Cigarette smoking and reactions to air pollutants Ro. J. SHEPHARD, MD, PH D There are many mechanisms whereby recent exposure to cigarette smoke augments the toxicity of common air contaminants: the total pollutant burden is increased, there is cumulative irritation of the airways, pollutants are deposited selectively in the airways, ventilatory patterns are altered, mucus production is increased, ciliary function is depressed, mucosal characteristics are altered, macrophage activity is depressed and specific allergic reactions may occur. In the longer term adverse changes of form and function may develop in the lining of the airways. II existe plusieurs m6canismes par lesquels une recente exposition & Ia fumee de cigarette augmente Ia toxicite des substances qui polluent couramment l'air: Ia charge totale des substances polluantes se trouve augment6e, il y a une irritation additlonnelle des voles respiratoires, les substances polluantes se deposent selectivement dans les voles respiratoires, les processus de ventilation sont modifies, Ia production de mucus est augmentee, Ia fonction cillaire est d6prim5e, les caract6ristlques des muqueuses sont modifi6es, l'activit6 macrophage est abaiss6e et certaines reactions allergiques specifiques peuvent survenir. A long terme, des modifica. tions ind6sirables de Ia forme et de Ia fonction des parois des voles respiratoires peuvent apparaitre.

Some 40% of the adult Canadian population are currently regular cigarette smokers.1 Further, a recent study from Toronto2 has confirmed the traditional view3 that those most likely to suffer exposure to air pollutants (skilled, semiskilled and unskilled workers from large urban areas) smoke cigarettes at an above-average rate. Many persons who are smokers blame all or some of their chest symptoms on exposure to air pollution. It is therefore useful as part of a health education program to explain to such individuals the ways in which both recent and long-term exposure to cigarette smoke can exaggerate reactions to air contaminants, turning a harmless level of exposure into an unacceptable one.4 Unfortunately too many studies of From the department of preventive medicine and biostatistics, University of Toronto Correspondence to: Dr. Roy J. Shephard, Department of preventive medicine and biostatistics, Faculty of medicine, University of Toronto, Toronto, Ont. M55 1A8

human responses to air pollutants have disregarded totally the smoking history, and few authors have considered the recent smoking pattern of the persons examined. Tests have often been conducted on health-conscious volunteers who have been life-long nonsmokers, and even when the population sampled has been more typical of a clinical practice, the nature of the usual short-term experiment (deliberate chamber exposure to a specific pollutant) has necessitated a long and poorly controlled abstinence from cigarettes. The objectives of the present report are to draw together available information on interactions between cigarette smoke and air pollutants and to indicate profitable avenues for further research. Recent smoking and responses to air pollutants There are several potential mechanisms whereby recent smoking could affect responses to air pollutants. Although in most instances the mechanism is inherently reasonable, often direct experimental proof is lacking. Increase of pollutant burden Cigarette smoke contains high concentrations of many toxic compounds. Recent smoking can therefore convert what would otherwise be an acceptable concentration of pollutant for an urban dweller into an unacceptable total burden. Documented constituents of cigarette smoke include particulate matter,5'6 various metals including iron, manganese, titanium, zinc, lead, nickel, arsenic, copper and chromium,7 aldehydes,6 organic acids,8 phenols,6 acrolein,9 nicotine,10 pyrenes and fluorenes,7 oxides of nitrogen,11 sulfur dioxide,1' ammonia,13 hydrogen cyanide,14 carbon monoxide5'15 and possibly specific allergens.16 In a number of instances the contaminant not only adds to the urban burden but even outweighs it. Hence cigarette smoke makes a major contribution to the total particulate count in the homes of smokers,16 and a cigarette can deliver 30 to 40 mg of solid matter to the lungs.7 The normal ambient concentration of carbon monoxide is 4 to 5 parts per million (ppm) and the maximum desirable 8-hour exposure is 13 ppm. However, accumulations of cigarette smoke in a crowded bar can yield carbon monoxide concentrations of 20 to 30 ppm, chainsmoking in a small car can yield 80 to

100 ppm and the smoke inhaled from a cigarette contains 10 000 to 40 000 ppm of carbon monoxide.15 Some of the irritant constituents of the atmosphere (such as sulfur dioxide and the oxides of nitrogen) plainly add to the irritation caused by the corresponding constituent of cigarette smoke. However, in other instances there is harmful interaction *between the air contaminant and the cigarette smoke. Atmospheric ozone can react with sulfur dioxide (itself a gas of relatively low toxicity) to produce the much more harmful sulfur trioxide.17 Cumulative irritation of airways Much of the recent experimental work on air pollution has involved the irritant gas ozone. Physiologic responses can be detected at concentrations occasionally encountered in the urban environment (around 0.35 ppm), and in general such responses can be attributed to stimulation of vagal irritant receptors in the airways.1841 It therefore seems likely that irritation caused by constituents of cigarette smoke such as ammonia, acrolein, the oxides of nitrogen and nicotine will enhance responses to atmospheric irritants such as ozone. Impulse traffic in various nerves has been determined directly in the rabbit,". and such experiments have shown that nasal, laryngeal and tracheobronchial receptors can be stimulated by cigarette smoke. However, further work is needed to determine whether there is a simple addition or a multiplication of the irritant effect when two pollutants are administered simultaneously. Selective deposition of pollutants It was shown some years ago that the toxicity for animals of sulfur dioxide was enhanced considerably when it was presented in association with a fine particulate aerosol..'57 Recent events in London, England have given dramatic epidemiologic support to this hypothesis. Air pollution control measures in central London have reduced greatly the particulate burden without much change in sulfur dioxide concentrations, and as a probable consequence there have been no recurrences of the lethal "smog" episodes of the 1950s. The particulate phase of cigarette smoke is a fine aerosol, with most particles smaller than 0.25 p.m. It is therefore carried readily into the finer structure of the lungs. There are good grounds for believing that individual

CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 379

particles can absorb irritants such as ozone and sulfur dioxide. Instead of being absorbed in the upper airway, the gases are then carried far into the bronchial tree..' The particles also provide a "surface", which greatly accelerates the normal interaction between ozone and sulfur dioxide, with formation of the more toxic sulfur trioxide.17'29'3' Altered ventilatory patterns The irritant constituents of cigarette smoke are known to produce reflex bronchospasm,7'22"3'31'3' often with associated hyperpnea. and increases of alveolar and residual volume.33'34 Such changes are reminiscent of those found during ozone exposure, and presumably augment the responses induced by this pollutant. The altered ventilatory patterns undoubtedly influence the deposition of aerosols and thus the human reactions to particulate air contaminants,36-38 although the full details of such effects have yet to be worked out. Increased mucus production Morning phlegm is a well recognized complaint of the smoker. It reflects both an immediate and a long-term increase of mucus secretion by the goblet cells of the airways in response to the irritant constituents of the smoke..'3' The short-term effect of the added mucus may be protective. It limits penetration of aerosols into the lungs of the smoker, much as in the person with chronic bronchitis,40'41 and may also shield the mucosa somewhat from irritant gases such as ozone. However, the long-term effect of the extra mucus is certainly harmful, hastening the development of chronic bronchitis. Depressed ciliary activity Exposure to cigarette smoke stimulates ciliary activity transiently, then for some 40 minutes movement is depressed. This, together with changes in the volume and viscosity of the mucus,4143 has a ffiarked effect in slowing the elimination of harmful particles from the larger airways. Altered mucosal characteristics Relatively prolonged exposure to cigarette smoke induces significant changes in the histologic and functional characteristics of the cells lining the air passages. Major abnormalities of the olfactory cells have been described," along with tracheal and bronchial gland hyperplasia,'5 irritation of the goblet cells, loss of columnar epithelium with hypertrophy of the nonciliated cells,46 damage of the respira-

tory bronchioles and alveolar ducts47 and alterations in the permeability of the epithelial cells to toxic materials.4' Loss of olfactory function removes one important protection against exposure to large doses of many contaminants and leads to falsely reassuring diminution of symptoms. Goblet cell irritation causes overproduction of mucus. Loss of columnar epithelium leads to delays in the elimination of toxic particles, while local changes in respiratory bronchioles could have a more direct influence on the toxicity of many irritants. Depressed macrophage activity Clearance of particulate matter from the alveoli and the finer air passages depends on its ingestion by alveolar macrophages. Hence, it is of concern that exposure to cigarette smoke causes alterations in the numbers, structure, motility and metabolic and phagocytic activity of pulmonary macrophages, with attendant changes in the clearance of particulate matter from the finer air passages.'5'49.3 A second important function of pulmonary macrophages is the production of surfactant; some.". but not all56'57 authors have found that repeated exposure to cigarette smoke leads to a loss of alveolar surfactant, with associated changes in the pressure/volume characteristics of the lung. Again, this is a reaction that can augment similar responses to air pollutants. Allergic reactions Several authors have described allergic reactions to cigarette smoke in a proportion of the population,14'58"0 although this finding is by no means universally accepted.'1 The existence of an allergic reaction seems reasonable in view of the severe dermatitis of some tobacco harvesters, although it is arguable that this could be caused by the spraying of the plants rather than by the tobacco itself. In a recent experiment about a quarter of persons with asthma complained of wheezing and tightness in the chest during a 2-hour stay in a chamber filled with cigarette smoke, and the same people showed large decreases of dynamic pulmonary gas flow during this exposure (R.J. Shephard, P. Pimm and F. Silverman: unpublished data, 1977). However, other persons with asthma and healthy persons showed little reaction other than eye irritation and coughing. If an allergic reaction is indeed mitiated by cigarette smoke, it could conceivably enhance responses to ozone, since other recent experiments in our laboratory have shown that sensitivity to ozone can be increased several-fold in the person with asthma.

380 CMA JOURNAL/FEBRUARy 18, 1978/VOL. 118

Specific observations on ozone toxicity Ozone is an irritant that has received much experimental attention recently. Nevertheless, there have been few direct observations of interactions between cigarette smoke and ozone. On general grounds one might anticipate an immediate additive response to the irritant constitutents of cigarette smoke and atmospheric ozone; however, there is also evidence that the lungs adapt to repeated exposure to irritants so that the smoker could have a smaller response to a given dose of irritants. Hazucha and colleagues'2 noted a somewhat greater overall reaction to ozone in smokers than in nonsmokers; for instance, immediately after a 2-hour ozone exposure the closing capacity of dependent parts of the lung was increased by 2.7% in the nonsmokers but by 10% in the smokers. In contrast, Kerr and associates'3 found that more symptoms were reported by nonsmokers than by smokers; however, we have already noted the possible fallacy of relying upon symptoms when olfactory receptors have been damaged by long-term exposure to cigarette smoke. Unfortunately, neither study had the potential to indicate acute effects of cigarette smoke since there was a long interval between the smoking of the last cigarette and chamber exposure to the irritant. The experiments of Kerr and associates lasted 6 hours, and the irritant receptors of their smokers were therefore deprived of their customary stimulation by cigarette smoke for a particularly long period. Some community studies have reported more symptomatic reactions in smokers than in nonsmokers without identifying the precise pollutants responsible.'4 Hammer and colleagues'5 carried out a prospective study correlating the daily symptom reports of Los Angeles nurses with the corresponding concentrations of photochemical oxidants. The smokers had more frequent complaints of eye discomfort, cough and chest discomfort than the nonsmokers. However, the effects of smoking were apparently additive rather than multiplicative, since both groups showed parallel increases of symptoms during episodes of intense pollution. There do not seem to have been any deliberate investigations of interactions between industrial ozone exposure and smoking. However, one report that may have some relevance concerns pilots of high-performance aircraft." The smokers lost three and a half times as much of their vital capacity as the nonsmokers during a high-altitude flight. The authors attributed this to the breathing of oxygen, but it is possible

that ozone exposure may have contributed.

Long-term interactions of cigarette smoke and air contaminants The main influence of smoking habits on chronic reactions to air contaminants is well documented and indeed is becoming accepted by the lay public. The person who works in a uranium or an asbestos mine is no longer surprised when a physician advises him that a combination of such employment and a high rate of cigarette smoking borders on self-imposed suicide. Recent research* suggests that smoking has not only an additive but also a multiplicative effect on the prevalence of both neoplasia5'749 and chronic bronchitis,7.7 and it is fortunate that in most underground mines smoking during working hours is forbidden because of the risk of explosion. Adverse effects of smoking are also well known in almost all dusty industries,74 including the mining of coal,75'7 uranium77 and gold,78 iron foundry work,79 work with asbestos,80 granite carving,81 textile work81 and grain handling.83 Cocarcinogenesis77 is a likely longterm response to cigarette smoking. Chronic obstructive lung disease is also a frequent late consequence of smoking, and this condition increases sensitivity to brief episodes of air pollution, as in the London smogs of 195284 and 1956,. and the smaller but equally tragic disasters of the Meuse Valley in 193O. and in Donora, Pennsylvania in l948... Conclusions We would all like to breathe completely clean air, both at home and at work, but the realities of a crowded industrial world are such that we are obliged to accept some contamination of both the workplace and the general urban atmosphere. Patients should not be allowed to use this circumstance as an argument in defence of cigarette smoking. There are good grounds for believing that both short- and long-term exposure to cigarette smoke increase the toxicity of many air contaminants. Short-term exposure to cigarette smoke adds little to the general atmospheric burden of some pollutants, but for other contaminants the concentration found in cigarette smoke far outweighs that in ambient air. Prolonged smoking also impairs body defence mechanisms to the point where unavoidable industrial exposure can induce chronic or *The literature on smoking and long-term exposure to air contaminants is so extensive that it is possible to cite only typical recent papers.

lethal disease. Such facts do not justify a casual attitude to industrial pollution. Attempts to improve air quality in both the general atmosphere and the industrial environment must continue. Nevertheless, there will likely remain some "dangerous" industries in which it is uneconomic to curb pollution completely; air quality may therefore be sufficient for the continued health of the nonsmoker while failing to protect all individuals who have both lung abnormalities and a high rate of cigarette smoking. If the contamination is confined to the workplace, the labour force should be restricted to nonsmokers. Equally, if economic circumstances force a person with diseased lungs to live in a section of a city with more general contamination of the atmosphere, it is important that he or she be persuaded to become a nonsmoker.

20. FOLINSBEE U, SILVERMAN F, Sanns,.n iLl: Exercise responses following ozone exposure. .1 Appi Physiol 38: 996, 1975 21. Idem: Decrease of maximum work performance following ozone exposure. I Appi Physiol 42: 531, 1977 22. SELLICK H, WIDDICOMBE JG: Activity of lung irritant receptors caused by cigarette smoke dust and histamine aerosol. I Physiol (Londj 210: 56. 1970 23. Idem: Stimulation of lung irritant receptors by cigarette smoke, carbon dust and histamine aerosol. I Appi Physiol 31: 15, 1971 24. Boussm. HA, RscasiiDsoN PS, WIDDICOMIB JG, et al: The response of laryngeal afferent fibres to mechanical and chemical stimuli. I Physiol (Lond) 240: 153, 1974 25. WmmcoMaE JG: Physiological responses to inhalation of cigarette smoke and other irritant gases and aerosols. Boll Soc hal Biol Sper 49 (suppl 18): 1, 1975 26. PATI'LE RE, BURGESS F: Toxic effects of mixtures of sulphur dioxide and smoke with air. I Pathol Bacteriol 73: 41. 1957 27. AMDUR MO: The influence, of aerosols upon the respiratory response of guinea pigs to sulfur dioxide. Indusir Hyg Q 18: 149, 1957 28. AlNswowrss M, SHEPHARD RJ: The intrabronchial distribution of soluble vapour at selected rates of gas flow, in Inhaled Particles and Vapours, DAVIEs CN (ed), Oxford, Pergamon, 1961 29. HAZUCHA M: Ellects of Ozone and Sulphur Dioxide on Pulmonary Function in Man, PhD thesis, McGill University, Montreal, 1973

The work of our laboratory is supported in part by a research grant from Health and Welfare Canada.

31.

30. MCJILTON

32.

References 1. The Smoking Habits of Canadians, 19651974, Ottawa, nonmedical use of drugs directorate, Health and Welfare Canada, 1976

2. SHEPHARD RJ, LABARsa R: Current attitudes of Canadian city-dwellers to cigarette smok-

ing. Can J Public Health (in press) 3. Chartbook on Smoking, Tobacco and Health, US Public Health Service publ no 1937, 1-46, Arlington, Va, US Dept of Health, Education, and Welfare, 1969 4. WALLER RE: The combined effects of amoking and occupational or urban factors in relation to lung cancer. Ann Occup Hyg 1567: 71, 1972 5. SWARTZ H: Tobacco smoke: a noxious air pollutant. A review (and comment). Part I of II. Rev Allergy 25: 397, 1971 6. GUILLERM A, BADER R, Hax J, et al: Composition de la fum6e de tabac. Analyse des facteurs de nuisance. Rev Tuberc Pneumol (Paris) 36: 187, 1972 7. WYNDER EL, HOFFMAN D: Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis, New York, Acad Pr, 1967, pp 1-730 8. ANASTASOY A, ASTAHOVA LG, MOKHNACHOV IG: Opredlyane Tyutneviya Dim K.hromatografiya. 1970 9. ARTHO A, KOCH Cigarettenrauches

10. 11. 12. 13. 14.

na Organichnite Kiselini v s Pomoshtta na Gazovata Bulgarski Tyutyun 15: 27,

R: Ueber den Gehalt des an Acrolein und Cyan-

wasserstoff. Lebenzmittelungterschung Hyg 60: 379, 1969 GINZEL KH: The action of nicotine and smoking on reflex pathways. Ausir I Pharmacol 48 (suppl 52): 30, 1967 GOLDSTEIN E: Evaluation of the role of nitrogen dioxide in the development of respiratory diseases in man. Calif Med 115: 21, 1971 HORTON AD, GuaRIN MR: Quantitative determination of sulphur compounds in the gas phase of cigarette smoke. I Chromatogr 90: 63, 1974 AYERS CW: Determination of ammonia in tobacco and smoke. Talanta 16: 1085, 1969 Aamo A, KOCH R: Ueber die Bestimmung von Cyanwasserstoff in Cigarettenrauch. Beth' Tobakforschung 5: 58, 1969

15. SassaN J, P1MM P. SHEPHARD RJ: Cigarette Smoke Accumulation in Public Places in Downtown Toronto, Toronto, York-Toronto Tuberculosis and Respiratory Diseases Association, 1975, pp 1-23

16. ZU5SMANN BM: Tobacco sensitivity in the allergic patient. Ann Allergy 28: 371, 1970 17. HAZUCHA M. BATEs DV: Combined effects of ozone and sulphur dioxide on human pulmonary function. Nature 257: 50, 1975

18. HOLMEs 0, TROQuEr J: Activit6 Electrique de fibres vagales efferentes pendant l'intoxication de l'ozone. I Physiol (Paris) 53: 364, 1968 19. BATES DV, BELL GM, BUINHAM CD, et al: Short term effects of ozone on the lung.

I Appl Physiol 32: 176, 1972

33. 34. 35. 36.

CE,

FRANK

R,

CHARLsON

37. UPPMANN M, ALBERT RE, PETERSON

38. 39. 40. 41.

RJ:

influence of relative humidity on functional effects of an inhaled S0.-aerosol mixture. Am Rev Respir Dis 113: 163, 1976 CLARKE BG, GIJYATr AR, ALPERS JH, et al: Changes in alrway conductance on smoking a cigarette. A study of repeatability and of the effect of particulate and vapour phase filters. Thorax 25: 418, 1970 SADOUL P. PHAM QT, FARZANEH N: Retentissements fonctionnels respiratoires de Ia fum6e de tabac, Rev Tuberc Pneumol (Paris) 36: 225, 1972 BUFF R, KOLLER EA: Studies on mechanisms underlying the reflex hyperpnoea induced by inhalation of chemical irritants. Respir Physiol 21: 371. 1974 CHIANG ST. WANG BC: Acute effects of cigarette smoking on pulmonary function. Am Rev Respir Dis 101: 860, 1970 SILVERMAN F, FoLINsBEE U, BARIJ4RD J, et al: Pulmonary function changes in ozone - interaction of concentration and ventilation. .1 Appi Physiol 41: 859, 1976 ALDAS JS, DoLovlcis M, CHALMERS R, et al: Regional aerosol clearance in smokers and non-smokers. Chest 59 (suppl 2): May 1971 liT:

The regional deposition of inhaled aerosols in man, in Inhaled Particles III. Proceedings of an International Symposium of British Occupational Hygiene Society, WALTON WH (ed), Old Woking, Surrey, England, Unwin, 1970 Mum DCF (ed): Deposition and clearance of inhaled particles, in Clinical Aspects of Inhaled Particles, Philadelphia, Davis, 1972, pp 1-20 LAWTHER PJ: Air pollution and health, in The Theory and Practice of Public Health, HoasoN W (ed), London, Oxford U Pr, 1969 ThOMSON ML, PAVIA D: Particle penetration and clearance in the human lung. Results In healthy subjects and subjects with chronic bronchitis. Arch Environ Med 29: 214, 1974 ALBERT RE, PETERSON liT sa, BOHNING DE,

et al: Short-term effects of cigarette smoking on bronchial clearance in humans. Arch

Environ Med 30: 361, 1975 42. IRAvANI J, MELVILLE GN: Mucocilidre Funktion und Inhalation des Zigarettenrauches. Pneumologie 150: 211, 1974 43. BONNING DE, ALBERT RE, LIPFMAN M, et al: Tracheobronchial particle deposition and clearance. A study of the effects of cigarette smoking in monozygotic twins. Arch Environ Health 30: 457, 1975 44. MATULIONIS Dli, LAMUSON RO: A preliminnary ultra-structural study of mouse olfactory nasal and tracheal epithella after exposure to cigarette smoke, in Proceedings of the University of Kentucky Tobacco and Health Research Institute, Tobacco and Health Workshop Conference, Lexington, Ky, Jan 11-13, 1972 45. RYLANDER R: Pulmonary cell responses to inhaled cigarette smoke. Arch Environ Health 29: 329, 1974 46. VIDIC B, RANA MW, BHAGAT BD: Reversible damage of rat upper respiratory tract caused by cigarette smoke. Arch Otolaryngol 99: 110, 1974 47. FREEMAN G, Jimos LT, FuRIOSI NJ, et al: Pathology of pulmonary disease from exposure to interdependent ambient gases (nitrogen dioxide and ozone). Arch Environ

Health 29: 203. 1974 48. SIMANI AS, INoUE 5, Hooo JC: Penetration

of the respiratory epithelium of guinea pigs following exposure to cigarette smoke. Lab

Invest 31: 75. 1974

CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 381

Aldornet* (methyldopa, MSD Std.) Methyldopa is contraindicated IN active hepatic diseases and hypersensitivity. it is important to recognize that a positive Ooombs test may occur. HemolytK. anemia and liver disorders have been reported with methyldopa therapy. INDICATIONS: Arterial hypertension. May be employed in conjunction with a diuretic and/or other antihypertensive drugs in patients with hypertension of various severity, or as the initial agent in patients for whom treatment should not be started with a diuretic. DOSAGE SUMMARY: ADULTS: Start usually with 250mg two or three times daily during the first 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. Smaller doses may be needed in presence of impaired renal function, or in older patients with an increased sensitivity or advanced arteriosclerotic vascular disease. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. CONTRAINDICATIONS: Active hepatic disease such as acute hepatitis and active cirrhosis; if previous methyldopa therapy has been associated with liver disorders or hemolytic anemia (see WARNINGS); hypersensitivity. WARNINGS: It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions. With prolonged methyldopa therapy, 10% to 20% of patients develop a positive direct Ooombs test, usually between 6 and 12 .hs of therapy. Lowest incidence is at daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a sitive direct Coombs test may develop hemolytic anemia. Prior existence or development of a positive direct d.mbs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, determine whether hemol.ic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Ooombs test which may interfere with cross matching of blood. At the start of methyldopa therapy, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. it may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy. If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be consideredif hemolytic anemia occurs,the drug should not be reinstituted.When methyldopa causesOoombs positivity alone or with hemolytic anemia,the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped. Should the need for transfusion arise in a tient receiving methyldopa, both a direct and an indirect Coombs test should be performed on his blood. In the a.ence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs testis also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed. Occasionally fever has occurred within the first three weeks of therapy, sometimes with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur, with onset usually within first 2 or 3 months of therapy. In some patients the findings are consistent with those of cholestasis. Rare cases of fatal hepatic necrosis have been reported. These hepatic changes may represent hypersensitivity reactions; periodic determination of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever unexplained fever occurs. Discontinue If fever, abnormalities in liver function tests, or jaundice occur. If related to methyldopa, reversion to normal has been characteristic when drug was discontinued. Do not reinstitute methyldopa in such patients and use with caution in those with history of previous liver disease or dysfunction. Reversible leukopenia with primary effect on granulocytes has been seen rarely. Rare cases of granulocytopenia have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Reversible thrombocytopenia has occurred rarely. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Use in Pregnancy: Use of any drug in women who are or may become pregnant requires that anticipated benefits be weighed against possible risks; possibility of fetal injury cannot be excluded. PRECAUTIONS: Use cautiously if there is a history of liver disease or dysfunction (see WARNINGS). Methyldopa may interfere with measurement of: uric acid by the phosphotungstate method, creatinine by the alkaline picrate method, and SG0T by colorimetric method. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. it is important to recognize this phenomenon before a patient with possible pheochromocytoma is subjected to surgery. Methyldopa is not recommended for treatment of patients with pheochromocytoma. Rarely, urine may darken when exposed to air after voiding. Stop methyldopa If involuntary choreoathetotic movements occur in patients with severe bilateral cerebrovascular disease. Patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to increased sensitivity and advanced arteriosclerotic vascular disease; this may be avoided by lower doses. Patients may require reduced doses of anesthetics. Hypotension occurring during anesthesia usually can be controlled by vasopressors. Dialysis removes methyldopa and hypertension may recur. ADVERSE REACTIONS: Central Nervous System: sedation, headache, asthenia, or weakness, usually early and transient. Dizziness, lightheadedness, symptoms of cerebrovascular insufficiency, paresthesias, parkinsonism, Bell's palsy, decreased mental acuity, involuntary choreoathetotic movements; psychic disturbances including nightmares and reversible mild psychoses or depression; toxic encephalopathy. Cardiovascular Bradycardia ag9ravation of angina pectoris; orthostatic hypotension (decrease daily dosage. edema (and weight galn) usually relieved by use of a diuretic; discontinue methyldopa If edema progresses or signs of heart failure appear. Gastrointestinal: Nausea, vomiting, distention, constipation, flatus, diarrhea, mild dryness of mouth, sore or "black" tongue, pancreatitis, sialadenitis. He,oatic: Abnormal liver function tests, jaundice, liver disorders. Hematolegic: Positive Ooombs test, hemolytic anemia, leukopenia, granulocytopenia, thrombocytopenia. Allergic: Drug-related fever, myocarditis. Other Nasal stuffiness, rise in BUN, breast enlargem., gynecomastia, lactation, impotence, decreased libido, dermatologic reactions including eczema and lichenoid eruptions, mild arthralgia, myalgia. F

FULL PRESCRIBING INFORMATION AVAILABLE ON REQUEST HOW SUPPLIED: Tablets ALD0MET* are yellow, film-coated, biconvex shaped tablets, supplied as follows: Ca 8737-each tablet containing 125mg of methyldopa, market MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290-each tablet containing 250 mgofmethyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733-each tablet containing 500mg of methyldopa marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293-Injection AL.M.* Ester hydrochloride, a clear colourless solution containing 250mg methyldopate hydrochloride per 5 ml, supplied inS ml ampoules. 1. Onesti, G.L.: When hypertension is complicated, Drug Therapy 566-78, June 1975. *Tradenlark MERCK

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49. LENTZ PE, Di Luzio NR: Peroxidation of lipids in alveolar macrophages. Production by aqueous extracts of cigarette smoke. Arch Environ Health 28: 279, 1974 50. WAIR GA, MARTIN RR: Chemotactic responsiveness of human alveolar macrophages: effects of cigarette smoking. Infect Immun 9: 769, 1974 51. YEAGER H JE, ZIMMET SM, SCHWARTZ SL:

Pinocytosis by human alveolar macrophages. Comparison of smokers and nonsmokers. I Clin Invest 54: 247, 1974 52. Low RB: Protein biosynthesis by the pulmonary alveolar macrophage: conditions of assay and the effects of cigarette smoke extracts. Am Rev Respir Dis 110: 466, 1974 53. KiLsuR. KH, McKENZIE W: Leukocyte recruitment to airways by cigarette smoke and particle phase in contrast to c.otoxicity of vapour. Science 189: 634, 1975 54. BaAcco M, CURTI PC: La Sostanza TensioAttiva Dell' Induito Alveolare: Constitutione Chimica, Origine e Funzione Nella Fisiologic Polmonere Vuore Acquisizioni Chimiche e Istochimiche. Ann Med Sondalo 18: 5, 1970 55. GINLAY TN, LADMAN AT: Low yield of pul-

monary surfactant in cigarette smokers. N Engi I Med 286: 223, 1972 56. GIAMMONA ST, Toces P. WEBB WR: Effects 'of cigarette smoke on incorporation of radioisotopically labeled palmitic acid into pulmonary surfactant and on surface actfvity of canine lung extracts. Am Rev Respir Dis 104: 358, 1971 57. CLEMENTS IA: Smoking and pulmonary surfactant. N Engi I Med 286: 261, 1972 58. BLUE JA: Cigarette asthma and tobacco allergy. Ann Allergy 28: 110, 1970 59. SAVEL H: Clinical hypersensitivity to cigarette smoke. Arch Environ Health 21: 146, 1970 60. HOsEN H: Tobacco sensitivity (C). Ann Allergy 29: 608, 1971 61. TAYLOR G: Tobacco smoke allergy - does it exist? in Environmental Tobacco Smoke Elfects on the Non-smoker. Report From a Workshop, Bermuda, 1974, RYLANDER R (ed), Geneva, U of Geneva Pr, 1974, pp 50-55 62. HAZUCHA M, SILVERMAN F, PARENT C, et al: Pulmonary function in man after short-term exposure to ozone. Arch Environ Health 27: 183, 1973 63. KERR HD, KULLE TI, MCILHONNY ML, et al: Effects of ozone on pulmonary function in normal subjects. An environmental-chamber study. Am Rev Respir Dis 111: 763, 1975 64. NELSON CI, SHY CM, ENGLISH T, et al: Family surveys of irritation symptoms during acute air pollution exposures. 1970 summer and 1971 spring studies. I Air Pollut Control Assoc 23: 81, 1973 65. HAMMER DI, HASSELBLAD V, Poamov B, Ct al: Los Angeles student nurse study. Daly

Symptom reporting and photochemical oxidants. Arch Environ Health 28: 255, 1974 66. BROWNING WH: Deleterious effects of cigarette smoking and 100 per cent oxygen on aircrew members in high performance aircraft. Aerosp Med 41: 39, 1970 67. ARCHER yE, WAGONER 1K, LUNDIN FE JR: Uranium mining and cigarette smoking effects on man. I Occup Med 15: 204, 1973 68. CARNOW BW, MasER P: Air pollution and pulmonary cancer. Arch Environ Health 27: 207, 1973 69. MCDONALD IC, BECKLAKE MR, Gians GW, et al: The health of chrysotile asbestos mine and mill workers of Quebec. Arch Environ Health 28: 61, 1974 70. HAMMOND EC, SELIKOFF II: The effects of air pollution. Epidemiological evidence, in Pneumoconiosis. Proceedings of an International Conference, Johannesburg, SssAPntO HA (ed), 1970, pp 368-73 71. Health Consequences of Sulphur Oxides: a Report from CHESS 1970-71, EPA 650/174-004, US Environmental Protection Agency, Research Triangle Park, NI, 1974, pp 1-434 72. WILLIAMS IR, lusTus CG: Evaluation of nationwide health costs of alr pollution and cigarette smoking. I Air Pollut Control Assoc 24: 1063, 1974 73. HOLLAND WW: The epidemiology of chronic

bronchitis. Community Health (Bristol) 6: 273, 1975 74. Rosssma CE, WEILL H: Synergism between dust exposure and smoking: an artefact in *the statistical analysis of lung function. Bull Physiopathol Respir (Nancy) 10: 717, 1974 75. PRATr PC: Introductory remarks concerning pathological changes in coalworkers' pneumoconiosis. Ann NY Acad Sci 200: 342, 1972 76. ROGAN JM, ATTFIELD MD, lAcossEN M, et al: Role of dust in the working environment in development of chronic bronchitis in British coal miners. Br I Ind Med 30: 217, 1973 77. ARCHER VE., WAGONER 1K, LUNDIN FE: Lung cancer among uranium miners in the United States. Health Phys 25: 351, 1973 78. PROWSE CM: Aspects of pulmonary function in silicosis in South African gold miners, in Pneumoconiosis. Proceedings of an International Conference, Johannesburg, op cit

continued on page 392 GMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 383

Absence of residual pulmonary parenchymal lesions with coccidjoidal involvement of the tracheobronchial lymph nodes is not unusual in coccidioidal meningitis.1'17 Central nervous system infection is usually the result of hematogenous dissemination; while the infection can remain focal, meningitis is more frequent. Basal meningitis, often complicated by obstructive hydrocephalus, is a common cause of death. The course of the meningitis may be protracted regardless of the form of treatment.18 In most patients skin-test reactivity and precipitating 1gM antibodies to the C. immitis antigen will develop shortly after the onset of pulmonary symptoms. If the infection becomes disseminated there is gradual diminution of cellular immune responsiveness as measured by skin reactivity against the C. immitis antigen, with an associated increase in the titre of CF IgG antibody to C. immitis.19 Serum CF titres of 16 and 32 indicate dissemination, whereas decreasing titres indicate a good prognosis.3 The deficiency in host defence allowing disseminated coccidioidomycosis to occur has not been elucidated completely. Opelz and Scheer7 described 74 patients with disseminated disease, of whom 68 demonstrated cutaneous reactivity to coccidioidin injected intradermally, and whose lymphocytes underwent blast transformation in vitro in response to the injection. Such lymphocyte transformation was, however, seen in three of the six patients who failed to demonstrate cutaneous reactivity to coccidioidin. The lymphocyte reactivity to coccidioidin but not to PHA or to allogeneic lymphocytes was abrogated in two of these patients by the addition of autologous plasma to the culture media. The authors made the tenuous suggestion that lymphocyte inhibitory plasma factors may play a role in certain cases of disseminated disease. Rea, Einstein and Levan8 evaluated the immunologic status of 25 patients with disseminated coccidioidomycosis and found that the response to dinitrochlorobenzene sensitization was diminished significantly in patients with higher serum titres of CF antibody to C. immitis. They postulated that nonspecific deficiency of cell-mediated immunity developed secondary to extensive disseminated disease. Catanzaro, Spitler and Moser9 reported unresponsiveness to a series of intradermal antigens as well as reduced in vitro lymphocyte transformation by PHA in four of eight persons with disseminated coccidioidornycosis. Transfer factor is a dialyzable extract of sensitized leukocytes that transfers reactivity from a skin-test-positive donor

Rn& TH, Bmsunr H, Lnv.w NE: Dliiito a skin-test-negative recipient.' Since 8. trochlorobenzene responsivity in disseminated persons with disseminated disease may coccidloidomycosis: an inverse correlation complement-fixing with antibody titers. I have abnormal function of T (thymusInvest Dermatol 66: 34, 1976 derived)-lymphocytes, enhancement of 9. CATANZARO A, SrnLaa LE, Morn KM: Cellular immune response in coccidloidomycoels. cell-mediated immunity with transfer Cell Immunol 360, 1975 factor may have therapeutic potential. 10. GRAYsIU, JR. 15: ELLENDOGEN C: Complications Several studies have reported immuwith the Ommaya reservoir in patients with granulomatous meningitis. I Neuroaurg 38: nologic and clinical improvement in 477, 1973 disseminated coccidioidomycosis fol- 11. SMALE LE, WAncirraa KG: Dissemination of coccidioidomycosis in pregnancy. Am I Ohlowing the use of multiple doses of stet Gynecol 107: 356, 1970 transfer factor obtained from the se- 12. HARRIs RE: Coccidioidomycosis complicating rum of persons having positive skin pregnancy. Report of 3 cases and review of the literature. Obstet Gynecol 28: 401, 1966 tests with coccidioidin."'6 However, DA, LEVINE HB, DEEEsINKI SC, clinical improvement does not follow 13. etSTEVENS al: Miconazole in coccidioldomycosis. IL Therapeutic and pharmacologic studies in transfer factor therapy as consistently man. Am I Med 60: 191, as do conversions of skin tests or mig- 14. KRULIG L, JAcoBs PH, LOEFFEL1976D: Pemphigus vulgaris and disseminated coccidioidomycosis. ration inhibition factor responses.21 Sabouradia 14: 5, 1976 The use of amphotericin B has im- 15. SMITH CE, SAITO MT, SIMoNs SA: Pattern of 39,500 serologic teats in coccidioidomycosis. proved the prognosis for patients with JAMA 160: 546, 1956 disseminated coccidioidomycosis. There 16. JENKINS VE, PosmEwAIm IC: Coccidloidal are reports of several patients surviving meningitis: report of four cases with necropsy findings in three cases. Ann Intern Med 35: for years and possibly even being cured 1068, 1951 of C. immitis meningitis after receiving 17. FErrER BF, KLINTWORTH GK, HENDRY WS: amphotericin B intrathecally."' The Mycotic Diseases of the Central Nervous System, Baltimore, Williams and Wilkins, 1967, prognosis remains poor, however, unp 77 less the disease is diagnosed early and 18. NORMAN DD, MILLER ZR: Coccidioldomycosis of central nervous system; case of 10 years' treated aggressively. The intrathecal duration. Neurology (Minneap) 4: 713, 1954 use of this drug is associated with a high 19. LEVIN AS, SPIThER LE, FUDENBERG HH: Transfer factor therapy in immune deficiency incidence of arachnoiditis, and a substates. Annu Rev Med 24: 175, 1973 stantial proportion of patients fail to 20. LAWRENCE HS: The transfer in humans of show clinical improvement.". The new delayed skin sensitivity to streptococcal M substance and to tuberculin with disrupted antifungal agent miconazole nitrate apleukocytes. I Clin Invest 34: 219, 1955 pears to be less toxic than amphotericin 21. GRAYsILL JR: Transfer factor in diseases of the central nervous system. Adv Neurol 6: B and is promising in the treatment of 107, 1974 some patients with fungal meningitis.'3"'4 22. WINN WA: Coccidioldal meningitis: a folWheezing following parenteral adminislow-up report, in Proceedings of the Second Coccidioidomycosis Symposium, Phoenix, Aritration of miconazole nitrate has not zona, 1965, MEuo L (ed), Tucson, U of Arizona Pr, 1967, p 55 been described previously; the patho23. ABERNATHY RS: Treatment of systemic myphysiologic cause is unknown. coses. Medicine (Baltimore) 52: 385, Coccidioidomycosis, although ende- 24. DERESINKI SC, LILLY RB? LEvIN HB, 1973 et al: Treatment of fungal meningitis with miconamic to the southwestern and western zole. Arch Intern Med 137: 1180, 1977 United States, Mexico and South America, may be seen in patients who have had limited exposure in an endemic area.3 Physicians should be aware of CIGARETTE SMOKING this disease, its manifestations and its potential for dissemination. The new continued from page 383 types of therapy offer some hope in the 79. GILSON JC, DAvIES TAL, OLDEAM DA: Study of respiratory responses to duration of treatment of disseminated coccidioidofoundry work, ibid, pp 445-49 mycosis, but early diagnosis and insti- 80. FOLIRNIER-MASSEY G, BECKLAKE MR: Pultution of therapy are imperative. monary function profiles in Quebec asbestos

References I. EMMONS CW, BINFORD CH, UTZ JP (eds): Coccidjoidomycosis, in Medical Mycology, Philadelphia, Lea & Febiger, 1970, p 207 2. PAPAGIANIS D: Coccidioides in the soil and the meninges. West I Med 119: 51, 1973

3. Lirrae.r ML, Moaowrrz PL, SEADEY JG:

Coccidioidomycosis and its treatment with amphotericin B. Am I Med 24: 568, 1958

4. Em.srarn HE: Coccidioidomycosis of the central nervous system. Adv Neurol 6: 101, 1974 5. GRAYDILL JR, SILvA 3 .71, ALFORD RH, et al: Immunologic and clinical improvement of progressive coccidioidomycosis following administration of transfer factor. Cell Immunol

8: 120, 1973 6. CATANZARO A, 5.rstaa L, MOSER KM: Immunotherapy of coccidioidomycosis. I Clin Invest 54: 690, 1974 7. OPELZ G, Scuaan MI: Cutaneous sensitivity and in vitro responsiveness of lymphocytes in patients with disseminated coccidloidomycosis. I Inject Dis 132: 250, 1975

392 CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118

workers. Bull Physlopathol R espir (Nancy) 11: 429, 1975 81. THERIAULT GP, PETEas JM, FINE U: Pulmonary function in granite shed workers of Vermont. Arch Environ Health 28: 18, 1974

82. MERCHANT IA, LUM5DEN JC, KnauaN KH,

83. 84.

85. 86.

et al: An industrial study of the biological effects of cotton dust and cigarette smoke exposure. I Occup Med 15: 212, 1973 KLEINFELD MA: A comparative clinical and pulmonary function study of grain handlers and bakers. Ann NY Acad Sci 221: 86, 1974 Ministry of Health: Mortality and morbidity during the London fog of December 1952, in Reports on Public Health and Medical Subjects 95, London; HMSO, 1954 LOGAN WPD: Mortality from fog in London, January, 1956. Br Med 1 1: 722, 1956 FIRKET J: Sur les causes des accidents survenus dans la vallEe de Ia Meuse, lors des broulliards de d6cembre 1930. REsultats de l'expertise judicisire falte par MM. Dehalu, Schoofs, Mage, Batta, Bovy Ct Firket. Bull Acad R Med Beig 11: 683, 1931

87. SCHRENK

HH, HEIMANN

H,

CLAYTON GD,

et al: Air pollution in Donora, Pa. Epidemiology of the unusual smog episode of October 1948. Public Health Bull 306: 1, 1949

Cigarette smoking and reactions to air pollutants.

Cigarette smoking and reactions to air pollutants Ro. J. SHEPHARD, MD, PH D There are many mechanisms whereby recent exposure to cigarette smoke augme...
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