Document bwEVkRkDD0eXNmO5Lg9o0Q2D

FMC Corporation 2000 Market Street Philadelphia Pennsylvania 19103 (215)299 6000 December 17, 1982 U- c* c- FMC Gregory R. Gorrell, Esq. Jackson, Kelly, Holt & O'Farrell P.O. Box 553 Charleston, West Virginia 25322 Deceived 0C 2 u M2 Robert A. Butler, Esq. Union Carbide Corporation Old Ridgebury Road Danbury, Connecticut 06817 , i/ Gary J. Triplett, Esq. Union Carbide Corporation 437 MacCorkle Avenue, S.W. South Charleston/ West Virginia 25303 ir. tsr<- / r ^ Gentlemen: Enclosed for your information please find the brief memorandum on liver cancer prepared by FMC1s Toxicology Department, which Hal Russell mentioned at yesterday's meeting. Naturally, we would appreciate receiving any information on this subject which you have at your disposal. We enjoyed meeting with you and look forward to a successful working relationship. Yours/very truly. Kenneth N. Klass Counsel KNK/arod cc: H.S.Russell D.C.Landgraf PRIVILEGED AND "CONFIDENTIAL MATERIAL SUBJECT TO PROTECTIVE ORDER" UCC 098112 J^rvTVp Chemical Research and Daveloprr.ent Center n_rLN-AJvbi Princeton Interoffice To Fletcher, MJ From Subject Rand, GM Liver Cancer Date December 10/ 1982 cc Nor veil, MJ Primary liver cell cancer is relatively uncommon in Europe and North America but in certain areas of the world, particularly where the population density is high, such as China, Africa, the Phillipines and Taiwan it is the most common form of cancer. The observed differences in the geographic distribution of primary liver cancer point to the importance of environmental factors. The frequent association of primary liver cancer with cirrhosis, a feature noted in most studies, points to the role of pronounced, repeated, prolonged or continuous liver cell injury. However, the results of animal experiments also indicate that carcinogenicity may be influenced by the dose, rate of administration and the age, sex and nutritional status of the animal, the species and other secondary factors. Liver cancer cannot be spoken of as if it were a single entity. Many kinds of tumors arise in human livers that are etiologically, epidemiologically and pathologically quite different. Precursor lesions in human liver cancer include most forms of chronic liver disease, the most common morphological expression of which is cirrhosis. The most prevalent type of liver cancer is primary hepatocellular carcinoma (PHC) or primary liver cell carcinoma which arises from hepatocytes (liver cells). The second most common type of primary liver cancer is the bile duct carcinoma or primary cholangiocellular carcinoma. Primary tumors may also be sarcomas arising from nonepithelial tissues in the livers. The process of malignant transformation is probably a-multistep phenomenon including sequential changes in hepatocyte populations, each of which is further removed from the normal than its predecessor. Cancer of the liver can be induced in animals by a large variety of chemicals (Table 1). Aflatoxins are the most potent liver carcinogens. They are the only compounds on this list that have been linked with a high incidence of liver cancer in humans but mainly in Africa. Doses on the order of a few parts per billion produce liver cancers in susceptible animals and even single doses produce cancers in rats 1 year after ingestion. However, there are marked differences in susceptibility among animal species, and continuous feeding for six years is required to produce unequivocal tumors in monkeys. UCC 098113 70-3 Fletcher, MJ December 10, 1982 The latency period of aflatoxin induced liver cancer in the human population of Africa is unkown, but the relative risk is 1.3. A summary of information on aflatoxin ingestion and liver cancer incidence in different countries of Africa is presented in Table 2. it can be seen that aflatoxin ingestion varied over a range of values from 3-5 to 222 ng/kg body weight per day. Estimated liver cancer incidence values ranged from a minimum of 1.0 to a maximum of 35.0 cases per 100,000 people per year. There was a positive correlation between the 2 parameters, in that high intake values were consistently associated with high incidence rates. The only organic agent which is positive in both animal studies (rats) and which also induces liver cancer (angiosarcoma) in humans (occupational exposure - plastic workers) is vinyl chloride monomer. The latency period is 12 - 29 years but the full potential risk of cancer has not yet been established. See Table 3 for additional information. The epidemiology literature also indicates that occupational exposure to arsenic (and related compounds) may also induce liver cancer but the details have not been completely clarified. The problem in this area is the complete absence of a valid biological model for experimental arsenic-induced cancer. The overall human frequency of liver cell carcinoma in various parts of the world may differ by as much as hundred fold, in Europe and the U.S. the frequency varies from 0.1% to 0.7% of all autopsies. In portions of Southeast Asia, there is a high frequency of carcinoma of the liver that includes both liver cell carcinoma and bile duct carcinoma, while the incidence of carcinoma of the liver is low, usually between 4% - 6% of patients with cirrhosis eventually develop a carcinoma of the liver. This contrasts with some areas in Africa where the frequency is about 40% of all men with cirrhosis. Carcinoma of the liver may occur in infancy and childhood, especially in male infants before the age of 2 years. Among adults, the disease is seen most often in men between the ages of 40 and 60 years in Europe and the United States, whereas in Africa the average is nearer 30 years of age. Carcinoma rarely arises in the absence of cirrhosis, but when it does, females are affected as often as males and they usually live less than 6 months. GHRsljl Table 1 Liver Carcinogens in Animals Naturally Occurring Compounds Mycotoxins Af latoxin Cyclochlorotine Luteoskyrin S terigmatocystin Pyrrolizidine alkaloids Isatidine Lasiocarpine Monocrotaline Retrorsine Cycasin Safrole Tannic Acid Synthetic Compounds Nitrosamine and nitrosamides Chlorinated Hydrocarbons Or ganochlorines Polychlorinated biphenyls Carbon Tetrachloride Chloroform TABLE 2 Summary of Current Evidence on Aflatoxin Ingestion and Liver Cancer Incidence Liver cancel Population Dietary aflatoxin intake (ng/kg/day) In adults (>15 yr) Men Women In total population (both sexes) No* Incidence^ No. Incidence No. Incidence Kenya (high altitude) 3-5 1 3.1 0 0 Thailand (Songkhla) 5-8 - - - - 2 2.0 Swaziland (highveld) 5-9 9 7.1 2 1.4 Kenya (medium altitude) 6-8 13 10.8 6 3.3 Kenya (low altitude) 10-15 16 12.9 9 5.4 Swaziland (middleveld) 8-15 24 14.8 5 2.2 Swaziland (Lebombo) 15-20 4 18.7 0 0 Thailand (Ratburi) 45-77 -- -- -- -- 6 6.0 Swaziland (lowveld) 43-54 35 26.7 7 5.6 Mozambique 222 - 35.0 - 15.7 25.4 "Periods covered were 1 yr in Thailand, 3 yr in Mozambique, and 4 yr each in Kenya and Swaziland. ^Number of cases in study population. cNumber of cases per 1001)00 population per year. UCC 098115 TABLE 3 Excels Cancers Attributable to Occupational Chemical substance Target organ NIOSH estimate of worker population' Incidence per 100,000 U.S. males6 Incidence per 100,000 U.S. males >40 yr old' Risk factor'* Rid: factor (100-fold decrease) Asbestos Lung, pleural and peritoneal mesothethim Arsenic Lung Benzene Blood Chromium Lung Coal tar pitch Lung volatiles and coke oven emissions Iron oxide Lung Nickel Lung Vinyl chloride Liver 5,000,000 1,500,000 2,000,000 150,000 60,000 100,000 50,000 20,000 72.1 72.1 12.7 72.1 72.1 72.1 72.1 0.02 194.3 194.1 27.7 194.3 194.3 12 1.12 8 1.08 3 1.03 40 1.4 6 1.06 194.3 5 1.05 194.3 10 1.10 0.02 400 4 -uniin \i7jn;. nnn n c `'Average annual age-adjusted (1970 U.S. census) incidence rate per 100,000 L-S. males (DHEW, 197S). d o o o SO 00 Os Exposures to Certain Chemical Substances at Different Levels of Risk Expected no. cases of cancer per year in workers >40 yr old Predicted no. cases of cancer per year if ail workers {>40 yr ok!) at highest risk Predicted no. cases of cancer per year if all workers 040 yr old) at reduced risk (i.e., 100-fold decrease) Predicted no. excess cases of cancer per year in workers >40 yr old at highest risk Predicted no. excess cases of cancer per year in workers >40 yr old at re duced risk (i.e., 100-fold decrease) 3530.9 42,370.8 3,954.6 38,839.9 423.7 1059.3 201.3 113 42.4 8,474.1 603.9 4,520 254.4 1,144 207.3 158.2 44.9 7,414.8 406.6 4,407 212 84.7 6 45.2 2.5 70.6 35.3 Negligible 353 353 1.5 74.1 38.8 Negligible 282.4 317.7 1.5 3.5 3.5 Negligible 'Average annual age-adjusted (1970 U.S. census) incidence rate per 100 000 U S males (>40 yr of age) (DHEW, 197S). ^Highest published risk data (Cole and Goldman, 1975).