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1.
Regul Toxicol Pharmacol ; 76: 231-3, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26873775

RESUMEN

Fish toxicity testing has been conducted since the 1860's in order to help define safe levels of chemical contaminants in lakes, rivers and coastal waters. The historical emphasis on acute lethality testing of chemicals has more recently focussed on long term sublethal effects of chemicals on fish and their prey species. Fish toxicity testing is now embedded in much environment legislation on chemical safety while it is recognized that animal use should be Replaced, Reduced and Refined (the 3Rs) where possible. The OECD Fish Toxicity Testing Framework provides a useful structure with which to address the needs of environmental safety assessment whilst implementing the 3Rs. This commentary aims to promote the implementation of the recommendations of the OECD Fish Toxicity Testing Framework.


Asunto(s)
Alternativas a las Pruebas en Animales , Monitoreo del Ambiente/métodos , Peces , Organización para la Cooperación y el Desarrollo Económico , Pruebas de Toxicidad , Contaminantes Químicos del Agua/toxicidad , Alternativas a las Pruebas en Animales/normas , Animales , Monitoreo del Ambiente/normas , Humanos , Organización para la Cooperación y el Desarrollo Económico/normas , Formulación de Políticas , Medición de Riesgo , Factores de Tiempo , Pruebas de Toxicidad/normas
2.
Adv Exp Med Biol ; 856: 9-32, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27671718

RESUMEN

Ten years elapsed since the OECD published the Guidance document on the validation and international regulatory acceptance of test methods for hazard assessment. Much experience has been gained since then in validation centres, in countries and at the OECD on a variety of test methods that were subjected to validation studies. This chapter reviews validation principles and highlights common features that appear to be important for further regulatory acceptance across studies. Existing OECD-agreed validation principles will most likely generally remain relevant and applicable to address challenges associated with the validation of future test methods. Some adaptations may be needed to take into account the level of technique introduced in test systems, but demonstration of relevance and reliability will continue to play a central role as pre-requisite for the regulatory acceptance. Demonstration of relevance will become more challenging for test methods that form part of a set of predictive tools and methods, and that do not stand alone. OECD is keen on ensuring that while these concepts evolve, countries can continue to rely on valid methods and harmonised approaches for an efficient testing and assessment of chemicals.


Asunto(s)
Seguridad Química , Guías como Asunto , Organización para la Cooperación y el Desarrollo Económico , Pruebas de Toxicidad/métodos , Estudios de Validación como Asunto , Ensayos Analíticos de Alto Rendimiento
3.
Altern Lab Anim ; 44(5): 417-429, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27805824

RESUMEN

The Adverse Outcome Pathway (AOP) concept is expected to guide risk assessors in their work to use all existing information on the effects of chemicals on humans and wildlife, and to target the generation of additional information to the regulatory objective. AOPs will therefore be used in the Organisation for Economic Co-operation and Development (OECD) chemical safety programme, as underlying scientific rationales for the development of alternative methods for hazard assessment, such as read-across, in vitro test methods or the development of integrated testing strategies that have the potential to replace animal tests. As a proof-of-concept, the OECD has developed an AOP for skin sensitisation, and as a follow-up has: a) implemented the AOP into the OECD QSAR Toolbox, so that information related to the Key Events (KEs) in the AOP can be used to group chemicals that are expected to act by the same mechanism and hence have the same skin sensitisation potential; b) developed alternative test methods for the KEs, so that ultimately chemicals can be tested for skin sensitisation without the use of animal tests. The development of integrated testing strategies based on the AOP is ongoing. Building on this proof-of-concept, the OECD has launched an AOP development programme with a first batch of AOPs published in 2016. A number of IT tools, which together form an AOP Knowledge Base, are at various stages of development, and support the construction of AOPs and their use in the development of integrated approaches for testing and assessment. Following the publication of the first batch of AOPs, OECD member countries will decide on priorities for their use in supporting the development of tools for regulatory use.


Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/organización & administración , Toma de Decisiones , Sustancias Peligrosas/efectos adversos , Sistemas de Registro de Reacción Adversa a Medicamentos/normas , Animales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Contaminantes Ambientales , Humanos
4.
Regul Toxicol Pharmacol ; 69(3): 496-511, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24874798

RESUMEN

The OECD validation study of the zebrafish embryo acute toxicity test (ZFET) for acute aquatic toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebrafish eggs (20/concentration and control) were exposed for 96h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV<30%) for most chemicals and laboratories. The reproducibility was lower (CV>30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute fish toxicity and fish embryo acute toxicity data, the ZFET is ready to be considered for acute fish toxicity for regulatory purposes.


Asunto(s)
Pruebas de Toxicidad Aguda/métodos , Contaminantes Químicos del Agua/toxicidad , Animales , Laboratorios , Dosificación Letal Mediana , Organización para la Cooperación y el Desarrollo Económico , Reproducibilidad de los Resultados , Pez Cebra
5.
ALTEX ; 41(3): 395-401, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38501278

RESUMEN

The 4th Annual Forum on Endocrine Disrupters organized by the European Commission brought together the authors of this article around the topic: "From bench to validated test guidelines: (pre)val­idation of test methods". Validation activities are meant to demonstrate the relevance and reliability of methods and approaches used in regulatory safety testing. These activities are essential to facil­itate regulatory use, still they are largely underfunded and unattractive to the scientific community. In the last decade, large amounts of funding have been invested in European research towards the development of approaches that can be used in regulatory decision-making, including for the identification of endocrine disrupters. There is a vast pool of candidate test methods for potential reg­ulatory applications, but most of them will not be used due to the absence of consideration of their relevance and reliability outside the method developer's laboratory. This article explains the reasons why such a gap exists between the outputs of research projects and the uptake in a regulatory context. In parallel, there are also increasing expectations from the regulatory science community that validation becomes more efficient with respect to time and resources. This article shares some of the lessons learned and proposes paths forward for validation of new methods that are not intended as one-to-one replacements of animal studies. This includes submitting only mature methods for validation that were developed following good practices and good documentation, proposing a greater emphasis on well-documented transferability studies, and adopting a cost-sharing model among those who benefit from validated methods.


Validation activities for methods intended to be used to assess chemical safety have a cost but also bring substantial benefits when the validated methods are established as OECD Test Guidelines, which results in mutual acceptance of data generated by the methods across OECD member and adhering countries. The article discusses some of the challenges faced when method validation is underfunded and unattractive for researchers. Proposals are made to improve the current situation, gain efficiency, and make validation a shared responsibility.


Asunto(s)
Alternativas a las Pruebas en Animales , Pruebas de Toxicidad , Alternativas a las Pruebas en Animales/métodos , Alternativas a las Pruebas en Animales/economía , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/economía , Animales , Reproducibilidad de los Resultados , Disruptores Endocrinos/toxicidad , Humanos , Estudios de Validación como Asunto
6.
Regul Toxicol Pharmacol ; 67(3): 506-30, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24161465

RESUMEN

Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e. mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance.


Asunto(s)
Alternativas a las Pruebas en Animales , Contaminantes Ambientales/toxicidad , Sustancias Peligrosas/toxicidad , Alternativas a las Pruebas en Animales/legislación & jurisprudencia , Alternativas a las Pruebas en Animales/métodos , Alternativas a las Pruebas en Animales/tendencias , Animales , Contaminantes Ambientales/química , Unión Europea , Regulación Gubernamental , Guías como Asunto , Sustancias Peligrosas/química , Proyectos de Investigación , Medición de Riesgo
7.
Environ Int ; 178: 108082, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37422975

RESUMEN

The predominantly animal-centric approach of chemical safety assessment has increasingly come under pressure. Society is questioning overall performance, sustainability, continued relevance for human health risk assessment and ethics of this system, demanding a change of paradigm. At the same time, the scientific toolbox used for risk assessment is continuously enriched by the development of "New Approach Methodologies" (NAMs). While this term does not define the age or the state of readiness of the innovation, it covers a wide range of methods, including quantitative structure-activity relationship (QSAR) predictions, high-throughput screening (HTS) bioassays, omics applications, cell cultures, organoids, microphysiological systems (MPS), machine learning models and artificial intelligence (AI). In addition to promising faster and more efficient toxicity testing, NAMs have the potential to fundamentally transform today's regulatory work by allowing more human-relevant decision-making in terms of both hazard and exposure assessment. Yet, several obstacles hamper a broader application of NAMs in current regulatory risk assessment. Constraints in addressing repeated-dose toxicity, with particular reference to the chronic toxicity, and hesitance from relevant stakeholders, are major challenges for the implementation of NAMs in a broader context. Moreover, issues regarding predictivity, reproducibility and quantification need to be addressed and regulatory and legislative frameworks need to be adapted to NAMs. The conceptual perspective presented here has its focus on hazard assessment and is grounded on the main findings and conclusions from a symposium and workshop held in Berlin in November 2021. It intends to provide further insights into how NAMs can be gradually integrated into chemical risk assessment aimed at protection of human health, until eventually the current paradigm is replaced by an animal-free "Next Generation Risk Assessment" (NGRA).


Asunto(s)
Inteligencia Artificial , Pruebas de Toxicidad , Humanos , Reproducibilidad de los Resultados , Pruebas de Toxicidad/métodos , Medición de Riesgo/métodos
8.
Mol Cell Endocrinol ; 504: 110675, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31830512

RESUMEN

Identifying the potential endocrine disruptor hazard of environmental chemicals is a regulatory mandate for many countries. However, due to the adaptive nature of the endocrine system, absence of a single method capable of identifying endocrine disruption, and the latency between exposure to endocrine disrupting chemical during sensitive life stages and the manifestation of adverse responses, satisfying the regulatory requirement needed to identify a chemical as an endocrine disruptor is a challenge. There are now a variety of validated regulatory tests that can be used in combination to provide evidence that a chemical affects the oestrogen, androgen, thyroid, and steroidogenic pathways of vertebrates, but most rely (at least to some extent) on animal testing and require considerable cost and time to produce the necessary data. Emerging research methods are able to evaluate other endocrine pathways, incorporate more sensitive endpoints, and combine multiple alternative methods to predict in vivo outcomes. Some research approaches may also bridge gaps that have been identified in current endocrine regulatory testing. For the near term, considering new endpoints in a regulatory context may require adding them to existing test methods in order to establish relationships between the traditional and the innovative. From the outset, endocrine testing has always required integration of multiple methods that provide data on different levels of biological organisation, thus, the area of endocrine disruption is particularly adaptable to adverse outcome pathway (AOP) frameworks and integrated test methods built around AOPs. Herein, we provide a review of the status of endocrine disruptors in the OECD context, examples where innovation from research is needed to improve or bridge gaps in endocrine testing, and suggestions for regulators and researchers to facilitate uptake of innovate methods for endocrine disruptor regulatory testing. The increase in several human complex human disorders that include an endocrine component and the alarming decrease in wildlife biodiversity are commanding directives to include the best, most informative, innovative approaches to accelerate the rate and throughput of chemical evaluation for endocrine disruption.


Asunto(s)
Conservación de los Recursos Naturales/métodos , Evaluación de Medicamentos/normas , Disruptores Endocrinos/farmacología , Guías de Práctica Clínica como Asunto , Sociedades Científicas/normas , Conservación de los Recursos Naturales/legislación & jurisprudencia , Evaluación de Medicamentos/legislación & jurisprudencia , Evaluación de Medicamentos/métodos , Disruptores Endocrinos/aislamiento & purificación , Humanos , Sociedades Científicas/organización & administración
10.
Comp Biochem Physiol C Toxicol Pharmacol ; 155(2): 407-15, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22115822

RESUMEN

Results are presented from a validation (with 5 laboratories) of the Fish Sexual Development Test (FSDT) developed to detect endocrine disrupters (EDs) and included in the OECD (Organisation for Economic Co-operation and Development) working program. The aromatase-inhibiting fungicide prochloraz was tested in zebrafish (Danio rerio) and fathead minnow (Pimephales promelas). The fish were exposed during sexual differentiation and development from 0 to 60 days post hatch (dph). After exposure, the vitellogenin (VTG) concentrations were quantified in head/tail homogenate and the sex ratio was determined (defined as female, male, intersex or undifferentiated). NOEC/LOEC and EC(x) designs were compared to optimize the test approach. Results show that both species are highly sensitive to prochloraz during sexual development. They respond by skewing of the sex ratio towards male phenotype and by a VTG decline in females. The NOEC/LOEC approach is preferred because sex ratio is difficult to analyze with a regression model. The mean NOEC/LOEC for prochloraz on the sex ratio was 43.3/134 µg/L and 101/293 µg/L for zebrafish and fathead minnow, respectively. The mean NOEC/LOEC on the decline in female VTG concentration was 65/110 µg/L and ~30/68 µg/L respectively. In conclusion, zebrafish and fathead minnow are suitable species in the FSDT and their sexual differentiation is equally labile to EDs.


Asunto(s)
Cyprinidae/fisiología , Imidazoles/toxicidad , Maduración Sexual/efectos de los fármacos , Pez Cebra/fisiología , Animales , Cyprinidae/metabolismo , Femenino , Fungicidas Industriales/toxicidad , Masculino , Nivel sin Efectos Adversos Observados , Análisis de Regresión , Razón de Masculinidad , Especificidad de la Especie , Pruebas de Toxicidad/métodos , Vitelogeninas/metabolismo , Pez Cebra/metabolismo
11.
Integr Environ Assess Manag ; 6(1): 2-11, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19558199

RESUMEN

The threshold of toxicological concern (TTC) concept proposes that an exposure threshold value can be derived for chemicals, below which no significant risk to human health or the environment is expected. This concept goes further than setting acceptable exposure levels for individual chemicals, because it attempts to set a de minimis value for chemicals, including those of unknown toxicity, by taking the chemical's structure or mode of action (MOA) into consideration. This study examines the use of the TTC concern concept for endocrine active substances (EAS) with an estrogenic MOA. A case study formed the basis for a workshop of regulatory, industry and academic scientists held to discuss the use of the TTC in aquatic environmental risk assessment. The feasibility and acceptability, general advantages and disadvantages, and the specific issues that need to be considered when applying the TTC concept for EAS in risk assessment were addressed. Issues surrounding the statistical approaches used to derive TTCs were also discussed. This study presents discussion points and consensus findings of the workshop.


Asunto(s)
Sistema Endocrino/efectos de los fármacos , Nivel sin Efectos Adversos Observados , Contaminantes Químicos del Agua/toxicidad , Animales , Salud Ambiental , Monitoreo del Ambiente , Humanos , Receptores de Estrógenos/agonistas
12.
Ecotoxicology ; 16(1): 161-7, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17219091

RESUMEN

The Organisation for Economic Co-operation and Development (OECD) Test Guidelines Programme is involved in the international harmonization and validation of test methods to evaluate effects of chemicals, including potential endocrine active substances. To meet their existing and foreseen regulatory needs in this area, OECD member countries have encouraged the development of test methods and their emergence at the OECD level. Validation activities are underway in countries and industry to ascertain the relevance and reliability of these tests to enable future regulatory acceptance. This includes work on development and (sexual) reproduction of aquatic invertebrates. What is the importance of mechanistic information in regulating chemicals, and how to address the issue of possible endocrine disruption in invertebrates while integrating these tests in a regulatory scheme are the current questions faced by the OECD countries.


Asunto(s)
Disruptores Endocrinos/toxicidad , Guías como Asunto , Agencias Internacionales , Invertebrados/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Cooperación Internacional , Invertebrados/crecimiento & desarrollo , Invertebrados/fisiología , Reproducción/efectos de los fármacos
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