A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

Makris, Susan L.; Raffaele, Kathleen C.; Allen, Sandra L.; Bowers, Wayne J.; Hass, Ulla; Alleva, Enrico; Calamandrei, Gemma; Sheets, Larry P.; Amcoff, Patric; Delrue, Nathalie; Crofton, Kevin M.

doi:10.1289/ehp.11447

Cited by 158 publications

(133 citation statements)

References 68 publications

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“…However, it should be noted that only a few studies were designed according to the OECD 426 guideline (OECD, 2007) for developmental neurotoxicity studies. The recommended test guidelines, considering, amongst others, time of exposure between implantation and weanling, way of administration and control for litter effects, have been demonstrated to provide the most reliable and reproducible data for assessing potential developmental neurotoxicity (Makris et al, 2009). In addition, appropriate statistical design and analyses appear essential prerequisites to formulate relevant hypotheses and draw conclusions on toxicity (Holson et al, 2008).…”

Section: Bde-99mentioning

confidence: 99%

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

195

147

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EFSA was asked by the European Commission to deliver a scientific opinion on polybrominated diphenyl ethers (PBDEs) in food. PBDEs are additive flame retardants which are applied in plastics, textiles, electronic castings and circuitry. PBDEs are ubiquitously present in the environment and likewise in biota and in food and feed. Data from the analysis of 19 PBDE congeners in 3,971 food samples were provided to EFSA by 11 European countries. Eight congeners were considered by the Panel on Contaminants in the Food Chain (CONTAM Panel) to be of primary interest: . The highest dietary exposure is to . Toxicity studies were carried out with technical PBDE mixtures or individual congeners. Main targets were the liver, thyroid hormone homeostasis and the reproductive and nervous system. PBDEs cause DNA damage through the induction of reactive oxygen species. The Panel identified effects on neurodevelopment as the critical endpoint, and derived benchmark doses (BMDs) and their corresponding lower 95 % confidence limit for a benchmark response of 10 %, BMDL 10 s, for a number of PBDE congeners: BDE-47, 309 μg/kg b.w.; BDE-99, 12 μg/kg b.w.; BDE-153, 83 μg/kg b.w.; BDE-209, 1,700 μg/kg b.w. Due to the limitations and uncertainties in the current database, the Panel concluded that it was inappropriate to use these BMDLs to establish health based guidance values, and instead used a margin of exposure (MOE) approach for the health risk assessment. Since elimination characteristics of PBDE congeners in animals and humans differ considerably, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that for BDE-47, -153 and -209 current dietary exposure in the EU does not raise a health concern. For BDE-99 there is a potential health concern with respect to current dietary exposure. 4 The term "intra-species" has been replaced by "inter-species" in the Summary and in Chapter 9.1. The chemical stability of the PBDE congeners varies with the individual structure. In general PBDE congeners with up to three bromine substituents and those with nine or ten bromine substituents are more sensitive to abiotic transformations. PBDE congeners with four to eight bromine substituents show the highest stability. PBDE congeners are particularly susceptible to photolysis, reductive debromination and radical reactions whereas they are less susceptible to oxidation and hydrolysis. In general, PBDE congeners are persistent and bioaccumulative with the exception of BDE-209 bioaccumulative properties of which seem to be species dependent. BDE-209 undergoes debromination reactions both in the abiotic environment and in biota, leading to formation of PBDE congeners containing seven to nine bromine atoms. © European Food SafetyBased on the composition of the technical PBDE mixtures, occurrence in the environment and in food, the Panel on Contaminants in the Food Chain (CONTAM Panel) considered the following eight PBDE congeners to be of primary interest: which are relevant for dietary PBDE exposur...

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Section: Bde-99mentioning

confidence: 99%

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

195

147

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“…The paradigm for regulatory testing of developmental neurotoxicology (DNT) has been the subject of much scientific debate and has been reviewed by expert groups (Raffaele et al, 2010, Makris et al, 2009). On-going discussions concern matters such as whether or not the OECD Test Guideline (TG) 426 for DNT testing (OECD, 2007) is sensitive and/or reliable enough to serve as a basis for the risk assessment of DNT in humans, and if corresponding guidance documents (OECD, 2008, OECD, 2004 are detailed enough.…”

Section: Discussion and Recommendationsmentioning

confidence: 99%

“…The OECD TG 426 (OECD, 2007) for DNT testing was developed mainly based on the already existing US EPA guideline for DNT testing (US EPA, 1998a). The US EPA DNT guideline was first issued in 1991 and was founded on scientific literature within the field of DNT, which first started to appear in the 1960's (Makris et al, 2009). It has since been extensively revised on a number of occasions (Fitzpatrick et al, 2008, Makris et al, 2009) and was for a long time the only DNT guideline available to testing laboratories.…”

Section: Introductionmentioning

confidence: 99%

“…The US EPA DNT guideline was first issued in 1991 and was founded on scientific literature within the field of DNT, which first started to appear in the 1960's (Makris et al, 2009). It has since been extensively revised on a number of occasions (Fitzpatrick et al, 2008, Makris et al, 2009) and was for a long time the only DNT guideline available to testing laboratories. Work to develop a DNT guideline to further accommodate the regulatory needs of OECD countries was initiated in 1995 by an OECD Working Group on Reproduction and Developmental Toxicity (OECD, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

Fritsche

Alm

Baumann

et al. 2015

EFSA Supporting Publications

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The goal of this systematic review performed under a contract with EFSA was the evaluation of information on assessment methods in the field of developmental neurotoxicity (DNT). Therefore, a systematic and comprehensive literature search and collection of scientific literature and all other relevant grey literature and website information (in English) from past 20 years until mid of April 2014 on the state of the art of in vivo DNT testing methods including novel and alternative non-mammalian models, in vitro test methods, in silico methods, read across and combination of testing methods in test batteries was performed. This systematic review identified a variety of methods covering early and later stages of neurodevelopment that have the ability to predict DNT of chemicals. Few in vivo models alternative to OECD TG 426 were identified. In general, the available published in vivo data is scattered and heterogeneous, making comparisons across exposure paradigms and compounds very difficult. Thus, to make more useful evaluations, publications with more consistent experimental designs are needed, and more focused in vivo-in vitro comparisons are needed to establish useful effect biomarkers and testing models. From the alternative methods, a testing strategy covering early and later neurodevelopmental stages (from stem cell to zebrafish larvae motor behaviour) can be assembled. For gaining regulatory acceptance, definition of biological application domains of alternative methods by performing e.g. in vitro -in vivo validation is needed. Moreover, protocols for cell-based and zebrafish assays need international standardization. With such standardized protocols, the test battery needs to be tested for its sensitivity and specificity by testing concentration-responses of known DNT positive and negative compounds across the different assays. Such data might then be used either for regulatory decision-making or compound prioritization in favour of a reduction of rodent guideline in vivo testing.

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“…Currently, as of January 2017, the CAS Registry (Chemical Abstracts Service), the world's largest database of chemical substances, lists more than 126 million unique organic and inorganic chemicals. Of these chemicals, only very few representatives have been evaluated for DNT in recent years [7,8]. The reason for this is possibly because existing guidelines for toxicity evaluation mostly involve animal experiments that are expensive, low in throughput, of poor predictive quality, often not reproducible and, because there is no legal obligation for alternative DNT standardized testing [9][10][11][12].…”

Section: Showcase: In Vitro-based Dnt Testingmentioning

confidence: 99%

On the Generation of Efficient Methodologies for Cell-Based Toxicity Screening by Comparative Protocol Analysis and Optimization

Mofrad¹,

Kuenzel²,

Friedrich³

et al. 2017

Single Cell Biol

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In cell biology in general and in high-throughput cell-based screening approaches in particular -e.g. for in vitrobased toxicity assessment -various methodologies or protocols are reported in the literature. In the case that a cell-based screening assay, for toxicity evaluation or for assessing another biological question, is to be established for the first time in a research lab, the researcher has to select a number of different protocols from the literature and to create an optimized protocol for the intended use. This is typically required, because optimized protocols, generated following comparative protocol analysis and optimization, are mostly rarely available. In another study, which we refer to as a showcase, we conducted a comparative analysis of three different protocols for neuronal NT2 cell differentiation, available in the literature. From this comparison, we generated an improved and optimized method, allowing for neuronal NT2 differentiation in monolayer cultures with high yield of NT2-N cells, allowing for systematic in vitro-based primary screening for developmental toxicants and neuro-toxicants at different stages of maturation. In this commentary, to prevent the same experiments from being repeatedly conducted in different labs around the world and at different times over and over again, we suggest generation of advanced and efficient methods by comparative protocol analysis and optimization, for application in a variety of research fields, related to cell and single cell biology. Keywords:In vitro DNT testing; NT2 human pluripotent stem cells; Protocol optimization; High-throughput screening Showcase: In vitro-Based DNT TestingEveryday products such as cosmetics, pharmaceuticals, textiles, detergents, plastic or pesticides, contain organic and inorganic chemical substances, that are potentially harmful to humans and the ecosystems. The number and volume of worldwide traded and registered chemicals has dramatically increased in recent years. Simultaneously, the incidence of neurological diseases, including mental retardation and autism, as well as developmental and learning disorders or hyperactivity disorder and attention deficit, has also increased [1][2][3]. The developing central nervous system (CNS) is particularly susceptible to damage by chemicals and therefore, assessment of the chemicals surrounding us on a daily basis for adverse effects on the maturing CNS -also referred to as developmental neurotoxicity (DNT) -is critical for human health and wealth [4][5][6]. Currently, as of January 2017, the CAS Registry (Chemical Abstracts Service), the world's largest database of chemical substances, lists more than 126 million unique organic and inorganic chemicals. Of these chemicals, only very few representatives have been evaluated for DNT in recent years [7,8]. The reason for this is possibly because existing guidelines for toxicity evaluation mostly involve animal experiments that are expensive, low in throughput, of poor predictive quality, often not reproducible and, because t...

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A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

Cited by 158 publications

References 68 publications

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

On the Generation of Efficient Methodologies for Cell-Based Toxicity Screening by Comparative Protocol Analysis and Optimization

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