Proposal for a revised Reference Concentration (RfC) for manganese based on recent epidemiological studies

In 1993, based on observations of subclinical neurological effects in workers, the United States Environmental Protection Agency (US EPA) published a Reference Concentration (RfC) of 0.05 μg/m3 for manganese (Mn). The geometric mean exposure concentration, 150 μg/m3 respirable Mn, was considered the lowest observable adverse effect level (LOAEL), and uncertainty factors (UFs) were applied to account for sensitive populations, database limitations, a LOAEL, subchronic exposure, and potential differences in toxicity of different forms of Mn. Based on a review of more recent literature, we propose two alternate Mn RfCs. Of 12 more recent occupational studies of eight cohorts with chronic exposure durations, examining subclinical neurobehavioral effects, predominantly on the motor system, three were considered appropriate for development of an RfC. All three studies yielded no observable adverse effect levels (NOAELs) of approximately 60 μg/m3 respirable Mn. Converting the occupational NOAEL to a human equivalent concentration (HEC) of 21 μg/m3 (for continuous exposure) and applying a UF of 10 to account for intraspecies variability yielded an RfC of 2 μg/m3. We also derived a similar RfC (7 μg/m3) using an Mn benchmark dose (BMD) as the point of departure. Overall confidence in both RfCs is medium.