Bone Cancer Among Female Radium Dial Workers. Latency Periods and Incidence Rates by Time After Exposure: Brief Communication 1.2

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1 Bne Cancer Amng Female Radium Dial Wrkers. Latency Perids and Incidence Rates by Time After Expsure: Brief Cmmunicatin 1.2 Anthny P. Plednak ABSTRACT-Bne cancer cases in 1,250 wmen expsed t radium while wrking in the luminus watch-dial industry between 191 and 1929 were analyzed fr times f appearance ("Iatency perids") and incidence rates ver time after first expsure. The lwest radium intake dse assciated with bne cancer, amng 751 wmen whse intake dses had been determined, was p.ci. Mean and median bne cancer latency perids tended t decline, but average survival amng wmen withut bne cancer als decreased with increasing intake level. Bne cancer incidence rates ver time were cmpared in 2 intake-dse grups ( and 2::750 p.ci) by means f an actuarial methd that takes cmpeting risks int accunt. Incidence rates were cnsistently higher in the higher intake-dse grup versus the lwer dse grup at each 5-year perid after first expsure. The variability in the dds ratis acrss the time perids was nt statistically significant, and the actuarial methd prvided IiUle evidence fr an effect f intake dse n the pattern f incidence rate ver time. With the use f similar methds, n significant variability was evident in the relative dds f bne cancer ver time after expsure between ne grup f wmen first expsed t radium at less than 18 years f age and anther grup expsed when 18 r mre years ld.-j Natl Cancer Inst 60: 77-82, Studies f the health effects f radium receive attentin primarily because f their relevance t ther "bnesee king" internal emitters, such as plutnium. In regard t studies f latency perid and the natural histry f cancer, radium-related bne cancers are f interest because the causal factr and expsure times are knwn with sme certainty. The assciatin between radium expsure and bne cancer was first reprted in 1929 by Martland (l). Aub et al. (2) reprted n 0 cases f radium expsure, including that led t stegenic sarcmas and 1 that led t fibrsarcma f the knee jint. These studies invlved radium-dial painters and persns given injectins f 228Ra arid/r 226Ra by physicians fr suppsed therapeutic effects. Bne cancers have als been reprted amng German patients given injectins f 224Ra during the years (,4). In varius studies f human neplasms, including radigenic leukemias, with knwn etilgic factrs and knwn times f expsure t thse factrs, mean and median latency perids tend t be largely independent f intensity (dse) and time f expsure (5). In bne cancers amng persns receiving injectins f 224Ra, a tendency fr shrter appearance times at higher skeletal dses was reprted; it was nted that at least part f this reprted effect culd have been due t the high mrtality rates, frm ther causes, f patients wh received the highest dses (5). The present study examines latency perids and incidence f bne cancers by time after expsure t radium, amng wmen wh wrked in the radium dial-painting industry. In cmparisns f bne cancer incidences in different dse grups, the prblem f "cmpeting risks" is cnsidered. MATERIALS AND METHODS In 1929, the V.S. Bureau f Labr Statistics (6) estimated that "nt mre than 2,000 persns" had wrked in the radium-dial industry frm abut 191. Nearly 1,400 female radium-dial wrkers have been identified thrugh varius surces, including emplyment lists, cmpany phtgraphs f wrkers, statements f c-wrkers, and self-referral. Apprximately 1,250 f the 1,400 dial wrkers were lcated (i.e., fllwed up in terms f mrtality); cpies f death certificates were btained and causes f death cded by nslgists at the Natinal Center fr Health Statistics. Measurements f the bdy's radium burden and clinical data were derived mainly frm studies dne at the Massachusetts Institute f Technlgy and at Argnne Natinal Labratry since the 1950's and frm studies dne as part fthe NewJersey Radium Research Prject ( ). Sme dial wrkers were lcated and their radium burden measured befre these prjects were initiated, thrugh the wrk f Martland and his assciates and surveys made by the V.S. Bureau f Labr Statistics (6). Recrds f all dial wrkers identified are centralized at Argnne. As f December 1, 1975, 751 f the 1,250 wmen had had at least ne medical examinatin as part f the abve-mentined studies. Sme bdy burden radium-measurements (N.=20) were based nly n the radium cntent f exhumed skeletal remains. Fr all 1,250 wmen, including thse fr whm bdy radium burden was nt measured, attempts are made t btain cpies f hspital recrds. Pathlgie data frm all surces were cded accrding t the Systematized Nmenclature f Pathlgy (7). Methds f measurement f the bdy's radium bur- ABBREVIATIONS USEO: X 2 hom Og = chi-square t assess variability r hmgeneity amng grup measures f assciatin; df = degree(s) f freedm; X 2 assc = chi-square t assess assciatin amng variables. 1 Received March 7,1977; acceptedjuly 21, Supprted by the U.S. Energy Research and Develpment Administratin. Center fr Human Radibilgy, Radilgical and Envirnmental Research Divisin, Argnne Natinal Labratry, Argnne, lll VOL. 60, NO. 1, JANUARY J NATL CANCER INST

2 78 POLEDNAK den were described in (8, 9). In living persns, gamma radiatin (frm daughter prducts f retained radn) is measured by scintillatin gamma-ray spectrmetry with the use f thallium-activated sdium idide crystals in a shielded undergrund vault, and the measurement f radn emanating frm the bdy is made n samples f exhaled breath (10). Althugh sme shrt-term retentin ccurs in sft tissues (11), radium (a bneseeking radinudide) is depsited in skeletal tissues. Fr this analysis, radiatin dse was defined as the initial systemic in take f 226Ra and 228Ra in micrcuries. This parameter, similar t the "injectin levels" used in animal txicity and carcingenesis experiments, is the initial quantity f radium entering the bld during the perid f expsure and is calculated frm the measured radium burden in the bdy by use f the retentin functin f Nrris et al. (12). Bth 226Ra and 228Ra were used in luminus paint, s that sme dial wrkers ingested bth istpes, primarily frm the practice f tipping r pinting the paint brush in the muth. The skeletal dse frm ingested 226Ra cntinues t increase (even 60 yr after intake) as the retentin f radn increases with time; skeletal dse frm 228Ra increases rapidly in the first few years as 228Ra decays, but plateaus are reached (at =25 yr) as the parent istpe disappears (1). On the basis f the rati f the dse f the tw istpes absrbed by the skeletn ver the first 0 years after in take (1), the dse parameter (expressed in JLCi) used in the fllwing analyses was: 226Ra intake+(2x 228Ra intake). Table 1 shws the distributin f in take dses In 751 wmen. TABLE l.-distributin fintake-dse levels in 751 wmen with measured bdy radium burden Intake dse, j.lci a < b N.fwrnen a [226Ra+(2x 228Ra)] intake, as defined in "Materials and Methds." b Highest intake dse was,205 j.lci. As f December 1, 1975, 58 f the 1,250 wmen had a diagnsis f malignant primary bne tumr dcumented by the fllwing surces: death certificate (11 cases); death certificate and antemrtem X-ray reprt (10 cases); autpsy reprt (12 cases); bipsy reprt (24 cases), with r withut ther surces; and ther (1 case; literature re prt). Althugh diagnstic cnfirrnatin and histlgic classificatin f all cases were nt pssible, the samples shuld be useful fr statistical analyses. The present analyses were cnfined largely t the 751 wmen with measured bdy radium burden, amng whm 6 (f the ttal 58) bne cancers ccurred. Of these 6 cases, nly 4 were ascertained frm death certificates alne (all 4 were cnfirmed by X-ray survey f the exhumed skeletal remains), whereas 18 were ascertained frm bipsy reprts (with r withut ther surces f dcumentatin). Latency perid was defined as the time frm first expsure (i.e., first emplyment in the radium-dial industry, ) t diagnsis f bne cancer; mean and median latency perids were cmpared acrss several dse grups. Bne cancer incidence rates in 5-year perids (after first expsure) were cmpared between tw dse grups; cmpeting risks (mrtality frm causes ther than bne cancer) were taken int accunt by the actuarial methd described by Pike and Re (14). A similar cmparisn f incidence rates was made fr tw age-at-first-expsure grups. RESULTS The relatinship between in take dse and mean latency perid in the 6 measured bne-cancer cases is shwn in table 2. The lwest intake dse at which bne TABLE 2.-Mean latency perid f6 bane cancercases, and survival fpersans withut bne cancer, by intake-dse level Survival after ex- psure,yr Intake dse jlci a N. Bne cancer cases Latency perid, yr Mean Me- dian sn Dial wrkers withut bne cancer N. Mean sn Median , , Ttal a See ftnte a, table 1. N bne cancers were fund arnng the 660 wrnen with in take dses f <200 jlci. cancer was knwn t ccur was /Lei. At higher dse levels (~750 jlci), the mean latency perid was lwer. Survival f ther female dial wrkers (withut diagnsed bne cancer) is als shwn; survival was calculated frm the year f first expsure t the year f death r t the last year knwn alive (1975; 1974 in 2 persns). These data shw that at least part f the decrease in mean latency perid with increasing int ak e dse may be related t early death frm ther causes (cmpeting risks) in the grups with high intake dses. Wmen with sme high intake dses culd have develped bne cancer (at later times) if they had nt died earlier frm ther causes. The effect f cmpeting risks was examined mre clsely. Table shws a cmparisn f incidence by time perid after expsure in tw in take-dse grups ( and ~750 JLCi). The 750-jLCi level was the lwest level at which mean latency perid appeared t dedine (table 2); als, tw nearly equal sarn ple sizes were prvided by use f this dse level fr subdivisin. In calculating incidence rates accrding t methds f Pike and Re (14), the number f wmen alive (withut J NATL CANCER INST VOL. 60, NO. 1, JANUARY 1978

3 BONE CANCER RATES IN WOMEN EXPOSED TO RADIUM 79 TABLE.-Bne cancer incidence in tw intake-dse grups, by time after first expsure ILCi, N. =51 2:750 ILCi, N. =40 Years after first P P p expsure N.fbne Prprtin f N.fbne P Prprtin f Bne cancer in- Bne cancer incancers wmen withut cancers wmen withut cidence rate" cidence rate? bne cancer" bne cancer" Odds ratis:" 2:750 VS ILCi "See (15). b The number f persns wh manifest a bne cancer in each time perid divided by the number at risk (n- 1 /2d, where n is the number alive at the start f the perid and dis the number dying f ther causes during the perid). C The prbability f nt develping a bne cancer by the end f each time perid; e.g., P 10 (at 45+ yr)= (l-pi)x (l-p2)x... (l-pio)' bne cancer) (n) at the start feach interval was adjusted fr the number f thse dying f causes ther than bne cancer (d) during the perid: N. at risk=n- I /2d. The frequency distributins f bne cancers (by time perid after expsure) were different in the tw intakedse grups (table ); e.g., ar ~0 years after initial expsure, the number f bne cancers in the lwer intake-dse grup was larger relative t that in the higher intake-dse grup. When mrtality frm ther causes was taken int accunt, hwever, the incidence rate was cnsistently higher in the higher in take-dse grup ar each time perid (table ). Text-figure 1 cmpares the prprtin f persns withut bne cancer (P) in the tw intake-dse grups, by time perid. "P" represents the prbability f nt develping a bne cancer by the end f each perid, after cmpeting risks are taken int accunt. After the first perid (0-4 yr), P was cnsistently lwer in the higher dse grup; the 95% cnfidence intervals fr P fr the tw intake-dse grups did nt verlap after the 5- t 9-year perid (text-fig. 1). Bne cancer incidence in the tw in take-dse grups, by time perid after ex ps ure, was analyzed statistically by a chi-square test fr cmbining data frm furfld tables (15). Because f small sarnple sizes, the data in table were cmbined int fur time perids (0-19,20 29, 0-9, and 40+ yr). The lgarithms f the dds ratis were used, as described by Fleiss (15). The quantity X 2 hmg assesses the degree f variability amng g (number f grups) measures fassciatin. The X 2 hmog was nt statistically significant (X 2=2.21; df=; P>0.50). The quantity X 2 a ssc assesses the signficance f the average degree f assciatin (here, between in take dse and bne cancer incidence); the X 2 assc was statistically significant (X 2 =12.89; df= 1; P<O.OOI). Average skeletal dses frm 226Ra and 228Ra expsure t time f diagnsis f bne cancer were available but nt used in these analyses; rather a time-invariant dse parameter (intake dse) was used. Hwever, the skeletal I.00.: , I ffi.90 u z «uw.80 z.70 g l :=>.60 ~ I-.50 = z.40 I a:.0 c, a: Cl. ", '+ 1\ I \ I 'T'.J.,I I, I I " : : ""I T I \ I T I I \ I :..&. :,,: I 'T' I,I I I J. +<, : : i :)..., : : 'T 1 I', I 1 1 I : '...: 1 ;- I, J.., :,...,: :... I I '., I I I "I?:750 JlCi I, I ',I... I I.20.L 1 : 1 I I I 1 00_ TIME AFTER FIRST EXPOSURE (years) TEXT-FIGURE I.-Prbabilities f nt develping a hne cancer by the end f each time perid (see table ) in tw in take-dse grups. Verticallines depict 95% cnfidence intervals. These are hypthetical prbabilities, assuming n remvals by death frm causes ther than bne cancer (see text). dse (t time f diagnsis) in the first diagnsed bne cancer in the #LCi intake-dse grup was 1,445 rads; skeletal dses fr the ther 15 patients in this intake-dse grup ranged frm 1,547 t 6,184 rads. In the ~750 #LCi intake-dse grup, the first diagnsed bne cancers ( patients 5-9 yr after first expsure) had skeletal dses f 6,1,9,507, and 18,02 rads; skele-tal dses in the remaining 17 patients ranged frm 5,046 t 44,441 rads. VOL. 60, NO. I, JANUARY 1978 J NATL CANCER INST

4 80 POLEDNAK Age at first expsure was als cnsidered in relatin t bne cancer incidence ver time. Divisin f the sample f 91 wmen with in take levels ~200 /LCi int age grups f <18 (N.=4) and ~18 (N.=48) years prvided nearly equal sample sizes; me an ages at expsure were 15.8 (±1.1 SD) years and 21. (±4.7) years, respectively. The prprtin f wmen withut bne cancer at the end f each time perid (text-fig. 2) was cnsistently lwer in the grup expsed at < 18 than in the grup expsed at ~ 18 years f age, which reflects the higher risks f bne cancer in the frmer grup. Nne f these prprtins fr the ~ 18-year grup, hwever, was greater than the upper limits fthe 95% cnfidence intervals f the prprtins fr the < 18 year grup (text-fig. 2). The tw curves were generally 1.00 ffi.90 u z 5.80 w ~.70 c I-.60 :::> ~.50 ~ z.40 ~.0 a.. ~.20 a...10 <18 years.. 18 years O~----J..._-L-_I J..._-L-_"---.J..._...L.-_" J / TIME AFTER FIRST EX POSURE (years) TEXT-FIGURE 2.-Prbabilities f nt develping a bne cancer by the end f each time perid in tw age-at-first-expsure grups «18 and ~18 years). Verticallines depict 95% cnfidence intervals fr the <18-year grup nly. These are hypthetical prbabilities (see text-fig. 1 and text). similar in shape, again with little indicatin f an effect f age at expsure n the pattern f incidence ver time. The bne cancer dds ratis fr the tw age-at-expsure grups were analyzed by the methd(l5) described abve. The data in table 4 were cmbined int five time perids (0-9, 10-19,..., 40+ yr). The average degree f assciatin between age at expsure and bne cancer incidence was nt statistically significant (X 2 assc = 1.11; df= 1; P>0.20), nr was the X 2 h Om Og (1.1; df=4; P>0.80). The pssibility f a cnfunding effect f intake dse n the age-at-expsure analysis was cnsidered. Mean lg in take dse was similar in the <18- and ~ 18-year- " TABLE 4.-Bne cancer incidence in tw age-at-first-expsure grups, by time after first expsure Years after first expsure <18 yr, NO.=4 N.f bne cancers Age at first expsure Bne cancer incidence b 0.024(' ~18 yr, N.=48 N.f bne cancers Bne cancer incidence" Odds rati" "See (15). b See ftnte b in table. ('Obtained by cmbining numbers f bne cancers and numbers f persns at risk fr tw 5-year intervals. ld expsure grups (i.e., 6.79± 1.04 SD and 6.58±0.80 SD, respectively; t= 1.09 by Studerit's t-test); the Spearman crrelatin cefficient between intake dse and age at expsure was nt statistically significant (r=-0.1; N=91; P>0.20 by the tw-tailed test). The <18-year-ld grup, hwever, included a greater prprtin fpersns with in take dses ~1,750 /LCi. Matching t within 100 /LCi prduced 28 pairs f wmen, wh shwed a pattern similar t that in text-figure 2. The abve analyses were limited t dial wrkers wh had bdy radium-burden measurements. Generalizatin f the findings n bne cancer-incidence rate, in relatin t in take dse and age at expsure, t the entire grup f 1,250 wmen wuld be hazardus. With the same methds used in table, bne cancer-incidence rates were cmpared by time after expsure in the measured grup (N.=751) and the ttal grup (N. = 1,250), the latter representing the "true" rates fr the ppulatin t which we wuld like t generalize ur results. The respective incidence rates fr the measured and the ttal grups fr each time-afterexpsure interval were: 0.4 vs. 0.6/100 at 0-9 years, 1.2 vs. 1.5/100 at years, 1.0 vs. 1.2/100 at years, 1.1 vs. 1.1/100 at 0-9 years, and 1.5 vs. 1.2/100 at 40+ years. The higher rates at early times after expsure in the ttal grup (vs. the measured) are reflected in the lwer mean latency perid fr 58 bne cancer patients (i.e., 24.4± 12.9 SD yr) than in the 6 measured patients (27.1±1. yr). Majr effrts at measuring bdy radium burden were nt begun until the mid-1950's; thus measurements were nt dne fr many persns wh died befre that time. DISCUSSION The present findings shuld be accepted with cautin because the data may be incmplete. Other bne cancers (f unknwn appearance times) may exist in this ppulatin; cnceivably, sme cases may have been caused by a variety f factrs r by factrs ther than the attributed ne. The upper end f the distributin f latency perids and incidence rates at the latest times J NATL CANCER INST VOL. 60, NO. 1, JANUARY 1978

5 BONE CANCER RATES IN WOMEN EXPOSED TO RADIUM 81 after expsure may have been affected by the tempral duratin f the study. All wmen have had a chance t survive 45 years after first expsure (i.e., frm r 1975), hwever, and the mst recently ascertained bne cancer was diagnsed in The present pattern f incidence rate ver time (table ) is nt unexpected in cancer induced by chrnic expsure f tissues at risk (i.e., by radium retained in the skeletn fr many years); i.e., a prbability f initiatin shuld cntinue t exist ver time. In acute expsure, initiatin events ccurring at early times after expsure culd result in early appearing cancers and subsequently decreasing incidence, as in leukemia induced by external radiatin (16). Acute expsure may nt necessarily imply shrt latency perids, hwever, because different mdels may be invlved in different types f cancer (17); e.g., lng latency perids with an acute expsure t an agent (nt retained in the bdy) culd reflect prmtin events ccurring many years after initiatin. The present data clearly supprt Pet's (18) bservatin that the "mean latency" f a particular cancer is "strngly dependent n the pattern f deaths frm ther causes" and shuld be used "extremely cautiusly, if at all, in describing the results f an experiment." This is evidenced when mean latency perid by in takedse grup (table 2) is cmpared with the ineidence rates ver time in the tw in take-dse grups (table ). Little evidence exists fr an effect f intake dse n the pattern f ineidence ver time after first expsure. Althugh the average r verall degree f asseiatin (X 2 assc) between intake dse and ineidence was statistically significant, the asseiatin was rather cnsistent r hmgeneus acrss the grups (i.e., fr the time perids). In a qualitative sense, this cnsistency is als evident in the cmparisn by intake-dse grup f the percentages f persns withut bne cancer, if ne assurnes that the ppulatin did nt die frm ther causes (text-fig.l). The actuarial methd (14) used here and the "cumulative ineidence" methd f Pet (18) are bth based n the relative stability f the sum f many, individually unstable incidence rates (19). Althugh the lwest intake dse (202.5 /LCi) in the bne cancer patients may be cnsidered the lwest (bserved) "tumrigenic" dse, f greater interest is the absrbed dse t cells at risk (i.e., bne cells r, mre speeifically, endsteal cells). Sme time may be required fr accumulatin f dse t these cells suffieient fr achieving a high prbability fr cancer initiatin. This culd explain the higher dds ratis f bne cancer incidence in the higher (vs. lwer) intake-dse grup (table ) at early (vs. later) time perids after expsure. The statistical test (X 2 homg) used here was insensitive t differences at early time perids because small sarnple sizes necessitated use f 0-19 years as the first time interval. The cnsistently higher in eidence in the ~750 (vs )-/LCi grup in all time perids culd be explained by a greater initiatin prbability due t higher skeletal dse. The absence f bne cancers at 0 4 years after radium expsure may reflect the time needed fr tumr grwth t symptmatic stages. In varius series f bne cancers fllwing therapeutic (external) radiatins, neplasms were 'first diagnsed after -5 years (20). Cmparing bne cancer ineidence rates in tw ageat-first-expsure grups «18 and ~ 18 yr) within the 91 wmen with an initial intake dse f ~200 /LCi (table 4; text-fig. 2), we fund the dds ratis «18 vs. ~ 18 yr) higher at earlier time perids (frm 0-9 t yr) after initial expsure than at later perids; but the variability amng the dds ratis (X 2 hom Og ) was nt statistically significant. In view f the small sampie sizes, the pssibility f an asseiatin between age at expsure and bne cancer ineidence rate and the pattern f ineidence rates ver time (r latency perids) cannt be excluded. Animal studies with varius carcingens shw different relatinships with age at expsure (21, 22), which may nt be unexpected (21). Inasmuch as an assciatin between bne cancer risk and bne grwth rate is well established (20, 2), an effect f age at expsure n risk f radium-induced bne cancer might be expected. Sme evidence (, 4) exists fr such an effect in humans given injectins f 22 4 Ra as juveniles (e.g., 1-5, 6-10 yr ld) versus thse given injectins as adults; but fllw-up is incmplete, and cmpeting risks were nt cnsidered. It shuld be nted that the present ppulatin shws less variability in age at expsure t radium in cmparisn with the 22 4 Ra cases. The pssible effect f in take dse and age at expsure n latency perid culd be examined nly in the measured grup; generalizatin f findings t the ttal grup is nt pssible. Bne cancer rates differ little between the measured grup and the ttal grup ver the tirne-after-expsure intervals cmpared, but dse bias in the measured grup may exist. T knw whether the respndent (i.c., measured) grup is selective with respect t expsure, utcrne, r bth is ften difficult (24). Effrts t btain measurements f bdy radium burden n the unmeasured dial wrkers are cntinuing, including exhumatin f the deceased and measurement f radium cntent f the skeletal rernains. REFERENCES (l) MARTLAND HS: Occupatinal pisning in manufacture flumi nus watch dials.jama 92:466-47,1929 (2) AUB JC, EVANS RD, HEMPELMANN LH, et al: Late effects f internally-depsited radiactive materials in man. Medicine 1:221-29,1952 () SPIESS H: 224Ra-induced tumrs in children and adults. In Delayed Effects f Bne-Seeking Radinuclides (Mays CW, Jee WS, Llyd RD, et al eds). Salt Lake City: University f Utah Press, 1969, pp (4) SPIESS H, MAYS CW: Bne cancers induced by 224Ra (ThX) in children and adults. Health Phys 19:71-71, 1970 (5) ARMENIAN HK, LILIENFELD AM: The distributin f incubatin perids f neplastic diseases. Am J EpidemiI99:92-100, 1974 (6) U.S. Bureau f Labr Statistics: Radium pisning. Mnthly Labr Rev 28: ,1929 (7) Cllege f American Pathlgists: Systematized Nmenclature f Pathlgy. Chicag: Cllege f American Pathlgists, 1965 (8) MALETSKOS CJ, BRAUN AG, SHANAHAN MM, et al: Quantitative evaluatin f dse-respnse relatinships in human beings with skeletal burdens fradium-226 and radium-228. In Assessment f Radiactivity in Man. Vienna: Internatinal Atmic Energy Agency, 1964, pp VOL. 60, NO. 1, JANUARY 1978 J NATL CANCER INST

6 82 POLEDNAK (9) EVANS RD: The effect f skeletally depsited alpha-ray emitters in man. Br J RadiI9: , 1966 (10) STEHNEY AF, NORRIS WP, LUCAS HF JR, et al: A methd fr measuring the rate f eliminatin f radn in breath. Am J Rentgenl Radium Ther Nucl Med 7: , 1955 (11) MARSHALL JH, LLOYD EL, RUNDO J, et al: Alkaline Earth Metablism in Man. Internatinal Cmmissin n Radilgical Prtectin. Publ N. 20. Oxfrd: Pergamn, 197 (12) NORRIS WP, SPECKMAN TW, GUSTAFSON PF: Studies f the metablism f radium in man. Am J Rentgenl Radium Ther Nucl Med 7: , 1955 ~1) ROWLAND RE, KEANE AT, LUCAS HF: A preliminary cmparisn f the carcingenicity f 226Ra and 228Ra in man. In Radinuclide Carcingenesis (Sanders CL, Busch RH, Ballu JE, et al, eds). Springfield, Va: U.S. Atmic Energy Cmmissin, 197, pp (14) PIKE MC, ROE FJ: An actuarial methd f analysis f an experiment in tw-stage carcingenesis. Br J Cancer 17: , 196 (15) FLEISS JL: Statistical Methds fr Rates and Prprtins. New Yrk: Wiley, 197, pp (16) JABLON S, KATO H: Studies fthe mrtality f A-bmb survivrs. 5. Radatin dse and mrtality, Radiat Res 50: , 1972 (17) POLEDNAK AP: Latency perids in neplastic disease. Am J Epidemil 100:54-56, 1974 (18) PETO R: Guidelines n the analysis f tumur rates and death rates in experimental animals. Br J Cancer 29: ,1974 (19) PETO R, ROE FJ, LEE PN, et al: Cancer and ageing in mice and men. Br J Cancer 2: , 1975 (20 Mss WT, BRAND WN, BATTIFORA H: Radiatin Onclgy. Ratinale, Technique, Results. Sr. Luis: Msby, 197 (21) BERRY G, WAGNER JC: Effect f age at inculatin f asbests n ccurrence f mesthelimas in rats. Int J Cancer 17:477 48, 1976 (22) NOMURA T: Cmparisn f tumur susceptibility amng varius rgans f fetal, yung, and adult ICR/Jcl mice. Br J Cancer :521-54, 1976 (2) SCRANTON PE JR, DECICCO FA, TOTTEN RS, et al: Prgnstic factrs in stesarcma. A review f 20 years' experience at the University f Pittsburgh Health Center Hspitals. Cancer 6: ,1975 (24) MACMAHON B, PUGH TF: Epidemilgy: Principles and Methds. Bstn: Little, Brwn & C., 1970, P 219 J NATL CANCER INST VaL. 60, NO. 1, JANUARY 1978