2014 Society of Toxicology Annual Meeting

Phoenix, Arizona, USA
March 23, 2014 – March 27, 2014
CC Exhibit Hall, Phoenix Convention Center

1) Agnes Forgacs, the 2012 ILSI North America Food and Chemical Safety Summer Fellow will present her work, “Evaluation of Food-Relevant Chemicals in ToxCast Phase II.”

Monday, 24 March 2014
9:30AM to 12:30PM
Poster Board #566

Abstract: Phase II of the ToxCast screening program evaluated 1892 chemicals across hundreds of in vitro assays aiming to help prioritize chemicals that may need more extensive toxicological evaluation and to identify targets for potential toxicity pathways. To identify bioactive food additives, the ToxCast chemical inventory was mined for food-relevant chemicals including direct food ingredients classified as Generally Recognized As Safe (GRAS), Food Contact Substances (FCS), and indirect food additives. Publicly available FDA sources including the Everything Added to Food in the US (EAFUS), GRAS and FCS databases identified 5,322 food-relevant chemicals. The 1892 ToxCast phase II chemicals included 828 food-relevant chemicals, of which 507 are FCS and 321 are either GRAS or direct food ingredients. The median AC50 values for food-relevant chemicals across assays generally ranged between 10-100 uM, consistent with the entire ToxCast chemical library. Chemotype similarity clustering identified 191 clusters using physical/structural properties, with 105 chemicals as singletons not included in the clusters. Enrichment analysis of in vitro assay hits within clusters was performed using a modified Fisher’s test. All assays showed enrichment in at least one chemical cluster, while most assays showed enrichment in <10 clusters. Eight food-relevant chemical clusters were enriched in more than 100 assays and 78 chemical clusters not enriched in any assay. Although biological activities in the in vitro assays do not necessarily lead to adverse effects in vivo, the results suggest that the clustering approach can identify physical/structural properties of food-relevant chemicals that elicit biological activity and the cellular pathways that are most frequently targeted. This work was sponsored by the ILSI NA Food and Chemical Safety Committee 2012 Summer Fellowship Program. This abstract does not necessarily reflect US EPA policy.

2) Mansi Krishan, the 2013 ILSI North America Food and Chemical Safety Summer Fellow will present her work, “Toxicology and Risk Assessment of Chemical Mixtures.”

Tuesday, 25 March 2014
9:00AM to 12:30PM
Poster Board #471

Abstract: Evaluation of potential health risk from simultaneous exposure to multiple chemicals has been one of the major challenges for toxicology research and risk assessment (RA). Terminology and problem formulation is complex and the framework for mixture RA varies greatly among different agencies. As part of the International Life Sciences Institute North America Technical Committee on Food and Chemical Safety, 2013 Summer Fellowship Program, we analyzed current methods to achieve the following: 1) Describe the landscape of RA for chemical mixtures; 2) Characterize differences in RA frameworks; and 3) Assess regulatory acceptance of these frameworks with a focus on food mixtures. Reviews were completed for mixture RA paradigms used by US federal agencies, nonprofit organizations (WHO, IPCS) and international agencies (EU). There are significant overlaps and differences between paradigms and there appears to be no single unified method, is apparent from our research. US EPA’s original framework forms the basis of most of the globally accepted methods for mixtures RA. Whole mixture, sufficiently similar mixture or componentbased approaches are used for mixture RA depending on data availability. Differences in hazard assessment approaches were found among agencies, including differences in criteria (e.g., mode of action, health outcome) for grouping chemicals in assessment groups. WHO, IPCS and EU recommend the use of a tiered approach and dose additivity as the default approach. We developed a framework based on a food mixture scenario to select the set of parameters to guide use of appropriate RA methods. These parameters include target population, exposure routes, availability of data on the exposure levels and toxicology interactions for the whole mixture or individual components. Future methods could incorporate high throughput screening data (e.g., toxicogenomics and biomonitoring) to improve risk characterization of food mixtures. Considering the current challenges in food mixtures such as heavy metals, pesticides and migrants from packaging, a case study was done to compare different methods and test their applicability to food safety assessments.

3) Work done in collaboration with USEPA NCCT, Bioseek, Attagene, and Tox21, titled “In Vitro Bioactivity in ToxCast Assays for Fruit and Vegetable Extracts”, will be presented as a poster.

Thursday, 27 March 2014
8:30AM to 12:00PM

Abstract: The ToxCast and Tox21 programs have generated in vitro screening data for over 1000 chemicals to aid in hazard identification and setting chemical testing priorities. These data, together with high-throughput pharmacokinetic data, are used to infer possible toxic responses and external concentrations required to elicit these effects. There is only limited experience in evaluating dose-response for natural products in these assays. In this study, juices were extracted from 30 organically grown fruits and vegetables. These juices were screened in concentration-response format across primary human cell and co-culture assays (BioMAP systems) to assess similarities of pathway responses of the extracts with those of database compounds. Bioactivities noted with unpeeled potato juice were immunomodulatory and tissue remodeling activities across endothelial, peripheral blood mononuclear and fibroblast cells. This pattern of response was similar to quercetin, a plant-derived flavonoid. Broccoli juice initiated anti-proliferative effects on endothelial, fibroblast and smooth muscle cells with significant similarity to mitomycin C (374 ng/mL; Pearson, r=0.806) and the fungicide mancozeb (40 uM; Pearson, r=0.776). To relate in vitro concentrations to administered dose, the filtered juice yield per g item was used with the plasma volume of a 70kg adult to approximate % juice present in systemic circulation after eating. This value was used as a surrogate for target tissue concentration. The activity described for broccoli was elicited at 0.5%, the amount of juice anticipated in the circulation following consumption of 2 cups of broccoli. Importantly, the bioactivities noted do not necessarily lead to adverse effects. These data provide context for assessing the in vivo relevance of in vitro concentration-response and bioactivity data generated in ToxCast and similar screening programs. This abstract doe not necessarily reflect EPA policy.

Learn more about the 2014 SOT Annual Meeting here.