Sensitivity and Predictability of Histopathology in Detecting Immunotoxicity

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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 has provided a database from which the sensitivity and predictability of a variety of tests commonly used for the screening of chemicals for immunotoxicity has 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. There is a considerable desire on the part of international organizations and industry to harmonize testing guidelines for a variety of endpoints, including immunotoxicity. Upon review of OECD 407 testing guidelines by a panel of experts, it was deemed that the current guideline was insufficient to detect substances with an immunotoxic potential in the standard 28 day toxicity testing protocol. The guidelines have subsequently been revised to include histopathologic evaluation of the spleen, thymus, lymph node (one covering route of administration and one distal), GALT and bone marrow. However, there is still considerable disagreement as to whether this extended histopathology would be sufficient to detect potential immunotoxicants, or whether functional tests should be required. These studies were initiated to address this issue. In April, 1998 a Workshop was held at NIEHS to establish the criteria for tissue evaluation. Standardized slide sets have been generated for 10 chemicals which were evaluated for their immunotoxicity via the NTP testing contract. To date each pathologist has evaluated 2 compounds, and a small working group was held to evaluate the comparability of the results. Upon completion of the histological evaluation, the information will be added to the NTP database and Dr. Chris Portier, a collaborator on the original risk assessment studies, will use statistical modeling to generate information on the sensitivity and predictability of extended histopathology overall, and for individual tissues, as compared to functional testing for use in risk assessment.