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

Stefan Kleinbeck,Marie Louise Lehmann,Marlene Pacharra,Klaus Golka,Michael Schäper,Thomas Brüning,Christoph Van Thriel,Meinolf Blaszkewicz

doi:10.1007/s00204-020-02703-8

Abstract

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.

Highlights

Occupational exposure limits (OELs) are thought to protect workers from acute and chronic health effects related to the chemicals they are exposed to (ACGIH 2019; DFG 2018)
In case of ethyl acrylate, an R D50 of 315 ppm has been reported which would lead to a tentative OEL of almost 10 ppm that is still higher than the No Observable Adverse Effect Concentrations (NOAECs) derived from human exposure studies (Kleinbeck et al 2017; Sucker et al 2019)
Since this study addressed two different aims, namely (a) the replication of previous results obtained for ethyl acrylate (Kleinbeck et al 2017) and (b) the investigation of possible temporal summation of sensory irritation across a simulated 5-day working week, the presentation of the results section is structured

Summary

Introduction

Occupational exposure limits (OELs) are thought to protect workers from acute and chronic health effects related to the chemicals they are exposed to (ACGIH 2019; DFG 2018). Among the acute effects of volatile chemicals, the avoidance of sensory irritation is of high relevance in the working environment (Brüning et al 2014; Nielsen and Wolkoff 2017). This critical end point was introduced and conceptually described by Yves Alarie in the early 1970s (Alarie 1973). Since the respective RD50 was related to many OELs (Nielsen et al 2007; Schaper 1993), indicating a systematic relationship (OEL ~ 0.03 × RD50) This relationship was mainly based on comparisons among animal studies (Bos et al 2002) and the extrapolation to humans is still difficult due to anatomical and physiological species differences of the upper airways (Brüning et al 2014). In case of ethyl acrylate, an R D50 of 315 ppm has been reported (de Ceaurriz et al 1981) which would lead to a tentative OEL of almost 10 ppm that is still higher than the NOAEC derived from human exposure studies (Kleinbeck et al 2017; Sucker et al 2019)

Methods

Results

Conclusion