US Environmental Protection Agency
Office of Pesticide Programs
 Tools for Integrated Approaches to
 Testing and Assessment
        June 25, 2009


The following tables reflect the Office of Pesticide Program's near (1-5 years) and long term (5-10 years) plans to incorporate new
scientific tools for Integrated Approaches to Testing and Assessment. The priority setting and screening tools listed in Tables 1 and 2
would be applied in the near term within our current assessment practice for making decisions regarding the safety of pesticides for
both humans and wildlife.

The tools listed in Table 1 are designed to make existing animal tests more focused on risk assessment and management needs by
guiding work on an individual chemical or prioritizing work for groups of chemicals.

The key objective of tools listed in Table 2 is to replace an animal test with reliable non-animal methods and to ensure the efficiency
of animal testing by using tiered testing or improving  study designs .

Table 3 represents the longer term effort that will transition our current practice into a new risk assessment paradigm using fewer
whole animal tests. This new paradigm relies on understanding how chemicals perturb toxicity pathways.

       Table 1: Priority Setting and Screening Computational Predictive Tools.
       Table 2: Replacement Tests or Modified Protocols to Traditional Animal Studies
       Table 3: Longer Term Tool Development to Support a Paradigm Shift in Testing and Assessment

The tools listed in Tables 1 and 2  will enable a transition into a new paradigm of toxicity testing. Essential to shifting toward a new
paradigm is the building of improved predictive models (i.e, Tables 1 & 2) along with fundamental research that  identifies critical
pathways of toxicity and establishes linkages across the different levels of biological organization (chemical interaction with a
molecular target, cellular response, tissue or organ effect and consequent adverse effect on the organism).

         Table 1. Priority Setting and Screening Computational Predictive Tools. In the near term (1-5 years), OPP plans to build
  capacity and expand its suite of computational tools to allow more efficient toxicity testing by quickly identifying the likelihood of
  potential toxicity effects without conducting the full set of in vivo toxicological studies.  These tools largely draw on profiles of
  substances with similar physio/chemical properties and biological modes of action.
                           Examples of
                     Examples of Tools
                     in Development or
                     Under Evaluation
                                                                          QSAR-Based Expert
                                                                            System for
                                                                          Metabolic Simulator
                                                                          FDA QSAR Models
                                                                          -expansion to
                                                                          pesticide chemicals
   Example OPP Milestones
 Enhance ability to predict
  chemical toxicity by developing
  new models and populating
  existing models with pesticide
  based training sets so that
  computational methods are
  more useful for pesticides
 Build upon already existing
  knowledge for use with data-
  limited chemicals, such as the
  pesticide inert ingredients,
  certain antimicrobial pesticides,
  metabolites and environmental
  degradates of pesticides as well
  as manufacturing process
 Reduce animal testing by
  appropriately directing data
  generation toward the most
  likely hazards/risk of concern
Models that use existing
 QSAR Models
 Expert Systems
 Knowledge Bases
 Read Across from
 EPI Suite
 PBT Profiler

 October 2007 - OPP's Residue of
 Concern Knowledgebase
 Subcommittee (ROCKS) is
 established to provide a systematic
 and consistent weight of evidence
 approach that fully utilizes
 available tools of computational
 toxicology to develop hazard
 determinations for pesticide
 metabolites, residues and
 environmental degradates of
 December 2007- EPA hosts
 Integrated Approaches to Testing
 and Assessment Organization for
 Economic Cooperation and
 Development (OECD) Workshop
 October 2008 -Letter agreement is
 signed between FDA and OPP to
 build toxicity databases on
 Pharmaceuticals and pesticides to
 support better hazard predictions
 across different chemical classes
 and modes of action
 2009- February OECD Expert
 Consultation and        F1FRA

Examples of
Examples of Tools
in Development or
 Under Evaluation
Example OPP Milestones
                                                                                               SAP       on QSAR-Based
                                                                                               Expert System for Predicting
                                                                                               Estrogenic Activity for food use
                                                                                               inert ingredients and antimicrobial
                                                                                              March 2009 - OPP and Canada's
                                                                                               Pest Management Regulatory
                                                                                               Agency (PMRA) conduct a
                                                                                               validation exercise for
                                                                                               approximately 50 pesticides with
                                                                                               three different QSAR models to
                                                                                               determine whether these models
                                                                                               could predict known pesticide
                           Models based on
                           generation of new data:
                               Profiling with in
                               vitro High Through-
                               put (HTS) Systems
                                   ToxCast  Research
                                   (http ://www. epa. gov/nc
                                         May 2009 - Analysis of HTS data
                                          on -300 pesticides (ToxCast Data
                                          Summit Meeting:
                                          http ://www. epa. gov/ncct/toxcast/s
                                         Spring-Summer 2009- Selection
                                          of additional chemicals (including
                                          inert ingredients and pesticide
                                          active ingredients) for evaluating
                                          the applicability of ToxCast to
                                          predict toxicity potentials
                                         2011- SAP meeting on ToxCast
                                          predictive application
                                         2012  - ToxCast implementation

       Table 2. Replacement Tests or Modified Protocols to Traditional Animal Studies. These models are intended to replace
       animal testing or reduce animal usage in in vivo tests in the near term (1-5 years).
  Examples of Current
  Examples of New
                                                                                                      Example Milestones
 To reduce, refine, and
  replace animal testing
  for those traditional
  animal studies
  performed for
  purposes of risk
  assessment or labeling.
 Non-testing computer-
 aided methods to
 determine need for a
 specific study
 In vitro model to replace
 an animal test
 Redesigned animal
 study that maximizes the
 information gained and
 results in a reduction in
 the number of animal
 studies performed
Standard animal toxicity
guideline tests
QSAR/SAR in lieu of
animal testing
  EPA White Paper on "Use of
  Structure-Activity Relationship
  (SAR) Information and
  Quantitative SAR (QSAR)
  Modeling for Fulfilling Data
  Requirements for Antimicrobial
  Pesticide Chemicals and
  Informing EPA's Risk
  Management Process" in support
  of proposed rule  on data
  requirements for  antimicrobial
  pesticides. (Docket: 2008-0110
  Document 0045)
                                                  Up and Down Method for
                                                  Acute Toxicity (LD50)
                                                  Testing (replaces
                                                  traditional Acute LD50
                                                  Toxicity Test)	
                                                  Draize rabbit eye test
                                                   Non-animal approaches
                                                   to labeling for eye
                                                   irritation hazards, e.g.,
                                                   Bovine Corneal Opacity
                                                   and Permeability,	
                                                     May 2009 Interim Pilot using
                                                     non-animal assays for labeling
                                                     antimicrobial cleaning products
                                                     for ocular irritation/hazard (at
                                                     http ://www. 1)

                                                                       EpiOcular, and
                                                                       Microphysiometer assays
                                            Guinea Pig Maximization
                                            or Buehler Test
                           Several in vitro assays
                           for skin sensitization are
                           under evaluation or
                           development that would
                           replace in vivo testing
  Currently under evaluation by
  ICCVAM; the assays are
  anticipated to be available for use
  over the next 1-3 years
                                            2-generation reproductive
                                            toxicity study
                                            Data Requirement:
                                            Reproduction and fertility
                                            effects (Guideline
                           Redesigned Extended
                           Reproductive Study
 November 2009: SAP review of
  Enhanced Fl Tiered Testing
 2010 EPA Test Guideline
 2012 New Data Requirement in
  40 CFR Part 158
                                                                       Work underway to
                                                                       design PK studies as part
                                                                       of standard toxicity
                                                                       studies to improve dose
                                                                       selection, dose response
                                                                       and species
Physiologically Based
Pharmacokinetic (PBPK)
Models to refine dose
selection and animal usage
in toxicity studies
 August 16 - 17, 2007: Assessing
  Approaches for the Development
  of PBPK Models of Pyrethroid
                                            Toxicogenomics data
                                            extracted from traditional
                                            animal studies.
                           Application of
                           toxicogenomics to inform
                           mode of action analysis,
                           human relevance, and
  Spring 2010. OPP/SAP to review
  the applicability of
  toxicogenomics in pesticide
  cancer assessment using
  conazoles as an example.	

Table 3.  Longer Term (5-10 years) Tool Development to Support a Paradigm Shift in Testing and Assessment.
                             Goal / Uses/Benefit
     Examples of Types of Tools
   Develop the means to move, in a scientifically credible and transparent
   manner, from a paradigm that requires extensive animal hazard testing and
   generation of exposure data, to a paradigm that provides the means to use a
   risk-based, hypothesis-driven approach that is based on full use of
   computational toxicology tools.  These tools must be grounded by
   knowledge of toxicity pathways that are perturbed under realistic exposure
   More accurate and focused risk assessments and risk management
   Risk assessments based on understanding of mode of action
   Substantial reduced reliance on animal testing
HTS and "omics" methods (genomics,
transcriptomics, proteomics,) to inform
mode of action  and identification of
toxicity pathways.
Virtual Organ Models (e.g., virtual liver
and embryo)
System biology approaches
New generation of environmental
modeling tools for fate and transport and
human exposure
Well characterized biomarkers of effect
and exposure