Immunotoxicogenomics: A Systems Approach

Abstract

Immunotoxicity can be defined as the adverse effects of toxicants on the immune system. Low-molecular-weight chemicals that are able to induce allergy can be divided into contact and respiratory sensitizers. These sensitizers differ not only in their relevant exposure routes and the clinical effects they can induce, but also in risk assessment. Various types of data suggest that the oxidative stress response pathway is the most significant one affected by contact sensitizer exposure. Less abundant, primarily toxicogenomics, data suggest that the PTEN pathway is the most significant pathway affected by respiratory sensitizer exposure. The chemical characteristics that determine whether a sensitizer is a contact or respiratory sensitizer are beginning to be understood. We hypothesize how the oxidative stress and PTEN pathways may result in the in vivo observations of preferential Th1 and Th2 responses by contact and respiratory sensitizers, respectively. While for contact sensitization risk assessment seems to be feasible, this prospect is still remote for respiratory sensitization, partly because a validated in vivo model and quantitative data are lacking. To be able to identify respiratory sensitizers, we propose to develop non-animal assays on the basis of human data. This proposition also holds for risk assessment of respiratory sensitization. We anticipate that development of non-animal assays as well as risk assessment will depend on a systems toxicology framework. Keywords: Keap1; Nrf2; PTEN; respiratory tract; risk assessment; toxicogenomics; sensitizer; skin; oxidative stress