Uncertainty Analysis and Updated User Guidance for Interspecies Correlation Estimation Models and Low Toxicity Compounds.

Interspecies correlation estimation (ICE) models are log-linear relationships of acute sensitivity between two species that estimate the sensitivity of an untested species from the known sensitivity of a surrogate. As ICE model use increases globally, additional user guidance is required to ensure consistent use across chemicals and applications. The present study expands ICE uncertainty analyses and user guidance with a focus on low toxicity compounds whose acute values (i.e., reported as mg/L) can be greater than those used to develop a model. In these cases, surrogate values may be outside the ICE model domain and require additional extrapolations to predict acute toxicity. We use the extensive, standardized acute toxicity database underlying ICE models to broadly summarize inter-test variability of acute toxicity data as a measure by which model prediction accuracy can be evaluated. Using the data and models found on the USEPA Web-ICE (), we created a set of "truncated" models from data corresponding to the lower 75th percentile of surrogate toxicity. We predicted toxicity for chemicals in the upper 25th percentile as both mu g/L beyond the model domain and converted to mg/L (i.e., "scaled" value) and compared these predictions with those from cross-validation of whole ICE models and to the measured value. For ICE models with slopes in the range 0.66-1.33, prediction accuracy of scaled values did not differ from the accuracy of the models when data were entered as mu g/L within or beyond the model domain. An uncertainty analysis of ICE confidence intervals was conducted and an interval range of two orders of magnitude was determined to minimize type I and II errors when accepting or rejecting ICE predictions. We updated the ICE user guidance based on these analyses to advance the state of the science for ICE model application and interpretation. Integr Environ Assess Manag 2024;00:1-12. Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Interspecies correlation estimation (ICE) models estimate acute toxicity and increase biodiversity in toxicity datasets. Interspecies correlation estimation models are validated for low toxicity compounds in which input is beyond model domain and has the same accuracy as traditional model use. User guidance for ICE model applications is updated to include recommendations for model input and confidence intervals. Interspecies correlation estimation models provide robust alternatives to animal test data for data-limited compounds.