Embed Size (px)
DESCRIPTION
This webinar will review the importance of the endocrine system for human health; EPA's regulatory history of how the current testing program developed; lessons learned from providing OSRI (Other Scientific Relevant Information) in response to Tier 1 Test Orders; conducting Tier 1 screens; and, integrating Tier 1 screening data with OSRI to generate Weight of Evidence documents that speak to whether further testing (Tier 2 studies) are needed and appropriate. More info at http://www.huntingdon.com/Chemical/Endocrinedisruptorscreeningprogram/Webinars
Citation preview
www.huntingdon.com
Endocrine Disruptor
Screening Program
Webinar week
20-23 January 2014
www.huntingdon.com
EDSP: Background, lessons learned,
and forecast for the future
Elliot Gordon
Elliot Gordon Consulting, LLC
http://ebgfox.wix.com/elliot-gordon
www.huntingdon.com
EDSP and You
Endocrine Update
3
www.huntingdon.com
Introduction
Presumptions
New to the Game
4
www.huntingdon.com
Introduction
Presumptions
New to the Game (First Test Orders from List 2)
5
www.huntingdon.com
Introduction
Presumptions
New to the Game (First Test Orders from List 2)
List 1 but not done
6
www.huntingdon.com
Introduction
Presumptions
New to the Game (First Test Orders from List 2)
List 1 but not done (List 2 Test Orders coming)
7
www.huntingdon.com
Introduction
Presumptions
New to the Game (First Test Orders from List 2)
List 1 but not done (List 2 Test Orders coming)
List 1 and done but Tier 2 looms
8
www.huntingdon.com
Introduction
Presumptions
New to the Game (First Test Orders from List 2)
List 1 but not done (List 2 Test Orders coming)
List 1 and done but Tier 2 looms
Lessons learned
9
www.huntingdon.com
Your Attention Please!
$1,000,000 per chemical.
10
www.huntingdon.com
$
$1,000,000 per chemical.
Waivers based on OSRI.
11
www.huntingdon.com
$
$1,000,000 per chemical.
Waivers based on OSRI.
12
OSRI: Other Scientifically Relevant Information
www.huntingdon.com
$$
$1,000,000 per chemical.
Waivers based on OSRI.
Number of screens required.
13
www.huntingdon.com
$$$
$1,000,000 per chemical.
Waivers based on OSRI.
Number of screens required.
Ability to form consortium.
14
www.huntingdon.com
$$$$
$1,000,000 per chemical.
Waivers based on OSRI.
Number of screens required.
Ability to form consortium.
Development of Weights of Evidence.
15
www.huntingdon.com
$$$$$
$1,000,000 per chemical.
Waivers based on OSRI.
Number of screens required.
Ability to form consortium.
Development of Weights of Evidence.
Tier 2 studies, if required.
16
www.huntingdon.com
Definition
A chemical that affects the endocrine system and
results in adverse biologic effects.
Not: a chemical that is included in Lists 1 or 2.
Not: a chemical that may show an effect in a
screening assay.
17
www.huntingdon.com
Timeline
1962
1970
1996
2009
2014
18
www.huntingdon.com
Timeline
1962 – Silent Spring
1970
1996
2009
2014
19
www.huntingdon.com
Timeline
1962 – Silent Spring
1970
1996
2009
2014
20
www.huntingdon.com
Timeline
1962 – Silent Spring
1970
1996
2009
2014
21
www.huntingdon.com
Timeline
1962
1970 – EPA
1996
2009
2014
22
www.huntingdon.com
Timeline
1962
1970 – EPA
1996
2009
2014
23
www.huntingdon.com
Timeline
1962
1970 – EPA
1996
2009
2014
24
www.huntingdon.com
Timeline
1962
1970
1996 – Our Stolen Future
2009
2014
25
www.huntingdon.com
Timeline
1962
1970
1996 – Our Stolen Future
2009
2014
26
www.huntingdon.com
Timeline
1962
1970
1996 – Our Stolen Future
2009
2014
27
www.huntingdon.com
Timeline
1962
1970
1996 – Our Stolen Future
2009
2014 “Endocrine Disruptor”
28
www.huntingdon.com
Timeline
1962
1970
1996 FQPA
2009
2014
29
www.huntingdon.com
Timeline
1962
1970
1996 FQPA
2009
2014
30
Food Quality Protection Act
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
31
James Delaney
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
32
Aggregate Risk
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
33
Aggregate Risk
Cumulative Risk
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
34
Aggregate Risk
Cumulative Risk
Extra Safety Factors
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
35
Aggregate Risk
Cumulative Risk
Extra Safety Factors
Registration every 15 years
www.huntingdon.com
Timeline
1962
1970
1996 – FQPA
2009
2014
36
Thou shall test pesticides
for estrogenic effects
www.huntingdon.com
FQPA Triggers Acronyms
EDSTAC
EDMVS
EDMVAC
37
www.huntingdon.com
FQPA Triggers Acronyms
EDSTAC
EDMVS
EDMVAC
38
Endocrine Disruptor Screening and Testing Advisory Committee
www.huntingdon.com
FQPA Triggers Acronyms
EDSTAC
EDMVS
EDMVAC
39
Endocrine Disruptor Screening and Testing Advisory Committee
Endocrine Disruptor Methods Validation Subcommittee
www.huntingdon.com
FQPA Triggers Acronyms
EDSTAC
EDMVS
EDMVAC
40
Endocrine Disruptor Screening and Testing Advisory Committee
Endocrine Disruptor Methods Validation Subcommittee
Endocrine Disruptor Methods Validation Advisory Committee
www.huntingdon.com
Timeline
1962
1970
1996
2009 – List 1, Tier 1 Test Orders Issued
2014
41
www.huntingdon.com 42
www.huntingdon.com 43
HPV: High Production Volume
www.huntingdon.com 44
HPV: High Production Volume
58 PAIs + 9 HPV/inerts = 67 Total
www.huntingdon.com
Timeline
1962
1970
1996
2009
2014 – List 2, Tier 1 Test Orders to be issued.
45
www.huntingdon.com 46
www.huntingdon.com 47
SDWA: Safe Drinking Water Act; PAI: Pesticide Active
Ingredient
FFDCA: Federal Food, Drug, and Cosmetics Act
www.huntingdon.com
EPA Steps
Screen
48
www.huntingdon.com
EPA Steps
Screen
Characterize
49
www.huntingdon.com
EPA Steps
Screen
Characterize
Assess risks
50
www.huntingdon.com
EPA Steps
Screen
Characterize
Assess risks
Mitigate
51
www.huntingdon.com 52
90 day clock, Registrant
150 day clock, Consortium
www.huntingdon.com 53
www.huntingdon.com 54
www.huntingdon.com 55
www.huntingdon.com 56
www.huntingdon.com 57
OSRI: Other Scientifically Relevant Information
www.huntingdon.com 58
www.huntingdon.com 59
www.huntingdon.com 60
www.huntingdon.com 61
www.huntingdon.com 62
or
www.huntingdon.com
Calendar
63
List 1
www.huntingdon.com
Calendar
64
List 2
www.huntingdon.com
Tier 2 Study List
65
Two-generation rat reproduction study
Japanese Quail Two-generation Test
Medaka Multigeneration Toxicity Test
Larval Amphibian Growth and Development
Mysid Two-Generation Toxicity Test
Harpacticoid Copepod Development & Reproduction Test
www.huntingdon.com
Registrant Groups
Endocrine Policy Forum (EPF)
CropLife America (CLA)
American Chemistry Council (ACC)
66
www.huntingdon.com
Registrant Groups
Endocrine Policy Forum (EPF)
CropLife America (CLA)
American Chemistry Council (ACC)
67
EPF: Ellen Mihaich [email protected]
www.huntingdon.com
NGOs
World Wildlife Fund (WWF)
Environmental Working Group (EWG)
Natural Resources Defense Council (NRDC)
68
www.huntingdon.com
Endocrine System
Hypothalamus
Pituitary
Ovary
Testes
Thyroid
69
www.huntingdon.com
Endocrine System
Hypothalamus
Pituitary
Ovary
Testes
Thyroid
70
www.huntingdon.com
Tier 1 Endpoints
Mechanistic effects
Apical effects
71
www.huntingdon.com
Tier 1 Endpoints
Mechanistic effects • Enzyme activity
Apical effects • Reproductive, developmental
72
www.huntingdon.com
Tier 1 Endpoints
Mechanistic effects • Enzyme activity
Apical effects • Reproductive, developmental
73
Hypothalamic pituitary gonadal axis: HPG axis
Hypothalamic pituitary thyroid axis: HPT axis
www.huntingdon.com
Tier 1
In Vitro
890.1150 Androgen Receptor Binding
890.1200 Aromatase
890.1250 Estrogen Receptor Binding
890.1200 Estrogen Receptor Transcriptional
Activation
890.1550 Steroidogenesis
74
www.huntingdon.com
Tier 1
In Vivo Mammalian (Rats)
890.1600 Uterotrophic
890.1400 Hershberger
890.1450 Female Pubertal
890.1500 Male Pubertal
75
www.huntingdon.com
Tier 1
In Vivo Non-Mammalian
890.1100 Amphibian Metamorphosis
890.1350 Fish Short-term Reproduction
76
www.huntingdon.com
77
www.huntingdon.com
78
www.huntingdon.com
79
Electronic Data Entry
www.huntingdon.com
Chemical Properties
Functional groups (reactivity)
Purity
Solubility
Vapor pressure
Stability
80
www.huntingdon.com
Chemical Properties
Functional groups (reactivity)
Purity
Solubility
Vapor pressure
Stability
Use one characterized batch for all studies
81
www.huntingdon.com
Laboratory Selection
Experience
Study Director
Technical Staff
Quality Assurance Unit (QAU)
82
www.huntingdon.com
Laboratory Selection
Experience
Study Director
Technical Staff
Quality Assurance Unit
83
Price
Location
Communications
www.huntingdon.com
Assay Management
Single Registrant/compound
84
www.huntingdon.com
Assay Management
Single Registrant/compound
More than one Laboratory.
A dedicated manager is helpful.
85
www.huntingdon.com
Assay Management
Multiple Registrants/compound
86
www.huntingdon.com
Assay Management
Multiple Registrants/compound
Form a Consortium.
A Consortium manager is necessary.
87
www.huntingdon.com
Androgen Receptor Binding 890.1150
In vitro.
Competitive binding to rat ventral prostate.
Target: HPG axis. (± A)
88
www.huntingdon.com
Aromatase Assay 890.1200
In vitro.
Enzymatic conversion by CYP 19 of androgen to
estrogen (steriodogenesis).
Target: HPG axis. (Synthesis of E)
89
www.huntingdon.com
Estrogen Receptor Binding 890.1250
In vitro.
ER binding – Rat Uterine Cytosol.
Target: HPG axis. (± E)
90
www.huntingdon.com
Estrogen Receptor Transcriptional Activation
890.1300
In vitro.
Binding of the estrogen receptor with a ligand.
Activates a luciferase reporter gene.
Target: HPG axis. (+ E)
91
www.huntingdon.com
Steroidogenesis 890.1550
In vitro.
Production of testosterone and estradiol/estrone.
Synthesis of T, E.
92
www.huntingdon.com
Uterotrophic 890.1600
In vivo estrogenic assay.
Measure uterine weight in in immature or
ovariectomized rats.
Target: HPG axis. (+ E)
93
www.huntingdon.com
Hershberger 890.1400
In vivo Androgenic assay.
Agonist or antagonist.
Weight of five key organs.
Target: HPG axis. (± A)
94
www.huntingdon.com
Female Pubertal 890.1450
In vivo study that targets HPT axis and HPG axis.
(± E, synthesis of E)
95
www.huntingdon.com
Male Pubertal 890.1500
In vivo study that targets HPT axis and HPG axis.
(± A, synthesis of T)
96
www.huntingdon.com
Amphibian Metamorphosis Assay 890.1100
Xenopus laevis tadpoles.
Targets: HPT axis.
97
www.huntingdon.com
Fish Short-Term Reproduction 890.1350
In vivo.
Fathead minnow, reproductive performance.
Targets: HPG axis.
(± E; ± A; Synthesis of E)
98
www.huntingdon.com
Mid-course Corrections
Tier 1 Data
SAPs (SAP: Scientific Advisory Panel)
Science advances
EPA procedures evolve
99
www.huntingdon.com 100
EPA procedures evolve
Central Data Exchange
http://www.epa.gov/cdx
www.huntingdon.com 101
Tox21: High-Throughput Screening
David Dix: High-throughput programs (HTP) such as Tox21 will
“dramatically impact” test orders for List 2 chemicals.
www.huntingdon.com
Scientific Advisory Panels
JAN 2013 Tools to Prioritize Chemicals
MAY 2013 Tier 1 Performance
JUN 2013 Tier 2 Ecotoxicity Tests
JUL 2013 Weight of Evidence
102
www.huntingdon.com
What’s on Your Mind?
When is List 2 coming out?
Is the waiver effort worth it?
What Labs should be chosen?
How long do we have to complete the studies?
Is a Weight of Evidence document necessary?
103
www.huntingdon.com 104
www.huntingdon.com 105
Data Review
Other webinars this week
Tuesday 21st
In vitro tests for endocrine disruption
Leslie Akhurst and Yen-Ling Cheung
Wednesday 22nd
EDSP Tier 1 In Vivo Mammalian Assays
Bob Parker
Thursday 23rd
Amphibian metamorphosis assay for the EPA’s EDSP
Carole Jenkins
HLS EDSP expert team
Ephi Gur – Team lead and Regulatory
Bob Parker – Toxicology
Will Davies – Toxicology
John Carter – In vitro technologies
Carole Jenkins – Aquatic toxicology
Contact via me
+44 (0) 1480 892031
