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What Information Fulfills EDSP Screening Requirements?. Steve Levine, Ph.D. Science Fellow Ecotoxicology & Risk Assessment Monsanto Company ISRTP Meeting September 9, 2009. Topics Covered. Background on the EDSP EDSTAC recommendations

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what information fulfills edsp screening requirements

What Information Fulfills EDSP Screening Requirements?

Steve Levine, Ph.D.

Science Fellow

Ecotoxicology & Risk Assessment

Monsanto Company

ISRTP Meeting

September 9, 2009

topics covered
Topics Covered
  • Background on the EDSP
    • EDSTAC recommendations
  • Functional equivalence and Other Scientifically Relevant Information (OSRI)
  • International Regulatory Guideline Studies
    • TOX
    • ECOTOX
  • WoE approaches
tier 1 screening
Tier 1 Screening
  • The number of substances planned for Tier 1 screening is staggering
    • Pesticides
    • Commercial chemicals
    • Cosmetic ingredients
    • Food additives
    • Nutritional supplements
    • Certain mixtures
  • Therefore, screening must be efficient, robust, and predictive at identifying potential EACs
edstac framework
EDSTAC Framework
  • Priority setting
    • Based on potential human exposure
      • residues in food and drinking water
      • residential
      • occupational
    • Higher priority given to chemicals likely to have human exposure via multiple pathways
  • Tier 1 screening
    • In vitro and in vivo assays
    • Identify chemicals that can potentially interact with the endocrine system
  • Tier 2 testing
    • Will establish the relationship between dose of an EAC and the potential effects observed
    • Assess risks humans and wildlife
edstac recommendations
EDSTAC Recommendations
  • Recommended a minimal number of screens & tests to make sound decisions, thereby, reducing the time needed to make decisions
    • T1S screens should be MoA based to identify specific types of endocrine activity
    • Should be broadly predictive (sensitivity & specificity)
    • Should produce data that can be interpreted as either positive or negative (minimize Type I & II error rates)
    • Should be inexpensive and relatively quick and easy to perform

Alternative Means to Meet

Tier 1 Screening

  • EDSTAC recommended that it should be permissible to meet T1S requirements by submitting data that are “functionally equivalent” to the data generated by the T1S battery
  • Functionally equivalent information could be submitted for one or more of the recommended T1S assays or for the entire battery
  • Pointed out that functionally equivalent informationexists for chemicals that have reproductive and developmental toxicity testing
functional equivalence osri
Functional Equivalence & OSRI
  • Functional equivalence = data of a suitable nature and quality even if different methods were used i.e., provides the same essential predictive information as T1S
  • OSRI = information that informs the determination as to whether the substance may have a similar effect produced by a substance that interacts with EAT systems
  • OSRI may either be (1) functionally equivalent to information obtained from the Tier 1 assays or (2) data from assays that perform the same procedure / function as EDSP Tier 1 Screens

EPA’s Approach for Considering OSRI

  • Overview paper @ www.regulations.gov
  • Anyone may submit OSRI not just Test Order Recipients
  • Submitters should provide the information or cite previously submitted information
  • Information will receive different weights in a WoE - the quality of the information will weigh heavily
  • Factors will include sensitivity, specificity, confidence in the conclusions and applicability across taxa
  • Factors will also include route & duration/frequency of administration, dose levels, age at exposure, species, number of test units, variability, and whether the data provides a basis for conclusions for potential interaction with the endocrine system in mammalian and non-mammalian systems
  • OSRI for Tier 1 or Tier 2: metabolism, carcinogenicity, reproductive and developmental, and toxicogenomic
osri from oppts and oecd tests
OSRI from OPPTS and OECD Tests
    • Sub-chronic (OPPTS 870.3100)
    • Chronic (OPPTS 870.4100)
    • Developmental/Teratology (OPPTS 870.3700)
    • 2-gen reproduction (OPPTS 870.3800)
    • Avian reproduction (OPPTS 850.2300)
    • Chronic invert reproduction (OPPTS 850.1300/1350)
    • Early Life-stage (OPPTS 850.1400)
    • Fish full life-cycle (OPPTS 850.1500)
osri will include
OSRI Will Include
  • Toxicity tests following international regulatory guidelines where full histopathology is carried out on:
    • Endocrine tissues (pituitary, thyroid, parathyroid, pancreas adrenal, ovary and testis)
    • Hormone sensitive male tissues (prostate, epididymides, seminal vesicles)
    • Hormone sensitive female tissues (mammary, uterus and reproductive tract)
  • And toxicity protocols that focus on reproduction, fertility and development for mammalian species and other taxa (birds, fish)
  • These studies provide the strongest evidence of potential endocrine effects and should be weighted above less comprehensive data
rat multi gen
Rat Multi-Gen
  • The 1996 USEPA guideline for a multiple generation reproductive and developmental toxicity assay was revised to include developmental benchmarks predictive of ED potential
    • A diverse set of female endpoints (ovaries, uterus, vagina, and mammary glands)
    • Day of vaginal opening and first estrus
    • Mating and fertility indices
      • number of implantation sites, estrous cyclicity
    • Male tissue weights and histopathology (testes, epididymis, prostate, and seminal vesicles) and other male parameters (sperm number and analyses)
bridging osri to t1s assays
Bridging OSRI to T1S Assays
  • High concordance between the results of rat multi-gen and the rat Uterotrophic assay
  • Consistency between MEDs for the Uterotrophic assay and estrogen-related LOEL/LOAEL in multi-generation testing
  • High concordance between the Uterotrophic assay and the ER binding assay & the stably transfected TA for a large number of chemicals
  • 2-gen data should meet the requirement for the pubertal assays:
    • Pubertal assays largely have redundant endpoints with the 2-gen study
osri to t1s assays ecotox
OSRI to T1S Assays - ECOTOX
  • Avian reproduction studies
    • Gold standard or highest tier of avian testing
    • Bobwhite quail and mallard duck
    • Studies do not include exposure during all relevant stages of development or organ histopathology
    • However, provides valuable information in a WoE context to assess potential effects of endocrine active substances
    • Sensitivity of 1-gen vs 2-gen Japanese quail?
  • Reproduction study design
    • Dietary exposure for ~10 weeks prior egg-laying
    • Photoperiod change initiates egg-laying
    • Exposure continues for ≥8 weeks
    • Endpoints: eggs laid, eggs damaged, eggs set, egg shell thickness, viable embryos, live embryos, hatchlings, 14-day survivors, eggs laid/female, eggs laid/female/day, 14-day survivors/female
osri to t1s assays ecotox1
OSRI to T1S Assays - ECOTOX
  • Fish full life cycle (FFLC) study
    • Gold standard for aquatic vertebrate ecotox testing
    • Entire LC is exposed = most sensitive life-stage is tested
    • ~260 to 300 days for FTHD minnows = T1S spp.
  • FFLC study design
    • ELS → growth & repro → ELS
    • First gen: hatching success, time-to-hatch, survival, growth and development, reproductive success (# of spawns, # of eggs)
    • Second-gen: time-to-hatch, survival, growth and development
principles for evaluating data in a woe
Principles for Evaluating Data in a WoE.
  • Consistent pattern of responses for a MoA (+ or -)
  • The nature and range of the biological effects observed
  • The shape of DRCs curves when available
  • The severity and magnitude of the effects
  • Interpretation made in the context of biological significance & biological plausibility
  • The presence or absence of responses in multiple taxa
  • Evaluate results in the context of natural variability using control data (historical and concurrent)
principles for evaluating data in a woe1
Principles for Evaluating Data in a WoE
  • Results from apical assays (MTD dose) need to be weighted appropriately when accompanied by decreases in BW or other potential confounders
  • In vivo results generally are considered to have more weight than in vitro results
  • Available in vitro assays should not be used as yes/no determinants to proceed to Tier 2 (ER binding example)
  • SARs = critical step in the WoE process
  • A WoE approach for OSRI must be developed along with the WoE framework for the T1S
closing thoughts
Closing Thoughts
  • SARs are OSRI and weighted appropriately
  • There will be instances where OSRI will meet all or some of the T1S requirements, particularly for food use pesticides.
  • Development of a transparent WoE approach is desperately needed not only in the interpretation of OSRI but for the T1S data before testing is required.