Medical studies needed to produce new data on which to base sound criteria for ambient air quality: inter-regional symposium on criteria for air quality and methods of measurement, Geneva, 6-12 August 1963

- -- - ---------------- WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE INTER-REGIONAL SYMPOSIUM ON CRITERIA FOR AIR QUALITY AND ME'lliODS OF MEASUREMENT t,THO/AP/18 31 July 1963 Geneva, 6-12 August 1963 ENCLIS.-1 ONLY MEDICAL STUDIES NEEDED TO PRODUCE NEW DATA ON WHICH TO BASE SOUND CRITERIA FOR AMBIENT AIR QUALITY by John R. Goldsmith, M.D. Head, Air Pollution Medical Studies California State Department of Public Health Berkeley, California * *Those who follow the world must hurry their footsteps" INTROOOCTION Many citizens of many countries of the world, particularly those in urban regions, are convinced that air pollution is not only offensive but harmful to the health. They seek control and prevention of pollution and look to the scientific community for evidence as to effects on human health cf the present and anticipated pollution levels. In the area of medical studies needed for air quality criteria, we have been lagging behind what is expected of us and we must "hurry our footsteps 11 in order that medical science can fulfil its promise, often implied, of securing a more healthful world. * Such medical studies require that either of two questions be attacked: 1. Do medical entities (for example, asthma, eye irritation, chronic bronchitis, lung cancer, or pulmonary emphysema) possess a possi- ble or probable relationship to exposure to polluted air? 2. Does a given pollutant or group of pollutants (known to be emitted or to be produced from the emissions of smelters, power plants, in- dustrial processes, household heating, or automobiles) have the capacity to interfere with health? From the poem, 11 The Eastern Suburbs", by Wei Ying-Wu from "Poems of the T 1ang Dynasty" 1 AP/18 page2 For purposes of this paper interference with health will be interpreted to mean (1) production of acute sickness or death, (2) production of chronic disease or life-span shortening, (3) production of significant interference with important functions of the body~ or (4) production of sensory irritation. While the first question is disease-oriented, and hence will be dealt with largely by epidemiological methods, there is an intimate relationship between epidemiological studies and the other criteria of interference with health. Not only are epidemiological methods needed for answering the obvious questions re- lating exposure to medical entities, but medical studies using experimental tech- niques frequently lead to methods of importance in epidemiological research. This is true, for example, of the current research on physiological responses to 11 tant 2~3,4~5,6,7,8 f . . th po u s. Indeed to seek a set o a1r quality cr1teria on e basis either of experimental studies or epidemiological studies alone would appear to be nearly impossible. Both are required and the intimacy with which they are related may determine the soundness of the set of criteria. One of the most important problems is the manner in which evidence concern- ing such health effects as acute illness, chronic disease, premature ageing or fatality could be used in air quality criteria. Certainly as episodes occur, epidemiological studies will contribute a great deal, but every such episode re- presents a failure of both public health and air pollution control and such epi- sodes should be increasingly rare. EXPERIMENTAL HUMAN EXPOSURES The scientists' approach to this problem is emotional~ coloured by the un- pardonable and unscientific acts committed upon inmates of German concentration camps. No medical scientist should ever undertake research which might produce chronic illness or death of experimental human subjects; nor should any be con- templated which would produce any ill effects which are not, to the best of available knowledge, completely and promptly reversible. The first difficult problem then has to do with the circumstances under which any deliberate human exposures to air pollutants under experimental circum- stances would be ethically justifiable and technically feasible. ethical and legal guides are indicated elsewhere. 9•10 Some of the AP/18 page 3 Technical problems of experimental h~~ exposure vary with the substance and response to be looked for, but some general requirements need to be stressed. The method of detecting a response must be of high sensitivity, and the response should be of the sort which is not available in experimental animals and which is of particular relevance to human health. The apparatus for exposure, for moni- toring,and for detecting the response should be as close in time and space as is possible. One desirable endpoint should be the reversible but significant im- pairment of important bodily fUnction. Examples of such studies are the respon- . ll 12 13 14 . . ses of the lungs and a~:M·Tays 3 9 , ' and the extens~ve exper~mental expo- sure systems using neuro-physiological responses carried out in the Soviet Union15 • When the effect being studied is sensory irritation, substantial importance attaches to both subjcctiveandDbjective criteria, though in some cases objective criteria must also be obtained using experjmental animals. Depending on the pol- lutant, objective responses to exposure may precede, that is, occur at a lower concentration, or follow~ that is, oo~llr at a higher concentration, than do s~b­ je.ctive responses. But in a technically satisfactory experiment, the opportunity to observe both should be included. RELATION OF CHRONIC DISEASE AND LIFE-SPAN SHORTENING TO REPEATED IRRITATION OR IMPAIRMENT The relationship betw€cn pollution and chronic diseases is of particular concern because: a) minute amounts of chemical and physical agents have been shown to cause some important chronic diseases of widespread prevalence; b) studies on chronic diseases are of long duration and of unusual complexity, and c) the in- creasing relative importance of chronic disease compared with acute illness. The prevailing patterns of research support tend to encourage studies of acute or short-term reactions, Air pollution is a potentially preventible environmental agent in chronic disease causation as contrasted to other less readily controlled determinants of chronic disease" Methods and procedures are needed which will give valid pre- dictions of the chronic disease potential of pollutant exposures. Also needed are methods for studying multiple and fluctuating exposures. Among the chronic conditions of greatest importance for study are lung cancer, pulmonary emphysema, asthma, bronchitis, and pulmonary fibrosis, as well as. life shortening. AP/18 page 4 A major research problem concerns the possibilit.y that significant and re- peated impairment in physiological function is an indicator of the possibility of the production of chronic disease or accelerated age1ng. 16 This idea presents itself because of reluctance to await proof that air pollution exposures result in chronic diseases, when the natural history of the disease may take many years to unfold. If one awaited proof that human life shortening or chronic disease production had in fact occurred, it would doom many of the persons exposed to later development of these effects. While this concept of a relationship between significant physiological impairment and the production of chronic disease will be very difficult to proveJ every effort should be made to obtain observations which may be relevant to it. This especially applies to continuous or repeated animal exposures to low levels ofpollutants a~d their cbservation over many years. Because of the possibility that there may be a relationship of physiological im- pairment to long-term effects, the California Air Quality Standards combine in one category of exposure effects both the production of significant interference with bodily function and the production of chronic disease. This grouping of air quality criteria provides an alternative to a costly and complex research problem, but the need for such research is not diminished by this decision. FATE OF INHALED OR ABSORBED POLLUTANTS Another general problem is concerned with the absorption, distribution, de- toxification, and excretion of pollutants. A good deal is known about the fate of inhaled carbon monoxide (it is apparently not metabolized, but excreted in nearly quantitative form in the expired air). 17 Much is known about the fate of inhaled sulfur dioxide, thanks to the work of Balchum et a1.18 A good deal has been published about the effects of atmospheric fluorides19' . 20 21 and atmospher~c lead ' on the body burden of these substances. A question of some significance is whether or not an increase in the storage in the body in atmospheric pollutant is itself an adequate criterion for air quality. There are some who feel that this is the case for lead, though it is probably not the case for fluorides where a certain amount of fluoride is widely felt to be desirable from the point of view of dental health. Perhaps the storage in the body of a pollutant which is capable of causing, if released into the circulation, one of the other health effects earlier listed should also be considered itself to be 22 a health effect within the framework of criteria of air quality. STUDIES ON AIR POLLl.JTA..lffS AFFECTING RESPIRATORY FUNCTION Effects on mechanics of respiration AP/-18 page 5 . 23 24 . As sho~m by Dubois et al, and by Dautrcbande· ~ ~ so-called ~nert dusts arc capable of produing a physiological response of increased airway resistance, the mechanism for which has been studied by others. 11 These experimental exposures~ however; a~e not always realistic and the effort to relate realistic exposures to such responses is most important. One does not know whether the small particle pollutants associated with photochemical pollution or metallic fumes in the vari-· o<J.s heavy industries also h:'1vc the potential to produce changes in airway calibre and hence airwe.y resistance. McDcrmott25 has simulated conditions of occupational exposure :i.n miners and produced significant responses. For realistic exposures 3 however, the combination of particulates and pollutant gases probably should be considered. Studies with oil and other organic mists arc needed. SulfUr dioxide is one of the earliest agents shown to have an effect on the h i +' • • 26 If t th . . 1 that th t . ti mec an cs o. rcs~1rat1on. one accep .s .e pr1nc1p c e mos sens1 ve group in the population is the one for which air quality criteria are. most impor- 27 tant~ then the matter of sensitivity to sulfur dioxide as observed by Sim and 28 Pattl8 as well as by others~ becomes of importance. It is.currently under in- vestigation and there are at least two questions that need to be answered~ l) the proportion, if any, of ~he goperal population likely to be sensitive to air pol- lutants such as sulfur dio~:j.de~_ as well as the levels at which they respond and the health stn.-~.,us- of' these individuals s and 2) whether thu response of sensitive individuals, if present, is through a different mechanism that that of the bulk of the population. Similar work is needed for other pollutants and for combina- tions. Effects on airway mechanics of f'imulated photochemical pollutants have been shown to exist by Murphy. 29 This work in animals, however, needs to be repeated in humans under properly controlled conditjons. The effects of nitrogen dioxide at levels likely to occur in community air pollution needs to be studied to answer two questions, First~what is the earliest physiologically detected respor.se and~ secondly~ what is the relationship of rea- listic exposures to the potential fo~ development of chronic disease. Very little is lmown about the earliest physiological response other than that acute exposures . . B 30~31 are capable of producing pulmonary edcma. Kle1ncrman and Wr1ght, and oren AP/18 page 6 have shown, respectively, the evolution of the acute lesion and the possibility that it will produce a pathologic change which resembles emphysema in rabbits and the capacity of soot to absorb nitrogen dioxide and carry it into the lung in a way which produces destructive alveolar lesions. The trend seems to be in the direction of the ability to reproduce in experimental animals from various types of exposures to nitrogen dioxide many of the features of chronic obstructive pulmonary diseases in man. Perhaps the most valuable studies to be done would be physiological studies of individuals whose occupation makes it likely that they will be exposed to nitrogen dioxide. Such exposures do occur in occupations32 and it is important to take advantage of them. The effects of ozDne have many common features resembling those of nitrogen dioxide. Indeed, one important study would be to determine L~ what manner both of these agents react with the surface materials lining the alveoli, since it is unlikely that either of them is absorbed as such. One therefore wishes to know what are their reaction products with alveolar lining substance since there is evidence that they may be quite active. The recent demonstration of the importance to respiratory fUnction of the surface active material lining the alveoli has led to the natural question as to whether some pollutants may inactivate or·inhibit this material. This possi- bility is even more attractive because of the demonstration by Hackney and Collier33 that continuous exposure to high partial pressures of oxygen will in- activate the substance and ~~ey have suggested that perhaps ozone will do so also. Both ozone and nitrogen dioxide also show cross tolerance34 suggesting a common mechanism. Occupation exposures to ozone are also common and efforts should be made to identify workmen exposed, particularly those who have low- level exposures over a long period of time in order to see whether the frequency of chronic respiratory disease is greater in such individuals. Bcnnett35 has demonstrated a reduction in the forced expiratory volume in one second, in per- sons who are repeatedly exposed to ozone over a period of several weeks. This was reported to be reversible, also over a period of several weeks. Such studies should be repeated in different population groups. AP/18 page 7 Experimentally, sulfuric acid ·mist when the particle size is small is known to be more toxic ~han -is an equal concentration of molecules of sulfur dioxide. Howe-ver, few studies on human .respiratory responses are reported and the8c should be obtained particularly· in the light of the hypothesis that the air pollution disasters of Dono~ and London are largely associated with sul~~ric acid mist. The evidence of Jones .~t al36 suggests that at l8ast one cf the initial reaction products of photochemical pollution jn the presence of sulfur dioxide is a mist of SQlfuric acid with very fine particle size. There must again be many oppor- tunities to coll9ct -'>·J.ch evidence on persons occupationally exposed to sulfilric acid mist if only pll~rsiological methods wo-:J.ld be applied to such populations. While other substances arc capable of affectir~ mechanics of respiration~ it is not likely ~hat the initial cr~teria for air pollution control would be set on the basis of these effects. Such substances would tnc·ludc hydrogen fluo- ride~ hydrogen sulfide~ beL~llium, and others such a~ phosgene, and chlorine. Effects on ~espiratory w~cus an0 ~i,i~~ e?~ivity 37 . The vmrk of Da.lhamm has indi~ated the effect cf sulfur dioxide on the slow- ing of ciliai.~' activity and j_nt.erference with mucus ·now. This work has been ex- tended by Kotj_n, Tremor and Falk3B liDO have discussed its possible relationship to carcinogenesis. Since the motion e>f r·espiratory mucus blanket can be studied conveniently in vitro as well as i:-1 intact subjo~t~. it 1'Kmld scorn worth,·<h..:.le to ci.eterm:!.ne the Jowe~t level at which the several pollutants arc likely to.produce a significantly deteC'"tablc eff\:ct. Here, as in some of the neuro-pllysiological studies a bi-phasic response iE- observed wi.th varie.tions in time and intensity of exposure. These obscrvo:tions always raise a difficult philosophic question as to whether a stirm..llating effec.t of pollution should be interpreted as potentially harmful_ Tnis qucstior1 should be further discussed, but at least one wa:y of re- solving the qucst:Lo!l Nould be to base air quaJity oriteria on any reliable biolo- gical response whett1er it.appe~rs to be a favourable or unfavourable one. STUDIES RELATnrc AIR POI.i.UTION EXPOSURES TO THE PRODUCTION OF PUlMONARY FIBROSIS Non-occupational pulmonary fibrosis has in the last decade more than doubled as a cause of death in the United States and in the State of California has AP/18 page 8 * :J9 40 increased fourfold ~ • While the effects of silica-containing dust in the production of pulmonary fibrosis is well established in man~ the effects of gas- eous air pollutants and of gaseous air pollutants in combination with particu- lates is not clearly established. Animal studies suggest that nitrogen dioxide is capable of producing fibrosis in experimental animals. 41 , 42 , 43 The possibi- lity that such changes occur in humans who areeKposed needs to be investigated by epidemiological studies of occupationally exposed populations and -·of popula- tions exposed to community air pollution. Fibrosis has been reported to be higher in areas of Tokyo which are high in pollution, and similar studies using the medi- 44 cal examiner's office could well be done elsewhere. In addition experimental studies are needed to obtain better understanding of the mechanism by which fibro- sis is produced. Effects of pollution on the central nervous system Carbon monoxide has long been known to decrease the visual sensitivity under conditions of inadequate illumination. While this can be demonstrated in the 45 laboratory very readily~ its importance to the safety of motor vehicle operators in a large city is not known. Further studies of thiE' sort would be very helpful. Recent Soviet work has indicated that changes in light sensitivity may occur in 46 two phases with first an increase and then a decrease, and many substances ap- pear capable of producing such a reaction. The effects of various pollutants on the electro-encephalogram and~ by inference, on the function of the cerebral cor- . 46 text have been extensively and effectively developed by Soviet sc~entists and show promise of providing very sensitive indications of the earliest effects, of pollution. The effects on conditioned reflexes also are a promising area for further studies. While the work of Nadel and Widdicombe11 has indicated the res- pensiveness of autonomic mechanisms in the respi1atory tract to pollutant expo- sures, more work is needed on the responses of the olfactory system3 the eye and the upper airway. Any review of the literature on taste and odour threshold cannot fail to show the variability of the findings r~9orted. * This increase is probably less, however, since death coding practices in California appear to l~~p in one cause interstitial pneumonitis unspeci- fied in infants with pulmonary fibrosis of non-occupational origin. The increase in this cause (ISC 525) in those over 5 years is from 0.7 to 1.6 per 100 000. AP/18 page 9 Some of the problems in this area have been reported on recently by Baker47 and some theoretical approaches to the quantification of sensory responses has 48 been recently presented by Stevens. While there can be no question of the im- portance of sensory irritation data to air quality criteria, the agreement upon standard test conditions is extremely important and the detection both of sub- jective and objective responses should be included in research studies. Much of the past work has been on the technique of finding the lowest level at which sensory responses would occur, and relatively little has been done on the complex consequences of sensory stimulation or irnitation. It is intuitively clear that many of the responses of corrnnunities to air pollution are in fact responses to these consequences and research on the relationship of sensory stimuli to atti- tude, to mood~ to working effectiveness, and to the physiological performance under stressful conditions are all areas where additional studies would be valu- able. Joint effects of gaseous and particulate pollutants 26 Amdur 1 s work has indicated that 0.ttention must be directed to the combined effects of particles and gases when studying physiological responses of the res- piratory system. Other studies have confirmed and extendcd49 this and it is now a reasonable working hypothesis that the efiects of the major categori~s of pol- lution are mostly a response 'to joint effects· of particles and gases. Here the importance of particle size has been recognized but studies to apply this know- ledge are scanty. Partially this nas been because instrumentation has posed dif- ficult problems. But because of the selective retention in the lung of micronic and S'•~-micronic particles much more attention needs to be given to monitoring for particles according to their particle size. This general problem applies to the evaluation of exposures to lead3 Pnd to sulfur dioxide, and to pollutants associated with soots and water droplets. When the ansv/Crs to the joint effects of pollutants are known, it is likely they ~~ill shed light on the baffling ques- tions associated with the air pollution disasters of Donora) London and the Meuse Valley. Some.of the uncertainties about the eye irritating effects of photo- chemical pollution may be resolved when careful attention is given to the parti- culate phase of photochemical pollution. Gaseous pollutants themselves may have complex relationships when more than one species is present and this is to be expected in most community pollution ex- posures. Relatively little work l1as been done and much more is needed along the AP/18 page 10 lines of the studies by Mitina50 who studied ~~e relationship between exposures to sulfur dioxide and nitroge11 dioxide and showed that these two pollutants had slightly antagonistic effects. The recognition tb~t sulfur dioxide and other primary irritants of high solubili 1;y :r-ave a oifferent response mechanism than do such substances as ozone and nitrogen dioxide which have less solubility suggests that these exposures acutely might have synergistic effects. Further studies of the development of tolerance are also desirable. We might seriously consider the ultimate goal of air quality c:.."'i teria to h'J ::~. realistic combina- tion of pollutants~ although this will need much additional research. One approach to the development of air quality criteria for complex pollu- ·bant mixtures is to develop biological indicators of pollutant effects. In one sens-e the vcgeta:~.ion damage frol!l photochemical :rollut5.on is an indication o'f the amount-of physico-cherr.ical synergism b~tween irradiated axides of nitrogen and hydrocarbons. The oxygen delivery capacity of the blood when exposed to several different pollutants may be another suitable indicator of the corr.bined effects of nitrogen dioxide end carbon monoxide. 51 Further work of this sort would be constructive. The photodynamic response of animals and protozoa to the expo~ sures of polynuclear hydrocarbons f·llowed by radin.tion is another example. 52 The effects of environmental temperature, humidity, radiation and pressure on pollutant effects The effects of carbon monoxide are clearly of greater consequence at re- latively high altitude than they are at sea level because of the diminished oxygen tension of the air. The effects of pollutants which interfere with res- piratory function may also be of greater consequence at high altitude and addi- tional studies on this are indicated. Sulfur dioxiue may be more toxic under conditions in which it is absorbed on to condensation nuclei or small water droplets because under these circumstances it w~y be oxidized to sulfur trioxide or hydrated to sulfuric acid. Since temperature and humidity themselves impose a physiological stress, some pollut,::mts may have greater effects under these circumstances and the assoc~_o.tion of po_l_JL-.t;jr~'l ::::-:r ~crt·.--ltion with high tempera- ture in Los Angelesfj) -w.-• .i with cold damp weather in England54o.nd the Eastcrn55 part of the United States n.rc exanples of the impact of '.'rea the:.."' variables on pollutant effects. r1uch more information is needed to a~)ply this sort of infor- mation to air quality criteria. The effects of radiation, of course, may deter- mine the extent to which photochemical reactions go to produce harmful products AP/18 page 11 but also the extent to which some of the emitted pollutants (oxides of nitrogen) may have effects in and of themselves. Studies of this type should make it pos- sible to decide whether different areas should have different types of air qua- lity criteria depending on their climate, geography, and altitude. DISCUSSION TI1is compilation regrettably is based only on the author's personal and limited acquaintance with present research and methcds, which have been used as a major basis for the report. An entirely different approach could be based on elaborating for air quality criteria a list of values as extensive as that used in occupational health. Hm'l'ever, such a list must almost inevitably be based on extensive extrapolation. Because control programmes for air pollution may require much more disrup- tive action than those in occupational health 3 this seems to indicate the desi- rability of scientifically sound predictive criteria. It is suggested that a compilation be made of additional medical studies needed and that it be distributed to medical investigators who may be interested. When work is done which answers some of the questions raised, it should be wide- ly reported3 possibly through the World Health Organization. Such a procedure would have the advantage of speeding up the communication of significant research findings and of holding out to medical scientists in many countries the challenge of answering questions of overwhelming public concern and importance. REFERENCES . - . AP/18 Annex page i 1. Ying-Wu2 Wei. "Poems of the T'ang Dynasty" translated by Soame Jenyms Murray ~ London 1944 2. 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