Appendix D (CRC-Aprac Meeting Held on 4/6/77) - Commentary on the Effects of O3 on Human Pulmonary Function Reported on a Visit to the Labs in Moers, Germany

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The following commentary on the effects of .O3 on human pulmonary function that were reported by von Nieding and \?agner i s based on references1to3 and on my visit to the laboratory in Ko ers, Germany, where the studies During 1975 - 1976,twelve healthy male volunteers employed atthe hospital, 24 t o 38 years old, were exposed to03,NO2, and S02,alone and in combination,usually for periods lasting two hours. The nost commonly used gas concentrations were 0.1 ppm o f 03, 5 ppm of N02, and 5 ppm of SOz. These are the maximum allowable concentrations for occupational settings for community air). relative humidity of 552. The lowest concentrations were administered only in Combination; The exposure chamber 17as at a temperature of 22OC and The studies were performed between 4 and 9 pn. They consisted of a 1 hour control period,two hours of exposure, and a one hour post - exposure during each hour of exposure. minute ventilation. The subjects probably breathed by nose during most of the exposure,although voii Nieding believed that their breathing may have been oral during exercise. The subjects exercised on a bicycle within the chamber for 15 minutes The exercise caused an approximate doubling of The methods of generating and monitoring the pollutant will be disc uc scd by Peter Mueller. seated in a pressure-plethysmograph and breathing quietly (Siemen's technique). The type of tracing obtaj.ned with this technique is shown in Figure1 (it i s my own drawing based 011 os cill o graphic tracings shown a t I-loers). Flow during inspiration and expiration was measured witha pneumotachograph (Y axis) ; pressure was measured atthe mouth (X axis). the L racing was expressed by a single value. It will be noted that some judgement is involved in assigning as ii lg le value to the slope of this ear lobe.02To " arterial ize " the blood, avaso - dilating ointment was applied artel - ial PO2 gradient co uh be calculated. exchange included arterial and alveolar Pco2 and the respiratory exchange The overall slope of b. P was measured on " arterial i zed " capillary blood obtained front the Alveolar Po vas also measured, from which the alveolar - Other measurcnients of g a s c. There were additional measurements of the thoracic gas volume, helium d.Functional measurements were made atthe cnd of the control period, after1 arid 2 hours of cxposurc, and 1 hour following the cncl of exposure.

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Kesul tsand Conunen t s a. The sham exposures were un associated r.rith significant fun cr ional b.There were no significant changes i n CV, slope of the nitrogen washout curve (phase 111 ofthe CV Pieasurement), orf low-volume curve. The absence of a change inclosing volume and of the last half of the f low-volume curve is evidence against narroraing of the small airways. Significant narrowing of the central airways would be expected to reduce peak flow rate and FEVI; significant narrowing of more per ipl iial airways vo ul dbe expected to reduce llaximum Nid Ex pira tory Flow Rate (KGR) and Haxircum Ex pira tory Flow Rate a t 25% of VC. extracted from The flow-volume curve. All of these values can be Apparently none were affected. c. Pa02: The mean control value of 84.6f1.3Torr (1) is low for healthy seated subjects at sea level. According to Mell enga ard(1966),the rang: of P,02 for individuals between 2 4 and 38 years of ageis97.7 - 93.9 Torr. If the subjects in the present study are assumed to have been healthy,the low values suggest either that the blood samples were not fully arterial i zed or that the technique underestimates the true value. is true, any slight changes in the degree of arterial iz ation could have profound effects on the measurement, independently .of functional changes occur ing If the former explanation The results obtained with exposure to03, NO2 and S02,alone and i n Combination (2,3) are s umar iz cd in Table 1. For simplicity only average *On 3/25, my Pa0 measured ina sample taken in von Nie ding ' s laboratory ear lobe and radial artery in the Pulmonary Division Lz b oratory,University of Washington Medical Center, gave values of 39 and 94 Torr,respectively (plI was 7.40in each sample) I vas seated on both occasions. this technique underestimates Pao2. Seven 2ays later, blood samples taken simultaneously from ny Several features of these results warrant coiniient: Essentially the same reduction in Pa02 (P<O. 01) occurred when all three gases were administered either individually or in combination,suggesting an "all-or-none1' phenomenon i n which "none" was never observed. i t might he surmised that some factor other than the pollutant gases, which was not measured, may have affected Pao2. effects were produced by the coinbinacion of gases. Certa-inly, no additive or synergistic The effect produced by 5 ppm of SO2 is surprising.This concentration (during2hours of exposure) is not Likely to damage either L he alveolar - capillary membrane or peripheral airways.Sign iii cant changes in cn li1)cr of the airways could alter ventilation - profusion ratios in the lung and account

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for this fallin PaO2. is evidence against such narrowing while the apparent effect of SO2 011 flow resistance in the central airways(Kt,Table 2) seems too slight to have Dut the lack of changes i n CV and flow-volume curves d . Rt: Flow resistance increased 0.5 CIU II2O/L/sec after two hours of exposure t o 0.1 ppm of O3(P<O- 01.) , and remained elevated during the A similar increase in Rt during exposure was noted for SO2(2 hour exposure). Among the single gases, NO2 caused the greatest increase in Rt after two This delay in recovery was also noted with K02. Once again,there were no additive or synergistic effects when either 03 and KO2orSO2 and KO2 \<ere combined, although the mixture of all three gases (?.LAIC) may have caused the greatest increase in R,. R, tended to increase during the sham exposure(not statistically During our visit, von Nie ding remarked that Ulmer in Germany had exposed healthy subjects to similar concentrations of NO2for the same length of tine and had observed increases in flow resistance,but no changes in Pa02. e. Symptoms were minimal, the most con;ri:on being throat irritation. by Ach, a parasyinpathomimetic agent, would be inflt.enced by previous administration of the pollutants,subjects were first exposed for two hours to mixtures of PI IK or MAK. Thereafter,they inhaled fixed volumes of 1,2 and 3% Ach, sequentially.Particle size was said to be 2-8 lim in diameter. Following adu in is t ration of each solution,Rt and thoracic gas volume were measured. KO time ~ 7 a sa ll owed for recovery between solutions,nor was tLFe allowed for recovery following the original exposure to HAii. The findings may b e stiuunarized as follows : The increases in Rt in response to Ach were smallest in control subjects (no previous exposure to pollutants),interRed i ate in subjects eirposed to t fI K(FI IK alone caused no change inRc), and greatest following >L?.According to the authors, the magnitude of the change in R, was a function of concentration,being greatest for 3% Ach (true of Figure4,reference2,but not true of Figure 3, same reference). Thoracic gas volune also increased ; whether the increase occurred in all3 groups of rub j ect s following all 3concentrations of Ach is not stated. The authors assign major significance to the finding that ambient air standards (I1I.I:) induce “a significant hyper reactivity of the bronchial tree. against irritant inhalator y challenges ” . in Figures3 and 4(reference2)arc based upon the original control values obtained before administration of the pollutant gases.Yetat the time that 12 Acl ~was given following HAK, R t almost certainly was still. elevated above control.Consequently, how much of the response vas related to delayed rc co very and how uiuch t o Ach is uncertain. The cxperirnent - and Interpretation - be cane

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increasingly more complex as each successive concentration of Ach was Unlike the present authors, Hazucha eta1 (1973) and Ketcham e t a1 (1376) found that impaired fl01.7 rate is a Eore sensitive indicator of response to 0 3 than are change in flow resistance. Hazucha e t a1 (1976) recently PEFR and NEFR50x) following two hours of exposure to0.2 ppm of 03. fell about 12-152 below control while none of the other parameters fell as much a s 10%; throat irritation,sub stern al pain and / o r cough were experienced 0.4 ppm of 03 was essentially no greater than to 0.2 ppm although symptons were level for functional impairment was about 0.25-0.30 ppn of 0 3 ; however, they relied on flow-volume parameters and did not measure flow resistance.Their subjects were living in Los Angeles, a community noted for photochemical smog. Inthe same study the initial functional response to Conclusions and Recomrnenda- tions Ny impression is that von Nie ding and Wagner are hardx ~ orkin gand prolific - von Nieding, although relatively young, has been c o - author of over 50 articles - but are often careless and naive.Peter I lu eller will have en une rated the deficiencies in their environmental system. These include an inadequate method of cleansing in take air through water before delivering the air to the exposure chamber (submicrometric particles and relatively insoluble gases ' are in completely removed) ; moreover, the water is al loved to stagnate for months. von Nieding and Wagner were in different to the evidence of dust collected within the chamber and to the pos sib lit y of experimental interference from community air pollution. They stated the belief that 1.1oers represents a pocket of clean air within an otherwise polluted region ; a recent publication by Oaggoner e t a1 (1976) undermines this belief. I have equal misgivings about their adequacy as physiologists. They appear t o have no explicit regime for the analysis of data (von Nie ding is chiefly responsible for the analysis of data). baseline values for Pao2 and about the nearly constant change that occurred i n Pa02 for any individual gas or combination of gases ; their interpretations of the functional effects arc occasionally naive for example, edema is postulated suggesting how likely - or unlikely this occurrence may be): they are lax in describing their methodology adequately for the reader; and their interpretation of the results is occasionally obtuse(see last line of They are unconcerned about the low Nonetheless,their work is part of the scientific and public record.Since it does have important rc gul n tory imp li cat jons I would rccoriurcnd that an effort be made t o have the. work repeated(including measurement of Pao2) flow

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resistance and (Aow-volurne curves) by competent, experienced in vc s ii gators in North America. I would suggest that two investigative tealits bc recruited to carry out the study, that: a deliberate effort be made to standardize all procedures so that close comparisons are possible,and that serious consideration be given to having each investigative team study an ali quo t of tlie same subjects for internal comparison. ii'hether to involve the Gernan investigators in additional studies should await the results of this initial

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9Torr tosu sure minus Control Recovery minus Colltrol based on graphs in references 2,3 R,, cmHzO Exposure minus Control Recovery minus Control based 011 graphs in reference2

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Present e dAcute effect of ozone on the human lung function. atVDI Kommission ReinhaL tung der Luf t Colloquium on Ozone and related substances in photochemical sniog, Uusselclorf, Sept.22 - 24,1976 2. von Nie ding,G. and Vagner, H.M.: Studies of the combined effects 3. von Nie ding,G. and TJagner, H.H.: Experimental studies on the short - term effect of air pollutants on pulmonary function in man: exposure to N02, 03 and SO2 alone and i n combination. International Union of Air Pollution Prevention Associations,pages 1-13. 4. Nellemgaard, K.: Alveolar - arterial oxygen difference : size and components in norn al man. Acta Ph y sio l. Scand., 67:lO, 1966 ozone plus moderate exercise on pulmonary function in healthy young men. Manuscript provided by Dr.N. Weaver, 1976. Pulmonary function in nian after short - term exposure to ozone. Arch. Environ. Health, 27:183, 1973. in man. Manuscript provided by Dr.N. h'eaver, 1976. on human health effects of air pollutants : 111. Two-hour exposure t o ozone alone and in combination with other pollutant gases. and Tr ard h, C.: Sulphate - light scattering ratio as an index of the role of sulfur in troph os ph eric optics.Hat ure, 261:120, 1976