risk assessment

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An Integrated Decision-tree Testing Strategy for Eye Irritation with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This paper presents some results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for eye irritation testing. The manuscript reviews numerous in vitro tests and their possible collation into test batteries, in silico models and a refined in vivo method (the low volume eye test), before combining the use of all these methods into an integrated testing strategy. The aim of this strategy is a reduction in the number of animal tests which would need to be performed in the process of fulfilling the REACH system criteria; this would also lead to a lowering of the number of animals required in compliance with the REACH system requirements.
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An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which
could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivostudies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.
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Assuring Consumer Safety Without Animal Testing: A Feasibility Case Study for Skin Sensitisation

Gavin Maxwell, Maja Aleksic, Aynur Aptula, Paul Carmichael, Julia Fentem, Nicola Gilmour, Cameron MacKay, Camilla Pease, Ruth Pendlington, Fiona Reynolds, Daniel Scott, Guy Warner and Carl Westmoreland

Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009. This animal testing ban is also linked to an EU marketing ban on products containing any ingredients that have been subsequently tested in animals, from March 2009 or March 2013, depending on the toxicological endpoint of concern. Consequently, the testing of cosmetic ingredients in animals for their potential to induce skin sensitisation will be subject to an EU marketing ban, from March 2013 onwards. Our conceptual framework and strategy to deliver a non-animal approach to consumer safety risk assessment can be summarised as an evaluation of new technologies (e.g. ‘omics’, informatics), leading to the development of new non-animal (in silico and in vitro) predictive models for the generation and interpretation of new forms of hazard characterisation data, followed by the development of new risk assessment approaches to integrate these new forms of data and information in the context of human exposure. Following the principles of the conceptual framework, we have been investigating existing and developing new technologies, models and approaches, in order to explore the feasibility of delivering consumer safety risk assessment decisions in the absence of new animal data. We present here our progress in implementing this conceptual framework, with the skin sensitisation endpoint used as a case study.
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Computational Toxicology Approaches at the US Food and Drug Administrationa

Chihae Yang, Luis G. Valerio, Jr and Kirk B. Arvidson

For over a decade, the United States Food and Drug Administration (US FDA) has been engaged in the applied research, development, and evaluation of computational toxicology methods used to support the safety evaluation of a diverse set of regulated products. The basis for evaluating computational toxicology methods is multi-factorial, including the potential for increased efficiency, reduction in the numbers of animals used, lower costs, and the need to explore emerging technologies that support the goals of the US FDA’s Critical Path Initiative (e.g. to make decision support information available early in the drug review process). The US FDA’s efforts have been facilitated by agency-approved data-sharing agreements between government and commercial software developers. This commentary review describes former and current scientific initiatives at the agency, in the area of computational toxicology methods. In particular, toxicology-based QSAR models, ToxML databases and knowledgebases will be addressed. Notably, many of the computational toxicology tools available are commercial products — however, several are emerging as non-commercial products, which are freely-available to the public, and which will facilitate the understanding of how these programs work and avoid the “black box” paradigm. Through productive collaborations, the US FDA Center for Drug Evaluation and Research, and the Center for Food Safety and Applied Nutrition, have worked together to evaluate, develop and apply these methods to chemical toxicity endpoints of regulatory interest.
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Non-Animal Approaches for Consumer Safety Risk Assessments: Unilever’s Scientific Research Programme

Paul Carmichael, Michael Davies, Matt Dent, Julia Fentem, Samantha Fletcher, Nicola Gilmour, Cameron MacKay, Gavin Maxwell, Leona Merolla, Camilla Pease, Fiona Reynolds and Carl Westmoreland

Non-animal based approaches to risk assessment are now routinely used for assuring consumer safety for some endpoints (such as skin irritation) following considerable investment in developing and applying new methods over the past 20 years. Unilever’s research programme into non-animal approaches for safety assessment is currently focused on the application of new technologies to risk assessments in the areas of skin allergy, cancer and general toxicity (including inhalation toxicity). In all of these areas, a long-term investment is essential to increase the scientific understanding of the underlying biological and chemical processes that we believe will ultimately form a sound basis for novel risk assessment approaches. Our research programme in these priority areas consists of in-house research as well as Unilever-sponsored academic research, involvement with EU-funded projects (e.g. Sens-it-iv, carcino - GENOMICS), participation in cross-industry collaborative research (e.g. COLIPA, EPAA) and ongoing involvement with other scientific initiatives on non-animal approaches to risk assessment (e.g. UK NC3Rs, US ‘Human Toxicology Project’ consortium).
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Read-across Estimates of Aquatic Toxicity for Selected Fragrances

Emiel Rorije, Tom Aldenberg and Willie Peijnenburg

Read-across as a non-animal testing alternative for the generation of risk assessment data can be useful in those cases where quantitative structure–activity relationship (QSAR) models are not available, or are less well developed. This paper provides read-across case studies for the estimation of the aquatic toxicity of five different fragrance substances, and proposes a pragmatic approach for expressing uncertainty in read-across estimates. The aquatic toxicity estimates and their uncertainties are subsequently used to estimate fresh water compartment Predicted No-Effect Concentrations (PNECs), with their two-sided 90% Confidence Intervals (CIs). These PNECs can be used directly in risk assessment. The results of the musk fragrance read-across cases (musk xylene, musk ketone and galaxolide) are compared to experimentally derived PNEC values. The read-across estimates made by using similarity in a hypothesised mechanism of action for (acute) toxicity of musk xylene gave a PNEC of 2μg/L (90% CI 0.0004–13.5μg/L) with the Species Sensitivity Distribution (SSD) approach. This estimated value is 1.8 times above the experimentally-based fresh water PNEC of 1.1μg/L. For musk ketone and galaxolide, the PNEC values based on the SSD approach and employing a toxicity mechanism-based read-across were 2.0 times greater, and 4.9 times below the experimentally derived PNEC values, respectively.
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Prioritisation of Polybrominated Diphenyl Ethers (PBDEs) by Using the QSPR-THESAURUS Web Tool

Igor V. Tetko, Pantelis Sopasakis, Prakash Kunwar, Stefan Brandmaier, Sergii Novoratskyi, Larysa Charochkina, Volodymyr Prokopenko and Willie J.G.M. Peijnenburg

The prioritisation of chemical compounds is important for the identification of those chemicals that represent the highest threat to the environment. As part of the CADASTER project (http://www.cadaster.eu), we developed an online web tool that allows the calculation of the environmental risk of chemical compounds from a web interface. The environmental fate of compounds in the aquatic compartment is assessed by using the SimpleBox model, while adverse effects on the aquatic compartment are assessed by the Species Sensitivity Distribution approach. The main purpose of this web tool is to exemplify the use of quantitative structure–activity relationships (QSARs) to support risk assessment.
A case study of QSAR integrated risk assessment of 209 polybrominated diphenyl ethers (PBDEs) demonstrates the treatment and influence of uncertainty in the predicted physicochemical and toxicity parameters in probabilistic risk assessment.
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Is Phenylbutazone a Genotoxic Carcinogen? A Weight-of-Evidence Assessment

Robert D. Combes

Published in silico, in vitro, in vivo laboratory animal and human data, together with information on biotransformation and data from structure–activity analyses with two decision-tree systems (ACToR and Toxtree), have been used in a weight-of-evidence (WoE) assessment to determine whether phenylbutazone (PBZ) is a genotoxic or a non-genotoxic carcinogen. This was undertaken to facilitate the risk assessment of human exposure to this veterinary drug via the consumption of horsemeat from treated animals. Despite problems with data interpretation at all tiers of the database, it was concluded that PBZ behaves like a genotoxic carcinogen with a threshold dose. This conclusion is based mainly on the results of a definitive rodent bioassay, and on the following observations: a) that PBZ has weak in vitro activity only at high concentrations in some genotoxicity assays, accompanied by high levels of cytotoxicity; b) that it (and a major metabolite) is able to cause sister chromatid exchanges in vivo in rodents; and c) that it can induce cytogenetic effects in vivo in humans. It also takes into account the known and predicted activities of the parent drug, some of its metabolites and two structural analogues, and, importantly, several of the drug’s other biochemical effects that are unrelated to toxicity. However, this conclusion is not fully supported by all the evidence, and much of the information is based on old papers. Therefore, more studies are required to establish whether the concentration thresholds seen in vitro would translate to dose thresholds for carcinogenicity, such that a safe dose-level could be defined for the purposes of assessing risk. It was disappointing that a WoE approach to evaluating all of the available hazard data, as is increasingly being advocated to improve the hazard identification paradigm, was unable to provide definitive answers in this case, particularly in view of the large numbers of animals that had been used to provide much of the information.

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