The Dossier for New Insecticide Active Ingredients
Purpose
Clarify types of safety data to collect for vector control insecticides.
Stimulate ideas and dialogue to improve the efficiency and accuracy (more predictive) of the testing paradigm.
Risk Management Goal:
“Deliver important public health protection and access to
benefits with increased efficiency and accuracy.”
Disclaimer: This is not a formal
proposal from the WHO or IVCC.
The Dossier for New Insecticide Active Ingredients
Determining the Dossier Requirements
Framework and Guiding Concepts (Vicki Dellarco)
Toxicology Requirements: Human Health Effects (Werner Bomann) and
Ecological Effects (Patrick Rose)
Risk Modeling (Patrick Rose)
Group Discussion (suggested topics)
Practicality of Proposed Testing Strategy and Ideas to Improve or Clarify
Regulatory or Review Body Acceptance of Nontraditional Methods
Issues Concerning Risk Modeling
Product Chemistry
Toxicology
Terrestrial and Aquatic Nontarget Organism
What would a dossier look like for vector control?
science to be more predictive.
Satisfying Requirements:
• Value of a decision framework to promote focus, consistency and
transparency in determining what information is needed.
• Importance of leveraging existing knowledge and best available
science to be more predictive.
[Code of Federal Regulations: http://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=defff547e08d4c95b31ba9bd2d56aa93&mc=true&n=pt40.26.158&r=PART&ty=HTML]
Global focus on Improving Toxicity Testing and Assessment:
(More Predictive and Efficient)
Problem Formulation and Hypothesis-Based Approaches in
a Risk-Based Decision Framework with Tiered Analysis.
ILSI/HESI Agricultural Chemical
Assessment Project, 2006
OECD, Integrated Approaches to Testing
and Assessment informed by AOP, 2008/15
ILSI/HESI Risk21 Project, initiated
2014
EPA/OPP Guiding Principles for Data
Requirements; 21 Century Strategic Vision
Focus on the information that matters.
Determining the Toxicology Dossier
Cellular Organ IndividualExposure/PK Molecular
Combine data from different sources, Computational, in vitro, and in vivo methods.
Approach Informed by Adverse Outcome Pathway Knowledge
1. Start with problem formulation and define vector control
exposure scenario. (use patterns/pesticide label).
2. Formulate and evaluate risk hypotheses by integrating existing
exposure and effects data.
3. Target further data generation where required to assess a given exposure.
Problem Formulation and Hypothesis-Based Approach in a
Risk-Based Decision Framework
4. Use a tiered approach defined by acceptable risk levels (simple
to more refined, as necessary).
What information other
than that derived from test
guidelines may provide
sufficient knowledge to
inform a risk assessment
with sufficient certainty for
the regulatory decision?
1. Start with problem formulation
and define vector control exposure
scenario.
2. Formulate and evaluate risk
hypotheses by integrating existing
exposure and effects data.
3. Target further data generation where required to inform regulatory decisions.
4. Use a tiered approach defined by
acceptable risk levels (simple to
more refined, as necessary).
Determining the Toxicology Dossier
Value of existing knowledge in addressing specific health effects.
Read-Across
Waiver
Alternative Ways to Satisfy Data (Information) Requirements
Improved Study
Designs
Note: Authorities should be consulted for alternative approaches.
Certain toxicology studies may be combined and/or
augmented to satisfy data requirements.
If a specified data requirement is not appropriate
for a particular product, a waiver can be requested.
Existing knowledge on the insecticide’s chemical class
may enable a chemical-to-chemical extrapolation.
Combination of the above
(weight-of-evidence)
EPA Guidance
• Acute Toxicity Studies.https://www.epa.gov/sites/production/files/docu
ments/acute-data-waiver-guidance.pdf.
• Neurotoxicity Battery, Subchronic
Inhalation, Subchronic Dermal and
Immunotoxicity Studies..https://www.epa.gov/sites/production/files/2014-
02/documents/part158-tox-data-requirement.pdf.
• A waiver could be requested for any
required data, e.g., developmental, reproductive, chronic/carcinogenicity
toxicity.
Waiver Rationales can be based on “Read-Across
Similarity Hypotheses” for the absence of an effect.
A data requirement could be waived, if based on strong scientific grounds.
A data requirement could be waived, if based on strong scientific grounds.
Waiver Rationale Based on Weight of Evidence
• Use/exposure, risk assessment impact.
• Physical-chemical properties.
• Toxicological data from existing
studies.
• Mode of action, toxicokinetics.
• Information on structurally similar chemicals.
Read-Across Assessment: Endpoint
information for a chemical(s) is used
to predict the same endpoint
(presence or absence) for another chemical that is considered to be
‘similar’ (structure, mode of action).
A data requirement could be satisfied by a “Read-Across Strategy”, if based on strong scientific grounds.
A data requirement could be satisfied by a “Read-Across Strategy”, if based on strong scientific grounds.
Reference Chemicals
Target Chemical
missing datareliable data
• Tools and guidance available
(ECHA, OECD, EPA), e.g., https://echa.europa.eu/support/registr
ation/how-to-avoid-unnecessary-testing-on-animals/grouping-of-
substances-and-read-across
• Pesticide regulatory examples,
including isomers, metabolites
and degradates; acute toxicity/formulations.
Using Biological Similarity to Strengthen Read-Across
Must be robust for regulatory acceptance
• Strengthen similarity rationale and increase confidence by
using concept of biological read-across.
• High quality data on structurally similar chemicals for endpoint of
interest.
• Supporting data on target chemical to bridge to reference
chemicals
• Data on toxicokinetics/metabolism, mode of action.
• Good coverage of chemical space.
Note: Authorities should be consulted for alternative approaches.
Cellular Organ IndividualExposure/PK Molecular
Combine data from different sources, Computational, in vitro, and in vivo methods.
Approach Informed by Adverse Outcome Pathway Knowledge
Framework for Determining the Toxicology Dossier
1. Start with problem formulation
and define vector control exposure
scenarios.
2. Formulate and evaluate risk
hypotheses by integrating existing
exposure and effects data.
3. Target further data generation where required to inform regulatory decisions.
Define exposure
scenarios to identify
populations of concern,
timeframes (durations,
frequencies), routes,
and magnitudes of
exposure that must be
assessed.
4. Use a tiered approach defined by
acceptable risk levels (simple to
more refined, as necessary).
• Treated Nets
• Sleeping under insecticidal nets
• Handling and washing of nets
• Do-it-yourself net treatment (dipping)
• Spraying (indoor/outdoor)
• Indoor residual spraying (IRS) by operators, and post application exposure (residents, operators).
• Larvicide outdoor spraying by operators, and post application
exposure (residents and operators).
• Indoor and outdoor space spraying by operators and post-application exposure (residents and operators).
Vector Control Exposure Scenarios
Vector Scenario Population Route Duration
Sleeping under treated nets
All ages
Dermal, Incidental
oral (inhalation
likely negligible)
Long-term
Net washing Adults, ChildrenDermal, Incidental
oral
Acute
Long-term
(20 washes over 3 yrs)
IRS Application Operators Dermal, Inhalation
Acute
Long-term
(72 days/365 days)
IRS Post-Application
Operators and
residents (all
ages)
Dermal,
Incidental oral
(inhalation likely negligible)
Acute
Long-term
(6 months interval)
Short-term?(< 6 month interval)
Exposure Scenarios (Based on WHO Models)
Potential Environmental Exposure Scenarios Associated with Vector Control Insecticides
• Treated nets:
• washing nets (aquatic organisms),
• disposal of treatment solution (aquatic organisms),
• sweeping dead insects outdoor (secondary poisoning of
birds) - likely to be minimal.
• Indoor residual spraying:• sweeping residues outdoor (soil organisms, birds) - likely to
be minimal, but depends on frequency of use and
persistence of the insecticide.
Formulating and evaluating risk hypothesis based on
exposure (spatial and temporal) and effects characteristics.
Traditional Test Guideline Studies Needed for Assessing Vector Control Scenarios:
• Product chemistry
• Acute toxicity studies (oral, dermal, inhalation; skin and eye irritation; dermal sensitization)
• Genetic toxicity studies (in vitro, in vivo)• 28/90 day rat (oral)• 90 day dog (oral)• 28/90 day rat (dermal)• Rat and rabbit prenatal developmental studies (oral)• Reproductive/fertility study (oral)• Chronic/cancer rat; cancer mouse (oral) (if >6 month human exposure)• Special studies (if an issue arises, e.g., neurotoxicity, endocrine, mode of action)• Oral ADME• Dermal rat (in vivo) and/or in vitro rat/human dermal absorption (if dermal pathway
needs to be refined.)
Toxicology Information (Human Health)
While regulatory authorities have tables of data requirements, certain
‘required’ data may not be needed or can be addressed in other ways
based on exposure, chemical properties, existing knowledge, etc.
While regulatory authorities have tables of data requirements, certain
‘required’ data may not be needed or can be addressed in other ways
based on exposure, chemical properties, existing knowledge, etc.
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, short-term or intermediate-term)
Inhalation exposure pathway
(repeated exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or 90-day oral
toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to refine estimates and endpoints, and address special toxicities (e.g., neurotoxicity, immunotoxicity, endocrine toxicity).
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative approach to
address, e.g., read-across/SAR, modified protocol,
mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential use
of an alternative approach to address,
e.g., read-across/SAR, modified
protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(short-term or intermediate-term)
If risk threshold is exceeded, proceed to
refine by conducting in vitro rat/human and
if required in vivo rat dermal penetration
study.
If there is a likelihood of effects presenting after a single dose,
use data from repeat dose studies to assess acute exposure
scenarios. If risk threshold is exceeded, proceed to refine
exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
Figure 1. Health Effects: Propose Testing Strategy for Vector Control Insecticides
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, short-term or intermediate-term)
Inhalation exposure pathway
(repeated exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to augment standard protocol or conduct separate studies to address special or target organ effects.
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(short-term or intermediate-term)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Step 1: Define vector control exposure scenarios (population, route, duration),
including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and
effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common
toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev tox, fertility)
• ADME studies (biological half life, etc)• Conduct preliminary risk assessments
Product Chemistry is a basic requirement for all scenarios: Significance of human and
environmental exposure can be assessed based on physical-chemical properties, and data
can be used in a weight-of-evidence approach to justify a waiver for test guideline studies.
Figure 1. Health Effects: Propose Testing Strategy for Vector Control Insecticides
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, short-term or intermediate-term)
Inhalation exposure pathway
(repeated exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to augment standard protocol or conduct separate studies to address special or target organ effects.
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(short-term or intermediate-term)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Step 1: Define vector control exposure scenarios (population, route, duration),
including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and
effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common
toxophore)
• findings on effects from mutagenicity battery, preliminary acute and oral rat short-term toxicity studies (e.g.14/28-day, dev tox, fertility)
• ADME studies (biological half life, etc)• Conduct preliminary risk assessments
Traditional: ADME studies are a basic requirement and should
be conducted prior to conducting repeated dose toxicity studies.
Nontraditional: To further refine the assessment consider
additional toxicokinetic data to guide dose selection, route-to-
route extrapolations (e.g., understanding first pass effects, oral absorption) and estimating internal or systemic dose for routes of
interest (versus administered dose).
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, repeat exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to refine estimates and endpoints, and address special toxicities (e.g.,neurotoxicity, immunotoxicity, endocrine toxicity).
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Dermal exposure
pathway
(acute, repeat exposure)
Inhalation exposure
pathway
(acute, repeat exposure)Traditional: 28 or 90-day Dermal Toxicity Test
Guideline
If risk threshold is exceeded, proceed to refine by conducting in vitro rat/human and if required in
vivo rat dermal penetration study.
Nontraditional: In lieu of traditional dermal
toxicology study, conduct comparative oral and
dermal PK (understand systemic dose) and dermal penetration studies.
If repeated inhalation exposure is
significant,
Traditional: 28 or 90-day inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, short-term or intermediate-term)
Inhalation exposure pathway
(repeated exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to augment standard protocol or conduct separate studies to address special or target organ effects.
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(short-term or intermediate-term)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Step 4. Conduct test guideline studies which may be used to derive reference
values - 28 or 90-day oral toxicity and prenatal studies - and assess vector
control scenario with oral values.
Consider need to address special or target organ effects.
Special Toxicities
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
Special Toxicities
Neurotoxicity (EPA requirement) A number of insecticides target the nervous system, some do
not.
Immunotoxicity (EPA requirement)Studies of most pesticides showed no effects on the immune
system (retrospective analyses by EPA and CropLife).
Endocrine toxicity (OECD and EPA Test Guidelines) Much attention and ongoing debate.
Special Toxicities(Neurotoxicity, Immunotoxicity, Endocrine Toxicity)
Test guideline studies already incorporate a number of measures to help determine whether or not a specialized study is needed.
If there are no alerts, consider waiver weight-of-evidence rationale:
Data on structural analogs, mode of action, early testing results from 14, 28, or 90-day, developmental/reproductive screening studies.
Waiver rationale could be further strengthened by incorporating additional endpoints
(e.g., hormonal measures) into traditional sub-chronic test guidelines or with in
vitro mechanistic data.
If a concern is raised by existing data, address by:
Traditional – follow specific test guideline (neurotoxicity, immunotoxicity).
Further investigate endocrine with in vitro or short term in vivo specifically designed studies, or do extended F1 study.
Nontraditional (Alternative) - Read-across (must be robust to predict a conservative NOAEL).
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, repeat exposure)
Inhalation exposure pathway
(acute, repeat exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to refine estimates and endpoints, and address special toxicities (e.g.,neurotoxicity, immunotoxicity, endocrine toxicity).
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(acute, repeat exposure)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
If exposure is long-term (>6 months)
Traditional: Multi-generation reproductive test guideline study.
Alternative: Extended F1 test guideline study, and if necessary add cohorts for
special toxicities (neurotoxicity, immunotoxicity)
Nontraditional: Read-across supplemented with early screening tests and mechanistic data (in vitro/in vivo). Must be robust.
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, repeat exposure)
Inhalation exposure pathway
(acute, repeat exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to refine estimates and endpoints, and address special toxicities (e.g.,neurotoxicity, immunotoxicity, endocrine toxicity).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(acute, repeat exposure)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
If exposure is long-term (>6 months)
C read-across/SAR, modified protocol,
mechanism studies, rat only).
Cancer
Traditional Approach:
• Oral rat chronic and rat/mouse cancer bioassays
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
Nontraditional: • Read-across strategy supplemented with mechanistic data
(in vitro/ in vivo) and relevant in vivo organ weight and histopathology data.
• Rat bioassay only supplemented with relevant data from shorter-term studies and mechanistic information.
Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,
• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)
• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev
tox, fertility)
• ADME studies (biological half life, etc)
• Conduct preliminary risk assessments
Incidental oral exposure pathway
(acute, repeat exposure)
Inhalation exposure pathway
(acute, repeat exposure)
If repeated inhalation exposure is
significant, conduct 28 or 90-day
inhalation rat toxicity study to
characterize port-of-entry and systemic effects.
Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or
90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.
Consider need to refine estimates and endpoints, and address special toxicities (e.g.,neurotoxicity, immunotoxicity, endocrine toxicity).
If exposure is long-term (>6 months)
Conduct oral rat chronic and rat/mouse cancer
bioassays (consider use of an alternative
approach to address, e.g., read-across/SAR,
modified protocol, mechanism studies, rat only).
New Active Ingredient
Reproduction
Tiered and
Iterative
Process
Consider reproduction rat (potential
use of an alternative approach to
address, e.g., read-across/SAR,
modified protocol, mechanism studies, endocrine screening)
Dermal exposure pathway
(acute, repeat exposure)
If risk threshold is exceeded,
proceed to refine by conducting in
vitro rat/human and if required in vivo
rat dermal penetration study.
If there is a likelihood of effects presenting after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded,
proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.
Acute exposure
Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides
If there is a likelihood of effects occurring after a single
dose, use data from repeat dose studies to assess acute
exposure scenarios. If risk threshold is exceeded, proceed to refine exposure
estimate or refine endpoint by conducting appropriate single dose study focusing on the endpoint of concern.
Figure 2. Ecological Effects: Proposed Testing Strategy for Vector Control Insecticides
Step 1: Define exposure scenarios.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of the physical-chemical properties of the substance.
Step 4: For each intended use evaluate the potential for exposure. Develop a representative exposure scenario and determine if exposure
is likely to be negligible.
Exposure to birds
Is there potential for exposure to birds via contaminated insects? (Sweeping from house)
If exposure is likely to be negligible, further assessment not required.
But if exposure in a significant amount cannot be ruled out, assessment of toxicity to
birds is required:
Acute/chronic studies with birds (or surrogate data from mammalian data as screening).
New Active Ingredient
Risk to soil organisms
If exposure to soil cannot be ruled out, assess:
Acute toxicity to earthworms (by studies or
screening step with equilibrium partition
calculation)
Toxicity to soil micro-organisms (carbon,
nitrogen transformation)
Chronic toxicity relevant?
Risk to aquatic organisms
If exposure to water cannot be ruled out, assess:
Acute toxicity to fish
Acute toxicity to aquatic invertebrates
Toxicity to algae
Chronic toxicity relevant?
Is substance likely to be persistent?
Assess DT50 in soil/water. If short (few
days), then unlikely to be persistent and
chronic exposure not relevant.
Consider frequency of intended uses, if
exceeds DT50 then prolonged exposure
cannot be ruled out and chronic toxicity is
relevant.
Bioaccumulative, Log Kow > 3?
If there is potential for bioaccumulation, secondary poisoning to
birds/mammals via fish and earthworms needs to be assessed.
Physical-chemical properties - Play a role in
assessing exposure potential.
• Degradation rate expressed as half-life (DT50)
• Octanol:water partition coefficient (log Kow)
• Soil-organic carbon:water partition coefficient (Koc)
Ecological Effects: Testing Strategy
Risk to soil organisms
If exposure to soil cannot be ruled out, assess:
• Acute toxicity to earthworms (by studies or screening step with equilibrium partition calculation)
• Toxicity to soil micro-organisms (carbon, nitrogen transformation)
• Chronic toxicity relevant?
Is substance likely to be persistent?
Assess DT50 in soil/water. If short (few days), then unlikely
to be persistent and chronic exposure is not relevant. Consider frequency of intended uses, if exceeds DT50
then prolonged exposure cannot be ruled out and chronic toxicity is relevant.
Step 1: Define exposure scenarios.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of the physical-
chemical properties of the substance.
Risk to aquatic organisms
If exposure to water cannot be ruled out, assess:
• Acute toxicity to fish
• Acute toxicity to aquatic invertebrates
Toxicity to algae
• Chronic toxicity relevant?
Step 4: For each intended, use evaluate the potential for exposure. Develop a
representative exposure scenario and determine if exposure is likely to be negligible.
Ecological Effects: Testing Strategy
Step 1: Define exposure scenarios.
Step 2: Formulate risk hypotheses for each exposure scenario.
Step 3: Evaluate risk hypotheses based on available knowledge of
the physical-chemical properties of the substance.
Step 4: For each intended use evaluate the potential for exposure.
Develop a representative exposure scenario and determine if
exposure is likely to be negligible.
Potential for exposure to birds via contaminated insects? (sweeping from
house etc)
➡If exposure is likely to be negligible, further assessment not required.
➡If exposure in a significant amount cannot be ruled out assessment of
toxicity to birds is required,
• Acute/chronic studies with birds (or surrogate data from mammalian
data as screening).
Bioaccumulative? (Log Kow > 3)
➡If there is potential for bioaccumulation, secondary
poisoning to birds/mammals via fish and earthworms
needs to be assessed.
What models are available?
• Various guidance documents and models for estimating exposure to insecticides are available, mostly in the US and Europe.
• The WHO has developed generic guidance / models for public health insecticides used in vector control.•Aim to harmonise the risk assessments for each type of
application. •Derived from US EPA and EU models.
•The WHO models (conservative assumptions) are useful for initial risk analyses - commonly used for vector control dossiers submitted to WHOPES.
• If the risk threshold is exceeded, refined input parameters and improved risk assessment models should be considered, as appropriate.
WHO Generic Risk Assessment Models – Vector ControlAll models are to be updated for 2017 – proposed changes issued
September 2016
ITNs Human Health Risk Assessment Model. Revised Edition, 2012.
Sleeping under nets, washing nets, conventional treatment of
nets with insecticide (does not include risks associated with manufacturing nets in a factory environment)
IRS Human Health Risk Assessment Model. First Revision, 2011.
Operator mixing/loading and application; residents living in
treated houses, residents who are also operators
Indoor and outdoor space spraying
Human Health and Environmental Risk Assessment Model. First Revision, 2011.
Operator mixing/loading and application; residents who return to treated houses, bystanders present during outdoor application
Environment: air, soil, surface water and aquatic sediment
Larviciding Human Health and Environmental Risk Assessment Model. First Revision, 2011.
Operator mixing/loading and application; residents who may come into contact with or use the treated waters
Environment: air, soil, surface water and aquatic sediment
Key elements of the models
•Deterministic risk assessment models
•Consider both adults and children (all age groups), and acute
and long term exposures
•Exposure algorithms, default values and unit exposures mostly
derived from US EPA residential exposure guidance documents
and European guidance / models
•Need to understand the exposure scenarios and underlying assumptions
•Total exposure estimates calculated by summing up all relevant
exposure routes and pathways
•Outdoor environmental risk assessments based on established
methods for agricultural pesticides
Provide first tier exposure assessments – they can be
modified with data for higher tier refinement if needed
Higher tier refinementsProblem formulation
•Dermal route is usually the major pathway for exposure
• Default of 100% absorption can be greatly improved by conducting a study
•Oral ingestion is an important route for infants and toddlers
•Default of 100% - actual absorption usually available from rate ADME
•Chemical specific data can be generated to replace defaults
•Consider complexity and cost; eg. PBPK modelling or exposure monitoring
could be expensive options.
•Probabilistic exposure (and hazard?) assessment
• Presents a number of challenges, data rich or data poor environment?
•There may be options to modify the exposure algorithms based
on new guidance (e.g. EPA and EU) or scientific literature
Determine the key drivers for exposure – where do you get
most “bang for your buck” in refinement options?
WHO ITN Model - Exposure estimation
Exposure
scenario
Population
groups
Exposure routes/pathways Refinement examples
Sleeping under
net
All Inhalation - v.p. >5x10-5 Pa Air monitoring
All Skin contact Dermal absorption,
translodgeable fraction
Infant and
toddler
Oral – hand to mouth
transfer and sucking nets
- breast milk (infants)2
Saliva extraction,
translodgeable fraction, oral
absorption
Washing of net Adult and child Dermal
Oral – hand to mouth
transfer
Dermal absorption, fraction
released in wash, oral
absorption
“Do-it-yourself”
net treatment1Adult and child Dermal
Oral – hand to mouth
transfer (lax scenario)Inhalation (poor ventilation
and v.p. as above)
Dermal absorption, transfer
fraction, oral absorption
1 Estimate of risks in optimal conditions (guideline scenario) or a lax standard scenario (some common deviations from use instructions)2 For insecticides with a long half life (e.g. >2 days): lipid soluble compounds (pKow ≥2) concentration = 5 x body burden; water soluble compounds = 1.4 x body burden
WHO ITN Model - Risk characterisation
Exposure scenario Population groups Risk characterisation1
Sleeping under net All Long term
Sleeping under net and net washing Adult and child Acute
“Do-it-yourself” net treatment (guideline
scenario), net washing and sleeping
under net
Adult and child Long term and acute
“Do-it-yourself” net treatment (lax
scenario), hand to mouth transfer, net
washing and sleeping under net
Adult and child Long term and acute
1 Ratio of the Estimated TWA systemic dose / long term TSD or Estimated maximal daily systemic intake / TSDAC Ratio <1 acceptableTWA = Time weighted average over 365 daysTSD = Tolerable systemic dose (NOAEL/Assessment Factor)
•Accidental swallowing of a concentrated insecticide formulation by a child (ITN “do-it-yourself”)
• Ingestion of liquid (20 mL), single tablet or single sachet compared with TSDAC
• Meaningless assessment as virtually every insecticide will fail
• Risk mitigation measures; eg. child resistant packaging, “bittering” agent
•Contaminated food stuffs from larviciding, space spraying or IRS
• Transfer from contaminated surfaces
• Crops grown in contaminated soil from irrigation with contaminated water or from sweeping the house (bioaccumulative / persistent insecticides) – measure actual levels
•Risk-benefit considerations
• Risk managers assess risks of potential toxicity vs. benefits of disease prevention; consider alternative insecticides or vector-borne disease control interventions
•Intentional misuses are not considered
• But possible re-use of empty insecticide packages for storing water is assessed
Other points from WHO models
Some key points
Human health risk assessment
• Exposure defaults use 75th percentiles rather than 95th percentiles or point estimates to reduce conservatism from multiplication of several estimated parameters.
• “Acute” exposure replaced by “short term” exposure (change in terminology) = maximal daily dose.
• Default adult body weight increased from 62 kg to 72 kg (US 16-21 yr female median).
• Dermal absorption defaults follow EFSA (EU) guidance (e.g. 25% concentrate, 75% dilution). Use concentrate value for nets and dried surface deposits.
Proposed changes Sept 16
Refinements of assumptions, parameters and algorithms Refinements of assumptions, parameters and algorithms – no fundamental changes to the risk assessment paradigms.
Human health risk assessment
• Default TSD assumes cumulative effect over repeated/continuous exposure, which is averaged over a year (TWA).
• Default UF of 100 modified where toxicity is related to Cmax rather than AUC. Assumes toxicokinetic variability is lower with Cmax effect and the TK components for interspecies and intraspecies variability are reduced by 50%.
• Risk assessment from exposure to a combination of a.i.s – synergy at low doses considered unlikely and default assumption is dose addition.
Environmental risk assessment – no change
Comments on proposed changes to WHO by 31st October !
Proposed Changes - Sept 16