Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: A conceptual approach

•Dosimetric models are essential tools for inhalation risk assessment.•Characterization of deposited or retained doses is key for dosimetric extrapolation.•Regulatory bodies could use different aerosol sizes for original and target populations.•Comparison of animal and human equivalent exposures can inform species׳ response.

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM10, inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or human equivalent concentration; REC or rodent equivalent concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported.