ICH AgChem – How Exposure-Driven Assessments Will Enhance

Confidence in Decision-Making

Dr Tina Mehta, FBTSGlobal Head of Human Health

10th Dec., 2018

“Safety Science Out of the Box”

Today: the agrochemical sector, globally, still requires the most amount of in vivo regulatory testing, principally to address hazard - not risk

WHY have a Hazard-Based system?It’s easier…It’s precautionary…It’s simpler to regulate…

Problem: Differential regulatory requirements…Does not assess Safety and Risk Does not follow Precautionary PrincipleDoes not support decision-making to allow risk managementDoes not follow 3Rs Principles

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What should we try to accomplish with our safety testing?

We should try to prevent adverse health and environmental outcomes

and notTo predict all possible adverse effects.

In principle: Scientific Approach – Intelligent Testing – Driven by Exposure

• i.e. it is doing the right work at the right time for the right reasons to enhance the efficiency of decision-making

Paracelsus: “All substances are poisons; there is none which is not a poison. The right dose

differentiates a poison and a remedy”

An intelligent strategy gives you the right safety information about your substance to protect the population based on relevant exposure – the Precautionary Principle

What is ICH AgChem?

4

Vision

Mission

Implementation of globally harmonised RA-based approach for regulatory decision-making

Coordinate industry effort to facilitate the transfer of science

Crop Protection Roadmap for Exposure-Driven Assessment

leading to…

…Regulatory Outcome Pathway

Driven by Modern Crop Protection Science

ParentMetabolites Impurities

Dietary Water Non-Dietary

Driver 1 Driver 2 Driver 3 Driver 4

Identify key exposure(s)

Default MoEs, TTC

Estimated Relevant Exposure by Route(s)

Utilize existing knowledge

Chemical Characterization

Scoping Exposure Scenarios

Exposure Drivers

Toxicokinetics

Estimated Exposures

Toxicokinetics guides early Safety Prediction

Fit-for-Concern Safety Characterization

Assessments and Defined

Uncertainties

Use toxicokinetics to derive internal dose by route

In silico

In vitro

In vivo

In silico alerts

In vitro screening alerts

Known interactions by

class

Early Safety Prediction

Modern Crop Protection Science RoadMap

Acute Assessment

SubchronicAssessment

Chronic Assessment

Labeling Information

Oral Reference Dose Dermal Reference Dose

Application of Appropriate Safety Factors

Inhalation Reference Dose

Toxicokinetics-Based Dose Selection

Study designs and dose selection

Hum

an H

ealth

ParentMetabolites

Air Water Soil

Driver 1 Driver 2 Driver 3 Driver 4

Identify key exposure(s)

Estimated Relevant Exposure by Route(s)

Utilize existing knowledge

Chemical Characterization

Scoping Exposure Scenarios

Exposure Drivers

Estimated Exposures

Fit-for-Concern Safety Characterization

Assessments and Defined

Uncertainties

In silico

In vitro

In vivo

In silico alerts

In vitro screening alerts

Known interactions by

class

Early Safety Prediction

Modern Crop Protection Science RoadMap

Acute Assessment

Chronic Assessment

Labeling Information

Consideration of Appropriate Levels of Concern

Study designs and dose selection

Envi

ronm

enta

l and

Eco

logi

cal

Globally harmonized, science-based framework centred on a consistent Risk Assessment & Management paradigm, based on the ICH principles (pharmaceutical and veterinary medicines)

Promoting Legislation embracing Exposure-Based Assessments in decision-making and harmonised review processes

Open interaction between regulators and stakeholders Remove cut-off criteria which are not relevant to actual Safety

Characterisation and Safe Use of products Use of hypothesis-driven scientific approaches resulting in the elimination of

studies not relevant or used (or useful) for Risk Assessment Improve footprint of products, provide better solutions for the

grower/consumer, allow free trade of treated commodities

Future Outcomes of ICH AgChem

ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

Regulatory Outcome Pathway for Modern Crop Protection ScienceLife Cycle Framework

Start:Exposure scenarios

Knowledge evaluation based on preliminary Risk

Assessment goals Identify data needs

Exposure, toxicokinetics

Preliminary Risk

Assessment

Efficacy

Submission to Authority

Use pattern(s)Physicochemical

propertiesEarly bioactivity information

Engage Authority

Ecological

Human

Fate

Refine Risk Assessment with

needed data

Consult Authority

AI approval

Product Life Cycle

New or expanded use

Confirm sufficiency of arguments and data

Consideration of alternatives

and acceptance of products

ROP

Routes of Exposure - FATE

Exposure Characterisation – Predicting Residues

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Multi-compartment model

Key Parameters/Information DT50 in air Molecular weight

DT50 in water Saturated vapor pressure

DT50 in soil Application rate Crop-specific DT50 Crop type

Partition coefficient: air/water (Kaw) Prehavest interval

Partition coefficient: octanol/water (Kow)

Plant mode of action (e.g. systemic or contact)

Partition coefficient: soil organic carbon-water (Koc)

Zhongyu et al., 2018. Dow Poster SOT

How much Exposure ?

MoE

Safe margins of exposure between human exposure and a dose that results in adverse effects…for example:

Problem Formulation

Development of Conceptual Model

Targeted data generation based on Problem Formulation / Conceptual Model

Application of relevant dataExposure & Safety

Risk Evaluation

New ICH AgChem Paradigm

Risk 21 Paradigm –

“ICH” AgChemRoadMap

Case Study 1: Non-AnimalFormulation Testing –

Acute 6-pack:Tier 1: Read-across

Tier 2: GHS/CLP Additive calculation method

Tier 3: in vitro assays for irritation (skin/eye) and

sensitisationGlobal implementation of

this approach

Progress with Tox 21 –Incorporate within a Risk21

Paradigm: AOPs/MoAsUse in silico/in vitro tools to

replace in vivo studiesHow to integrate AOP into a

“Regulatory Outcome Pathway”?

Identify key area needs

3Rs: Promote Redundancy of TestingImmunotoxicity Assay

Mouse Bioassay1 Year Dog Study90-Day InhalationAcute toxicity tests

Exposure-driven waiversTarget: Focussed-triggered testing

EXPOSURE- BASED AgCHEM

Redundancy of the cancer bioassay• EPAA project exploring predictive opportunities to waive carcinogenicity studies – huge 3Rs impact

Define data needs for selected use scenarios to I-D redundancies in toxicity testing• Consumer/occupational/bystander – “Fit for Concern” testing gives huge 3Rs benefit

TK Framework development• Utility of systemic exposure, including IVIVE principles – better informed testing impacts 3Rs

Exposure-Based Waivers for toxicity testing• Review of EPA waiver evaluations – huge opportunities for 3Rs impact globally

Cumulative Risk Assessment

• Understanding the mixture of concern – exposure-relevant assessment addresses 3Rs

Examples of ICH AgChem Projects

16Zhongyu et al., 2018. Dow Poster SOT

Examples of ICH AgChem Projects

Incorporating new technologies advances science…

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Dietary RA

Drinking Water(PRZM, PRZM-

GW)

Residues in Crops

(DynamiCrop) Early Stage Exposure

Assessment

Reaping the benefits of smarter, “fit-for-concern”, integrated and tiered testing strategies

Zhongyu et al., 2018. Dow Poster SOT

How can integration of science with intelligent testing be core to decision-making for Agrochemicals, globally?

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Estimating Chronic NOAELs with Enhanced Short-Term Toxicological Studies

Short-term study Transcriptome

PODShort-term

study apical POD

Chronic study apical POD

Two lines of data support that chronic NOAELs in 2 species can be reasonably predicted and are human health protective

Zhongyu et al., 2018. Dow Poster SOT

The RISK21 Roadmap

0.01

0.1

1

10

100

Estim

ate

of T

oxic

ity(m

g/kg

)Lo

wH

igh

Mod

0.0001 0.01 0.1 1 10

Estimate of Exposure (mg/kg)

0.001 100HighModLow

Problem Formulation:•What is it?•Where used?•How used?•How much?•What do we already know?

Biomonitoring

Probabilistic

Deterministic

Worstcase

Mode of Action

In vivo

In vitro

QSAR / TTC

1

4

3

2

Providing Enough Precision for the Decision

Application of IATA, Tox21, and RISK21

Full Regulatory

Studies Package

Risk21 Stepwise

Assessment

Lead Effect Neurotoxicity Neurotoxicity

Other EffectsNone significant;

from full package

None significant;

from ToxCast assays

Short term relevant

NOEL1mg/kg from dog study 1mg/kg from dog study

Long term relevant

NOEL1mg/kg from dog study 1mg/kg from dog study

Number of animals

used2000+ 24

New Active Ingredient/Product portfolio… Predicted GAPs (efficacy/marketability) – input data TTC Estimated residue profiling (prediction, generic residue default ranges,

monitored levels) Default values based on exposure data (e.g. dermal absorption) Estimated non-dietary/dietary exposure using models Predicted human exposures

Example: Maximum predicted chronic exposure 0.0138 mg/kg/day→ Test 100x = 2 mg/kg/day, e.g. Chronic dose levels: 2, 7, 20 mkd

• Use these doses and TK info to understand concentration for in vitro studies, i.e. IVIVE• Take these minimum dose levels for animal studies

• Now we can define our testing strategy…we already know we have safe uses…akin to confirmatory data?

Let’s use our imagination….

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No animals have been used up to

this stage…

Human relevant testing: Dose levels based on predicted exposures (example):Using MoE (100X)Subchronic dose levels: 40, 120, 360Chronic dose levels: 2, 7, 20Acute dose levels: 8, 25, 75

Limited in vivo testing to address key end-points of concern at relevant doses equivalent to predicted human exposures• No need for MTD testing• Refined study designs relevant to

concerns• Prevent non-specific, high-dose

toxicity

Testing Strategy - Estimated Relevant Exposure

In silicoalerts

In vitro screening

alerts

Known interactions

by class

Early Safety Prediction in

Relevant Test

Systems

Use toxicokinetics to derive internal dose by

route

In vivo confirmation

Devtox/Repro?

Genotox?

In silicotools

In vitro tools

TargetOrganToxicity?

Carc?

Neurotox/ Immunotox?

Fit for Concern:Acute, Subchronic, Chronic concerns?Labelling information?

No animals have been used up to

this stage…

Uses of TK Data (Systemic Exposure) in Risk Assessment

1. Hazard Identification

Internal dose

a. Test species selection

b. Route of administration

c. Dose level

selection

d. Human exposure

based doses

2. Dose-Response

Assessment

Internal dose

a. Address all life stages

b. Route-to-route

extrapolation

c. IVIVE

d. Test in human and

animal tissues

3. Exposure Assessment

Internal dose

a. Selection of

biomarkers

b. Refine default model

c. PBPK

d. Aggregate/ Cumulative

4. Risk Characterisation

Internal dose

a. Integrated MoA

b. CSAFs

c. Set ‘internal’

RfCs

d. BE approach

5. Risk Management

Internal dose

a. Human PBPK

b. Compare to biomonitoring

data

c. Test in human

tissues at BM levels

d. IVIVE

Link to external

exposure

Fit for concern testing At relevant

concentrations

Relevant risk

Decision-Making Contexts – Conflicts?

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Does ICH AgChem allow us to fulfil all of following requirements?

Animal Use Directive 2010/63/EU - 3Rs Principles PPP Regulation 1107/2009 – Cut-off criteria but Risk Assessment based CLP Regulation 1272/2008 - Hazard Assessment using available data -

intrinsic properties What is the purpose of classification? Protection goals? Historically vs Now?

• Production, occupational and transport needs vs emergency use/inappropriate handling - expected exposure levels?

• We have improved knowledge, methods of production, technology, user safety/PPE…

Leads to misrepresentation of actual risk, leading to potential substitution with products/processes of greater risk or uncertainty, and implementation of 2° legislation, which can impact public perception and lifestyle choices.

Better understanding of exposure to help reduce concern

Better communication of the risk-benefit when using relevant exposure levels

Use fewer animals/3Rs

Protective of non-target species

Shorter review time to provide more effective/safer products to the market faster

Provide improved products for farming solutions

Protect global food supply

Cheaper to develop so lower price for the growers

Improved realistic impact analyses

What prevents acceptance ofthe paradigm? Benefits…

Creating a new vision for agrochemical human health assessment

• An opportunity to shift the paradigm to safety and risk characterisation and

assessment

• Opportunities to improve the focus of data and testing for public health

protection

Using the Best Science available

Global development and harmonisation

Global basis for Risk Assessment and Management

ICH AgChem

What’s your vision for

safe PPPs?

Let’s drive away the hazards…

Thank-you!

Non-Dietary: Operator

GAP(Default) Dermal Absorption

Active Substance (AS) – External Exposure (e.g. Dermal)

In vivo AS/metabolite Exposure

OPEX Model for AS Internal Exposure

ADME/TK/modelling

Dietary: Consumer

Compare with TTC

Monitoring data, Preliminary residue data, STMR, MRL, ADI/ARfD

ADME/TK/Modelling

In vivo levels AS/metabolites

Active Substance (AS) – Oral Exposure

PRiMo for Human Exposure

Example of exposure-based assessment for human health (UHM)

External Exposure Scenario

Estimated exposure

Characterise internal exposure

Relevant safety profileExternal

Exposure Scenario

Estimated exposure