title: Dose-dependent transitions in mechanisms of toxicity: case studies.
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.
authors.affiliation: US FDA National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bogdanffy
authors.forename: James S
authors.initials: JS
authors.lastname: Bus
authors.forename: Steven D
authors.initials: SD
authors.lastname: Cohen
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
authors.forename: Raymond M
authors.initials: RM
authors.lastname: David
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Doerrer
authors.forename: David C
authors.initials: DC
authors.lastname: Dorman
authors.forename: David W
authors.initials: DW
authors.lastname: Gaylor
authors.forename: Dale
authors.initials: D
authors.lastname: Hattis
authors.forename: John M
authors.initials: JM
authors.lastname: Rogers
authors.forename: R Woodrow
authors.initials: RW
authors.lastname: Setzer
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: Kendall
authors.initials: K
authors.lastname: Wallace
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced* / Q000378:metabolism; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D019855:Ethylene Glycol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D005485:Flutamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D005557:Formaldehyde / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D008345:Manganese / Q000008:administration & dosage / Q000493:pharmacokinetics; D020149:Manganese Poisoning / Q000378:metabolism; D008752:Methylene Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology; D011374:Progesterone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D014753:Vinyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D015032:Zinc / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D018712:Analgesics, Non-Narcotic; D000726:Androgen Antagonists; D002070:Butadienes; D004000:Dichloroethylenes; D004852:Epoxy Compounds; D047492:Peroxisome Proliferator-Activated Receptors; D014753:Vinyl Compounds; D005557:Formaldehyde; C029297:vinylidene chloride; C014290:hydroxyflutamide; D000082:Acetaminophen; D008345:Manganese; D011374:Progesterone; D008752:Methylene Chloride; D005485:Flutamide; D019855:Ethylene Glycol; D015032:Zinc; C011566:vinyl acetate; C009068:propylene oxide