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
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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
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List 1 EDSP Tier 1 Screening
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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.issue1/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
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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 (WREL)
– 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)
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EPF - Endocrine Activity: Consideration of Potency
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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)
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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)
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Dow’s SRP: Epigenetics and Human Health Risk Assessments
 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.
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Dow’s Predictive Toxicology Platforms
Using 21st Century Tools to help characterize biological activity early in
product development
Gene expression
profiling
Cell Cultures
Physical-Chem
properties, ADME
QSAR,
Cheminformatics
Model Organisms
DATA INTEGRATION
(Predictive Models)
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References
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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.
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References
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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.
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