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Philippe Vanparys

Bio: Philippe Vanparys is an academic researcher from Johnson & Johnson Pharmaceutical Research and Development. The author has contributed to research in topics: Genotoxicity & Micronucleus test. The author has an hindex of 25, co-authored 39 publications receiving 2398 citations. Previous affiliations of Philippe Vanparys include Johnson & Johnson & Janssen Pharmaceutica.

Papers
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Journal ArticleDOI
TL;DR: It was concluded that better guidance on the likely mechanisms resulting in positive results that are not biologically relevant for human health, and how to obtain evidence for those mechanisms, is needed both for practitioners and regulatory reviewers.
Abstract: Workshop participants agreed that genotoxicity tests in mammalian cells in vitro produce a remarkably high and unacceptable occurrence of irrelevant positive results (e.g. when compared with rodent carcinogenicity). As reported in several recent reviews, the rate of irrelevant positives (i.e. low specificity) for some studies using in vitro methods (when compared to this "gold standard") means that an increased number of test articles are subjected to additional in vivo genotoxicity testing, in many cases before, e.g. the efficacy (in the case of pharmaceuticals) of the compound has been evaluated. If in vitro tests were more predictive for in vivo genotoxicity and carcinogenicity (i.e. fewer false positives) then there would be a significant reduction in the number of animals used. Beyond animal (or human) carcinogenicity as the "gold standard", it is acknowledged that genotoxicity tests provide much information about cellular behaviour, cell division processes and cellular fate to a (geno)toxic insult. Since the disease impact of these effects is seldom known, and a verification of relevant toxicity is normally also the subject of (sub)chronic animal studies, the prediction of in vivo relevant results from in vitro genotoxicity tests is also important for aspects that may not have a direct impact on carcinogenesis as the ultimate endpoint of concern. In order to address the high rate of in vitro false positive results, a 2-day workshop was held at the European Centre for the Validation of Alternative Methods (ECVAM), Ispra, Italy in April 2006. More than 20 genotoxicity experts from academia, government and industry were invited to review data from the currently available cell systems, to discuss whether there exist cells and test systems that have a reduced tendency to false positive results, to review potential modifications to existing protocols and cell systems that might result in improved specificity, and to review the performance of some new test systems that show promise of improved specificity without sacrificing sensitivity. It was concluded that better guidance on the likely mechanisms resulting in positive results that are not biologically relevant for human health, and how to obtain evidence for those mechanisms, is needed both for practitioners and regulatory reviewers. Participants discussed the fact that cell lines commonly used for genotoxicity testing have a number of deficiencies that may contribute to the high false positive rate. These include, amongst others, lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g. Aroclor-induced rat S9), impaired p53 function and altered DNA repair capability. The high concentrations of test chemicals (i.e. 10 mM or 5000 microg/ml, unless precluded by solubility or excessive toxicity) and the high levels of cytotoxicity currently required in mammalian cell genotoxicity tests were discussed as further potential sources of false positive results. Even if the goal is to detect carcinogens with short in vitro tests under more or less acute conditions, it does not seem logical to exceed the capabilities of cellular metabolic turnover, activation and defence processes. The concept of "promiscuous activation" was discussed. For numerous mutagens, the decisive in vivo enzymes are missing in vitro. However, if the substrate concentration is increased sufficiently, some other enzymes (that are unimportant in vivo) may take over the activation-leading to the same or a different active metabolite. Since we often do not use the right enzyme systems for positive controls in vitro, we have to rely on their promiscuous activation, i.e. to use excessive concentrations to get an empirical correlation between genotoxicity and carcinogenicity. A thorough review of published and industry data is urgently needed to determine whether the currently required limit concentration of 10mM or 5000 microg/ml, and high levels of cytotoxicity, are necessary for the detection of in vivo genotoxins and DNA-reactive, mutagenic carcinogens. In addition, various measures of cytotoxicity are currently allowable under OECD test guidelines, but there are few comparative data on whether different measures would result in different maximum concentrations for testing. A detailed comparison of cytotoxicity assessment strategies is needed. An assessment of whether test endpoints can be selected that are not intrinsically associated with cytotoxicity, and therefore are less susceptible to artefacts produced by cytotoxicity, should also be undertaken. There was agreement amongst the workshop participants that cell systems which are p53 and DNA-repair proficient, and have defined Phase 1 and Phase 2 metabolism, covering a broad set of enzyme forms, and used within the context of appropriately set limits of concentration and cytotoxicity, offer the best hope for reduced false positives. Whilst there is some evidence that human lymphocytes are less susceptible to false positives than the current rodent cell lines, other cell systems based on HepG2, TK6 and MCL-5 cells, as well as 3D skin models based on primary human keratinocytes also show some promise. Other human cell lines such as HepaRG, and human stem cells (the target for carcinogenicity) have not been used for genotoxicity investigations and should be considered for evaluation. Genetic engineering is also a valuable tool to incorporate missing enzyme systems into target cells. A collaborative research programme is needed to identify, further develop and evaluate new cell systems with appropriate sensitivity but improved specificity. In order to review current data for selection of appropriate top concentrations, measures and levels of cytotoxicity, metabolism, and to be able to improve existing or validate new assay systems, the participants called for the establishment of an expert group to identify the in vivo genotoxins and DNA-reactive, mutagenic carcinogens that we expect our in vitro genotoxicity assays to detect as well as the non-genotoxins and non-carcinogens we expect them not to detect.

387 citations

Journal ArticleDOI
TL;DR: In this paper, the authors present a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals, which is a major concern for the current state of the art.
Abstract: Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et al., 2011) and its independent review (Hartung et al., 2011), the present report proposes a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals. Five whitepapers were commissioned addressing toxicokinetics, skin sensitization, repeated-dose toxicity, carcinogenicity, and reproductive toxicity testing. An expert workshop of 35 participants from Europe and the US discussed and refined these whitepapers, which were subsequently compiled to form the present report. By prioritizing the many options to move the field forward, the expert group hopes to advance regulatory science.

215 citations

Journal ArticleDOI
TL;DR: There is no convincing evidence that any genotoxic rodent carcinogens or in vivo genotoxins would remain undetected in an in vitro test battery consisting of Ames+MNvit.
Abstract: In vitro genotoxicity testing needs to include tests in both bacterial and mammalian cells, and be able to detect gene mutations, chromosomal damage and aneuploidy. This may be achieved by a combination of the Ames test (detects gene mutations) and the in vitro micronucleus test (MNvit), since the latter detects both chromosomal aberrations and aneuploidy. In this paper we therefore present an analysis of an existing database of rodent carcinogens and a new database of in vivo genotoxins in terms of the in vitro genotoxicity tests needed to detect their in vivo activity. Published in vitro data from at least one test system (most were from the Ames test) were available for 557 carcinogens and 405 in vivo genotoxins. Because there are fewer publications on the MNvit than for other mammalian cell tests, and because the concordance between the MNvit and the in vitro chromosomal aberration (CAvit) test is so high for clastogenic activity, positive results in the CAvit test were taken as indicative of a positive result in the MNvit where there were no, or only inadequate data for the latter. Also, because Hprt and Tk loci both detect gene-mutation activity, a positive Hprt test was taken as indicative of a mouse-lymphoma Tk assay (MLA)-positive, where there were no data for the latter. Almost all of the 962 rodent carcinogens and in vivo genotoxins were detected by an in vitro battery comprising Ames+MNvit. An additional 11 carcinogens and six in vivo genotoxins would apparently be detected by the MLA, but many of these had not been tested in the MNvit or CAvit tests. Only four chemicals emerge as potentially being more readily detected in MLA than in Ames+MNvit--benzyl acetate, toluene, morphine and thiabendazole--and none of these are convincing cases to argue for the inclusion of the MLA in addition to Ames+MNvit. Thus, there is no convincing evidence that any genotoxic rodent carcinogens or in vivo genotoxins would remain undetected in an in vitro test battery consisting of Ames+MNvit.

203 citations

Journal ArticleDOI
TL;DR: Under the REACH system policy, it will be most probably necessary to test several thousand chemicals for their toxicological properties.
Abstract: The new European chemicals policy for the Registration, Evaluation, Authorisation and Restriction of Chemicals (the REACH system), requires the routine toxicological testing of chemicals produced in volumes of more than one tonne per year, in order to enhance environmental and consumer safety (1). Under the REACH system policy, it will be most probably necessary to test several thousand chemicals for their toxicological properties.

160 citations

Journal ArticleDOI
TL;DR: The ECVAM Scientific Advisory Committee (ESAC) concluded from the results that the three in vitro embryotoxicity tests had been sufficiently validated and could be applied to the assessment of the embryotoxic potential of drugs and other chemicals.
Abstract: The major limitations of the validated in vitro embryotoxicity tests identified at the 2003 workshop were immediately taken into account by ECVAM in a proposal for an Integrated Project in the EU 6th Framework Programme, entitled ReProTect (22). Since 2004, a consortium of more than 36 laboratories involved in this project have been evaluating existing and newly developed in vitro models for reproductive processes and their integration into a testing strategy. This strategy should provide detailed information on the hazard potentials of chemicals to the mammalian reproductive cycle

142 citations


Cited by
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01 Jan 2006
TL;DR: A new tripartite, harmonised guideline is proposed in the Quality topic area on the “Comparability of Biotechnological / Biological Products Subject to Changes in their Drug Substance and /or Drug Product Manufacturing Process”.
Abstract: A new tripartite, harmonised guideline is proposed in the Quality topic area on the “Comparability of Biotechnological / Biological Products Subject to Changes in their Drug Substance and /or Drug Product Manufacturing Process”. For establishing these comparisons, it is necessary to address both product and process aspects which, while in some instances region-specific, are uniform in their principles and are necessary to support changes in manufacturing processes yielding products defined within the scope of Q6B. When the Quality aspects have been addressed, experts from the Safety and Efficacy groups will be invited to consider issues in the preclinical and in the clinical areas, as appropriate.

1,008 citations

Book ChapterDOI
27 Sep 2012
TL;DR: This updated Test Guideline 430 provides an in vitro procedure allowing the identification of non-corrosive and corrosive substances and mixtures in accordance with UN GHS.
Abstract: Other methods and guidelines not included in this publication may be judged to be appropriate in testing chemicals in certain scientifi c, legal, and administrative contexts.The OECD Council Decision on Mutual Acceptance of Data (12th May 1981; C[81]30) affi rms that data generated in one country in accordance with the OECD Test Guidelines – and additionally in accordance with the OECD Principles of Good Laboratory Practice – should be accepted in OECD countries for purposes of assessment and other uses relating to protection of man and the environment. The full text of this Decision and the OECD Principles of Good Laboratory Practice may be found in the Appendix to the OECD Guidelines for Testing of Chemicals.

851 citations

Journal ArticleDOI
TL;DR: Bioavailability results and kinetic considerations suggest that 10–20% of ingested low-dose Cr(VI) escapes human gastric inactivation, and the incompleteness of gastric detoxification argue against a threshold in low- dose extrapolation of cancer risk for ingested Cr( VI).
Abstract: Drinking water supplies in many geographic areas contain chromium in the +3 and +6 oxidation states. Public health concerns are centered on the presence of hexavalent Cr that is classified as a known human carcinogen via inhalation. Cr(VI) has high environmental mobility and can originate from anthropogenic and natural sources. Acidic environments with high organic content promote the reduction of Cr(VI) to nontoxic Cr(III). The opposite process of Cr(VI) formation from Cr(III) also occurs, particularly in the presence of common minerals containing Mn(IV) oxides. Limited epidemiological evidence for Cr(VI) ingestion is suggestive of elevated risks for stomach cancers. Exposure of animals to Cr(VI) in drinking water induced tumors in the alimentary tract, with linear and supralinear responses in the mouse small intestine. Chromate, the predominant form of Cr(VI) at neutral pH, is taken up by all cells through sulfate channels and is activated nonenzymatically by ubiquitously present ascorbate and small thi...

775 citations

Journal ArticleDOI
TL;DR: A statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity is found.
Abstract: There are thousands of environmental chemicals, including many industrial chemicals and pesticidal active and inert ingredients, with the potential for significant human exposures but for which toxicity information is either limited or nonexistent (Judson et al. 2009). This data gap is due largely to the high cost and length of time required to conduct animal testing in rodents and other species. A complete set of regulatory tests for a single chemical (including those for carcinogenicity and for chronic, reproductive, and development toxicity) uses thousands of animals and costs millions of dollars. In addition, traditional animal tests often yield limited information on mechanism of action, and hence on the cellular pathways that could lead to toxicity in humans. Such mechanistic information is key to moving beyond default approaches for extrapolating from high-dose animal toxicity tests to estimation of human risk at realistic exposure levels. There is a pressing need to screen the large backlog of chemicals for their potential toxicity and, ultimately, their contribution to human diseases. The National Research Council (2007) advocated the use of mechanistically informative in vitro assays based on human cells or human cell constituents that measure effects on “toxicity pathways” leading to human disease. The U.S. Environmental Protection Agency (EPA), through its ToxCast program (Dix et al. 2007) and the Tox21 collaboration with the National Toxicology Program and the National Institutes of Health Chemical Genomics Center, is pursuing similar objectives and applying many of the ideas represented in the National Research Council report (Collins et al. 2008; Kavlock et al. 2009). ToxCast is a large-scale experiment using a battery of in vitro, high-throughput screening (HTS) assays, applied to a relatively large and diverse chemical space, to develop methods to predict potential toxicity of environmental chemicals at a fraction of the cost of full-scale animal testing. Three major goals of ToxCast are to a) identify in vitro assays that can reliably indicate alterations in biological processes of relevance to in vivo toxicity; b) develop signatures or prediction models based on multiple assays, along with computed or available chemical properties, that can achieve higher predictive power than single assays or chemical structure alone; and c) use these combined in silico and in vitro assay-based signatures to screen large numbers of previously untested environmental chemicals. The ToxCast data set provides a rich resource for identifying chemically induced changes in biological pathways that are associated with in vivo end points and that could potentially lead to human disease. Chemicals whose properties and assay profiles match these predictive signatures can be prioritized for more in-depth testing, which may include nontraditional, mechanism-focused in vivo tests. In this article, we provide an overview of the entire ToxCast phase I assay results data set and present initial analyses and findings.

536 citations