Document qa44Xr1nmm5NwNnKzJOd7wdak
PLAINTIFF'S EXHIBIT
Yale University
New Haven, Connecticut 06510
Connecticut Cancer Epidemiology Unit 30 College Street
(203) 436-8904
J. WISTER MEIGS, MTS., 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
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A00588
Wn.' Influence ui OiiUUiUULiimai ntd Emrtrmmmuial AsDeereu -
Bnposueo on Malignant Mesothelioma in Connecticut^ ms-ir?7
by
H. C. Levinsohn J. W. Meigs M. J. Teta
Presentation to the Connecticut Thoracic Society, November 4, 1980
UCC 017515
A00589
The Tnfliianua nf Pr r m Hfl'miil rr"! Fr---t r-nni"" f rl i^nlrrrt"'' ''-t'JEvt** on
the Inoidonee of Malignant Mesothelioma in Connecticut^
1^77
by H. C. Levlnsohn, 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'b "cumulative asbestos consumption", which Includes asbestos emis sions 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 3
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 As warranted. The present
study has been designed to
A0052C
re-examine the identified cases of malignant mesothelioma recorded in the
UCC 017516
CTR and attempt to determine the role of various etiological factors, auch
as occupational and environmental asbestos exposures. In view of the jrb*Sug&zth
Ipmwisdtinrt possible diagnostic errors, which our results verify, a thorough
review of available histological material is being undertaken.
UCC 017517 2- -
A0053 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).
J pT ,-----------'-p
lu Llie'ltU-0 CKb'llti Utulth Ouganlsstiam) 1976) LlamiflLtiun^^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 random sample of approximately 700 decedents (1935-75) aged 20 to 98 years from the Division of Health Statistics of the Connecticut Department of Health. 5trw( c 5 . Descriptive epidemiology for this research pertains primarily to the fortythree year time Interval. Future case-control comparisons will include ^cases (215) diagnosed after 1954 (Table 1), and controls (604) 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
| o.c.4 o -f occupational and medical data prior to 1955 and the ineasaedmg awareness of mesothelioma associated with ttirtiWr time period (1935-197^. 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 these digit 1970 D. 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,
rfff-1^77.
and controls^ This will form the basis for classification of study subjects
- 3-- UCC 017518
Aoo?fn
/
' Ay '
^
Table 1. Sex, age and diagnostic heracteristies of cases of malignant
mesothelioma and other pleural tumours diagnosed in Connecticut,
1935-1977
Diagnosis0
Pleural aesothelloam Pleural tiaaour (other than Msothelloaa)
Peritoneal mesothelioma Mesothelioma at Other sites I at unknown sites
Total
Males
102 (M)fr 24 (12)
Females Total
Mean age
45 (37) 14 (8)
147 (131) 38 (20)
61 (62) 62 (63)
Percent 'pesltie'b histology
Percent autopsj*
93 (95)\ 71 (85) \
X (38)
/f 35 (37)
20 OB)
13 (11) 33 (29)
/58 (59) 94 (97)
\
89 (88)
29 (21) 175 (H5)
20 04) 92 (70)
49 (35) 267 (215)
52 (54) 59 (60)
84 / 86)
& (93)
>k 33 (41) \4 (45)
* WHO (1976) ^ 9CCN| 4986>CededField Htaaber 19 (US Department of Health, Education, and Welfare. National Cancer
Institute (1976)
f (Nu. NWBpJlid/hio. 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).
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- r-
A00594
III. Results
Descriptive Epidemiology 'ulJ"*
The MSe incidence rate for mesothelioma in Connecticut is 2.I/million for the years 1935-1977. Vjn aHjuului tm.tiftiin.i- ^ptes 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 ratio is approximately 2:1; the mean age at diagnosis is fifty-nine years. (Wm^L 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 302 of the cases resided at time of diagnosis (Fig. 3). Since these locations have comprised 20-302 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
ay pm(e f (IMA). All 6 areas exhibit a similarly increaslng*,lncidenceVld.th -ehc Bridge port IMA Lilli UlgliMbL UVUialiK The Stamford IMA's mesothelioma rate shows a*. sharp increase since 1965 (Fig. 4).
UCC 017521
A 00 5 8b
(D
mas
od -n 2
1 ---------------- 1-----------------r
b>
o
CX O
UCC 017522 - 7"
* 0
RATE/100,000
AGE-ADJUSTED INCIDENCE RATES OF MESOTHELIOMA IN CONNECTICUT BY YEAR OF DIAGNOSIS AND SEX
400596
GEOGRAPHICAL MAPPING OF CASES OF MESOTHELIOMA (1 9 3 5 -1 9 7 7 )
BY TOWN OF RESIDENCE AND 1960 LABOR MARKET AREA
- 5-
UCC 017523
AGE-ADJUSTED INCIDENCE RATES OF MESOTHELIOMA FOR CONNECTICUT MALES BY YEAR OF DIAGNOSIS AND LABOR MARKET AREA
RATE/ 100,000
1935-44
45-54
55-64
65-74
75-77 A 005
SLIDE REVIEW
Tin in linn I I iTI'n i 11 111TTI
i iimplf 11 in in mnl iiiinimj iiT in i
idyiM ffmf f'"* ***-*"
tiy-fu. ... .Blirt-f.il.
1. .[aIiaullhliryyywTf-<Tap-
CUUUMLMf
- nrjL. Malignant mesothelioma is a very rare disease, expected in only 2 A
persont^for every million at risk. Resistance to acceptance of mesothelioma
as a disease entity persisted until the late 1960'sf despite
35
report'Of >8 RlmoluglLallj proveneases of pleural meaothellUHia associatea
Wag*r
tt
with Capr rrrridnUtr nntrrrrtrff-fitlfln In fn i1 fl m IMs widely publiohad mahl/e/ac^
iDuffr LliDJillL
association of mesothelioma with asbestos exposure / ^mwawer, created the
fx be ftlWucbeA
^
jfpi potential *>- diagnostic bias*
In addition to its rarity and the subsequent lack of asuBaimsu,{positive o(4ee
diagnosis of mesothelioma is^complicated by its confusion with other forms
of cancer. (Dr. Vldone's 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 distinqulsh mesothelioma from a metastasis from another primary site.
1 the light ef Shooe-diffieultries\jj^ examined, for all CTR reported
cases of mesothelioma and for all pleural tumors other than mesothelioma
(1935-77), the histological basis for diagnosis (tableB 2,3). For 12Z (32)
Ai'CSMe w*j examined of the cases, no 1----m
at time of diagnosis,
ti'^iV\ sf
i/*<(-&
while available apcilsicBB myi fsen biupiiji LCTtf 'ft e l Issue-.
Overall only 44Z (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 33Z to 40Z.
These results suggested the advisability of a case review, <whieh was
r^* t`"'t1 * f^r-lnigr frf-t*1! *f fii1t-,1' ,lt*1 v--1 1~VJ K,to^n1ffgifn1
Mt-o-r-fni nt1 Hn mt
tif. Dr. Romeo Vldone, chief pathologist at St.
UCC 017525 -- A> ~
A00599
Raphael's Hospital, Is presently .asviawlag the medical records (except oc
cupational data) and slides we have obtained for cases diagnosed after 1954.
Sou.jM~
iW A*
Cooperation was elicited from 37 hospitals, of which 30 have provided us
A
with the materials requested.
(Dr. Vldone-Summary of Findings)
UCC 017526
A0060C
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UCC 017527
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UCC 017528
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UCC 017529 " Z/'-
A00603
References Bradman, L., Rublno, R. A., end Christine, B. (1977) Asbestos end Mesothelioma in Connecticut. APCA Journal. 27 121-126
Brockman, L. (1977b) A Study of Airborne Asbestos Fibers in Connecticut. Paper presented at the Workshop on Asbestos: p^finltions and Measurement Methods. Rational Bureau of Standards, Gaithersburg, Maryland
^Bfruckman, L. and Rubino, R. A. (1978) Monitored Asbestos Concentrations in Connecticut. APCA Journal. 28, 1221-1226
... .nny'if.r , i1 't ii ' ------------
Pfrlce and Lee City Directory (1890-1977) The Price and Lee Company, Rev Haven, Connecticut
IT. 5. Department of Commerce, Bureau of the Census: 1970 Census of the Population. Alphabetical Index of Industries and Occupations (1971), Washington, 2>. C., U. S. Government Printing Office
World Health Organization: ICP-0 International Classification of Diseases for Oncology. (1978) Geneva, Switzerland
UCC 017530 t.
*00604
Hilton C. Levinaohn,Corporate Medical Director, Raybeatoa-Manhattan, Inc. and Lecturer, Tale School of Epidemiology and Public Health (addreaa: Raybestos-Manhattan, Inc., 100 Oakviev Drive, Trumbull, Connecticut 06611, U. S. 1.)
J. Viater Meigs, Director, Connecticut Cancer Epidemiology Unit and Clinical Profeaaor of Epidemiology, Tale School of Epidemiology and Public Health (addreaa: 30 College Street, Hew Haven, Connecticut 06520, U. S. 1.)
Mary Jane Teta, laaociate in Research, Connecticut Cancer Epidemiology Unit, Tale School of Epidemiology and Public Health (addreaa: 30 College Street, lev Haven, Connecticut 06520, U. S. A.)
UCC 01753]
A0060h
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.
Sable II and III ll-luofc-eofca ewe ef the1
fej jor deficiencisfe in the data available for study, namely the low autopsy rate
for the pleural nesotheliomata and the inadequacy of the cypca of eiooua-
available and used for diagnostic purposes.
It has been our experience that occupational histories are not routinely obtained
It jts apparent from our study of increased iiv^the lite 1950 duqe a diagnostic biaS'-whlch might
UCC 017532
his disease ppear< d to /nt 'oent increi,ae after 1955.
A006G6
Comment on the significance of the findings or. the slide review.
It is evident that until the physicians or hospitals investigating cases of
OCtoffttW k-
*. on
malignancy appreciate the importance of environmental facts * the etiology of A'
these diseases, no attempt can be made to apportion the blame to any particular
factor unless adequate histories are availa ale containing complete information on
lifestyle, habits, hobbies, part-time activities and details of occupation and
industry. It is also essential particularly in the case of a rare tumor which
cay present diagnostic eiffaculties,to obtain sufficient tissue for study before 44\ I? JoAfeeEhol
the final diagnosis is cade. Whenever a tumor is found where me association exists
between it and a particular occupational or environmental factor, every' attempt
should be mace to fully document all the wrrew facts and to subsequently verify
the diagnosis by means of a full autopsy.
UCC 017533
AO 060?
v < -rr.!'-:-c */ Jii'i:-Ut- lo: ;r \ t*5
Do: o' vt _r. ii*j' kT,c nr.
aio*n'.>*
t.c. rr.*L* 5`it- r.jc i-ter irti'.rc fur c/irumt
recL^ri?. tynow*:a- of thr krit-ej* with riex*-
n;eir.fei.u:)t in dosage* from 0.5 to 2.5
mp caiiy intermittently for tec years.
During this period, the skiu of her fore
arms became extremely thin. and she
s: uatio: ce*. en-pec a: to; site o: a localize: herpes s.rr.pit). :r.;'c::io:. tha: ha: occurred or. rnv L-ppt* it: and had not heaiec for approximate;;, one year. J: was removed by a Mohs'
surgical procedure at a local universi
ty center, and a diagnosis of base-
iir.siime? ^hert- ctk*r r.as resulted iron, pulmonary canter t a
thoracic or peritonea' mesothelioma, it is important to identify the tissue alterations directly attributable to occupational contact with the respira
experienced aeverai episodes of subcuta squamous cell carcinoma was made ble asbestos fiber.
neous- extravasalior of biood.
again. At that time, the dermatolo
As we have counseled family survi
Or the fourth hospital day, she was transformed to the x-ray department, where it was noted that she had two superficial tears id the side of the Jefi forearm with paping margins Attempts were made to suture the skiD edges togeth
er. but the sutures tore throupr the shuc. The edges were held together with strips
of steriie tape.
gist performing the chemosurgery
mentioned how umtsua) the lesion was, inasmuch as there were not supposed to be such things as bast-
squamous carcinomas Both wounds healed without any unusual event.
After the first occurrence, 1 con tacted L'r Herman Pinkus in Detroit,
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 the examination. These procedures
On one other occasion during her hospi and he stated that there were about a will not only aid the beneficiaries but
tal stay, similar iesiocs developed during the course of transport to and from ber bed for other diagnostic procedures These lesions failed to heal during her hospital stay, and gross evidence of infection was DOt noted
Comment--Transport by handling
of the forearms, even though careful ly done, resulted in serious, poorly healing tears of the skiD in this
overweight, weak woman. Even though extra care was taken after the
initial episode, there was recurrence. Jr. this cast there was no complaint or dissatisfaction expressed by the pa
tient or the family, but such episodes
have the potential for risk of coropensabit injury. Certainly there have been allegations of hospital-based
injury with lesser justification.
dozen cases iD the literature at that will also prove of worth to physicians
time. I saw him at a meeting shortly in familiarizing them with the find
after the chemotherapy, and be com ings characterizing a greatly under
mented on the unusual nature of this diagnosed jot-generated disease.
condition occurring more than once,
Furthermore, such postmortem
though be was more aware of its data will aid in our knowing what
occurrence than he had beer, before. actually happens to a worker under
There is an embarrassing situation certain conditions of exposure and
about this personally. aDd tha; is that will help to rectify the inaccurate
1 am a dermatologist.
conclusions drawn from the current
There were no other forms of ther underreporting of occupationally as
apy used on these lesions with either sociated disease.
surgery, antibiotics, or photodynamic
inactivation, nor am 1 a smoker. 1 haie had an occasional localized
herpes simplex injectioncuring the j
am
LKr*e o'
m: Coktom*
&cnoo o* Moiune
Lot Anp*t
past 20 years.
! Safety of Ipecac Syrup
***.,,, L Gt^ 1C
j
AijDon
(aroup SC |
7c
the
Editor.--On
behalf
of
the
C*wcpo
: American Association of Poison Co r-
Ji would be prudent for physicians
tro! CeDLers. 1 am concerned about
hospitalizing patients who have been
receiving steroid therapy to place a warning Dole on the chart advising hospital personnel to use extreme care when bathing, assisting, or transporting such patients.
1 Of *"* MD
C/pwr*g)r CmIf*
The Autopsy and Asbestos Exposure
To the Editor.--In the article entitled "The Autopsy: Past, Present, and Future" by Andersor. and co-workers (242 1056. JP79/. the fa!' in the rate of autopsies is decried, and several
the titlmg of a recent JAMA article, "Death Resulting From Jpecac Syrup
Poisoning" (242:1927,1980). 1 am wor ried tha: 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
Carcinoma at the Site of He*pes Simplex Infection
To ti,f Editor --The JorRWL recently published a letter entitled "Carcino
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 giver, emphasis
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
ma at the Site of Herpes Simplex Infection" (243.2396, 19S0). My letter is to note further the occurrence of such a situation. I personally had basosQuamoL's 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 ur.mrsitv hospital. I was approximately 55 years old at that time.
in recent years by the epidemiologic and clinical information gathered in connection with the 2sbestos-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 often do not have accompanying symptoms, os yet, nor have they caused any disability*, as yet There
ipecac as an 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, 1 think that it would be unfor
tunate indeed were the inference drawn that single emetic doses were risky.
Wi_iiam D
Ch'tO *-> * Orttc;/*>cfiL
fcnC MeOiCA'
Ar>'enrr Axe>mtor> O* Po-on Control
JAMA. Oct 10. 1980--Vol 244. No. 15
A 0 0 608
Letiers 1675
UCC 017534
The Influence of Occupational and Environmental Asbestos Exposure on the Incidence of Malignant Mesothelioma in Connecticut
by
H. C. Levinsohn J. W. Meigs M. J. Teta
UCC 017535
A 00603
The Influence of Occupational and Environmental Asbestos Exposure on the Incidence of Malignant Mesothelioma in Connecticut.
by H. C. Lewinsohn, J. . Meigs, and M. J. Teta
Introduction
Bruckman et al. (1977.) 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 State's "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 (19351972) 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
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
Aooe1j
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, 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 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 basi3 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
k.
and products associated with asbestos (Hutchison, 1976; Levine, 1978; Weston, 1976). Thi3 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 1954) 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^) had 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 of pleural tumors, not mesothelioma.
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A00614
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 few per million.
Set.
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 (
^ X1 + B2 X2 + B3 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, X3). 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
A006 1 b
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).
A A Ax
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 3756 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 (IHA) 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:
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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 267
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 1977, there remains a serious
question of diagnostic reliability. A case review will be undertaken.
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9-
Acknowledgements
The authors wish to acknowledge the technical assistance of Linda Mowad of the Connecticut Cancer Epidemiology Unit and Kathleen Pinto of Raybestos-Manhattan, Inc.
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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. Rational 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
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11.
Landis, E. J., Cooper, M. M., Kennedy, T., Koch, G. G. (1978) A Computer Program for Testing Average Partial Association in ThreeWay 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 OSHA 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
A 0062C
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12.
Hilton C. Levinsohn,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.)
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Figure 1. Age-adjusted Incidence Rates by Decade of Diagnosis, Pleural and Peritoneal Mesothelioma, Connecticut, 1935 - 197^
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Table 1.
CTR Reported Cases of Mesothelioma and Other Pleural Tumors Diagnosed Between 1935 &nd 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
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MJ0623
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DECADE OF DIAGNOSIS
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Table 1.
Diagnosis
Period 1935-77
Primary Pleural Tumors (T63) 185
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>
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UCC 017553
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Table 4.
Diagnosis
Peritoneal Mesothelioma
No. 29
Other mesothelioma (not pleural or peritoneal)
35
Pleural tumors, not mesothelioma
20
"Positive Histology"^*' Autopsy 9656 8856 88% 40%
85% 36%
1. SEER, 1976, Code/Field Number 19
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