Kevin McNally- PhD
- Associate principal scientist at Certara
Kevin McNally
- PhD
- Associate principal scientist at Certara
About
66
Publications
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Introduction
I'm an applied statistician with a particular expertise in Bayesian statistics, the design and analysis of computer experiment, and statistical problems associated with PBPK models
Current institution
Publications
Publications (66)
Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling aims to understand how a drug is absorbed, distributed, metabolized, excreted, and acts in a human or animal body. The Simcyp Simulator is a well‐known commercial PBPK/PD simulation software offering many options. It can, for example, use multiple compounds and population...
Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as "forever chemicals"...
Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not on...
The Advanced REACH Tool (ART) is the most detailed exposure model currently available for estimating inhalation exposures to dusts, vapours, and aerosols under a broad range of exposure scenarios. The ART follows a Bayesian approach, making use of a calibrated source-receptor model to provide central estimates of exposures and information on exposu...
Introduction: A physiologically based biokinetic model for di (2-ethylhexyl) adipate (DEHA) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHA following a single oral dosage of 50 mg to two male and two female volunteers.
Methods: The model was parameterized using in v...
A physiologically based pharmacokinetic model for di-(2-ethylhexyl) terephthalate (DEHTP) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHTP following a single oral dose of 50 mg to three male volunteers. In vitro and in silico methods were used to generate parameters...
An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was refined to improve the simulations of the venous blood concentrations of the primary monoester metabolite, mono-(2-propylheptyl) phthalate (MPHP). This was considered a significant deficiency that should be addressed because the primary metabolite o...
In this article, we have responded to the key statements in the article by Koivisto et al. (2022) that were incorrect and considered to be a biased critique on a subset of the exposure models used in Europe (i.e. ART and Stoffenmanager®) used for regulatory exposure assessment. We welcome scientific discussions on exposure modelling (as was done du...
A computational workflow which integrates physiologically based kinetic (PBK) modelling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC), Markov Chain Monte Carlo (MCMC) simulation and the Virtual Cell Based Assay (VCBA) for the estimation of the active, free in vitro concentration of chemical in the reaction medium was de...
The dermal Advanced REACH Tool (dART) is a tier 2 exposure model for estimating dermal exposure to the hands (mg min −1) for non-volatile liquid and solid-in-liquid products. The dART builds upon the existing ART framework and describes three mass transport processes (deposition (D hands), direct emission and direct contact (E hands), and contact t...
A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, bi...
A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertain...
Engineering models, resolved using the finite element method, are used to model through-life changes in material properties and the resulting internal brick stresses in graphite moderator bricks within an advanced gas-cooled reactor (AGR). These models require inputs that describe the loading conditions of the moderator brick and coded relationship...
Measured data are generally preferred to modelled estimates of exposure. Grouping and read-across is already widely used and accepted approach in toxicology, but an appropriate approach and guidance on how to use existing exposure measurement data on one substance and work situation for another substance and/or work situation is currently not avail...
An advanced gas cooled reactor core is constructed using a large number of nuclear graphite components that make up channels for fuel and control rods which interlock through a keying system. The fuel channels are formed with cylindrical bricks which are subjected to fast neutron and radiolytic oxidation during reactor operation, leading to deforma...
A physiologically based pharmacokinetic model for Hexamoll® diisononyl-cyclohexane-1, 2-dicarboxylate was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to asses...
An advanced gas cooled reactor core is constructed using a large number of nuclear graphite components that make up channels for fuel and control rods which interlock through a keying system. The fuel channels are formed with cylindrical bricks which are subjected to fast neutron and radiolytic oxidation during reactor operation, leading to deforma...
The dermal Advanced REACH Tool (dART) is a tier 2 exposure modelling tool currently in development for estimating dermal exposure to the hands (mg.min-1) for non-volatile liquid and solids-in-liquid products. The dART builds upon the existing ART framework and describes three mass transport processes (deposition (D_hands), direct emission and direc...
This article describes the development of a mechanistic model for underpinning the dermal Advanced REACH Tool (dART), an extension of the existing ART model and its software platform. It was developed for hand exposure to low volatile liquids (vapour pressure ≤ 10 Pa at 20°C) including solids-in-liquid products. The model is based on an existing co...
The irradiation-induced dimensional changes of nuclear graphite lead to identifiable changes in the bore shape of the moderator bricks when compared with their start-of-life condition. Through-life brick bore shape changes are complex due to the changes in stress states within the brick and the alignment of fuel within the channel. Furthermore ther...
A computational workflow was developed to facilitate the process of quantitative in vitro to in vivo extrapolation (QIVIVE), specifically the translation of in vitro concentration-response to in vivo dose-response relationships and subsequent derivation of a benchmark dose value (BMD). The workflow integrates physiologically based pharmacokinetic (...
A computational workflow was developed to facilitate the process of quantitative in vitro to in vivo extrapolation (QIVIVE), specifically the translation of in vitro concentration-response to in vivo dose-response relationships and subsequent derivation of a benchmark dose value (BMD).
The workflow integrates physiologically based pharmacokinetic...
A computational workflow was developed to facilitate the process of quantitative in vitro to in vivo extrapolation (QIVIVE), specifically the translation of in vitro concentration-response to in vivo dose-response relationships and subsequent derivation of a benchmark dose value (BMD).
The workflow integrates physiologically based pharmacokinetic...
The structural integrity of nuclear graphite bricks is important in Advanced Gas-cooled Reactors (AGRs) as they
not only provide moderation but channels for fuel, cooling and control rods. AGR graphite moderator bricks are
subjected to fast neutron irradiation and radiolytic oxidation during reactor operation, leading to component
dimensional and m...
The presence of a high-affinity metabolic pathway for low level benzene exposures of less than one part per million (ppm) has been proposed although a pathway has not been identified. The variation of metabolite molar fractions with increasing air benzene concentrations was suggested as evidence of significantly more efficient benzene metabolism at...
Physically based models, resolved using the finite element (FE) method are often used to model changes in dimensions and the associated stress fields of graphite moderator bricks within a reactor. These models require inputs that describe the loading conditions (temperature, fluence and weight loss ‘field variables’), and coded relationships descri...
Physically-based models are often used to model changes in geometry and the associated stress fields of graphite moderator bricks within an advanced gas-cooled reactor (AGR). These models require inputs that describe the loading conditions, and coded relationships describing the behaviour of material properties. Material relationships are primarily...
Physically-based models are often used to model changes in geometry and the associated stress fields of graphite moderator bricks within an advanced gas-cooled reactor (AGR). These models require inputs that describe the loading conditions, and coded relationships describing the behaviour of material properties. Material relationships are primarily...
The UK fleet of seven graphite moderated Advanced Gas-cooled Reactors (AGR) are the only power producing nuclear reactors in the world that have a graphite moderated core cooled by carbon dioxide gas operating at > 500°C. The graphite core cannot be replaced and during its lifetime the graphite core is subject to the combined ageing effects of irra...
The risk assessment of environmental chemicals and drugs is undergoing a paradigm shift in approach which seeks the full replacement of animal testing with high throughput, mechanistic, in vitro systems. This new approach will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of spe...
Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and uri...
A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources...
Physically based models, resolved using the finite element (FE) method, are often used to model changes in geometry and the associated stress fields of graphite moderator bricks within a reactor. These models require inputs that describe the loading conditions (field variables), and coded relationships describing the behaviour of material propertie...
This paper describes a Bayesian model for the assessment of inhalation exposures in an occupational setting; the methodology
underpins a freely available web-based application for exposure assessment, the Advanced REACH Tool (ART). The ART is a higher
tier exposure tool that combines disparate sources of information within a Bayesian statistical fr...
In 2009, a series of experiments were conducted by Sandia National Laboratories at a large-scale test complex in Albuquerque, New Mexico, in which Liquefied Natural Gas (LNG) was released onto the surface of a large pool of water and then ignited. These experiments involved the largest releases of LNG ever performed, with the spills covering a circ...
The risk assessment of environmental chemicals and drugs is moving towards a paradigm shift in approach which seeks the full replacement animal testing with high throughput, mechanistic, in vitro systems. This new vision will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of spec...
A methodology is presented for global sensitivity analysis of consequence models used in process safety applications. It involves running a consequence model around a hundred times and using the results to construct a statistical emulator, which is essentially a sophisticated curve fit to the data. The emulator is then used to undertake the sensiti...
A global sensitivity analysis is performed on Phast’s dispersion model for simulating jet releases of dense-phase carbon dioxide (CO2). The releases studied consist of above-ground, unconfined, horizontal, steady-state orifice discharges, with orifices ranging in diameter from ½ to 2 inch (12.8 to 50.4 mm), and the liquid CO2 reservoir maintained a...
Gas-cooled, graphite-moderated nuclear reactors suffer ageing and degradation to the graphite during service posing a threat to the functionality of the core, and potentially, the safe operation of the reactor. Thus, the importance of modelling and measuring reactor core graphite properties and performance increases especially as continued use beyo...
There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or r...
This paper provides an outline of the Advanced REACH Tool (ART) version 1.0 and a discussion of how it could be further developed. ART is a higher tier exposure assessment tool that combines mechanistically modelled inhalation exposure predictions with available exposure data using a Bayesian approach. ART assesses exposure for scenarios across dif...
Physiologically based pharmacokinetic (PBPK) models have a potentially significant role in the development of a reliable predictive toxicity testing strategy. The structure of PBPK models are ideal frameworks into which disparate in vitro and in vivo data can be integrated and utilized to translate information generated, using alternative to animal...
This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and isocyanates in the UK polyurethane industry. Urine samples (n=446) were collected from 90 different workers. MbOCA levels were below the limit of detection in 170 samples and 26 were above the UK Biological Monitoring Guidance Value (BMGV) of 15 μmol MbOCA/mol...
The main objective of the study was to gather information about the current controls and levels of exposure to 4,4'-methylene-bis (2-chloroaniline) (MbOCA) in a representative cross section of workplaces that use it to manufacture polyurethane elastomers. The study also aimed to investigate whether controls and guidance could be improved and to inv...
