Marty M S, Allen B, Chapin R E, Cooper R, Daston G P, Flaws J A, Foster P M D, Makris S L, Mylchreest E, Sandler D, Tyl R W
The Dow Chemical Company, Midland, Michigan 48674, USA.
Birth Defects Res B Dev Reprod Toxicol. 2009 Dec;86(6):470-89. doi: 10.1002/bdrb.20208.
The U.S. EPA revised the Reproduction and Fertility Effects Test Guideline (OPPTS 870.3800/OECD 416) in 1998, adding numerous endpoints in an effort to incorporate new methodologies, improve the sensitivity for detecting reproductive toxicants, and more efficiently utilize study animals. Many of these new endpoints have not been used in regulatory reproductive toxicology studies prior to their inclusion in the test guidelines; thus, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute (ILSI) initiated the Reproductive Endpoints Project to examine the utility of these new endpoints.
This report provides a retrospective analysis of 43 multi-generation studies (16 in Wistar rats, 27 in Sprague-Dawley rats) conducted according to the latest version of the test guidelines. It focuses on vehicle (negative) control values (means and ranges) for the various endpoints to examine inter-laboratory variability.
Based on the compiled data, the most variable endpoints across laboratories and their associated coefficients of variation (CV) for each generation were: percent abnormal sperm (166-205%), testicular spermatid concentration (126-147%), postimplantation loss (97-104%), primordial follicle counts (69%, only measured in P2 females), and epididymal sperm concentration (52-57%). Absolute and relative prostate and thymus weights, weanling uterine weights, and anogenital distance had CVs of 25-50%. Sources of variability included procedural differences between laboratories, inherent biological variability, and/or small sample sizes for some endpoints.
These inter-laboratory control data provide a means for laboratories to review their performance on reproductive toxicity measures, and provide perspective for interpreting their own control data and data from treated animals.
美国环境保护局（EPA）于1998年修订了《生殖与生育影响测试指南》（OPPTS 870.3800/经合组织416），增加了许多终点指标，旨在纳入新方法、提高检测生殖毒性物质的灵敏度，并更有效地利用实验动物。在这些新终点指标被纳入测试指南之前，它们中的许多尚未在监管生殖毒理学研究中使用；因此，国际生命科学研究所（ILSI）的健康与环境科学研究所（HESI）启动了生殖终点项目，以研究这些新终点指标的实用性。
本报告对根据最新版测试指南进行的43项多代研究（16项在Wistar大鼠中进行，27项在Sprague-Dawley大鼠中进行）进行了回顾性分析。它侧重于各种终点指标的赋形剂（阴性）对照值（均值和范围），以检查实验室间的变异性。
根据汇总数据，各实验室中每一代变异性最大的终点指标及其相关变异系数（CV）为：异常精子百分比（166 - 205%）、睾丸精子细胞浓度（126 - 147%）、着床后损失（97 - 104%）、原始卵泡计数（69%，仅在P2雌性大鼠中测量）以及附睾精子浓度（52 - 57%）。前列腺和胸腺的绝对重量和相对重量、断奶时子宫重量以及肛门生殖器距离的CV为25 - 50%。变异性来源包括实验室之间的程序差异、固有的生物学变异性和/或某些终点指标的样本量较小。
这些实验室间对照数据为实验室提供了一种手段，可用于评估其在生殖毒性测量方面的表现，并为解释其自身的对照数据以及来自受试动物的数据提供参考。
