Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: Examples with vinyl chloride and trichloroethylene

Pathway-based toxicity: history, current approaches and liver fibrosis and steatosis as prototypes

“…the idea of incorporating mechanistic biochemical information into toxicological assessment is not new; it began with dose-response modeling efforts (for example, see Clewell et al, 1995) and mode-of-action frameworks, such as those developed by the International Program on Chemical Safety (IPCS) to determine human relevance of modes-of-action of pesticides and industrial chemicals leading to carcinogenic (Boobis et al, 2006) and non-carcinogenic (Boobis et al, 2008) toxicity, and the creation of mode-of-action pathways commonly used in drug development (e.g., Iorio et al, 2010) and applied to human disease (e.g., Schadt and lum, 2006). these efforts were novel in applying mechanistic information about the chemical-biomolecular inter-1 History of pathway-based approaches to toxicology 1.1 Introduction experience over several decades of characterizing chemical toxicity has led to the realization that a new approach is warranted.…”

Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data

“…However, it is discouraging to note that these tissue-dose based potencies for TCE are very similar to those for VC (Clewell et al, 1995), despite the strong epidemiological evidence suggesting that VC is a more potent human carcinogen than TCE. Clearly, pharmacokinetics alone does distinguish the relative potencies of these two compounds.…”

Exposure assessment of trichloroethylene.

“…Clewell et al (19) developed a physiologically based pharmacokinetic model for TCE that can be used to estimate the longterm average inhaled air concentration that would result in a measured blood concentration, assuming no other TCE exposure. The model can also estimate the long-term average ingested dose that would result in a measured blood concentration, assuming no other TCE exposure.…”