Sensory irritation as a basis for setting occupational exposure limits

Abstract

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEChuman” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAECanimal.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acet...

n ‐Butyl acrylate [MAK Value Documentation, 2017]

“…A NAEC (no adverse effect concentration) of 5 ml/m 3 is obtained from the LOAEC of 15 ml/m 3 by dividing the LOAEC by a factor of 3 according to the method of Brüning et al (2014). MAK values of 1 and 2 ml/m 3 were calculated from the BMDL 05 and the NAEC to extrapolate the effects in the olfactory epithelium of rats to a NOAEC for humans (1:2), taking into consideration the preferred value approach.…”

“…The purpose of this supplement was to re-evaluate local irritation based on the proposals made by Brüning et al (2014) and to review the benchmark concentrations calculated in the 1996 supplement (supplement "n-Butyl acrylate" 1999).…”

Dimethyl sulfoxide (DMSO) [MAK Value Documentation, 2016]

“…In 2014, the Commission adopted a method for the derivation of MAK values for substances that have effects on the upper respiratory tract and eyes that is based on physiological and empirical aspects and which also includes criteria for the classification of the substance as a sensory irritant (Brüning et al 2014). The MAK value is reviewed here on the basis of this procedure.…”

“…A concentration of 70 ml/m 3 is obtained by applying the method described by Brüning et al (2014), taking into account the intensification of the effects after chronic exposure, extrapolation of the effects on the respiratory epithelium to exposed persons and an additional correction because of the 7-day exposure per week instead of 5-day workplace exposure. The MAK value of 50 ml/m 3 has therefore been retained.…”

Dipropylene glycol [MAK Value Documentation, 2016]

“…In 2014, the Commission started using a physiologically and empirically-based method for deriving MAK values for substances that have an effect on the upper respiratory tract and eyes; it also describes criteria for classification as a sensory irritant (Brüning et al 2014). The critical effect of dipropylene glycol, focal inflammation in the liver of male rats, is systemic (documentation "Dipropylenglykol" 2007, available in German only).…”