A Physiological-Based Pharmacokinetic Model For The Broad Spectrum Antimicrobial Zinc Pyrithione: II. Dermal Absorption And Dosimetry In The Rat.

The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose-response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [14C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [14C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose-response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT equivalents from different routes of exposure in the rat.

A new paradigm in threshold of toxicological concern based on chemoinformatics analysis of a highly curated database enriched with antimicrobials.

A new database of antimicrobial-enriched chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 1357 chemicals with 276, 54, and 1027 substances in Cramer Classes I, II, and III, respectively. To enrich the chemical space of the No-/Lowest-Observed-Adverse Effect Level (NOAEL/LOAEL) database, a reference Antimicrobial (AM) Inventory (681) was established for chemical inclusion. To this database, the three existing TTC datasets were combined via robust data fusion process. From the final AM TTC Dataset, the fifth percentiles were derived to be 2.7, 0.43, and 0.12 mg/kg-bw/day for Cramer Classes I, II, and III, respectively. Considering the high percentage of AMs being Cramer Class III, the thresholds are remarkably stable across various TTC datasets. Based on the AM-enriched database, a set of AM categories stratified across potency were developed to classify AMs beyond the capability of the conventional Cramer Tree approach. Grouping the query chemical within the AM category, further distribution analyses were conducted to identify subclasses and differentiate potency. This study proposes a new framework for potential assessment of chronic toxicity made possible with the power of modern reliable databases and chemoinformatic methods.

A physiologically based pharmacokinetic model for the broad-spectrum antimicrobial zinc pyrithione: I. Development and verification.

The broad-spectrum antimicrobial zinc pyrithione (ZnPT) is used in numerous products ranging from in-can preservative/mildicide in paints to antidandruff shampoo. Although products containing ZnPT have a long history of safe use, regulatory agencies routinely set limits of exposure based upon toxicological considerations. The objective of this study was to create a physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose-response analysis of ZnPT-induced toxicity, reversible hindlimb weakness, the endpoint that has been used as the basis for ZnPT risk assessments. A rat oral PBPK model was developed that includes compartments for plasma, liver, kidneys, muscle, brain, and rapidly and slowly perfused tissues. Pyrithione metabolism to 2-(methylsulfonyl)pyridine (MSP) and glucuronide conjugates was incorporated into the model. The model was parameterized and optimized based upon data from single-dose intravenous (iv) and oral gavage pharmacokinetic studies of radiolabeled pyrithione ([14C]PT) administered as zinc [14C]-pyrithione (Zn-[14C]PT) to adult female rats. It was further evaluated and refined using data from repeated, multidose oral gavage and dietary studies of Zn[14C]PT in the adult female rat that included measurements of plasma PT concentration, the putative toxic species. The model replicated the observed short-term elimination kinetics of PT in plasma and [14C]PT in whole blood following single doses and longer term temporal patterns of plasma and blood concentrations during repeated dosing schedules. The model also accounted for production and rapid elimination of S-glucuronide conjugates (SG) of 2-pyridinethiol and 2-pyridinethiol-1-oxide in urine, as well as production and slower elimination of MSP, the major [14C]PT species in blood within several hours following administration of ZnPT. The model provided internal dosimetry predictions for a benchmark dose (BMD) analysis of hindlimb weakness in rats, and was used to combine gavage and dietary studies into a single internal dose-response model with area under the curve (AUC) for plasma PT as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT from different routes of exposure in the rat.