Sensitivity and Predictability of Histopathology in Detecting Immunotoxicity

确定可能对免疫系统造成伤害的化学品具有相当大的公共卫生意义，因为免疫功能的改变可导致超敏反应性疾病、自身免疫性疾病或传染性疾病或肿瘤的发病率增加。 在过去15年中，使用标准化测试小组收集的实验动物数据提供了一个数据库，从该数据库中评估了通常用于筛选化学品免疫毒性的各种测试的灵敏度和可预测性。这些结果已被用作免疫毒性风险评估的指南，并已成为许多监管活动的基础。 1998年4月，在NIEHS举办了一次研讨会，以确定研究设计，以确定扩展组织病理学作为免疫毒性指标的灵敏度和可预测性，并与国家毒理学计划功能测试组合进行比较。 为10种化学品生成标准化载玻片集，这些化学品先前已使用功能测试对其免疫毒性进行了评价。 切片的组织学评价已完成，数据已格式化，以纳入免疫毒理学数据库。 Russell Helms和Chris Portier博士（原始风险评估研究的合作者）已接近完成病理学评分的数据分析。 数据表明，对于大多数结局，病理学家之间存在良好的一致性。 然而，即使是变量具有良好的协议有一些证据不一致的病理学家。 对每位病理学家的评分进行直接比较表明，即使在一致性良好的情况下，某些人往往更保守，而其他人则更能够辨别出细微的变化。 其他分析通过调查同一组织类型中所有测量值之间的相关性来检查病理学家对单个组织评级的一致性。 当来自所有病理学家的数据结合起来时，四种组织中的每一种的测量似乎与该组织的其他测量高度相关。 然而，当独立检查每位病理学家的相关性时，仅胸腺评价保持相同的高度相关性。 对于脾脏、骨髓和淋巴结测量，每位病理学家的结果相关性较差，这引起了对这些组织中每种不同测量的病理学家评级一致性的担忧。 最终分析将比较组织学评价和功能试验的能力，以确定化合物是否具有免疫毒性。

The identification of chemicals that have the potential to cause injury to the immune system is of considerable public health significance, as alterations in immune function can lead to increased incidence of hypersensitivity disorders, autoimmune or infectious diseases or neoplasias. Experimental animal data collected over the past 15 years using standardized testing panels have provided a database from which the sensitivity and predictability of a variety of tests commonly used for the screening of chemicals for immunotoxicity have been evaluated. These results have been used as guidelines for risk assessment in immunotoxicity and have been the basis for a number of regulatory activities. In April 1998 a Workshop was held at NIEHS to establish study design to determine the sensitivity and predictability of extended histopathology as an indicator of immunotoxicity as compared with the National Toxicology Program functional testing battery. Standardized slide sets were generated for 10 chemicals, which had previously been evaluated for their immunotoxicity using functional tests. The histological evaluation of the slides has been completed and the data have been formatted for incorporation into the Immunotoxicology database. Russell Helms and Dr. Chris Portier, a collaborator on the original risk assessment studies, have nearly completed the data analysis of the pathology scoring. The data indicate that for a majority of the outcomes, there was good agreement between the pathologists. However, even for variables with excellent agreement there was some evidence of inconsistency among pathologists. A direct comparison of the ratings for each pathologist indicates that, even where there was good agreement, certain individuals tended to be more conservative while others were more able to discern subtle changes than others. Additional analyses examined the consistency of a pathologists ratings in a single tissue by investigating the correlation among all the measures in the same tissue type. When data from all pathologists were combined, measures in each of the four tissues seemed highly correlated with the other measures from that tissue. However, when correlations were examined for each pathologist independently, only the thymus evaluations maintained the same high degree of correlation. For spleen, bone marrow and lymph node measures, the outcomes for each pathologist were less well correlated, raising concern about the consistency of a pathologists ratings across different measures in each of these tissues. The final analysis will compare the ability of the histologic evaluation and function tests to determine whether a compound is considered immunotoxic.