. TheDatabase on Radiogenic Cancer in Animals(DRCA) described herein includes virtuallyall publicly accessible data (up to the year2000) on the induction of cancer in labora-tory mammals following radiation exposure.This review provides a descriptive overview ofthe attributes of the experiments included inthe database, along with a qualitative assess-ment of the nature of the dose-response rela-tionship for radiation carcinogenesis at lowdoses in experimental animals. In a subse-quent review, a quantitative meta-analysis ofthis same database is presented designed toevaluate the extent to which these data areconsistent with the LNT hypothesis.

SOURCES OF DATA

A comprehensive source of information onradiation carcinogenesis in mammals is theInternational Radiobiology Archives of Long-Term Animal Studies, hereafter referred to asIRA 1996 (Gerber et al. 1996; 1999). IRA1996 provides a succinct description, includingrelevant references, of experiments on radia-tion carcinogenesis in animals conducted byresearch institutions in North America, Europe,and Asia. However, IRA 1996 does not containall of the experiments on radiation carcino-genesis using laboratory mammals, excluding,for example, some experiments in which no

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effects were seen among exposed animals.As a consequence, additional articles on radi-ation carcinogenesis were identified through aMEDLINE search through to September 2000,using the keywords rat, mouse, dog, ioniz-ing radiation, alpha, beta, gamma, neutrons,x-rays, cancer, and neoplasms.

Paper copies of identified publicationsappearing in peer-reviewed journals, annualreports of research institutions, and confer-ence proceedings were obtained. Each ofthese articles was reviewed to ascertain rele-vance to radiation carcinogenesis in animals.Publications pertaining to a similar experiment,but published at different times, sometimeswith different first author names and in dif-ferent journals, or reports to illustrate differentaspects of radiation effects in mammals, wereidentified and set apart in order to avoid dupli-cate entries. Papers containing all of the infor-mation necessary for inclusion in the database(species and strain of experimental animal, typeof radiation, mode of administration, body ororgan doses, dose rate (when available), andtype of cancer of interest) were selected asappropriate sources of data for the database iflow radiation doses were used in the exper-iments. Criteria for inclusion of data into thedatabase are described in more detail later.

DEFINITIONS

An experiment is defined in terms of theprotocol used to develop the information onthe relationship between radiation dose andthe occurrence of one or several types of can-cer in one or several organs or tissues in animalsof the same gender, or both genders together, ofa particular species and strain, following expo-sure to a specific type of radiation with a givenmode of administration and dosing regimen.Ullrich and Storer (1979b) conducted an exper-iment in which ovarian cancer, carcinoma ofthe Harderian gland, and carcinoma of thepituitary gland were reported in male andfemale RFM f/Un mice exposed to externalgamma radiation from 137Cs from birth to age70 d at doses ranging from 0.1 Gy to 1.5 Gy.

A dataset is defined as the ensemble of dataconcerning the relationship between radiationdose and the occurrence of a particular type ofcancer in a particular organ or tissue.

A dose level refers to a specific dose withina dataset for which cancer occurrence ratesare reported. An experiment may contain oneor more datasets, and there are generally sev-eral dose levels within a single dataset. In thedatabase, radiation doses are expressed in grays(Gy) and dose rates in Gy/min. (The dose unitsievert is specific to humans.)

Ionizing radiation induces a large vari-ety of cancer types in experimental animals.(More specifically, the cancer type refers tothe detailed designation of the malignancyobserved in animals, such as bronchogeniccarcinoma.) Some studies are concerned onlywith a particular type of cancer in a particu-lar organ, whereas others are concerned withseveral types of cancer in several organs. Whiteet al. (1994) examined only the incidence ofbone sarcoma in dogs following the injectionof a solution of 226Ra, whereas Covelli et al.(1988) determined the incidence of 6 typesof cancer in 16 organs following whole-bodyneutron irradiation. The designations of can-cer type and tumor site (target organ) in thedatabase are kept as close as possible to thedesignation found in original sources. However,the cancer types are also grouped into broadercancer classes (such as leukemias, lymphomas,carcinomas, sarcomas, or unspecified when noprecise information was found in the source) insome publications.

A cancer outcome refers to specific type ofcancer, the total number of cancers of a similarnature, or all cancers combined.

The term cancer incidence refers to the inci-dence of a particular cancer outcome presentin the datasets. Cancer incidence is the ratio ofthe number of cancer cases to the number ofanimals (controls or exposed). This may referto the incidence of a particular type of can-cer, such as osteosarcoma, or to the combinedincidence of several similar outcomes, such asall leukemias or all sarcomas. The incidence ofcancer is denoted Ie in exposed groups, andIc in control groups. Cancer incidence is not

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reported in a uniform manner in the litera-ture. In some papers, the number of cancercases observed in animals is given explicitly,whereas in others cancer incidence is the uncor-rected ratio of the number of tumor-bearinganimals to the number of necropsied animals(Upton et al. 1970). In other papers the age-adjusted incidence is reported (Ullrich andStorer 1979a; 1979b; 1979c). Some authorsnoted the adjusted cancer incidence using sev-eral methods: Kusama and Yoshizawa (1982)reported the observed, uncorrected cancerincidence in addition to corrected incidencerates using the standardized, Cutler–Ederer, andKaplan–Meier methods. In the database, theobserved, uncorrected cancer incidence is used,unless the authors provided only corrected inci-dence values. It is not expected that the useof either corrected or uncorrected cancer inci-dence values would significantly modify theshape of the dose-response curve at the lowestdose levels, which do not significantly affect thelongevity of exposed animals.

DATA INCLUSION CRITERIA

The primary objective of this review was toexamine the shape of the dose-response curvefor radiation carcinogenesis in animals at lowdoses. In order to evaluate dose response asaccurately as possible in the low-dose region,a primary criterion for inclusion of data inthe database is that organ or body dose isexpressed in terms of absorbed dose. Thiscriterion is always met in the case of exter-nal radiation (gamma, neutrons, and x-rays).However, the “dose” of internally depositedradionuclides is expressed in terms of absorbeddose in some publications and in terms ofintake quantity (e.g., microcuries or becquerelsper unit weight, with no mention of the totalcorresponding absorbed dose accumulated intarget organs) in others. Datasets for which theabsorbed dose is unavailable were excludedfrom the database.

In order to avoid obfuscation of radiationrisks by reduced survival of the experimentalanimals, it was also required that the expectedlife span not be reduced by more than 10%,

compared to that of the corresponding controls.Doses at which life span was reduced by morethan 10% were excluded from the database.

Although the definition of “low-dose” issomewhat arbitrary, this review focused primar-ily on experiments involving doses below 1 gray.However, doses above 1 gray were includedin the database, provided that life span wasnot shortened by more than 10%. This appliesmostly to experiments with beta radiation.

An exception to the preceding selection cri-teria involved an important experiment aimedat determining the risk of lung cancer in ratsat low doses and dose rates of inhaled radonprogeny (Morlier et al. 1994). This experimentwas omitted because its focus was on dose raterather than dose effect. It is worth noting thatthe experiment shows a clear increase in lungcancer risk when the low exposure is deliveredat a high exposure rate and no change whenthe same low exposure is delivered at a muchlower exposure rate. However, since that par-ticular experiment was conducted at only onedose level, data were not suitable for inclusionin the database.

Some datasets in the database displayed nocancer outcomes in either control or exposedanimals at any dose level. These datasets wereincluded because animals exposed at higherdoses in the same experiment developed can-cers, but were subject to excessive life shorten-ing and thus did not meet the inclusion criteria.Such datasets are retained because they showthat no cancers occur at dose levels that do notentail significant life shortening (even if thesedoses are excessively high compared to currentradiation protection standards).

FORMAT OF THE DATABASE

Data on experimental conditions and can-cer occurrence are summarized in two formats.Detailed information for each experiment anddataset, including experimental conditions andcancer type, were assembled in EXCEL spread-sheets of the form illustrated in Figure 1. An SASdatabase was then constructed to serve as thebasis for more in-depth statistical analysis. Thestructure of the SAS database is detailed in

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FIGURE 1. Example of EXCEL tables used to collect experimental data and information.

Appendix I. Information on species and strainsis kept as it appears in source documents tofacilitate the comprehension of dose-responsegraphs generated from the EXCEL and SASdatabases. Major attributes of the datasets aredescribed next.

Animal Species and Strains in theDatabaseThe species and strains of experimental

animals included in the DRCA are summa-rized in Table 1. The most frequently usedspecies were the mouse, rat, dog (with theexception of the Saint Bernard dog used inone experiment, the beagle dog was usedin all datasets involving dogs included inthe database), and Syrian hamster. The deermouse (Peromyscus maniculatus) and grasshop-per mouse (Onychomis leucogaster) were usedin one experiment because of their uniquecharacteristics in radionuclide uptake andretention (Taylor et al. 1985).

GenderIn most experiments, the exposed groups

were comprised of males, females, or bothgenders together. Cancer incidence rates wereusually reported for each gender separately;

however, in some studies cancer incidence isreported for both males and females com-bined. The distribution of animals by gender inthe datasets is provided in Table 2.

Age at ExposureAge at exposure is well known to influ-

ence the induction of radiogenic cancer (NRC2006; UNSCEAR 2000). Animals were gener-ally exposed to radiation as young adults, butradiation effects were also studied followingirradiation in utero and irradiation in matureadults. van den Heuvel et al. (1995) examinedradiation carcinogenesis in the offspring of miceinjected with a 241Am solution, and Benjaminet al. (1998) exposed beagle dogs to gammaradiation at 8, 28, and 55 d after conceptionand at 2, 70 and 365 d after birth.

Cancer TypesCarcinoma is the most frequent type of

cancer in the database, followed by sarcoma,leukemia, and lymphoma.

EXPOSURE REGIMEN

Attributes of the radiation exposure reg-imen, such as radiation type, mode of

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TABLE 1. Species of Experimental Animals in Datasets Includedin the Database

SpeciesNumberof datasets

Percentage(%)

MouseB6CF1 14 1.8BALB/c 42 5.3BALB/c (offspring) 14 1.8BALB/c/An N Bdf 6 0.8BALB/c/An NBd 21 2.6BC3F1 81 10.1C3H/He 1 0.1C57 × A F1 26 3.3C57BL 2 0.3C57BL/6J 26 3.3C57BL/Cnb 40 5.0C57BL/Do albino 10 1.3C57BL/Do black 10 1.3C57BL/Do 6 0.8C57Bl/6N ×

C3H/He F18 1.0

CBA 3 0.4CBA/Cne 26 3.3CBA/H 25 3.1CF1 3 0.4NMRI 8 1.0Onychomis 4 0.5Peromyscus

maniculatus4 0.5

RF 26 3.3RF/Un 128 16.0RFM 8 1.0RFMf/Un 22 2.8SAS/4 13 1.6

RatBN/Bi 6 0.8F344 2 0.3F344/Crl 7 0.9F344/N 1 0.1Holtzmann 2 0.3Sprague-Dawley 49 6.1WAG/Rij 16 2.0Wistar 19 2.4

DogBeagle 117 14.6St. Bernard 2 0.3

HamsterSyrian hamster 2 0.3Total 800 100.0

exposure (external or internal, whole-bodyor partial), and modalities of administrationof radiation doses (such as dose rate anddose fractionation), influence the inductionof radiogenic cancer in mammals (UNSCEAR1993). Experiments reported in the literaturedemonstrate a wide range of radiation expo-sure regimens.

TABLE 2. Gender of Experimental Animals in Datasets Includedin the Database

GenderNumberof datasets

Percentage(%)

Male 302 37.8Female 415 51.9Male and female 83 10.4Total 800 100.0

Exposure Regimen: Mode ofAdministrationRadiation doses were administered from

external sources for gamma, neutron, andx-rays irradiation and from internally depositedradionuclides for beta and alpha emitters,although the skin of the animals was exposedto an external source of beta radiation inone experiment (Albert et al. 1961). Internallydeposited radionuclides were administered byinhalation, injection, ingestion, or trachealinstillation. Table 3 presents the distribution ofdatasets according to the mode of administra-tion of radiation exposures.

Exposure Regimen: Whole-Body VersusPartial IrradiationSome authors studied the radiosensitivity of

specific organs under whole-body and partialirradiation. Deringer et al. (1955) examined theinduction of radiogenic cancer in the ovariesof mice following whole-body irradiation, butwith a shield over the ovary region, and irradi-ation of the ovary region alone with the rest ofthe body being shielded. Coggle (1988) stud-ied the incidence of lung cancer in mice after

TABLE 3. Mode of Radiation Deposition in Datasets Included inthe Database

Mode of depositionNumberof datasets

Percentage(%)

InternalInhalation 86 10.8Injection 120 15.0Ingestion 12 1.5Instillation 3 0.4

External 579 72.4Total 800 100.0

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irradiation of the thorax with x-rays or neutrons.In case of internal exposure from radionuclides,irradiation occurs in organs or tissues wherethese radionuclides are deposited and in otherorgans in which radionuclides are transportedby metabolic processes.

Exposure Regimen: Dose and Dose RateDose rates from internally deposited

radionuclides (alpha and beta emitters)decrease as a function of the physical half-life of the internally deposited radionuclideand as a function of the rates at which theradionuclide is cleared from target organs.When the intake is fractionated, the totaldose is delivered in a series of consecutivessubdoses, each delivered at decreasing doserates. Therefore, dose rates for internallydeposited radionuclides are highly variable.The total accumulated dose to an organ canbe delivered in a few days, as in the case ofa single injection of tritiated water (Johnsonet al. 1995), and at low rates, as in the caseof a single administration of a bone-seekingalpha emitter like 226Ra (White et al. 1994), orin a series of increasing–decreasing dose ratesadministered in rapid succession, as in the caseof repeated administrations of a short-livedradionuclide (Muggenburg et al. 1996).

In the case of internally deposited alphaand beta emitters, dosimetry data such asradionuclide buildup and clearance rates inorgans and variation in dose rate over timeare not included. The influence of radionuclidebuildup and clearance, as well as that of doserate, is not taken into account in the currentassessment of the shape of the dose-responsecurve at low doses of ionizing radiation.

Doses from gamma, neutron, and x-raysources are delivered at a constant dose rate.Doses from these types of external radiationrange from 5 mGy to 4 Gy, with dose rates from3 × 10−8 Gy/min to more than 1 Gy/min. Theinfluence of dose rate was investigated in detailfor gamma radiation and neutrons. Upton et al.(1970) exposed animals to neutrons at dosesvarying from 16 mGy to 3.32 Gy at dose ratesranging from 3 × 10−8 to 0.85 Gy/min. Ullrich

and Storer (1979c) exposed animals to gammaradiation at doses varying from 0.1 to 1.5 Gy atdose rates ranging from 3.7 × 10−5 Gy/min to0.45 Gy/min.

DOSE RANGES BY RADIATION TYPE

The distribution of doses varies betweentypes of radiation, as illustrated in Figures 2,3, 4, 5, and 6. Table 4 shows the range ofradiation doses administered to the animalsfor each type of radiation, as well as numbersof datasets, experimental animals, and cancercases by radiation type. Neutron experimentshave the largest number of datasets, followedby gamma, x, alpha, and beta irradiation.

Alpha radiation doses in the database rangefrom 0.002 to 9.57 Gy. Less than 10% of thedoses delivered by internally deposited alphaemitters were below 50 mGy. The bulk of alphadoses ranged from 100 to 500 mGy. About15% of the alpha doses were at or above 1 Gy(Figure 2).

Beta radiation doses range from 0.002 to310 Gy. More than 80% of beta doses wereabove 1 Gy. Unlike gamma and x-radiation, thedistribution of beta doses is nearly continuous,with two major modes at 0.1 and 1.0 Gy. Lessthan 10% of the doses from beta radiation werebelow 800 mSv (Figure 3).

Gamma radiation doses in the databaserange from 0.1 to 3.29 Gy. Approximately 40%of the data on radiation carcinogenesis follow-ing gamma irradiation were obtained at dosesat or below 500 mGy. There is a gap between0.5 and 0.8 Gy where no results are availablefor gamma radiation. Approximately 60% of theresults for gamma radiation are at doses above800 mGy (Figure 4).

Neutron doses range from 0.005 to3.32 Gy. The largest number of dose levelsfrom neutron irradiation was between 100 and500 mGy; about 25% of the doses are less than100 mGy (Figure 5).

X-ray doses in the database range from0.04 to 4.00 Gy. Approximately 55% of thedoses from x-rays were below 500 mGy, witha gap between 0.5 and 1 Gy. Results for x-rays

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TABLE 4. Total Number of Animals Used in Experiments and Total Number of Cancers Observed

Type of radiation

Alpha Beta Gamma Neutrons X-rays Total

Number of datasets 143 80 173 250 154 800Dose min (Gy) 0.002 0.002 0.100 0.005 0.040Dose max (Gy) 9.57 310.00 3.29 3.32 4.00Number of control animalsa 6,447 4,602 11,373 7,284 7,405 37,111Number of cancers in controlsc 1,665 794 5,359 4,880 1,864 14,562Number of exposed animalsb 10,794 11,136 29,778 22,862 13,412 87,982Number of cancers in exposedc 3,980 2,916 21,666 17,390 6,682 52,634Total number of animals used in experiments 17,241 15,738 41,151 30,146 20,817 125,093

aIn some instances, the same group of control animals is common to several experiments and appears in different publications,sometimes under different first author names, and, therefore is common to several datasets. Datasets with identical numbers of controlsanimals were examined to identify control groups common to several datasets. After verification in original publications, only one of theidentical groups of control animals was kept in a copy of the database for the purpose of animal counting.

bMany experiments are comprised of several datasets pertaining to different types of cancer or groups of cancer types (e.g., “allsarcomas and carcinomas” or “all cancers”). To avoid double counting, data pertaining to each experiment (Exp_ID) were examined toselect only one dataset per experiment with the largest number of dose levels (in some datasets, highest dose level data were omitteddue to excessive life shortening).

cTo avoid double counting, data for experiment (Exp_ID) that contain more than one dataset were examined to eliminate datasetsthat regroup cancer types (e.g., “All sarcomas and carcinomas”). Alternatively, after verification in original publications, the “All cancer”category was used in the calculation of the total number of cancers. In experiments containing only one dataset, that datasets was usedin the calculation of total number of cancers. Datasets used to calculate the total number of cancers were kept in a separate copy of thedatabase.

below 50 mGy are available at 14 distinct doses(Figure 6).

RADIOGENIC DATABASE

The database on radiogenic cancer inanimals includes 800 datasets drawn from262 experiments (Table 4). The databaseincludes 87,982 exposed and 37,111 unex-posed (control) animals (although the truenumber is lower due to the fact thatsome control groups are common to sev-eral experiments—gamma and neutron irradi-ation, for example). This represents the largestdatabase on experiments on radiation carcino-genesis in animals assembled to date. Thissection presents results derived from the DCRAthat inform the evaluation of shape of the dose-response curve for radiation carcinogenesis atlow doses.

CANCER INCIDENCE IN CONTROLS

No cancers were observed in some controlgroups. The proportion of control groups with-out cancers ranged from a maximum of 11.9%

in experiments with alpha radiation to 0 (zero)% in experiments with gamma radiation. Thatobservation is important because when thereare no cancer outcomes in control animals, itis only possible to detect either no increase oran increase in cancer risk, but not a decrease inrisk, following radiation exposure.

DOSE RESPONSE

The primary objective of the presentreview was to describe the database thatwas assembled to examine the shape of thedose-response relationship for radiation car-cinogenesis in the low dose region. A visualexamination of the dose-response relationshipsobserved in datasets included in the databasereveals six major categories of dose-responseshapes: (1) apparent J-shapes (in which can-cer incidence in exposed animals is less thanthat in controls at all dose levels); (2) apparenthockey-stick-like, in which cancer incidenceseems to be the same in control and exposedanimals, up to a dose level at which the can-cer rate increases; (3) no apparent effect, inwhich there is no discernible pattern in dose

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response over the range of dose levels usedin an experiment; (4) no occurrence of can-cer in control and exposed animals; (5) cancerincidence is greater in exposed than in con-trol animals at all dose levels; and (6) inverseU-shapes. (For simplicity, the term “J-shaped” isused here to include both apparent “J-shaped”and “U-shaped” dose-response curves, withthe only difference being whether or not thetumor response rate increases above that incontrols after the initial decrease.) The numberof dose-response curves following into each ofthese categories is shown in Table 5.

An example of rising cancer incidence withincreasing dose is shown in Figure 7, withthe rate of occurrence of all cancers in miceafter neutron irradiation elevating monotoni-cally with dose (Maisin et al. 1996). Thereare several datasets in which all the exposedgroups exhibit significantly lower cancer inci-dence than their respective controls: Figure 8shows a J-shaped dose-response in which can-cer incidence is lower in exposed than controlanimals at all dose levels for all reticulum cellsarcomas in mice following gamma irradiation

(Ullrich and Storer 1979a), whereas Figure 9 isa “true” J-shaped dose-response.

There are a number of datasets in which itis difficult to discern a difference in cancer inci-dence between exposed and control animals;for example, the incidence of lymphoma inmale BALB/c mice following exposure to 137Csat all dose levels shown in Figure 10 cannot bedistinguished from that in unexposed controls(Maisin et al. 1983). There are also datasets inwhich no cancers are observed in both con-trol and exposed animals with no significant lifeshortening, even at relatively high doses. Thereare 15 such datasets in x-ray experiments, 6 inbeta experiments, 18 in alpha experiments,and 4 in neutron experiments. The absenceof any cancer outcomes in exposed animalsat all dose levels is observed at doses up to1 Gy for cancer in adrenal glands, uterus, lym-phatic system, and skin in mice exposed tox-rays. Furthermore, as shown in Figure 11, notonly has the 226Ra injected in albino C57Bl/Dofemale not induced cancers in exposed ani-mals but also the observed longevity of theexposed animals increased with dose. In that

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TABLE 5. Number of Datasets With Various Dose-Response Shapes

Type of radiation

Alpha Beta Gamma Neutrons X-rays All

Type of dose response Number % Number % Number % Number % Number % Number %

No cancer in controls 69 48.3 31 38.8 2 1.2 33 13.2 51 33.1 188 23.5

Apparent J-shapea 51 35.7 12 15.0 70 40.5 75 30.0 38 24.7 246 30.8Apparent hockey-stick shapeb 30 21.0 23 28.8 10 5.8 19 7.6 16 10.4 98 12.3No apparent effectc 10 7.0 5 6.3 27 15.6 55 22.0 29 18.8 126 15.8

No cancers in controls andexposed animalsd

17 11.9 6 7.5 0 0.0 4 1.6 15 9.7 42 5.3

Total J-shape, hockey-stickshape, no apparent effect orabsence of cancers incontrols and exposed animals

108 75.5 46 57.5 107 61.8 153 61.2 98 63.6 512 64.0

Cancer incidence increases withdosee

26 18.2 22 27.5 49 28.3 72 28.8 45 29.2 214 26.8

Inverse U-shapef 9 6.3 12 15.0 17 9.8 25 10.0 11 7.1 74 9.3Total cancer increase and

inverse U-shape35 24.5 34 42.5 66 38.2 97 38.8 56 36.4 288 36.0

Grand total 143 80 173 250 154 800

Note. Dose-response shapes are not necessarily statistically significant because at the lowest dose levels, and frequently at all doselevels, confidence intervals include the no-effect value. Furthermore, there are no confidence intervals when there is no cancer in controlor exposed groups. The classification reflects a visual examination of the location of cancer incidence points on graphs, with verificationof the direction of the dose-response slope from experimental incidence values.

aCancer incidence decreases below incidence in controls at the lowest dose levels, then increases with dose above value in controls;or cancer incidence below that in controls at all dose levels.

bThreshold-like dose-response. Cancer incidence is the same in exposed and control animals at the lowest dose level(s), then increaseswith dose.

cCancer incidence in controls and exposed is distributed around the no-effect value, with no specific pattern.dNo cancer in control and exposed groups.eCancer incidence in exposed animals exceeds that in controls at all dose levels.f Cancer incidence in exposed animals exceeds that in controls at the lowest dose levels, then decreases—sometimes below incidence

in controls—at higher dose levels.

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FIGURE 7. Incidence rates for all cancers in male C57BL mice exposed to fission neutrons at an age of 21 d (Maisin et al. 1996). Thedataset ID is 485. The 90% confidence intervals for binomial parameters (cancer incidence rates) were computed using the Clopper–Pearson method (color figure available online).

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FIGURE 8. Incidence rates for reticulum cell sarcoma in female RFM f/Un mice irradiated with 137Cs at 70 d of age (Ullrich and Storer1979a). The dataset ID is 295. The 90% confidence intervals for binomial parameters (cancer incidence rates) were computed using theClopper–Pearson method (color figure available online).

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FIGURE 9. Incidence rates for lymphoma in male BALB/c mice exposed to 137Cs (Maisin et al. 1983). The dataset ID is 269. The 90%confidence intervals for binomial parameters (cancer incidence rates) were computed using the Clopper–Pearson method (color figureavailable online).

experiment, the highest dose to the skeletonwas 7.43 Gy but it must be noted that num-ber of animals involved was small (58 controls;38 exposed in total) (Taylor et al. 1983).

As an example of a hockey-stick-like doseresponse (Figure 12), the cancer incidence in

exposed animals is the same as in controls at allbut the highest dose level (myeloid leukemia inmice exposed to x-rays; Covelli 1988).

In order to evaluate dose-response trendsacross the database on radiogenic cancer inanimals, the shape of the dose response was

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FIGURE 10. Bone sarcoma in albino C57Bl/Do female mice following injection of 226Ra (Taylor et al. 1983). The dataset ID is 88 (colorfigure available online).

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FIGURE 11. Incidence rates of all carcinomas and sarcomas in male C57Bl mice irradiated once with 137Cs at 84 d of age (Maisin et al.1988). The dataset ID is 279. The 90% confidence intervals for binomial parameters (cancer incidence rates) were computed using theClopper–Pearson method.

examined for each dataset included in theDRCA, involving low linear energy transfer(low-LET) radiation and high-LET radiation.Linear energy transfer is a measure of energydeposition per unit distance traveled by radia-tion in a tissue, and, consequently, of the den-sity of ionization produced by the radiation asit traverses the tissue. X-, beta- and gamma-rayscause only a few dozen ionization when theytraverse a cell; thus, they are called sparsely

ionizing or low-LET radiation. In contrast, theheavier particles (alpha particles and neutron)are termed densely ionizing or high-LET radi-ations because they transfer more energy perunit length as they traverse the cell (NRC 2006).This analysis provides an overall impression ofthe shape of the dose-response curve for radi-ation carcinogenesis at low doses, based on allof the data reported in the scientific literatureup to the year 2000.

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FIGURE 12. Hockey-stick-shaped incidence of cancer in mice exposed to x-rays (Covelli et al 1988). Dataset ID is 675 (color figureavailable online).

Dose Response: Alpha EmittersThese experiments were conducted on

rats (Wistar, Sprague-Dawley), mice (NMRI,CF1, C57), dogs (beagles, Saint-Bernard), deermice (Peromyscus maniculatus) and grasshop-per mice (Onychomys leucogaster). Alpha emit-ters were administered by tracheal instillation,injection, or inhalation.

The dose rate from internally depositedalpha emitters is not constant; it is governedby their rate of intake into, and clearancefrom, target organs. The radiation doses usedreported by the authors range from 2 mGy forinhaled 239PuO2 in rats (Sanders and Sanders1993) to 8.95 Gy for injected 226Ra in dogs(Lloyd et al. 1999a; 1999b).

In total, about 10,800 animals wereexposed to internally deposited alpha emit-ters and about 6,500 animals were used ascontrols. The total number of cancers observedin exposed animals was about 4000, comparedto 1665 cancers in control animals (Table 4).The number of animals in control groups wasquite variable, from 4 dogs (Mays et al. 1989)to 1052 rats (Sanders and Sanders 1993).

In 24.5% of the 143 datasets, someevidence of a positive association betweenradiation exposure and cancer incidence was

seen. There were no cancers in 11.9% and noapparent affect in 7% of the datasets. J-shapedor hockey-stick-like dose responses was seenin 56.6% of the datasets (Table 5). The highestproportion of J-shaped dose responses (47%)was in the group of datasets with less than 1%cancer incidence in controls.

Dose Response: Beta EmittersThese experiments were conducted on rats

(Fischer, Sprague-Dawley, Holtzmann), mice(CBA/H, CF1, several strains of C57 mice), andbeagle dogs. Either males or females alone,or both genders together, were used. The ageat exposure ranges from prenatal to 70 or84 d for mice, and as young adults (360 to500 d) for dogs. These experiments comprised80 datasets and a total of 314 dose levels.Beta emitters were administered to the animalsby injection, inhalation or ingestion. In oneexperiment, beta radiation was delivered forthe induction of skin cancer (Albert et al. 1961).

The dose rate from internally depositedbeta emitters is not constant; it is governed bytheir rate of intake into, and clearance fromtarget organs. The radiation doses reported bythe authors range from 2 mGy (Mays and Lloyd1972) to 310 Gy (Lundgren et al 1980). Higher

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doses, ranging from 9 Gy to 240 Gy were usedin experiments aimed at determining a doseresponse for the induction of skin cancer bybeta emitters (Albert et al 1961).

In total, of about 11,100 animals wereexposed externally or to internally depositedbeta emitters and about 4600 animals wereused as controls. The total number of can-cers observed in exposed animals was approx-imately 3000, compared to 800 control ani-mals. The number of animals in control groupsvaried from 6 dogs (Mays and Lloyd 1972) to1049 rats (Lundgren et al. 1996). The numberof animals in exposed groups was between 1 to4 rats for experiments on skin cancer (Hulse1962), and 1025 for mice exposed to inhalable144CeO2 (Lundgren et al 1980).

There were in total 80 datasets with ani-mals exposed to beta radiation. Of these, evi-dence of an rise in cancer incidence withincreasing dose (at all dose levels or inverseU-shape) was observed in 42.5%; J-shapeddose-response shapes, hockey-stick-like dose-response shapes, no discernible effect, or nocancers in control and exposed animals wereseen in 57.5% of datasets (Table 5). Thehighest proportion of apparent J-shaped doseresponses was seen in the datasets with acancer incidence in controls between 10 and25%. It should be noted that experiments withbeta emitters often involved high doses (of theorder of tens, and sometimes even hundredsof grays); in some cases, the increase in cancerrates was reported only at higher doses.

Dose Response: Gamma RadiationExperiments with gamma radiation were

conducted on WAG/Rij rats, mice (B6CF1, sev-eral strains of C57J, several strains of BALB,and several strains of RFM), and beagle dogs.Animals received in utero as well as postna-tal irradiation in experiments conducted byKusama and Yoshizawa (1982) and Benjaminet al. (1998). Most experiments were con-ducted at several dose levels, and some authorsstudied the induction of radiogenic cancer for avariety of dose rates (Ullrich and Storer 1979c;Upton et al. 1970). The doses used in gamma

experiments ranged from 100 mGy to 3.29 Gy,with dose rates from 4 × 10−7 to 4 Gy/minspanning 7 orders of magnitude. The sourcesof gamma radiation were 60Co and 137Cs.

In total, about 29,800 animals wereexposed externally to gamma radiation with11,373 used as controls. In total, 21,666 can-cers were observed in exposed compared to5359 in control animals (Table 4). The numberof animals in control groups was quite vari-able, ranging from 40 rats (Bartstra et al. 1998)to more than 4000 mice (Ullrich and Storer1979a; 1979b; 1979c). Cancer outcomes wereobserved in all control groups for experimentswith gamma radiation.

The distribution of the 173 datasets withanimals exposed to gamma-radiation by dose-response pattern is as follows (Table 5). In 66(38.2%) of the datasets, cancer incidenceincreases monotonously with dose or displayedan inverse U-shaped dose response, whereas107 (61.8%) of the datasets displayed an appar-ent J-shape, hockey-stick shape, or no apparenteffect. The most striking examples of J-shapeddose responses in experiments with gammaradiation are those reported by Ullrich andStorer (1979a) (Figure 8) and by Maisin et al.(1988) (Figure 9). In both examples, cancerincidence rates in the exposed groups aresignificantly below that in controls at severalconsecutive dose levels.

Dose Response: NeutronsThese experiments were conducted on

rats (Sprague-Dawley, BN/Bi, WAG/Rij) andmice (RF/Un, BABL/An NBd, BALB/c, B6CF1,CBA/H, C57BL/Cnb, CBA/Cne, BC3F1,SAS/4). The age at first exposure rangedfrom prenatal (Di Majo et al. 1990) to about110 d (Mole and Davids 1982). Although mostexperiments were conducted at a single doserate and various dose levels, the role of doserate in neutron radiation carcinogenesis wasinvestigated by Upton et al. (1970), who useda wide array of doses (5 mGy to 3.32 Gy, aspan of about 3 orders of magnitude) anddose rates (3 × 10−8 to 0.85 Gy/min, a spanof 7 orders of magnitude). Overall, neutron

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doses ranged from 5 mGy to 3.32 Gy, a spanof 3 orders of magnitude). The energy of theneutrons was from 0.5 to about 14 MeV, withsome experiments mentioning only the use offast neutrons.

In total, of about 22,800 animals wereexposed to neutrons and approximately7300 animals were used as controls. The totalnumber of cancers observed in exposed animalswas close to 17,400, compared to approxi-mately 4880 cancers in controls (Table 4). Thenumber of animals in control groups was quitevariable, from 19 rats (Broerse et al. 1978) to739 mice (Thompson et al. 1985).

Among 250 datasets, 38.8% show someevidence of a positive dose-response (Table 5),55 (22.0%) demonstrated no clear evidenceof an effect, and 94 (37.67%) exhibited eitherJ-shaped or hockey-stick-like dose-responses.There were no cancers either in exposedor control animals in 1.6% of the datasets.J-shaped dose responses varied from lessthan 28% in datasets with 1 to 10% cancerincidence in control groups, up to 54% indatasets with cancer incidence above 25% incontrols.

Dose Response: X-RaysThese experiments were conducted on rats

(WAG/Rij, Sprague-Dawley, BN/Bi) and mice(BC3F1, several strains of C57 mice, CBA,CBA/H, RF/Un, SAS/4). Collectively, theseexperiments comprise 154 datasets. Most x-rayexposures were delivered acutely, with theexception of one experiment in which ratswere exposed chronically (Gragtmans et al.1984). The doses used in x-ray experimentsvaried from 40 mGy to 4 Gy (a range of twoorders of magnitude), with dose rates rangingfrom 10−5 to 5.5 Gy/min (spanning 6 orders ofmagnitude).

Approximately 13,400 animals wereexposed to x-rays and about 7400 animalsused as controls. The total number of cancersobserved in exposed animals was approxi-mately 6,700 compared to 1,860 cancers incontrols (Table 4). The number of animalsin the control groups varied from 19 BN/Bi

rats (Broerse et al. 1978) to 800 mice (Molet al. 1983).

In 36.4% of 154 datasets with animalsexposed to x-rays, there was some evidence ofan elevation in cancer incidence with increas-ing dose (Table 5). J-shaped or hockey-stick-likedose responses or no apparent effect wereobserved in 98 (63.6%) of the datasets forx-rays. A J-shaped dose response was observedin 38 (24.7%) of the x-ray datasets. Amongdatasets with less 1% cancer incidence in con-trols, the proportion of J-shaped dose-responserelationships exceeded 50%.

CONCLUSIONS

This review described a comprehensivedatabase on radiation carcinogenesis in ani-mals presenting results of an examination ofdose-response patterns in a large body ofexperiments, in which animals were exposedto various types of radiation at low dosesor at doses that do not considerably reducetheir life span. Although the primary objectiveof this study was to examine dose-response-relationships at low doses (below 1 gray), ourinclusion criteria resulted in incorporation ofsome datasets with relatively high exposurelevels above 1 gray. With all types of radia-tion exposure, more datasets exhibited eitherJ-shaped, hockey-stick-like, or no discernibleeffect (64%), whereas 36% of the datasetsexhibited a positive dose-effect relationshipover the whole dose range or at several ofthe lowest dose levels (Table 5). Overall, therewas no evidence of an effect in about 16%of all datasets. In 0 to 11.9% of the datasetsthere were no cancers either in exposed or incontrol animals.

The relatively high proportions of appar-ent J-shaped dose responses (25 to 69% ofthe datasets with nonzero number of can-cer cases in the control groups), especiallyin datasets with a low cancer incidence incontrol animals, are of interest. It should benoted that the distributions of the datasets bydose-response pattern reported here are basedon the results of visual examination withoutstatistical considerations (Table 5), and in some

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cases the distinction between datasets with“evidence” or “lack of evidence” of carcino-genic effect is ambiguous.

The present database includes a total of262 experiments, comprised of 800 datasets,on radiation carcinogenesis in animals, makingit the largest database of this type assembledto date. However, some of these experimentsare uninformative with respect to the shape ofthe dose-response curve for radiation inducedcancer in the low dose region. In particu-lar, experiments in which no cancers wereobserved in either experimental or controlanimals provide no information on dose-response; there were 42 such datasets in thedatabase. Experiments with only a controlgroup and single dose group provide minimal

information on the shape of the dose response;there are 53 such datasets. In addition, exper-iments with only three dose levels do notpermit a statistical test of whether a (saturated)quadratic model provides a better fit to thedata than a linear model; there were 258 suchdatasets. In total, 341 of the 800 datasets inthe DRCA are essentially noninformative withrespect to the main question of interest here:What is the shape of the dose-response curvefor radiation induced cancer at low doses?The detailed statistical analysis conducted byCrump et al. (2012) makes allowance for thesenoninformative datasets, and weighs the evi-dence for and against both the linear no-threshold hypothesis and the hormesis hypoth-esis in an objective, quantitative manner.

APPENDIX I: LAYOUT OF THE DATABASE ON RADIOGENIC CANCER IN ANIMALS (DRCA)

SAS VariableName Attribute Column Length Description

DATA_ID NUM 1–3 3 Dataset sequence numberEXP_ID NUM 5–7 3 Experiment sequence numberINT_NO CHAR 9–18 10 International Radiological Archive numberAUTH_ID NUM 20–21 2 Sequence number for last nameAUTHOR CHAR 23–36 14 Last name of the first authorRAD_TYPE NUM 38 1 Radiation type:

1. Alpha2. Beta3. Gamma4. Neutron5. X-ray

RAD_NUC CHAR 40–65 26 Type of radionuclides or radiationMODE_ADM NUM 67 1 Administration mode:

1. Inhalation2. Injection3. Ingestion4. External5. Instillation

EXPOSURE NUM 69 1 Exposure type:1. Acute2. Intermediate3. Chronic9. Others

SEX NUM 71 1 Gender:1. Male2. Female

SPECIES CHAR 73–96 24STATUS NUM 98 1 Animal status:

1. Control2. Case

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SAS VariableName Attribute Column Length Description

AGE_EXP NUM 100–102 3 Age at exposureNO_FRAC NUM 104–105 2 Number of dose fractionationSEP_DAY NUM 107–111 5.2OVER_DAY NUM 113–115 3 Over daysDOSE NUM 117–123 7.3 Dose administered (Gy)DOSERATE NUM 125–133 9 (11.8) Dose rate (Gy/m)NO_ANIM NUM 135–138 4 Number of animalsNO_CASE NUM 140–143 4 Number of animals with tumorsOUTCOME CHAR 145–186 42SITE CHAR 188–226 39CLASS NUM 228 1 Tumor classification:

1. Carcinoma2. Leukemia3. Lymphoma4. Sarcoma5. Carcinoma & Sarcoma9. Others

YEAR CHAR 230–274 45 ReferenceNOTE CHAR 276–319 44 Description on dose or dose rate

APPENDIX II: SUMMARY OFINDIVIDUAL DATASETS IN THEDATABASE ON RADIOGENIC CANCERIN ANIMALS

Appendix II (400 pages with plots of alldatasets) is available online.

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