Prioritysetting for the Endocrine Disruptor Screening Program: Pesticide Active Ingredients

1
Priority-setting for the Endocrine Disruptor
Screening ProgramPesticide Active Ingredients

• Penelope A. Fenner-Crisp
• Office of Pesticide Programs
• U.S. Environmental Protection Agency

2
Food Quality Protection Act Mandates

• EPA MUST
• Screen pesticides (both actives and others) for
  estrogenic effects that may affect human health
• ( may include other effects)
• Develop a screening and testing program by August
  1998
• Implement the screening and testing program by
  August 1999
• Report to Congress by August 2000

3
Proposed Implementation Strategy

• Current Size of the Universe
• 950 pesticide active ingredients currently
  registered in U.S.
• 450 have uses on food/feed
• ( 2500 other ingredients (inerts))

4
Proposed Implementation Strategy

• Proposed elements of the strategy
• Issue exemptions
• Sort and prioritize other (inert) ingredients
  using the EDPSDB
• Revise 40 CFR 158 to include EDSP
• Run Pilot program with 25-50 active ingredient
  substances
• Issue orders periodically for groups of
  substances

5
Proposed Implementation Strategy

• Exemptions-
• Issue exemptions for those biological
  substance(s) or other substance(s) . anticipated
  not to produce any effect in humans similar to an
  effect produced by a naturally occurring
  estrogen or other such endocrine effect.
• Would cover both active and other (inert)
  ingredients

6
EPAs ENDOCRINE DISRUPTOR SCREENING
PROGRAM Currently-registered Other Ingredients
(Inerts)
Total Universe of Chemicals
Est 87,000
SORT
All other Chemicals
Commercial Chemicals lt 10,000 lbs Production
Polymers
Exempted Chemicals
HTPS
Category 1 Hold
Category 2 Insufficient Data, Set Priorities
for Tier 1 Screening
Category 4 Adequate Data
Category 3 Need Tier 2 Test Data
Tier 1 Screening
Tier 2 Testing
Hazard Assessment
7
Proposed Implementation Strategy

• Currently-registered Other Ingredients
• Formerly known as inerts
• Will be sorted for priority along with other
  substances using the EDPSDB
• Special attention will be given to overlap with
  chemicals also on TSCA inventory, especially
  those identified for the HPV and Childrens
  Chemical Evaluation programs

8
EPAs ENDOCRINE DISRUPTOR SCREENING PROGRAM
To-be-registered Pesticides-Actives and Others
Total Universe of Chemicals
Est 87,000
SORT
All other Chemicals
Commercial Chemicals lt 10,000 lbs Production
Polymers
Exempted Chemicals
HTPS
Category 1 Hold
Category 2 Insufficient Data, Set Priorities
for Tier 1 Screening
Category 4 Adequate Data
Category 3 Need Tier 2 Test Data
Hazard Assessment
Tier 1 Screening
Tier 2 Testing
9
Proposed Implementation StrategyTo-Be-Registered
Active and Other Ingredients

• Amendment of 40 CFR 158 to include EDSP
  components
• Requirements may vary with class and use pattern,
  e.g.,
• Requirements may or may not apply at all
• Requirements may be required prospectively or
  triggered

10
EPAs ENDOCRINE DISRUPTOR SCREENING PROGRAM
Already-registered Pesticide Actives
Total Universe of Chemicals
Est 87,000
SORT
All other Chemicals
Commercial Chemicals lt 10,000 lbs Production
Polymers
Exempted Chemicals
HTPS
Category 1 Hold
Category 2 Insufficient Data, Set Priorities
for Tier 1 Screening
Category 4 Adequate Data
Category 3 Need Tier 2 Test Data
Hazard Assessment
Tier 1 Screening
Tier 2 Testing
11
Part 158 Toxicology Data Requirements- Human
Health
Acute oral toxicity Acute dermal Acute
inhalation Primary eye irritation Primary dermal
irritation Dermal sensitization 2 Subchronic
feeding studies 2 Chronic feeding studies 2
Carcinogenicity studies 2 Prenatal
developmental toxicity studies Two-generation
reproduction study General metabolism study
Mutagenicity studies
Dermal penetration 21-day dermal toxicity study
Subchronic inhalation or dermal study (2
Immunotoxicity studies) Acute or subchronic
delayed neurotoxicity Acute neurotoxicity
study Subchronic or chronic neurotoxicity
Developmental neurotoxicity Scheduled controlled
operant behavior Peripheral nerve
function Sensory evoked potential

12
Part 158 Toxicology Data Requirements- Ecological
Effects
Avian and Mammalian Species Avian oral
LD50 Avian dietary LC50 Wild mammal
toxicity Avian reproduction Simulated and actual
field testing
Aquatic Organisms Freshwater fish LC50 Acute
LC50 freshwater invertebrates Acute LC50
estuarine and marine organisms Fish
early life stage and aquatic invertebrate life
cycle Fish life cycle Aquatic organism
accumulation Simulated or actual field testing
13
Already-registered Pesticide Actives
Category 3 Need Tier 2 Test Data
Category 3/4 Have Adequate Data
pre-EDSP, But Need Refinement of Toxicity
Profile for EAT Potential
Category 4 Adequate Data
Tier 2 Testing 2-Generation Study Designs
Tailored testing Screens Less Comprehensive
tests Special Studies
Hazard Assessment
14
PROPOSED SCREENING BATTERY (Tier 1)

• In vitro Screens
• ER Binding / Reporter Gene Assay
• AR Binding / Reporter Gene Assay
• Steroidogenesis Assay with minced testis
• In vivo Screens
• Rodent 3-day Uterotrophic Assay (sc)
• Rodent 20-day Pubertal Female Assay with Thyroid
• Rodent 5-7 day Hershberger Assay
• Frog Metamorphosis Assay
• Fish Gonadal Recrudescence Assay

15
SCREENING BATTERY EXAMPLE 1

• In vitro Screens
• ER Binding or Reporter Gene Assay
• AR Binding or Reporter Gene Assay
• Placental aromatase
• Steroidogenesis Assay with minced testis
• In vivo Screens
• Rodent 3-day Uterotrophic Assay (sc)
• Rodent 20-day Pubertal Male Assay with Thyroid
• Rodent 20-day Pubertal Female Assay w/ Thyroid
• Rodent 5-7 day Hershberger Assay
• Frog Metamorphosis Assay
• Fish Reproduction Screening Assay
• Assays in yellow may replace assays in red

16
SCREENING BATTERY EXAMPLE 2

• In vitro Screens
• ER Binding or Reporter Gene Assay
• AR Binding or Reporter Gene Assay
• Steroidogenesis Assay with minced testis
• In vivo Screens
• Rodent 3-day Uterotrophic Assay (sc)
• In-utero Assay
• Rodent 20-day Pubertal Female Assay w/ Thyroid
• Rodent 5-7 day Hershberger Assay
• Frog Metamorphosis Assay
• Fish Reproduction Screening Assay
• Assay in yellow may replace assays in red

17
TIER 2 TESTING BATTERY

• Multi-generation studies of reproduction and
  development in
• Mammals
• Birds
• Fish
• Invertebrates
• Amphibians

18
TIER 2 TESTING BATTERYLESS COMPREHENSIVE TESTS

• Alternative or Single-generation studies of
  reproduction and development in
• Mammals
• (Alternative test could be in utero assay
  described in Screening Battery Example 2)
• Birds
• Fish
• Invertebrates
• Amphibians

19
Proposed Implementation StrategyAlready-Register
ed Active Ingredients

• Original Proposal
• Implement EDSP on timetable for FIFRA
  Reregistration and/or FQPA Tolerance Reassessment
  mandates

20
Proposed Implementation StrategyAlready-Register
ed Active Ingredients

• Current Proposal-
• Phase 1- Pilot Program with 25-50 potentially
  high EAT hazard concern substances
• Later Phases
• Periodic issuance of FFDCA Section 408p orders
  for additional substances
• May make use of EDPSDB
• May integrate with timetable for Registration
  Renewal

21
Proposed Implementation StrategyAlready-Register
ed Active Ingredients

• Selection process for Phase 1
• Will identify chemicals of potential concern
• from both a human health and ecological effects
  perspective
• using existing published hazard/risk assessments
  (e.g., REDs), internal databases, Data Evaluation
  Records (i.e., study reviews), open literature
  and expert scientific judgment

22
SummaryProposed Implementation Strategy

• Issue exemptions
• Sort and prioritize other (inert) ingredients
  using EDPSDB
• Revise 40 CFR 158 to include EDSP (for
  to-be-registered substances)
• Run Pilot program for 25-50 (already-registered)
  active ingredient substances
• Issue orders periodically for groups of
  (already-registered) substances