Subchronic to chronic exposure extrapolation: Toxicologic evidence for a reduced uncertainty factor

Acceptable human exposure guidelines for noncarcinogens are usually based on laboratory test no‐observed‐adverse‐effect levels (NOAELs), which are downwardly adjusted by fixed 10‐fold uncertainty factors. One such factor adjusts subchronic data to estimate corresponding values for lifetime exposures. Matched ninety‐day and two‐year toxicity studies in rodents were evaluated to biologically assess the sufficiency or excess of the 10‐fold uncertainty factor for subchronic‐to‐chronic data extrapolation. Studies conducted by the oral and inhalation routes of exposure were evaluated. NOAELs and lowest‐observed‐adverse‐effect levels (LOAELs) in the subchronic (sc) and chronic (c) studies were compared in terms of NOAEL and LOAEL ratios. The mean and median NOAEL_SC/NOAEL_C ratios for 23 oral studies were 2.4 and 2.0, respectively. Data from 9 inhalation studies yielded mean and median ratios of 4.5 and 4.0, respectively. Only one oral or inhalation study had a NOAEL_SC/NOAEL_C ratio as high as 10, and 22 of the 23 oral studies had ratios of 5 or less. These findings indicate that uncertainty factors less than 10 are sufficient to downwardly adjust subchronic data for lifetime exposures.