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The Limiting Factors , . in Understanding the iVatura[ History J" of Tobacco SrnoiCe i:rfects y , l r ~J . 4 in the Lung MARIO C: BAT7IIGELL! ©iNision of'Pufmonary! Medicine University of North Carolirlta ' Chapel H(ill, North Carolina 27514 The function of' the respiratory apparatus ultimately consists of matching a certain ventiltttory tlow to a corTeaponding flow of blood at the alveolar membrane: The deceptive simpiicity of these elements of respiratory physioi- ogy hardly betrays the vast array of the pathological factors toward which the respiratory apparatus is vulrnerable and that eventually lead to respiratory im- pairrttent and failure in an aimost infinite compiexity of steps aad phasp. Ventilatory disorders, for instance, are tht: direct or mediated consequence of mechattical deranaements, such as obstructive lesions (tunctional or structurai~ or power failure of either a musculhr or neuroloeical nature-either one the possible consequencr of pharrnacoio¢ical, infectiouss toxic, oral'ternative ctioll ogy: Perfusiion chan2es, similarly may derive from a constellhtion of factors~ such as embolic phenomena, infecuous processes, or esrd'iac pump failure or its inadequacy. Each of these; in turn, mary be the possible consequence of untoward exposure to noxious factors, cigarette smoke included. tAlthough ir is convenient to enter a discussion of potential and actual causes in this context, it is considerably more diflicult to analyze the realistic events in detail in any Aiven and real ina-tnnce. Often the blz: k box cF the natural hi'story of respirstory diseases ts very much ti¢htly seaied altd inscruta- ble. This is particulariy true in the intertnediate and early, phasts ot' the d'asease process. Our knowledee of pathoiory, although consiidectbl', is discontinuouss and incomplete, a series of snapshots whenn the facts call for a high-grade movie sequence: The actual chain of e+unts; going from health to disease, remainss largcly an unresolved mystery. The transition between health and dise:ues. ;Ls eloquently commented in a recent paper by Thuribeck (19791, urgently needs clariftcation througtt structure-function cotrelative studies. In the particular casc of cigarette-smoke injury of the tripir.ttory function; the end points are well identifned, but the intermediate steps ure not4 Cellular', tissue, and organ d:unage are known mostlv in their conclu+ive and' adv;utced stages, when the reversibility of the injµry is limited or, cis fior the ccue ot' neoplutic changes„ laurgely not expectctll For pre+•entive intervention, this 1005053094 r

limitation in the knowledge retains a major importance. In term5 of prospective ~: projections. for instance: the definition of a safe cigarette. the as ailable data are painftillv inadequate. Missing are the quantitative parameters. the sequence in chronology of each aberrancy, and the intetaelation between different' and dkcrete processes making up the whole natural history of the injury. To establish a dose-effect relationship, a much needed step in modeling tox- icolo¢icall vrocesses, these dimensions must be secured for each exposure ' modalitv. and for each chemical or combinationi ofi'chemicals and suspected agcnts, or. in other words, for each dose characteristic. If correctioni must be ai attempted~ the very process causing injury needs to be better identitied in details of natural history. with adequate rneasurements obtained along, a time ~ sequence. Otherwise the only option available for prevention would' be un- wj-' selected and total, abolition of tobacco use, a solution ideally jusritied but ;:~ realistically impractical. The appropriate questions. then, are: Do we know the morphological details of cigarette smoke inhalation to a degree adequate to formulate .apro- priate standards of' use or safety?' Do we know the relationships linking the ,; :~ ; charrcteristics of exposure (i.e., dose) i to the relevant morphological' and funa tional aspects of effect in relation to their specific features of reversible and irreversible outcome? Do we know this, with accuracy sufficient to extrapolate elements of guidance usefull in engineering a, safe product''' We speak of emphysema, of chronic bronchitis, of obstructive respiratory Iesions, of neo- ,.; plastic effects, often neglecting that these are the far advanced results of a process that has progressed usually for years and, often for decades. These advanced results have destroyed details of cytological physiology and their f ne .• morphological cotrelates, which at earlier times must have characterized the progress of injury. The search tor eari!v aspects of this history has traditionally concluded in the identification of the following five separate phases (Bates 1979) in the natural history of chronic airways disorders: 1. hypertrophy of mucous glands in large ainvays: 2. alteration of physical' properties of the lung; 3, morphological changes of small airways; 4. early loss of alveoli: • 5. regional nonuniformity of these changes leading to altered ventilation-' perfusion relationship. Some of the difficulties inherent to these studies are: 1. longitudinal morphological studies of human tissue; 2. tetli,tic animal modcls for chronic disease: 3, correlative studies of structure and function. Recenr views have been voiced against this sequence, questioning, for instance the hypcrsccretoty phase as an obligatory step in this pathological .L 0'IJ5QP if-~!V~S

U Clmitiny Factors of Tobaew Smok*J166 sequence, even deeper doubts are shadowing an elementary understanding; of the problem of neoplssia. lndeed; to be speciffc. the question of independent carcinogenicity of the major individual constituents of tobacco smoke, in the J*~--~ actual context of'human exposure. remains larcely conjecturat. 71 Not the least of the concern in this context of complexity is offered by the wide constellation of putati*.e or real (and proven) respiratory effects in re Psponse to tobacco smoke, which are listed here without any attempt to rank them in importance or chronological order a°; {r ,~1„ ~ { ~ ~,I I 1. reflexes. { T: ,. 2. secnetions, 3. smooth muscle activation, 4. surface chantes. 5. permeability effects. 6: chemotaxis, 7: immune mechanism. 8'. hyperrtrophy, 9. metapiasia. 10. proliferation. . Having reco¢nized the varietyy of consequences resulting from exposure and having identifed the main agents participating in this exposure, we are left still with disturbiit, ;aps in knowledge. The main variables that are recognized .; .; ;.. .-! to influence andicontrol toxicolbgical effects are: . l. nature:of agent. 2. effectiive~quantity (intensity and!dttration).. ' 3. nature of actions, 4. host factors (susceptibilicy, etc:). , ~ The details of information on this matter can be oni.• sunnised. perhaps on aa qualitative base. without much data for their respective quantitative values. 1'n summary, it is prudent to conclude that the problem waits to be better defined in its constituent detailk betore its solution can oeaccomplished. Unless the details are known in their temporal' and dosimetric characteristics (which chemical, which process, which locus„which tiine, etc.): the black bux will not i offer wide avenues of remedy and correction.~A vigorous programof research. : coordinated in scope and pursued with, the support of funding commensurate ~ with the magnitude of the task in quesoion, still awaits conception and' im• plementatimn. It is consoling to realize that the solution ot`the cigarette smoking toxicolbgy will represent a milestone in pulmonary medicine, well beyond the immediate saving of lives and health. For the moment, the question posed by the definition of a safer tobacco product may be rcasonably answered with the~st:ucmznt advocating combustion that generates less g,ueous products and less particulates. In plain words, the dose must be sltL,hed. 1005053096

681 M.C. Batdgali . REFERENCES Bates. D.W:. 1979. Chronic brunehitis. and emphysema: The search for their natural history, In~ The Lrne in the tranritirn benaeen IJealthi and disease (eds. P.T. Macklem and'S_ Permutt). voi, 12. Marcel DcU:er Inc.. New York. Fletcher. C.M: and R. Peto. 1'976. The natural history of chronic airtlow obstruction. Brdl. Lrtt. Union Tuberc. S3:78! Thuribeck. W.:W. 1979. Changes in lung structure. In The Lung in the transition benruen hea/th und'disru.re teds: P.T. \4acklem and S. Permuttu h+tarcel' Dektcer Inc.. New York. : , _ CIOMMEMTS. s w'YNDER: The end& point in chronic obstructive pulmonary, diseass (COPDI. in terms of a less: harmful cigarette„ is far more difficult to measure a'tan~ the end, point of 1un; cancer and' myor.irdial infarction. I wonder whether you~ ebuld! comment' on this from an epidemiologic standpoint: that is, wharwould be~the first endpoint that you would be lookins for in a study of COPD? ~ BATTtGEL1:1: Probably a singlie indicator of incipient effect does not exist. It is more likely a choire of several indicators that would be used: simulta, neously andl changed as new data become available. 'Ihe tests eurrentlv accepted for small airways, such as the tlow rates at lower luns volumes and the middle -maximal expiratory rates, are currently considered the most sensitive indicators. Of coursz, clinical subjective evidence of ab- norm'al'. airways (cough. sputum, etc.) and the mea.surement of diffusion function may be additional irldices, encompassing,emphysematous change in addition ttD bronchitis. _ However, these are coarse indicators, limited to the effects of cigarette smoke on the airways quite independently of'any effect caused on other systems (i.e. cardiovascular system). and in fact witnout much~ direct correlation with the neopiastic effects on respiratory, ttissues