10/18/2016 1 Endocrine Disruption and the Environment Ellen Mihaich, Ph.D., DABT PCPC Environmental Safety Workshop October 25, 2016 1 Endocrine Policy Forum • Consortium of List 1 test order recipients and other interested/involved parties • Self-funded • Represents >95% of List 1 test order recipients • Additional stakeholders include CLA, ACC, ACI, CSPA, API, and consulting companies • Objective to address regulatory and policy issues, technical guidance and science advocacy • To undertake collaborations to tackle common areas of interest 2 US EPA’S LEGISLATIVE MANDATES (1996) Food Quality Protection Act o Must screen pesticides (including inerts) for possible estrogenic effects that may affect human health o Must use appropriate validated test systems or other scientifically relevant information o Can include other endocrine effects Safe Drinking Water Act (SDWA) o Can screen drinking water contaminants to which substantial numbers of persons are exposed “Substantial numbers” and “may be found in sources of drinking water “ not defined 3
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
10/18/2016
1
Endocrine Disruption and the Environment Ellen Mihaich, Ph.D., DABT
PCPC Environmental Safety Workshop
October 25, 2016
1
Endocrine Policy Forum
• Consortium of List 1 test order recipients and other interested/involved parties
• Self-funded
• Represents >95% of List 1 test order recipients
• Additional stakeholders include CLA, ACC, ACI, CSPA, API, and consulting companies
• Objective to address regulatory and policy issues, technical guidance and science advocacy
• To undertake collaborations to tackle common areas of interest
2
US EPA’S LEGISLATIVE MANDATES (1996)
Food Quality Protection Act oMust screen pesticides (including inerts) for possible
estrogenic effects that may affect human health oMust use appropriate validated test systems or other
scientifically relevant information oCan include other endocrine effects
Safe Drinking Water Act (SDWA) oCan screen drinking water contaminants to which
substantial numbers of persons are exposed “Substantial numbers” and “may be found in sources
of drinking water “ not defined
3
10/18/2016
2
EDSP HISTORY: 1996 TO TODAY
1996-1998 Endocrine Disruptor Screening and Testing Advisory
Committee (EDSTAC)
o EPA multi-stakeholder advisory committee evaluates methods for priority setting,
screening, testing, and communications as key program elements
1999 to Today: Endocrine Disruptor Screening Program (EDSP)
o EPA adopts EDSTAC recommendations, creates EDSP, and in coordination with
OECD, works to standardize/validate screening and test protocols and guidelines
2009 1st Tier 1 List finalized: contained 67 pesticides and pesticide inerts
2013 Second Tier 1 List finalized; 109 chemicals (41 pesticides)
o Office of Management and Budget has not approved the Information Collection
Request (ICR) from EPA
o No test orders can be released until OMB approval of the ICR
Work is ongoing to prioritize the list of “10,000” chemicals for screening so
current List 2 chemicals may not be chosen ultimately
4
EDSTAC Conceptual Framework
Tier 1 Screening ◦ Eleven In Vitro and In Vivo Assays
◦ Identify chemicals that can potentially interact with the endocrine
system (Estrogen, Androgen, and Thyroid pathways)
◦ Maximize sensitivity to minimize false negatives
◦ A battery of screening assays, with deliberate redundancy
Tier 2 Testing: ◦ Multigen studies in a range of species
◦ Confirm endocrine activity detected in Tier 1 and characterize
adverse effects and
◦ Establish NOAELs and LOAELs for risk assessment for regulation
of the substance
5
OECD Conceptual Framework
• Compendium of data / test methods useful for the identification and assessment of potential endocrine disrupters
• Five levels with increasing information • Entering at all levels and exiting at all levels is possible
• Conceptual framework is not a test strategy • Enter and exit at any level
6
10/18/2016
3
OECD Conceptual Framework
Mammalian and Non-Mammalian Toxicology
Level 1
Existing Data and
Non-Test Information
• Physical & chemical properties, e.g. MW, reactivity, volatility,
biodegradability
• All available (eco)toxicological data from standardized or non-
standardized tests
• Read across, chemical categories, QSARs and other in silico predictions,
Fish short-term screening assay Medaka extended 1-generation study
Amphibian metamorphosis assay Larval amphibian growth and development test
Avian 2-generation reproductive test
* Tier 1 screens cost $750,000 to $1 million per chemical
Current EDSP Test Guidelines
List 1 Results
52 chemicals (primarily pesticides) were screened in most, if not all, of the tier 1 screens
oEPA evaluated all of the data and wrote weight of evidence reports All reports and study summaries are publically available on the EPA
website
There was no evidence for potential interaction with any of the endocrine pathways for 20 chemicals
For 14 chemicals that showed potential interaction with one or more pathways, EPA already has enough information to conclude that they do not pose risks.
Of the remaining 18 chemicals, all 18 showed potential interaction with the thyroid pathway, 17 with the androgen pathway, and 14 with the estrogen pathway.
11
EPA Overall Conclusions
For several of the chemicals displaying activity in the Tier 1 screening assays, EPA determined they have enough information to conclude that they do not pose risks. EPA recommended the following higher tier studies: o A comparative thyroid assay for 4 chemicals that showed interaction
with the thyroid pathway in mammals (not one of the validated Tier 2 tests)
o A medaka extended one-generation reproductive test (MEOGRT) for 13 chemicals that showed potential interaction with the estrogen or androgen pathways in wildlife
o A larval amphibian growth and development assay (LAGDA) for 5 chemicals that showed potential interaction with the thyroid pathway in wildlife
12
10/18/2016
5
A Tier 2 Quandary
• Tier 2 is for determining adverse effects and to provide data for risk assessment
• In regulatory toxicology we test at levels that achieve some effect
• How will we determine if that effect is specifically endocrine related? • Not as much of a problem in the US where regulations are based
on risk but,
• In Europe, deciding if the effect is “endocrine” or may have implications for authorization based solely on hazard
13
Ecotoxicological Hazard and Risk Assessment
SETAC Pellston™ Workshop
• 48 global experts brought together to address the controversy
over hazard and risk Some scientists believe that EDS can be reliably assessed using the standard risk
assessment paradigm,
Others do not believe this is sufficiently precautionary and propose risk
management on the basis of hazard alone
• 6 case studies evaluated
• Cross-cutting issues identified
• Conclusion: Provided that environmental exposure, relevant
taxa and life-stages, delayed effects, and concentration-
response relationships are adequately characterized then
conducting environmental risk assessment of EDC is
scientifically sound.
14
A Cross-Cutting Issue: Challenges in Assigning an Endocrine MOA
• Use of Weight of Evidence
• Establishing Biological Plausibility • Computational/in vitro approaches • In vivo concordance
• Essentiality of Key Events • Adverse Outcome Pathway (AOP)
• Empirical Evidence • Do the pieces fit??
• Confounding Factors • Systemic/overt toxicity • Stress • Infection • Organ specific toxicity • Nutritional status
15
10/18/2016
6
WHO/IPCS Definition
• WHO IPCS 2002:
An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.
16
In silico
In vitro
In vivo screening
In vivo definitive
Weight of Evidence = Endocrine disruptor +
Mechanism
Incr
easi
ng
po
wer
Adverse Effect
Increasin
g po
wer
17
The Dilemma of Many Endpoints
Chance of a Clean Chemical Screening “Clean”
(1- p)n
• Tier 1 Endocrine Screening Battery:
• 89 endpoints; if all independent
(0.95)89 = 0.01
(0.99)89 = 0.41
• 89 endpoints; if every 4th independent:
(0.95)22 = 0.32
(0.99)22 = 0.80
18
10/18/2016
7
If Only WoE Was This Easy!
Courtesy of Tim Ward 19
WOE Conceptual Framework
1. Define Explicit Hypotheses • 8 Total for Tier 1
4. Weight Endpoints Quantitatively or Rank-Ordered
based on Explicit Criteria and Data
5. Weight Results within the context of known positives
and negatives
6. Develop Narrative Interpretation listing all assumptions
20
Framework: Borgert et al. 2011 Reg Tox Pharm 61:185-191
Relevance weightings: Borgert et al. 2014, Birth Defects Research, Part B, 101:90-113
Ranking Endpoints
• No hypothesis can be decided on the results of a single assay – Battery Approach
• Rank the relevance (Wrel) of each endpoint for deciding each hypothesis • Rank #1: specific & sensitive for the hypothesis; interpretable
without other endpoints; in vivo endpoints rarely confounded by artifacts or non-specific activity.
• Rank #2: specific & sensitive for the hypothesis; interpretable alone, but less informative than Rank #1, often due to potential confounding; in vitro assays, many in vivo endpoints
• Rank #3: Relevant but only when corroborative of Rank #1 and #2 endpoints; many apical in vivo endpoints.
• No Response (NR)
21
10/18/2016
8
Relevance Rankings By Hypothesis: Estrogen Agonist