Dose-dependent transitions in mechanisms of toxicity

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

131 Scopus citations

Abstract

Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/ hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226-294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12-13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of the workshop was to examine approaches to dose-response analysis, learn from the case study examples, and gather feedback from invited participants on the impact of dose-dependent transitions on the risk assessment process. The second forum consisted of a workshop in March 2003 at the Society of Toxicology Annual Meeting in Salt Lake City, UT. This paper addresses the issues discussed at both workshops, and presents the consensus conclusions drawn by expert participants.

Original languageEnglish (US)
Pages (from-to)203-225
Number of pages23
JournalToxicology and Applied Pharmacology
Volume201
Issue number3
DOIs
StatePublished - Dec 15 2004

Bibliographical note

Funding Information:
The development of this report was funded in part by the U.S. Environmental Protection Agency. The report was reviewed by the EPA National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the agency nor does mention of trade names or commercial products constitute endorsement or recommendations for use.

Funding Information:
Another approach is to involve stakeholders in the development of the mechanism-based risk assessment. A recent cancer risk assessment for formaldehyde ( Chemical Industry Institute of Toxicology (CIIT) Centers for Health Research, 1999 ) used this approach. While the bulk of the technical work on this assessment was conducted by CIIT, the work was guided by a steering committee with representatives from EPA, the chemical industry, and CIIT. Regular meetings of the steering committee during development of the assessment helped to ensure that issues of concern were identified and addressed, and generally helped to obtain the buy-in of the stakeholders. The culmination of the process was an ad hoc peer-review meeting funded by EPA and Health Canada. Health Canada has since released a document consistent with the assessment (Formaldehyde. Priority substances list assessment report. ISBN 0-662-29447-5. Cat. No. En40-215/61E), and the German MAK commission also promulgated a new formaldehyde regulation supported in part by the assessment (Deutsche Forschungsgemeinschaft. List of MAK and BAT values 2000. Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Report No. 36, Wiley-VCH). Other regulatory agencies, including EPA and California EPA, are currently evaluating the assessment.

Funding Information:
Financial support for the February 2003 workshop was provided by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the HESI Project Committee on the Use of Mechanistic Data in Risk Assessment, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency.

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 partial financial support, for this project.

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • Dose-dependent transitions
  • Dose-response
  • Mechanisms of toxicity

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