Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data.

A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.

Mode of action: inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of beta-catenin--developmental effects of valproic acid.

Valproic acid (VPA) has long been known to cause spina bifida, a neural tube defect, and other effects in fetuses of women treated with this drug. Toxicological tests in laboratory mice and rats at human therapeutic doses also show neural tube and other defects. Studies show that VPA alters Wnt signaling in human and animal cells, inducing Wnt-dependent gene expression at doses that cause developmental effects. Structural analogues of VPA that do not have this effect on Wnt signaling do not cause developmental effects. Similarly, Trichostatin A, a compound that mimics VPA in its effects on Wnt gene expression, also causes similar developmental effects. Alteration of Wnt signaling is empirically well supported as the postulated mode of action (MOA) for VPA's developmental effects in animals. VPA causes alteration of Wnt signaling in both human and animal cells systems at the same dose levels. The correspondence of effects on signaling and of effects on development in animals and humans supports the view that alteration of Wnt signaling is a relevant MOA in humans.