M11 PM Internal Exposure
Monday, 14 November 2005: 1:50 PM - 5:30 PM in 343-344

(MAC-1118-072639) Paracelsus got it wrong: fugacity makes the poison!.

Mackay, D.¹, Arnot, J.¹, ¹ Trent University, Peterborough, Ontario, Canada

ABSTRACT- A perspective is offered on the relative merits of internal and external exposure as metrics of chemical toxicity. External exposure implies a two-stage process of toxicant delivery followed by disruption. Internal exposure focuses only on the disruption stage. The delivery stage being essentially one of transport is more readily measured, correlated, and predicted. The disruption stage being biochemical in nature is more difficult to quantify, but it is the true metric of inherent toxicity or potency. It is suggested that viewing these processes through the lense of fugacity clarifies their roles. The delivery stage involves the conversion of an external concentration to a fugacity then estimation of an internal/external fugacity ratio using bioaccumulation, biomagnification, metabolic or pharmacokinetic information. The disruption stage involves estimation of a critical internal tissue, fluid or body fugacity from biochemical mode-of-action information. Internal exposure assessment is simply a comparison of internal and critical fugacities whereas external exposure involves the external and critical fugacities. Both are useful, but for different purposes. Examples are presented illustrating the calculation of the fugacities and the time-dependence of the internal:external fugacity ratio. It is clear that "poisoning" arises because the magnitude and duration of the external chemical fugacity causes the internal fugacity to reach the critical fugacity, thus it is fugacity, not dose that makes the poison.

Key words: toxicity, internal dose, exposure assessment, mode-of-action