A physiologically-based pharmacokinetic model of methotrexate incorporating hepatic excretion via multidrug-resistance-associated protein 2 (Mrp2) in mice, rats, dogs, and humans.

An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2).

Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models From acslX to Berkeley Madonna, MATLAB, and R Language: Oxytetracycline and Gold Nanoparticles As Case Examples.

Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslX. However, acslX has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications.

An epimer of deoxynivalenol: purification and structure identification of 3-epi-deoxynivalenol.

In an investigation of deoxynivalenol (DON)-transformation products by Devosia mutans 17-2-E-8, the major product was identified as 3-epi-DON. This DON-transformation product was analysed by liquid chromatography and identified by congruent retention time and UV/Vis spectrum, as well as mass spectrometric data. Nuclear magnetic resonance (NMR) experiments including correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC) and nuclear overhauser effect (NOE) were conducted for structural characterisation of 3-epi-DON.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life.

Lifetime PCB 153 bioaccumulation and pharmacokinetics in pilot whales: Bayesian population PBPK modeling and Markov chain Monte Carlo simulations.

Physiologically based pharmacokinetic (PBPK) models for wild animal populations such as marine mammals typically have a high degree of model uncertainty and variability due to the scarcity of information and the embryonic nature of this field. Parameters values used in marine mammals models are usually taken from other mammalian species (e.g.

Application of Bayesian population physiologically based pharmacokinetic (PBPK) modeling and Markov chain Monte Carlo simulations to pesticide kinetics studies in protected marine mammals: DDT, DDE, and DDD in harbor porpoises.

Physiologically based pharmacokinetic (PBPK) modeling in marine mammals is a challenge because of the lack of parameter information and the ban on exposure experiments. To minimize uncertainty and variability, parameter estimation methods are required for the development of reliable PBPK models. The present study is the first to develop PBPK models for the lifetime bioaccumulation of p,p'-DDT, p,p'-DDE, and p,p'-DDD in harbor porpoises.

A physiologically based pharmacokinetic model of rifampin in mice.

One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature.

An in silico approach for evaluating a fraction-based, risk assessment method for total petroleum hydrocarbon mixtures.

Both the Massachusetts Department of Environmental Protection (MADEP) and the Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG) developed fraction-based approaches for assessing human health risks posed by total petroleum hydrocarbon (TPH) mixtures in the environment. Both organizations defined TPH fractions based on their expected environmental fate and by analytical chemical methods. They derived toxicity values for selected compounds within each fraction and used these as surrogates to assess hazard or risk of exposure to the whole fractions.

Computational toxicology: Physiologically based pharmacokinetic models (PBPK) for lifetime exposure and bioaccumulation of polybrominated diphenyl ethers (PBDEs) in marine mammals.

Due to migration of harbour porpoises towards more polluted areas like the North Sea and their sensitivity towards pollution, there is a need for proper conservation measures for this species. As a consequence, knowledge about the pollutant's kinetics is required. The present study is the first to investigate the kinetics of PBDEs in marine mammals using PBPK modeling as a non-destructive tool for describing the chemical's kinetics in a protected animal species.

Antiproliferative activity of pomiferin in normal (MCF-10A) and transformed (MCF-7) breast epithelial cells.

Pomiferin and osajin are prenylated isoflavones from Osage orange fruit that both have potent antioxidant activity in a variety of assays. Pomiferin, in particular, has strong activity against the superoxide anion in a photochemiluminescence (PCL) assay system. In vitro, pomiferin, but not osajin, demonstrated selective antiproliferative activity against the tumorigenic breast epithelial cell line MCF-7 (IC(50) = 5.

A non-invasive approach to study lifetime exposure and bioaccumulation of PCBs in protected marine mammals: PBPK modeling in harbor porpoises.

In the last decade, physiologically based pharmacokinetic (PBPK) models have increasingly been developed to explain the kinetics of environmental pollutants in wildlife. For marine mammals specifically, these models provide a new, non-destructive tool that enables the integration of biomonitoring activities and in vitro studies. The goals of the present study were firstly to develop PBPK models for several environmental relevant PCB congeners in harbor porpoises (Phocoena phocoena), a species that is sensitive to pollution because of its limited metabolic capacity for pollutant transformation.

Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment.

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures.

Pharmacokinetics and physiologically-based pharmacokinetic modeling of nanoparticles.

The worldwide commerce involving nanoparticles will soon reach $1 trillion and already we have more than 600 commercial products containing nanoparticles. Because nanoparticles are invisible and little is known about their toxicities, there has been concern about health effects in humans. As toxicology is a continuum of pharmacokinetics and pharmacodynamics, this is a review of recent advances on pharmacokinetics and physiologically-based pharmacokinetic (PBPK) modeling involving nanoparticles.

Physiologically based pharmacokinetic (PBPK) models for lifetime exposure to PCB 153 in male and female harbor porpoises (Phocoena phocoena): model development and evaluation.

Physiologically based pharmacokinetic (PBPK) models were developed for the most persistent polychlorinated biphenyl (PCB 153) in male and female harbor porpoises (Phocoena phocoena) to elucidate processes such as uptake, distribution, and elimination. Due to its limited metabolic capacities, long life span, and top position in marine food chains, this species is highly sensitive to pollution. The models consist of 5 compartments, liver, blubber, kidney, brain, and a compartment which accounts for the rest of the body, all connected through blood.

Isolation of deoxynivalenol-transforming bacteria from the chicken intestines using the approach of PCR-DGGE guided microbial selection.

Background: Contamination of grains with trichothecene mycotoxins, especially deoxynivalenol (DON), has been an ongoing problem for Canada and many other countries. Mycotoxin contamination creates food safety risks, reduces grain market values, threatens livestock industries, and limits agricultural produce exports. DON is a secondary metabolite produced by some Fusarium species of fungi.

Effect of PCBs on the lactational transfer of methyl mercury in mice: PBPK modeling.

MeHg and PCB exposure to lactating mice were analyzed and a physiologically-based pharmacokinetic (PBPK) model was developed to describe the lactational transfer of MeHg in mice. The influence of albumin on the lactational transfer of MeHg was incorporated into the PBPK model. Experimental results with lactating mice and their pups showed that co-exposure with PCB congeners increased the lactational transfer of MeHg to the pups, which was associated with the rise of albumin levels in maternal blood.

Predicting activation enthalpies of cytochrome-P450-mediated hydrogen abstractions. 2. Comparison of semiempirical PM3, SAM1, and AM1 with a density functional theory method.

Predicting the biotransformation of xenobiotics is important in the chemical and pharmaceutical industries, as well as in toxicology. Here, we extend and evaluate the rapid methodology of Korzekwa, Jones, and Gillette (J. Am.

Population physiologically based pharmacokinetic modeling for the human lactational transfer of PCB-153 with consideration of worldwide human biomonitoring results.

Background: One of the most serious human health concerns related to environmental contamination with polychlorinated biphenyls (PCBs) is the presence of these chemicals in breast milk.

Objectives: We developed a physiologically based pharmacokinetic model of PCB-153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB-153.

Computational and ultrastructural toxicology of a nanoparticle, Quantum Dot 705, in mice.

We conducted pharmacokinetic and toxicology studies on Quantum Dot 705 (QD705) in male ICR mice for up to 6 months after a single intravenous dose. Time-course sacrifices were carried out at 1, 4, and 24 h; 3, 7, 14, and 28 days; and 6 months on groups of six mice per time point. Mass balance studies were also carried out at 24 h, 28 days, and 6 months.

Computational toxicology of chloroform: reverse dosimetry using Bayesian inference, Markov chain Monte Carlo simulation, and human biomonitoring data.

Background: One problem of interpreting population-based biomonitoring data is the reconstruction of corresponding external exposure in cases where no such data are available.

Objectives: We demonstrate the use of a computational framework that integrates physiologically based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of environmental chloroform source concentrations consistent with human biomonitoring data. The biomonitoring data consist of chloroform blood concentrations measured as part of the Third National Health and Nutrition Examination Survey (NHANES III), and for which no corresponding exposure data were collected.

Adaptation of Arabidopsis to nitrogen limitation involves induction of anthocyanin synthesis which is controlled by the NLA gene.

Plants can survive a limiting nitrogen (N) supply by developing a set of N limitation adaptive responses. However, the Arabidopsis nla (nitrogen limitation adaptation) mutant fails to produce such responses, and cannot adapt to N limitation. In this study, the nla mutant was utilized to understand further the effect of NLA on Arabidopsis adaptation to N limitation.

Isolation and purification of phenylethanoid glycosides from Cistanche deserticola by high-speed counter-current chromatography.

Five phenylethanoid glycosides (PhGs), echinacoside, cistanoside A, acteoside, isoacteoside and 2'-acetylacteoside, were isolated and purified from Cistanche deserticola for the first time by high-speed counter-current chromatography (HSCCC) using two biphasic systems, one consisting of ethyl acetate-ethanol-water (5:0.5:4.5, v/v/v) and another of ethyl acetate-n-butanol-ethanol-water (0.

A possible role of multidrug resistance-associated protein 2 (Mrp2) in hepatic excretion of PCB126, an environmental contaminant: PBPK/PD modeling.

3,3',4,4',5'-Pentachlorobiphenyl (PCB126) is a carcinogenic environmental pollutant and its toxicity is mediated through binding with aryl hydrocarbon receptor (AhR). Earlier, we found that PCB126 treated F344 rats had 110-400 times higher PCB126 concentration in the liver than in the fat. Protein binding was suspected to be a major factor for the high liver concentration of PCB126 despite its high lipophilicity.

Application of PBPK modeling in support of the derivation of toxicity reference values for 1,1,1-trichloroethane.

PBPK modeling has been increasingly applied in chemical risk assessment for dose, route, and species extrapolation. The use of PBPK modeling was explored in deriving toxicity reference values for 1,1,1-trichloroethane (1,1,1-TCE). This effort involved a 5-step process: (i) reconstruction of several published PBPK models for 1,1,1-TCE in the rat and human; (ii) selection of appropriate pharmacokinetic datasets for model comparison; (iii) determination of the most suitable PBPK model for supporting reference value derivation; (iv) PBPK model simulation of two critical studies to estimate internal dose metrics; and (v) calculation of internal dose metrics for human exposure scenarios for reference value derivation.

Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes.

Both arsenic and benzo[a]pyrene (BaP) inhibit terminal differentiation and alter growth potential in normal human epidermal keratinocytes (NHEK) in vitro. To identify molecular alterations that may be involved in these cellular processes, microarray analysis was carried out on NHEK treated with BaP or arsenic. The gene expression microarray results measuring mRNA levels were as follows: (1) in total, the expression of 85 genes was induced and 17 genes was suppressed by 2.