and to delineation of inherent uncertainties. The framework analyses ensure rigor in supporting and communicating the outcome of risk assessment and in facilitating the direction of resources to research to fill critical data gaps. The transparency promoted by framework analyses is expected to contribute to increased consistency in decision-making regarding modes of induction of cancer and later implications for dose-response analysis.

Mode-of-action analyses are based on the assumption that tumors in a single tissue are induced by a single mode of action, although in early stages several (seemingly competing) pathways may contribute. Mode of action is increasingly considered to incorporate toxicokinetics because often the critical first key event (which can be rate-limiting in the context of dose-response relationships) is activation to a toxic metabolite.

In the following chapters, the committee evaluates EPA’s presentation and evaluation of the potential adverse health effects of exposure to tetrachloroethylene. Chapter 2 provides a brief overview of the toxicokinetics of tetrachloroethylene because understanding how the body handles tetrachloroethylene is critical for understanding its effects in the later chapters focused on specific organ systems. Chapter 3 presents an evaluation of the neurotoxic effects of tetrachloroethyelene; such effects were the basis of EPA’s derivation of the RfC and RfD for tetrachloroetheylene, so the review focuses on evaluating the strengths and weaknesses of available studies and their utility in deriving reference values. Chapter 4 reviews EPA’s presentation of the reproductive and developmental toxicity of tetrachloroethylene. That is followed by a chapter on the genotoxicity of tetrachloroethylene, which factors into the consideration of cancers of the liver (Chapter 6), kidney (Chapter 7), hematopoietic system (Chapter 8), and other organs (Chapter 9). Those toxicology reviews are followed by an assessment of EPA’s derivation of the noncancer reference values (Chapter 10) and cancer-risk values (Chapter 11). Chapter 12 provides the committee’s recommendations for future reassessments of tetrachloroethylene.