Document rBJqvrebGOg4NYe0O8Y2oDd6V

Yale University New Haven, Connecticut 06510 Connecticut Cancer Epidemiology Unit 30 College Street (203) 436-8904 J. Wister Meigs, M.D., Director October 13, 1980 Dr. Hilton C. Lewinsohn Raybestos-Manhatten, Inc. 100 Oakview Drive Trumbull, Connecticut 06611 Dear Dr. Lewinsohn, Please review and give me a call. I haven't yet included the sample of the listing. I haven't heard from Dr. Vidone yet. I outlined your section briefly. V(^ry truly yours, JT:bav Enclosure V ----- JAne Teta, M.P.H. Research Associate UCC 017514 AQ0588 The iRflueste ui OucUimLiulial gg* Em/liuiiiumiml Aalmsnjb^ Bwpooure 9i> the. IimiTigllg^Hr Malignant Mesothelioma in Connecticut^ ms-i<n7 by H. C. Levinsohn J. W. Meigs M. J. Teta Presentation to the Connecticut Thoracic Society, November 4, 1980 UCC 017515 A00589 Tha-Influenoa of OiiupaLlonal and Environmental Anbastoe Exposure on the Inetdonae of Malignant Mesothelioma in Connecticut^ H77 by H. C. Lewinsohn, J. W. Meigs, and M. J. Teta I. Introduction and Aims Bruckman et al. (1977a) reported that "the combined sex age-adjusted mesothelioma incidence rate (AAR) per 100,000 Connecticut population has exhibited a possible ten-fold increase since 1935..." They ac knowledge that the available statistics might be subject to diagnostic error but, nevertheless, postulate that the rapid increase in the State's mesothelioma incidence rate is closely related to the increase in the State's "cumulative asbestos consumption", which Includes asbestos ern^issions from industrial sources, motor vehicles, and building demolition. One criticism of their study is the failure to make available complete occupational exposure histories for the 133 diagnosed (1935-1972) cases of mesothelioma drawn from the Connecticut Tumor Registry (CTR). The Air Compliance Unit of the Connecticut Department of Environmental Protection has monitored asbestos concentrations in Connecticut (Bruckman, 1977b; Bruckman, 1978) and proposed an ambient air standard for Connecticut of 30ng/m , measured over a thirty-day interval. The rapid increase in the State's mesothelioma Incidence reported in 1977 is referred to as justifica tion for this proposal. A second criticism is the failure to Investigate the degree of certainty in these diagnoses and to institute a pathological review, if it Ae warranted. The present study has been designed to A0052C re-examine the identified cases of malignant mesothelioma recorded in the ..f- UCC 017516 CTR and attempt to determine the role of various etiological factors, such as occupational and environmental asbestos exposures. In view of the SuggsrJ- .frnBulaJgnd possible diagnostic errors, which our results verify, a thorough review of available histological material is being undertaken. UCC 017517 -2- A005S 1 II. Methodology The CTR has identified 229 cases of malignant mesothelioma as well as 38 other pleural tumors, not mesothelioma, which were diagnosed in the state between 1935 and 1977 (Table 1). A r>PiT lu Llm 1LU-U (Will llcuith OBgenltfnffani 1976$ ulmgaificatiutr^Medical, demo graphic, and occupational data have been collected for the cases and for the respective spouses of cases diagnosed 1955-1977. Similar information has been gathered for a Tandom sample of approximately 700 decedents (1935-75) aged 20 to 98 years from the Division of Health Statistics of the Connecticut Department of Health. Sc~r w/i c dLS . Descriptive epidemiology for this research pertains primarily to the forty- three year time interval. Future case-control comparisons will include^cases (215) diagnosed after 1954 (Table 1), and controls (604) whose deaths occurred during this sane time period. This procedure yields a case-control ratio of approximately 1:3, while reducing sources of error resulting from the limited | ecC-A O *f occupational and medical data prior to 1955 and the awareness of mesothelioma associated with time period (1935-191^. The Price and Lee City Directories were searched for job title and name of specific employer or industry for cases, controls and spouses at 1, 10, 20, 30, 40 and 50 years prior to date of diagnosis, death or until the subject was less than twenty years old. An occupational history search was attempted for spouses to coincide with these intervals for their corresponding cases. The thaee digfrt 1970 U. S. Census industrial and occupational codes (U. S. Dept, of Commerce, 1971) were assigned to the employment Information ascertained from medical histories, death certificates, and City Directories. A machine readable listing of job and Industry titles has been developed for all cases, spouses, and controls. This will form the basis for classification of study subjects Aon- : 1 UCC 017518 'TA^Le .. -- Table 1. Sex, age and diagnostic ^htfracteri sties of cases of malignant mesothelioma and other pleural tumours diagnosed in Connecticut, 1935-1977 Diagnosis0 Pleural mesothelioma Pleural tumour (other than aiesothelioma) Peritoneal mesothelioma Mesothelioma at other sites 6 at unknown sites Total Males 102 ()* 24 (12) Females Total Mean age 45 (37) 147 (131) 61 (62) 14 (8) 38 (20) 62 (63) Per^rt 'positive*^ histology Percent autopsjed* 93 (95)\ 71 (as) \ (38) y* 35 (37) 20 08) 13 01) 33 (29) 58 (59) 94 (97) / \ 89 (88) 29 (21) 175 045) 20 (14) 92 (70) 49 (35) 267 (215) 52 (54) 59 (60) 84 ^86) (93) >v 33 (41) V (45) tf WHO (1976) ^'SCCHi 4986-4pededFie1d Number 19 (US Department of Health, Education, and Welfare, National Cancer Institute (1976) deceased) * 100 ^ Numbers in brackets refer to the period 1955-1977 . Into asbestos exposure categories for future case-control comparisons (sample from listing Fig. 1). UCC 017520 - f- A00594 III. Results Descriptive Epidemiology Hie ovOtte incidence rate for mesothelioma in Connecticut is 2.|/million for the years 1935-1977. TVsa aHjuulml lnulflciin- jfyptes per 100,000 population (using the 1950 US population as a standard) increased for both sexes, but there was a rapid rise from about 1960 for males (Fig. 2). The male-female Qve*w^L ratio is approximately 2:1; the mean age at diagnosis is fifty-nine years. Survival time from date of diagnosis to date of death is approximately ten months. Ten cases were reported in an area (New London) where shipyards are located, and five of these were identified between 1975 and 1977 (Fig. 3). The geo graphical distribution of mesothelioma shows evidence of urban clusters in the 5 largest cities (Bridgeport, Hartford, Waterbury, Stamford, New Haven) where 30% of the cases resided at time of diagnosis (Fig. 3). Since these locations have comprised 20-30% of Connecticut's population (1940-1977), the suggested urban effect may reduce to a factor of population density. These 5 large cities and New London are also centers of Labor Market Areas (LMA). All 6 areas exhibit a similarly increasing* incidence^Hyith the Bridge port Uik Lilli IrtglUiblL UVUialfe. The Stamford LMA's mesothelioma rate shows a*> u<tf|p sharp increase since 1965 (Fig. 4). UCC 017521 -C, - A0059b AGE-ADJUSTED INCIDENCE RATES OF MESOTHELIOMA IN CONNECTICUT BY YEAR OF DIAGNOSIS AND SEX RATE/100,000 , # o- No Ool oA Ool Oo) GEOGRAPHICAL MAPPING OF CASES OF MESOTHELIOMA (1 9 3 5 -1 9 7 7 ) BY TOWN OF RESIDENCE AND 1960 LABOR MARKET AREA - s- UCC 017523 AGE-ADJUSTED INCIDENCE RATES OF MESOTHELIOMA FOR CONNECTICUT MALES BY YEAR OF DIAGNOSIS AND LABOR MARKET AREA C/> Q 3 o 3 CL O rs> o X ZO O CD - no ox^ Cl < <D UCC 017524 * - f- i-------r------ 1-------r o o b> oo oq RATE/100,000 o* IoO CO 00 1935-44 45-54 55-64 65-74 75-77 A0Q5 SLIDE REVIEW JHiese dtiycfip'tlve reSulCS- "gwbare completeness and accuracy of case lAgni-i --tia&le-. Hirr't'H Yy f'iii frt r it! fit-tiii fn lln jinil H 7 'ftf 'fttric- CUHAMtMf Malignant mesothelioma Is a very rare disease, expected in only 2 A persons for every million at risk. Resistance to acceptance of mesothelioma as a disease entity persisted until the late 1960'sf despite Wug,ncifs 1900 35 mpoil Uf ^"hlmolugltallj! proven cases-of pleural aieaeiLlielUJflta associated with Capr rr^^idolito asbestos -ficldo in Se. AT Ira. t 'Sinks widely pnbliohod toMicfzeJ C\n^ Cmf* Cioc-dolile . association of^mesothelioma with asbestos exposure /^mnaver, created the potential diagnostic bias# In oddities to its rarity and the subsequent lack.Of uwui'MUMbL, {positive diagnosis of mesothelioma is^complicated by its confusion with other forms of cancer. (Dr. Vidonets discussion of simulators.) The controversy over criteria for positive diagnosis is well-documented in the literature. Most experts agree, however, that without an autopsy it is difficult to distin guish mesothelioma from a metastasis from another primary site. In the -light of t-hooo diffieul-ties\fcib examined, for all CTR reported cases of mesothelioma and for all pleural tumors other than mesothelioma (1935-77), the histological basis for diagnosis (tables 2,3). For 12% (32) of the cases, no \i'ssu& a*-n^a1 at time of diagnosis, tod&uJ * while available specimens vary* f gen biupsji LIT P & C L la sue,. Overall only 44% (105) of the 238 deceased cases are known by the CTR to have been autopsied. The percentages for all categories, except peritoneal mesothelioma, are low,ranging from 33% to 40%. These results suggested the advisability of a case review* <which was hy hnpr-1#fg# wf . -4h nn*H1.K1a Mgfnlngirnl mat-AT-fal nt- Mn c Hm^vu.*hr? Dr. Romeo Vidone, chief pathologist at St. UCC 017525 ~~ A> ~ A00599 Sb^ji*4l Raphael's Hospital, Is presently jpaviawing the medical records (except oc cupational data) and slides we have obtained for cases diagnosed after 1954. Cooperation was elicited from 37 hospitals, of which 30 have provided us A with the materials requested. (Dr. Vidone-Summary of Findings) UCC 017526 A006QC f foe (?o_5^s /3<-S/J -for D v-i <ilT'C*> t ucj(Ui/''rW *> ^ --T ^ /^TW.vw^. p)<u*r* ! ^ Ttseis ' ty^lc/< <* .Pi'*-<j *iS>'3 --- A Vi7a.U< - /-^_y IfotlltUlb^_____ J 3 _ .. _.. 3, _ 3 v jVrf* Z*1 `c. H*&m* j7* J.. ... V fkx-* PTt< wa 4m^ 27 .. ~~ y.. J ---7 ---- ---. -- 3/ h ........--... . - .. ........ i / ll -3T -- H<s>H*4**w *".._.. _.. V!... .. ... -- _ -- _ -- .._...-- ...... 1. trH+.r ^/-x S" 1 5 j'fe ............... - .... ........ ------- . .. - -------- i ..... t ______ _ _ J5'... ._ ..3 ----- --------- -2... -2.0 1 247 UM C__ Qf7<) S pe <4 euA^s ^rrw^ fe>/3 ^)S ^ .r* -<^_fi-ccjfi/yiy ^ k. r ^ ^ ...a^h(f$y^ -0 r ^ A0060 1 k: UCC 017527 /*. - # p 3 *. /VrKJUv&4| 0$ ^/f'77 A*u/.'2 S?'v ^/t / (; > .... ^7..... ""..... ?<>/ f)~ j77 -> - c$; ' /7> [ it- iih*"'----- UCC 017528 AaaaQ.2 /-- 9 l'fc S A. ^r^ 4o r i >sf <o/^ , 'ZL+_Jl <J-f, CtKZjft C-C- / *v J? *S f 'fzaL^-v-c. <. . jO ic sa\(9 & CcV-^fl C4-^/ C>Cc*^|g S l~f-> VC/r'H'*fc k-'Sj. 'O_.f'j'-eS_ A,4 tlai'el c |<rf - tir~A es^V,'/-/ (?s-~1 ~h> f > K. / n e7/lsi /U^# /'Ov^ C7 ^ ^ -f/^sr 6> ^ ' / "tar / r^c^r^s ) cuCcj /7j% V^Hr^Ji y J-* <o*- o*f 6c*es, X f J c* $bLA~jf - TZ-*. i^sjL -- Qr' } *c^tS j-r ^ t *v ftr^uM /l-S * ^ ^ * /Hs>jv-c. ^<ch~~ /'.s r ^ fii 2l^i <rL^>.j i ) JMZ* . -f-/TM--- C-/7C. /J $!'-7"? v ^ /t- v *' v^ **-- jp/.-H.r*J n Jt' , /7^` 71 J UCC 017529 - /T" A 0 06 0 3 A References Bradman, L., Rublno, R. A., and Christine, B. (1977a) Asbestos and Mesothelioma in Connecticut. APCA Journal. 27 121-126 Bradman, L. (1977b) A Study of Airborne Asbestos Fibers in Connecticut. Paper presented at the Workshop on Asbestos; Definitions and Measurement Methods. National Bureau of Standards, Gaithersburg, Maryland . truckman, L. and Rublno, R. A. (1978) Monitored Asbestos Concentrations in Connecticut. APCA Journal. 28, 1221-1226 Price and Lee Citv Directory (1890-1977) The Price and Lee Company, Rev Haven, Connecticut * V. S. Department of Commerce, Bureau of the Census: 1970 Census of the Population. Alphabetical Index of Industries and Occupations (1971)9 Washington, D. C., D. S. Government Printing Office .- -t- - -, ` --in- Verld Hralth Organization: ICD-0 International ClumHration of Mg.ag.g for Oncology. (1976) Gram, Svltgarland UCC 017530 ^ 00QQ4 Hilton C. Levinsohn,Corporate Medical Director, Raybestos-Manhattan, Inc. and Lecturer, Tale School of Epidemiology and Public Health (address: Raybestos-Manhattan, Inc., 100 Oakview Drive, Trumbull, Connecticut 06611, U. S. A.) J. Vister Meigs, Director, Connecticut Cancer Epidemiology Unit and Clinical Professor of Epidemiology, Tale School of Epidemiology and Public Health (address: 30 College Street, Hew Haven, Connecticut 06520, U. S. A*) Mary Jane Teta, Associate in Research, Connecticut Cancer Epidemiology Unit, Tale School of Epidemiology and Public Health (address: 30 College Street, Vev Haven, Connecticut 06520, U. S. A.) UCC 017531 A0060b DISCUSSION Although this study was undertaken initially in an attempt to discover whether it would be feasible to determine the environmental factors responsible for the increase of malignant mesothelioma in the State of Connecticut, it has suffered from the lack of detail in available records. labl-o LI -ana -HI..il-lwrtnwfca one of the1 Iq^jor deficiencies in the data available for study, rarnoly the low autopsy rate ifor the pleural mesotheliomata and the inadequacy of the types of tiooua- available and used for diagnostic purposes. It has been otir experience that occupational histories are not routinely obtained UCC 017532 his disease ppear< d to /nt'ot increis; sre after 1955 A00606 Comment on the significance of the findings on the slide review. It is evident that until the physicians or hospitals investigating cases of Oa{atfel cC o>~\ malignancy appreciate the importance of environmental facts *' A ' the etiology of ' these diseases, no attempt can be made to apportion the blame to any particular factor unless adequate histories are available containing complete information on lifestyle, habits, hobbies, part-time activities and details of occupation anc industry. It is also essential.particularly in the case of a rare tumor which may present diagnostic difficulties,to obtain sufficient tissue for study before 441 iV HjJLfpclaal the final diagnosis is cade. VTnenever a tumor is found where m> association ^exists between it and a particular occupational or environmental factor, every attempt should be made to full}* document all the widicui facts and to subsequently verify the diagnosis by means of a full autopsy. UCC 017533 aooqo? ,, i j r. n g tne pas: ;.t ar. a e.m .a* v;. r- c "-zb:!::;.. however, with tre w c.- aZrr.:: .? \( '..'it hus: rjt'. iu: ir,\ est: ra s:: uaiKT ce'-en-pec a: me s:te of a pas.-mg of time tio: o: vt..t,: jcs- anc ar. u**e* aboorri)r.a. r.asD Sne had :>eer treatt-c fur cnromc recurring t-ynovr.it of the knees with bexanei/.asont ir. oosapes from 0.5 to 1.5 mg caiiy intermittently for tec years. During this period, the skin of her fore localized herpes s: rr.pitx :r.: t-rtior. ir. most instances where death has tha: hac occurred or. my uppe* iip . resutted from, pulmonary cancer t * a and had not heajec for approximately j thoracic or peritoneal mesothelioma. one year. It was removed by a Mohs' I it is important to identify the tissue surgical procedure at a local universi alterations directly attributable to arms became extremely thin, and she ty center, and a diagnosis of baso- occupational contact with the respira experienced several episodes of subcuta squamous cell carcinoma w-as made ble asbestos fiber. neous extravasation of blood again. At that time, the dermatolo As we have counseled family survi Or the fourth hospital day, she was transported to the x-ray department, where it was noted that she had two superficial tears in the skin of the left forearm with gaping margins Attempts were made to suture the skin edges togeth er. but the sutures tore througr the skin. The edges were held together with strips gist performing the chemosurgery roentioned how uDusua! the lesion was, inasmuch as there were not supposed to be such things as baso squamous carcinomas. Both wounds healed without any unusual event. After the first occurrence, J con vors of such persons dying of asbestosis or its related disease states, or both, to request a necropsy to lend substance to a worker's compensation claim, it is strongly suggested that all physicians or house staff caring for such patients urge relatives to permit of sterile tape. tacted Dr Herman Pinkus in Detroit, the examination. These procedures Or, one other occasion during her hospi | and he stated that there were about a will not only aid the beneficiaries bu: tal stay. Similar lesions developed during the course of transport to and from her bed for other diagnostic procedures. These iesions failed to heal during her hospital stay, and gross evidence of infection was not noted dozen cases in the literature at that time. I saw him at a meeting shortly after the chemotherapy, and he com mented on the unusual nature of this condition occurring more than once, though he was more aware of its will also prove of worth to physicians in familiarizing them with the find ings characterizing a greatly under diagnosed job-generated disease. Furthermore, such postmortem data will aid in our knowing what Comment--Transport by handling occurrence than he had been before. actually happens to a worker under of the forearms, even though careful There is an embarrassing situation certain conditions of exposure and ly done, resulted in serious, poorly about this personally, and that is that will help to rectify the inaccurate healing tears of the skin in this I am a dermatologist. conclusions drawn from the current overweight, weak woman. Even There were no other forms of ther underreporting of occupationally as though extra care was taken after the apy used on these lesions with either sociated disease. initial episode, there was recurrence. surgery, antibiotics, or photodynamic > jr>. SofMccA fr.io*. MD Ir. this case there was no complaint or inactivation, nor am J a smoker. 1 1 Lni*erit* o' Scwlfi*^ C-aluomit i dissatisfaction expressed by the pa have had an occasional localized i ; tien: or the family, but such episodes herpes simplex infection curing the { Seno o* Maoiein* Lot fcnpatct I have the potential for risk of com- past 20 years. I pensabie injury. Certainly there have been allegations of hospital-based j Safety of Ipecac Syrup Mapiia L Gtor MD ! Alioon Meoizj: Group. SC J To the Edito~.--On behalf of the injur" with lesser justification. ' Cnicapc American Association of Poison Cen h would be prudent for physicians tro! Centers. 1 am concerned about hospitalizing patients who have been j receiving steroid therapy to place a warning note on the chart advising hospital personnel to use extreme care when bathing, assisting, or j transporting such patients. l_oth T D: ^MD Cooney Coir* Carcinoma at the Site of h'e'pes Simplex Infection i Toth( Editor. -- The Journal recently published a letter entitled "Carcino ma at the Site of Herpes Simplex Infection" (243.2396, 1980). My letter is to note further the occurrence of such a situation. I personally had basosquamous carcinoma develop on two occasions. The first occurrence was approximately five or six years ago at the site of a vaccination for small pox that I had received for traveling. After the vaccination site did not heal for one year, I became (suspicious and had it excised at the local university hospital. I was ap proximately 55 years old at that time. The Autopsy and Asbestos Exposure To tfte Editor.--In the article entitled "The Autopsy: Past, Present, and Future" by Anderson and co-workers (242:3056. 2P79>. the fall in the rate of autopsies is decried, and several cogent reasons are presented for a return to the previous high number of such examinations, a goal formerly pursued by dedicated house officers. One additional need for postmor tem reviews has been given emphasis id recent years by the epidemiologic and clinical information gathered in connection with the asbestos-related disease. Because workers are now beginning to present radiological and altered physiological evidence of the effects of the inhalation of free asbes tos fiber, years to decades after initial work exposure, a problem in work er's compensation adjudication has arisen. The changes elicited through clinical study, although present, most ofteD do not have accompanying symptoms, as yet, nor have they caused any disability, as yet There the titling of a recent JAMA article, "Death Resulting From Ipecac Syrup Poisoning" (243:1927,1980). I am wor ried that the index slammer or scan ner--particularly if he is of the older school reared in aD era of gastric lavage for management of poison ings--may inadvertently conclude that the typical emetic dose of syrup of ipecac was responsible. In reality, the dose was three to four bottles per day for three months--thus repre senting a long-term poisoning. As noted by the authors, syrup of ipecac as aD emetic agent has a remarkable safety record; its current availability over-the-counter and in the home permits an enormous saving of needless visits to emergency rooms for the treatment of accidental inges tions. J think that it would be unfor tunate indeed were the inference drawn that single emetic doses were risky. ' WuuamO Rdofbtsdk. MD Chilo-eno Orthopedic Krsprtol ond Mt-diCft? Como* Anoenpfcr. Asoc.<ai>on * Fofion Control Contort Seattle Jama, Oct 10, 1990--Vol 244. No. 15 A 0 0608 Letters 1675 UCC 017534 The Influence of Occupational and Environmental Asbestos Exposure on the Incidence of Malignant Mesothelioma in Connecticut by H. C. Lewinsohn J. W. Meigs M. J. Teta UCC 017535 Aooeoa The Influence of Occupational and Environmental Asbestos Exposure on the Incidence of Malignant Mesothelioma in Connecticut. by H. C. Lewinsohn, J. W. Meigs, and M. J. Teta Introduction Bruckman et al. (1977a) reported that "the combined sex ageadjusted mesothelioma incidence rate (AAR) per 100,000 Connecticut population has exhibited a possible ten-fold increase since 1935* They acknowledge that the available statistics might be subject to diagnostic error but, nevertheless, postulate that the rapid increase in the State*s mesothelioma incidence rate is closely related to the increase in the Statefs "cumulative asbestos consumption", which includes asbestos emissions from industrial sources, motor vehicles, and building demolition. One criticism of their study is the failure to make available complete occupational exposure histories for the 133 diagnosed (1935" 1972) cases of mesothelioma drawn from the Connecticut Tumor Registry (CTR). The Air Compliance Unit of the Connecticut Department of Environmental Protection has monitored asbestos concentrations in Connecticut (Bruckman, 1977b; Bruckman, 1978) and proposed an ambient air standard for Connecticut of 30ng/m^, measured over a thirty-day interval. The rapid increase in the State's mesothelioma incidence A0Qq -I c UCC 017536 2. reported in 1977 is referred to as justification for this proposal. The present study has been designed to re-examine the identified cases of malignant mesothelioma recorded in the CTR and attempt to determine the role of various etiological factors, such as occupational and environmental asbestos exposures. In view of the acknowledged possible diagnostic errors, which our results verify, a thorough review of available histological material will be undertaken. Methodology The CTR has identified 267 cases of malignant mesothelioma of the pleura (147) and peritoneum (33)> other mesotheliomas, including breast, ovary, synovial membrane, testis, spermatic cord, perivesical tissue, cervical glands, brain, esophagus, bone and sternum (49), and other pleural malignant tumors, not mesothelioma (38), which were diagnosed in the State between 1935 and 1977 (Table 1). Disease topology and morphology are coded according to the ICD-0 (World Health Organization, 1976) classification. Medical, demographic, and occupa tional data have been collected for the cases and for their respective spouses. Similar information has been gathered for a random sample of approximately 700 decedents (1935-76) aged 20 to 98 years from the Division of Health Statistics of the Connecticut Department of Health (Table 2). Descriptive epidemiology for this research pertains primarily to the forty-three year time interval. Statistical modeling and future UCC 017537 Aooe11 3. case-control comparisons include cases (215) diagnosed after 195^ (Table 1), and controls (605) whose deaths occurred during this same time period. This procedure yields a case-control ratio of approximately 1:3> while reducing sources of error resulting from the limited occupational and medical data prior to 1955 and the increasing awareness of mesothelioma associated with the later time period (1955-1977). The Price and Lee City Directories, utilized as an occupational data source for the three populations, were available for approximately sixty-six percent of Connecticut towns from 1890 to date ( with the exception of smaller towns). Directories were searched for job title and name of specific employer or industry for cases, controls and spouses at 1, 10, 20, 25, 30 > ^0 and 50 years prior to date of diagnosis, death or until the subject was less than twenty years old. An occupational history search was attempted for spouses to coincide with these intervals for their corresponding cases. The three-digit 1970 U. S. Census industrial and occupational codes (U. S. Dept, of Commerce, 1971) were assigned to the employment information ascertained from medical histories, death certificates, and City Directories. Industrial coding was determined on the basis of product descriptions for each specific employer which were found in the manufacturing directories of Connecticut, published by the State Department of Labor (1957> 1966, 1973) and from the Price and Lee Directories for non-manufacturing industries. From the complete listing of job and industrial codes a subset was selected by H. C. Lewinsohn, utilizing published sources indicating occupations A006 1 2 UCC 017538 4. and products associated with asbestos (Hutchison, 1976; Levine, 1978; Weston, 1976). This will form the basis for probable asbestos expsoure classifications. The City Directory data over five decades provides information on duration of exposure. With a categorical response variable of occupational asbestos exposure, two fundamental research interests can be tested: 1. Whether cases and controls differ significantly with respect to job-related asbestos exposure (Relative Risk) and 2. The nature of the relative contributions of occupation, spouse occupation and geo graphical residence to the incidence of mesothelioma in Connecticut (Logistic Regression). In addition, the health experience of spouses of occupationally exposed cases and spouses of non-exposed cases can be compared. Results Of all cases diagnosed as pleural mesothelioma, twenty-one percent (31) had unknown staging (SEER, 1976) and sixty percent did not have an autopsy. The forty-nine cases of mesothelioma of other or unknown site have a mean age of fifty-two years and sixty-seven percent are without autopsies. The male-female ratio is approximately 1.5:1 (Table 3) The question of the accuracy of classification of cases of malignant pleural tumors into mesothelioma and other pleural tumors naturally arises. The mean ages and the male-female ratios are similar for these two groups and the ''other pleural tumor" UCC 017539 A006 1 3 5. group exhibits weak diagnostic confirmation, i.e., seventy-one percent positive histology and only thirty-five percent autopsied. A discriminant function analysis of these two groups of cases (diagnosed after 195*0 on the basis of age, sex, survival, time, stage, and number of tumors yields a sixty percent misclassification. This result suggests that: 1. Either these variables are not sufficiently powerful discriminators of pleural mesothelioma from other pleural tumors, or 2. The two groups, as a result of mis-assignment of a substantial number of cases to the incorrect category, now lack the heterogeneity one would expect from distinct categories. If consideration is limited to cases identified after 1954> when recorded clinical detail in general improved, as well as an increasing awareness of this form of cancer, the number of cases with solid diagnostic confirmation and characteristics consistent with the natural history of mesothelioma are strikingly few. Of the 131 cases classified as pleural mesothelioma, 124 (95%) bad histological material, (specimen from biopsy, frozen section, surgery, autopsy or D and C) examined and autopsies were performed on forty-five cases (38$). The proportion autopsied is disappointingly small. Table 4. shows the percentages of subjects with these two diagnostic critieria for mesothelioma cases of other or unknown site, for peritoneal mesothelioma, and cases 6f pleural tumors, not mesothelioma. UCC 017540 A006 1 4 6. As a result of these findings, it is imperative that a slide review and a re-examination of hospital clinical reports for all cases of mesothelioma and other pleural tumors be undertaken. A commitment has been received from an independent pathologist for this aspect of the study. The following data analyses are subject to change subsequent to this procedure. Descriptive Epidemiology Between 1935 and 1977> the CTR identified 229 cases of mesothelioma, 2.Z yielding an overall crude incidence rate of four per million. Age-adjusted incidence rates per 100,000 population (using 1950 U. S. population as a standard) for pleural and peritoneal mesothelioma consistently increase and exhibit a rapid rise beginning about 1955 - .04 (1935 - 44); .07 (1945 - 54); .18 (1955 - 64) (Figure 1.). We are in the process of generating these rates through 1977. Of these cases, 195 (85%) were reported after 1954. The male-female ratio is approximately 2:1; the mean age at diagnosis is fifty-nine years. Survival time from date of diagnosis to date of death is approximately ten months. A logistic regression model of the form: Log ^ JE- ) = A + B1 X1 + B2 X2 + X3. was fit in order to examine the incidence of pleural mesothelioma (binary response variable) as a function of the categorical explana tory variables - time, age and sex (X^, X2, X^). Connecticut population figures supplied by the Connecticut State Department of Health were A used for denominator data in the estimate of disease probability (P). UCC 017541 A 0061b 7. The three and two-way interactions of time, age and sex were found to be unimportant and the main effects model provided a reasonably good fit (p> 0.1). From the estimates of the model parameters (B^, B^, B^), changes in relative risk (here approximated by the odds ratio) over time intervals, age categories, and sex groups are approximated. Persons exposed between 1975 - 77 carry 3*5 times the risk of pleural mesothelioma as those exposed between 1955 - 64. With progression across the age intervals: 45-54, 55-64, 65-74,...the individual risk of this disease is 1.5 times greater than in the preceding ten year age group. As one might expect, males have three times the risk of females. In assessing these results, the poor diagnostic confirmation outlined in Table 3 should be borne in mind. The geographical distribution of cases of mesothelioma throughout Connecticut shows evidence of urban clusters in the five largest cities where 30$ of the cases resided at the time of diagnosis. Since these locations have comprised from 37$ to 20$ of Connecticut's population (1940 - 1977)> the suggested urban effect reduces to merely being a factor of population density. These five large cities are also centers of Labor Market Areas (LMA) of which there are eighteen in the State. Application of the CochranMantel-Haenszel Test of Average Partial Association (Landis et-al., 1978) between these five LMA's and time of diagnosis (1935-77)> while controlling for population age differences, suggests the following: UCC 017542 A006 1 6 8. 1. Incidence trends (i.e., the manner in which an area's cases distribute over given time intervals) are primarily the same for four out of five LMA's tested. One region suggests a greater proportion of its cases appearing in more recent years than the others (p=.04). This is readily explicable by the substantial in-migration experienced by this one area and its increasing industrialization as opposed to the other highly industrialized areas whose populations have gradually decreased over time and are, therefore, more comparable for analysis. 2. With the exclusion of this one LMA, the others indicate a similar distribution of their cases of mesothelioma over time (p=.17) This possibly implies similar patterns of asbestos exposure for the four large industrial regions of Connecticut. Until such time as the mesothelioma incidence has been adjusted for the previously mentioned diagnostic weaknesses and possible misclassifications and until the occupationally exposed cases have been identified, it is not possible to determine the role of environmental asbestos exposure, if any, in the remaining cases. Summary Medical, occupational, and demographic data were collected for 26? cases of malignant mesothelioma and other pleural tumors, their spouses, and 605 controls. Methodology was developed for classification of subjects into probable asbestos exposure categories on the basis of product and job descriptions. Although disease incidence rates exhibit a rapid increase from 1955 to 1977y there remains a serious question of diagnostic reliability. A case review will be undertaken. UCC 017543 A006 1 7 9. Acknowledgements The authors wish to acknowledge the technical assistance of Linda Mowad of the Connecticut Cancer Epidemiology Unit and Kathleen Pinto of Raybestos-Mahhattan, Inc. UCC 017544 A006 1 8 10. References Bruckman, L., Rubino, R. A., and Christine, B. (1977a) Asbestos and Mesothelioma in Connecticut. APCA Journal, 27, 121-126 Bruckman, L. (1977b) A Study of Airborne Asbestos Fibers in Connecticut. Paper presented at the Workshop on Asbestos: Definitions and Measurement Methods, National Bureau of Standards, Gaithersburg, Maryland Bruckman, L. and Rubino, R. A. (1978) Monitored Asbestos Concentrations in Connecticut. APCA Journal, 28, 1221-1226 Connecticut Labor Department: Directory of Connecticut Manufacturing and Mechanical Establishments (1957) Wethersfield, Connecticut Connecticut Labor Department: Directory of Connecticut Manufacturing and Mechanical Establishments (1966) Wethersfield, Connecticut Connecticut Labor Department: Directory of Connecticut Manufacturing and Mechanical Establishments (1973) Wethersfield, Connecticut Cox, D. R. (1969) The Analysis of Binary Data: London; Methuen and Company, Ltd., pp. 14-29 Hutchison, M. K. (1976) A Guide to the Work-Relatedness of Disease, Washington, D. C., U. S. Department of Health, Education and Welfare (U. S. Government Printing Office) UCC 017545 AG06 1 9 11. Landis, R. J., Cooper, M. M., Kennedy, T., Koch, G. G. (1978) A Computer Program for Testing Average Partial Association in Three Way Contingency Tables (Parcat) Biostatistical Technical Report #18 Levine, R. J. (ed.) (1978) Asbestos: An Information Source. Washington, D. C., U. S. Department of Health, Education and Welfare (DHEW Publication Number (NIH) 79-1681) Price and Lee City Directory (1890-1977) The Price and Lee Company, New Haven, Connecticut U. S. Department of Commerce, Bureau of the Census: 1970 Census of the Population. Alphabetical Index of Industries and Occupations (1971)> Washington, D. C., U. S. Government Printing Office U. S. Department of Health, Education and Welfare, National Cancer Institute Cancer Surveillance Epidemiology and End Results Reporting. SEER Program (1976), Washington, D. C., U. S. Government Printing Office Weston, R. F. (1976) Technical Feasibility and Economic Impact of QSHA Proposed Revision to the Asbestos Standard. Prepared for the Asbestos Information Association/North America. Washington, D. C., Figure 2-1, p. 2-3. World Health Organization: ICD-0 International Classification of Diseases for Oncology. (1976) Geneva, Switzerland A0062C UCC 017546 12. Hilton C. Lewinsohn,Corporate Medical Director, Raybestos-Manhattan, Inc. and Lecturer, Yale School of Epidemiology and Public Health (address: Raybestos-Manhattan, Inc., 100 Oakview Drive, Trumbull, Connecticut 06611, U. S. A.) J. Wister Meigs, Director, Connecticut Cancer Epidemiology Unit and Clinical Professor of Epidemiology, Yale School of Epidemiology and Public Health (address: 30 College Street, New Haven, Connecticut 06520, U. S. A.) Mary Jane Teta, Associate in Research, Connecticut Cancer Epidemiology Unit, Yale School of Epidemiology and Public Health (address: 30 College Street, New Haven, Connecticut 06520, U. S. A.) UCC 017547 A 0062 1 Figure 1 Age-adjusted Incidence Rates by Decade of Diagnosis, Pleural and Peritoneal Mesothelioma, Connecticut, 1935 - 197^ UCC 017548 A00622 Table 1. CTR Reported Cases of Mesothelioma and Other Pleural Tumors Diagnosed Between 1935 and 1977 Table 2. Sources of Data and Variables Table 3. Sex, Age and Diagnostic Characteristics of Malignant Mesothelioma Cases and Other Pleural Tumors Diagnosed in Connecticut, 1935 - 1977 Table 4 Diagnostic Evidence for Disease Groups UCC 017549 &00G2 3 Sc+' CD CD >oOooo o-Fr O 00 rho h on roo ro DECADE OF DIAGNOSIS UCC 017550 A00624 Table 1. Diagnosis Period 1935-77 Primary Pleural Tumors (T63) I85 Mesothelioma (M905) Other 147 38 Peritoneal Mesothelioma (T58, M905) Mesothelioma Elsewhere 33 49 Site not pleura or peritoneum Site unknown (T99) 37 12 Period 1955-77 151 131 ' 20 29 35 27 8 267 267 215 215 UCC 017551 A0062b '^ar Variables Population * rH cd o aH r--1 O O H P -p ocd a S3 a(D bD a} o H rH T3 aft <D O H ft ft Sf*t cd 1 Utoo a O rH rH CD Q fOt ft -P cod T3 ft O CD CSO3 cod o Cd -p H X! CD ft O Ucd o43 bO -P cd a CD Q TCdD t 43 -P cd CD TJ fot aCD cd S3 CD CD SCO3 CD 2 cd O O ft ok CQ H 43 -SP3 ft CD cd Sh boD a CD g. O t--aft1 Q CD O H ft H O CD ft CQ foSth CQ So3 H -P ft H Sh O CD CD Q CQ u -P CD OS3 >o &TJ O raHft CD CD CD Sh CD O 4 cm nd CD cd S3 t *OH QCD P ft CD Sh cd H CD S3 SOh rj O CD CSD3 CD CD T3 rafHt O CD ft -P CD TOS33 bO 5 rH a) O Sh SS3h H ft -P -P O H +3 cd H S3 CD 1 r'dH sH g. O rHft a CD S3 acSoSid33 CD CD TJ O O u> -p CSQ3 TSJ3 M CQ CD rodo 43 *O"3 CQ CD CD CD CD cCdQ oSf3t O CO CD rH SOPh S3 O O CD k CD CD CO CD S3 ocCdQ Oft CO k CO rH O -SPh S3 oO CD k CD CD CO CD S3 ocCdQ Oft CO *k CD oi--1 u -p oSo3 CD k CD CD CD <D S3 oCcdD Oft CO CD rH O u 43 oSo3 CD cnk CD CQ CD ocCdQ oSf3t CO 43 33 CQ O a43 CD S3 rH CD cd fHt TJ S3 H CD 43 H 43 O CrDt Sh CfDt fctd ft<D CD SH fHt 43 s CO rON O o fot O rH CD CD H Soh <3 (D 1 CD ft a CD lr\ CD aCD O cd cn H ft S3 cd ON U 43 O CD U cd EH CD ft BSh S3 rH k_^ O 43 H cd CD CO > Eh -- CD O CD Sh CD CD CD S4 43 CQ CQ CO 43 H cn H CQ H O cd S3 H O O cod Q rON O bO 43 ft H bD rH CD u& CD H 5 43 H CQ k ft H 43 5 k VO CD ft BoSh cd > CD Sh VO Td 3s 43 O CO *t3 S3 O 4o3 On rH C 3 CD CD rH ft T3 ft .cd k CD cd O *H 43 D-- O -op 43 43 >H a CD CD Sh cd s l/N s s On rH fUHt Td S3 cd rH cd H Sh 43 CD S3 Td S3 H CD CD S3 Td CD O S3 O CD O rH cd S3 CO O H s=> 43 cd o r ON rH &o oo UCC 017552 CO CM CO O o <3 Source >CPO<* T03) -h=Oe*. he. LoCnN he. oOoN hooenn. 3Q he. -=f CD H -P -P 03 *H H oC(3 33 pH on Ov iCH*- he. - ON he. - CO he. 00 00 <D 0P} VO s<13 CM 00 VO LfN CM LTN on rE,aH0h) rH P=4 t/N -=t r-t m rH CoM OV LTV CM ON rH * COrHM -d* CM O CM OV CM LTV i--I i C'- 00 on on on on vE--o CM c8 00 i 3 Poa ao "--' *H rH O *H hao p a ?o a H rH rH rH rH *H .2 a rH rH a oO Xi xi xi xi p p aa P hP PP S oP O P O H O a xi p H rH rH P> -H o Ph S ph s Ph S so rH Po E-h UCC 017553 on Fh rO TOO3 VC--O ON rH PWWh CO A00627 Table 4. Diagnosis Peritoneal Mesothelioma No. 29 Other mesothelioma (not pleural or peritoneal) 35 Pleural tumors, not mesothelioma 20 nPositive 9&% 88$ 85$ Autopsy 88$ 40$ 38$ 1. SEER, 1976, Code/Field Number 19 UCC 017554 A00628