Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop

Ellison, Corie A.; Blackburn, Karen; Carmichael, Paul L.; Clewell, Harvey J.; Cronin, Mark T.D.; Desprez, Bertrand; Escher, Sylvia; Ferguson, Steve S.; Grégoire, Sébastien; Hewitt, Nicola J.; Hollnagel, Heli M.; Klarić, Martina; Patel, A.; Salhi, Sabrina; Schepky, Andreas; Schmitt, Barbara G.; Wambaugh, John F.; Worth, Andrew

doi:10.1016/j.yrtph.2019.01.016

Cited by 34 publications

(39 citation statements)

References 54 publications

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“…Also, the sufficiency and relevance of PBPK model structure and the sensitivity of model output to in vitro and in silico derived model parameters was investigated using an approach based on global sensitivity analysis (GSA). The latter is part of the ongoing development of a 1 https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri OJ:L:2011:012: FULL&from FR 2 Concentration in human biological material at which, and below which, there is no risk of adverse health effects good PBPK modelling practice (Barton et al, 2007;Loizou et al, 2008;Barton et al, 2009;WHO, 2010;Paini et al, 2017;Ellison et al, 2019;Fabian et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

et al. 2021

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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, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

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Section: Introductionmentioning

confidence: 99%

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

et al. 2021

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“…The model was parameterized with in vitro and in silico methods, that is, measured intrinsic hepatic clearance scaled from in vitro to in vivo and predicted octanol–water partition coefficient (PC) (Log P ow ) values which, in turn, were used to predict parameters such as plasma unbound fraction and tissue:blood PCs. Also, the sufficiency and relevance of PBPK model structure and the sensitivity of model output to in vitro and in silico derived model parameters was investigated using an approach based on global sensitivity analysis (GSA) as part of the ongoing development of a good PBPK modeling practice (Barton et al, 2007; Loizou et al, 2008; Barton et al, 2009; WHO, 2010; Paini et al, 2017; Clewell et al, 2019; Ellison et al, 2019; Fabian et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Development, Testing, Parameterization, and Calibration of a Human Physiologically Based Pharmacokinetic Model for the Plasticizer, Hexamoll® Diisononyl-Cyclohexane-1, 2-Dicarboxylate Using In Silico, In Vitro, and Human Biomonitoring Data

2019

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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 assess structure, biological plausibility and behavior prior to simulation and analysis of human biological monitoring data. The model provided good simulations of the urinary excretion (Curine) of two metabolites; cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (OH-MINCH) and cyclohexane-1, 2-dicarboxylic acid mono carboxyisononyl ester (cx-MINCH) from the biotransformation of mono-isononyl-cyclohexane-1, 2-dicarboxylate (MINCH), the monoester metabolite of di-isononyl-cyclohexane-1,2-dicarboxylate. However, good simulations could be obtained, with and without, a lymphatic compartment. Selection of an appropriate model structure was informed by sensitivity analysis which could identify and quantify the contribution to variability in Curine by parameters, such as, the fraction of oral dose that directly entered the lymphatic compartment and therefore by-passed the liver and the fraction of MINCH bio-transformed to cx-MINCH and OH-MINCH. By constraining these parameters within biologically plausible limits the presence of a lymphatic compartment was deemed an important component of model structure. Furthermore, the use of sensitivity analysis is important in the evaluation of uncertainty around in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This type of approach could expand the use of physiologically based pharmacokinetic models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

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“…Partosch et al (2015), Coecke et al (2013), as well as Hartung (2017) have developed the argument for an internal TTC further. The concept gained some traction with a push from the cosmetics industry (Ellison et al, 2019). Here, we clearly overlap with the blood level determinations of toxicants and their metabolites in the exposome.…”

Section: What Is In the Box For Alternatives To Animal Testing?mentioning

confidence: 89%

The exposome – a new approach for risk assessment

Sillé

Karakitsios

Kleensang

et al. 2020

ALTEX

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Other 'omes existed even then, such as biome (collection of living things) and rhizome (system of roots), many of them based on the Greek suffix '-ome' -meaning, roughly, 'having the nature of.' But it was the glamorization of 'genome' by megabuck initiatives such as the Human Genome Project that really set the trend in motion, says Alexa McCray, a linguist and medical informatician at Harvard Medical School in Boston, Massachusetts. IntroductionClaiming a new 'ome has become fashionable in the post-human genome era. Monya Baker (2013), in her piece in Nature, claimed the number to be in the thousands. She wrote: "Botanist Hans Winkler had no idea what he was starting back in 1920, when he proposed the term 'genome' to refer to a set of chromosomes.

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Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop

Cited by 34 publications

References 54 publications

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

Development, Testing, Parameterization, and Calibration of a Human Physiologically Based Pharmacokinetic Model for the Plasticizer, Hexamoll® Diisononyl-Cyclohexane-1, 2-Dicarboxylate Using In Silico, In Vitro, and Human Biomonitoring Data

The exposome – a new approach for risk assessment

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