Dose-dependent transitions in mechanisms of toxicity.
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.
Slikker
William
W
US FDA National Center for Toxicological Research, Jefferson, AR 72079, USA.
Andersen
Melvin E
ME
Bogdanffy
Matthew S
MS
Bus
James S
JS
Cohen
Steven D
SD
Conolly
Rory B
RB
David
Raymond M
RM
Doerrer
Nancy G
NG
Dorman
David C
DC
Gaylor
David W
DW
Hattis
Dale
D
Rogers
John M
JM
Setzer
R Woodrow
RW
Swenberg
James A
JA
Wallace
Kendall
K
D000818:Animals; D018736:DNA Adducts / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008658:Inactivation, Metabolic; D012107:Research Design; D018570:Risk Assessment
D018736:DNA Adducts