Risk Assessment in Immunotoxicology: I. Sensitivity and Predictability of Immune Tests

We have previously reported on the design and content of a screeningbattery involving a "tier" approach for detecting potentialimmunotoxic compounds in mice (Luster et al., 1988, Fundam.Appl. Toxicol. 10, 2–19). This battery has now been utilizedto examine a variety of compounds by the NIEHS ImmunotoxicologyLaboratory, the National Toxicology Programsponsored laboratories,and by the Cell Biology Department at the Chemical IndustryInstitute of Toxicology. The database generated from these studies,which consists of over 50 selected compounds, has been collectedand analyzed in an attempt to improve future testing strategiesand provide information to aid in quantitative risk assessmentfor immunotoxicity. Studies presented here have establishedthe ability of each of the tests or test combinations in thescreening battery to detect immunotoxic compounds. Efforts arecurrently underway using this database to determine the relationshipsbetween these immune tests and susceptibility to challenge withinfectious agents or transplantable tumor cells. The presentanalyses indicated that the performance of only two or threeimmune tests are sufficient to predict immunotoxic compoundsin rodents (>90% concordance). The tests that showed thehighest association with immunotoxicity were the splenic antibodyplaque forming cell response (78%) and cell surface marker analysis(83%). The relationship between immunotoxicity and carcinogenicity,as well as genotoxicity, was also determined. These analysessuggested that potential immunotoxic compounds are likely tobe rodent carcinogens (p = 0.019) although for compounds thatare not immunotoxic the carcinogenic status is unclear. Therewas no relationship observed between immunotoxicity and mutagenicityas determined using in vitro genotoxicity tests. The significanceof these observations is discussed in terms of the relationshipbetween immunotoxicity tests and biological/toxicological processesconcerned with human health (e.g., infectious disease).