Changing variance and skewness as leading indicators for detecting ozone exposure-associated lung function decrement

  • Nan-Hung Hsieh
  • Yi-Hsien Cheng
  • Chung-Min LiaoEmail author
Original Paper


The objective of this study was to develop a novel risk analysis approach to assess ozone exposure as a risk factor for respiratory health. Based on the human exposure experiment, the study first constructed the relationship between lung function decrement and respiratory symptoms scores (ranged 0–1 corresponding to absent to severe symptoms). This study used a toxicodynamic model to estimate different levels of ozone exposure concentration-associated lung function decrement measured as percent forced expiratory volume in 1 s (%FEV1). The relationships between 8-h ozone exposure and %FEV1 decrement were also constructed with a concentration–response model. The recorded time series of environmental monitoring of ozone concentrations in Taiwan were used to analyze the statistical indicators which may have predictability in ozone-induced airway function disorders. A statistical indicator-based probabilistic risk assessment framework was used to predict and assess the ozone-associated respiratory symptoms scores. The results showed that ozone-associated lung function decrement can be detected by using information from statistical indicators. The coefficient of variation and skewness were the common indicators which were highly correlated with %FEV1 decrement in the next 7 days. The model predictability can be further improved by a composite statistical indicator. There was a 50 % risk probability that mean and maximum respiratory symptoms scores would fall within the moderate region, 0.33–0.67, with estimates of 0.36 (95 % confidence interval 0.27–0.45) and 0.50 (0.41–0.59), respectively. We conclude that statistical indicators related to variability and skewness can provide a powerful tool for detecting ozone-induced health effects from empirical data in specific populations.


Ozone Lung function Statistical indicators Toxicodynamic model Time-series dynamics Probabilistic risk assessment 



The authors acknowledge the financial support of the National Science Council of Republic of China under Grant NSC 100-2313-B-002-012-MY3.


  1. Anenberg SC, Horowitz LW, Tong DQ, West JJ (2010) An estimate of the global burden of anthropogenic ozone and fine particulate matter on premature human mortality using atmospheric modeling. Environ Health Perspect 118:1189–1195CrossRefGoogle Scholar
  2. Backus GS, Howden R, Fostel J, Bauer AK, Cho HY, Marzec J, Peden DB, Kleeberger SR (2010) Protective role of interleukin-10 in ozone-induced pulmonary inflammation. Environ Health Perspect 118:1721–1727CrossRefGoogle Scholar
  3. Balmes JR (2009) Can traffic-related air pollution cause asthma? Thorax 64:646–647CrossRefGoogle Scholar
  4. Biggs R, Carpenter SR, Brock WA (2009) Turning back from the brink: detecting an impending regime shift in time to avert it. Proc Natl Acad Sci USA 106:826–831CrossRefGoogle Scholar
  5. Carpenter SR, Brock WA (2006) Rising variance: a leading indicator of ecological transition. Ecol Lett 9:308–315Google Scholar
  6. Chen KS, Ho YT, Chou YM (2003) Photochemical modeling and analysis of meteorological parameters during ozone episodes in Kaohsiung. Taiwan Atmos Environ 37:1811–1823CrossRefGoogle Scholar
  7. Chen CH, Xirasagar S, Lin HC (2006) Seasonality in adult asthma admissions, air pollutant levels, and climate: a population-based study. J Asthma 43:287–292CrossRefGoogle Scholar
  8. Chen E, Schreier HMC, Strunk RC, Brauer M (2008) Chronic traffic-related air pollution and stress interaction to predict biologic and clinical outcomes in asthma. Environ Health Perspect 116:970–975CrossRefGoogle Scholar
  9. Dakos V, Scheffer M, van Nes EH, Brovkin V, Petoukhov V, Held H (2008) Slowing down as an early warning signal for abrupt climate change. Proc Natl Acad Sci USA 105:14308–14312CrossRefGoogle Scholar
  10. Dakos V, van Nes EH, Donangelo R, Fort H, Scheffer M (2010) Spatial correlation as leading indicator of catastrophic shifts. Theor Ecol 3:163–174CrossRefGoogle Scholar
  11. Depuydt PO, Lambrecht BN, Joos GF, Pauwels RA (2002) Effect of ozone exposure on allergic sensitization and airway inflammation induced by dendritic cells. Clin Exp Allergy 32:391–396CrossRefGoogle Scholar
  12. Drake JM, Griffen BD (2010) Early warning signals of extinction in deteriorating environments. Nature 467:456–459CrossRefGoogle Scholar
  13. Fakhrzadeh L, Laskin JD, Laskin DL (2002) Deficiency in inducible nitric oxide synthase protects mice from ozone-induced lung inflammation and tissue injury. Am J Respir Cell Mol Biol 26:413–419CrossRefGoogle Scholar
  14. Freijer JI, van Eijkeren JCH, van Bree L (2002) A model for the effect on health of repeated exposure to ozone. Environ Modell Softw 17:553–562CrossRefGoogle Scholar
  15. Frey U, Brodbeck T, Majumdar A, Taylor DR, Town GI, Silverman M, Suki B (2005) Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature 438:667–670CrossRefGoogle Scholar
  16. Gerrity TR, McDonnell WF (1989) Do functional changes in humans correlate with the airway removal efficiency of ozone? In: Schneider T, Lee SD, Wolters GJR, Grant LD (eds) Atmospheric ozone research and its policy implications. Elsevier, Amsterdam, pp 293–300Google Scholar
  17. Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Duncher M, Maire P (2008) The Hill equation: a review of its capabilities in pharmacological modeling. Fund Clin Pharmacol 22:633–648CrossRefGoogle Scholar
  18. Guttal V, Jayaprakash C (2008) Changing skewness: an early warning signal of regime shifts in ecosystems. Ecol Lett 11:450–460CrossRefGoogle Scholar
  19. Hill AV (1910) The possible effects of the aggregation of the hemoglobin on its dissociation curves. J Physiol 40:4–7Google Scholar
  20. Hsieh NH, Liao CM (2013) Fluctuations in air pollution give risk warning signals of asthma hospitalization. Atmos Environ 75:206–216CrossRefGoogle Scholar
  21. Inoue H, Aizawa H, Nakano H, Matsumoto K, Kuwano K, Nadel JA, Hara N (2000) Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs: possible role of interleukin-8. Am J Resp Crit Care Med 161:249–256CrossRefGoogle Scholar
  22. Jakab GJ, Spannhake EW, Canning BJ, Kleeberger SR, Gilmour MI (1995) The effects of ozone on immune response. Environment Health Perspect 103:77–89CrossRefGoogle Scholar
  23. Jerrett M, Burnett RT, Pope CA, Ito K, Thurston G, Krewski D, Shi YL, Calle E, Thun M (2009) Long-term ozone exposure and mortality. N Engl J Med 360:1085–1095CrossRefGoogle Scholar
  24. Kim SE, Kumar A (2005) Accounting seasonal nonstationarity in time series models for short-term ozone level forecast. Stoch Environ Res Risk Assess 19:241–248CrossRefGoogle Scholar
  25. Kleeberger SR, Ohtsuka Y, Zhang LY, Longphre M (2001) Airway responses to chronic ozone exposure are partially mediated through mast cells. J Appl Physiol 90:713–723CrossRefGoogle Scholar
  26. McConnell R, Berhane K, Gilliland F, London SJ, Islam T, Gauderman WJ, Avol E, Margolis HG, Peters JM (2002) Asthma in exercising children exposed to ozone: a cohort study. Lancet 359:386–391CrossRefGoogle Scholar
  27. McDonnell WF, Stewart PW, Smith MV (2010) Prediction of ozone-induced lung function responses in humans. Inhal Toxicol 22:160–168CrossRefGoogle Scholar
  28. Moral FJ, Rebollo FJ, Méndez F (2014) Using an objective model to estimate overall ozone levels at different urban locations. Stoch Environ Res Risk Assess 28:455–465CrossRefGoogle Scholar
  29. Mudway IS, Kelly FJ (2000) Ozone and the lung: a sensitive issue. Mol Aspects Med 21:1–48CrossRefGoogle Scholar
  30. National Research Council (2008) Estimating mortality risk reduction and economic benefits from controlling ozone air pollution. National Academy Press, Washington 2008Google Scholar
  31. Neuhaus-Steinmetz U, Uffhausen F, Herz U, Renz H (2000) Priming of allergic immune responses by repeated ozone exposure in mice. Am J Respir Cell Mol Biol 23:228–233CrossRefGoogle Scholar
  32. Park SK, O’Neill MS, Vokonas PS, Sparrow D, Schwartz J (2005) Effects of air pollution on heart rate variability: the VA normative aging study. Environ Health Perspect 113:304–309CrossRefGoogle Scholar
  33. Scheffer M, Bascompte J, Brock WA, Brovkin V, Carpenter SR, Dakos V, Held H, van Nes EH, Rietkerk M, Sugihara G (2009) Early-warning signals for critical transitions. Nature 461:53–59CrossRefGoogle Scholar
  34. Schelegle ES, Morales CA, Walby WF, Marion S, Allen RP (2009) 6.6-Hour inhalation of ozone concentrations from 60 to 87 parts per billion in healthy humans. Am J Resp Crit Care Med 180:265–272CrossRefGoogle Scholar
  35. Tank J, Biller H, Heusser K, Holz O, Diedrich A, Framke T, Koch A, Grosshennig A, Koch W, Krug N, Jordan J, Hohlfeld JM (2011) Effect of acute ozone induced airway inflammation on human sympathetic nerve traffic: a randomized, placebo controlled, crossover study. PLoS ONE 6:e18737CrossRefGoogle Scholar
  36. Venegas JG, Winkler T, Musch G, Melo MFV, Layfield D, Thavalekos N, Fischman AJ, Callahan RJ, Bellani G, Harris RS (2005) Self-organized patchiness in asthma as a prelude to catastrophic shifts. Nature 434:777–782CrossRefGoogle Scholar
  37. Weinhold B (2008) Ozone nation: ePA standard panned by the people. Environ Health Perspect 116:A302–A305CrossRefGoogle Scholar
  38. World Health Organization (2006) Air quality guidelines for particulate matter, ozone, nitrogen dioxide and sulfur dioxide. World Health Organization Press, Washington 2006Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Nan-Hung Hsieh
    • 1
  • Yi-Hsien Cheng
    • 2
  • Chung-Min Liao
    • 2
    Email author
  1. 1.Institute of Labor, Occupational Safety and HealthMinistry of LaborNew TaipeiRepublic of China
  2. 2.Department of Bioenvironmental Systems EngineeringNational Taiwan UniversityTaipeiRepublic of China

Personalised recommendations