Publications by authors named "Alicia Paini"

40 Publications

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies.

Arch Toxicol 2021 Apr 13. Epub 2021 Apr 13.

Directorate F-Health, Consumers and Reference Materials, Unit F3 Chemicals Safety and Alternative Methods, European Commission, Joint Research Centre (JRC), Via E. Fermi, 2749. TP126, 21027, Ispra, VA, Italy.

The EU Directive 2010/63/EU   on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.
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http://dx.doi.org/10.1007/s00204-021-03034-yDOI Listing
April 2021

Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models.

Toxicol In Vitro 2021 Mar 1;73:105133. Epub 2021 Mar 1.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.

Nominal effect concentrations from in vitro toxicity assays may lead to inaccurate estimations of in vivo toxic doses because the nominal concentration poorly reflects the concentration at the molecular target in cells in vitro, which is responsible for initiating effects and can be referred to as the biologically effective dose. Chemicals can differentially distribute between in vitro assay compartments, including serum constituents in exposure medium, microtitre plate plastic, headspace and extracellular matrices. The partitioning of test chemicals to these extracellular compartments reduces the concentration at the molecular target. Free concentrations in medium and cell-associated concentrations are considered better proxies of the biologically effective dose. This paper reviews the mechanisms by which test chemicals distribute between in vitro assay compartments, and also lists the physicochemical properties driving the extent of this distribution. The mechanisms and physicochemical properties driving the distribution of test chemical in vitro help explain the makeup of mass balance models that estimate free concentrations and cell-associated concentrations in in vitro toxicity assays. A thorough understanding of the distribution processes and assumptions underlying these mass balance models helps define chemical and biological applicability domains of individual models, as well as provide a perspective on how to improve model predictivity and quantitative in vitro-in vivo extrapolations.
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http://dx.doi.org/10.1016/j.tiv.2021.105133DOI Listing
March 2021

Towards a systematic use of effect biomarkers in population and occupational biomonitoring.

Environ Int 2021 Jan 15;146:106257. Epub 2020 Dec 15.

State Secretariat for Economic Affairs (SECO), Labour Directorate Section Chemicals and Work (ABCH), Switzerland. Electronic address:

Effect biomarkers can be used to elucidate relationships between exposure to environmental chemicals and their mixtures with associated health outcomes, but they are often underused, as underlying biological mechanisms are not understood. We aim to provide an overview of available effect biomarkers for monitoring chemical exposures in the general and occupational populations, and highlight their potential in monitoring humans exposed to chemical mixtures. We also discuss the role of the adverse outcome pathway (AOP) framework and physiologically based kinetic and dynamic (PBK/D) modelling to strengthen the understanding of the biological mechanism of effect biomarkers, and in particular for use in regulatory risk assessments. An interdisciplinary network of experts from the European chapter of the International Society for Exposure Science (ISES Europe) and the Organization for Economic Co-operation and Development (OECD) Occupational Biomonitoring activity of Working Parties of Hazard and Exposure Assessment group worked together to map the conventional framework of biomarkers and provided recommendations for their systematic use. We summarized the key aspects of this work here, and discussed these in three parts. Part I, we inventory available effect biomarkers and promising new biomarkers for the general population based on the H2020 Human Biomonitoring for Europe (HBM4EU) initiative. Part II, we provide an overview AOP and PBK/D modelling use that improved the selection and interpretation of effect biomarkers. Part III, we describe the collected expertise from the OECD Occupational Biomonitoring subtask effect biomarkers in prioritizing relevant mode of actions (MoAs) and suitable effect biomarkers. Furthermore, we propose a tiered risk assessment approach for occupational biomonitoring. Several effect biomarkers, especially for use in occupational settings, are validated. They offer a direct assessment of the overall health risks associated with exposure to chemicals, chemical mixtures and their transformation products. Promising novel effect biomarkers are emerging for biomonitoring of the general population. Efforts are being dedicated to prioritizing molecular and biochemical effect biomarkers that can provide a causal link in exposure-health outcome associations. This mechanistic approach has great potential in improving human health risk assessment. New techniques such as in silico methods (e.g. QSAR, PBK/D modelling) as well as 'omics data will aid this process. Our multidisciplinary review represents a starting point for enhancing the identification of effect biomarkers and their mechanistic pathways following the AOP framework. This may help in prioritizing the effect biomarker implementation as well as defining threshold limits for chemical mixtures in a more structured way. Several ex vivo biomarkers have been proposed to evaluate combined effects including genotoxicity and xeno-estrogenicity. There is a regulatory need to derive effect-based trigger values using the increasing mechanistic knowledge coming from the AOP framework to address adverse health effects due to exposure to chemical mixtures. Such a mechanistic strategy would reduce the fragmentation observed in different regulations. It could also stimulate a harmonized use of effect biomarkers in a more comparable way, in particular for risk assessments to chemical mixtures.
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http://dx.doi.org/10.1016/j.envint.2020.106257DOI Listing
January 2021

A Review of Tools as Alternatives to Animal Testing: Principles, Resources and Applications.

Altern Lab Anim 2020 Jul 29;48(4):146-172. Epub 2020 Oct 29.

School of Pharmacy and Biomolecular Sciences, 4589Liverpool John Moores University, Liverpool, UK.

Across the spectrum of industrial sectors, including pharmaceuticals, chemicals, personal care products, food additives and their associated regulatory agencies, there is a need to develop robust and reliable methods to reduce or replace animal testing. It is generally recognised that no single alternative method will be able to provide a one-to-one replacement for assays based on more complex toxicological endpoints. Hence, information from a combination of techniques is required. A greater understanding of the time and concentration-dependent mechanisms, underlying the interactions between chemicals and biological systems, and the sequence of events that can lead to apical effects, will help to move forward the science of reducing and replacing animal experiments. modelling, assays, high-throughput screening, organ-on-a-chip technology, omics and mathematical biology, can provide complementary information to develop a complete picture of the potential response of an organism to a chemical stressor. Adverse outcome pathways (AOPs) and systems biology frameworks enable relevant information from diverse sources to be logically integrated. While individual researchers do not need to be experts across all disciplines, it is useful to have a fundamental understanding of what other areas of science have to offer, and how knowledge can be integrated with other disciplines. The purpose of this review is to provide those who are unfamiliar with predictive tools, with a fundamental understanding of the underlying theory. Current applications, software, barriers to acceptance, new developments and the use of integrated approaches are all discussed, with additional resources being signposted for each of the topics.
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http://dx.doi.org/10.1177/0261192920965977DOI Listing
July 2020

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment.

Environ Int 2020 10 4;143:105978. Epub 2020 Aug 4.

European Commission, Joint Research Centre (JRC), Ispra, Italy. Electronic address:

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals. One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature. The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment. Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations.
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http://dx.doi.org/10.1016/j.envint.2020.105978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684529PMC
October 2020

Key read across framework components and biology based improvements.

Mutat Res 2020 05 16;853:503172. Epub 2020 Mar 16.

BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany. Electronic address:

At the 2019 annual meeting of the European Environmental Mutagen and Genomics Society a workshop session related to the use of read across concepts in toxicology was held. The goal of this session was to provide the audience an overview of general read-across concepts. From ECHA's read across assessment framework, the starting point is chemical similarity. There are several approaches and algorithms available for calculating chemical similarity based on molecular descriptors, distance/similarity measures and weighting schemata for specific endpoints. Therefore, algorithms that adapt themselves to the data (endpoint/s) and provide a good ability to distinguish between structural similar and not similar molecules regarding specific endpoints are needed and their use discussed. Toxico-dynamic end points are usually in the focus of read across cases. However, without appropriate attention to kinetics and metabolism such cases are unlikely to be successful. To further enhance the quality of read across cases new approach methods can be very useful. Examples based on a biological approach using plasma metabolomics in rats are given. Finally, with the availability of large data sets of structure activity relationships, in silico tools have been developed which provide hitherto undiscovered information. Automated process is now able to assess the chemical - activity space around the molecule target substance and examples are given demonstrating a high predictivity for certain endpoints of toxicity. Thus, this session provides not only current state of the art criteria for good read across, but also indicates how read-across can be further developed in the near future.
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http://dx.doi.org/10.1016/j.mrgentox.2020.503172DOI Listing
May 2020

New approach methodologies (NAMs) for human-relevant biokinetics predictions. Meeting the paradigm shift in toxicology towards an animal-free chemical risk assessment

ALTEX 2020 8;37(4):607-622. Epub 2020 Jun 8.

RIVM - The National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) to supervise this process was formulated. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the fields of stem cells, organoids and organ-on-a-chip models provide promising tools to meet these research needs in the future.
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http://dx.doi.org/10.14573/altex.2003242DOI Listing
June 2020

PBPK model reporting template for chemical risk assessment applications.

Regul Toxicol Pharmacol 2020 Aug 2;115:104691. Epub 2020 Jun 2.

Health and Environmental Sciences Institute, 740 15th Street, NW, Suite 600, Washington, DC, 20005, USA. Electronic address:

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.
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http://dx.doi.org/10.1016/j.yrtph.2020.104691DOI Listing
August 2020

Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures - A review.

Comput Toxicol 2019 May;10:158-168

European Commission, Joint Research Centre, Ispra, VA, Italy.

The role of Physiologically Based Kinetic (PBK) modelling in assessing mixture toxicology has been growing for the last three decades. It has been widely used to investigate and address interactions in mixtures. This review describes the current state-of-the-art of PBK models for chemical mixtures and to evaluate the applications of PBK modelling for mixtures with emphasis on their role in chemical risk assessment. A total of 35 mixture PBK models were included after searching web resources (Scopus, PubMed, Web of Science, and Google Scholar), screening for duplicates, and excluding articles based on eligibility criteria. Binary mixtures and volatile organic compounds accounted for two-thirds of the chemical mixtures identified. The most common exposure route and modelled system were found to be inhalation and rats respectively. Twenty two (22) models were for binary mixtures, 5 for ternary mixtures, 3 for quaternary mixtures, and 5 for complex mixtures. Both bottom-up and top-down PBK modelling approaches are described. Whereas bottom-up approaches are based on a series of binary interactions, top-down approaches are based on the lumping of mixture components. Competitive inhibition is the most common type of interaction among the various types of mixtures, and usually becomes a concern at concentrations higher than environmental exposure levels. It leads to reduced biotransformation that either means a decrease in the amount of toxic metabolite formation or an increase in toxic parent chemical accumulation. The consequence is either lower or higher toxicity compared to that estimated for the mixture based on the additivity principle. Therefore, PBK modelling can play a central role in predicting interactions in chemical mixture risk assessment.
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http://dx.doi.org/10.1016/j.comtox.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559215PMC
May 2019

Regulatory assessment and risk management of chemical mixtures: challenges and ways forward.

Crit Rev Toxicol 2019 02 1;49(2):174-189. Epub 2019 Apr 1.

European Commission, Joint Research Centre (JRC) , Ispra , Italy.

This paper summarizes current challenges, the potential use of novel scientific methodologies, and ways forward in the risk assessment and risk management of mixtures. Generally, methodologies to address mixtures have been agreed; however, there are still several data and methodological gaps to be addressed. New approach methodologies can support the filling of knowledge gaps on the toxicity and mode(s) of action of individual chemicals. (Bio)Monitoring, modeling, and better data sharing will support the derivation of more realistic co-exposure scenarios. As knowledge and data gaps often hamper an in-depth assessment of specific chemical mixtures, the option of taking account of possible mixture effects in single substance risk assessments is briefly discussed. To allow risk managers to take informed decisions, transparent documentation of assumptions and related uncertainties is recommended indicating the potential impact on the assessment. Considering the large number of possible combinations of chemicals in mixtures, prioritization is needed, so that actions first address mixtures of highest concern and chemicals that drive the mixture risk. As chemicals with different applications and regulated separately might lead to similar toxicological effects, it is important to consider chemical mixtures across legislative sectors.
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http://dx.doi.org/10.1080/10408444.2019.1579169DOI Listing
February 2019

Insights into in vitro biokinetics using Virtual Cell Based Assay simulations.

ALTEX 2019 28;36(3):447-461. Epub 2019 Mar 28.

European Commission, Joint Research Centre, Ispra, Italy.

The Virtual Cell Based Assay (VCBA) is an in silico model that simulates the biokinetics of chemicals in in vitro test systems. Simulations by the VCBA can indicate the degree to which the bioavailable concentration varies across chemicals and experimental conditions, thereby providing important contextual information when comparing the results of different in vitro toxicity experiments. The simulated results can also be used to support in vitro to in vivo extrapolation of toxicity data, especially when the VCBA is coupled to a physiologically based kinetic model. The VCBA requires only a limited number of physicochemical properties as input parameters to model the fate of a chemical in the in vitro environment; optionally, in vitro toxicity concentration-response curves can be used to optimise the toxicity and effects model. In this work, we selected 83 chemicals previously tested in vitro and used the in vitro data to optimise the toxicity and effects model, simulating the 3T3 BALB/c cell line in a 96-well microplate with 5% serum supplementation. We then used the optimised parameters to simulate alternative experimental conditions. By incorporating a diverse group of chemicals, the simulations show the impact of different physicochemical properties on chemical fate and how the different partitioning (to protein, lipid and plastic) and kinetic (evaporation and degradation) events are intrinsically connected. The results of VCBA simulations were interpreted in the light of the domain of applicability of the different QSARs incorporated in the model and the underlying assumptions and uncertainties of the VCBA.
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http://dx.doi.org/10.14573/altex.1812101DOI Listing
January 2020

Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods: Scientific and regulatory perspectives.

Environ Int 2019 05 8;126:659-671. Epub 2019 Mar 8.

Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environment et travail), UMR_S 1085, F-35000 Rennes, France.

Humans are continuously exposed to low levels of thousands of industrial chemicals, most of which are poorly characterised in terms of their potential toxicity. The new paradigm in chemical risk assessment (CRA) aims to rely on animal-free testing, with kinetics being a key determinant of toxicity when moving from traditional animal studies to integrated in vitro-in silico approaches. In a kinetically informed CRA, membrane transporters, which have been intensively studied during drug development, are an essential piece of information. However, how existing knowledge on transporters gained in the drug field can be applied to CRA is not yet fully understood. This review outlines the opportunities, challenges and existing tools for investigating chemical-transporter interactions in kinetically informed CRA without animal studies. Various environmental chemicals acting as substrates, inhibitors or modulators of transporter activity or expression have been shown to impact TK, just as drugs do. However, because pollutant concentrations are often lower in humans than drugs and because exposure levels and internal chemical doses are not usually known in contrast to drugs, new approaches are required to translate transporter data and reasoning from the drug sector to CRA. Here, the generation of in vitro chemical-transporter interaction data and the development of transporter databases and classification systems trained on chemical datasets (and not only drugs) are proposed. Furtheremore, improving the use of human biomonitoring data to evaluate the in vitro-in silico transporter-related predicted values and developing means to assess uncertainties could also lead to increase confidence of scientists and regulators in animal-free CRA. Finally, a systematic characterisation of the transportome (quantitative monitoring of transporter abundance, activity and maintenance over time) would reinforce confidence in the use of experimental transporter/barrier systems as well as in established cell-based toxicological assays currently used for CRA.
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http://dx.doi.org/10.1016/j.envint.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441651PMC
May 2019

Finding synergies for 3Rs - Toxicokinetics and read-across: Report from an EPAA partners' Forum.

Regul Toxicol Pharmacol 2018 Nov 23;99:5-21. Epub 2018 Aug 23.

Scientific Consultancy - Animal Welfare, Germany.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. Currently, lacking toxicokinetic data often prevent the application of read-across. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetics parameters required for read-across; case studies exemplifying how toxicokinetic data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to collate a contemporaneous list of open toxicokinetics tools that assist risk assessment.
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http://dx.doi.org/10.1016/j.yrtph.2018.08.006DOI Listing
November 2018

Capturing the applicability of in vitro-in silico membrane transporter data in chemical risk assessment and biomedical research.

Sci Total Environ 2018 Dec 14;645:97-108. Epub 2018 Jul 14.

European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy.

Costs, scientific and ethical concerns related to animal tests for regulatory decision-making have stimulated the development of alternative methods. When applying alternative approaches, kinetics have been identified as a key element to consider. Membrane transporters affect the kinetic processes of absorption, distribution, metabolism and excretion (ADME) of various compounds, such as drugs or environmental chemicals. Therefore, pharmaceutical scientists have intensively studied transporters impacting drug efficacy and safety. Besides pharmacokinetics, transporters are considered as major determinant of toxicokinetics, potentially representing an essential piece of information in chemical risk assessment. To capture the applicability of transporter data for kinetic-based risk assessment in non-pharmaceutical sectors, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) created a survey with a view of identifying the improvements needed when using in vitro and in silico methods. Seventy-three participants, from different sectors and with various kinds of expertise, completed the survey. The results revealed that transporters are investigated mainly during drug development, but also for risk assessment purposes of food and feed contaminants, industrial chemicals, cosmetics, nanomaterials and in the context of environmental toxicology, by applying both in vitro and in silico tools. However, to rely only on alternative methods for chemical risk assessment, it is critical that the data generated by in vitro and in silico methods are scientific integer, reproducible and of high quality so that they are trusted by decision makers and used by industry. In line, the respondents identified various challenges related to the interpretation and use of transporter data from non-animal methods. Overall, it was determined that a combined mechanistically-anchored in vitro-in silico approach, validated against available human data, would gain confidence in using transporter data within an animal-free risk assessment paradigm. Finally, respondents involved primarily in fundamental research expressed lower confidence in non-animal studies to unravel complex transporter mechanisms.
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http://dx.doi.org/10.1016/j.scitotenv.2018.07.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162338PMC
December 2018

Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity.

Toxicol In Vitro 2018 Oct 20;52:131-145. Epub 2018 Jun 20.

U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC, United States.

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.
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http://dx.doi.org/10.1016/j.tiv.2018.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760245PMC
October 2018

Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways.

Toxicol Sci 2018 06;163(2):346-352

Department of Physiology, University of Lausanne, CH 1005 Lausanne, Switzerland.

Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, "tissue resident cell activation", "increased pro-inflammatory mediators", and "leukocyte recruitment/activation," is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless, the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.
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http://dx.doi.org/10.1093/toxsci/kfy047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309953PMC
June 2018

Aggregate Exposure Pathways in Support of Risk Assessment.

Curr Opin Toxicol 2018 Jun 29;9:8-13. Epub 2018 Mar 29.

National Exposure Research Laboratory, U.S. Environmental Protection Agency, Durham, North Carolina 27709, United States.

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of the Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.
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http://dx.doi.org/10.1016/j.cotox.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935252PMC
June 2018

Ab initio chemical safety assessment: A workflow based on exposure considerations and non-animal methods.

Comput Toxicol 2017 Nov;4:31-44

Procter & Gamble, Egham, United Kingdom.

We describe and illustrate a workflow for chemical safety assessment that completely avoids animal testing. The workflow, which was developed within the SEURAT-1 initiative, is designed to be applicable to cosmetic ingredients as well as to other types of chemicals, e.g. active ingredients in plant protection products, biocides or pharmaceuticals. The aim of this work was to develop a workflow to assess chemical safety without relying on any animal testing, but instead constructing a hypothesis based on existing data, modelling, biokinetic considerations and then by targeted non-animal testing. For illustrative purposes, we consider a hypothetical new ingredient x as a new component in a body lotion formulation. The workflow is divided into tiers in which points of departure are established through testing and prediction, as the basis for estimating a safe external dose in a repeated use scenario. The workflow includes a series of possible exit (decision) points, with increasing levels of confidence, based on the sequential application of the Threshold of Toxicological (TTC) approach, read-across, followed by an "ab initio" assessment, in which chemical safety is determined entirely by new testing and to extrapolation by means of mathematical modelling. We believe that this workflow could be applied as a tool to inform targeted and toxicologically relevant testing, where necessary, and to gain confidence in safety decision making without the need for animal testing.
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http://dx.doi.org/10.1016/j.comtox.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695905PMC
November 2017

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition.

Arch Toxicol 2018 Jan 5;92(1):41-82. Epub 2017 Dec 5.

In Vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Universitätsstr. 10, PO Box M657, 78457, Konstanz, Germany.

Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson's disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor deficits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor deficits are mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson's disease development.
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http://dx.doi.org/10.1007/s00204-017-2133-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773657PMC
January 2018

In vitro to in vivo extrapolation for high throughput prioritization and decision making.

Toxicol In Vitro 2018 Mar 5;47:213-227. Epub 2017 Dec 5.

National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, USA. Electronic address:

In vitro chemical safety testing methods offer the potential for efficient and economical tools to provide relevant assessments of human health risk. To realize this potential, methods are needed to relate in vitro effects to in vivo responses, i.e., in vitro to in vivo extrapolation (IVIVE). Currently available IVIVE approaches need to be refined before they can be utilized for regulatory decision-making. To explore the capabilities and limitations of IVIVE within this context, the U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series. Here, we integrate content from the webinars and workshop to discuss activities and resources that would promote inclusion of IVIVE in regulatory decision-making. We discuss properties of models that successfully generate predictions of in vivo doses from effective in vitro concentration, including the experimental systems that provide input parameters for these models, areas of success, and areas for improvement to reduce model uncertainty. Finally, we provide case studies on the uses of IVIVE in safety assessments, which highlight the respective differences, information requirements, and outcomes across various approaches when applied for decision-making.
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http://dx.doi.org/10.1016/j.tiv.2017.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393693PMC
March 2018

Virtual Cell Based Assay simulations of intra-mitochondrial concentrations in hepatocytes and cardiomyocytes.

Toxicol In Vitro 2017 Dec 11;45(Pt 2):222-232. Epub 2017 Sep 11.

European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, EURL ECVAM, Ispra, Italy. Electronic address:

In order to replace the use of animals in toxicity testing, there is a need to predict human in vivo toxic doses from concentrations that cause adverse effects in in vitro test systems. The virtual cell based assay (VCBA) has been developed to simulate intracellular concentrations as a function of time, and can be used to interpret in vitro concentration-response curves. In this study we refine and extend the VCBA model by including additional target-organ cell models and by simulating the fate and effects of chemicals at the organelle level. In particular, we describe the extension of the original VCBA to simulate chemical fate in liver (HepaRG) cells and cardiomyocytes (ICell cardiomyocytes), and we explore the effects of chemicals at the mitochondrial level. This includes a comparison of: a) in vitro results on cell viability and mitochondrial membrane potential (mmp) from two cell models (HepaRG cells and ICell cardiomyocytes); and b) VCBA simulations, including the cell and mitochondrial compartment, simulating the mmp for both cell types. This proof of concept study illustrates how the relationship between intra cellular, intra mitochondrial concentration, mmp and cell toxicity can be obtained by using the VCBA.
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http://dx.doi.org/10.1016/j.tiv.2017.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745147PMC
December 2017

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications.

Regul Toxicol Pharmacol 2017 Nov 1;90:104-115. Epub 2017 Sep 1.

European Commission, Joint Research Centre, Directorate Health, Consumers and Reference Materials, Via E Fermi 2749, 21027 Ispra, Italy.

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes.
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http://dx.doi.org/10.1016/j.yrtph.2017.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656087PMC
November 2017

Improving substance information in USEtox , part 2: Data for estimating fate and ecosystem exposure factors.

Environ Toxicol Chem 2017 12 17;36(12):3463-3470. Epub 2017 Aug 17.

Joint Research Centre (JRC), Directorate D-Sustainable Resources, European Commission, Ispra, Italy.

The scientific consensus model USEtox has been developed since 2003 under the auspices of the United Nations Environment Programme-Society of Environmental Toxicology and Chemistry Life Cycle Initiative as a harmonized approach for characterizing human and freshwater toxicity in life cycle assessment and other comparative assessment frameworks. Using physicochemical substance properties, USEtox quantifies potential human toxicity and freshwater ecotoxicity impacts by combining environmental fate, exposure, and toxicity effects information, considering multimedia fate and multipathway exposure processes. The main source to obtain substance properties for USEtox 1.01 and 2.0 is the Estimation Program Interface (EPI Suite™) from the US Environmental Protection Agency. However, since the development of the original USEtox substance databases, new chemical regulations have been enforced in Europe, such as the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and the Plant Protection Products regulations. These regulations require that a chemical risk assessment for humans and the environment is performed before a chemical is placed on the European market. Consequently, additional physicochemical property data and new toxicological endpoints are now available for thousands of chemical substances. The aim of the present study was to explore the extent to which the new available data can be used as input for USEtox-especially for application in environmental footprint studies-and to discuss how this would influence the quantification of fate and exposure factors. Initial results show that the choice of data source and the parameters selected can greatly influence fate and exposure factors, leading to potentially different rankings and relative contributions of substances to overall human toxicity and ecotoxicity impacts. Moreover, it is crucial to discuss the relevance of the exposure factor for freshwater ecotoxicity impacts, particularly for persistent highly adsorbing and bioaccumulating substances. Environ Toxicol Chem 2017;36:3463-3470. © 2017 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.
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http://dx.doi.org/10.1002/etc.3903DOI Listing
December 2017

From in vitro to in vivo: Integration of the virtual cell based assay with physiologically based kinetic modelling.

Toxicol In Vitro 2017 Dec 27;45(Pt 2):241-248. Epub 2017 Jun 27.

Chemical Safety and Alternative Methods Unit, EURL ECVAM, Directorate F - Health, Consumers and Reference Materials, Joint Research Centre, European Commission, Ispra, Italy.

Physiologically based kinetic (PBK) models and the virtual cell based assay can be linked to form so called physiologically based dynamic (PBD) models. This study illustrates the development and application of a PBK model for prediction of estragole-induced DNA adduct formation and hepatotoxicity in humans. To address the hepatotoxicity, HepaRG cells were used as a surrogate for liver cells, with cell viability being used as the in vitro toxicological endpoint. Information on DNA adduct formation was taken from the literature. Since estragole induced cell damage is not directly caused by the parent compound, but by a reactive metabolite, information on the metabolic pathway was incorporated into the model. In addition, a user-friendly tool was developed by implementing the PBK/D model into a KNIME workflow. This workflow can be used to perform in vitro to in vivo extrapolation and forward as backward dosimetry in support of chemical risk assessment.
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http://dx.doi.org/10.1016/j.tiv.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742636PMC
December 2017

Improving substance information in USEtox , part 1: Discussion on data and approaches for estimating freshwater ecotoxicity effect factors.

Environ Toxicol Chem 2017 12 17;36(12):3450-3462. Epub 2017 Aug 17.

Joint Research Centre (JRC), Directorate D-Sustainable Resources, European Commission, Ispra, Italy.

The scientific consensus model USEtox is recommended by the European Commission as the reference model to characterize life cycle chemical emissions in terms of their potential human toxicity and freshwater aquatic ecotoxicity impacts in the context of the International Reference Life Cycle Data System Handbook and the Environmental Footprint pilot phase looking at products (PEF) and organizations (OEF). Consequently, this model has been systematically used within the PEF/OEF pilot phase by 25 European Union industry sectors, which manufacture a wide variety of consumer products. This testing phase has raised some questions regarding the derivation of and the data used for the chemical-specific freshwater ecotoxicity effect factor in USEtox. For calculating the potential freshwater aquatic ecotoxicity impacts, USEtox bases the effect factor on the chronic hazard concentration (HC50) value for a chemical calculated as the arithmetic mean of all logarithmized geometric means of species-specific chronic median lethal (or effect) concentrations (L[E]C50). We investigated the dependency of the USEtox effect factor on the selection of ecotoxicological data source and toxicological endpoints, and we found that both influence the ecotoxicity ranking of chemicals and may hence influence the conclusions of a PEF/OEF study. We furthermore compared the average measure (HC50) with other types of ecotoxicity effect indicators, such as the lowest species EC50 or no-observable-effect concentration, frequently used in regulatory risk assessment, and demonstrated how they may also influence the ecotoxicity ranking of chemicals. We acknowledge that these indicators represent different aspects of a chemical's ecotoxicity potential and discuss their pros and cons for a comparative chemical assessment as performed in life cycle assessment and in particular within the PEF/OEF context. Environ Toxicol Chem 2017;36:3450-3462. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
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http://dx.doi.org/10.1002/etc.3889DOI Listing
December 2017

Automated workflows for modelling chemical fate, kinetics and toxicity.

Toxicol In Vitro 2017 Dec 18;45(Pt 2):249-257. Epub 2017 Mar 18.

Chemical Safety and Alternative Methods Unit, EURL ECVAM, Directorate F - Health, Consumers and Reference Materials, Joint Research Centre, European Commission, Ispra, Italy.

Automation is universal in today's society, from operating equipment such as machinery, in factory processes, to self-parking automobile systems. While these examples show the efficiency and effectiveness of automated mechanical processes, automated procedures that support the chemical risk assessment process are still in their infancy. Future human safety assessments will rely increasingly on the use of automated models, such as physiologically based kinetic (PBK) and dynamic models and the virtual cell based assay (VCBA). These biologically-based models will be coupled with chemistry-based prediction models that also automate the generation of key input parameters such as physicochemical properties. The development of automated software tools is an important step in harmonising and expediting the chemical safety assessment process. In this study, we illustrate how the KNIME Analytics Platform can be used to provide a user-friendly graphical interface for these biokinetic models, such as PBK models and VCBA, which simulates the fate of chemicals in vivo within the body and in vitro test systems respectively.
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http://dx.doi.org/10.1016/j.tiv.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745146PMC
December 2017

The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data - A case study with caffeine.

Toxicology 2017 12 10;392:119-129. Epub 2017 Mar 10.

Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy.

Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (C), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.
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http://dx.doi.org/10.1016/j.tox.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699174PMC
December 2017

The virtual cell based assay: Current status and future perspectives.

Toxicol In Vitro 2017 Dec 18;45(Pt 2):258-267. Epub 2017 Jan 18.

Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM, Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy.

In order to replace the use of animals in toxicity testing, there is a need to predict in vivo toxic doses from concentrations that cause toxicological effects in relevant in vitro systems. The Virtual Cell Based Assay (VCBA) estimates time-dependent concentration of a test chemical in the cell and cell culture for a given in vitro system. The concentrations in the different compartments of the cell and test system are derived from ordinary differential equations, physicochemical parameters of the test chemical and properties of the cell line. The VCBA has been developed for a range of cell lines including BALB/c 3T3 cells, HepG2, HepaRG, lung A459 cells, and cardiomyocytes. The model can be used to design and refine in vitro experiments and extrapolate in vitro effective concentrations to in vivo doses that can be applied in risk assessment. In this paper, we first discuss potential applications of the VCBA: i) design of in vitro High Throughput Screening (HTS) experiments; ii) hazard identification (based on acute systemic toxicity); and iii) risk assessment. Further extension of the VCBA is discussed in the second part, exploring potential application to i) manufactured nanomaterials, ii) additional cell lines and endpoints, and considering iii) other opportunities.
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http://dx.doi.org/10.1016/j.tiv.2017.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742635PMC
December 2017

How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

Toxicol Sci 2017 02 19;155(2):326-336. Epub 2016 Dec 19.

European Commission, Joint Research Centre, Ispra 21027, Italy.

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.
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http://dx.doi.org/10.1093/toxsci/kfw207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340205PMC
February 2017

Multiscale modelling approaches for assessing cosmetic ingredients safety.

Toxicology 2017 12 4;392:130-139. Epub 2016 Jun 4.

European Commission Joint Research Centre, Institute for Health and Consumer Protection, Systems Toxicology Unit, Via Enrico Fermi 2749, Ispra, VA, Italy.

The European Union's ban on animal testing for cosmetic ingredients and products has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the focus of the COSMOS project was ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. In our experience, mathematical or computer modeling and in vitro experiments are complementary. We present here a summary of the main models and results obtained within the framework of the project on these topics. A first section presents our work at the organelle and cellular level. We then go toward modeling cell levels effects (monitored continuously), multiscale physiologically based pharmacokinetic and effect models, and route to route extrapolation. We follow with a short presentation of the automated KNIME workflows developed for dissemination and easy use of the models. We end with a discussion of two challenges to the field: our limited ability to deal with massive data and complex computations.
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http://dx.doi.org/10.1016/j.tox.2016.05.026DOI Listing
December 2017