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Acute diesel exhaust exposure and postural stability: a controlled crossover experiment Curran, Jason; Cliff, Rachel; Sinnen, Nadine; Koehle, Michael; Carlsten, Chris Jan 8, 2018

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SHORT REPORT Open AccessAcute diesel exhaust exposure and posturalstability: a controlled crossover experimentJason Curran1,2 , Rachel Cliff1,2, Nadine Sinnen3, Michael Koehle4 and Chris Carlsten1,2,5*Abstract: Recent epidemiological evidence connects ambient air pollutants to adverse neurobehavioural effects inadults. In animal models, subchronic controlled exposures to diesel exhaust (DE) have also showed evidence ofneuroinflammation. Evidence suggests that DE not only affects outcomes commonly associated with cognitivedysfunction, but also balance impairment. We conducted a controlled human exposure experiment with 28 healthysubjects (average age = 28 years (SD = 7.1; range = 21–49); and 40% female) who were exposed to two conditions,filtered air (FA) and DE (300 μg PM2.5/m3) for 120 min, in a double-blinded crossover study with randomizedexposures separated by four weeks. Postural stability was assessed by the Balance Error Scoring System (BESS), abrief, easily-administered test of static balance. The BESS consists of a sequence of three stances performed on twosurfaces. With hands on hips and eyes closed, each stance is held for 20 s. “Error” points are awarded for deviationsfrom those stances. Pre- and immediately post-exposure BESS “error” point totals were calculated and the differencebetween the two timepoints were compared for each of the two exposure conditions. A mixed effect modelassessed the significance of the association. While our data demonstrates a trend of reduced postural stability inresponse to exposure to DE, exposure was not significantly associated with BESS value. This is the first study toinvestigate changes in postural stability as a result of exposure to DE in human subjects.Keywords: Air pollution, Traffic, Diesel exhaust, Exposure, Balance, Postural stability, Crossover design, BessIntroductionTraffic-related air pollution (TRAP) is a major contributorto the outdoor air pollution mix and has been heavily im-plicated in cardiovascular and respiratory disease [1, 2].Emerging epidemiological evidence connects ambient airpollutants to adverse cognitive and neurobehaviouraleffects in adults [3]. Human studies have further demon-strated that living in areas with elevated air pollution is as-sociated with decreased cognitive function [4–8], andelevated risk of dementia [9] and autism [10].Controlled exposure to diesel exhaust (DE), mean-while, has been reported to elicit a general cortical stressresponse in human subjects [11], elevate cytokine ex-pression and oxidative stress in different regions of therat brain [12], contribute to neuroinflammation and po-tentially lead to a rise in early markers of neurodegener-ative disease [13].Evidence suggests that DE not only affects outcomescommonly associated with cognitive deficits, such as im-paired recall memory and perceptual motor speed, but isalso linked to balance impairment (indicating dysfunc-tion of vestibular, cerebellar, and associated afferent andefferent pathways for postural control) [14]. Postural sta-bility or control represents a complex motor skill that ischaracterized by the ability to balance and orient thebody’s position in space, and can be adversely affectedby injury or disease to the vestibular system and/orbrain, including Parkinson’s disease [15]. Cognitive fac-tors are thought to play a role in the control of stabilityduring activities such as walking and standing [16]. Add-itionally, environmental and occupational exposures,such as those to ambient air manganese and lead, havebeen reported to provoke poor postural balance [17, 18].Human studies to date have provided limited insightinto the acute effects of exposure to DE on postural stabil-ity. We conducted a crossover experiment with adult sub-jects who were exposed to DE under controlled settings,and hypothesized that DE inhalation would result in de-creased postural stability, as assessed by the Balance ErrorScoring System [19], a brief and easily-administered test* Correspondence: carlsten@mail.ubc.ca1School of Population and Public Health, Faculty of Medicine, University ofBritish Columbia, 2206 E Mall, Vancouver, BC V6T 1Z9, Canada2Department of Medicine, Division of Respiratory Medicine, Chan-YeungCentre for Occupational and Environmental Respiratory Disease, University ofBritish Columbia, Vancouver, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Curran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 DOI 10.1186/s12995-017-0182-5of static balance. The Effects of Air Pollution on Cognition(EAPOC) study marks one of the largest human con-trolled DE exposure studies.MethodsSubject recruitment and screeningA total of 36 study subjects were recruited via posters inor near Vancouver, B.C. transportation hubs, online no-tices, and e-mail notifications to the local health author-ity list-serve.An initial telephone screening assessed the suitability ofpotential subjects according to set of inclusion and exclu-sion criteria that included: (i) subjects between the ages of19 and 49; (ii) healthy; (iii) nonsmoker; (iv) speaking andreading proficiency in English; (v) not pregnant or breast-feeding; and, (vi) absence of co-existing medical condi-tions or medications that could interfere with the studyprotocol. Subjects were also excluded based on having(vii) a moderate-to-high degree of claustrophobia, and(viii) the presence of implanted metal that could interferewith functional magnetic resonance imaging (fMRI),which were considered as part of a separate component ofthis study not covered in this article.A secondary screening of subjects included an in-person medical/health questionnaire and brief physicalexam by our study clinician. Each qualifying subject wasthen presented with a detailed outline and explanationof the study protocol, and written and informed consentwas obtained. Consent forms were approved by the Uni-versity of British Columbia Clinical Research EthicsBoard (# H12–03025), Vancouver Coastal Health EthicsBoard (# V12–03025), and Health Canada’s ResearchEthics Board (# 2012–0040).Environmental exposure procedureStudy participants were exposed to two conditions: filteredair (FA) and DE (300 μg PM2.5/m3, nominally) for120 min, in a double-blinded, crossover study with ran-domized inhalation exposures separated by four weeks.Using a system previously reported [20], exposures wereconducted in the Air Pollution Exposure Laboratory(APEL), which creates fresh DE, suitably aged (4 min) anddiluted for human experimentation at realistic and safeconcentrations. The DE dose reflects the short-term, high-ambient PM exposures commonly occurring in busytransport corridors of large cities [21], and certain occupa-tional settings where diesel-powered machinery and gen-erators are used [22]. The DE exposure is standardized to300 μg PM2.5/m3, which aligns with the most common DEhuman health effects studies [20]. Blinding to exposureconditions was previously validated [23].Peripheral blood was collected before and at threetime points following the exposure (0-h; 3-h post-exposure; 24-h post-exposure) as part of a separate com-ponent of this study not covered in this article. Detailsof this blood collection procedure and serum/plasmaanalysis has been previously documented [24].During the exposure session, participants alternatedbetween rest (40 min/h) and cycling on a stationary bike(20 min/h) at a light effort with a load set to achieve aminute ventilation of approximately 15 L/min/m2 bodysurface area. Participants were closely monitored duringthe 120-min exposure and vitals, including heart rate,blood pressure and peripheral oxygen saturation, weremeasured at 20-min intervals (Table 1 and Fig. 1).Postural stability assessment (balance error scoringsystem)The BESS protocol is considered a useful test for assessingbalance and one that is easy to administer [25]. A system-atic review of the protocol concluded that BESS has con-struct validity and moderate to good reliability to assessstatic balance [26]. During the secondary screening andprior to data collection, each subject participated in aTable 1 Diesel exhaust and filtered air exposure characteristics (averages and variability) from DE and FA runs in the EAPOC studyFiltered air Diesel exhaustMean Standard deviation Mean Standard deviationTemperature (°C) 26.6 0.6 26.4 1.2Relative humidity (%) 32.1 8.5 35.5 7.5PM2.5 concentration (μg/m3) 2.4 7.1 289.6 58.0TVOC (ppb) 124.5 103.0 1425 364.5CO2 (ppm) 794.1 109.0 2098 353.5CO (ppm) 0.7 0.9 11.5 2.85NO (ppb) 26.7 34.6 7778 2211NO2 (ppb) 51.9 59.8 283.1 238.7NOx (ppb) 64.7 55.1 8062 2331TVOC (total volatile organic compounds); PM2.5 (particulate matter aerodynamic diameter < 2.5 μm); CO2 (carbon dioxide); CO (carbon monoxide); NO (nitrogenoxide); NO2 (nitrogen dioxide); ppb (parts per billion); ppm (parts per million)Curran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 Page 2 of 6BESS orientation/learning session, and was also asked tomaintain the same pre-test routine including the samemode of travel to the laboratory, pretest meal and caffeineintake, for each day of exposure. BESS assessments wereconducted immediately prior to each randomized expos-ure and immediately following the exposure. Briefly, theBESS consists of a sequence of three stances (double legstance, single leg stance, and tandem stance) performedon two surfaces (firm floor and medium density foam)[26] (Fig. 2). With hands on hips and eyes closed, eachstance is held for 20 s. “Error” points are awarded for ex-plicit deviations, including opening eyes, lifting hands offhips, abduction or flexion of the hip beyond 30 , or step-ping or stumbling. Higher score totals reflect worse per-formance on the test, and all tests were video recordedand scored by a blinded kinesiologist experienced in theadministration of the BESS. This evaluation method haspreviously been shown to have an ICC of 0.88 [19].Statistical analysisStatistical analysis was conducted using R (https://www.r-project.org/). Pre- and post-exposure BESS “error” pointtotal means for each of the six stances were reported. Thescores of all stances were summed for each for each ex-posure condition, and the difference between baseline andpost-exposure aggregate scores created a delta value. Nor-mality and order effects were tested. A mixed effect modelwas performed to assess the significance of the associ-ation. P-values of <0.05 were considered significant.ResultsSubject characteristicsOf the 36 recruited candidates, 28 healthy adult partici-pants (average age = 28 years (SD = 7.1; range = 21–49);and 40% female) completed the study’s two exposurecondition sessions. Complete sets of before and after ex-posure BESS assessments were recorded for each of the28 participants.BESS assessment scores aggregatedTable 2 shows the average concentration of each BESSstance at baseline and post-exposure to DE or FA. TheBESS scores for all six stances were summed, and deltavalues between the baseline and post-exposure timepointswere calculated for each exposure condition. Normalitywas assessed and the delta values were found to approxi-mate a normal distribution. Order effects were tested by apaired t-test and found to be absent (p-value = 0.52).A mixed effect model assessed the significance of theassociation between exposure condition and the BESSdelta value. In addition to the inclusion of a four-weekwashout period to counter potential carryover effects,our initial model evaluated the interaction between ex-posure and order and found no significant carryover ef-fect (p-value = 0.66). Our data did demonstrate a trendof reduced postural stability in response to exposure toDE (Fig. 3). The mean change in BESS scores weregreater following DE exposure (effect estimate: 1.50; 95%CI, 0.02 to 2.98), while the mean change following FAexposure was in a similar direction but was of lessermagnitude and not significant (effect estimate: 0.53; 95%CI, −0.94 to 2.01). In the mixed model, exposure did notsignificantly impact BESS delta score (p-value = 0.36), assuggested by the overlap in confidence intervals sur-rounding the estimates of effect for each exposure.DiscussionTo our knowledge, this is the first study of its kind to in-vestigate the effects on postural stability, or static balance,following an acute DE exposure in healthy humans. AsFig. 1 Outline of the EAPOC study design. Each crossover condition (FA/DE) was separated by a four-week washout periodCurran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 Page 3 of 6part of the greater EAPOC study – one of the largestknown human controlled exposure studies of air pollution– we hypothesized that an exposure to DE approximating300 mg/m3 PM2.5 would negatively disrupt postural stabil-ity as measured by the BESS protocol, relative to a shamexposure. Results from our study involving 28 healthyadult subjects suggest that acute exposure to DE, with PMlevels approximating those intermittently present in highlypolluted cities such as Beijing, China and New Delhi,India, does not cause a significant impact to an individual’sstatic balance. Trends in the direction of an adverse effect(i.e. worsening balance) following DE were observed,potentially motivating more extensive or detailed examin-ation of the role of traffic-related air pollution on factorsthat control postural stability. It may be that BESS scoreswould be further compromised at a later timepoint, as-suming neuroinflammation is delayed by slow penetrationof particulate matter into the central nervous system, orin a more susceptible population, such as the elderly.In a case-control study examining the effects ofchronic DE exposure in 10 railroad workers and six elec-tricians, Kilburn found balance impairments in the DEexposed group relative to the reference group of workers[14]. However, these results are difficult to interpret asFig. 2 Stances used in Balance Error Scoring System (BESS): (i) double-leg stance; (ii) single-leg stance (standing on the non-dominant limb); (iii)tandem stance; (iv) double-leg stance with foam; (v), single leg on foam; and, (vi) tandem stance on foamCurran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 Page 4 of 6participant selection was nonrandom, potential con-founding variables were incompletely controlled, andcontributions likely attributable to acute versus chronicexposures were difficult to distinguish.A limitation of our study is that our acute 2-h expos-ure is inconsistent with the chronic PM exposure studiesto date that have found adverse associations with cogni-tive endpoints. While this was intentional, as we won-dered about the specific effects of short-term exposures,it may be that only prolonged exposures induces suffi-cient inflammation to induce change across the neuro-cognitive spectrum. Furthermore, if such changes indeedexist, the BESS assessment may not be sufficiently sensi-tive to pick up such signals following this acute expos-ure. Crossover experiments typically provide greaterstatistical power than parallel-group trials of similar size,and allow considerably smaller sample sizes for compar-able type I and type II error risks [27, 28]. Regardless,the inconclusive, but suggestive, results may motivatefurther investigation using a similarly designed studywith a greater sample size. As suggested earlier, anotherlimitation to our study include the recruitment ofhealthy adults as opposed to alternative populations whoare inherently more susceptible to the CNS effects of airpollution [4, 5, 29, 30].AbbreviationsAPEL: air pollution exposure laboratory; BESS: balance error scoring system;CNS: central nervous system; CO: carbon monoxide; CO2: carbon dioxide;DE: diesel exhaust; EAPOC: effects of air pollution on cognition; FA: filteredair; FMRI: functional magnetic resonance imaging; ICC: intraclass correlationcoefficient; NO: nitrogen oxide; NO2: nitrogen dioxide; PM: particulate matter;PM2.5: particulate matter aerodynamic diameter less than 2.5 μm inaerodynamic diameter); Ppb: parts per billion; Ppm: parts per million;TRAP: traffic-related air pollution; TVOC: total volatile organic compoundsAcknowledgementsThe authors would like to acknowledge Health Canada for their funding support,and Dr. Robin Shutt and Dr. Ling Liu for their collaborations throughout the study.FundingA Health Canada contract provided the funding for this study. The fundingbody participated in an advising role.Availability of data and materialsThe datasets used and analyzed during the current study are available fromthe corresponding author on reasonable request.Authors’ contributionsJC conceptualized the study and the design, recruited subjects, supervisedthe exposures, and analyzed and interpreted the patient data. RC performedthe balance assessments and supervised the exposures. MK advised andconsulted on the use of the Balance Error Scoring System (BESS). NSreviewed and scored all Balance Error Scoring System (BESS) videos. CC wasthe study’s principal investigator and conceptualized the study and thedesign, as well as conducted the physical exams on subjects and supervisedthe general operations of the Air Pollution Exposure Lab (APEL). All authorsread and approved the final manuscript.Ethics approval and consent to participateConsent forms were approved by the University of British Columbia ClinicalResearch Ethics Board (# H12–03025), Vancouver Coastal Health Ethics Board(# V12–03025), and Health Canada’s Research Ethics Board (# 2012–0040). Allsubjects participating in the study provided informed, written consent.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Fig. 3 A sum of all Balance Error Scoring System (BESS) stancescores at baseline and post-exposure timepoints for sham condition(filtered air) and diesel exhaust conditionTable 2 A summary of the BESS scores for each of the six stances and two exposure conditions. Values are presented as mean(standard deviation)Filtered air (FA) Diesel exhaust (DE)BESS Stance Baseline (n = 28) Post-exposure (n = 28) Baseline (n = 28) Post-exposure (n = 28)Double-leg stance on firm floor 0.00 0.00 0.00 0.00Single-leg stance on firm floor 2.14 (1.98) 2.25 (1.97) 2.39 (2.45) 2.29 (2.29)Tandem stance on firm floor 1.11 (1.69) 0.57 (0.96) 0.68 (0.94) 1.07 (1.54)Double-leg stance on foam 0.00 0.00 0.11 (0.31) 0.04 (0.19)Single-leg stance on foam 6.29 (2.27) 6.82 (1.94) 6.54 (1.99) 6.96 (1.93)Tandem stance on foam 3.86 (2.01) 4.29 (2.42) 3.86 (2.41) 4.71 (2.46)Sum of all stances 13.39 (5.81) 13.93 (5.51) 13.57 (6.37) 15.07 (5.94)Curran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 Page 5 of 6Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1School of Population and Public Health, Faculty of Medicine, University ofBritish Columbia, 2206 E Mall, Vancouver, BC V6T 1Z9, Canada. 2Departmentof Medicine, Division of Respiratory Medicine, Chan-Yeung Centre forOccupational and Environmental Respiratory Disease, University of BritishColumbia, Vancouver, Canada. 3Copeman Healthcare Centre, Suite 300 – 808Nelson Street, Vancouver, BC V6Z 2H2, Canada. 4School of Kinesiology,University of British Columbia, Medical Sciences Block C, Room 118, 2176Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. 5Vancouver GeneralHospital, 2775 Laurel St., 7th Floor, Vancouver, BC, Canada.Received: 28 June 2017 Accepted: 22 December 2017References1. Brook RD, Rajagopalan S, Pope CA, Brook JR, Bhatnagar A, Diez-Roux AV, etal. 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Traffic-related air pollution and cognitive function in a cohort of older men.Environ Health Perspect. 2011 May 1;119(5):682–7.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Curran et al. Journal of Occupational Medicine and Toxicology  (2018) 13:2 Page 6 of 6


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