Area under the curve as a dose metric for promotional responses following 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.
An underlying basis of risk assessment is that an equivalent risk for a specified dose metric exists that allows for extrapolation of dose-response relationships between species. To better understand the use of area under the curve (AUC) as a dose metric for complex biological responses following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a study was designed using a physiologically based pharmacokinetic model in the female Sprague-Dawley rat that would result in equivalent AUCs of total liver TCDD with differing patterns of exposure. In the first group, rats received a high peak dose of 3500 ng TCDD/kg twice per week in the first week followed by a lower TCDD dose of 81 ng/kg twice per week for the remainder of the study. In the second group, rats received a gavage dose of 350 ng TCDD/kg in corn oil twice per week for the study duration of 15 weeks. Age-matched control rats received corn oil as a vehicle control. Placental glutathione S-transferase (PGST)-positive foci were measured in representative liver lobes by immunohistochemistry, as a representative complex biological response resulting from TCDD exposure. The median volume fraction was 0.045% in control rats and was significantly elevated in TCDD treatment groups. However, the volume fraction of PGST-positive foci was significantly higher in the TCDD group given the high peak dose during the first week of TCDD treatment compared with the group receiving the same average daily dose over the study duration: 0.74 versus 0.20%, respectively. These findings suggest that the peak magnitude of TCDD in liver rather than AUC may play a significant role in the induction of complex biological responses by TCDD.
Kim
Amy H
AH
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kohn
Michael C
MC
Nyska
Abraham
A
Walker
Nigel J
NJ
D000818:Animals; D019540:Area Under Curve; D002273:Carcinogens / Q000633:toxicity; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D004052:Diethylnitrosamine; D012313:RNA