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T0: W. T. Hoyt FROM: Leonard-S. Zahn~ CC: WDH RFG SCS RCH SUBJECT: Congress of European Society of Toxicology, Rome, March 28-30, 1983. There were several presentations on cadmium at this meeting, one dealing with its presence in the blood of smokers. One might consider this of statistical significance because there were only about 50 oral presentations, about half the number of poster pre- senitations. However, there clearly was no indication that the organizers had sought to place any special emphasis on studies dealing with the health effects of this metallic chemical. regard to the poten'tial toxicity of air pollutants other than a The meeting itself had the mix one expects at such sessions, with a noticeable exception: virtually nothing,was reported in -- passing mention. coverage, as far as could be determined. three other countries elsewhere in the world. There was no press participants (most of whom were Italians) representing,pharma- ceutical companies. Scientists were there from 19 European and Attendance was quite good, between 550-600, with many of the The highlights: 1. "Effect of smoking on cadmium and lead blood level's"' -- G. ORSSAUD', Paris. This poster presentation, noting that lead and cadmiumiseem to be involved inivarious ailments, reported a study of the "sources" of these metals different from occupational settings. The subjiect population consisted of 440 healthy French civil service workers aged 2'4-55 and without occupational exposure. Their smoking habits were determined by questionnaire and mea- suremenits were made of blood levels of cadmium, lead and carboxy- hemoglobin. Smokers' levels of cadmium and lead were significantly higher than those of nonsmokers. The increase in smokers vs. non- smokers wa's higher for caftium'than for lead. Smokers who inhaled (deeply, apparently) had higher cadmium levels than nonsmokers, but no effect was seen onilead levels. . eonard a L__ PUBLIC RELATIONS COUNSEL ' an,Gd~Assoc.iateslnc 13 LINCOLN'ROAD •P.O. BOX 223'•GREAT NECK, N:Y. 11022 •(516)482-5715 April 27, C 83 i

2. Orssaud and his colleagues also had data on the l'evels of the two substances in relation to how long subjects had stopped smoking. While the levels dropped as time passed, they still were muchihigher than~in nonsmokers. This could~ reflect the cumulative properties of the metals. Blood lead was strongly correlated with alcohol consumption and also with age; drinking, however, did not seem to affect cad- mium levels. ' The conclusion was that the relationship with smoking was stronger for cadmium than for lead. Tobacco seems to be the main source of cadmiumifor non-occupationally exposed persons. 2. "Epidemiological and experimental evidence on the pul- monary carcinogenicity of inorganic arsenic with special ref- erence to interacting factors" -- GORAN'PERSHAGEN, Stockholm. Pershagen has done both epidemiologic and experimental studies on inorganic arsenic and its relationship to lung cancer. . L.,_ .. , ~.. _.. .- .~,:i . .., ~.:,~ 1.-.e.. . .. ,... ~.. .., .._. . _i;~:.i:-S...-t. ..:.~Z . .... . . Epidemiology: A case-control study was done of 228 deceased workers at a copper smelter in northern Sweden; 76 of the workers had died~of lung cancer, according to their death certificates. Information about smoking habits of these individuals was ob- tained in personal interviews with next of kin. (Arsenic is emitted during copper smelting.) Pershagen computed an age standardized rate ratio for death from lung cancer and reported these figures: the rate ratio was 3.0 for arsenic-exposed nonsmokers, 4.9 for smokers without ar- senic exposure, and 14.6 for arsenic-exposed smokers. This, he said, indicates a multiplicative, rather than an additive, effect of arsenic exposure and smoking. Experimental Research: Arsenic trioxide, the most common arsenic compound found in smelters but not a very strong car- cinogen (according to Pershagen), was tested in hamsters via intratracheal instillation. There were 3 lung cancers in 47 animals treated with the arsenic and none in 104 controls. There also was an increased incidence of pulmonary adenomas, papillomas and adenomatoid lesions in the arsenic-exposed animals.(About 20% of the animals lived~more than two years; the oldest more than 30 months.) Othier animals also were exposed' either to a combination of arsenic trioxide and~benzo(a)'pyrene (BP) or BP alone. Tumor in- duction by both was about the same. This finding doesn't support the hypothesis that the multiplicative interaction between occu- pational arsenic exposure and smoking in the epidemiologic study was due to an interaction between arsenic and BP. Other factors may be of importance, e.g., the promoting action of tobacco smoke and a higher retention of arsenic inithe lungs of smokers because of impaired lung clearance.

3. The research provides strong evidence that arsenic trioxide can cause lung cancer, Pershagen said. The finding of a positive interaction between arsenic and BP in relation to ad!enomatous lung tumors suggtsts that there may be an important synergistic reaction between arsenic and tobacco smoking in occupationally exposed~individuals. Pershagen, who also conducted some inhalation~experiments to determine lung retention of arsenic, did point out that the use of charcoal carbon as a carrier dust in the instillation tests may have been of importance; he did not explain this further. He also mentioned that sulfuric acid was used in another aspect of the animal work and'indicated this may have affected the results. 3. In a poster presentation, BENGT'R.G. DANIELSSON, Uppsala, Sweden, summarized a number of experimental studies dealing with the toxic effects of certain metals on male reproductive organs. He cited a 1956 animal study that reported cadmium may cause complete testicular necrosis. More recent work on cadmium has. found a possible adverse effect.on sperm-producing tissue. Other animal tests have reported that arsenic accumulates in seminal ducts, indicating that semen is exposed' to it for a long period of time with potential adverse effects. 4. ALAIN DUBREUIL, Chatenay-Malabry, France, had a poster describing research with nickel chloride on an epithelial cell line (A 549) of human lung origin and believed derived from type II alveolar cells. The work is continuing in an effort to d'eter- mine dose response data. The most significant result to date is the effect of the nickel on the growth rate of the cells. 5. D. GERMANO, Messina, Italy, in a poster presentation, reported that cadmium alters arterial baroreflex (pressure re- flex) control of heart rate in rats. The work was undertaken be- cause of research claiming that cadmium exposure produced chronic hypertension in experimental animals. Germano used cadmium chlor- ide in his tests and said that while it alters control of heart rate, there's no evidence it's related to the induction of hyper- tension. 6. DENNIS V. PARKE, Guildford,, England, talked about active metabolites in toxicology, particularly the roles of the differ- ent "species" of cytochromes P-450 and P-448. The former, he noted, is primarily coniecerned~ with detoxication and its highest activity occurs in the liver. The latter is not concerned mainly with detoxication but probably with endogenouls metabolism and biosynthesis:oS steroid, hormones; they do, however, metabolize foreign chemicals and when they do, they tend to activate them. ~ i i - j He said' there's.been considerable work showing that P-448 has a much greater ability than P-450 to reduce the reactive intermediates of carcinogens and other toxicants. Many more polly- cyclic aromatic hydrocarbons, polyamines and other toxic chlem- icals are activated by P-448'than by P-450.There's increasing.

evidence that both cytochromes are present in the same tissues. 7. M.B. ROBERFROID, Brussels, spoke on the formation of free radicals as a me~hanism of chemical toxicity. His was chiefly a review presentationlin which he noted that bothithe production, and biochemical effects of free radicalis might be involved in carcinogenesis either at the initiation or promotion step. The concept of "rad1cophily" has recently been developed, he said, and the possibility now exists that artificial radicophiilic substances could be used to protect cells from the carcinogenic activity of free radicals. (A radicophile reportedly traps free radicals and produces a stabilized radical that ca:niform:a com- pound from the combination of two identical molecules. In other words, the free radical is neutralized.) (Roberfroid's presence at the meeting,was unexpected; he'd been scheduled to speak at the Tobacco and Cancer symposium in Brussels two days before, but did not appear because of a reportedlilliness.) -END- RECEIVED MAr - 2 1983 E. DUi3BS