Application of partition coefficient methods to predict tissue:plasma affinities in common farm animals: Influence of ionisation state.

Tissue affinities are conventionally determined from in vivo steady-state tissue and plasma or plasma-water chemical concentration data. In silico approaches were initially developed for preclinical species but standardly applied and tested in human physiologically-based kinetic (PBK) models. Recently, generic PBK models for farm animals have been made available and require partition coefficients as input parameters.

Application of a generic PBK model for beef cattle: Tissue/fluid correlations of paracetamol and NSAIDs.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol can be administered off-label to cattle. Since the use of these veterinary medicines in cattle may pose a public health risk after meat consumption, it is important to translate measured concentrations in urine and tissues into concentrations in meat for human consumption. A generic physiologically-based kinetic (PBK) model for cattle can enable this translation.

TKPlate 1.0: An Open-access platform for toxicokinetic and toxicodynamic modelling of chemicals to implement new approach methodologies in chemical risk assessment.

This publication is linked to the following EFSA Supporting Publications articles: http://onlinelibrary.wiley.com/doi/10.

Establishing allometric relationships between microsomal protein and cytochrome P450 content with body weight in vertebrate species.

Data from in vitro studies are routinely used to estimate in vivo hepatic clearance of chemicals and this information is needed to parameterise physiologically based kinetic models. Such clearance data can be obtained from laboratory experiments using liver microsomes, hepatocytes, precision-cut liver slices or recombinant enzymes. Irrespective of the selected test system, scaling factors are required to convert the in vitro measured intrinsic clearance to a whole liver intrinsic clearance.

Fipronil and fipronil sulfone in chicken: From in vitro experiments to in vivo PBK model predictions.

In 2017 a large-scale fipronil contamination in eggs occurred in several European countries. Fipronil and its metabolites have the potential to be transferred into the eggs of laying hens, thereby entering the human food chain. Here, first the metabolism of fipronil was measured in vitro using chicken liver S9.

In vitro metabolism of lidocaine in subcellular post-mitochondrial fractions and precision cut slices from cattle liver.

In vitro models are widely used to study the biotransformation of xenobiotics and to provide input parameters to physiologically based kinetic models required to predict the kinetic behavior in vivo. For farm animals this is not common practice yet. The use of slaughterhouse-derived tissue material may provide opportunities to study biotransformation reactions in farm animals.

Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen.

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics.

Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs.

The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone.

Human Variability in Carboxylesterases and carboxylesterase-related Uncertainty Factors for Chemical Risk Assessment.

Carboxylesterases (CES) are an important class of enzymes involved in the hydrolysis of a range of chemicals and show large inter-individual variability in vitro. An extensive literature search was performed to identify in vivo probe substrates for CES1 and CES2 together with their protein content and enzymatic activity. Human pharmacokinetic (PK) data on Cmax, clearance, and AUC were extracted from 89 publications and Bayesian meta-analysis was performed using a hierarchical model to derive CES-related variability distributions and related uncertainty factors (UF).

Metabolism and pharmacokinetics of pharmaceuticals in cats (Felix sylvestris catus) and implications for the risk assessment of feed additives and contaminants.

In animal health risk assessment, hazard characterisation of feed additives has been often using the default uncertainty factor (UF) of 100 to translate a no-observed-adverse-effect level in test species (rat, mouse, dog, rabbit) to a 'safe' level of chronic exposure in farm and companion animal species. Historically, both 10-fold factors have been further divided to include chemical-specific data in both dimensions when available. For cats (Felis Sylvestris catus), an extra default UF of 5 is applied due to the species' deficiency in particularly glucuronidation and glycine conjugation.

Inter-phenotypic differences in CYP2C9 and CYP2C19 metabolism: Bayesian meta-regression of human population variability in kinetics and application in chemical risk assessment.

Quantifying variability in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. In this context, genetic polymorphisms in cytochromes P450 (CYPs) drive inter-phenotypic differences and may result in reduction or increase in metabolism of drugs or other xenobiotics. Here, an extensive literature search was performed to identify PK data for probe substrates of the human polymorphic isoforms CYP2C9 and CYP2C19.

Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics.

In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics.

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors.

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure.

Ecological risks of imidacloprid to aquatic species in the Netherlands: Measured and estimated concentrations compared to species sensitivity distributions.

Recent declines of insects' biomass have been a major point of interest. While several causes, including use of neonicotinoids like imidacloprid, have been suggested, scientific underpinning is limited. The aim of our study was to assess the potential risk of imidacloprid for freshwater fauna in the Netherlands and to validate the SimpleBox model to allow application elsewhere.

Human variability in influx and efflux transporters in relation to uncertainty factors for chemical risk assessment.

Transporters are divided into the ABC and SLC super-families, mediating the cellular efflux and influx of various xenobiotic and endogenous substrates. Here, an extensive literature search was performed to identify in vivo probe substrates for P-gp, BCRP and OAT1/3. For other transporters (e.

Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment.

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e.

An open source physiologically based kinetic model for the chicken (Gallus gallus domesticus): Calibration and validation for the prediction residues in tissues and eggs.

Xenobiotics from anthropogenic and natural origin enter animal feed and human food as regulated compounds, environmental contaminants or as part of components of the diet. After dietary exposure, a chemical is absorbed and distributed systematically to a range of organs and tissues, metabolised, and excreted. Physiologically based kinetic (PBK) models have been developed to estimate internal concentrations from external doses.

Generic physiologically based kinetic modelling for farm animals: Part I. Data collection of physiological parameters in swine, cattle and sheep.

Physiologically based kinetic (PBK) models for farm animals are of growing interest in food and feed safety with key applications for regulated compounds including quantification of tissue concentrations, kinetic parameters and the setting of safe exposure levels on an internal dose basis. The development and application of these models requires data for physiological, anatomical and chemical specific parameters. Here, we present the results of a structured data collection of anatomical and physiological parameters in three key farm animal species (swine, cattle and sheep).

Pay the PIED Piper: Guidelines to Visualize Large Geochemical Datasets on Piper Diagrams.

The Piper diagram has increased in popularity since its 1944 introduction and is now one of the most familiar and effective tools in the hydrogeologist's toolbox. Within the Piper diagram, three points on three related plots fully display the major ionic species of a water sample. Recently the size and availability of datasets have increased as additional field measurements and modeling results are shared more effectively in online databases.

Generic physiologically based kinetic modelling for farm animals: Part II. Predicting tissue concentrations of chemicals in swine, cattle, and sheep.

The development of three generic multi-compartment physiologically based kinetic (PBK) models is described for farm animal species, i.e. cattle, sheep, and swine.

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Physiologically based kinetic (PBK) models in the 10 most common species of farm animals were identified through an extensive literature search. This resulted in 39 PBK models, mostly for pharmaceuticals. The models were critically assessed using the WHO criteria for model evaluation, i.

Relative information from thermal infrared imagery via unoccupied aerial vehicle informs simulations and spatially-distributed assessments of stream temperature.

Stream temperature is a measure of water quality that reflects the balance of atmospheric heat exchange at the air-water interface and gains or losses of water along a stream reach. In urban areas, stormwater sewers deliver water with varying magnitude and temperature to streams at variable timescales. Understanding the impacts of stormwater through space and time is therefore difficult to do with conventional approaches like in situ sensors.

Inferring watershed hydraulics and cold-water habitat persistence using multi-year air and stream temperature signals.

Streams strongly influenced by groundwater discharge may serve as "climate refugia" for sensitive species in regions of increasingly marginal thermal conditions. The main goal of this study is to develop paired air and stream water annual temperature signal analysis techniques to elucidate the relative groundwater contribution to stream water and the effective groundwater flowpath depth. Groundwater discharge to streams attenuates surface water temperature signals, and this attenuation can be diagnostic of groundwater gaining systems.