Biological uncertainty exists in extrapolating animal models: for example, anti-fibrotic drugs targeting TGF-β can reverse liver fibrosis in rat models, but clinical Phase III had to be terminated for inducing human cholangiocarcinoma, because the TGF-β-signal threshold of rat hepatic-stellate cells is three times that of humans. This evidence concerns the gene TGFB1 and cholangiocarcinoma.