A short-term inhalation study to assess the reversibility of sensory irritation in human volunteers

• Published in: Archives of toxicology Vol. 94; no. 5; pp. 1687 - 1701
• Main Authors: Kleinbeck, Stefan, Schäper, Michael, Pacharra, Marlene, Lehmann, Marie Louise, Golka, Klaus, Blaszkewicz, Meinolf, Brüning, Thomas, van Thriel, Christoph
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2020; Springer Nature B.V
• Subjects: Acrylates - toxicity; Administration, Inhalation; Adult; Air Pollutants, Occupational - toxicity; Animals; Biochemical markers; Biomedical and Life Sciences; Biomedicine; Blinking; Chemoreceptors; Environmental Health; Exposure limits; Eye; Eye movements; Female; Healthy Volunteers; Humans; Immune response; Inhalation; Inhalation Exposure - statistics & numerical data; Irritants; Irritation; Male; Markers; Occupational Exposure; Occupational health; Occupational Medicine/Industrial Medicine; Odor; Odorants; Odors; Organ Toxicity and Mechanisms; Perception; Performance enhancement; Pharmacology/Toxicology; Rabbits; Ratings; Respiration; Respiratory tract; Sensory evaluation; Sensory Thresholds; Threshold Limit Values; Toxicology; Ethyl acrylate; Objective measures of irritation; Eye blinking frequencies; Biochemical markers of neurogenic inflammation; Perceptual ratings; 5-Day controlled exposure study; Sensory irritation
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-020-02703-8

Sensory irritation is an acute adverse effect caused by chemicals that stimulate chemoreceptors of the upper respiratory tract or the mucous membranes of the outer eye. The avoidance of this end point is of uttermost importance in regulatory toxicology. In this study, repeated exposures to ethyl acrylate were analyzed to investigate possible carryover effects from day to day for different markers of sensory irritation. Thirty healthy subjects were exposed for 4 h on five subsequent days to ethyl acrylate at concentrations permitted by the German occupational exposure limit at the time of study. Ratings of eye irritation as well as eye blinking frequencies indicate the elicitation of sensory irritation. These markers of sensory irritation showed a distinct time course on every single day. However, cumulative carryover effects could not be identified across the week for any marker. The rhinological and biochemical markers could not reveal hints for more pronounced sensory irritation. Neither increased markers of neurogenic inflammation nor markers of immune response could be identified. Furthermore, the performance on neurobehavioral tests was not affected by ethyl acrylate and despite the strong odor of ethyl acrylate the participants improved their performances from day to day. While the affected physiological marker, the increased eye blinking frequency stays roughly on the same level across the week, subjective markers like perception of eye irritation decrease slightly from day to day though the temporal pattern of, i.e., eye irritation perception stays the same on each day. A hypothetical model of eye irritation time course derived from PK/PD modeling of the rabbit eye could explain the within-day time course of eye irritation ratings repeatedly found in this study more precisely.