Document DDZbj8Y2vqnm5jjdqMRDG1MdQ

PROPOSAL rOR A HISTORICAL PROSPECTIVE MORTALITY STUDY OP POLTCHLORIMATED BIPHEHYL EXPOSED WORKERS sackgroowp The polychlorinated biphenyls (PCB's) have attracted such attention since the late 19S0's when technological developments In gas chromatography and ness spectrometry made the detection of PCB's at low levels In the environment possible. PCI's bams been in use since 1929 in transformers, lubricants, acarbonless" dopllcatlng paper, fireproof eealants, plastics, adhesives, and many other produets. Their resistance to biodegradation, photodegradation, and oxidation nada them Invaluable In soores of uses but also made them more stable as residual pollutants when released Into the environment. PCI's are highly lipid soluble compounds. Lipid solubility enables a proportion of food chain PCI residues to bo stored in the fat depots of the body. The first reports of PCB'a in the environment cams from Sweden, where Jensen (19##)1 identified residues of PCS's In fish from various Swedish waters. Rlsebrough at al (19#S)2 found PCS and DDT in marina ecosystems of the Peclfle Ocean. Early reports of wildlife effects included egg shell thinning and baby seal effeets, but subsequent studies have failed to conclusively show PCB's as the causative mpeat. The first report of possible PCS effeets on huawns oeourred in 19CS, when over 1,000 Japanese were involved in an epidemic of Yusho, an acnelike skin disease which was traced to rice oil contaminated with PCB's. However, it was later shown that the rice oil also contained a high level of polychlorinated dlbensofurans (PCCP's), possibly dua to use of the contaminating PCB as a high temperature heat transfer medium. It was shown that PCDP's are relatively more concentrated in the liver. HONS 216067 2- ud the investigators' findings clssrly iadiestsd ths necessity to py greater attention to PCDP's for clarification of ths nature of Tusho.3 Miilo scuts offsets froa relatively high PCB exposure levels ere known end eon be svoided by Appropriate control smasuras, sttsntion hss more recently been focused on the chronic effects resulting froa long-term low levels of exposure to PCI's. Animal tests hove proved to be equivoceble. the fnrlrnnasnf 1 Protection Agency considers PCB's to be suspect carcinogens besed on its own eniael tests. Monsanto's extensive two-year chronic oral toxicity tests of Arochlor 1242, 1254, and 1240 in both rets end beagles at dose levels of 1, 10, and 100 ppa concluded that PCB's were noneareiaogenie. lyperplasie, hypertrophy, and several benign tuaors were observed in tin livers of the rets, hut there was no evidence of malignancy in any of the test animals.4 Other investigators have shown liver tissue effects ranging from - hyperplasia to well-differentiated hepatocellular earcinoaas in rats or nice fed with various PCI-containing diets. For example, Kimbrough at el (1572)3 fad rats with Arochlor 1254 and 1240, and found hyper trophy, lipid aecosulation, and adenofibrosis in liver tissue, but A~ockl,<~ foisid no malignancy, the same investigator fed Arochlorl254 to mice for 11 months and reported the induction of malignant hepatomas in the test animals.* the recent Motional Canoer Institute report 7 of its carcinogenicity tests on Arochlor 1254 concluded that the substance was not carcinogenic in Pischar 344 rats under the conditions of the bioasssy. However, they allude to the non-significant occurrence of gastrointestinal traet carcinomas and hepatocellular proliferative lesions in their test animals as possibly being related to the Arochlor diet. there have bean vary few epidemiological studies of human populations NONS 216063 -3- exposed to lew levels of PC*'* over long period. The itobil oil Coapany released e study in 197 conducted by Dr. Anita Satin* in which e significant nwber of melanomas end pancreatic cancers were found in exposed chemical workers. While these results received publication, the study was severely criticised9 due to deficiencies in the identifi cation of the study cohort, failure to Identify other potentially carcinogenic chemicals to which the workers and research personnel were exposed, and other problems which left the results of the Mobil study highly in doubt. A preliminary study of PCS-expoaad workers was begun at Monsanto shortly after the Mobil study in response to the need for a valid epidemiological study of the effect of PCS's on hrmens. The study focused on workers at the Knomarich Plant, where PCS's were manufactured from 193d until production ceased in 1977. Mo mslanomas or pancreatic canoars were fotaid, but an excess incidence of long cancer deaths was seen, lowever, due to the preliminary nature of the study, several necessary steps to complete the epldeadology study remained unfinished, such as following up on the mortality experience of ever 301 of the study cohort who were lost-to-follow-up. In addition, no minimal limits on exposure time were used in the preliminary study. Thus, no attempt was made to distinguish betwean the workers exposed for years the worker exposed for a fow days. The investigators involved In the preliminary Monsanto PCS study realised thebe deficiencies and advised that the study population should be further defined and evaluated so that e valid, comprehensive report could result. Therefors, due to the preliminary nature of the epidemiological date available and the Inconclusive toxieologieal data, it ia necessary to pursue further epidaadclogic study in order to evaluate the chronic effects of PCB-expoeure to man with more complete vital information on a verified, exposed worker cohort. HONS Z16069 -4- tnu>ogg or the army this epidemiological study will investigate the aortality experience of workers sxpossd to polychlorinated biphonyIs in thoir asnufseturo. Through studying this eohort ws'intend to (11 identify groups of workers thet hove PCS exposure of.a sufficient latency to deaonstrate any chronic health-effects, and (2) analyse the mortality experience of these workers with attention given to malignant neoplasms especially of the lung, liver, skin, and pancreas. - WPDY POPULATION The Monsanto plants involved in the U.S. manufacture of PCI's are the W.C. Knaaerich plant in Sauget, Illinois, and the Anniston, Alabama plant, tines the preliminary study, upon - which the proposed study Is based, involved the Kruanrich plant alone, the proposed study will deal solely with the Xrusmrich The study population from the Kruanrich plant consists of all me waged employees who hews worked at least six months in a job involving exposure to PC* after December 31, 1944,and prior to , .* ,0 . Deeeaber 31, 1995. This population includes aetive, retired, and terminated employees. Through interviewing plant personnel, it was determined that exposure levels of workers involved in the manufacture of PCB's did not vary considerably! therefore, all waged workers involved in the manufacture of PCP's will be considered,to have a comon exposure level. MOMS 216070 erk histories for all peat and present Xrusnrich employees have been obtained and screened far PCl-departrwnt work by tha i/Jl**"* Department ef medicine and Environmental Maalth (DDES). a /'"V plant-doveloped computer Hating ef all PCS department vorkara ^J^r****' haa alao baan auppllad to tha WEI, and tha computer Hating . baa baan croaa-ehecked with tha hand work history aaareh In ordar to inaure eeaplatanaaa. St abeuld be noted that acme workare, e.g., maintenance, may baea bad significant exposures to PCb'a, but ara not included in the atudy duo to exposure earifioation difficultiea. Per each worker tha following information baa baan obtained) name, aocial aacurity number, amployaa number, race, aax, data ef birth, data of bira, data of termination (if applicable), and aa detailed a mark hiatory aa la available, for thoee known to have died, the data and place of death, and a copy of the death certificate are belay obtained. MOkTAI.ITY POI&OW-PP 1. All active employees,and retirees who are currently receiving penalon cheoka will be assumed to be alive aa of December 31, 1977. 3. All peraoaa known to have died on or after January 1, 1979, will be assumed to be alive for the purposes of this atudy. 3. Personnel folders and pension fllaa will be aearehad for death certificates or for pertinent information about the decedent if no death eertificate ia preaent. 4. The names of persons for which there la no information on vital atatua will be reviewed with plant personnel for any information which they can provide. HONS 216071 - $. Other follow-up procedures, xuch es Veteran's Administration files, Polk Directories searches, telephone directories searches, and state driver's license files will be used, if. necessary, to determine the vital status of lost-to-follow-ups. . A state death certificate will be obtained for every person known to have died. ' 7. An experienced, trained nosologist will review and code all death certificates for the underlying cause of death to the International Classification of Diseases. Seventh Revision. ' ANALYSIS .. The data will be analysed using the modified life-table method. In this method of analysis,the age, race, cause, time-specific .- - mortality rates in a standard population are applied to person ' years classified by age, race, and time-specific subgroups of the worker population at risk (i.e. exposed) over the years of observation intervals. A standard mortality ratio will be calculated as the ratio of the sum of the observed deaths to the sias f the expected deaths xlOO. Hie person-years of observation will be calculated by year of Observation and age at observation as shown in Appendix A. Person-years of observation will be accumulated from date of first exposure to FCB's to the earliest of the following events; I) date of death, 2) December 31, 1977, the cut-off ascertainment date, or 3) date at which the study member was lost-to-follow-up. MOWS 216072 -7The expected ntaber of deaths will be eeleuleted using United States annual Mortality rates, or county rates, if available, for every year fro* 1945-1977. If annual county Mortality data is unavailable, the 1950-59 expected nuabere of eancer deaths based on U.S. rates will be adjusted by cause for the local county death rates according to the ratio of the local county rate to the U.S. rate using U.S. Cancer Mortality by Cotxity s 1950-69. A standard Mortality ratio will be calculated for certain selected causes of death (Appendix B) David C. Musch HONS 216073 I APPENDIX A PERSON-YEARS OP OBSERVATION BY YEAR OP OBSERVATION AND AGE AGE 15-24 25-34 35-44 45-54 55-44 45-74 75-04 5 + 1945-491 '1950-54 1940-44 1945-49 1970-74 1 HONS 216074 /VrtoSO'K 3 I Ki i--ri ch PCS Stmdy Cauae of Death with I.C.D. Raakr (favtath larliioa) Haltenant neoplaeae (140-205) Buccal Cavity and Pharyns (1*0-148) Dignative Organa and Ferltoaeen (150-130*. 157-159) Biliary Peeeagee and Liver (155-15**) Other Parte of Dlgeetlve Syaten (laeldael) Reaplratory Syaten (100-1*4) Sronehwa, Lang, and Trachea (102-103) Other Parte of Reeplratory lyetan (Reeidwal) Ceeite-Urftnary Syaten (177-101) Leufcanla and Alewhenla (204) Lyaphoearcona and Other Heoplaaaa of Lynphatlc and Hematopoietic Tlaanea (200-203. 205) *11 Other Meopleena (Maldeal) Dlseasea of the Cardlovaacwlar Syaten (330-334, 400-400) Disease! of the Reapiretory Syaten (470*527) Dlaeaaea of the Dlgeetiv* Syaten (530-507) *11 Other Dlaeaaea (Reaideal) All External Cauaea (E800-E998) Expected P.M.S. HONS 216075 REFERENCES 1. jmtn S., Htw Scientists. Vol. 32, p. (12. 2. Rlssbrough, R. H. et *1, "Chlorinated Hydrocarbons in'Karina Ecosystems," Nature, Vol. 220, No. 1098, 1968. 3. Hagayaoa, Junya et al, "Determination of Chlorinated Dibanzo- furana in Kanechlors and Yusho Oil," Bulletin of Environmental Contamination and Toxicology, Vol. 15, No. 1, 1978. 4. Report to Monsanto Company - "Two Year Chronic Oral TOxicity Kith Arochlor 1242 in Albino Rats and Beagles" (unpublished), November 12, 1971 and March 24, 1975. 5. Kimbrough, R. D., and Linder, R. X., and Gaines, T. B., "Morphological Changes in Liver of Rats red With Polychlorinated Biphenyls," Archives of Environmental Health, Vol. 25, pp. 354-64, 19 72. .. jtimb rough, R. D., and Linder, R. E., "Induction of Adenofibrosis and Hepatomas of the Liver in RALB/oo Mice by Polychlorinated Biphenyls (Arochlor 1254)", Journal of the National Cancer Institute, Vol. 53, No. 2, pp. 547-552, 1974. 7. National Cancer Institute, BIQASSAY OP AROCHLOR 1254 FOR POSSIBLE CARCINOGENICITY. Technical Report Series No. 38, 1978, DHEW Publication No. (NIH) 78-838. 8. Bahn, Anita K. , REPORT ON PAULSBORO. N.J. MOBIL OIL PLANT STUDY, April 27, 1976. (unpublished) 9. Lawrence, Charles, "PCB? and Melanoma," New England journal of Medicine, Vol. *296, No. 2, January 13, 1977. " HONS 216076