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

133 Scopus citations

Abstract

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
Volume201
Issue number3
DOIs
StatePublished - Dec 15 2004

Bibliographical note

Funding Information:
The HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity extends its appreciation to the HESI Project Committee on the Use of Mechanistic Data in Risk Assessment for providing the scientific foundation, as well as financial support, for the development of these case studies. Appreciation is also extended to Samuel M. Cohen (University of Nebraska Medical Center), Curtis D. Klaassen (University of Kansas Medical Center), and James E. Klaunig (Indiana University School of Medicine) for their careful scientific review of this manuscript prior to submission for publication. The HESI Project Committee thanks Ms. Cyndi Nobles (ILSI Health and Environmental Sciences Institute) for her excellent administrative support during the project. About HESI The ILSI Health and Environmental Sciences Institute (HESI) is a global branch of the International Life Sciences Institute, a public, non-profit scientific foundation with branches throughout the world. HESI provides an international forum to advance the undestanding and application of scientific issues related to human health, toxicology, risk assessment, and the environment. HESI is widely recognized among scientists from government, industry, and academia as an objective, science-based organization within which important issues of mutual concern can be discussed and resolved in the interest of improving public health. As part of its public benefit mandate, HESI's activities are carried out in the public domain, generating data and other information for broad scientific use and application. Further information about HESI can be found at http://hesi.ilsi.org .

Keywords

  • 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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