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MEMORANDUM TO: W. T. Hoyt FROM: Hilda 2ahn SUBJECT: International Conference on Environment and Lung Disease, Taormina, Sicily, March 22-27, 1983 + 1983 CC : WDH' SCS RFG R C H! Scientists from many disciplines -- pulmonary medicine, epi- d~emioliogy, chemistry, meteorology, heart disease, climatology, pub lic health, etc. -- were on hand to give an overview of the perils of pollution. Statues, buildings and the lungs of man are its ma- jor victims, the combustion engine and industrial dusts the major pollutants. A relationship between chronic bronchitis and poll!u-', tion, the subject of numerous papers, was pretty well accepted,but for lung cancer_the culprit was cigarette smoking. Italian scientists. elementary -level and ~frequently cited ,data;; mostly from U.S. studies, that were fairly old. Most of the papers were given by Many of the more than 325 scheduled presentations were on an Child~ren there are starting-:to smoke as early as age five, and doctors were criticized for doing,little or nothing about it.. (Indeed, many at the meeting were smokers and made no effort to conceal it.) There were, however, a few papers on antismoking campai~gns in some areas of Italy. A symposium on active and passive smoking presented some affirmation of the negative effects of passive smoking. A British scientist exonerated carbon monoxide in tobacco smoke as a factor in heart disease and chronic airflow obstruction. Smoking itself is decried by virtually everyone, the symposium~chairman said, but there's no real fight'against the custom, at least not in Italy. against smoking at a session on chronic obstructive lung disease. He strongly, and specifically, warned against smoking by women because, in his experience, most of them can't or won't quit. J.W. LEMOINE of Fontainebleau, France, delivered a tirade Two drugs, Ambroxol and N-acetylcysteine, were credited in a few papers with decreasing excess mucus in~the respiratory tract reportedly caused by smoking. One speaker mentioned that the World Heal!th Organization has organizedia group to do a study on the "microcliimate." For a foreigner in Taorminia,,the conference was frustrating, O W interminable and hilarious -- and often all' at the same time. Ses- ~ sions started at 8 a.m. and ended at 10:30 p.m. (or later). It was G3- not uncommon for time slots to be shifted without advance warning. ~ ~ eonard Jzahn andAs RUBLIC RELATIONS COUNSELi soriates;lnc. 13 LINCOLN ROAD •P.O: BOX 223 •GREAT NECK, N.Y. 11022 •(516)482-5715

2. If all the speakers had showed up, I'd still be there. Luckily, the organizers raniout of money tolpay transportation costs for a number of invited scientists and translators; unluckily, this meant that about a third of the sessions went untranslated. Most of the participants were Italian, so this wasn't a serious problem for themi. But it was for many among the approximately 650 regis- trants from about two dozen countries around the world. Even the translators were harried because they didn't get texts to trans- late, and they could hardly cope with the breakneck speed of many presentations. Ther'efore, while some of the data in the following summary may be lacking, the conclusions are not. The highlights: 1. At a session on,active and passive smoking: A. "Is the carbon monoxide (CO) in cigarette smoke associated with chronic airflow obstruction or ischemic heart disease?" -- C.D.R. BORLAND, Cambridge, England. The so-called Whitehall Study, done in England in the late 1960s, : covered . some.-18, 000 male,' `civil.-servants aged' 40-64 of whom 7,270 were smokers. Since then, researchers have determined~the CO content of the cigarettes smoked by the study population. Borland reexamined the Whitehall data for indications of an association between the smokers' CO exposure, their mortality from heart disease and the severity of chronic airflow obstruction. He found that the higher the CO yield of a cigarette, the better the subjects' forced expiratory volume in one second (FEV-1, a: measurement of pulmonary function), though the figures weren't significant. The relative risk for heart disease fell as the CO level rose, though this effect also was not considered significant. - . FEV-1 was significantly reduced the longer one smoked. High nicotine content also impaired airflow, according to the data. "Our results from this epiderniological study are against CO having a role in coronary heart disease and against CO having,a role in chronic airflow obstruction. We must look harder, there- fore, for the ingredient responsible. We would not recommend that the manufacturers start producing lower CO-yielding cigarettes because there's no guarantee that they may be any safer." B. "Polycyclic aromatic hydrocarbons (PAHs) and heavy metals in the environment: syngenesis - synoccurrence-syncarcinogenesis?" -- G. MULLER, Heidelberg, West Germany. Muller, a geologist, explained that coal combustioniproduces very high atmospheric concentrations of both PAHs (including benzo(a)pyrene, BaP) and heavy metals, including highly toxiic cadmium. These compounds also accumulate in the soil and sediments 0

3: of all bodies of water because of their high insolubility. He estimated that worldwide, 5,000 tons of BaP are emitted annually by coal combustion. The more coal burned, the higher the cadmium concentrations become because BaP and the metal are pro- duced in parallel proportions. Cigarette smoke also produces a combination of BaP and cadmium. Cadmium as a primary or cocarcinogen was recently substan- tiated in West Germany (at Schmallenberg), Muller said. It was found that 71% of Wistar rats exposed to cadmium chloride aerosols for 18 months developed primary lung cancers. Liver and kidney cancers were also increased. - The cadmium concentrations of cigarette tobacco depends,on the soil on which it is grown. Industrialized countries raise tobacco that is heavily enriched with cadmium. Africa, Sri Lanka and China have tobaccos with low levels. European soils resuLt in tobaccos with cadmium concentrtions 10 or 20 times higher than`any other vegetable found in nature. Even if levels are low in the soil, such as in Ontario,tobacco leaves seem to take up cadmium from the air. Muller said that in the past he asked~ the tobacco industry to use tobacco with the lowest possible level of cadmium in order to prevent the induction of cancer. C. "Passive smoking in the home: a risk factor for airway obstruction in adults" -- J.F. TESSIER, Bordeaux, France. Data were presented from~a cooperative French study on the long-term effects of passive smoking that encompasses 23,000 sub- jects in seven cities. (The study is called PAARC, for atmospheric polilution~and chronic respiratory infection.) Adults aged 40 or, over, with or without passive smoking,exposure, were evaluated. It was found that nonsmokers of both sexes, living with those who smoked less than 10 grams of tobacco daily, had an FEV-1 , significantly lower than those married to nonsmokers. This dif- ference wasn't explained by professional or educational status, size of the family or atmospheric pollution. . A dose-response relationship was shown for FEV'-1 and exposure to passive smoke. Tessier noted that the respiratory function of female smokers was better than that of male smokers. She added that a spouse has a right to ask his or her partner to stop smoking. D. "Ambient smoke: effects 'in albino rat fetuses" -- M. MARINO, Naples. Experiments were done with pregnant albino rats and controls to test for the effects of ambient smoke, not direct inhalation. The rats were sacrificed after exposure and the fetuses were re-

S 4. moved for study. The fetuses from smoke-exposed mothers showed signs of imma- ature development and motor disturbances and they also weighed less than norma3.. There was a: large percentage of fetal resorption but a less dramatic placental weight loss in the fetuses fromi exposed animals. E. "Dim!ethylnitrosamine (,DMN): a: test for the risk of lung cancer from smokirig" -- F. ORECCHIO:, Rome. This confused report dealt with DMN which, Orecchio said, was present in cigarette smoke and is related to the develiopment of lung cancer. DMN also is found elsewhere in the environment. He had some rather fractionated and abstruse data of enzyme measurements he's trying to use as a test of susceptibility to lung cancer in smokers and nonsmokers. His data, based on120 subjiects who apparently were hospital patients, showed that half of those who were smokers (number not givenY had no enzymatic activity; the nonsmokers had fairly high levels. Enzymatic activi:ty:measur.ements'in.smoker,s:;,a.nd",;n.onsmokers may indicate their susceptibility to:lulng cancer in terms of exposure to cigarette smoke, he saild. F. "Smoking, chronic bronchitis and environmental factors" -- V. NITTI, Naples. An epidiemioliog,ical study done in Naples a few years ago was reported. It dealt with the occurrence of bronchitis among smokers and nonsmokers in various occupations. Smoking nurses and doctors in a hospital setting had a 23'% incidence of bronchitis; other hospital personnel who smoked had a 31% incidence. The trend was similar for both sexes. Police officers who smoked had a 21% rate, foundry workers a 40% rate and white collar workers a 23% rate. The heaviest smokers showedithe most lung,deterioration whether exhibiting symptoms or not. G. "Preliminary results of an epidemiological study of the tobacco habits of Algerian!doctors at home" -- D. LARBAOUI, Algiers. The Medical Association of Algeria mailed questi~onniaires to members asking about their smoking habits. Reply rate was 480. The responses showed: For males, 42% currently smoke, 43% are nonsmokers, 15% are ex-smokers.~For females, more than 85%o are ~ nonsmokers, 8% are ex-smokers, 7°k currently smoke. .~ Filtered cigarettes are used by 95% of the smokers, the w majority of whom are from 31-50 years of age. Most of the ex- ~ smokers are over 50. Respiratory impairment (coughing, shortness (Y) . C,0

s ~ 5. C of breath) was reported by 46% of the smokers, 25° of the ex- smokers and 5% of the nonsmokers. H. "Respi-ratory carcinogenesis from smoking" -- G. PESCETTI, Turin, Italy. Tobacco contains more than 1,000 carcinogeniic substances, so it's no surprise that 1 out of 8 heavy smokers develops a pulmo- nary neoplasia during his or her life. Though enzyme inducibility depends on a number of variables, individuals with lung cancer have great enzymatic activity. There also seems to be a genetic factor in lung cancer. I. "The role of smoking in the genesis of destructive pul- monary disease" -- G. L. SCARPA, Sassari, Italy. Tobacco is the most potent carcinogenic agent in the world, Scarpa said in citing some old U.S. data. He discussed the role of tobacco in disrupting the balance between proteases and anti- proteases and the resultant loss of lung tissue. Experiments have shown;; that_,the. alveolar, macrophage,s.,,o,f smokers are different than those of nonsmokers, he said. Also, smokers have 30% less alpha- 1-antitrypsin than do nonsmokers. 2. "Drugs and mucociliary clearance. The effects of N-acetylcysteine (NAC)" -- T. TODISCO, Perugia. ' Cigarette smoking stops the flow of mucus in the lungs and impairs ciliary structure, he said. It decreases mucociliary clearance by about 30% and causes chromosomal damage and alveolar wall destruction. The integrity of alveolar macrophages recovers after cessa- tion of smoking, but the ciliary function doesn't. NAC could im- prove ciliary function. (NAC is used to reduce the viscosity of mucus and facilitate its removal.) (In another paper, Todisco reported finding that about 20qo of normal nonsmokers have slow mucociliary function.) 3. "The role of NAC in chronic bronchitis."' -- A. B'LASI,. Naples. Inian effort to change the course of chronic bronchitis, 495 subjects with the disease were treated with NAC. The drug was found to restore glutathione availability and prevent the most acute stages of the disease. (Glutathione is a respiratory carrier of oxygen.). NAC seems to protect against the effects of cigarette smoke and other pollutants, Blasi said. One could say that a smoker who takes NAC might be protected against chronic bronchitis. He sug- gested that perhaps the drug has even wider usage.

6. 4. "Clinical study of the effects of Ambroxol on lung function tests in cigarette smokers without other pulmonary diseases" -- P. C. CURTI, Sondalo, Italy. Cigarette smoke damages the small airways as particulates are deposited on alveolar surfactant and stimulate its production. After it was found that albino mice treated with Ambroxol produced less surfactant, 30 healthy smokers aged 39 or more were given 60 mg of the drug twice daily for a monthi. Sputum was col- lected daily and examined. Curti said the treatment caused an improvement in some pul- monary functions and that carboxyhemoglobiniwas reduced signi- ficantly. He recommended cessation of.smoking but, failing that, Ambroxol will be of help. Ambroxol, produced by drug companies in Italy and Germany, has been used in Europe for the last two years to control brbnchitic secretions and surfactanit production. It's a metabolite of bromhexine, which is used in expectorants and mucolytics. ....i'.i.... . ., . . , . . .;L., . -A. ..r~ ~ . ., < .., .. 'e.~~. .i . -a;L.a:~.: . . .. - . _ . . . . . . 5. "Alterations of the phagocytic activity of alveolar macrophages from contaminants in the air" -- E. POZZI, Pavia. The major damage from cigarette smoke is to alveolar macro- phages (AMs). Morphological changes occur leading to inhibition of the cells' phagocytic action, especially in heavy smokers. These changes occur more during acute, rather than chronic, exposure to smoke. Moderate to light smoking seems to stimulate AM activity. 6. "Mechanisms of response to inhaled pollutants in the respiratory tract" -- J.G. WIDDICOMBE, London. Inhaled pollutants can settle in various parts of the res- piratory tract from the nose to the alveoli. Their action depends on theiir nature, the damage they may do to the respiratory epi- thelium, and their possible penetration of the epitheliium. - Pollutants activate mucus secretion, change ciliary activity, stimulate macrophages and, if sufficiently severe, stimulate the production of substances that destroy epith.elial cells. The nervous system is also affected. Besides coughing and! sneezing, there can be changes in respiratory smooth muscle tone and in ventilation. Constriction of the bronchi and larynx also is seen. Widdicombe used cigarette,smoke blown into the larynx of a cat as an example of the body's reaction to pollutants. The cat QN1. stopped breathing for several seconds, he said. When it recovered,,j its breathing pattern was far slower than normal. He didn't say `W how long that lasted. ~ ~ N

7. 4 7~~C ~~,131-FIl;'MI' wie. C`f•o Cl.oc.?) 11 Most of the experiments were done in animals, he said, but *`bG". he's certain that the reactions are the same in humans. e0Ao-~, A ~, (.~L(, T 7. "Cardiopulmonary effects of occupational exposure to ~ solvents",-- DOMINGO AVIADO, Short Hills, NJ. S~~Y•_ Iinhaled organic solvents in and out of the workplace are re- sponsiible for mildito severe forms of cardiopulmonary disease, de- pending onidose.'Exposure to the solvents can cause bronchocon- stricticn, myocardial depression and cardiac arrhythmias. Absorption of most organic compounds causes central nervous system depression that could cause asphyxia from parallysis. Thils, too, would~depend on dosage. However, it must be recognized that when a worker is exposed to solvents and'develops cardiopulmonary disease, a causal rela- tionship cannot immediately be established unless other personal risk factors are known; the most important of these are use of alcohol anditobacco. Tolerance can develop to these, but hardly everr to solvents Solvents and outdoor pollutants have similar toxicological effects on the respiratory system; they also may act synergis- tically. Prevention of exposure to solvents isn't siimply. Most of them are found in household items. Preventing adverse effects may depend onimaking safe solvents. 8. "Byssinosis. Epi.demiologicaL and etiological studiles" -- M. AZEVEDO:„ Lisbon. . . A study of workers in three cottonimills in Portugal found that of 386 subjects reporting lower airway disease, 72 had bys- sinosis, 107 had chronic bronchitis, 94 had asthma, 58 had work- related complaints, and 55 had occasional: symptoms rellated to respiratory infections. Nearly two-thirds of the 72'with byssinosis were nonsmokers. Most of the smokers reported chronic cough and sputum production, as did nearly 31% of the nonsmokers. Nearly two-thi~rds of the chronic bronchitics were smokers. She concluded that bothibyssinosiis and chronic bronchitis in the workers were influenced by cottonidust exposure and smoking and not by other factors. - „ ;,,.. ,... . 9. "Prevalence study onachronac bronchi'ltis (CB) in Tuscany i~n two urbanipopuliat'ions: connection with air pollution and life- style" -- L.F. SIGNORINI, Florence, Italy. A prevalence study of CB was done in subjects who had lived for at least 10 years in a small, industrial, non-metropolitan area. There were two groups: 73:7 subjects exposed only tolcommon urban air pollution, and 600 subjects additionally exposed to r

8. '' cement dust pollutioni. Smoking was found to be a primary risk factor in both groups,, while alcohol and occupational exposure seemed to be additional factors that may act synergistilcally with smoking. The findings strongly suggested that the cement dust exposure of the second group also was a:potent factor relatedito CB. " 1.0. "Envlronmental factors influencing lung function in children" -- S. SPINACI, Turini. The healith effects of indoor and outdoor polluti~on levels in nearLy 2,400 children,aged 11 from two urban and one rural com- munity were evaluated by questionnaires and~seven lung function measurements. Lung function parameters tended to be significantly higher in liess polluted areas. There we•re:no differences for social class or i~ndoor pollution, but male children were found to be affected by their mothers" smoking _ ,. .. According to the data, outdoor pollution and passive smoking resulted~iin a smalli but significant decrease in lung function. 11'. "The risk of pulmonary tumors from ilonizimg radiation" Mi. DI PAOLA, Rome. Lung cancer can be caused by ionizing radiation though the effects may vary wi'th dosage. Lung cancer continues to be high in Hi~roshima andiNagasaki years after'the atomicbombs were dropped there:. Citizens above age 50 at the time of the explosions have the highest lung cancer rates; those under 35 years have little or no lung cancer. He citedithe high incidence of Lung cancer in uraniumiworkers in the U.S. and Yugoslavia:and the synergi1stic effects of ciga- rette smoke. The highest lung cancer rates in Italy are found in the northern provinces around Cremona and Ferrara where there's a great deal of fog (not further explaimedi). Cancer is multifactoriali, Dii Paola said',, and'it's impossible to say what specific agent is responsible. WyA ~s ai~Mluxw~, 12. "Cytotoxic and'co-mutagenic effects of asbestos in ce1L ~lea 0(II7 culiture" -- B. REISS, Valhallia, NY (American Health Foundation,). ~', Reiss said she's developed an assay for the cytoxicity of yi A&s ti asbestos fibers that is an improvement over previous methods. ~,16 ~ Using her test, she found that chrysotile was.more cytoxic than: ` I`,t. tha amn~citanr t~rnt~iAnlit.o flnrms nf Achastns_ A't l_ ' ~ ~~~~~ ZZS..- (. /-.l Though asbestos,is very cytotoxic, she said, it's not muta- genic. Yet, when chrysotile is added to celil cultures containing, BaP, which is very mutagenic, there's,a synergistic effect. The asbestos functions as a cocarcinogen. It doesn't itself affect the f*4 416- t

9. \. DNA, but it helps substances like BaP act more quickly. than the general population," she said. "Those who smoke have a 100 times greater incidence." "Asbestos workers have a 10 times higher incidence of.cancer 13. "Genetic toxicoliogy of airborne chemicals and complex mixtures with emphasis on human health hazards" -- M.D. WATERS, Chapel Hill, NC. , various bioassays and epidemiologic data. explained the genetic toxicology of knownior suspected human res- piratory tract carcinogens and then evaluated them by means of In what was mainly an instructive presentation, Waters first lung cancer and mouse skin tumor initiation data suggest that exposure to roofing,tar is a third as potent as coke oven He provided some examples: Epid~emioliogic studies of human emissions and that cigarette smoke condensate is only carcinogenic than coke oven emissions. 4. "Epidemiological val'idation of'cancer of the tract by occupation~and the environment" -- E. CONTI, smoking increases the risk of developing the disease, he said. 0.0024 less Lu~ng cancer is the most prevalent form of cancer in Italy and He offered~figures from San Marino, an independent state has many industries and'its socioeconomic status is high. within Italy, showing it has the highest incidence of stomach cancer in the world, higher even than that of Japan. San Marino Conti contended that diet and smoking were the major risk, factors for cancer. 15. "Cancer atrributable to automobile gases" -- W. BLUMER, Nestal, Switzerland. Blumer described his experiences as a local doctor tending patients who live adjacent to a heavily traveled road withinia deep valley. (Data from a study in this area were published.sev- eral years ago.) He has found that those living next to the road for at least 1-0 years had a cancer death rate nine times higher than those living in a traffic-free area. High concentrations of hydrocarbons and lead were found along the road. Blumer said he has treated thousands of patients with symp- toms of excess lead levels in their blood. Symptoms receded as Lead'was excreted in the urine. Suirprisingly, persons living near ~ the traffic artery who had been treated with a metal binding w compound remained almost totally free of cancer: 1.7% for those .~ treated, 17% for those who weren't. He said almost all recognized CJ ~ +A

tumor inhibitors possess metal binding qualities. 16. "Identification of fibers and mineral pollutants in the human lung from1bronchoalveolar lavage (BAL)" -- P. DeVUYST, Brussels. ` A study done to test the value of BAL concluded that mineral analysis of the lavaged material is an important aid in the diag- nosis of lung dis,ease. La:vage isn"t proof of disease since healthy people were found to have asbestos or other fibers in their lungs, but it can confirm the presence or exposure to some dusts. DeVuyst also concluded that interstitial lung disease devel- ops more often when exposure to industrial asbestos is heavy. On the other hand, pleural disease and mesothelioma occurs mostly in persons with intermittent, casual or unknown exposure to asbestos. He has 60 cases of pleural disease and 42 have had low exposure. He's had false negative results for mesothielioma. He conceded that BAL may not be a good indicator of fibers implicated in the disease.'Of his mesothelioma cases, 25% had less than one asbestos _ . . body per cc o_f BAL 'f.Ltaid.'' :It`'s` known ``"that' ~not all mesotheliomas ' are asbestos related~," he said. 17. "An epidemiological study of the effects of air pollution on the airways in the Rotterdam area" -- A.M.J. WEVER, Leiden, The Netherlands. In the Rotterdam area, with its large petrochemical industry and high pollution levels, a study was done on 396 women to evalute the effects of pollution on their airways. The subject population consisted of 396 women, all housewives aged 18-42, who were selected at random~to-eliminate the effects of occupational exposure. The women were divided into four groups according to their degree of chronic non-specific lung diseases and smoking habits. Symptoms of cough, phlegm, dyspnea, wheezing or eye irritations were recorded by th~e subjects in a daily diary for one year. Only sulfur dioxide (S0!-2) levels were used as anindicator of air pollution. S0-2' was significantly related to coughing and phlegm production, especially in the smokers. There was no cor- relation between the polilutant and dyspnea and wheezing. Wever showed a: slide portraying a smoker and a:smoking chimney. "These two will destroy your lungs," he said. 18. "Environmental factors in asthma among inner city 0 residents of New York City" --~I.F. GOLDSTEIN, New York. ~ For the past decade, Goldstein's environmental epidemiology ~ group at Columbia University has been studying non-whites (mostly j blacks and~Hispanics) of low socioeconomic status (,SES), in parts ~ of New York City, Brooklyn and the Bronx. Comparisons have been