Pharmacokinetic-pharmacodynamic models for categorical toxicity data.
We propose a pharmacokinetic-pharmacodynamic (PK/PD) model (with possibly different choices for the PD link) for categorical toxicity data analysis. This is extension of the one-comportment model that applies to toxic endpoints categorised by grades (e.g., benign, mild, severe, and very severe). The model assumes that the area under the curve (AUC) of the internal quantity of the chemical substance is the critical dose-metric that drives the acute toxic phenomenon. That model handles time-varying concentrations and takes into account follow-up time, i.e., time at which effects are observed. Moreover the model bridges mechanistically based dose-response models and standard dose-response models, retaining the advantages of both. We use Markov chain-Monte Carlo (MCMC) simulations to fit the model to mortality data for mice exposed to chlorine, rats exposed to ammonia, and categorical data (different severity levels) from acute exposures of rats and humans to hydrogen sulfide.
Diack
Cheikh
C
INERIS, Institut National de l'Environnement Industriel et des Risques, Parc ALATA, BP2, 60550 Verneuil en Halatte, France. cheikh.diack@wanadoo.fr
Bois
Frédéric Y
FY
D000393:Air Pollutants / Q000633:toxicity; D000641:Ammonia / Q000633:toxicity; D000818:Animals; D019540:Area Under Curve; D002713:Chlorine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide / Q000633:toxicity; D016015:Logistic Models; D008297:Male; D008390:Markov Chains; D051379:Mice; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D010600:Pharmacology; D051381:Rats
D000393:Air Pollutants; D002713:Chlorine; D000641:Ammonia; D006862:Hydrogen Sulfide