Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods: Scientific and regulatory perspectives.

摘要: Humans are continuously exposed to low levels of thousands industrial chemicals, most which poorly characterised in terms their potential toxicity. The new paradigm chemical risk assessment (CRA) aims rely on animal-free testing, with kinetics being a key determinant toxicity when moving from traditional animal studies integrated vitro-in silico approaches. In kinetically informed CRA, membrane transporters, have been intensively studied during drug development, an essential piece information. However, how existing knowledge transporters gained the field can be applied CRA is not yet fully understood. This review outlines opportunities, challenges and tools for investigating chemical-transporter interactions without studies. Various environmental chemicals acting as substrates, inhibitors or modulators transporter activity expression shown impact TK, just drugs do. because pollutant concentrations often lower humans than exposure internal doses usually known contrast drugs, approaches required translate data reasoning sector CRA. Here, generation vitro interaction development databases classification systems trained datasets (and only drugs) proposed. Furtheremore, improving use human biomonitoring evaluate transporter-related predicted values developing means assess uncertainties could also lead increase confidence scientists regulators Finally, systematic characterisation transportome (quantitative monitoring abundance, maintenance over time) would reinforce experimental transporter/barrier well established cell-based toxicological assays currently used