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C April ( , 1983 TO: W. T. Hoyt CC: WDH FR'OM: SCS Hilda Zahn RFG RCH SUBJECT; International Conference on Environment and Lung Disease, Taormina, Sicily, March 22-27, 1983 . ~ tion, the subject of numerous papers, was pretty well accepted,but pollutants. A relationship between chronic bronchitis and pollu- Scientists from many disciplines -- pulmonary medicine, epi- demiology, 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 Many of the more than 325 scheduled presentations were on an for lung cancer the culprit was cigarette smoking. studies, that were fairly old. Most of the papers were given by elementary. level, and frequently. .c.ited_,data.;. mostly from U.S. Italian scientists. Children 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 campaigns 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. J.W. LEMOINE of Fontainebleau, France, delivered a tirade 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. 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 W.orld Health Organization has organized a group to do a study on the "microclimate." For a foreigner in Taormina,.the conference was frustrating, interminable and hilarious -- and often all at the same time. Ses- sions started at 8 a.m. and ended at 10:30 p.mi. (or later). It was not uncommon for time slots to be shifted without advance warning. eonard ahn RUBLIC RELATIONS COUNSEL andAssociateSlnG 13 LINCOLN ROAD •P.O. BOX 223 ^GREAT NECK, N.Y. 11022 •(516)482-5715

2. c If all the speakers had showed'up, I'd still be there. Luckily, the organizers ran out of money to pay transportation costs for a number of inviited scientists and translators; unluckily, this meant that about a third of the sessions went untranslated. Most of the participauts were Italian, so this wasn't a serious problem for them. But it was for many among the approximately 650 regis- trants from about two dozen countries around' the world. Even the translators were harriiedibecause 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. civ.il!- 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 consid!ered~ significant. FEV-1 was significantly reduced the longer one smoked. Hiigh nicotine content also impaired airflow, according to the data. "Our results from this epidemiological 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. "Pollycycliic aromatic hydrocarbons (PA'Hs) and heavy metals in the environment: syngenesis - synoccurrence-syncarcinogenesis?" -- G. MULLER, Heidelberg, West Germany. Muller, a geologist, explained that coal combustion produces very highlatmospheric concentrations of both PAHs (includingg ~ benzo(a)pyrene, BaP) and'heavy metals, including highly toxic cadmium. These compounds also accumuliate in the soil and sediments C.: ~ ~. C~1

4 C 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 cocarcinogeniwas recently substan- tiated in West Germany (at Schmallienberg), 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. Industrializedicountries 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 ai r. . ._ . . ..... . ...., 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 1'ong-term effects of passive smoking that encompasses 23',000 sub- jects in seven cities. (The study is called PAARC, for atmospheric pollution and chronic respiratory infection.) Adults aged 4O or over, with or without passive smoking exposure, were evaluated. It was found that nonsmokers of bothisexes, 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 famil'y or atmospheric pollution. A dose-response relationship was shown for FE'V-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 preg;nant 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-

4. moved~ for study. C The fetuses from smoke-exposed mothers showed signs of imma- ature development and motor disturbances and'they also weighed less than norma.l. There was a large percentage of fetal resorption but a less dramatic placental' weight loss in the fetuses from exposed animals. E. "Dimethylnitrosaimine (DMN): a test for the risk of lung cancer fromismokirig" -- F. ORECCH'I0, Rome. This confused report dealt with DMN which, Orecchio said, was present in cigarette smoke an~d is related to the development 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 subjects who apparently were hospital patients, showed that half of those who were smokers (number not given) had no enzymatic activity; the nonsmokers had fairly high levels. Enzymatic activity measur;ements in:smokers_and:,nonsmokers may indicate their susceptibility to lung cancer in terms of exposure to cigarette smoke, he said. F. "Smoking, chronic bronchitis and environmental factors" -- V. UITTI, Naples. An epidemiological 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 23A incidence of bronchitis; other hospital personnel who smoked had a 31% incid'ence. 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 showed the most liung deterioration whether exhibiting symptoms or not. G. "Preliminary results of an epidemiological study of the tobaccolhabits of Algerian doctors at home" -- D. LARBAOUI, A1 giers. The Medical Association of Algeria mailed questionnaires to members asking about their smoking habits. Reply rate was 4,8%a. The responses showed: For males, 42% currently smoke, 43% a;re nonsmokers, 15% are ex-smokers..For females, more than 85%P are nonsmokers, 8% are ex-smokers, 7% currently smoke. ~ CJ ~ Filtered cigarettes are used by 95% of the smokers, the majority of whom are from 31-501years of age. Most of the ex- ~++ smokers are over 501. Respiratory impairmenit (coughing, shortness ~ ~ ~ {

of breath) was reported by 46ya of the smokers, 25° of the ex- smokers and 5% of the nonsmokers. H. "Respiratory carcinogenesis from smoking" -- G. PESCETTI, Turin, Italy. Tobacco contains more than 1,000 carcinogenic 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 macr,ophages..,of 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 (;hromosomal 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 20%0 of normal nonsmokers have slow mucociliary function.) 3. "The role of NAC in chron~ic bronchitis." -- A. BLASI, Naples. In an 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.1 NAC seems to protect against th~e 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. C 4. "Clinical study of the effects of Ambroxol on lwng function tests in cigarette smokers without other pulmonary diseases" -- P. C. CURTI, Sondalo, Italy. d 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 withAmbroxol produced less surfactant, 30 healthy smokers aged. 39 or more were given 60 mg,of the drug twice daily for a. month. Sputum was col- lected daily and examined. Curti said the treatment caused an improvement in some pul- monary functions and that carboxyhemoglobin was 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 bronchitic secretions and surfactant production. It's a metabolite ;. of_. bromh~exine,;'which~; is;_,used, in;,".e.xpectorants and mucolytics. ~ 5. "Alterations of the phagocytic activity of alveolar macrophages from contaminants in the air" -- E. POZZI, Pavia. The maSor 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 their nature, the damage they may do~to the respiratory epi- thelium, and their possible penetrationiof the epithelium. Pollutants activate mucus secretion, change ciliary activity, stimulate macrophages and, if sufficiently severe, stimulate th~e production of substances that destroy epithelial cells. The nervous system is also affected. Besid~es coughing and sneezing, there can be changes in respiratory smooth muscle tone and in ventilation. Constriction of the bronchi and larynx also is seen. S I Widdicombe used cigarette smoke blown into the liarynx of a cat as an example of the body's reaction to pollutants. The cat ~ stopped breathing for several seconds, he said. When it recovered~,,j its breathiing pattern was far slower than normal. He didn't say `W how long that lasted. ~ CD

s 7. C Most of the experiments were done in~animals, he said, but he's certain that the reactions are the same in humans. 7. "Cardiopulmonary effects of occupational exposure to solvents" --.DOMINGO AVIADO, Short Hills, NJ. Inhaled organic solvents in and out of the workplace are re- sponsible for mild to severe forms of cardiopulmonary disease, de- pending on dose.`Exposure to the solvents can cause bronchocon- striction, myocardial depression and cardiac arrhythmias. Absorption of most organic compounds causes central nervous system depression that could cause asphyxia from paralysis. This, 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 and tobacco. Tolerance can develop to these, but hardly ever.. to solvents. Solvents and outdoor pollutants have similar toxicological effects onithe respiratory system; they also may act synergis- tically. Prevention of exposure to solvents isn't simply. Most of themiare found in household items. Preventing adverse effects may depend on making safe solvents. 8. "Byssinosiis,. Epidemiological and etiological studies" -- M. AZEVEDO, Lisbon. A study of workers in three cotton mills 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 related to respiratory infections. Nearly two-thirds of the 72 withs byssinosis were nonsmokers. Most of the smokers reported chronic cough and sputum production, as did nearly 31% of the nonsmokers. Nearly two-thirds of the chronic bronchitics were smokers. She concludedithat both byssinosis and chronic bronchitis in the workers were influenced by cottonidust exposure and smoking and'not by other factors. 9. "Prevalence study on chronic bronchitis (CB) in Tuscany in two urban populations: connection withiair pollution.and life- style" -- L.F. SIGNORINI, Florence, Italy. p W A prevalence study of CB was done in subjects who had lived CZ11 . for at least 10 years in a small, industrial, non-metropolitan ,~ area. There were two groups: 737 subj;ects exposed only to common ~ urban air pollution, and 600 subjects add1tionally exposed to ~

cement dust pollution. Smo'king,was found to be a primary risk fa:ctor in both groups, while al!cohol-And occupational exposure seemed to be additional factors that may act synergistically with smoking. The findings strongly suggested that the cement dust exposure of the second group also was a potent factor related to CB. 10. "Environmental factors influencing lung,function in children" -- S. SPINACI, Turin. The health effects of indoor and outdoor pollution levels in nearly 2,400 children aged 11i from two urbaniand on~e rural com- munity were evaluated by questionnaires and seuen lung' function measurements. Lung function parameters tended to be significantly higher in less polluted areas. There were no differences for social class or indoor pollution,, but male children were found to be'affected by their mothers' smoking. '.Y... ~.... • . ..:....... ,..'~~, . ~. , .6-_.,. .. ... . ..r.,e.... a. <.~:4. . ~V.. . .. . .. .. . , - . ._ According,to the data, outdoor pollution and passive smoking resulted~ in a small but significant decrease in lung function. 11. "The risk of pulmonary tumors from ionizing radiation" - M. DI PAOLA, Rome. Lung cancer can be caused by ionizing radiation though the effects may vary with dosage. Lung cancer continues to be high in Hiroshima and Nagasaki 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 cited the high incidence of lung cancer in uranium workers in the U.S. and Yugoslavia and the synergistic 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 explained). Cancer is multifa:ctorial, Di Paola said, and it's impossible to say what specific agent is responsible. 12. "Cytotoxic and~co-mutagenic effects of asbestos inicell culture" -- B. REISS, Valhalla, NY (American Health Foundation). Reiss said~ asbestos fibers she's d'eveloped'an assay for the cytoxicity of tha:t is an improvement over previous methods. Using her test, she found that 'chrysotile was more cytoxic than the amosite or crocidolite forms of asbestos. Though asbestos is very cytotoxic, she said, it's n~ot muta-,,rb genic. Yet, when chrysotile is added to cell cultures containing *-I BaP, which is very mutagenic, there's a: synergistic effect. The I asbestos functions as a cocarcinogeni. It doesn't itself affect the

t 9 C DNA, but it helps substances like BaP act more quickly. "Asbestos workers have a 10 times higher incidence of cancer than the general population," she said. "Those who smoke have a 100 times greater incidence." 13. "Genetic toxicology of airborne chemicals and complex mixtures with emphasis on human health hazards" -- M.D. WATERS, Chapel Hill, NC., In what was mainly an instructive presentation, Waters first explained the genetic toxicology of known or suspected human res- piratory tract carcinogens and then evaluated them by means of various bioassays and epidemiologic data:. He provided some examples: Epidemiologic studies of human lung cancer and mouse skin tumor initiation data suggest that exposure to roolfing tar is a third as potent as coke oven emissions and that cigarette smoke condensate is only 0.0024 less carcinogenic than coke oven emissions. 14. "Epidemiological`'validation of 'dancer of the respiratory tract by occupationiand the environment" -- E. CONTI, Rome. Lung cancer is the most prevalent form of cancer inlItaly and smoking increases the risk of developing the disease, he said. He offered figures from San Marino, an independent state within Italy, showing it has the highest incidence of stomach cancer in the world,, higher_even than that of Japan. San Marino has many industries and its socioeconomic status is high,. Conti contended that diet and smoking were the znaj'or risk factors for cancer. 115. "Cancer atrributa:ble to automobile gases" -- W. BLUMER, Nestal, Switzerland. Blumer described his experiences as a local doctor tending patients who live adjacent to a heavily traveled roadlwithin a 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 10 years had a cancer deathirate 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. Surprisingly, persons living near the traffic artery who had beenitreated with a metal binding, compound remained almost totally free of cancer: 1.7% for those treated, 17% for those who weren't. He said almost all recognized

tumor inhibitors possess metal binding qualities. 16. "Identification of fibers and minerali pollutants in the human lung fromibronchoalveolar 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 di.ag- nosis of lung disease. Lavage 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 mesothelioma. He conceded that BAL may not be a good indicator of fibers implicated in the disease. Of his mesot.helioma cases, 25_X had less than one asbestos body per cc` of BAL, •flui'd it'; s'knowni "th•atl"not all mesotheliomas are asbestos related," he said. , .17. "Aniepidemiological study of the effects of air pollution on the airways in the Rotterdam area" -- A.M.J. WEVER, Leiden, The Netherlands. In the Rotterdamiarea, with its large petrochemicall industry and high pollution levels, a study,was done on 3:96 women to evalute the effects of pollution.on their airways. The subject population consistedlof 396 women, all housewives aged 18-42, wh~o 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 the subjects in a daily diary for one year. Only sulfur dioxide (SO-2) levels were used as anind.icator of air pollution. SO-2 was significantly related to coughing and phlegm production, especially in the smokers. There was no cor- relation between the pollutant 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 residents of New York City" -- Z.F. GOLDSTEIN, New York. For the past decade, Gold'.stein~'s environmentali epidemiology group at Columbia University has been studying non-whites (mostly blacks and Hispanics): of low socioeconomic status (SES) in parts of New York City, Brooklyn and the Bronx. Comparisons have been