Quantitative and qualitative concordance between clinical and nonclinical toxicity data

Although rodent toxicity testing plays an important role in evaluating human hazards of environmental and industrial chemicals, evaluating the concordance of the rodent testing results with human effects is challenging because these chemicals cannot be tested in humans. In this study, we evaluate the quantitative and qualitative concordance of lowest observed adverse effect levels (LOAELs) and adverse endpoints between in vivo and in vitro models of human health and human clinical trials of pharmaceuticals. Rodent human equivalent dose-adjusted LOAEL (LOAELHED) values and human LOAEL values for the sensitive effect in each species were moderately correlated in a protective context. When matched rodent and human effects were evaluated, the quantitative correlation in dose did not improve, and the qualitative balanced accuracy in effects was low, suggesting limited predictivity. Absolute differences in rodent LOAELHED and human LOAEL values were nearly 1 log10 unit with rodent LOAELHED values consistently higher; however, rodent LOAELHED values were less than the human LOAEL values for >95% of drugs when divided by typical composite uncertainty factors. In comparison, in vitro bioactivity administered equivalent dose (AED) values showed a similar moderate correlation and absolute differences with human LOAEL values, but in vitro bioactivity AED values were consistently lower. When in vitro bioactivity AED values were compared with rodent LOAELHED values, the correlation was lower and differences larger relative to human LOAEL comparison. Overall, the study expands previous efforts evaluating the concordance of rodent toxicological testing results with human responses and presents objective expectations for alternative toxicity testing approaches.