Search

Background: Humans are exposed to combinations of chemicals. In cumulative risk assessment (CRA), regulatory bodies such as the European Food Safety Authority consider dose addition as a default and sufficiently conservative approach. The principle of dose addition was confirmed previously for inducing craniofacial malformations in zebrafish embryos in binary mixtures of chemicals with either similar or dissimilar modes of action (MOAs). Objectives: In this study, we explored a workflow to select and experimentally test multiple compounds as a complex mixture with each of the compounds at or below its no observed adverse effect level (NOAEL), in the same zebrafish embryo model. Methods: Selection of candidate compounds that potentially induce craniofacial malformations was done using in silico methods--structural similarity, molecular docking, and quantitative structure-activity relationships--applied to a database of chemicals relevant for oral exposure in humans via food (EuroMix inventory, n = 1,598). A final subselection was made manually to represent different regulatory fields (e.g., food additives, industrial chemicals, plant protection products), different chemical families, and different MOAs. Results: A final selection of eight compounds was examined in the zebrafish embryo model, and craniofacial malformations were observed in embryos exposed to each of the compounds, thus confirming the developmental toxicity as predicted by the in silico methods. When exposed to a mixture of the eight compounds, each at its NOAEL, substantial craniofacial malformations were observed; according to a dose-response analysis, even embryos exposed to a 7-fold dilution of this mixture still exhibited a slight abnormal phenotype. The cumulative effect of the compounds in the mixture was in accordance with dose addition (added doses of the individual compounds after adjustment for relative potencies), despite different MOAs of the compounds involved. Discussion: This case study of a complex mixture inducing craniofacial malformations in zebrafish embryos shows that dose addition can adequately predicted the cumulative effect of a mixture of multiple substances at low doses, irrespective of the (expected) MOA. The applied workflow may be useful as an approach for CRA in general. https://doi.org/10.1289/EHP9888, Introduction Current human risk assessment of toxicological effects of exposure to chemical compounds is mainly focused on single compounds. (1) However, both humans and other organisms are actually exposed to [...]

Heightened concern over endocrine-disrupting chemicals is driven by the hypothesis that they could reduce reproductive success and affect wildlife populations, but there is little evidence for this expectation. The pharmaceutical [...]

Regulatory toxicology urgently needs applicable alternative test systems that reduce animal use, testing time, and cost. European regulation on cosmetic ingredients has already banned animal experimentation for hazard identification, and public awareness drives toward additional restrictions in other regulatory frameworks as well. In addition, scientific progress stimulates a more mechanistic approach of hazard identification. Nevertheless, the implementation of alternative methods is lagging far behind their development. In search for general bottlenecks for the implementation of alternative methods, this manuscript reviews the state of the art as to the development and implementation of 10 diverse test systems in various areas of toxicological hazard assessment. They vary widely in complexity and regulatory acceptance status. The assays are reviewed as to parameters assessed, biological system involved, standardization, interpretation of results, extrapolation to human hazard, position in testing strategies, and current regulatory acceptance status. Given the diversity of alternative methods in many aspects, no common bottlenecks could be identified that hamper implementation of individual alternative assays in general. However, specific issues for the regulatory acceptance and application were identified for each assay. Acceptance of one-in-one replacement of complex in vivo tests by relatively simple in vitro assays is not feasible. Rather, innovative approaches using test batteries are required together with metabolic information and in vitro to in vivo dose extrapolation to convincingly provide the same level of information of current in vivo tests. A mechanistically based alternative approach using the Adverse Outcome Pathway concept could stimulate further (regulatory) acceptance of non-animal tests. [ABSTRACT FROM AUTHOR]

Toxicologic pathology is a classical discipline in the toxicology arena, and despite various emerging techniques, still is a major cornerstone in the process of hazard identification and risk characterization. Most knowledge derives from laboratory animal studies and, to a lesser extent, human data. Currently interest is growing in applying toxicological pathology for lower animals, in particular fish as being the most developed aquatic genus. This is triggered by the interest in so-called endocrine disrupting chemicals (endocrine disrupters, EDCs), xenobiotics that interfere with the endocrine system and thus may affect reproduction and/or development, and for which pathology is an essential technique in general in vivo studies. As the aquatic ecosystem is a major recipient of pollutants, fish constitute an important potential target and can be used as a research and bio-monitoring tool.For this goal knowledge of the pathological responses of fish to EDCs is essential and therefore we have studied the responses of laboratory fish to a set of reference endocrine modulating chemicals. In this paper, such effects are compared with known response patterns in mammals, thereby accounting for the specific aspects of anatomy and physiology in fish. [Copyright &y& Elsevier]

Studies the effects of waterborne exposure of octylphenol and oestrogen on pregnant viviparous eelpout and her embryos in ovario. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on experimental biology.