Dose-dependent transitions in mechanisms of toxicity: Case studies

William Slikker, Melvin E. Andersen, Matthew S. Bogdanffy, James S. Bus, Steven D. Cohen, Rory B. Conolly, Raymond M. David, Nancy G. Doerrer, David C. Dorman, David W. Gaylor, Dale Hattis, John M. Rogers, R. Woodrow Setzer, James A. Swenberg, Kendall Wallace

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003.

Original languageEnglish (US)
Pages (from-to)226-294
Number of pages69
JournalToxicology and Applied Pharmacology
Issue number3
StatePublished - Dec 15 2004


  • Acetaminophen
  • Butadiene, ethylene glycol
  • Dose response
  • Dose-dependent transitions
  • Formaldehyde
  • Manganese
  • Mechanisms of toxicity
  • Methylene chloride
  • Peroxisome proliferator-activated receptor
  • Progesterone/ hydroxyflutamide
  • Propylene oxide
  • Vinyl acetate

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