Tobacco Documents Online

C MEMORANDUM TO: W. T. Hoyt CC: WDH RFG SCS RCH FROM: Leonard-.S. Zahn SUBJECT: British Association for Cancer Research, Annual Meeting, York, March 23'-25, 1983 e A few bits of interesting information, one relating to the rain, rain, rain. The meeting featured a symposium on - environmental carcinogenesis during which an American scientist, producing an agent that affects "innocent" .were offered at this well-attended meeting that took place in typical British weather: hypothesis that macrophages may indirectly cause cancer by FRED F. KADLUBAR, Jefferson, AR, talked about carcinogenic aromatic amines 'in cigarette smoke and elsewhere.: . Physicians Radio Network of New,York,.,.which broadcasts to doctors A science writer based in Dublin covered the meeting for only in certain cities. The writer indicated he'd also submit some articles to various print media in the U.S. The highlights: 1. "Genetic damage initiated in somatic cells by oxygen-derived radicals produced by normal metabolic reactions" -- B.J. PHILLIPS, Carshalton, Surrey, England. Oxygen-derived radicals have been implicated in chemical carcinogenesis and tumor protion (and in the mechanisms of certain anticancer agents), Phillips said. Active forms of oxygen have been shown to be genotoxic -- they cause damage to cellular DNA. A lot of active oxygen~species can be generated by many normal body processes. Phagocytic cells such as macrophages, when activated by a foreign compound, produce superoxide, an oxygen radical that is "pushed into" the cellular liquid where it's converted to hydrogen peroxide. Thus, it may be that chronic stimulation of phagocytic cells by particles, "perhaps even asbestos, could lead to chronic production of superoxide and subsequent genetic damage to "innocent cells" in the neighborhood. Phillips is testing this theory in cultures of Chinese hamster ovary cells and, peritoneal macrophages. Nothing happens to the hamster cells when they alone are treated with phorbol myristate acetate (PMA, a potent stimulator),. But when PMA-treated peritoneal macrophages are in the same culture as the hamster cells, the macrophages produce oxygen radicals to cause eonard aL __ PUBLIC fiELATIONSCOUNSEL anf ~d~A~ssaciates,InG 13'LINCOLN ROAD •P.O. BOX 223 •GREAT NECK, N.Y. 11022 •(516)482-5715

genetic damage. 2. C Hie has done one experiment "which tenids to support the idea that macrophages_are carcinogenic," Phillips said, but there's still a long way to go. The macrophages do not produce only superoxide and'they do interfere with the division of other adjacent cells in a complex manner. However, "the results look fairly promising." ~ PMA has been shown to induce superoxide production in cells other than macrophages, and this may be a mechanism of tumor production, he said, He seemed to be half-jesting in his conclusion: One shouldn't trust a genetic toxicologist. He (,or she) can find that almost anything is mutagenic or carcinogenic, including macrophages. adduct formation and methods for adduct detection" -- KADLUBAR, a 2. "Aromatic amines and nitroaromatic hydrocarbons as environmental carcinogens: metabolic activation, carcinogen-DNA scientist at the National Center for Toxicological Research, carcinogenic aromatic amines and nitroaromatic hydrocarbons that are widely distributed in the environment. His focus is on their detection and how they operate in the body. delivered a.lengthy, h-ighl'y technicall paper.on his work on - They are found in cigarette smoke, diesel engine exhaust, effluents of coal oil and shale oil, and particles in polluted air. They also are present in specific chemicals such as vinly chloride, in certain metal compounds,in asbestos and in cooked foods (as pyrolisates of amino acids).. A number of aromatic amines have been found~in cigarette smoke, among themithree "known" bladder carcinogens: _ 4-aminobiphenyl, 2-naphthylamine and ortho-toluidine. There's considerable variability between cigarette brands in the amounts of the amines. In general, however, the amounts seem to be related to the concentrations of both protein and nitrate in the tobacco. This is consistent with the hypothiesis that aromatic amines are formed by ammoniationiof pyrolized protein in the burning ember of the cigarette. And it's further supported by the presence of much higher amounts of amines in sidestreamismoke, which contains much more ammonium Further, Kodlubar continued, the presence of carcinogenic aromatic amines in cigarette smoke is consistent with a number of epidiemiologic studies that have indicated an increased incidence of bladder cancer in smokers. Kodlubar went on to discuss _other sources of the amines and nitroaromatics and to review what's known or hypothesized about their metabolic activation pathways. Limited tests show that one substance isolated from airborne particles, 1-nitrosopyrene, is a potent mammary carcinogen in rats and that another,. 6-nitrosopyrene, induces lung tumors in newborn mice.

3. ( He said he's working on a technique he hopes will measure the presence of carcinogenic DNA adducts in exposed populations. The technique, a modificatiomof a method reported by others, involves carcinogen-modified' DNA. 3. T.M. SORAHAN, Birmingham, England, reported a further analysis of a study, published in 1967, that found a statistically significant excess of cancer of the prostate in workers in a nickec,.l-cadmium battery factory. Information on the workers was updated to January 1981 and thenisubjected to a variety of statistical configurations and analyses that led Sorahan to conclude: No new evidence has been provided which suggests an association between occupational exposure to cadmium oxide (hydroxide) dust and cancer of the prosta te. 4. A study by SUZANNE ECCLES, Sutton, Surrey, indicated that retinoids (Vitamin A analogs) had an inhibitory effect on the growth and metastasis of murine sarcomas and carcinomas. The study covered both cell culture and whole animal tests, and Eccles concluded that the retinoid effects were due to stimuLation of host antitumor effector cells, possibly monionuclear phagocytes." 5. MANFRED RAJEWSKY, Essen, West Germany, described'his method of detecting and quantifying specific carcinogen-DNA adducts in mammalian cells by high-affinity monoclonal antibodies. The technique employs a computer-based image analysis. and he said it's now possible to monitor cells from biopsy material for the presence of the DNA adducts as well as for their capacity to enzymaticaliy remove the,adducts from the DNA prior to DNA repair. 6. A major lecture by JAMES A. MILLER, Madison, WI, was mostly a review of his research on naturally occurring carcinogens with emphasis on ethyl carbamate (or urethan, a drug once widely used to treat certainileultemias) and' two spice flavors, safrole and estragole. As with synthetic carcinogens, he said, most of the nat urally occurring carcinogens require conversion into ultimate carcinogens. -END-

RECE1VED MAY - 2 1983 BE. DUBBS