Dose-dependent transitions in mechanisms of toxicity: case studies.
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.
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
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
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