Document XzB4KxYGwQ8n024ZgVmyRqVeg

1 m YalcUnivxrsity P.O. Box > >.>-> Yiit Station, Sew Haven, Cl 065/0 SCHOOL OF MEDICINE ! i J C.eJar Street Departmill of Internal Medicine Occupational Medicine Program February 8, 1983 Attorney Robert Carter 400 Orange Street P.O. Box 1729 New Haven, Connecticut 06507 Dear Mr. Carter: At your request I have reviewed the records obtained by my colleagues and students In the Occupational Medicine Program regarding Messers Ozolins and Ardis who were evaluated in consultation In 1981. My role in this particular matter has been a somewhat unusual one for me and a somewhat complex one and I will try to elaborate it as I describe the presently available data base. Initial contact with Mr. Ozolins occurred in November of 1980 when his wife called the Occupational Medicine Program for information regarding a possible association between her husband's glioblastoma and his former work as a research organic chemist. To my knowledge she had been referred by a friend. The basis of the consultation was really quite straight forward as it was related by the patient's wife. Her husband as well as 2 other research chemists with whom he had worked closely, a Dr. Ardis and a Dr. Karabinos had all, within a relatively short period of time, been diagnosed as having malignant glioblastoma multiforme. All 3 men had worked as research chemists in a single relatively small facility dating back to approximately 1960. Because of a spate of epi demiologic and toxicologic literature which had been appearing during the pro ceeding 12-24 months several members of my staff including Dr. Robins and a senior medical student, Carola Greengard proceeded to attempt to establish some detailed exposure information from Mrs. Ozolins and family members of his two co-workcrs in the explicit hope that this information could enhance the present state of knowledge available to us about this disease. Prior to him death in late March of 1981 Ms. Greengard visited Mr. Ozolins on 4 occasions to exchange information. This culminated in the generation of the list of exposures to organic chemicals which you have provided me in your cover letter. In addition, members of my staff were in telephone communication with Mrs. Ardis on at least one occasion in an attempt to establish parallel exposure information. Further, Dr. Robins, during this period of time made contact on several occasions with Dr. Sorensen;then medical director of the Olin-Winchester facility, to assist in the elaboration of exposure data. Ac no time did I or any other members of my staff participate directly in the medical care of Mr. Ozolins nor did we have opportunity to meet family members of his co-workers. OLI 6461 2- - a jruary 8, 1983 Subsequent to Mr- Ozlins death and again premised on the distressing and striking coincidence of 3 cases of an unusual disease among co-workers in a small faciltiy coupled with the then active investigations going on in the area of environmental causes of this disease, I made contact with the new corporate medical director of the Olin Corporation to offer my assistance in the further investigation of this problem. Subsequently Dr. Robert Gilligan, Corporate Medical Director and I met on several occasions to exchange available information and to discuss some of the potential opportunities for further investigation of the problem. Later in the year I had the pleasure of meeting with Dr. Mark Hammill of Maryland, a consultant to the Olin Corporation to review with him plans for a broad-based retrospective cohort study of organic chemists in the research facility. Since the end of 1981 my involvement with this matter has been limited to continu ing contact with scientists working with the Olin Corporation to investigate this apparent epidemic. I remain unaware of any detailed data which has been generated from this work as yet nor of its conclusion. Since you have specifically requested of me an opinion regarding the likelihood that the causes of your clients were re lated to their work as organic chemists at the Olin Corporation, I will reiterate for you what I have said in many contexts including comments I made for the benefit of Mr. Ozlins' and Mr. Ardis' families upon their request, to Dr. Gilligan upon his, to Dr. Hammill and to yourself. Specifically, without the benefit of completion of the present study and without the benefit of the advances in our understanding of glioblastoma which 1 anticipate will be forthcoming within the next decade I.must confess that on the face of if it ann^ra v*rY Hhrl) Mini r i ill IT HlTlllill hip exists between exposures to organic chemicals and subsequent development of glio blastoma as has occurred among these three reecaeeh acieirtlsla at Olin. The basis for this opinion which I readily confess will require modification as more evidence comes forward is first, the known potential in the animal model for a wide variety of organic chemicals to. Induce this particular tumor type; second, the several studies alluded to earlier suggesting from an epidemiologic point view the clustering of glioblastoma among individuals exposed to a variety of organic chemicals including oil refinery workers, petro-chemical workers, vinyl chloride workers and organic chemists; and third, because with the benefit of both a biological and epidemiologically reasonable prior hypothesis the coincidence of 3 cases occurring in co-workers in a relatively small facility seems most unlikely on the face of it to have occurred by chance alone. Consistent with the state of the art, of course, I cannot name the specific Individual chemical exposure which 1 believe is causal In these cases nor would it be fair to say that an association between work with organic chemicals and glioblastoma is an unequivocally established and proven scienfitic fact in 1983. Nonetheless^! do believe that the weight of the presently available evidence favors a causal relationship in the cases in question and 1 have made this opinion known to all of tile' participating parties. I do wish to reiterate that although I do understand the need for the legal pro ceedings to go on even in the face of incomplete information that my principal concern and role in this matter remains that of the scientist. It was to my own office that the clustering of cases in question was first reported. It was our office that, working with the family members and some of their former colleagues as well as scientists around the country assembled the exposure lists which you OLI 6462 A, * -3- February 8, 1983 have returned, and hopefully it will be our office which will be able to assist Olin scientists in furthering the state of our present understanding. Although your own immediate attentions are necessarily otherwise I hope you can appreciate the seriousness of my own role. Sincerely yours. A f MRC'.mm CC: Dr. Robert Gilligan Mark R. Cullen, M.D. Asst. Professor of Medicine Director, Yale Occupational Medicine Program * OLI 6463 EDWARD S. GREENWALO. M.D.. P.C. 838 Pclhamdale Avenue New Rochelle, n. Y. 10801 ,(914) NE 2-Z124 February 3 1983 Robert F. Carter Attorney at Law Clendenen and Lesser 400 Orange Street PO Box 1729 New Haven, CT 06507 Dear Mr. Carter: I have reviewed the medical records that you have sent me on Mr. Ozolins and Dr. Ard is. I also reviewed the very brief summary on Mr. Karabinos. There is no doubt that all three had malignant gliomas. Dr. Ard is and Mr. Ozolins both died of their gliomas. We do not have follow-up information on Mr. Karabinos. Your letter states that all three worked at the Olin Chemical Company, Mr. Ozolins and Dr. Ardeis in the 1950's, 1960's and 1970's at Olin in New Haven, and Mr. Karabinos in the 1950's and 1960's at Olin in New Haven. In another letter you wrote to Dr. Cullen, a copy of which you sent me, you state that Dr. Ardeis was in charge of a vinyl chloride,?`ffirMassachusetts.' I assume this was for the Olin Chemical Company. Mr. Ozolins was diagnosed as having his malignant glioma on Sept ember 18, 1980, and he died on April 7, 1981. Mr. Karabinos had his malignant glioma diagnosed on January 26, 1977. Dr. Ard is, who died on December 8, 1980, had his malignant glioma diagnosed on March 17, 1980. Thus we see that all three patients developed malignant glioma approximately 25 to 30 years after their first exposure to chemicals at the Olin Company. You also gave me a list of chemicals that Mr. Ozolins and Dr. Ard is were exposed to. Dr. Ard is was exposed to vinyl chloride which"is highly suspedt as' a cause of malignant gliomas in humans, and also he was exposed to acrylonitrile which has produced malignant gliomas in animals. Mr. Ozolins was exposed to bis chloromethyl ether and acrylonitrile, both known to produce malignant gliomas in animals. They were also exposed to many other chemicals. The question as to whether the chemical exposures of these three men were the cause of their malignant gliomas is one that I will try to answer itr the rest of this letter. I am not a biostatistician so I cannot give you numerical evidence to show that this cluster is sig nificant statistically. I understand that Dr. James Robins will do the statistical work to test the hypothesis further. The origin of malignant gliomas is from the normal glial cells of the brain. These cells serve as supporting cells for the neural el ements of the brain. The major glial cells of the brain are the astro cytes which comprise the vast majority of the intraparenchymal cells of the brain. They function as supporting tissue for the neurons. There are also oligodendrocytes and ependymal cells which line the fluid-filled cavities of the central nervous system. In adults most glial tumors arise from the astrocytes and occur in the cerebral hem ispheres. Cell cultures of astrocytes from rats have been studied by a OLI 6464 -2number of investigators. In these c 11 cultures, normal glial cells are grown. Malignant transformation of these cells in eultuire has been produced by adding carcinogens to these cultures. In addition, injection of carcinogens into the veins of mice and rats, as well as inhalation and oral ingestion of carcinogens in these animals have produced brain tumors. The latent period between giving these carcin ogens and the appearance of the brain tumors has been about 200 days, a relatively long period in the life span of these animals. These latency periods of 200 days correspond to the proposed latency period of 20 to 40 years for~numan Drain tUfltors. In other words, investig ate rs-\vHoniave*^oun^_an--associatTon~He^ween chemical exposure and the later development of brain tumors in humans postulate a 20 to 40 year latent period before these tumors develop. A number of chemical compounds have produced brain tumors in rats when given by the oral, nasal or intravenous route. Also brain tumors have appeared in the offspring of pregnant rats given these agents during pregnancy. These experimental methods have been used to deter mine what compounds are carcinogenic in rats. The brain tumors which occur in experimental animals, particularly the rat, resemble the brain tumors that are found in humans. Dr. Harry Zimmerman, over the last 30 years, has implanted carcinogens in various parts of the brain and has produced malignant gliomas resembling those of humans. In his experiments, the type of malignant glioma or glioma produced depended to a great extent on the area where the pellet was placed. The con clusion drawn from these experiments are that carcinogens can produce tumors in the brain in experimental animals, thatthese tumors arise from the normal glial cells, and that these tumors are produced in the same way that human tumors are produced by malignant transformation of glial cells. It is now well known that carcinogens or cancer-producing chemicals can produce tumors in experimental animals. What evidence do we have that these chemicals can produce malignant tumors in the brains of humans? The first suggestion that exposure to chemicals could lead to brain tumors in humans was in 1949 when Dr. Thomas F. Mancuso suggested an association of malignant neoplasms of the brain and central nervous system with the rubber industry. In April B82, a symposium was held at the New York Academy'of Sciences f and'a number of investigators presented their data concerning the relationship of the various chem ical exposures to the development of brain tumors. Dr. Mancuso presented figures from rubber workers in Summit County, Ohio, and found an approx imately double incidence of brain tumors in those working in the rubber industry. Reeve presented data from union employees at _the_ Texas City, Texas refinery m which the incidence of brain cancers was"lncreased.' In Dow Chemical workers in Texas, Reeve .found a 2h times expected number of brain tumors. Alexander presented <iata from petrochemical pTaht' in Texas City, Texas, in which there were about twice as many deaths as expected, and Thomas studied unionized employees in oil retineries in petrochemical plants in Texas and again found a slightly greater than twice the expected number of brain cancers. There were several studies performed by industry investigators that did not find JLncrease in ex pected Incidence Of brain tumors in chemical arid petroleum refinery workers, xnese papers were criticized in the conference for including worTcers in the industry who were not exposed to chemicals, possibly diluting out the chemically induced brain tumors. In the same meeting, Nicholson studied chemical and petrochemical engineers in Texas and OLI 6465 -3- Louisiana. They found ten brain tumors in operating engineers in chemical plants as opposed to 3.12 expected. Englund, in Sweden, found rubber industry workers to have a slight but definite increase of brain tumors, while Olin, studying chemists in Sweden, found five brain tumors vs 1.2 expected. Other studies have been published which indicate that rubber in dustry workers have an increased incidence of brain tumors and also agricultural workers exposed to chemicals have an increased incidence of brain tumors. In addition, Waxweiler studied employees exposed to vinyl chloride in four plants of the United States, and found three brain tumors vs 0.9 expected. The concensus of the conference was that the number of studies correlating exposJTfe to chemicals' in Ihe dBfelftifcal, petrochemical, oil refinery and rubber Industries indlcatea tnat there wa'ia u reul u*y6ciAtion between exposure to these chemicals and the devetopmynt Uf 'biaifl tuiiwisl particularly aliohl astnma multi forme or malignant astrocytoma. These latter two terms are synonymous. Mal ignant astrocytomas are the same as glioblastoma multiforme. Reviewing all the data on association between exposure to chem icals in humans and the animal data with carcinogen production of brain tumors in rats, it is my opinion that there is a strong probab ility that the brain tumors which developed in Mr. Ozolins, Dr. Ard is and Mr. Karobinos were related to the many chemicals that they were exposed to in their work for the Olin Chemical Company. I hope that this information is sufficient for your purposes. If it is necessary, I could further amplify on the data obtained in the numerous studies published in the literature on the relationship between brain tumors and industrial exposure in the United States and Sweden. I could also go into greater details of the production and means of production of brain .tumors in rats. Sincerely yours ESG/mlk Edward S. Greenwald, M.D OLI 6466