Asthma Occurrence Epidemiologic Evidence for Asthma and Exposure to Air To: between Occupational, Indoor, and Community Air Pollution Research Ralph J. Delfino Epidemiology Division, Department of Medicine, University of Califor (Outdoor ambient sir pollutant exposures in communities are relevant tothe acute exacerbation and possibly the onset of asthma. However the complexity of pollutant mintazes and etiologic hetcrogencity of asthma has made it difficult to identify causal components in those mixtures. Occupational exposures associated wih asthma may yield clues to causal components in ambient aie polation because such exposures ae often identifiable as singl-chemical agents () particulate mar (PM) < 10and < 25 umvin aerodynamic diameter (PMyo and PM 5, respestivels), Os sulfur diode (S03), and black smoke (an indicavor of soe, inlading diesel exhaust [DED (8-1, Diminished lung function growth sone of the posible adverse , 1,600 ppbs formaldehyde, 260 yg/m’). They saw increases in acutrophils and B lymphocytes in lavage Aids, Bronchial biopsies showed increased inflammatory cells (neutrophils, mast cells, CD4*, and CD8" T lympho- «ytes) and significant increases in expression of endothelial adhesion molecules and the ligands. Increases in neutrophils an platclecs were found in peripheral blood. ‘There were no significant changes in lung function, but the effect on the asthmatic hung remains to be ested Tn summary, PAHS from fossil fuel combustion may contribute 0 worsening res piratory allegic responses and induction of the intial clinical eypresion (38). Potential targets for PAHS inchude antigen-preseating cells, macrophages, mast eels, respiratory epithelial cell, and posbly Ty.2 cells direct All ofthese cells are shoughe to possibly play 2 role inthe ajuvant effects of DEPs on allergic inflammation (38). Experimental findings hhave shown thar whereas DEPs alone have a nonspecific effect in increasing cytokine pro- duction, DEPs plus ragweed antigen selects against a Ty profile while stimulating a Ty.2- type response (38). The clinical relevance of these experimental findings remains to be «established, especially for asthma. The rele- ‘ance to public health and to epidemiologic Findings of air pollution health effects also remains to be established. The ability of PAHs to exacerbate disease severity among asthmatic individuals has not been diceely investigated in an epidemiologic study. The following review of the epidemiologic literature involves complex exposure mixtures that contain «clatvely high concentrations of PAHs along with other potentially causal pollucans Occupational Evidence for Respiratory Effects of DE ‘Occupational exposures to DEP can be high, thus giving researchers the opportunity to «examine associated health effects. Exposures range from 1 0 100 yg/m for S-he averages in oceupations such as trucking oF trupsporta- tion where mixed automobile and teuck expo- sures are expected. Exposures are much higher for other occupations such as under- ground mining, which ses diesel equipment ‘operated in enclosed spaces, and range from 100 0 1,700 pgln? (4. ‘A-case report of three slroad workers is the only paper linking new-onset asthma to occupational DE exposures (28). The workers developed asthma after exposure to locomo: tive exhaust while riding immediately behind alead engine. However, all had been working for the railroad for many yeas, which leaves pen a role for chronie exposures. They had no previous history of asthma or other chronic lower respiratory disease and were nonsmokers. One subject had a history of seasonal rhinitis, and one had a family history ‘of asthma and rhinitis, suggesting underlying susceptibility. The diagnosis was confirmed by spirometry, airways hyperreactivity to methacholine, and exercise challenge. Two workers showed reversibility in. ung function deficits with an inhaled bronchodilator; the ‘other showed reversibility 3 years hue. All three experienced asthma symproms upon reexposure to locomotive DE, and one showed peak expiratory low (PER) rate fill ‘with work exposure. All developed persistent asthma with exacerbations occurring with ‘ations triggers including exertion, cold ar, and passive smoke, One other paper reported 4 similar high-exposure event involving 13. railroad workers, 0 of whom complained of chest tightness and wheezing, but no other diagnostic data were provided (49) In addi- tion to the above case report, & number of cross-sectional occupational studies of DE- ‘exposed workers have been conducted. ‘An early study of 200 coal miners found no association berween diesel exposure and respiratory health (50). A beteer-designed study by Reger etal. (52) showed adverse effects in 823 miners in diesel coal mines fre- aqueney-matched 10 823 miners in nonclesel coal mines by age, height, smoking status, and yeas underground. Persistent cough and phlegm were significantly higher in diesel exposed workers, hut the opposite was found for dyspnea: there was no difference in wheezing. Compared with nondiesal workers dlcsel workers also had significant decrements in FVC, FEV, and forced expiratory flow rate at 75% and 90% of EVC (FEF;5 and ‘owe 110|sumtevewr-4| vcs 2002 + Environmental Health PerspectivesFEF) but no evidence of obstruction using the ratio FEV /FVC. Other studies were con: dicted by some of the same investigators in coal mines. One study of acute effec of DE during an 8-hr work shift in 90 coal miners compared dese-expased and unexposed min- ers (52), Investigators found tha crose-shif deficits in FEV;, FVC, and forced expiratory flow rate at 50% of EVC (FEFs0) were arester for diesel-exposed subjects, hut not significant. The same group conducted 8 S-year prospective study of 280 diesel exposed and 838 unexposed miner in difer ent mines (53). They found no significant ageadjused differences in 5-year changes in FEV; or EVC, or in chronic cough, phlegm, or breathlessness. However, diesel-exposed western miners who unl dhe eastern min €s,provded the contol group, showed a sig nifcan deficit in FEE. An incernal analysis of diese-exposed workers based on cum tive year of diesel exposure was negative ‘A seady by Gamble etal, (34) of 283 diesel bus garage workers compared with blue-collar conttols, showed garage workers bua sigiicanly higher incidence of cough, phlegm and wheezing adjsed for age, rcs, and smoking. However, pulmonary function was, on average, higher in garage workers than the contol by all ace and smoking si ts categories adjusted for age and height. An Jeznal comparison based on tenute showed progressively decreasing FEV), FVC, and FEF so adjusted for age, height, race, and smoking status. The internal comparison also showed a consistent increwe in prevalence of Aspnes, wheeze, and cough wi tenure. The sain research group stidied 259 sie miners in ive mines with dfferene diesel expesures (2 with extensive diesel use, 2 with limited use, 1 with none) (55). There was a non- significant increased trend in cough and dsp- nee anda significant trend in phlegm by years of rena in diese-espesd jobs but no assci- ation with lung Function adjusted for smok- ing age. and height. The adjusted prevalence of cough and phlegen was also higher than thar ofa blue-collar comparion group, but lung function did nr dir ‘None of the above papers compared groups based on any actual pollutant measurements. However, the same 259 salt miners discussed above were studied with personal samples of NO; and respirable part eles (eylone sampler). The personal samples were sed to estimate cumulive exposure by tenure, with NOy asa surogate mesure of diesel exposure (56). Cough, dyspnea, and pulmonary funsion (FVC, FEV}, peak ow; FER, FEE;s) were not associated with ex mated cumulative NO» (mean 200-2,500 ppb) or respirable particle exposure (mean 200-700 yig/m). Only phlego was assoc ated with the exposures. Gamble ce al. (57 Asthma Occurrence + Epidemiologic evidence for asthma and air toxics also used personal samples of NOz and respirable particles to assess acute effect in 232 of the 283 diesel bus garage worker in their previous paper discussed above. Both NOs (mean 280 ppb) and respirable paces (mean 240 jgien exposures were associated with increased postwork shife symptoms of cough, difficule oF labored breathing, chest tightness, and wheeze bur not lang Funetion, Atleld et al. (58) studied 630 miners in six potash mines in New Mexico with diferent ‘exposures and exposure durations to under: ‘ground DE, They also used personal passive samples of NO; (range 100-3300 ppb). Internal analysis showed average percent pre- dicted FEV, and FVC were not asociaved with particular mines in nonsmokers or smokers (adjusted for pack years) Lang func- tion and symptoms were not asaciated with predicted cumulative NO} exposure, However, when years of exposure were exis ined, lung function actually improved and there was no trend in symptoms (cough, phlegm, dyspnea), suggesting a harvesting cffece that selected againse workers with adverse pulmonary responses. Robertson etal (59 studied 44 marched paits of cal miners differendly exposed to NOs and found no dit ference in respiratory symptoms or FEV, Purdham etal. (60) found that work shift changes in FEV, among 17 stevedores employed in ferry operations did not differ from those of 11 office controls. Area mea- surements of NOs, formaldehyde, and acetaldehyde were also not different, but poor precision was possible, Other occupational studies have exam- ined workers exposed to automobile exhaust, which can include diesel fumes as well. Stutlies by Speizer and Ferris (61,62) com: pared two groups of policemen with diferent exposure levels to auto exhaust and found no significane differences in sy monary function. Ayres proms ar pul- al, (63) showed tunnel workers had worse pulmonary fine tion and more respiratory symptoms than bridge workers with lower exposutes. Ulvestad et al. (64) compared 221 tunnel workers with 205 heavy-construction wotk- cers. They found tunnel workers, but not hheayy-construction workers, had significant decreases in percent predicted FVC and FEV, with temure, adjusted for smoking and atopy by radioimmunoassay test (RAST), Tunnel workers reported significantly more respira- tory symptoms than referent workers, and prevalence of chronic obstructive pulmonary dliscase was aso higher. However, inn eariee study there were no differences in the preva- lence of respiratory symptoms between tunel and turnpike workers, although both may hhave been highly exposed (65). A. snall study (of 89 workers on roll-on rol-ff ships, car fer- ries, and a bus garage showed significant Environmental Health Perspectives.» yout 110|stewo 4 | Aucus 2002 FEV, and FVC decrements during workdays after several days with na exposure (66) The above occupational studies, most of Which are cross-sectional in design, reveal a mixed picture of adverse and null effects, ‘Other pollurane exposures such as coal dust could have been responsible for postive aso ations in internal comparisons, as well as far positive and negative findings in between- group comparisons because both groups were Lswally in occupational groups exposed (0a borne pollutants. Control for adverse smok- ing effects, which were generally strong, may also have been inadequate or subject 10 unde ected multicollinearity or interaction, However itis likely chac the healthy worker effect strongly influenced findings. Therefore, the limiced findings of adverse effects in working men supports che expectation of stronger associations in susceptible individ- aly in the general population, including peo- ple with current asthma, children, and the Evidence fora healthy worker effce is that in many of the scudies. workers had higher baseline FEV, values compared wich those of control groups oF with advancing tenure (50.51,33.54,58,60). There is other evidence in the occupational literature on diagnosed occupational asthma in bakers, and fm allepic sensitization wo plinum salts and co TDD thac risk is greatest i the initial 1- to ar period of employment (67). Except for the case report of “diesel asthma” (18), none ‘of the occupational studies reviewed abave performed standard spirometric tests to dia, nose asthma, and none followed workers prospectively from the start of employment Epidemiologic Evidence for Pollutant Mixtures Containing PAHs: Environmental Tobacco Smoke indoor i pollutant high in PAHs is environmental tobacco smoke (ETS). ETS also contains other toxi air pol Tuan, including 29 air coxies of 49 major ‘components (68), making it difficult to ascribe efleets to any one pollutant. Serum IgE is higher in smokers than in nonsmokers (69-72) and is possibly higher in ETS. exposed bjs (7279. This suggests an acute enhancement of IgE responses i pos ble but whether the inital expression of alr gic sensitization is enhanced by ETS is in clispute. A quantitative meta-analysis of stud ies up to April 1997 showed no association bbeeween parental smoking dusing pregnancy or infancy and atopie sensitization by skin prick tests (SPS) in children wiehous asthma ‘or wheezing disorders (73). There was consid crable inconsistency across studies (73). Other more-recent reviews have concluded that the relationship between ETS exposure 577‘Asthma Occurrence * Delfino in school-age children and the development of both asthma and allergy is poorly under- stood (74,75). A recent study of 5.762 school-age children had sulficient power to find a significant association berween in ero exposure to maternal smoking without subse- quent ETS exposure and history of physician- diagnosed asthma, current asthma, and aha requiring medication (76) The same study showed that although current or past ETS exposure occurring only after bieth was associated with reports of wheezing, it was not associated with asthma prevalence. Furthermore, combined i ate plus postna tal exposures did aoe increase risk of asthma beyond in wero exposures alone. The finding that maternal smoking during pregnancy has a stronger relationship to asthma onsec than later ETS exposures was supported by several other studies tha separated maternal it wero exposures from postnatal exposures (77-82) Tris conceivable that én ater exposuses t0 ETS shifts the immune response toward a "Ty2-ype patiern as.a result ofthe adjuvant action of PAH components interacting with in user allergen exposutes, which are now believed to lead 10 atopic sensitization before birth (83,44). Ie is plausible chat postnatal coexposures would do the same, but the «pidemiologic data are inconsistent for the relationship between ETS exposure and childhood asthma incidence (On the other hand, there i a preponder- ance of evidence linking ETS to acue exacer- baions of asthma in asthmatic children, A recent ret analysis concluded thar studies showed an excess incidence of wheezing. in smoking households, particularly” in nonatopic children, suggesting a “wheezy bronchitis paetrn; however in children with diagnosed asthma, parental smoking was associated with greater severity rather than incidence (78). A quantitative meta-analysis of sedis up to April 1997 for 25 studies of asthma prevalence showed a pooled odds fatio (OR) for asthma of 1.21 (95% confi dence imcral [CI 1-10-1.34) i either pa ‘ent smoked (85). Well-condueted panel seudies are still needed co evaluate acute exposure-response relationships using repeated measures methods. A recent daily panel study aver 3 months in 74 asthmatic children showed that acute asthma symptom, severity, PEF, and bronchodilacor use was associated with ETS exposure (86) “There is less informacion abour adult: ‘onset asthma. A cohort study of 451 non: smoking asthinatic adults found that acute asthma severity, asthma-specific quality of life, and heale status were associated with selF-reposted ETS exposure (87). Cohort studies have also shown inereased risk of | developing adult asthma from ETS (88), including occupational exposures (89). 578 Among 3.914 nonsmoking adults followed 10 years. the relative tsk for asthma onset from 10 years of working with a smoker was 1.45 (959% C1 1.21, 1.75) (85). A large sur vey of 4.197 never-smoking adults showed an clevated risk of physician-iggnosed asthma fram any ETS exposure [OR 1.39 (95% Cl 1.04-1.86)] bue no increased risk of allergic rhinitis (90). Reviews that have included ‘other epidemiologic studies have concluded that although ETS is consistently associated sh slr th ons sabre jess limited and the magnitude of effects are small, with limiced dose-response informa- ‘ion (91,92). One question that remains to be answered is what are the chemical determi nants of associations between asthma and ETS, which isa complex mixture of parle and gas-phase components? Do PAHs play a major roe in these associations? Epidemiologic Evidence for Exhaust The urban exposure most relevant to the potential importance of PAHs to asthma exposure to aucomobile and track trafic, An catlicr descriptive study spurced interest in potential adjuvanc effects of DEP on IgE- mediated respiratory allergic responses (9. ‘This was a cross-sectional study of 3,133 Japanese persons chat showed the prevalence of cedar pollen alley was higher near busy highways despite equivalene local exposure £0 cesar pollen in lessbusy areas, No epidemiologic studies have used quanctarive exposure estimates of either DEP or ambient PAHS, However, European research has had access to black smoke mea- surements. A panel study of 61 (77% on asthma medications) children in the summer Showed stonger associations for black smoke than for PMjo in teation to PEF, respiratory symptoms, and bronchodilator use (94). The authors hypothesized thar black smoke may be a better surogate for fine particles emitted Dy deel engines o or ber hema that may be the causal components in DE Ambiene NO, could additionally serve as 2 marker for traffic exposure. Studnicka et al (95) expliccy used outdoor NOy asa surto fate to show “tralfc-elated pollution” was ‘ssciated with asthma prevalence among 843 children living in ateas of lower Austria with- ‘ou local industrial emissions of ar pollution. Numerous epidemiologic studies have shown associations between traffic density tnd asthma prevalence or morbidity. All but fone were conducted in Europe and Asia (Table 2) Fiffcon of chese have been in chil dren (96-170), four in adules (111-114), and fone study in both children and adules (115). {Al bu seven have been purely eros-sectional studies, Krier et al, (709) conducted @ cross-sectional study of atopic sensitization and asthma diagnosis but had a prospective ‘outcome assessment of atopic symptoms for 1 year along with seasonal NO> measurements (Other designs include three case-control seudies of hospital admissions (97,99, 108), and one case-control study of California Medicaid claims for asthma (105). Another seudy was a mixture of erose-scctional, survey nested case-control, and historical cohort (110. One study of adult Japanese women was erosscctional for symptom prevalence and also ested longitudinal models for 10 seasonal repeated measutes for lung function ina subsample (112). leven looked at raffic density, but no ar pollution measurements wete used in effect estimates or as confirma- tiom of exposure gradients (95-98,100, 101 104, 105,108, 116,113,114); four had vaffic eosity, black smoke andlor NO» (102,103, 111,112} and five wsed combustion-telated sir pollution measurements near the home (CO, benzene, and/or NOs) 2s modeled sur- rogates for traffic exposures (99,106,107, 109,115). Hirsch ec al. (107) briefly men- tioned results for truck traffic, focusing instead on predicted home ex fone hundred cighty-two T-km? grid messute sents of CO, benzene, NOs. SOs, and Oy Pershagen et al, (99) used predicted NO} from modes involving traffic data near the home and background ambient NOs data, wid home esidence time asa weighting Fac toe, Oosteree etal. (1/5) investigated respira tory symptom prevalence and asthma in relation to busy and quiet streets predicted with model caleulations of NO) concentra tions using the Dutch CAR (Calculation of Air Pollution from Road rafic) model (217). Only foue studies have separately assessed exposures from truck venus automobile tra fic (102-104,113}, two of which exarnined the sime children in South Holland using actual |-year measurements of trafic density iy relation co lung function (102) and symp- toms (103). Another study in Germany had ‘only self-reported tuck trafic density in ear tion to symptoms (98). Except for one study (113), all of the above studies examining truck rfc showed increased risks in respite Cory symptoms including wheeze from higher truck traffic density near the home (98,103, 104). The Holland studies showed greater increased risks in respiracory symp- toms including wheeze (103) and lang fane- tion deficits (102) from higher tuck craic than from automobile density near the home. [Both Holland studies confirmed the possible relevance of DE by finding tha back smoke measurements a the children’s schools were also associated with increased symptoms (105) and lung function deficits (102). A vue 110 suze | Aucus 2002 + Environmental Health PerspectivesAsthma Occurrence + Epidemiologic evidence for asthma and air toxies Tole 2 fedamilgje ses fhe rlatnship betwen aha prvalnen or mori and afc exposures. Fefrence Design andlocabon of uy. htiton—Sobjectages ly ang characeisies Bxpesures Heath oxteamas ests wera Gossaecea Talfederay tai cn te lg hneton TV. 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Nowediayhaie Line aks weueupelee 4-11 yas soca wth cin TA a [cor sistvastlsn fo nsenea” —rendaatatsscwal ro af wabesame coh ‘cad wit and up ve ve te 1.1 ‘ron wire 7 years ons om elsigto sstrce leat patton (eC 02 1 22nd 12]86% C13 126, pte Netigham wea, Uns Kngon. fem tere ‘alr tien Flee hong asus age anc set 1 hus TAlurietinnirst iw s22: kinase ress: yvasatonetoat ast! vite made pt Shy 18 9288) ‘mers 29-1 hgh» 32 vena ore te ert 127 BER C218 and 922 Tete (22728 Fecha race Chet 288 es con Felncct ahs ast py rd secin ats Teper wa, rsdn ‘tty was sonnet asda ee ak ‘Sr 2828conre who ‘apart owe erie TATOR TES 2 13H) ron ws ‘301180102132 expec iho 76S asst beth and Insets tI 8 tre aso ssn whe, ‘a oe ‘ou of asia ah oot 8 ets. fe she cng deta neon se ‘ite ae, ox sal as. eral soak ste postve butt acant. ist rer ar psiton wteae nce see st TA O08, OF 155% C1 Bi) 0 lan Talis (excnaes Environmental Health Perspectives = vous 1101 sumstenr 41 Avis! 2002 581Asthma Occurrence + Delfino Tle 2 Comin Aetrenco Oosighandloewon of cy anen Subject oges land characteris Exposures oath oeteomas Aesuts Trswe Caeser Tite desea Bray ay Pespoioy sane Gone ot ager oaaTe as ano a(t Hien Nees, ‘sees ven quel secs couphcagh wihglegn, te cho oie, xo yf asa, ‘er: Scheer -15 yh fey hgh re 72% ee fae tonsa compara wit cn ‘her im a ste wt ite tals merge usr ype bo ane hs) ts 07s vig la ty ate seasoned wth 1 ont abo aca im oss sectoral. te sae. (Westen adtabso ey. ee wth ar a ‘je S000 00 vane doy ts Wea ry, 090 ee “wrsin= Ist Hein =2A1L 181-2388 Lint ow Wa! sn ae Nataieal ia Css set Aart mass fr ghia ‘eo, ‘eds th vain am ots ‘winery tae 50000900 hice TBhvay ct del powered was ‘frre any oad wih ae trvie ‘eats woven on), 38-58 0-1 386, Tiere at sere are Ce sector, ‘sean Siva ates, Sen ‘autem orl ty age elas 8H tne malta real in seston Sie St NW Son Teac txinal gs ta 240 {Dante ie 40 11 2-20 ‘owt ere ne a sare tess meer ita acs 1-3 yes ay diac de eens ‘3 NOyereonatins bse on ‘ned ote es nen tafe ety AR TT. ‘tia ae ety on uy ‘eens m0. vohicoxoy Distance mje toy , except for an unexpected inverse asoc'= ation in boys for PM, The association of acute asthma with CO is supported in a Seatle panel study of 133 asthmatic children and is kly explained by more causal compo nents of vehicle exhaust and other combus- tion byproducs (119, Icis possible tht asociations between allergic respiratory illnesses and raffie density ae due to NAAQS criteria air pollutants, par- ticularly NO», which is directly related to local trafic density (120. Kemet et al. (109) assessed his posible in a study of 306 chile dren 9 years of age living atleast 2 years in a home ‘near major roads in Germany (Table 2}. Using passive samples with Palms tubes, weekly average concentrations were measured for personal NO3 in March and September, and for outdoor home or near- hhame NO. at 158 locations in each of four seasons (levels at home addresses were inter plated). lnvestgutors shoved that outdoor NO; was 2 good predictor of home traffic density Pearson 7.0.70) but a poor predictor for personal NOs expose (7, 0.37) refcting the known importance of indoor NOs Environmental Health Perspectives » vows 170] suman &|Avcis 2002 sources. They followed the children with weekly parental questionnaires for atopic symptoms for 1 yar. In suburban areas there was lcd variation in outdoor NO, (range 43-46 ngim’) and inclusion of suburban subjects (= 104) in regression models decreased parameter estimates and increased standard errors. For urban areas (x = 202), they found thar avopic sensitizations to pollen, to house dust mite oe eat, and ro mill ‘or egg (by SPTS or RAST) were each signifi- cantly associated with outdoor NO3 (ORS ranged from 3.5 to 5.0) but nat predicted personal NO». They aso found that outdoor NO>, but not predicted personal NO, wat signilicanly associated with report of at leat | week with symptoms of wheezing and of allergic rhinitis. Relationships for atopy and thinitis symproms by quartile of outdoor NOs suggested a dose-response relationship (Figure 2), Although an ever diagnosis of hay fever (n = 35) was associated with outdoor NO, diagnosed asthma was not (» = 25) The maximum outdoor NOp of the urban sites was 36 ppb (67.5 pglns), which is far less than the U.S. EPA NAAQS of 53 ppb annval mean (100 yey), The overall resuls suggest thar oucdoor NOs was serving a a marker for more causal aiborne agents rather than a direct effect of NO» High personal exposures to PAHS near busy strets were possible in che study by Krimer eval. (109, as well as other sues in Table 2 for high walfic density. Dubowsky et al, (121) measuted total real-time, particle ‘bound PAHs from three nonsmoking indoor sies with different cafic densities character ine of urban, semiutban, and suburban res dences. Diaries were used to deter flees of cooking and indoor combustion event (eg. candles). A sigificane contribution of trafic related PAHS to indoor PAHs was detected Indoor peaks occured daring morning rsh hour on weekdays only (max = 65 ng/m? for urban locations). The geometric means of PAHs corrected for indoor sources were urban, 31 ngim’s semiurban, 19 ng/m’s and suburban, 8 gin? 52) eu tm is i: ' ‘ BE Fg = w e 7 Dutdoor NO, (umn) Figure 2. Relationship of symptoms of allergies 1is (3) and of stopie sensitization againet pollen {0} to quartiles of exposure to ovtdnar heme NO; ‘n 202 chron 9 years of ag living in urban areas ‘of Germany, Adaptad fram Kram a (19, 583Asthma Occurrence + Delfino Despite the suggestion that NOs may be acting a a sitogate pollutant, the repiraory effects of NO are still important. However, the magnitudes of efleets of NO» on asthma are noc entirely cleat, and there are consder- able inconsistencies in the experimental litera- ture. Some studies have shown alterations in Tung Function, airway responsiveness, or symptoms, whereas others Rave not, even at high concentrations [reviewed by Bascom et al (3). Data that suppor the craffc density studies come from a clinial crossover study that used ambient exposures of 20 mild pollen-allergic adule asthmatic individuals (122, Subjects showed ealy- and late-phase bronchospastic reactions to pollen allergen challenge tha were greater 4 hr afer a 30-min exposure in a car parked in a road tunnel (30-min median NO, 157 ppb; median PMs, 95 pg/m’) compared witha low con- trol exposure ia suburban horel (24h badge NO, 22 ppb). Specific airway resistance 15 nin afer allergen challenge increased 44% in 12 subjects exposed to road cunnel NO3 > 159 ppb compared with 24% for their contol exposures (p < 0.05). The higher NO tunnel exposures were associated with significantly more symptoms and beta-agonist inhaler wse 18 hr afte allergen challenge. In addition, EV, decreased significantly more than. with contol exposures 3-10 hr afer allergen chal- Tenge (8.5 vs. 6.896). Effecs were smaller using PM or PMas a che exposure metric; "The authors compaced their results with those from eatlier chamber studies using 265 ppb NO, before alleigen challenge. They con- clued that although those results also showed an enhancement ofealy- and lae-phaseasth- rnatie reactions (123,123), effects were greater for lower NO, exposures in the tunnel, suggesting othr pollutants were important. ‘Other agents aside from cither NAAQS criteria aie pollutants or air tories could ‘explain some part ofthe association of aschma and allergy outcomes with traffic density Latex allergsn found on respirable rubber tre particles is likely common in urban ait {125,126 and could lead to sensitization and respiratory symptoms. [n addition, the phys cal action of motor vehicles on road dust which is known to contain pollen grains, could lead to the production and resuspen sion of smaller respirable pollen fragments (G7. Other allergenic bioatosos such as Fun- gal spores could be fragmented and resus- pended as well. Interactions betwe pollutants and allergens could also influen elects. Allegenic molecules could be deliv- cred co target sites in the airways on diesel Carbon particles. as evidenced in fire using the rye grass pollen allergen Lol pl (127. Another study using immunogold labeling techniques found chat indoor home soot par~ ticles, primarily in the submicrometer size 584 range, had bound antigens of eat (Feld 1), dog (Can £1), and birch pollen (Bec v 1), and this adsorption was replicated in vitro with DEP particles (728). Other biologic interactions beoween pollutants and allergens ‘on airways tac favor inflammatory reactions have been hypothesized (129), including enhancement of allergen sensitization in asthmatic children with ETS exposure (130) and pollurant-induced enhancements of the antigenicity of allergens (131,132). Summary of the Potential Role of PAHs in Asthma Experimental evidence supports the biologic pleat ofa role for PAHs from fol Fuel combustion products in the onset and ‘exicerbation of asthma. However, the occu pational data on DE and asthma onset are limited to one three-case series. In addition, spite high exposures, overall inconsistency is found in occupational studies of respira tory symptoms or lung function and diesel/gas exhaust exposures. Bias from the healthy worker effect is likely given the expectation of avoidance behavior among individuals with respiracory sensitivity co inhaled irrivanes, including asthmatics. This bbchavior has been hypothesized to result from a toxicant-induced loss of tolerance (33). The inconsistent and weak occupa nal evidence docs not rule out different dose-response relationships for asthma in nonoceupational sectings. Epidemiologic results showing associations between child hood asthma and ETS may be explained, in part, by PAHs. Positive results in cpidemiio- logic studies of asthma and traffic-related exposures also may be explained, in part, by PAHs. ‘The question that remains is, what are the determinants of asthma associations ‘with complex mixtures of ETS-related and. tralic-elated particle components and gases? Coherence with Traffic Studies by Trends in Asthma and Urbar n ‘The above review gives the overall impression shar asthma, related respiratory symproms, Jung function deficits, and atopy are higher among people living near busy traffic. Some data coherent with this view are found in scudies showing a higher prevalence of asthma and atopic conditions in more developed ‘Westernized countries and in urban com- pared with rural areas [reviewed by Beasley et al, (134) and Weinberg (139), For instance studies in Africa have shown that pediatric asthma is rare in rural regions, whereas ‘African children living in urban areas have experienced an increasing incidence of fasthma (135). The wrban-rural differences have tended to narrow as tural Africans became more Westernized (135). This suggests that the increase of asthma seen in developed couneries may be attributable 10 some component() of urbanization, inclad- ing automobile and truck traffic. However, this urbanization gradient is nora consistent finding across the literarure (136). For instance, in the traffic exposure-response study by Monenémery et al (114) (Table 2), although there were significant association of asthma symptoms and diagnosis co craffic density, there were no urban-rural differ ences, In addition, some recent studies that Specially examined farming environments, found a decreased risk of asthma and atopy among childeen living on farms (137,138), particulaely where there is regular contact twth farm animal, This prompted these Jnvestigators to hypothesize that a “protective farm factor” may reflect the influence of microbial agents on Ty versus Ty2 cell development or reflec the development of immunotolerance (137,138) This possbi ity in addon to potentially high levels of confounding by uacontrolled factors that vary by geogeaphy, makes it difficule co Clearly interpre the crossectional suis on urban vrs rural areas or ecologic studies of international dilferences Formaldehyde, Asthma, and Atopy in Children The following section will examine the epi- demiologc literature on the relationship of asthima and atopy in children to formalde- inde. This serve to exemplify one ofthe few low molecular weight agents associated with asthina in both the oecupational (22) and nonoccupational literature, and to exemplify an ar toxic that has fects from low to high Exposure levels, However, there ae litle avtlable nonoccupational daa on the isk of asthma onset from formaldehyde, One study pasively measured formalde hyde over 2 weeks in the homes of 298 chil dren and 613 adults (139). In log-linear ‘models controling for SES variables and eth nicity the study found a significandy higher prevalence of physican-diagnosed asthma nd chronic bronchitis in children 6-15 years ‘of age living in homes with higher formalde- hyde concentrations over 4 ppb (six asthma and sic bronchitis cases). However, the room- Specific measurements revealed thatthe asso- ‘Gation was attributable wo high formaldehyde concentrations (560 ppb) in kichens, pat tly those homes with ETS exposures (five tsthma cases, five bronchitis case), suggesting possible confounding by other factors not measured. In andom effess models const ling for SES and ETS, they found significant inverse associations between morning PEF rates and average formaldehyde from dhe bed oom, and between evening PEF and house- hhold average formaldehyde. There was no ‘owe 10 sume 4| Avast 2002 + Environmental Health Perspectivesapparent threshold level. The PEF finding was independent of ETS, but the effects of age of of andaropomoephic factors were not ‘mendioned. Symproms of chronic cough and wheeze were higher, and PEF lower, in adults living in houses with higher formaldehyde levels. There was a significant interaction berween formaldehyde and tobacco smoking in relation co cough in adults, Passive mea- surements of NOz did nor confound the associations in children or aduls, ‘Other nonaccupational data on formalde- hyde relae indirectly to asthma. Wantke el (140) evaluated levels of specific IgE to formaldehyde using RAST in 62 eight-year- old children attending (for 2.5 years) one school with particleboard paneling and urea foam window framing. The children were transferred to a brick building (23-29 ppb formaldehyde) because of elevated formalde- hhyde levels in particleboard classrooms (43-75 ppb) and complaints of headache, cough, thintis, and nosebleeds, Symptoms and spe- cific IgE were examined beloce and 3 months afer cesation of exposure. At baseline, three children had RAST clases > 2 (positive) and 21 had clases 2 1.3 (elevated) whereas all 19 control children attending another schoo! had classes < 1.3. After transier, the RAST classes significantly decreased from 1,7 £ 0.5 to 12 + 0.2 (p < 0.002), and symptoms decreased, However, IgE levels did not correlate with symptoms. None ofthe children had asthma, Garrect etal. (141) hypothesized that formaldehyde may adversely affect the lower respiratory tract by inereasing the rik of aller gic sensitization to common allergens. They studied 43 homes with at last one asthmatic child (53 asthmatic, 30 nonasthmatic) and 37 homes wit only nonasthmatic children (0 = 65). Atopy was evaluated in the children (7-14 years of age) with SPTs for allergy co 12 common animal, fungal, and pollen aller gens. Formaldehyde was measured passively throughout the homes over 4 day in four di ferent times af 1 year. Acopic sensitization by SPT was associated with formaldehyde levels IOR for 20 g/m? increase, 1.42 (95% CI 0.99-2.04)]. Across three formaldehyd exposure categories, there was also a signif cant increase in the number of postive SPTs and in the wheal ratio of allergen SPT aver histamine SPT. Mean respiratory symptom scores were significantly and positively asso ated across the three categories significant positive association berween par ent-reported, physician-diagnosed asthma and formaldehyde, bur this was confounded by history of parental asthma and parental allergy. Its unclear why these familial dete. minants were created 38 confounders rather than effect modifiers, although knowledge of asthma by parents may lead to bias in the assessment of asthma in thie children Asthma Occurrence + Epidemiologic evidence for asthma and ait toxics Several other studies of nonasthmaic subjets have examined health outcomes and biomarkers that are relevant to asthma, Franklin ec al. (142) studied 224 childze 6-13 years of age with no history of upper or lover respiratory tact diseases, using expired nitic oxide (eNO) as a marker for lower air- ‘way inflammation (143). Formaldchyde was passively monitored in the children’s homes For 3-4 dys, Maximum end expiratory eNO. was measured in each child with a fast= response chemiluminescence analyzer. They found no effect of formaldehyde on lung function. However, controlling for age and atopy (by SPT), eNO was significantly ele- vated c© 15.5 ppb (95% CL 10.5, 22.9) in homes with 2 50 ppb formaldehyde com= pared with 8.7 ppb eNO (95% CL 7.9, 9.6) in homes with < 50 ppb formaldehy: ‘Authors did not report the ctss-sectional rise ‘of axopy to common allergens fiom exposure to formaldehyde. They hypothesized chae formaldehyde causes inflammation and the release of cytokines, which leads ta the upeeg ulation of inducible NO synthetase. This View was supported by another study chae Found intranasal exposure co 400 ppb Formaldehyde in healthy subjects caused cosinophilia in the nasal epithelium (14. Given thac a hey marker of the asthmo= genic effects of formaldehyde may be specific IgE to formaldehyde-albumin, other air voxis could be similarly screened to evaluate ther potential influence on atopic responses Experimental Evidence for VOC Mixtures Some experimental evidence in controlled Jhuman exposure studies supports an respira cory inant mechanism for VOCs (45,146), but the human experimental research on lower respiratory oF pulmonary immunologic effects of VOCS is scarce apar from studies of agents asociated with occupational asthma (eg. TDI, formaldehyde) Koren et al. (146) conducted a random ined crossover chamber study of 14 healthy nonsmoking young adult men, Subjects were posed for 4 he 1 week apart to clean air and 25 p/m’ of a VOC mistre typical of indoor industrial microenvironments, Nasal lavage performed immediately ater exposure andr later showed iat nce neutrophils ae both time points. Harving ct al. (147) conducted a randomized crossover amber study of 11 asthmatic individuals who were hyperreactive to histamine Subjects were exposed for 90 min, 1 week apart to clean air and VOC. mixtures a 2.5 and 25 ugim’. Investigators found FEV, decreased 10 91% of baseline wich 25 g/m’, but this was nor significantly differen from sham exposure, and there was no change in histamine reactiviey. Iris possible that the Environmental Health Perspectives + vow 110/ surname 41 Avous 2002 null results do not reflect inflammatory changes that influence small airways, which could be missed with FEV, measurements, What may be occurring in nacural environ: ments is another story, with mixed expo- sures possibly interacting undera wide range of exposure-dose conditions. This is best investigated with epidemiologic designs Epidemiologic Evidence for VOC Mixtures Indirect evidence ofa role for ambient VOCs in asthma comes from research linking a buildup of indoor inrcants including VOCs and bioaerosos in office buildings to 8 non- specific cluster of symptoms called che "sick building syndrome,” which includes upper and lower respiratory tact sympeoms, eye ination, headache. and fatigue. Other stud ies have also found new-onser asthma occu in relation to particular noncesicencal indoor environments, especially where prob- lems with ventilation systems or dampness have been found (75). I is possible that fan- tal spores or other acroallergens, myeowoxins and endocosins could increase in parallel with VOCs under conditions of inadequate air exchange at work, and be responsible for some ofthese findings, Epidemiologic evidence inking indoor with asthma or elated respira outcomes come largely fram cross-see- I studies. A survey of 627 students 13-14 years of age attending 11 schools in Uppsala, Sweden, showed self-reported asthma prevalence (= 40) was higher in schools with higher VOCs (148), Oxher risk factors (e.g. acroallergens) were n trolled for in this association. In addition, passive, noc active, VOC measurements were associated with asthma. Norhick eal. (149), using a survey sam- ple of 600 adults 20-44 years of age in Uppsala, Sweden seleted a nonrandom sub- sample of 47 subjects reporting asthma attacks or nocturnal breathlessness the lst 12 months or repocting eurent use of asthma medications. A random subsample of 41 ‘other subjects was selected from the survey poo! with negative responses. Logistic regres sion models adjusted forage, se, smoking, ‘carpeting, and house dust mites, bur not ddampnes, which was significant. There were no effets on daytime breathlessness from cancentratons of 2-hractive VOC samples in the homes. Nocturnal breathlessness was associated with toluene, CB-aromates, cr pees, and formaldehyde in adjusted models Bronchial hypertesponsvenes was correlated oly with limonene. PEP variability was correlated onl with expres. ‘Wieslnder et al. (150 aime w examine respiratory symptoms and asthma outcomes 585Asthma Occurrence + Delfino last year. They selected an enriched random sample of 562 adult subjects, including asymptomatic responders along with all reporting asthma or nocturnal dyspnea (216 subjects), using the same survey source popu lation as Norback et al. (/49) in Uppsala ‘Asthma was defined as positive bronchial hyperresponsiveness to methacholine plus asthma sympcoms (99 subjects). Thiery-rwo percent of homes and 23% of workplaces ‘were painted within the last year. Total VOC was elevated by 100 g/m? in 62 newly painted homes. Logistic regression models adjusted for age, sex, and current smoking but not ETS. Asthma prevalence ‘yas greater for newly painted homes [OR 1.5, (95% CI 1.0-2.4), consistent with greater differences in VOCs (especially 2.2.4. trimethyl 1,3-pentanediol disoburyrate and Formaldehyde), Blood easinophil concentea- tions were also clevated in newly painted homes. In newly painted workplaces, asth- smalike symptoms were significantly increased (wheeze, dyspnea), bur there was no associa- tion with bronchial byperresponsiveness oF cosinophils. There were no associations for newly painted homes ot workplaces and axopy (SPT), serum eosinophilic cationic protein, seram IgE, PEF variability (1 week, self administeted, ice daly), or in-cinie FEV}. Biases in the above cross-sectional seudics in Uppal inchade potential seletion bias and the posibilitythat health outcomes preceded exposures. Dicz eta. (151) studied 266 newborn children boro with birth weight of 1,500-2,500 g, or with elevated IgE in cord bo, oF wih a postive primary family his- tory of atopic disease. Concenttations of 25 VOCS were monitored indoors during the frst 4 ecko of life. Parents fll out gues tionnairs afiee 6 weeks and 1 year of age Posenatal respiratory infections were associ- ated with benzene > 5.6 ugiim® [OR 24 (9500 CL 1.3, 45)] and sqyrene > 2.0 yg/m! (OR 2.1 (95% C1 11, 4.2). Wheezing was sssocated with reports of restoration (includ- ing painting and installation of carpeting) during the fst year of fe, but noe with otal for specifi Ig atthe age of 1 year. These ‘models controled for heating, gas cooking homme size, new furnituee. and animals but didnot contro for significant effects of ETS, which was correlated with benzene All ofthe above stacies of indoor VOCS may be subject co unmeasured confounding by other causal agens that increase indoors under low vertilstion conditions. including seroallergens, of that are cortelated with VOCS far ar reasons. Most, bur not al, of the studies conttolled for ETS. The research to date is too sparse to ealuat causality from indoor home VOCs, but there is even les information eo evaluate the public health 586 impact on respiratory health from outdoor VOCS, which include some of the same compounds found indoors Ware eal, (152) conducted a seudy in a large chemical manufacturing center in the Kanawha Valley, West Virginia. They sue- veyed 74 clementary schools with interviews of 8,549 children in and out ofthe valley and measured passive 8-wcck samples of 5 peto- Jeum-related VOCs (toluene, mp-xyleme, Fpenzene, xylene, decane) and 10 process- related VOCs (11, -aichloroethane, carbon tetrachloride, Lbutanel, chloroform, per- chloroethylene, methyl isobutyl Ketone, 1,2- dichloroethane, styrene, mesityl oxide, 2ethoxyethyl acetate). Higher VOC concen- ‘rations were found in che valley. Cross-see- tional results showed children in the valley had higher cates of physician-diagnosed asthma [OR 1.27 (95% CI 1.09, 1.48)] Compesite indicators for lower respiratory symptoms in the last year were weakly pos tively associated with petrleum-related VOC levels [OR per 10 pg/m’, 1.05 (95% CL 1.02, 1LO7)] and process-telated VOCs levels [OR per 2 pgim’, 1.08 (95% Cl 1.02, 1.14)] Asthma diagnoses were weakly positively associated with petroleum-related VOCs [OR 1.05 (954% CI 1.02, 1.08)] but nox process- related VOCs (OR 0.99). One schol with high petroleum-rlated VOCs strongly influ ‘enced the model. The average concentrations measured in the Kanawha study do noc differ om average level in large urban areas 1 the Kanawha study compared with a Los Angeles ambient exposure study, for ample, average toluene was 9.7 ygim’ ver sus 13 uglm:, respectively, and for benzene 3.2 jg? versus 3.5 yglm', respectively (153). In a study of 51 residents of Los Angeles, personal and indoor air concencea ‘ions ofall prevalent VOCs except carbon serachlorde were higher than outdoor ambi ent concentrations (154). Also, personal eal time exposures can be even higher, particularly while in cars (759) For exarmple, measure- ments of toluene taken inside cars in New York Cy ranged fiom 26 co 56 g/m? and for ‘benzene range! fom 9011 ygh (256. Conclusions Considerable progress has been made in iden- fying risks to asthma morbidity from the tnajorctiteria air pollutants sich as ambient Og and particle mas, aswel as fom major types of air pollutant mistares,paciculry FETS, Like ambien parile mass though, the caus components of ETS are poorly under: sto. Lees kre abou asta sks fom primary emissions fnked to ear and ck fel which compared with ETS may be an equally importanc mixed-poluan exposure Boch ETS and eae exhaust plants co tain some of the same toxic air pollutants, including PAHs. Experimeneal data support the biologic plassibiliey of a role of PAHS in allege espitatocy responses. However, the ‘ceupational epidemiology literature on re piratory outcomes and exposures o desl and futomobile emissions is inconsistent, likely due to major methodologic flaws. Th nonoecupational epidemiology iteratuce on trafic related exponires, on the other hands mote consistent, pariculaely when better designed studies ae considered. These studs commonly showed an increase in the prexar lence of ath, atopy, upper and lower re piratory symproms and lung function deficits in relation to higher exposures to cralfic (Table 2). Other air toxics commonly encountered in both indoor and outdoor ambien air include a large aumber of VOCs, including a known occupational asthmogen, formaldehyde. At present. however, both the human experimental and epidersiologc lier atute is Timid a few studies. What is needed now isto advance epidemiologic research on reionships of asthma onset and ‘exacerbation to at toxics exposures. I willbe important o disentangle eices of ai toxis from major air pollutants regularly monitored by governments such as particle mass black smoke, or NOs. Stdies eld acs on air toxics identified as asthmogeni in occupa sional studies (eg. certain metal compounds) and on other air toxies expected to have adverse respiratory effets based on biologic mechanisms (eg, PAHS) Statics mos likely to yield clear and valuable information include well-designed prospective cohort sts to ascertain the elevance of at txics tw asthma onsct and chronicity and repeated measures studies 0 evaluate acute exposure- dlose-response relationships in suscepaible individual. Key design issues that have been only pray addressed to date include accurate exposure assesment, including pesonal and tnicroenvironmental component, and aceu- rate outcome assent inching validated and objective physiologic measurements of acute and chronic ill health outcomes Despite limitations ia the currene state of Kanowledge about air toxics and asthma, this review gives suicien evidence to justify ‘more intesive investigation. 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