MIXTURE TOXICITY--EVALUATION OF AN IMPROVED METHODOLOGY

混合物毒性--改进方法的评估

• 批准号: 2157487
• 负责人: DOUGLAS A DAWSON
• 金额: $ 6.45万
• 依托单位: ASHLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2157487
• 关键词: Xenopus; bioassay; chemical structure function; chemicals; dosage; embryo /fetus cell /tissue; evaluation /testing; physical state; plant poisons; technology /technique; toxicant interaction; toxicant screening

DESCRIPTION: (Adapted from the Investigator's Abstract) Accurate chemical mixture toxicity assessment has been hindered by improper use of chemical mixture toxicity models and inadequate or inappropriate testing and evaluation methods. The work proposed herein will evaluate an improved mixture testing method coupled with a new, modern approach for evaluating such toxicity. The new methodology combines the advantages of the 'fixed-dose' and the 'fixed-ratio' approaches using Xenopus laevis embryos as the model organism. The method uses concentration-response data to determine mixture toxicity via comparison with the 'dose-addition' and the 'independence' models of mixture toxicity. Testing will include 15 chemical combinations, each incorporating 36 treatments. The 15 combinations selected for testing will bring forth a rigorous evaluation of the relationship of toxicity models to common or different mechanisms of toxicity. The model chemicals to be tested in combinations are osteolathyrogens, chemicals which induce improper connective tissue cross-linking in developing embryos. This misdevelopment can be brought about by at least four distinct mechanisms. By combining the new testing and evaluation scheme with these select combinations the following can be determined: (1) the effectiveness of the new approach in determining mixture toxicity (combined effects); (2) the relationship of the combined effects to mixture toxicity models; (3) the relationship of osteolathyrogenic mechanisms to the combined effect obtained; and (4) the relationship between the sites of lesions in the embryo, the mechanisms of osteolathyrism, chemical structure, and the number of lesions per site for each combined effect observed. Upon successful completion of the study, the methodology will be useful in further studies of mixture toxicity hazards related to human and environmental health.

描述：（根据研究者的摘要改编）精确化学物质 混合毒性评估受到化学不当的使用而受到阻碍 混合毒性模型，不适当或不适当的测试和 评估方法。 本文提出的工作将评估改进的 混合测试方法以及一种新的现代方法评估 这样的毒性。 新方法结合了 使用Xenopus laevis胚胎的“固定剂量”和“固定比例”方法 作为模型生物。 该方法使用浓度响应数据 通过与“剂量加成”进行比较确定混合毒性和 混合毒性的“独立”模型。 测试将包括15种化学物质 组合，每种都结合了36种治疗方法。 15个组合 选择进行测试将对 毒性模型与常见或不同机制的关系 毒性。 组合测试的模型化学品是 骨肌元，诱导不当结缔组织的化学物质 开发胚胎的交联。 可以带来这个误解 大约是至少四个不同的机制。 通过结合新测试 和这些选择组合的评估方案可以是 确定：（1）新方法在确定 混合毒性（综合效果）； （2）合并的关系 对混合毒性模型的影响； （3）关系 骨肌发育机制，达到了所获得的综合作用； （4） 胚胎中病变部位之间的关系， 骨层，化学结构和每个部位的病变数量 观察到的每个组合效应。 成功完成研究后， 方法学对于混合毒性危害的进一步研究将很有用 与人类和环境健康有关。