Center for Integrative Toxicology, Food Safety Toxicology Center, Department of Pediatrics/Human Development, College of Human Medicine, Michigan State University, East Lansing, Michigan 9924, USA.
Hum Exp Toxicol. 2010 Jan;29(1):21-9. doi: 10.1177/0960327109354663.
Faced with the reality of our current methods of drug discovery and toxicity assessment of all chemicals is less than perfect, the Report, ''Toxicity Testing in the 21( st) Century: A Vision and a Strategy'', posed a reality check on all scientific efforts to find new conceptual and technical approaches for being better predictors of potential human health effects. This Commentary is a challenge to both the current paradigms and techniques to test chemicals for their potential toxicities. While, clearly, our scientific understanding of the mechanisms of chemical-induced toxicity and of the pathogeneses of all human diseases are not complete, the state of scientific understanding seems not only sufficient to know what we are now doing is not sufficient, but that it is adequate enough to make a new paradigm and technological change. Basically, the challenge includes the opinion that human exposure to chemicals, that are associated with one or more health endpoints (birth defects, cardiovascular diseases, cancer, reproductive and neurological dysfunctions), is the result of epigenetic , not mutagenic or genotoxic, mechanisms. In addition, it is postulated that the adult human stem cell should be considered the ''target'' cell for the important chemical-induced health effects. To test this hypothesis that altering the quantity and quality of adult stem cells by chemical exposures during in utero, neonatal, adolescent, adult and geriatric phases of life can lead to health consequences, it is recommended that 3-D in vitro cultures be used on male and female human adult stem cells from a few major organs (e.g., heart, brain, liver, lung, kidney, breast, prostate ). Altered stem cell biology (e.g., increase or decrease in the stem cell numbers in specific organs; altered apoptotic and differentiation frequencies), as well as measured cell-cell communication, should be seriously considered as toxicity endpoints.
面对我们当前药物发现方法和所有化学物质毒性评估都不完美的现实，报告《21 世纪的毒性测试：愿景与策略》对所有旨在寻找新概念和新技术方法以更好地预测潜在人类健康影响的科学努力进行了现实检验。本评论既是对当前测试化学物质潜在毒性的范式和技术的挑战，也是对当前测试化学物质潜在毒性的范式和技术的挑战。虽然我们对化学物质诱导毒性的机制和所有人类疾病的发病机制的科学理解显然还不完全，但科学理解的现状不仅足以知道我们现在所做的还不够，而且足以实现新的范式和技术变革。从本质上讲，这一挑战包括这样一种观点，即人类接触与一个或多个健康终点（出生缺陷、心血管疾病、癌症、生殖和神经功能障碍）相关的化学物质是表观遗传而不是诱变或遗传毒性机制的结果。此外，有人假设，成年人类干细胞应被视为重要的化学诱导健康效应的“靶”细胞。为了验证这一假设，即在胎儿、新生儿、青春期、成年和老年期，通过化学暴露改变成年干细胞的数量和质量会导致健康后果，建议使用 3-D 体外培养方法对来自几个主要器官（如心脏、大脑、肝脏、肺、肾脏、乳房、前列腺）的男性和女性人类成年干细胞进行培养。改变的干细胞生物学（例如，特定器官中干细胞数量的增加或减少；改变的细胞凋亡和分化频率）以及测量的细胞间通讯应被视为毒性终点。
