A Bayesian population physiologically based pharmacokinetic absorption modeling approach to support generic drug development: application to bupropion hydrochloride oral dosage forms.

We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters ("safe space") in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.

Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene.

BACKGROUND: Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment. OBJECTIVES: In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population. METHODS: Male mice from 45 strains were intragastrically dosed with PERC ([Formula: see text]) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism-associated genes [ Acot1 (Acyl-CoA thioesterase 1), Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-1)/Hepatitis A virus cellular receptor 1 ( Havcr1)] were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD. RESULTS: Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism-associated genes ( Acot1, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/ Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/ Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC. DISCUSSION: Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism-toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. https://doi.org/10.1289/EHP5105.

Anemia risk in relation to lead exposure in lead-related manufacturing.

BACKGROUND: Lead-exposed workers may suffer adverse health effects under the currently regulated blood lead (BPb) levels. However, a probabilistic assessment about lead exposure-associated anemia risk is lacking. The goal of this study was to examine the association between lead exposure and anemia risk among factory workers in Taiwan. METHODS: We first collated BPb and indicators of hematopoietic function data via health examination records that included 533 male and 218 female lead-exposed workers between 2012 and 2014. We used benchmark dose (BMD) modeling to estimate the critical effect doses for detection of abnormal indicators. A risk-based probabilistic model was used to characterize the potential hazard of lead poisoning for job-specific workers by hazard index (HI). We applied Bayesian decision analysis to determine whether BMD could be implicated as a suitable BPb standard. RESULTS: Our results indicated that HI for total lead-exposed workers was 0.78 (95% confidence interval: 0.50-1.26) with risk occurrence probability of 11.1%. The abnormal risk of anemia indicators for male and female workers could be reduced, respectively, by 67-77% and 86-95% by adopting the suggested BPb standards of 25 and 15 µg/dL. CONCLUSIONS: We conclude that cumulative exposure to lead in the workplace was significantly associated with anemia risk. This study suggests that current BPb standard needs to be better understood for the application of lead-exposed population protection in different scenarios to provide a novel standard for health management. Low-level lead exposure risk is an occupational and public health problem that should be paid more attention.

Ceramics manufacturing contributes to ambient silica air pollution and burden of lung disease.

Inhalation of silica (SiO2) in occupational exposures can cause pulmonary fibrosis (silicosis), lung function deficits, pulmonary inflammation, and lung cancer. Current risk assessment models, however, cannot fully explain the magnitude of silica-induced pulmonary disease risk. The purpose of this study was to assess human health risk exposed to airborne silica dust in Taiwan ceramics manufacturing. We conducted measurements to characterize workplace-specific airborne silica dust in tile and commodity ceramic factories and used physiologically based alveolar exposure model to estimate exposure dose. We constructed dose-response models for describing relationships between exposure dose and inflammatory responses, by which health risks among workers can be assessed. We found that silica contents were 0.22-33.04 % with mean concentration ranges of 0.11-5.48 and 0.46-1763.30 µg m(-3), respectively, in commodity and tile ceramic factories. We showed that granulation workers in tile ceramic factory had the highest total SiO2 lung burden (∼1000 mg) with cumulative SiO2 lung burden of ∼4 × 10(4) mg-year. The threshold estimates with an effect on human lung inflammation and fibrosis are 407.31 ± 277.10 (mean ± sd) and 505.91 ± 231.69 mg, respectively. For granulation workers, long-term exposure to airborne silica dust for 30-45 years was likely to pose severe adverse health risks of inflammation and fibrosis. We provide integrated assessment algorithms required to implement the analyses and maintain resulting concentration of silica dust at safety threshold level in the hope that they will stimulate further analyses and interpretation. We suggest that decision-makers take action to implement platforms for effective risk management to prevent the related long-term occupational disease in ceramics manufacturing.

Assessing the potential exposure risk and control for airborne titanium dioxide and carbon black nanoparticles in the workplace.

PURPOSE: This study assessed the potential exposure risks for workers in the workplace exposed to airborne titanium dioxide nanoparticles (TiO(2)-NPs) and carbon black nanoparticles (CB-NPs). The risk management control strategies were also developed for the NP engineering workplace. METHODS: The method used in this study was based on the integrated multiple-path particle dosimetry model to estimate the cumulative dose of nanoparticles (NPs) in the human lung. The study then analyzed toxicological effects such as pulmonary cytotoxicity and inflammation and evaluated the health risk associated with exposure to NPs in the workplace. Risk control measures such as the use of ventilating systems and N95 respirator protection are also discussed. RESULTS AND DISCUSSION: This study found that: (1) the cumulative dose of CB-NPs was greater than that of TiO(2)-NPs in human lungs; (2) there is a potential health risk to workers exposed to TiO(2)-NPs and CB-NPs in the absence of control measures in the workplace, with higher health risks associated with CB-NPs than TiO(2)-NPs; and (3) the use of a ventilating system and an N95 respirator offers greater protection in the workplace and significantly reduces the health risks associated with NP exposure. CONCLUSION: The present risk management control strategy suggests that the most effective way to reduce airborne NPs is to incorporate the use of a ventilating system combined with N95 respirator protection. This will enable the concentrations of TiO(2)-NPs and CB-NPs to be reduced to acceptable exposure levels.