Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

Although 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. The objective of the study was to illust...

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Bibliographic Details
Published in:Environmental health perspectives 2021-11, Vol.129 (11), p.117006
Main Authors: Gayrard, Véronique, Moreau, Jessika, Picard-Hagen, Nicole, Helies, Virginie, Marchand, Philippe, Antignac, Jean-Philippe, Toutain, Pierre-Louis, Leandri, Roger
Format: Article
Language:English
Subjects:
Animals
Bioaccumulation
Bioavailability
Bisphenol A
Clearances
Contaminants
Data analysis
DDE
Design
Design analysis
Dioctyl phthalate
Dosage
Environment models
Environmental Pollutants - toxicity
Extrapolation
Food contamination & poisoning
Hazardous materials
Hexachlorobenzene
Hexachlorocyclohexane
In vivo methods and tests
Intravenous administration
Life Sciences
Metabolites
Nitrous oxide
Nonlinear Dynamics
Perfluorooctane sulfonic acid
Perfluorooctanoic acid
Pesticides
Phthalates
Polybrominated diphenyl ethers
Rabbits
Risk assessment
Risk Assessment - methods
Sampling designs
Toxicity
Toxicity Tests
Toxicokinetics
Toxicology
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Summary:Although 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. 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. The intravenous (IV) and oral serum concentrations of eight hazardous environmental contaminants including 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (pp'DDE), ( ), 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. 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 ). The longer MRT of the other compounds (1-48 d) resulted either from their extremely low clearance (lower than for PFOA and PFOS) or from their very large volume of distribution ( ) ranging from 33 to . Estimates of CL, , and bioavailability were used to compute the oral loading and daily maintenance doses required to attain a nominal steady-state serum concentration of . 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. 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.
ISSN:0091-6765
1552-9924
DOI:10.1289/EHP8957