5 research outputs found
Skin sensitisation and epidermal disposition: the relevance of epidermal disposition for sensitisation hazard identification and risk assessment. The report and recommendations of ECVAM workshop 59.
Skin Sensitisation and Epidermal Disposition: The Relevance of Epidermal Disposition for Sensitisation Hazard Identification and Risk Assessment
This is the XXth report of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main goal of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which have scientific relevance and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would be best achieved by the organisation of ECVAM workshops each addressing a specific topic, and at which selected groups of independent international experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward*.
A Workshop on Skin Sensitisation and Epidermal Disposition was held at ECVAM (Ispra, Italy) on 30/31 January 2006 under the chairmanship of David Basketter, Unilever Safety and Environmental Assurance Centre, UK. The current status of approaches used to measure the disposition of chemicals in skin compartments was reviewed, with particular emphasis on proposing recommendations on how best to use such information to reduce refine and/or eliminate the need for animal testing, according to the 3 Rs principle. The key focus was the relevance of information on epidermal disposition and how best to integrate such information into non-animal testing strategies for skin sensitisation.JRC.I.2-Validation of biomedical testing method
PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: Recommendations from a joint EPAA – EURL ECVAM ADME workshop
Absorption, distribution, metabolism and excretion (ADME) determine target tissue doses upon human exposure to chemicals. In this respect, ADME is a critical piece of information in the framework of chemical risk assessment. This is especially true in an era where risk assessment must increasingly be based on in vitro toxicity experiments. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro - in vivo comparison). Much of the information needed can be generated at tissue/cell or sub-cellular level using in vitro and/or in silico (data-based such as QSAR - Quantitative Structure Activity Relationship) tools. Finally, (computer) modelling serves to integrate disparate in silico and in vitro findings in order to simulate whole body processes.
However, there are few freely-available computational modelling platforms currently available in the public domain. Also, the absence of a complete toolbox of in silico and in vitro prediction tools to provide estimates for kinetic parameters is currently a problem. Although some ADME processes can be reasonably estimated in vitro or in silico, important gaps withhold physiologically-based toxicokinetic (PBTK) modelling from wider use for in vitro to in vivo dose extrapolation. Examples of gaps include unknown applicability domains and lack of high-throughput models to measure the following: (1) penetration of barriers, (2) partitioning between blood and tissues and (3) metabolic clearance.
This paper is based on a joint EPAA - EURL ECVAM expert meeting and provides a summary of the state of art of in silico and in vitro ADME models used to deliver parameter values for basic (Tier 1) PBTK modelling. Furthermore insights and concrete recommendations are provided to in silico QSAR and in vitro test developers, toxicologists, safety assessors and regulators on priorities to further progress towards a new integrated in silico / in vitro risk assessment paradigm for systemic toxicity without or with significantly fewer animals.
The paper, (1) describes a set of critical in vitro and in silico methods providing credible input data for Tier 1 PBTK modelling; (2) defines recommendations for public availability of PBTK modelling tools; (3) provides concrete suggestions where to address the scientific issues to foster progress with a new integrated risk assessment framework; (4) identifies gaps and lists a set of recommendations for initiating PBTK assessment in R&D and standardization and optimization efforts.JRC.I.5-Systems Toxicolog
PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment Recommendations from a joint EPAA - EURL ECVAM ADME workshop
Information on toxicokinetics is critical for animal-free human risk assessment. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro-in vivo comparison). Data on absorption, distribution, metabolism and excretion in humans (ADME) could be generated using in vitro and QSAR tools. Physiologically-based toxicokinetic (PBTK) computer modelling could serve to integrate disparate in vitro and in silico findings. However, there are only few freely-available PBTK platforms currently available. And although some ADME parameters can be reasonably estimated in vitro or in silico, important gaps exist. Examples include unknown or limited applicability domains and lack of (high-throughput) tools to measure penetration of barriers, partitioning between blood and tissues and metabolic clearance. This paper is based on a joint EPAA - EURL ECVAM expert meeting. It provides a state-of-the-art overview of the availability of PBTK platforms as well as the in vitro and in silico methods to parameterise basic (Tier 1) PBTK models. Five high-priority issues are presented that provide the prerequisites for wider use of non-animal based PBTK modelling for animal-free chemical risk assessment