Aniline-induced methemoglobinemia in dogs: pitfalls of route-to-route extrapolations.

Two groups of four beagle dogs each were exposed head-only to aniline vapor in concentrations of 155 or 174 mg/m(3) air for a duration of 4 h in order to attain a targeted total exposure dose of approximately 15 mg aniline/kg body weight. One group of dogs received this calculated dose also by gavage. Dose estimates were made either by the determination of aniline-serum albumin adducts or by repeated measurements of the respiratory minute volume during the inhalation exposure period. The magnitude of methemoglobin (MetHb) produced following each route served as the basis for comparison. MetHb levels were maximal at the end of the inhalation exposure period, attaining approximately 5%, whereas administration by gavage produced a maximum MetHb response of 26%. Measurements of respiratory minute volumes in individual dogs appear to suggest that variability in MetHb formation depends solely on the rate of uptake (ventilation). The concentration of aniline-serum albumin adducts and the extent of MetHb formation showed a nonproportional relationship. In summary, this study demonstrates that for aniline, an agent known to be bioactivated by a hepatic first-pass metabolism, the conversion of findings obtained from oral dosing to inhalation exposure concentrations is subject to overestimating dramatically the magnitude of MetHb formation likely to occur following inhalation exposure. As to whether the fivefold lower potency by inhalation is solely related to the hepatic first-pass bioactivation, to the rate of delivery, or to a less than 100% retention of the inhaled vapor within the respiratory tract remains to be elucidated. This study demonstrates some of the pitfalls that can occur in context with route-to-route extrapolations and reinforces many of the concerns related to such extrapolations.