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Alternative Testing Strategy Example: Bioactivity Profilign of Diverse Engineering Nanomaterials via High-throughput Screening in ToxCast
Citation:
Wang, A. Alternative Testing Strategy Example: Bioactivity Profilign of Diverse Engineering Nanomaterials via High-throughput Screening in ToxCast. Presented at Society of Risk Analysis Annual Meeting, Baltimore, MD, December 07 - 12, 2013.
Impact/Purpose:
Showcasing the process and resutls of nanomaterial screening in ToxCast, as an example of alternative testing strategy for nanomaterials in the SRA Advanced Workshop on Nanoscale Materials - What Can We Learn from Big Data Sets?
Description:
Most of the over 2800 nanomaterials (NMs) in commerce lack hazard data. Efficient NM testing requires suitable toxicity tests for prioritization of NMs to be tested. The EPA’s ToxCast program is evaluating HTS assays to prioritize NMs for targeted testing. Au, Ag, CeO2, Cu(O2), TiO2, SiO2, and ZnO nanoparticles, their ion and micro counterparts, carbon nanotubes (CNTs), asbestos, and pesticides containing nano-Cu(O) - total 62 samples - were screened at 6 -10 concentrations each for 262 bioactivity/toxicity endpoints in cells and zebrafish embryos. Cellular stress and immune response pathways were primarily affected. NM’s core chemical composition was more important than size for bioactivity. NMs had similar profiles as their ion counterparts, suggesting ion shedding was a key factor in mechanism of action. Ag, Cu, and Zn (nano, ion) were more cytotoxic and active in more assays than others. While 3 asbestos samples had similar immune response profiles, 6 CNTs had profiles distinctive from asbestos. Potential bioactivity targets that were not directly measured were suggested by reference profiles similar to our data, e.g. similar profiles of a microtubule stabilizer interfering with mitosis and our nano-TiO2. Dividing endpoints into cytotoxicity and various function domains, we developed a ToxPi-based ranking approach for in vitro bioactivity. Samples active in more domains at lower concentrations were ranked higher than samples active in fewer domains and/or at higher concentrations. Ag, Cu, and Zn samples were ranked as high in vitro bioactivity; asbestos, Au, CeO2, some CNTs, and some TiO2 samples were ranked as low. Recognizing our assays using submerged cells may have limited sensitivity to inhalation effects, we are exploring prioritization approaches for various purposes. We demonstrated that HTS assays can identify affected cellular pathways, predict targets, and may be useful for ranking NMs for specific purposes. This abstract does not reflect EPA policy.