Institute for Health and Consumer Protection IHCP

Ispra, Italy

Institute for Health and Consumer Protection IHCP

Ispra, Italy
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Christensen F.M.,Institute for Health and Consumer Protection IHCP | Johnston H.J.,Napier University | Stone V.,Napier University | Aitken R.J.,Institute of Occupational Medicine IOM and SAFENANO | And 3 more authors.
Nanotoxicology | Year: 2011

This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-titanium-dioxide (nano-TiO2) based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision-making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also short-term inhalation following spray applications may cause risks. Main future work should focus on generating occupational and consumer inhalation exposure data, as well as toxicity data on absorption following inhalation, repeated dermal contact, and contact with damaged skin. Also relevant seems further information on possible neurotoxicity and genotoxicity/carcinogenicity, as well as establishing a No Observed Adverse Effect Level (NOAEL) for acute inhalation of nano-TiO2. © 2011 Informa UK, Ltd.

Bouvier D'Yvoire M.,European Commission | Bremer S.,European Commission - Joint Research Center Ispra | Casati S.,European Commission - Joint Research Center Ispra | Ceridono M.,European Commission - Joint Research Center Ispra | And 9 more authors.
Advances in Experimental Medicine and Biology | Year: 2012

The development of alternative empirical (testing) and non-empirical (nontesting) methods to traditional toxicological tests for complex human health effects is a tremendous task. Toxicants may potentially interfere with a vast number of physiological mechanisms thereby causing disturbances on various levels of complexity of human physiology. Only a limited number of mechanisms relevant for toxicity ('pathways' of toxicity) have been identified with certainty so far and, presumably, many more mechanisms by which toxicants cause adverse effects remain to be identified. Recapitulating in empirical model systems (i.e., in vitro test systems) all those relevant physiological mechanisms prone to be disturbed by toxicants and relevant for causing the toxicity effect in question poses an enormous challenge. First, the mechanism(s) of action of toxicants in relation to the most relevant adverse effects of a specific human health endpoint need to be identified. Subsequently, these mechanisms need to be modeled in reductionist test systems that allow assessing whether an unknown substance may operate via a specific (array of) mechanism(s). Ideally, such test systems should be relevant for the species of interest, i.e., based on human cells or modeling mechanisms present in humans. Since much of our understanding about toxicity mechanisms is based on studies using animal model systems (i.e., experimental animals or animal-derived cells), designing test systems that model mechanisms relevant for the human situation may be limited by the lack of relevant information from basic research. New technologies from molecular biology and cell biology, as well as progress in tissue engineering, imaging techniques and automated testing platforms hold the promise to alleviate some of the traditional difficulties associated with improving toxicity testing for complex endpoints. Such new technologies are expected (1) to accelerate the identification of toxicity pathways with human relevance that need to be modeled in test methods for toxicity testing (2) to enable the reconstruction of reductionist test systems modeling at a reduced level of complexity the target system/organ of interest (e.g., through tissue engineering, use of human-derived cell lines and stem cells etc.), (3) to allow the measurement of specific mechanisms relevant for a given health endpoint in such test methods (e.g., through gene and protein expression, changes in metabolites, receptor activation, changes in neural activity etc.), (4) to allow to measure toxicity mechanisms at higher throughput rates through the use of automated testing. In this chapter, we discuss the potential impact of new technologies on the development, optimization and use of empirical testing methods, grouped according to important toxicological endpoints. We highlight, from an ECVAM perspective, the areas of topical toxicity, skin absorption, reproductive and developmental toxicity, carcinogenicity/genotoxicity, sensitization, hematopoeisis and toxicokinetics and discuss strategic developments including ECVAM's database service on alternative methods. Neither the areas of toxicity discussed nor the highlighted new technologies represent comprehensive listings which would be an impossible endeavor in the context of a book chapter. However, we feel that these areas are of utmost importance and we predict that new technologies are likely to contribute significantly to test development in these fields. We summarize which new technologies are expected to contribute to the development of new alternative testing methods over the next few years and point out current and planned ECVAM projects for each of these areas. © 2012 Landes Bioscience and Springer Science+Business Media.

Broeders S.,Scientific Institute of Public Health WIV ISP | Barbau-Piednoir E.,Scientific Institute of Public Health WIV ISP | Vandermassen E.,Scientific Institute of Public Health WIV ISP | Debode F.,Walloon Agricultural Research Center | And 2 more authors.
European Food Research and Technology | Year: 2013

Seen the growing number of genetically modified (GM) crops being developed, the need for cost- and time-effective detection methods is increasing to enable continuing the necessary effective control on food and feed products. This need can be achieved by performing an intensive screening combined with decision support tools like the CoSYPS matrix which permits reducing the number of events to be identified. To allow an extra covering power of the CoSYPS and to be able to include new EU-authorised GM events, two new SYBR®Green real-time PCR (qPCR) methods targeting two promoter sequences (pNOS and pFMV) were developed. These methods were validated using acceptance parameters such as the specificity, sensitivity and repeatability. In addition, the methods were transferred to a second laboratory, namely the Institute for Health and Consumer Protection, to test the reproducibility. Furthermore, the applicability and practicability of the methods were tested by using proficiency test samples. The two methods allow a specific and sensitive detection of the targets in food and feed samples and can be used efficiently in different laboratories. © 2013 Springer-Verlag Berlin Heidelberg.

Bouwmeester H.,Wageningen University | Lynch I.,University College Dublin | Marvin H.J.P.,Wageningen University | Dawson K.A.,University College Dublin | And 16 more authors.
Nanotoxicology | Year: 2011

This paper presents the outcomes from a workshop of the European Network on the Health and Environmental Impact of Nanomaterials (NanoImpactNet). During the workshop, 45 experts in the field of safety assessment of engineered nanomaterials addressed the need to systematically study sets of engineered nanomaterials with specific metrics to generate a data set which would allow the establishment of dose-response relations. The group concluded that international cooperation and worldwide standardization of terminology, reference materials and protocols are needed to make progress in establishing lists of essential metrics. High quality data necessitates the development of harmonized study approaches and adequate reporting of data. Priority metrics can only be based on well-characterized dose-response relations derived from the systematic study of the bio-kinetics and bio-interactions of nanomaterials at both organism and (sub)-cellular levels. In addition, increased effort is needed to develop and validate analytical methods to determine these metrics in a complex matrix. © 2011 Informa UK, Ltd.

Vanparys P.,Altoxicon BVBA | Corvi R.,Institute for Health and Consumer Protection IHCP | Aardema M.,Procter and Gamble | Aardema M.,Marilyn Aardema Consulting LLC | And 4 more authors.
Altex | Year: 2011

A prevalidation study on the cell transformation assays in SHE cells at pH 6.7, SHE cells at pH 7.0 and Balb/c 3T3 cell line was coordinated by ECVAM focussing on issues of standardisation of protocols, within-laboratory reproducibility, test method transferability and between-laboratory reproducibility. The Validation Management Team concluded that standardised protocols are now available that should be the basis for future use. The SHE pH 6.7, and the SHE pH 7.0 protocols and the assays system themselves are transferable between laboratories, and are reproducible within- and between-laboratories. For the Balb/c 3T3 method, some clarifications and modifications to the protocol were needed to obtain reproducible results. Overall, three methods have shown to be valuable to detect rodent carcinogens.

Parry J.M.,Safechem Consultants | Parry E.,Safechem Consultants | Phrakonkham P.,Institute for Health and Consumer Protection IHCP | Corvi R.,Institute for Health and Consumer Protection IHCP
Mutagenesis | Year: 2010

The ability of the in vitro mammalian cell tests currently used to identify genotoxins has been shown to be limited by a high rate of false-positive results, triggering further unnecessary testing in vivo. During an European Centre for the Validation of Alternative Methods workshop on how to improve the specificity of these assays, testing at high concentrations was identified as one possible source of false positives. Thus far, Organisation for Economic Co-operation and Development genotoxicity test guidelines have required testing of chemicals using mammalian cells in vitro should be undertaken to concentrations as high as 10 mM (5000 μg/ml). Recently, a draft revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use genotoxicity test guidelines has recommended that testing concentrations should be reduced to 1 mM (500 μg/ml). To assess the impact that this lowering would have on the outcome of in vitro genotoxicity testing, we established a database of 384 chemicals classified as rodent carcinogens and reported Ames test results and the test concentrations that produced positive results in the mouse lymphoma assay (MLA), in vitro chromosome aberration (CA) assay and in vitro micronucleus test. Genotoxicity testing results were illustrated for 229 and 338 compounds in the MLA and in vitro CA assay, respectively. Of these test compounds, 62.5% produced positive results in the MLA, of which 20.3% required testing between 1 and 10 mM. A total of 58.0% produced positive results in in vitro CA assays, of which 25.0% required testing between 1 and 10 mM. If the testing concentration limit for mammalian cell assays was reduced to 1 mM, 24 (6.25%) potential carcinogens would not be detected in any part of the standard in vitro genotoxicity test battery (Ames test, MLA and in vitro CA assay). Further re-evaluation and/or retest of these compounds by Kirkland and Fowler [Kirkland, D. and Fowler, P. (2010) Further analysis of Ames-negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern. Mutagenesis 25, 539-553] suggest that the current 10 mM top concentration can be reduced without any loss of sensitivity in detecting rodent carcinogens. © The Author 2010. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.

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