ML20126J786

Std Order for DOE Work: Reanalysis of Tri-State Leukemia Survey Data, Issued to Anl.Statement of Work Encl

ML20126J786
Person / Time
Issue date:	08/28/1979
From:	Minogue R NRC OFFICE OF STANDARDS DEVELOPMENT
To:
Shared Package
ML19262A508	List: IA-81-132, Std Order for DOE Work: Reanalysis of Tri-State Leukemia Survey Data, Issued to Anl.Statement of Work Encl ML19262A507 ML20008F757 ML20126J758 ML20126J764 ML20126J768 ML20126J772 ML20126J776 ML20126J786
References
CON-FIN-A-20679, FOIA-81-132, FOIA-81-172 10-79-68, NUDOCS 8105050291
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s. NRC s ca*,i 173 u s.NuCLt AR REGULATORY CCMMISSION QRQE A NUMBE A (2.n ~ f D-1 P Q . STANDARD ORDER FOR DOE WORK. i AVG 2 8'1979 IISUED TO: (DOE Othcel. ISSUED DY: INRC OlDu) ACCOUNTING CITATION APPROPRI ATION SYMSOL. . Chicago Operations Office Office of Standards Development C4R NUM Sr. A PERFORMING ORGANIZATION ANS LOCATION 10-10-01-06-3 -l FIN NUMBER t Argonne National Laboratory , pgg, WORK PERIOD. THIS ORDER t FIN TITLE.. _ FIXED O ESTIMATED G - f FROM: TO: 5 Reanalysis of the Tri-State Leukemia Survey Data 9-1-79 9-30-80 i 03 LIGATION AVAILABILITY rnCVfDED BY: i f n A. THIS ORDER S 67,000

8. TOTAL CF CROERS PLACED PRIOR TO THIS CATE wtTH THE PERFCRMING ORGANIZATION 5

VNDE54 THE SAVE "APPROPRI ATION SYMBOL" AND THE FIRST FOUR 03GITS OF THE S B&R NousER ciTeo AeOve. 518.000 TOTAL OR DERS TO DATE. (TOTAL A & B) S '585,000

0. AMOUNT INCLUDED IN "C" APPLICABLE TO THE " FIN NUMCER" CITED IN THIS ORDER.

S 63.000 l FINANCI AL FLEXIBILITY: I O FUNDS WILL NOT BE REPROGRAMMED BETWEEN FINS, LINE D CONSTITUTES A LIMITATION ON OBLIGATIONS 'AUTHORIZ E D. O FUNDS MAY CE REPROGRAMMED NOT TO EXCEED 210% OF FtN LEVEL UP TO $50K. LINE C CONST! i ON 03LIGATf 0NS AUTHORIZED. STANDARDTERV.S AND CCNOITIONS PROVIDED DOE ARE CONSIDERED PART OF THIS ORDER UNLESS OTHERWIS'i NOTED. 1 ATTACHMENTS: THE FOLLOWING ATTACHMENTS ARE HEREBY SECURl[Yi MADE A PART OF THIS ORCER: O WORK CN THIS CRDER IS NOT CLASSIFIED. O(STATEMENT O F WOR A O WORK ON THIS ORDER INVOLVES CLASSIFIED O ADDITIONALTER*JS AND CONDITIONS INFORMATION. NRC FORM 18715 ATTACHED. O OTHER t REMARKS: I I

Reference:

Form 189, submitted B-9-79 for $67.,000. l fl0TE: SD cannot fund capital equipment costs. i i f i I 3 ISSUING AUTHOP.iTY ACCEPTING ORG ANIZATION ggbT 4 ( "/S,wydtr J sic N a tu RE SIGN A TURK s.'[z?/99 'f y Robert B. dinogu'e i Ti tL E E T6TLE Director, Office: cf Star.dards Deve1 Cement i t NRC FCRM 173 (2 78) p li; H10 5.05 0% i f 1 =

I = ? STATEMENT OF WORK REANALYS:S OF THE TRI-STATE LEUXEMIA SURVEY DATA WITH SPECIAL REFERENCE TO THE LEUKEMOGENIC POTENTIAL OF DIAGNOSTIC LRAYS FIN: A20679, B&R: 10-19-03-06-3 1.0 tiACKGROUND L The present controversy surrounding the magnitude and extent of human health effects from low-levels of ionizing radiation necessitates continued research efforts in this area. Of particular interest, are . data regarding populations exposed to low and/or chronic levels of low LET ionizing radiation, such as is reflected in the Tri-state data base, the subject of the presently proposed reanalysis. l The objectives of this project are to produce testable theories and hypotheses regarding the leukemogenic potential of diagnostic x-rays and to identify or reject some of the less plausible models proposed by other workers. c 2.0 WORK REOUIRED Perform a re-analysis of the adult portion of the Tri-state data, accomplishing the following specific tasks: i a) calculate age-standardized relative risks of adult leukemia for non-overlapping x-ray exposure categories-develop absolute risk estimates which can be related to existing absolute risk estimates for low-level low-LET radiation leukemogenesis b) investigate possible relationships between radiation exposure, disease, and leukemogenesis in adults - discuss these findings in the con, text of susceptible subgroups for radiation leukemogenesis c) investigate the possible influence of other variables e.g., temporal aspects of exposure, ethnic, socioeconomic on the relationship between diagnostic x-ray exposure and leukedogenesis s d) develop explanatory models and generate testcble hypotheses to I account for the Tri-state data 3.0 _ REPORTING REOUIREMENTS 3.1 MONTHLY LETTER STATUS REPORT Each month the performing organization shall submit a brief letter status report which summarizes: _ the work performed during the previous i month, personnel time expenditures during the previous month, and costs generated against the work effort. Any change to cost projections should be indicated. n y, v ,n .e

+ ,t {,- ~2-i

3.2. QUARTERLY AND FINAL. TECHNICAL REPORTS i

i . Each quarter the performing organization ~ sha11' submit a report whic!' describes the work performed - the final report shall be submitted -for NRC staff review in draft form for NRC policy, management, regu-latory, and legal issues.. j '4.0.NEETINGS AND TRAVEL'- .j .i As deemed necessary to keep fully abreast of progress of the contract, [ and'to gather and disseminate in formation relating to the cor.5plettorr i of. the contract. 5.0 NRC FURNISHED MATERIAL None. 6.0 PERIOD OF PERFORMANCE Performance under this contract will commence on the effective date of. this contract and will be completed, including the final report, within a period of'one year. 7.0 ' TECHNICAL DIRECTION h Mr. Stephen C. Whitfield (301) 443-5860 has'been designated as the NRC technical monitor for this effort. I \\ 8.0 DISPOSAL OF PROPERTY .N/A. j 4 t 1 i s i f t i f

.m hP n. NUCLEAR REGULATORY CO.*.1M(SSION PROGRAM BUDGET

1. TITLE

" Reanalysis of the Tri-state Leukemia Survey Data with Special Reference to the Leuke=ogenic Potential. G NNE of Diagnostic X-rays" A AL Z BUDGET ACTIVITY NO. ABORATORY %l DOE 40-10-01-01 NRC 10-19-03-06-3 ANL 8M420 U of C AUA US00E 1 S0!ENTIST RESPONS!SLE

4. WORK STARTED H. E. Ginevan/D. Grahn FY 1979 5 RELATED WORK ('r/ith Same Contractor or Others)

DOE GK-01-02-01-1, Hunan Health Effects fro ' Energy Generation NRC 60-19-30-01 (A2059/SM419) Projection Models for Health Ef fecti Assess =ent G. PERSON POWER AND CCrT DATA FY 1DSO FY 1980 PR ESIDEN T'S' INCREM. FY 1979 SUDGET R E QUIR E. FY 1981 6a. DlRECT PERSON PCWER (Person Years) SCIENTIFIC R E G Ul"AR 0.1 0.9 1,o TEMP. PAID BY ANL TOTAL SC;ENTIFic 0. *i 0.9 1.0 OTHE R TECHNICAL REcytAR TEMP. PAID BY ANL TOTAL OTHER TECHNIC.SL TOTAL TERSON YEARS 0.1 049 1.0 E b. CPER ATING CCSTS (in Thousandsl ciREcT SALARIES $3 $30 $36 l MATERIALS AND OERVICES 1 3 6 MAJOR PROCUMEMENTS 0 0 s 0 INDIRECT COSTS 2 26 30 TOTAL COST $6 $61* $72 Sc. CAPITAL ECUIPMENT (In Thoeunds, 3 $0 $0 $0 1 f e veel

• IT1979 Carryover

(coat.ru.tient * -i., '6d. MAJCR PROCURE 5ENTS (In Thousands) None 6e. _ COST (RECAP OF SUBACTIVITIES (In Thousands) Not Applicable 7. EXPLANATION OF MAJOR PROCUREhENTS Not Applicable 8 EXPLANATION C7 CAPITAL EQUIPFENT The requested $5,000 for capital equipment in FY 1979 is to cover the ' cost of a desired purchase of a 1200 baud CRT/hard copy work station, at an estimated cost of $5,000.

• Since the proposed study involves data analysis and mathematical modeling almost exclusively, an additional modern high speed work station is required.

ne terminals which we have at present were ace,uired for and are fully utilized by engoin2 Projects. Further, existing terminals are rather slow (300 baud) and thus 1111 suited to large scal'e. data.analysise and modeling applications. 4 4 e v e e 9 9 e" k i

vanonu,n no r a n NUCLEAR REGULATORY COMMISSIGN PROGRAM SUDGET

1. TITLE

" Reanalysis of the Tri-state Leuke:aia' Survey Data with Special Reference to the Leukesogenic Potential ,,GCQNNe i k A3 1h Ah of Diagnostic X-rays" AQORATORYg

2. BUoGET ACTIVITY No.

V" doe 40-10-01-01 NR'C 10-19-03-06-3 l / A NI. 8M420 U of C AUA USD05 9. INTROD0CTION t I Several recent papers (Bross et al.,1979; Bross and Natarajan, 1972, 1977-Berte11, 1977), based on the Tri-statT~1eukemia survey data (Grahas et al., 1963), have suggested that low-level exposure to diagnostic X-rays may pose a greater hazard to human health than previously thought. These conclusiens are far from universally accepted (Boice and Land,1979; Ginovan,1979), and indeed are contra-dicted in part by the original Tri-state studies (Graham et al.,1966; Gibson et al., 1972). However, they do raise some questions as to the appropriate interpretattien ~ of these data which can only be resolved by extensive reanalysis.. We have a complete copy of the Tri-state data base, and propose to perform such a reanalysis. The questions to be addressed En11 into two major areas, the shape of the adult dose-response function (that is, to what extent does increasing X-ray ex-l posure to adults increase adult leukemia risk), and the degree to which preconception, intrauterine, and postnatal exposure of children increases their leukemia risk.

10. ADULT STUDIES The original Tri-state analysis, a retrospective case control study, which in-cluded 1414 leukemia c~ases and 1370 controls matched for age and sex, attempted to determine the effect of adult X-ray exposure on adult,leuke=ia risk. This investi-gation showed an apparent increasing, risk of'nonlymphatic leukemia with X-ray dose in males, but no effect in females (Gibson et al.,1972). The analysis suffers from two main defects. First, ' leukemia risks were calculated for overlapping exposure cate-gories. That is, risks for persons exposed to 11 or more,16 or more, 21 or more, and 41 or more X-ray films were calculated. The problem with this approach is tha-the highest exposure is contained in all lower categories. Since the individuals in' this category do, for nonly=phatic leukemia in males, show elevated leukemia risks, this tends to inflate the risk for all other categories"(Ginevan,1979).

The second major shortcoming of the original Tri-state analysis is tha$ all X-ray exposures up to 1 year prior to leukemia diagnosis were censidered. This cculd be a source of bias for two reasons: (1) Studies of the Hiroshima-Nagasaki survivors i (Land and Norman,1978) suggest that there is a latent period of 5 years or more between radiation exposure and enset of leukemia, and that the latent period increase: with decrearing dose. L' nile one may argue that complete correspondence between the case of the atomic bomb victims and the case of very low-IcVel X-ray exposures is not to be expected, the fact remains that the temporal aspects of the X-ray exposures in the Tri-state survey have not been censidered in any detail. (2) This first source of bias is cceplicated b;. -he fact that leukemics may exhibit height:ned sensitivity to pneumonia and other infectious disease prior to showing definite symptems of leukemia r...a

scono w cas. K eale, 1971;. Stewart and Kne' ale, 1969). Since sick people are often X-rayed, it may be that excess X-ray exposures occurring within a few years of diagnosis. are caused by leukemia rather. than vice versa. It may also be that this is not the case in the Tri-state data. To date, the question has not been considered. ~ De

• studies of Bross et 'a1. (1979) and Berte11 (1977) also examine the Tri-state adult X-ray exposure data,7itI~ the thesis that X-rays, in very small doses, cause large increases in leukemia risks. The shortcomings of these studies, which are numerous, are considered in detail by Bolce and Land (1979) and Ginevan (1979). One major problem is that the authors use specially developed statistical procedures that bear little correspondence to conventional analyses and which have not been subject to adequate peer review. Thus, the value of these studies is pro *qlematical. A further difficulty is that each paper restricts its attention to' a subset of the Tri-state data (all males with nonlymphatic leukemia and males 45-65 years of age with nonlymphatic leukemia, respectively) that best illustrates the authors' contentions, and gives no attention to the rest of the Tri-state data or, indeed, to other rele-i vant Icukemia studies' (i.e., Stewart, et al.,1962; Gun: and Atkinson, 1964).,

hhatever the cause of this oversight, the fact remains that the omitted data: appear to support the general conclusion"that small doses of diagnostic X-rays in adults are relatively harmless (Ginevan,1979), rather than supporting the central argument of Bross et al. (1979),and Berte11 (1977). Finally, as in the original Tri-state study, neithE o~7 these investigations considers the possibility of a latent 5 period, or the possibility that apparent excess diagnostic X-ray exposures were the result of a preleukemic condition.

11. STUDIES OF PRECONCEPTION, PRENATAL, AND POSTNATAL X-RAY EXPOSURES OF CHILDREN

~ Three investigations have dealt extensively with the prenatal exposure portion i of the Tri-state leukemia data (Graham et al.,1966; Bross and Natarajan,1972, 1977). The original Tri-state case controT~ analysis, which included 139 cases and 844 controls *(Graham et a_1,., 1966),. considered preconception irradiation of parents and postnatal X-ray exposures of the children as well. i In the original Tri-state analysis of children's e:coosures (Graham et al.,1966) it was estimated that children exposed in u nro experien'ced'a relative leukemia risk of 1.40. nis is in reasonable agreement with some other studies of the effect of intrauterine X-ray exposure (MacMahon, 1962; Stewart et al., 1958; Stewart, 1973). i Their overall conclusions, hosever, are: far from unequivocal for several reasons. First, not all studies of intrauterine radiation have found excess leukemia risk, Court Brown et al. (1960), for example, followed about 40,000 children who had re-ceived intrauterine X-ray exposure. Nine leukemia case's were observed as opposed to 10.5 expected. On the basis of this observation, it is unlikely (p < 0.05) that the i relative risk in the exposed group could have been as large as 1.5. There are also some rather peculiar features in the intrauterine exposure per-tion of the Tri-state data. For example, only 27 cases and 54 controls actually re-ceived intrauterine radiation in the sense that the mother received an abdominal ex-posure. Another subset was comprised of 67 cases and 137 controls whose mothers had received nonabdominal exposure. hhen these tuo subsets were combined, and all cases of irradiation during pregnancy were considered (many presumably involving little fetal exposure) - a total of 94 cases and 191 controls - the relative risk of leuke-mia was approximately 1.40, or the sate risk as that of those who had actually re-ceived abdo.ninal exposure. Put another way,. the presumptive X-ray dosage to the child seemed less it.rportant than whether or not the mother had been X-rayed. I e

b ? 'f 4 8ttm v.fsS8d NUC' LEAR REGULATORY COMMISSION ' PROGRAM BUDGET f k i

t.. TITLE -

i " Reanalysis of the Tri-state Leukemia' Survey Data - with Special Reference to the Leukemogenic Potential G A~y/qN EOyA\\ ! of Diagnostic X-ra'ys"- ABOR ATOR,

2. BUoGET ACTIVITY No.

Nl oos 40-10-01-01 NRC 10-19-03-06-3 Am. SM420. U of C AUA US00E . H is impression is reinforced by the observation that those children whose j mothers had reported preconception X-ray exposure,to any site showed an even higher relative risk than those children who had received actual intrauterine exposure (1.59 vs.1.4).. Even more perplexing is the ' observation that children whose fathers j had preconception irradiation (~to any site) showed a relative risk of 1.3.. A final odd feature of the data is that'the form of postnatal irradiation most strongly . associated with increased leukemia risk is dental X-rays. As noted by Miller (1969), r many' of these results are biologically. implausible. i The papers of Bross and Natarajan (1972,1977) are interesting in that they ? .suggest the existence of a small subgroup in the population that is particularly prone to' leukemia and which is also particularly sensitive to radiation. The prob-lem with their approach is, first, that all of the analyses presented ignore the r fact that 'much of the intrauterine " exposure" considered consists.of nonabdominal X-rays. A disturbing aspect of their second paper (Bross and Natarajan,1977) is that of the original Tri-state data of 319 cases and 884 controls (Graham e_t, aJ,., 1966), only 133 cases and 393 controls are considered. No discussion of potential i bias generated by discarding over half the data is provided. Finally, the second paper attempts to " prove" hypotheses generated in the first using the same data, or i at least part of them and, further, utilizing the same sort of idiosyncratic statis-I tical methodology found in Bross et al. (1979) which, as mentioned earlier, has not j been subject to adequate peer review, n us, these. studies are of questionable value. l ) Clearly, in view of th'e many anomalous findings generated in the original Tri-J state analysis of the child X-ray exposure data (Graham et, al.,1966), and the sus-pect nature of the subsequent analyses of subsets of these data (Bross and Natarajan, i 1972, 1977), a careful re-examination of these data is needed. i 8 -12. PROPOSED STUDIES The overall goals of the proposed studies are to produce testable theories and j hypotheses regarding the leukemogenic potential of diagnostic X-rays and to. identify or reject some of the less plausible models proposed by other workers. i The first priority in our reanalysis of the Tri-state data will be calculation ~ of age standardised relative risks of adult leukemia for non-overlapping X-ray expo-sure categorics, for both sexes, and for all Icukemia types considered in the origi-na) Tri-state study '(acute ' lymphatic, chronic lymphatic, acute myelogenous, chronic myelogenous). As in the original study, statistical procedures involving the relative { risk statistic or odds ratio discussed by Wolf (1955), Haldanc (1956), Sheehe (1966), and Fleis* GC ;) will be crplcyed. In these calculations the si:e of the age strata used will be minimi.:ed as much as possible. In at least two studies (Bross g al,, s fevert f [

\\'03 tin at cal I u

1979; Burtell,1977) age strata 20

years wide were used. Such broad categories, especially in a disease like leukemia, whose incidence increases greatly with age j

4 :.: '(Doll, 1965)T provide inadequate.standardisation. That is, leukemia risk increases i with age and;. if X-ray exposure tends to either increase or decrease with age (most likely the former), a positive or negative associa.tlon might we11' result from in-l appropriate standardi:ation. In addition to age,L sex,. and X-ray exposure history, tlie adult portion of the Tri-state data includes information on disease history. This. variable will receive-l Particular scrutiny because, as mentioned earlier, some studies have suggested that persons with undiagnosed leukemia are particularly vulnerable to infectious diseases l such.as pneumonia (Kneale,1971; Stewart and Kneale,1969). We will determine if ~ ' these observations are supported by the Tri-state data. Information on the temporal aspects of X-ray exposure is also available. This will be utili:ed to examine the question of whether the pattern of X-ray expc urt. shown by the cases in the Tri-state study is consistent with a latency' period hy-pothesis (Land and Norman,1978). In both the disease history and temporal exposu:e history investigations, conventional rel.ative risk analyses will be used- (Wolf,19.i5; Haldane, 1956; Sheche, 1966; Fleiss, 1973). The Tri-state data also contain information on such factors as ethnicity, edu-cation, occupation, and religion. While there seems little a priori. reasdn to think that such variables would . greatly influence X-ray / leukemia relationships,it seems best to have considered all possibilitius. We 'will therefore'use either the stratification by multivariate con-founder score methodology suggested by Miettinen (1976).together with discriminant function methodology (Lachenbruch and Goldstein,1979), or the multivariate log linear methods discussed by Bishop et al. (1975) and Fienberg (1977) to consider the possibility that some mul'tivariable7 uiEtion may, in fact, be responsible for ob-served X-ray / leukemia associations. The choli:e =of the first or second approach will b'e dictated by examination of the data. These last, analyses should be taken to be wholly exploratory, but might be valuable aids in hypothesis generation. The final phase in t> a reanalysis of the adult portion of the Tri-state data will be devoted to construction of mathematical and verbal models which, based on the foregoing analyses, best describe the Tri-state data. In this last phase and throughout our studies considerable emphasis will be placed on integ' ation of our r findings with the results of other adult leukemia surveys (Gun: and Atkinson, 1964; Stewart et al., 1962; Stewart and Kneale, 1969; Kneale, 1971; Bross et_ al_., 1979; Bert e11, 1977) to provide the most complete picture possible of the relationship between adult leukemias and diagnostic X-rays. Some progress in re-evaluation of the adult portion of the Tri-state data has already been made. The resulting paper, which has been accepted for publication in Health Physics (Ginevan,1979), is included as Appendix I in the copies sent' to NRC. Re-evaluation of the chi 1d portion of the Tri-state data will address the many anomalous features of the original analysis. As in the adult data, conventional re-lative risk analyses will be used for the most part. k

• Jc.~-e.numns e

NUCLEAR REGULATORY COMMISSION PROGRAM SUDGET

1. TITLE

" Reanalysis of the Tri-state Leukemin' Survey Data with Special Reference to the Leukemogenic Potential ARGONNE of Dia'nostic X-rays" AJk1A1 g Aq0RAIORY

2. BUDoET ACTIVITY No.

v --d ooE 40-10-01-01 NRC 10-19-03-06-3 ANL 8M420 ~ U of C AUA USDOE First of all, it is of importance to decemine the degree to which preconception, intrauterine (used here in the sense that the mother received any X-ray exposure during pregnancy), and postconception X-ray exposures are confounded. That is, it is not made clear in the original study the degree to which the elevated risk seen in children who received preconception irradiation may be a result of subsequent intra-uterine or postnatal exposure or, similarly, the degree to which preconception ir-radiation may inflate observed risks of postnatal or intrauterine radiation. It seems reasonable to hypothesi:e that, especially in the era of the general practi-tioner (almost half the cases were born between 1945 and 1954), certain doctors would 6 be more likely to order X-rays, which would in turn be reflected as large numbers of children showing all three types of expcsure. It may be that the data will not allow t the independent effects of the three sorts of irradiation to be sorted out,. but the atte..:pt should be made and the results should be clearly stated. An examination ci possible models of leukemia inheritance (ile., through a singic dominant or recessive gene, through the interaction of several genes, etc.) would also be of interest. These models would be used in examining the increase in leuhe-mia incidence in children whose parents had been irradiated prior to conception and in determining whether this increased leukemia risk can be. explained by a population genetic model and the available data on radiation effects on mutation rates (UNSCEAR, 1977). Such models could also be useful in sorting out the question of possibly con-founded pre, natal, intrauterine, and postnatal X-ray exposures. That is, for the con-founded case, the genetic model could furnish at le'ast an upper bound on the possible effect of prenatal exposure; A third area which deserves close attention is the question of the association of children's disease history with leukemia risk and X-ray exposure. As noted above, it has been claimed' that there is a subgroup of children who are particularly likely. to contract leukemia and vho are particularly sensitive to leukemia induction by diagnostic X-rays (Bross and Natarajan, 1972, 1977). This claim, which is based largely on disease history data, deserves re-examination within the context of the complete data set. Such a re-analysis would also have considerable bearing on the question of whether or not undiagnosed leukemics are particularly prone to bacterial diseases such as pneumonia (Kneale, 1071; Stewart and Kneale, 1969). A fpurth worthwhile area of inquiry concerning the child portion of the Tri-state data involves recalculation of risks of leukemia given different radiation ex-posures using multivariate conicunder scores (Miettinen,1976). This method is preferred because the large number of potentially important variables (year of birth, age at diagnosis (case) or intervieu (control), parity number, presence / absence of provicta riscarri 4u cr stillbirths, mother's age, father's age, father's education and/or cccupanon, ethnicity, etc.), together with the somewhat small lowerl

acennnu.noa ber of cases (319) renders a multivariate log linear analysis (Bishop et al,., n 1975; Fienberg,1977) difficult if not impossible. As in the adult data the con-founder variables would be generated using discriminant analysis procedures (Lachen-bruch and Goldstein,1979). As in the adult data considerable. emphasis will be placed on the last phase 1 which will consist of construction of verbal and mathematical models which will U provide an integrated descriptien of what the Tri-state data show concerning the effects of prenatal, intrauterine, and postnatal X-ray exposure on children's risk of contracting leukemia. In this phase particular attention will be focused en integrating the results of our analyses of the Tri-state data with the findings of other workers (MacMahon,1962; Stewart et al.,1958; Stewart, 1973; Court Brown et. al.,1960; Graham e_t a1.,1966; Bross~aH Fatarajan, 1972,1979). The most direct result of the proposed research will be a better understanding of what the Tri-state data really say about the leukemogenic potential of diagnostic X-rays, both in the area of dose response relationships and in identifying factors other than X-rays that may influence an individual's risk of contracting leukemia. We hope this understanding will shed light on the relevance of other studies of leukemia and diagnostic X-rays and more general questions of radiation carcinogenesis as well. 13. PROPOSED SCHEDULE OF EFFORT The proposed schedule of effort is shown in Figure 1. The analyses of the adult' and child data form two non-overlapping but related one year projects. Each analy-sis is presently conceived as having four major, overlapping, related' phases, each of about three months duration. Toward the end of the data analysis effort, a seven-month period will be devoted to model building and integration of our findings with those of other workers. The Inst six months of effort is devoted exclusively to this ir.st task because it is our view that a coherent synthesis is perhaps the most valuable contribution this sort of study can make, and is at the same time the most difficult task to do well. Results of our studies will be publishes 'in the open literature. Such publica-tions, often out of necessity, place a premium on brevity. Nonetheless, it is our belief that details, particularly in the context of standard setting, regarding the exact analyses employed and results obtained are of great'.importance. Therefore, to make comprehensive accounts of our studies generally available, details will be pre-sented in the form of Argonne reports. .? 14 LITERATURE CITED Berte11, R. 1977. X-ray exposure and premature aging. Journal of Surgical Oncology 9: 379-391. Bishop, Y. M. M., S. E. Fienberg and P. W. Holland. 1975. Discrete Multivariate Analysis. MIT Press. Cambridge, MA, 557+X pp. Boice, J. D. and C. E. Land. 1979. Adult leukemia following diagnostic x-rays? (Review of report by Bross, Ball, and Falen on a Tri-state leukemia survey.) American Journal of Public Health 69: 137-145.

.. ~. - _-_m n 6 o -- ec......,, w - NUCLEAR REGULATORY CO).1 MIS 310N ID ENr. No. PROGRAM BUDGET

1. TITLE ; -

" Reanalysis of the Tri-state Leukemia Survey Data with Special Reference to the Leukemcgenic Potential, MG NNE of Diagnosti,c.X-rays" Ap Od Ak A RATORY

2. BUoGET ACTIVITY No.

"U" doe. 40-10-01-01 NRC 10-19-03-06-3 ANI. SM420 U of C.AUA USDOE Bross,.I. D. J., M. Be'; and S. Falen. 1979. Dosage response curvo for' the one rad range:. adult risks from diagnostic radiation. American Journal of Public Henith 69: 130-136.. Bross, I. D. J., and N. Natarajan. 1972. Leukemia from low level radiation.. New { England Journal of Medicine 287: '107-110. + ' Bross, I. D. J. and N. Natarajan. 1977'. Genetic, damage from diagnostic radiation. JAMA 237: 2399-2401. Court Brown,.W. M.~, R. Doll and A. B. Hill. 1960. The incidence of leukemia follow-i ing exposure to diagnostic radiation ~in utero.- British Medical Journal 2: 1539-1545. , Doll, R. 1965. 'The epidemiological picture. In: Current Research in Leukemia. Cambridge University Press, pp. 280-299. { Fienberg, S. E. 1977. The Analysis of Cro's-classified Categorical Data. MIT s Press. Cambridge, MA, 150+X pp. t t Fleiss, J. L. 1973. Statistical Methods for Rates and Procortions. Wil y, NY, f 223+XII'I pu. l Gibson, R., S. Graham, A. Lillienfeld, L. Schu=an, J. B. Dowd,' M. L. Levin. 1972. Irradiation in the epidemiology of leukemia among adults. Journal of the l National Cancer Institute 48: 301-311.. Ginevan, M. E. 1979. Nonlymphatic Icukemias and diagnostic x-rays: the ev'idence i T reconsidered. Health Physics. In press.

Graham, S., M. L. Levin, A. M. Lillienfeld, J. E. Dowd, L. M. Schuman, R. Gibson,

{ L. H. Hempelmann, P. Gerhardt. 1963. Methodological problems and design i of the tri state leukemia survey. Annais of the New York Academy of Sciences-107: 557-569. 1 ? - Graham, S., M. L. Levin, A. M. Lillienfeld, L*. M. Schuman, R. Gibson, J. E. Dowd and. 'l L. Hempelmann. 1906'. Preconception, intrauterine, and postnatal irradiation as related to leukemia. National Cancer Institute Monographs 10: 347-371. }

Gun

:, F. E.,

n.,d H. R. Atkinson. 1964 N2 dical radiaticas and leukemia: a retro-spective curvey. Eritish Medical Journal 7: 350-393. } t e..... _,_--..-.,..,,-.,....__,,.,.......~s

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~ ADULT STt! DIES ~ C.it!LD.STtKt!.E.S .l.-I Il i ' Calculation of leukemia risk for Analyses to separate non-overlapping ef fects of preconcep. tion intrauterine and emposure categories. postnatal I-trradletlon. g...........-........... I I l 6 f Consideration of pre-j conception irradiation In the context of Consideration of population senctic disease history data, theory. 1 1 1 1 i i i Consideration of temporal aspects of Cor. sideration of disease history I-ray estesure data. e .d.a.ta 1 I 1 + I Construction and Construction and evaluation of snulti-evalcation of a.ultl-variate confounder variate confounder variables. varlables. I J I 1 i i I i 1 j Synthesis of nodels in Synthesis of rodels in g the context of the pre-ceding analyses and the the context of the pre-results of other studies. . ccding analyses and the reshlts of other studies. - ~. - - - i I I 1 i s i f#

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