How Healthy Is Healthy? Comparison Between Self-Reported Symptoms and Clinical Outcomes in Connection with the Enrollment of Volunteers for Human Exposure Studies on Sensory Irritation Effects

  • D. Rosenkranz
  • J. Bünger
  • F. Hoffmeyer
  • C. Monsé
  • V. van Kampen
  • M. Raulf
  • T. Brüning
  • K. SuckerEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1271)


Controlled human exposure studies on sensory irritation effects are usually performed with healthy volunteers. Therefore, in most studies pre-screening by a health questionnaire and a detailed medical examination are combined. The aim of this report is to investigate whether self-reported information about smoking and health status is sufficient or whether additional clinical tests are necessary for a successful and safe enrollment of healthy volunteers. There were 409 volunteers (55% female; 17–57 years; 79% non-smokers) who declared interest in participation in the study. However, 87 subjects failed to meet specific inclusion criteria, and further 138 had to be excluded due to the presence of chronic health problems. In effect, 184 subjects passed the initial questionnaire screening and proceed to further examination. Medical examination included electrocardiogram, blood and urine screening, and an olfactory function test. Atopy status was assessed by skin prick or specific IgE testing. Lung function and a methacholine challenge test were performed to assess respiratory health and bronchial hyperresponsiveness. Overall, only 107 non-smoking subjects (58% female; 19–40 years) who had no respiratory diseases, allergies, or chronic illnesses could be finally selected. Out of the 107 subjects, 8 were excluded due to positive cotinine tests, laboratory test results outside the reference range, or atypical ECGs. In another 12 subjects, obstruction or a bronchial hyperreactivity was diagnosed. Among the remaining 87 healthy subjects, 26 were classified as atopic and further two as hyposmic. In conclusion, although young and non-smoking volunteers considered themselves healthy by questionnaire, 20% showed signs of a heart, liver, or airway disease, and additional 24% were classified as atopics. This suggests that more detailed clinical testing may be necessary to safely exclude those who may adversely react to controlled exposure with sensory irritants.


Clinical examination Clinical outcome Exposure study Health Self-report Sensory irritation 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The recruiting and testing procedures were reviewed and approved by the Ethics Committee of the Ruhr University Bochum, Germany.

Informed Consent

All individual participants included in the study gave written informed consent. Prior to participation, the participants received information on the study requirements and a written declaration of consent. They were informed verbally and in writing about the study design, possible dangers, and their freedom to withdraw at any time. They received financial compensation for participation.


  1. ATS (1995) American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152(5 Pt 2):S77–S121Google Scholar
  2. Baskoy K, Ay SA, Altundag A, Kurt O, Salihoglu M, Deniz F, Tekeli H, Yonem A, Hummel T (2016) Is there any effect on smell and taste functions with levothyroxine treatment in subclinical hypothyroidism? PLoS One 11(2):e0149979PubMedPubMedCentralGoogle Scholar
  3. Baur X, Huber H, Degens PO, Allmers H, Ammon J (1998) Relation between occupational asthma case history, bronchial methacholine challenge, and specific challenge test in patients with suspected occupational asthma. Am J Ind Med 33(2):114–122PubMedGoogle Scholar
  4. Boesveldt S, Postma EM, Boak D, Welge-Luessen A, Schöpf V, Mainland JD, Martens J, Ngai J, Duffy VB (2017) Anosmia – a clinical review. Chem Senses 42(7):513–523PubMedPubMedCentralGoogle Scholar
  5. Borkenau P, Ostendorf F (2008) NEO-Fünf-Faktoren-Inventar nach Costa und McCrae. Hogrefe (Article in German), GöttingenGoogle Scholar
  6. Brener ND, Billy JO, Grady WR (2003) Assessment of factors affecting the validity of self-reported health-risk behavior among adolescents: evidence from the scientific literature. J Adolesc Health 33(6):436–457PubMedPubMedCentralGoogle Scholar
  7. Brüning T, Bartsch R, Bolt HM, Desel H, Drexler H, Gundert-Remy U, Hartwig A, Jäckh R, Leibold E, Pallapies D, Rettenmeier AW, Schlüter G, Stropp G, Sucker K, Triebig G, Westphal G, van Thriel C (2014) Sensory irritation as a basis for setting occupational exposure limits. Arch Toxicol 88(10):1855–1879PubMedPubMedCentralGoogle Scholar
  8. Claeson AS, Palmquist E, Lind N, Nordin S (2016) Symptom-trigger factors other than allergens in asthma and allergy. Int J Environ Health Res 26(4):448–457PubMedGoogle Scholar
  9. Crawford JR, Henry JD (2004) The positive and negative affect schedule (PANAS): construct validity, measurement properties and normative data in a large non-clinical sample. Br J Clin Psychol 43(Pt 3):245–265PubMedGoogle Scholar
  10. Dwivedi AM, Johanson G, Lorentzen JC, Palmberg L, Sjögren B, Ernstgård L (2015) Acute effects of acrolein in human volunteers during controlled exposure. Inhal Toxicol 27(14):810–821PubMedPubMedCentralGoogle Scholar
  11. Ernstgård L, Gullstrand E, Löf A, Johanson G (2002) Are women more sensitive than men to 2-propanol and m-xylene vapours? Occup Environ Med 59(11):759–767PubMedPubMedCentralGoogle Scholar
  12. Ernstgård L, Iregren A, Sjögren B, Johanson G (2006a) Acute effects of exposure to vapours of acetic acid in humans. Toxicol Lett 165(1):22–30PubMedGoogle Scholar
  13. Ernstgård L, Iregren A, Sjögren B, Svedberg U, Johanson G (2006b) Acute effects of exposure to hexanal vapors in humans. J Occup Environ Med 48(6):573–580PubMedGoogle Scholar
  14. Ernstgård L, Löf A, Wieslander G, Norbäck D, Johanson G (2007) Acute effects of some volatile organic compounds emitted from water-based paints. J Occup Environ Med 49(8):880–889PubMedGoogle Scholar
  15. Ernstgård L, Iregren A, Juran S, Sjögren B, van Thriel C, Johanson G (2009) Acute effects of exposure to vapours of standard and dearomatized white spirits in humans. 2. Irritation and inflammation. J Appl Toxicol 29(3):263–274PubMedGoogle Scholar
  16. Ernstgård L, Andersen M, Dekant W, Sjögren B, Johanson G (2010a) Experimental exposure to 1,1,1,3,3-pentafluoropropane (HFC-245fa): uptake and disposition in humans. Toxicol Sci 113(2):326–336PubMedGoogle Scholar
  17. Ernstgård L, Norbäck D, Nordquist T, Wieslander G, Wålinder R, Johanson G (2010b) Acute effects of exposure to 1 mg/m(3) of vaporized 2-ethyl-1-hexanol in humans. Indoor Air 20(2):168–175PubMedGoogle Scholar
  18. Ernstgård L, Norbäck D, Nordquist T, Wieslander G, Wålinder R, Johanson G (2013) Acute effects of exposure to vapors of 3-methyl-1-butanol in humans. Indoor Air 23(3):227–235PubMedGoogle Scholar
  19. Fahrenberg J, Hampel R, Selg H (1994) Das Freiburger Persönlichkeitsinventar. Revidierte Fassung. Hogrefe (Article in German), GöttingenGoogle Scholar
  20. Fiedler N, Kipen H, Ohman-Strickland P, Zhang J, Weisel C, Laumbach R, Kelly-McNeil K, Olejeme K, Lioy P (2008) Sensory and cognitive effects of acute exposure to hydrogen sulfide. Environ Health Perspect 116(1):78–85PubMedGoogle Scholar
  21. Fornazieri MA, Neto AR, de Rezende Pinna F, Gobbi Porto FH, de Lima Navarro P, Voegels RL, Doty RL (2016) Olfactory symptoms reported by migraineurs with and without auras. Headache 56(10):1608–1616PubMedGoogle Scholar
  22. Gminski R, Marutzky R, Kevekordes S, Fuhrmann F, Bürger W, Hauschke D, Ebner W, Mersch-Sundermann V (2011) Chemosensory irritations and pulmonary effects of acute exposure to emissions from oriented strand board. Hum Exp Toxicol 30(9):1204–1221PubMedGoogle Scholar
  23. Hey K, Juran S, Schäper M, Kleinbeck S, Kiesswetter E, Blaszkewicz M, Golka K, Brüning T, van Thriel C (2009) Neurobehavioral effects during exposures to propionic acid--an indicator of chemosensory distraction? Neurotoxicology 30(6):1223–1232PubMedGoogle Scholar
  24. Hoffmeyer F, Sucker K, Rosenkranz N, Berresheim H, Monse C, Brüning T, Bünger J (2013) Reproducibility of sensitivity to capsaicin assessed by single breath inhalation methodology. Adv Exp Med Biol 755:71–78PubMedGoogle Scholar
  25. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G (1997) “Sniffin’ sticks”: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 22(1):39–52PubMedGoogle Scholar
  26. Hummel T, Kobal G, Gudziol H, Mackay–Sim A (2007) Normative data for the “Sniffin’ Sticks” including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol 264(3):237–243PubMedGoogle Scholar
  27. Ihrig A, Hoffmann J, Triebig G (2006) Examination of the influence of personal traits and habituation on the reporting of complaints at experimental exposure to ammonia. Int Arch Occup Environ Health 79(4):332–338PubMedGoogle Scholar
  28. Jacinto T, Malinovschi A, Janson C, Fonseca J, Alving K (2017) Differential effect of cigarette smoke exposure on exhaled nitric oxide and blood eosinophils in healthy and asthmatic individuals. J Breath Res 11(3):036006PubMedGoogle Scholar
  29. Johansson A, Löwhagen O, Millqvist E, Bende M (2002) Capsaicin inhalation test for identification of sensory hyperreactivity. Respir Med 96(9):731–735PubMedGoogle Scholar
  30. Juran SA, van Thriel C, Kleinbeck S, Schäper M, Falkenstein M, Iregren A, Johanson G (2012) Neurobehavioral performance in human volunteers during inhalation exposure to the unpleasant local irritant cyclohexylamine. Neurotoxicology 33(5):1180–1187PubMedGoogle Scholar
  31. Juran SA, Johanson G, Ernstgård L, Iregren A, van Thriel C (2014) Neurobehavioral performance in volunteers after inhalation of white spirits with high and low aromatic content. Arch Toxicol 88(5):1127–1140PubMedGoogle Scholar
  32. Kiesswetter E, Sietmann B, Zupanic M, van Thriel C, Golka K, Seeber A (1999) Neurobehavioral aspects of the prevalence and etiology of multiple chemical sensitivity. Allergologie 22(12):719–735Google Scholar
  33. Kleinbeck S, Juran SA, Kiesswetter E, Schäper M, Blaszkewicz M, Brüning T, van Thriel C (2008) Evaluation of ethyl acetate on three dimensions: investigation of behavioral, physiological and psychological indicators of adverse chemosensory effects. Toxicol Lett 182(1–3):102–109PubMedGoogle Scholar
  34. Kleinbeck S, Schäper M, Zimmermann A, Blaszkewicz M, Brüning T, van Thriel C (2017) Prediction of human sensory irritation due to ethyl acrylate: the appropriateness of time–weighted average concentration × time models for varying concentrations. Arch Toxicol 91(9):3051–3064PubMedGoogle Scholar
  35. Kleinbeck S, Pacharra M, Schäper M, Blaszkewicz M, Golka K, Brüning T, van Thriel C (2018) Sensorische Irritationen durch Ameisensäure: Reagieren allergische Probanden stärker auf kontrollierte Expositionen? (Sensory irritations due to formic acid: Do allergic subjects react more strongly to controlled exposures?) In: Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin e.V. (Hrsg.): Dokumentation der 58. Jahrestagung der DGAUM, 7–9. März 2018 in München (page 50) (Article in German)Google Scholar
  36. Lang I, Bruckner T, Triebig G (2008) Formaldehyde and chemosensory irritation in humans: a controlled human exposure study. Regul Toxicol Pharmacol 50(1):23–36PubMedGoogle Scholar
  37. Laux L, Glanzmann P, Schaffner P, Spielberger CD (1981) Das state–trait–Angstinventar. Beltz (Article in German), WeinheimGoogle Scholar
  38. Müller JU, Bruckner T, Triebig G (2013) Exposure study to examine chemosensory effects of formaldehyde on hyposensitive and hypersensitive males. Int Arch Occup Environ Health 86(1):107–117Google Scholar
  39. Muttray A, Gosepath J, Brieger J, Faldum A, Pribisz A, Mayer-Popken O, Jung D, Rossbach B, Mann W, Letzel S (2009) No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways. Int Arch Occup Environ Health 82(4):481–488PubMedGoogle Scholar
  40. Muttray A, Gosepath J, Brieger J, Faldum A, Zagar C, Mayer–Popken O, Jung D, Roßbach B, Mann W, Letzel S (2015) No acute effects of an exposure to 50 ppm methyl methacrylate on the upper airways. Int Arch Occup Environ Health 88(8):1043–1051PubMedGoogle Scholar
  41. Naka A, Riedl M, Luger A, Hummel T, Mueller CA (2010) Clinical significance of smell and taste disorders in patients with diabetes mellitus. Eur Arch Otorhinolaryngol 267(4):547–550PubMedGoogle Scholar
  42. NASEM (2017) National Academies of sciences, engineering, and medicine. In: Controlled human inhalation–exposure studies at EPA. The National Academies Press, Washington, DC. Scholar
  43. Nordin S, Brämerson A, Lidén E, Bende M (1998) The Scandinavian odor–identification test: development, reliability, validity and normative data. Acta Otolaryngol 118(2):226–234PubMedGoogle Scholar
  44. Nordin S, Millqvist E, Löwhagen O, Bende M (2004) A short chemical sensitivity scale for assessment of airway sensory hyperreactivity. Int Arch Occup Environ Health 77(4):249–254PubMedGoogle Scholar
  45. Nordin S, Palmquist E, Bende M, Millqvist E (2013) Normative data for the chemical sensitivity scale for sensory hyperreactivity: the Västerbotten environmental health study. Int Arch Occup Environ Health 86(7):749–753PubMedGoogle Scholar
  46. Oleszkiewicz A, Schriever VA, Croy I, Hähner A, Hummel T (2019) Updated Sniffin’ Sticks normative data based on an extended sample of 9139 subjects. Eur Arch Otorhinolaryngol 276(3):719–728PubMedGoogle Scholar
  47. Pacharra M, Kleinbeck S, Schäper M, Blaszkewicz M, van Thriel C (2016a) Multidimensional assessment of self–reported chemical intolerance and its impact on chemosensory effects during ammonia exposure. Int Arch Occup Environ Health 89(6):947–959PubMedGoogle Scholar
  48. Pacharra M, Kleinbeck S, Schäper M, Juran SA, Hey K, Blaszkewicz M, Lehmann ML, Golka K, van Thriel C (2016b) Interindividual differences in chemosensory perception: toward a better understanding of perceptual ratings during chemical exposures. J Toxicol Environ Health A 79(22–23):1026–1040PubMedGoogle Scholar
  49. Pacharra M, Kleinbeck S, Schäper M, Blaszkewicz M, Golka K, van Thriel C (2017) Does seasonal allergic rhinitis increase sensitivity to ammonia exposure? Int J Hyg Environ Health 220(5):840–848PubMedPubMedCentralGoogle Scholar
  50. Pullerits T, Ternesten–Hasséus E, Johansson EL, Millqvist E (2014) Capsaicin cough threshold test in diagnostics. Respir Med 108(9):1371–1376PubMedGoogle Scholar
  51. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J, ERS Global Lung Function Initiative (2012) Multi–ethnic reference values for spirometry for the 3–95–yr age range: the global lung function 2012 equations. Eur Respir J 40(6):1324–1343PubMedPubMedCentralGoogle Scholar
  52. Seeber A, van Thriel C, Haumann K, Kiesswetter E, Blaszkewicz M, Golka K (2002) Psychological reactions related to chemosensory irritation. Int Arch Occup Environ Health 75(5):314–325PubMedGoogle Scholar
  53. Shusterman D (2014) Occupational irritant and allergic rhinitis. Curr Allergy Asthma Rep 14(4):425PubMedGoogle Scholar
  54. Sucker K, Hoffmeyer F, Monsé C, Jettkant B, Berresheim H, Rosenkranz N, Raulf M, Bünger J, Brüning T (2019) Ethyl acrylate: influence of sex or atopy on perceptual ratings and eye blink frequency. Arch Toxicol 93(10):2913–2926Google Scholar
  55. Sundblad BM, Larsson BM, Acevedo F, Ernstgård L, Johanson G, Larsson K, Palmberg L (2004) Acute respiratory effects of exposure to ammonia on healthy persons. Scand J Work Environ Health 30(4):313–321PubMedGoogle Scholar
  56. Ternesten–Hasséus E (2016) Long–term follow–up in patients with airway chemical intolerance. J Occup Environ Med 58(4):421–426PubMedGoogle Scholar
  57. van Thriel C, Kiesswetter E, Blaszkewicz M, Golka K, Seeber A (2003a) Neurobehavioral effects during experimental exposure to 1-octanol and isopropanol. Scand J Work Environ Health 29(2):143–151PubMedGoogle Scholar
  58. van Thriel C, Seeber A, Kiesswetter E, Blaszkewicz M, Golka K, Wiesmüller GA (2003b) Physiological and psychological approaches to chemosensory effects of solvents. Toxicol Lett 140–141:261–271PubMedGoogle Scholar
  59. van Thriel C, Kiesswetter E, Schäper M, Blaszkewicz M, Golka K, Seeber A (2005) An integrative approach considering acute symptoms and intensity ratings of chemosensory sensations during experimental exposures. Environ Toxicol Pharmacol 19(3):589–598PubMedGoogle Scholar
  60. van Thriel C, Blaszkewicz M, Schäper M, Juran SA, Kleinbeck S, Kiesswetter E, Wrbitzky R, Stache J, Golka K, Bader M (2007a) Chemosensory effects during acute exposure to N-methyl-2-pyrrolidone (NMP). Toxicol Lett 175(1–3):44–56PubMedGoogle Scholar
  61. van Thriel C, Kiesswetter E, Schäper M, Blaszkewicz M, Golka K, Juran S, Kleinbeck S, Seeber A (2007b) From neurotoxic to chemosensory effects: new insights on acute solvent neurotoxicity exemplified by acute effects of 2-ethylhexanol. Neurotoxicology 28(2):347–355PubMedGoogle Scholar
  62. van Thriel C, Schäper M, Kleinbeck S, Kiesswetter E, Blaszkewicz M, Golka K, Nies E, Raulf-Heimsoth M, Brüning T (2010) Sensory and pulmonary effects of acute exposure to sulfur dioxide (SO2). Toxicol Lett 196(1):42–50PubMedGoogle Scholar
  63. Wålinder R, Ernstgård L, Johanson G, Norbäck D, Venge P, Wieslander G (2005) Acute effects of a fungal volatile compound. Environ Health Perspect 113(12):1775–1778PubMedPubMedCentralGoogle Scholar
  64. Wålinder R, Ernstgård L, Norbäck D, Wieslander G, Johanson G (2008) Acute effects of 1-octen-3-ol, a microbial volatile organic compound (MVOC) – an experimental study. Toxicol Lett 181(3):141–147PubMedGoogle Scholar
  65. Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54(6):1063–1070PubMedGoogle Scholar
  66. Ziegler AE, Zimmer H, Triebig G (2008) Exposure study on chemosensory effects of epsilon-caprolactam in the low concentration range. Int Arch Occup Environ Health 81(6):743–753PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • D. Rosenkranz
    • 1
  • J. Bünger
    • 1
  • F. Hoffmeyer
    • 1
  • C. Monsé
    • 1
  • V. van Kampen
    • 1
  • M. Raulf
    • 1
  • T. Brüning
    • 1
  • K. Sucker
    • 1
    Email author
  1. 1.Institute for Prevention and Occupational Medicine of the German Social Accident InsuranceInstitute of the Ruhr University Bochum (IPA)BochumGermany

Personalised recommendations