Presentation on theme: "1 Endocrine Disruption: An Update of Industry Activities Sue Marty, PhD, DABT Senior Toxicology Leader The Dow Chemical Company Midland, MI, USA EDC Advisory."— Presentation transcript:
1 Endocrine Disruption: An Update of Industry Activities Sue Marty, PhD, DABT Senior Toxicology Leader The Dow Chemical Company Midland, MI, USA EDC Advisory Group for UNEP Geneva, Switzerland 12 December 2014
2 Industry Activities Many activities, but this presentation is limited to List 1 EDSP Tier 1 Screening Endocrine Policy Forum (EPF) Activities: –Consortium of Tier 1 test order recipients and other interested stakeholders –EPF Objective: address regulatory and policy issues and provide technical guidance Industry support for AOPs Dow’s Strategic Research Program (Epigenetics) Dow’s Predictive Toxicology Program
3 List 1 EDSP Tier 1 Screening Contributed data to evaluate Tier 1 assays prior to 2009 EDSP 52 chemicals evaluated as part of List 1 Approximately $50M to complete Tier 1 screening for List 1 Some weight-of-evidence assessments published Some “learnings” from EDSP Tier 1 screening have been published in Birth Defect Research Part B (Vol. 101; 2014) http://onlinelibrary.wiley.com/doi/10.1002/bdrb.2014.101.issue- 1/issuetoc http://onlinelibrary.wiley.com/doi/10.1002/bdrb.2014.101.issue- 1/issuetoc –Better use of OSRI to evaluate endocrine activity –Lessons from in vitro, in vivo mammalian and in vivo non-mammalian EDSP Tier 1 assays –A framework for weight-of-evidence assessments for potential endocrine activity –Use of potency and exposure to interpret endocrine data
4 EPF - Endocrine: Weight of Evidence Framework for objective, systematic and transparent approach to WoE Weights experimental endpoints based on relevance for supporting 8 hypotheses for endocrine activity (W REL ) –Rank 1 = specific and sensitive, interpretable without addl data, rarely confounded –Rank 2 = specific and interpretable, but less informative due to oversensitivity, in vitro endpoints, etc. –Rank 3 = relevant, but only corroborative of Rank 1 and 2 (e.g., Apical endpoints)
5 EPF - Endocrine Activity: Consideration of Potency Contextualize endocrine results in terms of potency and exposure One example in adult males… –The endocrine system discriminates potent endogenous hormones from a more concentrated background of structurally similar endogenous molecules with low hormonal potential (i.e., distinguish important hormone signals from background noise)
6 Adverse Outcome Pathways Support the AOP approach to defining and evaluating endocrine pathway activity Industry has contributed to AOPs in the Wiki Tool and is currently working on AOPs related to thyroid pathways (EPA lead)
7 Heritable modifications that regulate gene expression Multi-year research program to evaluate potential adverse effects due to heritable, transgenerational epigenetic changes Conclusions: –Incomplete understanding of normal/dynamic variation in epigenome What epigenetic changes are adverse? –Some case studies (DES, vinclozolin) for applying epigenetics in safety assessment –Future research: 1) Examine the potential causal relationship between epigenetic alterations and adverse apical endpoints; 2) Understand the dose-response relationships between causal epigenetic alterations compared to apical effects. Dow’s SRP: Epigenetics and Human Health Risk Assessments
8 Dow’s Predictive Toxicology Platforms DATA INTEGRATION (Predictive Models) Model Organisms Gene expression profiling Physical-Chem properties, ADME Cell Cultures QSAR, Cheminformatics Using 21 st Century Tools to help characterize biological activity early in product development
9 References Alyea, R.A., Gollapudi, B.B., and Rasoulpour, R.J. (2014). Are we ready to consider transgenerational epigenetic effects in human health risk assessment? Environ. Mol. Mutagen. 55, 292-298. Alyea, R.A., Moore, N.P., LeBaron, M.J., Gollapudi, B.B., and Rasoulpour, R.J. (2012). Is the current product safety assessment paradigm protective for epigenetic mechanisms? J. Pharmacol. Toxicol. Methods 66, 207-214. Becker, R.A., Hayes, S.M., Kirman, C.R., Aylward, L.L., and Wise, K. (2014). Interpreting estrogen screening assays in the context of potency and human exposure relative to natural exposure to phytoestrogens. Birth Defects Res. (Part B) 101, 114-124. Borgert, C.J., Baker, S.P., and Matthews, J.C. (2013). Potency matters: Thresholds govern endocrine activity. Regul. Toxicol. Pharmacol. 67, 83-88. Borgert, C.J., Stuchal, L.D., Mihaich, E.M., Becker, R.A., Bentley, K.S., Brausch, J.M., Coady, K., Geter, D.R., Gordon, E., Guiney, P.D., Hess, F., Holmes, C.M., LeBaron, M.J., Levine, S., Marty, S., Mukhi, S., Neal, B.H., Ortego, L.S., Saltimiras, D.A., Snajdr, S., Staveley, J., and Tobia, A. (2014). Relevance weighting of tier 1 endocrine screening endpoints by rank order. Birth Defects Res. (Part B) 101, 90-113. Coady, K.K., Lehman, C.M., Currie, R.J., and Marino, T.A. (2014). Challenges and approaches to conducting and interpreting the Amphibian Metamorphosis assay and the Fish Short-term Reproduction assay. Birth Defects Res. (Part B) 101, 80-89. Juberg, D.R., Borghoff, S.J., Becker, R.A., Casey, W., Hartung, T., Holsapple, M.P., Marty, M.S., Mihaich, E.M., Van Der Kraak, G., Wade, M.G., Willett, C.E., Andersen, M.E., Borgert, C.J., Coady, K.K., Dourson, M.L., Fowle III, J.R., Gray, L.E., Lamb, J.C., Ortego, L.S., Schug, T.T., Toole, C.M., Zorrilla, L.M., Kroner, O.L., Patterson, J., Rinckel, L.A., and Jones, B.R. (2014). Lessons learned, challenges and opportunities: The U.S. Endocrine Disruptor Screening Program. ALTEX 31, 63-78.
10 References LeBaron, M.J., Coady, K.K., O’Connor, J.C., Nabb, D.L., Markell, L.K., Snajdr, S., and Marty, M.S. (2014). Key learnings from performance of the U.S.EPA Endocrine Disruptor Screening Program (EDSP) tier 1 in vitro assays. Birth Defects Res. (Part B) 101, 23-42. LeBaron, M.J., Rasoulpour, R.J., Klapacz, J., Ellis-Hutchings, R.G., Hollnagel, H.M., and Gollapudi, B.B. (2010). Epigenetics and chemical safety assessments. Mutat. Res. 705, 83-95. Marty, S. (2014). Introduction to “Screening for Endocrine Activity – Experiences with the US EPA’s Endocrine Disruptor Screening Program and Future Considerations”. Birth Defects Res. (Part B) 101, 1-2. Marty, M.S., and O’Connor, J.C. (2014). Key learnings from performance of the Endocrine Disruptor Screening Program (EDSP) tier 1 rodent uterotrophic and Hershberger assays. Birth Defects Res. (Part B) 101, 63-79. Rasoulpour, R.J., LeBaron, M.J., Ellis-Hutchings, R.G., Klapacz, J., and Gollapudi, B.B. (2011). Epigenetic screening in product safety assessment: are we there yet? Toxicol. Mech. Methods 21, 298-311. Stump, D.G., O’Connor, J.C., Lewis, J.M., and Marty, M.S. (2014). Key lessons from performance of the U.S.EPA Endocrine Disruptor Screening Program (EDSP) tier 1 male and female pubertal assays. Birth Defects Res. (Part B) 101, 43-62. Tinwell, H., Colombel, S., Blanck, O., and Bars, R. (2013). The screening of everyday life chemicals in validated assays targeting the pituitary-gonadal axis. Regul Toxicol Pharmacol. 66, 184-196.