European Centre For Ecotoxicology And Toxicology Of Chemicals Research Articles

An assessment of the ECETOC TRA Consumer tool performance as a screening level tool

BackgroundThe European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) Consumer tool was developed to fill in a methodology gap for a high throughput, screening level tool to support industry compliance with the European Union’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation.ObjectiveTo evaluate if the TRA Consumer tool has met its design of being a screening level tool (i.e., one which does not under-predict potential exposures).MethodsThe TRA Consumer tool algorithms and defaults were reviewed and performance benchmarked vs. other consumer models and/or empirical data. Findings from existing reviews of the TRA consumer tool were also considered and addressed.ResultsTRA predictions based on its default inputs exceeded measured exposures when available, typically by orders of magnitude, and were generally greater than or similar to those of other consumer exposure tools. For dermal exposure from articles, there was no evidence that a diffusivity approach would provide more appropriate exposure estimates than those of the TRA. When default values are refined using more specific data, the refined values must be considered holistically to reflect the situation being modeled as some parameters may be correlated.SignificanceThis is the first evaluation of the ECETOC TRA consumer tool in its entirety, considering algorithms, input defaults, and associated predictions for consumer products and articles. The evaluation confirmed its design as a screening level tool.Impact StatementThe ECETOC TRA Consumer tool has been widely applied to generate exposure estimates to support chemical registrations under the EU REACH regulation. This evaluation supports the appropriateness of the TRA as a screening level exposure assessment tool. It also warrants additional measurements of consumer exposure, especially for article use scenarios, to aid the development of consumer exposure tools and chemical risk assessment.

Theme (concept) paper ‐ Advancing Aggregate Exposure to Chemicals in EU (ExpoAdvance)

Theme (concept) paper ‐ Advancing Aggregate Exposure to Chemicals in EU (ExpoAdvance)

Solvent Transfer-Efficiency of Risk Management Measures.

A series of laboratory simulations were conducted in order to determine the airborne protection that might be afforded by different combinations of workplace exposure controls typically encountered when handling volatile solvents (e.g. solvent transfer). These conditions, referred to as risk management measures (RMMs) under the Registration, Evaluation and Authorisation of Chemicals Regulation (REACH), are typically described using standard phrases in safety data sheets [and specifically those of the European Phrase Catalogue (EUPhraC)]. Ethanol was used as a model compound and its emissions were monitored continuously with a portable IR spectrometer at 3000 cm−1. The average emission reduction performance of the investigated RMMs (e.g. containment, extract ventilation, drum pump) exceeded 90%. They present suitable ways to reduce airborne solvent exposure in a workplace and confirmed the initial expectations derived at by the European Solvents Industry Group (ESIG) and the European Centre For Ecotoxicology and toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) model.

Framework for the quality assurance of ’omics technologies considering GLP requirements

‘Omics technologies are gaining importance to support regulatory toxicity studies. Prerequisites for performing ‘omics studies considering GLP principles were discussed at the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Workshop Applying ‘omics technologies in Chemical Risk Assessment. A GLP environment comprises a standard operating procedure system, proper pre-planning and documentation, and inspections of independent quality assurance staff. To prevent uncontrolled data changes, the raw data obtained in the respective ‘omics data recording systems have to be specifically defined. Further requirements include transparent and reproducible data processing steps, and safe data storage and archiving procedures. The software for data recording and processing should be validated, and data changes should be traceable or disabled. GLP-compliant quality assurance of ‘omics technologies appears feasible for many GLP requirements. However, challenges include (i) defining, storing, and archiving the raw data; (ii) transparent descriptions of data processing steps; (iii) software validation; and (iv) ensuring complete reproducibility of final results with respect to raw data. Nevertheless, ‘omics studies can be supported by quality measures (e.g., GLP principles) to ensure quality control, reproducibility and traceability of experiments. This enables regulators to use ‘omics data in a fit-for-purpose context, which enhances their applicability for risk assessment.

Applying 'omics technologies in chemicals risk assessment: Report of an ECETOC workshop

Prevailing knowledge gaps in linking specific molecular changes to apical outcomes and methodological uncertainties in the generation, storage, processing, and interpretation of 'omics data limit the application of 'omics technologies in regulatory toxicology. Against this background, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop Applying 'omics technologies in chemicals risk assessment that is reported herein. Ahead of the workshop, multi-expert teams drafted frameworks on best practices for (i) a Good-Laboratory Practice-like context for collecting, storing and curating 'omics data; (ii) the processing of 'omics data; and (iii) weight-of-evidence approaches for integrating 'omics data. The workshop participants confirmed the relevance of these Frameworks to facilitate the regulatory applicability and use of 'omics data, and the workshop discussions provided input for their further elaboration. Additionally, the key objective (iv) to establish approaches to connect 'omics perturbations to phenotypic alterations was addressed. Generally, it was considered promising to strive to link gene expression changes and pathway perturbations to the phenotype by mapping them to specific adverse outcome pathways. While further work is necessary before gene expression changes can be used to establish safe levels of substance exposure, the ECETOC workshop provided important incentives towards achieving this goal.

The challenge of the application of 'omics technologies in chemicals risk assessment: Background and outlook

This survey by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) highlights that ‘omics technologies are generally not yet applied to meet standard information requirements during regulatory hazard assessment. While they are used within weight-of-evidence approaches to investigate substances’ modes-of-action, consistent approaches for the generation, processing and interpretation of ‘omics data are not applied. To date, no ‘omics technology has been standardised or validated. Best practices for performing ‘omics studies for regulatory purposes (e.g., microarrays for transcriptome profiling) remain to be established. Therefore, three frameworks for (i) establishing a Good-Laboratory Practice-like context for collecting, storing and curating ‘omics data; (ii) ‘omics data processing; and (iii) quantitative WoE approaches to interpret ‘omics data have been developed, that are presented in this journal supplement. Application of the frameworks will enable between-study comparison of results, which will facilitate the regulatory applicability of 'omics data. The frameworks do not constitute prescriptive protocols precluding any other data analysis method, but provide a baseline for analysis that can be applied to all data allowing ready cross-comparison. Data analysis that does not follow the frameworks can be justified and the resulting data can be compared with the Framework-based common analysis output.

A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.

Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.

Relevance of the rat lung tumor response to particle overload for human risk assessment-Update and interpretation of new data since ILSI 2000.

The relevance of particle-overload related lung tumors in rats for human risk assessment following chronic inhalation exposures to poorly soluble particulates (PSP) has been a controversial issue for more than three decades. In 1998, an ILSI (International Life Sciences) Working Group of health scientists was convened to address this issue of applicability of experimental study findings of lung neoplasms in rats for lifetime-exposed production workers to PSPs. A full consensus view was not reached by the Workshop participants, although it was generally acknowledged that the findings of lung tumors in rats following chronic inhalation, particle-overload PSP exposures occurred only in rats and no other tested species; and that there was an absence of lung cancers in PSP-exposed production workers. Since the publication of the ILSI Workshop report in 2000, there have been important new data published on the human relevance issue. A thorough and comprehensive review of the health effects literature on poorly soluble particles/lung overload was undertaken and published by an ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) Task Force in 2013. One of the significant conclusions derived from that technical report was that the rat is unique amongst all species in developing lung tumors under chronic inhalation overload exposures to PSPs. Accordingly, the objective of this review is to provide important insights on the fundamental differences in pulmonary responses between experimentally-exposed rats, other experimental species and occupationally-exposed humans. Briefly, five central factors are described by the following issues. Focusing on these five interrelated/convergent factors clearly demonstrate an inappropriateness in concluding that the findings of lung tumors in rats exposed chronically to high concentrations of PSPs are accurate representations of the risks of lung cancer in PSP-exposed production workers. The most plausible conclusion that can be reached is that results from chronic particle-overload inhalation studies with PSPs in rats have no relevance for determining lung cancer risks in production workers exposed for a working lifetime to these poorly soluble particulate-types.

Evaluation of the ECETOC TRA model for workplace inhalation exposure to ethylbenzene in Japan

The European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) that is positioned as a Tier 1 model for screening assessment in Europe can contribute to improvement of the independent work environment of workers if utilized in Japanese workplaces. In this study, estimated values of ethylbenzene obtained using ECETOC TRA were compared to measured values, and applicability of ECETOC TRA to the Japanese workplace was studied. Measured values and the work content collected from exposure field surveys conducted by the Japanese government in FY 2009 and FY 2010 were utilized for this study. The 137 tasks in 17 companies evaluated were related to manufacturing and painting. The process categories (PROCs) related to ECETOC TRA were selected for manufacturing (PROC 2, 3, 4, 5, 8a, 8b, 9, 13, 14 or 15) and painting (PROC 7 or 10). The results showed that most of the estimated values of manufacturing work were above the measured values, and just 3 of 52 tasks were below the measured values. On the other hand, the estimated values of painting work below the measured values were observed in 27 of 85 tasks. In particular, it was observed that the estimated values were below the measured values in 22 of 38 tasks for roller painting work (PROC 10). The 24 tasks for which 20 ppm was exceeded were related to painting work, and 4 of 10 tasks for PROC 7 and 13 of 14 tasks for PROC 10 were below the estimated values. All of the work for which the estimated values were below the measured values consisted of the hull block painting in ship building work. Though the painting work performed at indoor workplaces in Japan was subject to regulations for ethylbenzene in 2013 and reduction measures are being developed, independent risk assessment and management by workers is required continuously at workplaces engaged in the production of ethylbenzene. ECETOC TRA can be adequately utilized as a Tier 1 model for screening assessment to perform independent risk assessment at Japanese workplaces engaged in the production of ethylbenzene.

A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping)

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) ‘Nano Task Force’ proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) that consists of 3 tiers to assign nanomaterials to 4 main groups, to perform sub-grouping within the main groups and to determine and refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial’s life cycle and biological pathways, i.e. intrinsic material and system-dependent properties, biopersistence, uptake and biodistribution, cellular and apical toxic effects. Use (including manufacture), release and route of exposure are applied as ‘qualifiers’ within the DF4nanoGrouping to determine if, e.g. nanomaterials cannot be released from a product matrix, which may justify the waiving of testing. The four main groups encompass (1) soluble nanomaterials, (2) biopersistent high aspect ratio nanomaterials, (3) passive nanomaterials, and (4) active nanomaterials. The DF4nanoGrouping aims to group nanomaterials by their specific mode-of-action that results in an apical toxic effect. This is eventually directed by a nanomaterial’s intrinsic properties. However, since the exact correlation of intrinsic material properties and apical toxic effect is not yet established, the DF4nanoGrouping uses the ‘functionality’ of nanomaterials for grouping rather than relying on intrinsic material properties alone. Such functionalities include system-dependent material properties (such as dissolution rate in biologically relevant media), bio-physical interactions, in vitro effects and release and exposure. The DF4nanoGrouping is a hazard and risk assessment tool that applies modern toxicology and contributes to the sustainable development of nanotechnological products. It ensures that no studies are performed that do not provide crucial data and therefore saves animals and resources.

Quantification of contributions of molecular fragments for eye irritation of organic chemicals using QSAR study

The eye irritation potential of chemicals has largely been evaluated using the Draize rabbit-eye test for a very long time. The Draize eye-irritation data on 38 compounds established by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) has been used in the present quantitative structure–activity relationship (QSAR) analysis in order to predict molar-adjusted eye scores (MES) and determine possible structural requisites and attributes that are primarily responsible for the eye irritation caused by the studied solutes. The developed model was rigorously validated internally as well as externally by applying principles of the Organization for Economic Cooperation and Development (OECD). The test for applicability domain was also carried out in order to check the reliability of the predictions. Important fragments contributing to higher MES values of the solutes were identified through critical analysis and interpretation of the developed model. Considering all the identified structural attributes, one can choose or design safe solutes with low eye irritant properties. The presented approach suggests a model for use in the context of virtual screening of relevant solute libraries. The developed QSAR model can be used to predict existing as well as future chemicals falling within the applicability domain of the model in order to reduce the use of animals.

Risk assessment of ‘endocrine substances’: Guidance on identifying endocrine disruptors

The European regulation on plant protection products (1107/2009) and other related legislation only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or wildlife species. This legislation would appear to make the assumption that endocrine active chemicals should be managed differently from other chemicals presumably due to an assumed lack of a threshold for adverse effects. In the absence of agreed scientific criteria and guidance on how to identify and evaluate endocrine activity and disruption within these pieces of legislation, a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. The first ECETOC technical report and associated workshop, held in 2009, presented a science-based concept on how to identify endocrine activity and disrupting properties of chemicals for both human health and the environment. Specific scientific criteria for the determination of endocrine activity and disrupting properties that integrate information from both regulatory toxicity studies and mechanistic/screening studies were proposed. These criteria combined the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. A key element in the data evaluation is the consideration of all available information in a weight-of-evidence approach.Both sets of data (evidence of the adverse effect in apical studies and conclusive mode of action knowledge) are essential in order to correctly identify endocrine disruption according to accepted definitions. As the legislation seeks to regulate chemicals on a mode of action rather than the more traditional approach of adverse endpoints, then conclusive evidence of the mode of action of concern should be presented. From a human safety perspective and in the absence of any compelling data that endocrine active chemicals exert their adverse effects through anything other than a threshold mechanism there is no scientific justification for not using a margin of exposure approach to risk assessment in order to best protect human health.

European solvent industry group generic exposure scenario risk and exposure tool

The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates.

Risk assessment of endocrine active chemicals: Identifying chemicals of regulatory concern

The European regulation on plant protection products (1107/2009) (EC, 2009a), the revisions to the biocides Directive (COM[2009]267) (EC, 2009b), and the regulation concerning chemicals (Regulation (EC) No. 1907/2006 ‘REACH’) (EC.2006) only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or wildlife species. In the absence of agreed guidance on how to identify and evaluate endocrine activity and disruption within these pieces of legislation a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. The resulting ECETOC technical report (ECETOC, 2009a) and the associated workshop (ECETOC, 2009b) presented a science-based concept on how to identify endocrine activity and disrupting properties of chemicals for both human health and the environment. The synthesis of the technical report and the workshop report was published by the ECETOC task force (Bars et al., 2011a,b). Specific scientific criteria for the determination of endocrine activity and disrupting properties that integrate information from both regulatory (eco)toxicity studies and mechanistic/screening studies were proposed. These criteria combined the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. A key element in the data evaluation is the consideration of all available information in a weight-of-evidence approach. However, to be able to discriminate chemicals with endocrine properties of low concern from those of higher concern (for regulatory purposes), the task force recognised that the concept needed further refinement. Following a discussion of the key factors at a second workshop of invited regulatory, academic and industry scientists (ECETOC, 2011), the task force developed further guidance, which is presented in this paper. For human health assessments these factors include the relevance to humans of the endocrine mechanism of toxicity, the specificity of the endocrine effects with respect to other potential toxic effects, the potency of the chemical to induce endocrine toxicity and consideration of exposure levels. For ecotoxicological assessments the key considerations include specificity and potency, but also extend to the consideration of population relevance and negligible exposure. It is intended that these complement and reinforce the approach originally described and previously published in this journal (Bars et al., 2011a,b).

Regulatory aspects on the use of fish embryos in environmental toxicology

Animal alternative tests are gaining serious consideration in an array of environmental sciences, particularly as they relate to sound management of chemicals and wastewater discharges. The ILSI Health and Environmental Sciences Institute and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) held an International Workshop on the Application of the Fish Embryo Test in March, 2008. This relatively young discipline is following advances in animal alternatives for human safety sciences, and it is advisable to develop a broad comparison of how animal alternative tests involving fish are viewed in a regulatory context over a wide array of authorities or advising bodies. These include OECD, Western Europe, North America, and Japan. This paper summarizes representative practices from these regions. Presently, the global regulatory environment has varying stances regarding the protection of fish for use as an experimental animal. Such differences have a long-term potential to lead to a lack of harmony in approaches to fish toxicity testing, especially for chemicals in commerce across multiple geographic regions. Implementation of alternative methods and approaches will be most successful if accepted globally, including methods of fish toxicity testing. An important area for harmonization would be in the interpretation of protected and nonprotected life stages of fish. Use of fish embryos represent a promising alternative and allow bridging to more technically challenging alternatives with longer prospective timelines, including cell-based assays, ecotoxicogenomics, and QSARs.

A weight-of-evidence (woe) approach for determining mode of action: an ecetoc case study

Integrated Environmental Assessment and ManagementVolume 4, Issue 3 p. 374-375 Department A weight-of-evidence (woe) approach for determining mode of action: an ecetoc case study† Paul Thomas, Paul Thomas paul.thomas@akzonobel.com AkzoNobel, Arnhem, The NetherlandsSearch for more papers by this authorMartin Holt, Martin Holt ECETOC, Brussels, BelgiumSearch for more papers by this authorPhilippe Lemaire, Philippe Lemaire Arkema, Paris, FranceSearch for more papers by this authorIan Malcomber, Ian Malcomber Unilever, Sharnbrook, United KingdomSearch for more papers by this authorDan Salvito, Dan Salvito RIFM, Hackensack, NJ, USASearch for more papers by this authorRoy Thompson, Roy Thompson AstraZeneca, Brixham, United KingdomSearch for more papers by this author Paul Thomas, Paul Thomas paul.thomas@akzonobel.com AkzoNobel, Arnhem, The NetherlandsSearch for more papers by this authorMartin Holt, Martin Holt ECETOC, Brussels, BelgiumSearch for more papers by this authorPhilippe Lemaire, Philippe Lemaire Arkema, Paris, FranceSearch for more papers by this authorIan Malcomber, Ian Malcomber Unilever, Sharnbrook, United KingdomSearch for more papers by this authorDan Salvito, Dan Salvito RIFM, Hackensack, NJ, USASearch for more papers by this authorRoy Thompson, Roy Thompson AstraZeneca, Brixham, United KingdomSearch for more papers by this author First published: 05 November 2009 https://doi.org/10.1002/ieam.5630040316Citations: 2 † This work was carried out by a task force from the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Brussels. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume4, Issue3July 2008Pages 374-375 RelatedInformation

Chemical pollution, respiratory allergy and asthma: a perspective

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop in June 2005 to address the speculation that exposure to specific chemicals, and/or chemical pollutants in general, may play an important role in the increased prevalence of allergy and asthma in 'westernized' societies. This paper summarises one perspective arrived at during this workshop. It was acknowledged that certain chemicals and certain types of pollution might trigger or exacerbate asthmatic reactions in sensitised subjects. However, overall levels of pollution appear not to have had a major impact upon the prevalence of atopic allergy. Epidemiological studies suggest that pollution may in some circumstances protect from acquisition of sensitisation. Increasing exposure to household chemicals may enhance pre-existing allergies, but evidence for their causation of allergy is lacking. Other risk factors considered included societal dietary changes and exposure to endotoxins. Future research needs were identified which included epidemiological studies employing exposure and biomonitoring data, studies on domestic exposure to chemicals and their association with the incidence of allergy and asthma, and prospective birth cohort studies employing well-defined aspects of lifestyle, diet, chemical and endotoxin exposure as factors that may drive susceptibility to allergy and asthma.

Testing Strategies to Establish the Safety of Nanomaterials: Conclusions of an ECETOC Workshop

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop in Barcelona, Spain, in November 2005 to develop testing strategies to establish the safety of nanomaterials. It brought together about 70 scientific and clinical experts from industry, academia, government agencies, research institutes, and nongovernmental organizations. The primary questions to be addressed were the following: What can we do today, and what do we need tomorrow? The three major themes of the workshop were: (1) the need for enhanced efforts in nanomaterial characterization; (2) methodologies for assessments of airborne and internal exposures to nanomaterials; and (3) evaluation of the hazard potential—primarily focusing on pulmonary or dermal routes of exposures. Some of the summary conclusions of the workshop included the following: For the development of nanoparticle characterization, the working definition of nanoparticles was defined as < 100 nm in one dimension or < 1000 nm to include aggregates and agglomerates. Moreover, it was concluded that although many physical factors can influence toxicity, including nanoparticle composition, it is dissolution, surface area and characteristics, size, size distribution, and shape that largely determine the functional, toxicological and environmental impact of nanomaterials. In addition, most of the information on potential systemic effects has thus far been derived from combustion-generated particles. With respect to the assessment of external exposures and metrics appropriate for nanoparticles, the general view of the meeting was that currently it is not possible or desirable to select one form of dose metric (i.e., mass, surface area, or particle number) as the most appropriate measure source. However, it was clear that the surface area metric was likely to be of interest and requires further development. In addition, there is a clear and immediate need to develop instruments which are smaller, more portable, and less expensive than the currently available state of the art instrumentation. With regard to a general testing approach for human health hazard evaluation of nanoparticles, a first step to determine potency may include a prioritization-related in vitro screening strategy to assess the possible reactivity, biomarkers of inflammation and cellular uptake of nanoparticles; however this process should be validated using in vivo techniques. A Tier 1 in vivo testing strategy could include a short-term inhalation or intratracheal instillation of nanoparticles as the route of exposure in the lungs of rats or mice. The endpoints that should be assessed include indices of lung inflammation, cytotoxicity, and cell proliferation, as well as histopathology of the respiratory tract and the major extrapulmonary organs. For Tier 2 in vivo testing for hazard identification, a longer term inhalation study is recommended, and this would include more substantive mechanistic endpoints such as determination of particle deposition, translocation, and disposition within the body. Additional studies could be designed with specific animal models to mimic sensitive populations. With regard to dermal exposures, currently there is little evidence that nanoparticles at a size exceeding 100 nm penetrate through the skin barrier into the living tissue (i.e., dermal compartment). The penetration of nanoparticles at a size less than 100 nm should be a topic of further investigation. Moreover, considering the impacts of dermal exposures and corresponding hazard potential of nanoparticles, it must be taken into consideration that the dermal uptake of nanoparticles will be an order of magnitude smaller than the uptake via the inhalation or oral routes of exposure. For the evaluation of the health risk of nanoparticles, it has to be determined whether they are harmful to living cells and whether, under real conditions, they penetrate through the skin barrier into the living tissue. For the evaluation of the penetration processes, in principle, three methods are available. Using the method of differential stripping, the penetration kinetics of nanoparticles in the stratum corneum and the hair follicles can be evaluated. This analysis can be carried out in vivo. Diffusion cell experiments are an efficient method for in vitro penetration studies. Also, laser scanning microscopy is well suited to test penetration kinetics, although requiring fluorescent-labeled nanoparticles. Emerging topics such as (1) environmental safety testing, (2) applications of nanoparticles for medical purposes, and (3) pathways of inhaled nanoparticles to the central nervous system were also briefly addressed during this workshop. However, it has become clear that these topics should be the subjects of separate workshops and they are not further addressed in this report.

Science and Policy in Risk Assessments of Chlorinated Ethenes

In this article the use of data obtained from standardized experimental methods, for example, as specified in OECD guidelines for the testing of chemicals, epidemiology data, and mechanism data obtained from nonstandardized experimental methods in carcinogen risk assessment is scrutinized using the most recent risk assessments made by International Agency for Research on Cancer (IARC), the MAK(MAK)-Kommission, World Health Organization (WHO), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), and American Conference of Governmental Industrial Hygienists (ACGIH) for the four chlorinated ethenes as examples. The analysis shows that there was little controversy among these risk assessors about the interpretation of standardized animal data. On the other hand, they differ in their interpretation of epidemiology data, in particular in their assessment of statistical significance including the use of meta-analyses, and in quality evaluation of studies initiated on the basis of a priori concerns for carcinogenicity. The selection of mechanism data for species extrapolation is diverse among these risk assessors. Furthermore, in some cases they refrain from transparently motivating significant claims about mechanisms of toxicity by avoiding to give (explicit) references to the sources of information forming the basis of these claims or conclusions. This practice is not according to the scientific standards that should be required of a risk assessment document, and it makes it difficult to follow the argumentation and consequently to scrutinize the scientific accuracy of the conclusions drawn. In this article it is concluded that in some of these risk assessment documents, the use of mechanism data is not according to the scientific standards that should be required. It is furthermore concluded that if the use of mechanism data in these documents are representative of risk assessments in general, then there is an urgent need for further development and implementation of quality criteria for the use of mechanism data in species extrapolation.

ECVAM, ECETOC and the EU chemicals policy.

ECVAM's initiatives in validation have received significant support from the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), especially through the provision of reference chemical data banks, which contain peer-reviewed, high-quality in vivo data on commercially available chemical substances. Chemicals have been selected from these ECETOC data banks for validation studies on alternative methods for skin corrosion and irritation and for eye irritation and, in addition, an ECETOC task force peer-reviewed the selection and classification, on the basis of in vivo data, of chemicals used in the validation of three alternative methods for developmental toxicity. More recently, ECVAM and ECETOC have been pursuing parallel initiatives on the proposed new EU chemicals policy, with the common goals of ensuring that industry and European Commission resources are used to investigate only those chemicals that pose a significant risk to human health and the environment, and that the Policy requires that any testing which is required follows the Three Rs principles of reduction, refinement and replacement.