Health & Environmental Research Online (HERO)


Chloroprene


218 References Were Found:

Technical Report
Technical Report

Incorporation of in vitro metabolism data in a physiologically based pharmacokinetic (PBPK) model for chloroprene

Author: Ramboll (2020) HERO ID: 5467423

[Less] A physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and human has . . . [More] A physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and
human has been developed that relies solely on in vitro studies for the estimation of model
parameters describing tissue metabolism and partitioning. The PBPK model accurately predicts in
vivo pharmacokinetic data from a 6-hr, nose-only chloroprene inhalation study conducted with
female B6C3F1 mice, the most sensitive species/gender for lung tumors in the 2-year bioassays
conducted with chloroprene. This PBPK model has been developed to support an inhalation
cancer risk assessment for chloroprene using in vitro data on the metabolism of chloroprene to
reactive epoxides in the lung target tissue of mice and humans. The approach for calculating
target tissue (lung) dose metrics was based on the PBPK modeling performed in support of the
inhalation cancer risk assessment for methylene chloride and represents the best available
science for determining the impact of species differences in metabolism of chloroprene.

Technical Report
Technical Report

Supplement: Uncertainty analysis of in vitro metabolic parameters and of in vitro to in vivo extrapolation (IVIVE) used in a physiologically based pharmacokinetic (PBPK) model for chloroprene

Author: U.S. EPA (2020) HERO ID: 6548798


The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Incorporation of in vitro metabolism data and physiologically based pharmacokinetic modeling in a risk assessment for chloroprene

Authors: Clewell, HJ; Campbell, JL; Van Landingham, C; Franzen, A; Yoon, M; Dodd, DE; Andersen, ME; Gentry, PR (2019) HERO ID: 6574149

[Less] Objective: To develop a physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, . . . [More] Objective: To develop a physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and human, relying only on in vitro data to estimate tissue metabolism rates and partitioning, and to apply the model to calculate an inhalation unit risk (IUR) for chloroprene.Materials and methods: Female B6C3F1 mice were the most sensitive species/gender for lung tumors in the 2-year bioassay conducted with chloroprene. The PBPK model included tissue metabolism rate constants for chloroprene estimated from results of in vitro gas uptake studies using liver and lung microsomes. To assess the validity of the PBPK model, a 6-hr, nose-only chloroprene inhalation study was conducted with female B6C3F1 mice in which both chloroprene blood concentrations and ventilation rates were measured. The PBPK model was then used to predict dose measures - amounts of chloroprene metabolized in lungs per unit time - in mice and humans.Results: The mouse PBPK model accurately predicted in vivo pharmacokinetic data from the 6-hr, nose-only chloroprene inhalation study. The PBPK model was used to conduct a cancer risk assessment based on metabolism of chloroprene to reactive epoxides in the lung, the target tissue in mice. The IUR was over100-fold lower than the IUR from the EPA Integrated Risk Information System (IRIS), which was based on inhaled chloroprene concentration. The different result from the PBPK model risk assessment arises from use of the more relevant tissue dose metric, amount metabolized, rather than inhaled concentrationDiscussion and conclusions: The revised chloroprene PBPK model is based on the best available science, including new test animal in vivo validation, updated literature review and a Markov-Chain Monte Carlo analysis to assess parameter uncertainty. Relying on both mouse and human metabolism data also provides an important advancement in the use of quantitative in vitro to in vivo extrapolation (QIVIVE). Inclusion of the best available science is especially important when deriving a toxicity value based on species extrapolation for the potential carcinogenicity of a reactive metabolite.

Technical Report
Technical Report

An umbrella Quality Assurance Project Plan (QAPP) for PBPK models

Author: U.S. EPA (2018) (ORD QAPP ID No: B-0030740-QP-1-1). Research Triangle Park, NC: U.S. Environmental Protection Agency. [EPA Report] HERO ID: 4326432

[Less] The U.S. Environmental Protection (EPA) Agency requires project managers and planners to develop a Quality . . . [More] The U.S. Environmental Protection (EPA) Agency requires project managers and planners to develop a Quality Assurance Project Plan (QAPP) as a tool for documenting the type and quality of data and model information that are needed for making environmental decisions. This document provides a QAPP that covers the basic data collection and modeling methodologies for physiologicallybased pharmacokinetic (PBPK) models. It is an “Umbrella” QAPP and intended to be applicable to multiple PBPK modeling projects. This QAPP conforms to EPA QA/G-5 (U.S. EPA, 2002a) and is an internal QA Project Plan in support of the U.S. EPA’s Human Health Risk Assessment (HHRA) research plan.

A PBPK model is a mathematical representation that describes the disposition of one or more chemicals in the body of a human or experimental animal in which organs or tissue groups are represented as compartments linked by blood flow that carries the chemical(s) between compartments. Put another way, a PBPK model is a quantitative statement of a set of hypotheses regarding the major determinants of absorption, distribution, metabolism and excretion (ADME). A key advantage of these models is that they can be used for various types of extrapolation including cross-species (animal to human), cross-route (e.g. inhalation to oral), and among exposure scenarios (Krishnan and Andersen, 1994), all of which can be used to facilitate human health risk evaluation and the setting of regulatory exposure levels. In addition to PBPK models, simpler pharmacokinetic (PK) with more empirically derived parameters can be used for the same types of extrapolation. Either form of PK model (PBPK models being a subset of all PK models) can be linked to a model describing some level of biological response, in which the combined dosimetry-response model is referred to as a biologically-based doseresponse (BBDR) model. In this QAPP the term “PBPK” will be used since it is presently the most commonly evaluated and applied model form of model expected to be evaluated and used. However, this QAPP is intended to apply equally well to classical PK and BBDR model forms.

Guidance on the use or application of PBPK models in U.S. EPA risk assessments is not the subject of this document, but can be found in U.S. EPA (2006).

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines

Authors: Gulec, C; Coban, N; Ozsait-Selcuk, B; Sirma-Ekmekci, S; Yildirim, O; Erginel-Unaltuna, N (2017) Experimental Cell Research 353:6-15. HERO ID: 3854369

[Less] ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. . . . [More] ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Correction to "Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology"

Authors: Wood, FL; Houston, JB; Hallifax, D (2017) Drug Metabolism and Disposition 45:1239. [Erratum] HERO ID: 6396114


The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Clearance prediction methodology needs fundamental improvement: trends common to rat and human hepatocytes/microsomes and implications for experimental methodology

Authors: Wood, FL; Houston, JB; Hallifax, D (2017) Drug Metabolism and Disposition 45:1178-1188. HERO ID: 6396113

[Less] Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role . . . [More] Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Weighted gene co-expression network analysis of pneumocytes under exposure to a carcinogenic dose of chloroprene

Authors: Guo, Y; Xing, Y (2016) Life Sciences 151:339-347. HERO ID: 3854370

[Less] AIMS: Occupational exposure to chloroprene via inhalation may lead to acute toxicity . . . [More] AIMS: Occupational exposure to chloroprene via inhalation may lead to acute toxicity and chronic pulmonary diseases, including lung cancer. Currently, most research is focused on epidemiological studies of chloroprene production workers. The specific molecular mechanism of carcinogenesis by chloroprene in lung tissues still remains obscure, and specific candidate therapeutic targets for lung cancer are lacking. The present study identifies specific gene modules and valuable hubs associated with lung cancer.

MAIN METHODS: We downloaded the dataset GSE40795 from the Gene Expression Omnibus (GEO) and divided the dataset into the non-carcinogenic dose chloroprene exposed mice group and the carcinogenic dose chloroprene exposed mice group. With a systemic biological view, we discovered significantly altered gene modules between the two groups and identified hub genes in the carcinogenic dose exposed group using weighted co-expression network analysis (WGCNA).

KEY FINDINGS: A total of 2434 differentially expressed genes were identified. Twelve gene modules with multiple biological activities were related to the carcinogenesis of chloroprene in lung tissue. Seven hub genes that were critical for the carcinogenesis of chloroprene in lung tissue were ultimately identified, including Cftr, Hip1, Tbl1x, Ephx1, Cbr3, Antxr2 and Ccnd2. They were implicated in inflammatory response, cell transformation, gene transcription regulation, phase II detoxification, angiogenesis, cell adhesion, motility and the cell cycle.

SIGNIFICANCE: The seven hub genes may become valuable candidates for risk assessment biomarkers and therapeutic targets in lung cancer.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions

Authors: Sterne, JAC; Hernán, MA; Reeves, BC; Savović, J; Berkman, ND; Viswanathan, M; Henry, D; Altman, DG; Ansari, MT; Boutron, I; Carpenter, JR; Chan, AW; Churchill, R; Deeks, JJ; Hróbjartsson, A; Kirkham, J; Jüni, P; Loke, YK; Pigott, TD; Ramsay, CR; Regidor, D; Rothstein, HR; Sandhu, L; Santaguida, PL; Schünemann, HJ; Shea, B; Shrier, I; Tugwell, P; Turner, L; Valentine, JC; Waddington, H; Waters, E; Wells, GA; Whiting, PF; Higgins, JPT (2016) British Medical Journal 355:i4919. HERO ID: 3220127


Journal Article
Journal Article

Carbamazepine-induced liver injury requires CYP3A-mediated metabolism and glutathione depletion in rats

Authors: Iida, A; Sasaki, E; Yano, A; Tsuneyama, K; Fukami, T; Nakajima, M; Yokoi, T (2015) 43:958-968. HERO ID: 5471440