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Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data.
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- Author(s): Gayrard, Véronique1 ; Moreau, Jessika1,2; Picard-Hagen, Nicole1; Helies, Virginie3; Marchand, Philippe4; Antignac, Jean-Philippe4; Toutain, Pierre-Louis5,6; Leandri, Roger1,2
- Source:
Environmental Health Perspectives. Nov2021, Vol. 129 Issue 11, p117006-1-117006-16. 16p. 1 Diagram, 6 Charts, 5 Graphs.- Subject Terms:
*Pollutants; *Animal experimentation; *Hydrocarbons; *Gas chromatography; *Water supply; *Toxicity testing; *Mass spectrometry; *Toxicology; *Ethylene; *Environmental exposure; Intravenous therapy; Oral drug administration; Time; Rabbits; Blood collection; Health outcome assessment; Risk assessment; Descriptive statistics; Data analysis software - Source:
- Additional Information
- Abstract: BACKGROUND: Although in vivo studies of internal exposure to hazardous substances have been carried out for many years, there is room for progress to improve their informative value while adhering to the four R’s: replacement, reduction, refinement, and responsibility rule. OBJECTIVES: The objective of the study was to illustrate how toxicokinetic (TK) study design and data analysis can be implemented under the 4R rule to plan a chronic dosage regimen for investigating TK/toxicodynamic (TD) relationships. METHODS: The intravenous (IV) and oral serum concentrations of eight hazardous environmental contaminants including 1,1-Dichloro-2,2-bis(pchlorophenyl) ethylene (pp'DDE), ß-Hexachlorocyclohexane (ß-HCH), hexachlorobenzene (HCB), 2,2'4, 4'-tetrabromodiphenyl ether (BDE-47), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di(2ethylhexyl)phthalate (DEHP), and bisphenol S (BPS) were obtained after mixture dosing in rabbits using a sparse sampling design. Data were comprehensively analyzed using nonlinear mixed effect (NLME) modeling. RESULTS: The short persistence of BPS and of the DEHP metabolite (mono-2-ethylhexyl phthalate), reflected by their mean residence times (MRT) of a few hours, was due to their efficient clearance (CL, 3.2 and 0.47 L/kg/h). The longer MRT of the other compounds (1–48 d) resulted either from their extremely low clearance (lower than 0.01 L/kg/h for PFOA and PFOS) or from their very large volume of distribution (VSS) ranging from 33 to 45 L/kg. Estimates of CL, VSS, and bioavailability were used to compute the oral loading and daily maintenance doses required to attain a nominal steady-state serum concentration of 1 ng/mL. Simulations with the NLME model were applied to predict the serum concentration profile and to contrast the differential rates of accumulation in the central vs. peripheral compartments. CONCLUSION: NLME modeling of the IV and oral TK of hazardous environmental contaminants, in rabbits while fulfilling the 4R rule, was able to provide the physiological basis for interspecies extrapolation of exposure rates in a TK/TD approach to risk assessment. https://doi.org/10.1289/EHP8957 [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Abstract:
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