Molecular toxicologists, biochemists, and cancer experts all have the capabilities at their fingertips to investigate the responses of organ and cellular systems to chemical stressors, but they are frequently unable to link these responses to whole animal exposures. This problem is particularly evident in the field of aquatic toxicology, because fish and other aquatic organisms are often exposed simultaneously to chemicals in water and to chemicals complexed with food, particulates, and dissolved organic material. One promising approach to dealing with this problem involves the use of physiologically-based toxicokinetic (PBTK) models. In this chapter, we describe recent progress toward the development and validation of PB-TK models for fish and show how these models can be used to understand the dynamic relationships between applied chemical dose and target organ dose.I-8

In aquatic toxicology, mechanistic studies involving histopathology, organ function, macromolecular binding, depletion of specific cellular constituents, carcinogenesis, cell death, etc., are usually related to either a water exposure concentration or to an applied single ormultiple bolus dose. Standard toxicity tests

with waterborne chemicals provide no information on the chemical dose received internally, while tests with single or multiple bolus doses provide an applied dose, but no insight on the dose received at the site of damage. This situation is further complicated by not knowing whether changes seen in the target organ are caused by the parent chemical or a reactive metabolite. PB-TK models are designed to address these concerns by providing estimates of the time course of both parent chemical and metabolites at the site of toxic action. Because these models are based on an animal's physiological and biochemical attributes, they can be used to extrapolate dosimetry estimates across species, regardless of exposure route.