Sensory irritation as a basis for setting occupational exposure limits

Area of Science:

• Toxicology
• Occupational Health
• Risk Assessment

Background:

• Local irritancy data integration into occupational exposure limits (OELs) requires standardized guidance.
• Regulatory toxicology faces challenges in assessing local toxicity endpoints for eyes and upper respiratory tract (URT).
• Understanding human and animal physiology of target sites is crucial for accurate risk assessment.

Purpose of the Study:

• To develop a framework for incorporating local irritancy data into risk assessment procedures for OEL derivation.
• To investigate the mechanisms of sensory and tissue irritation in the eyes and URT.
• To establish a default interspecies extrapolation factor (iEF) for local irritants.

Main Methods:

• Review of human and rodent ocular and URT morphology and physiology.
• Development of a conceptual model for sensory and tissue irritation pathways.
• Empirical derivation of an iEF using human volunteer and animal inhalation studies for selected irritants.

Main Results:

• Two distinct pathways for local irritation: sensory irritation (nerve-mediated) and tissue irritation (epithelial damage).
• Experimental data from human and animal studies allowed derivation of 'sensory NOAEChuman' and 'irritative NOAECanimal'.
• A default interspecies extrapolation factor (iEF) of 3 was determined for extrapolating animal data to humans for local sensory irritants.

Conclusions:

• The proposed conceptual model aids in understanding local irritancy mechanisms.
• A default iEF of 3 is recommended for extrapolating animal data to humans for local sensory irritants in the absence of human data.
• Substance-specific approaches should be considered when sufficient individual data are available.