Prediction of noncancer toxicologic outcomes in rodent bioassays of 37 chemicals from the National Toxicology Program was evaluated. Using the nonneoplastic lesions noted by NTP pathologists, we evaluate both agreement in toxic lesions across experiments and the predictive value of the presence (or absence) of a lesion in one group for other groups. We compare lesions between mice and rats, male mice and male rats, and female mice and female rats in both short-term and long-term bioassays. We also examine whether lesions found in a specific organ in a short-term test are also found in the long-term test of the same chemical. We find agreement (concordance) across species for specific lesions, as evaluated by the Kappa statistic, ranging from 0.58 (for concordance of nasal lesions between female mice and rats in long-term studies) to -0.14 (lung lesions between mice and rats in long-term studies). Predictive values are limited by the relatively small numbers of observations of each type of lesion. Positive predictive values range from 100% to 0%. Comparing the lesions found in short-term tests to those found in long-term tests resulted in Kappa statistic values from 0.76 (spleen lesions in male rats) to -0.61 (lung lesions in female mice). Positive predictive values of short-term tests for long-term tests range from 70% to 0%. Overall, there is considerable uncertainty in predicting the site of toxic lesions in different species exposed to the same chemical and from short-term to long-term tests of the same chemical.

The goal of this study was to systematically evaluate the choices made in deriving a chronic oral noncancer human health reference value (HHRV) for a given chemical by different organizations, specifically those from the U.S. Environmental Protection Agency, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This analysis presents a methodological approach for comparing both the HHRVs and the specific choices made in the process of deriving an HHRV across these organizations. Overall, across the 96 unique chemicals and 171 two-way organizational comparisons, the HHRV agreed approximately 26% of the time. A qualitative method for identifying the primary factors influencing these HHRV differences was also developed, using arrays of HHRVs across organizations for the same chemical. The primary factors identified were disagreement on the critical or principal study and differential application of the total uncertainty factor across organizations. Of the cases where the total UF was the primary factor influencing HHRV disagreement, the database UF had the greatest influence.

Rodent species are commonly used in traditional toxicology testing guidelines to predict human health toxicity outcomes. The use of a consistent species in test guidelines is important for maintaining consistency and comparability between tests and testing guidelines. This recommendation was operationalized for this study as the implicit assumption of uniform species and species-sex sensitivities. This investigation analyzed the uniformity assumption using data from National Toxicology Program Technical Reports (and where applicable Toxicity Reports), which provide data from both short-term and chronic rodent toxicity tests. These data were extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Minimum best-fit benchmark doses (BMD) and benchmark dose lower limits (BMDL) were determined and a minimum best-fit BMD10 and BMDL10 estimated for every chemical and study duration. Endpoints of interest included non-neoplastic lesions, final mean body weights, and mean organ weights. The distribution of findings was then assessed to determine the most sensitive species and species-sex combinations associated with the minimum best-fit BMDL10. Data indicated that species and species-sex sensitivity for this group of chemicals is not uniform and that rats are significantly more sensitive than mice for non-cancerous outcomes observed, depending upon study duration. There are also indications that male rats may be more sensitive than other species-sex groups in certain situations.