Rethinking Carcinogenicity Assessment For Agrochemicals ...Class/Read across. Guidance Document with...

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2020 Society of Toxicology Carcinogenesis Webinar Series Rethinking Carcinogenicity Assessment For Agrochemicals Retrospective Analysis Sabitha Papineni, DVM, Ph.D Corteva TM Agriscience 19 February 2020

Transcript of Rethinking Carcinogenicity Assessment For Agrochemicals ...Class/Read across. Guidance Document with...

Page 1: Rethinking Carcinogenicity Assessment For Agrochemicals ...Class/Read across. Guidance Document with WoE Framework Case Studies ReCAAP Project Overview Regulatory ... Halauxifen acid:

2020 Society of Toxicology Carcinogenesis Webinar Series

Rethinking Carcinogenicity Assessment For Agrochemicals

Retrospective Analysis

Sabitha Papineni, DVM, Ph.D

CortevaTM Agriscience

19 February 2020

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✓This speaker is employed by CortevaTM Agriscience

✓This speaker has no other conflict of interests to declare

✓ Any opinions expressed in this presentation are those of the speaker and do not necessarily reflect the opinions of CortevaTM

Agriscience

Disclosure

Page 3: Rethinking Carcinogenicity Assessment For Agrochemicals ...Class/Read across. Guidance Document with WoE Framework Case Studies ReCAAP Project Overview Regulatory ... Halauxifen acid:

Regulatory Testing of Agrochemicals

• An agrochemical product undergoes >100 rigorous studies to support the health, safety and environmental

assessments required for registrations.

• From a mammalian toxicology perspective, agrochemicals have the most comprehensive data requirements

of any chemical sector, including pharmaceuticals.

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Mammalian Toxicology Testing Requirements

• ADME Studies

• Acute Toxicity Testing• oral, dermal, inhalation, skin & eye irritation, sensitization

• Subchronic Toxicity Testing (Rat, Mouse & Dog)

• Chronic Toxicity Testing (Rat)

• Carcinogenicity Testing (Rat & mouse)

• Reproductive Testing (Rat)

• Developmental/Teratogenicity (Rat & Rabbit)

• Mutagenicity/Genotoxicity Testing (In vitro & In vivo)

• Neurotoxicity (Acute & Subchronic)

• Repeated Dermal (Rat or Rabbit)

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18 or 24 mon

Mouse 2 year Rat At least

560 rats

At least

400 Mice

Rodent Cancer Bioassay Agrochemicals

Default Data Requirement

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EPA’s Commitment to End Animal Testing by 2035

• The EPA will reduce its requests for, and our funding of, mammal studies by 30 percent by 2025 and eliminate

all mammal study requests and funding by 2035.

• Any mammal studies requested or funded by the EPA after 2035 will require Administrator approval on a case-by-case

basis.

https://www.epa.gov/newsreleases/administrator-wheeler-signs-memo-reduce-animal-testing-awards-425-million-advance

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Cancer Bioassay Weight of Evidence Criteria

Cancer

Bioassay

WoE

Criteria

Rodent Cancer Bioassay

Earlier recognition of pesticides that pose or do not

pose carcinogenic risk

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“ReCAAP”

Rethinking

Carcinogenicity

Assessment

for

Agrochemicals

Project

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Check-box

approach

Studies Required

Acute Oral Toxicity

Acute Dermal Toxicity

Acute Inhalation Toxicity

Acute Eye Irritation

Acute Dermal Irritation

Skin Sensitization

90-Day Oral Toxicity in Rodents

90-Day Oral Toxicity in Non-rodents

21/28-Day Dermal Toxicity

90-Day Dermal Toxicity

90-Day Inhalation Toxicity

Developmental Toxicity in Rodents

Developmental Toxicity in Non-rodents

Reproduction and Fertility Effects

Chronic Toxicity in Rodents

Chronic Toxicity in Non-rodents

Carcinogenicity in Rats

Carcinogenicity in Mice

Weight of Evidence

approach

Rodent Cancer

BioassayMetabolism

Sub-chronic

Genotoxicity

Exposure

Hormone

Disruption

Immune

Suppression

Read-across

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Based on scientific understanding of

potential triggers and indicators of

carcinogenesis

Cancer

Bioassay

WoE

Criteria

Immune SuppressionSubchronic

Data

Genotoxicity

Pesticidal

MoA

Mechanistic Data

Exposure

Hormonal Perturbation

ADME

Chemical Class/Read

across

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Guidance

Document

with

WoE

Framework

Case

Studies

ReCAAP Project Overview

Regulatory

Review

Identify Gaps

Retrospective

Review

Rodent Cancer

Bioassay

Phase I Phase II Phase III

Metabolism

Sub-chronic

Genotoxicity

Exposure

Hormone

Disruption

Immune

Suppression

Read-across

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Cancer Bioassay WoE Criteria

Cancer

Bioassay

WoERodent Cancer Bioassay

Uncertainty/

Data gapsFocused

data generation

No Bioassay needed

➢ Completion of retrospective analysis

➢ Determine if the WoE predicts the cancer risk by comparing it to the bioassay results

➢ Identify any gaps and revise the criteria accordingly

➢ Develop a guidance document with WoE framework for carcinogenicity assessment

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Cancer Classification

Not Likely to be Carcinogenic to Humans at doses that do not induce cellular

proliferation in the liver or thyroid glands (1)

Not Likely to be Carcinogenic to Humans at doses that do not cause

urothelium cytotoxicity (1)

Not Likely to be Carcinogenic to Humans at doses that do not induce a

proliferative response in the liver (1)

Likely to be Carcinogenic to Humans (2)

Suggestive Evidence of Carcinogenic Potential (4)

Not Likely to be Carcinogenic to Humans (6)

Case Studies Chemical Distribution (n = 15)

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Halauxifen-methyl

Case Study

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What is Halauxifen-methyl?

• Herbicide also known as ArylexTM

• Rapidly hydrolyzed in the liver to Halauxifen acid

Halauxifen acid

(Primary metabolite)Halauxifen-methyl

ester

(Parent molecule)

Systemic Exposure is to Halauxifen acid

Rapid

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Current Chromatogram(s)

min10 20 30 40

mAU

0

200

400

600

800

1000

1200

1400

Area: 12

32.39

11.3

34

Area: 34

8.177

16.0

65

Area: 48

006.8

30.7

33

Area: 25

44.21

37.8

67

Area: 13

8.361

40.0

48

Print of window 38: Current Chromatogram(s)

Instrument 1 6/24/2010 10:40:45 AM Page 1 of 1

Halauxifen acid: 0-12 hr urine

(male- 10 mg/kg)

(7.7 mg/kg acid recovery )

Halauxifen-methyl and Halauxifen acid

Bioequivalence

Halauxifen

Halauxifen

Acyl

glucuronide

O-demethylated

Halauxifen

and conjugates

Current Chromatogram(s)

min0 10 20 30 40

mAU

0

100

200

300

400

500

600

700

800

900

Area: 27

2.756

9.35

9

Area: 20

92.18

11.9

59

Area: 20

0.322

16.6

45

Area: 37

217.5

32.4

74

Area: 41

7.627

37.5

09

Area: 26

23.75

38.0

76

Area: 14

7.648

40.2

08

Print of window 38: Current Chromatogram(s)

Instrument 1 6/24/2010 10:42:32 AM Page 1 of 1

Halauxifen

Halauxifen

Acyl

glucuronideO-demethylated

Halauxifen

and conjugates

Halauxifen Methyl: 0-12 hr urine

(male- 10 mg/kg)

(8.1 mg/kg acid recovery)

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Bridging Package on

Halauxifen-methyl

Bridging Data Strategy• Core data package was developed on Halauxifen acid

• Halauxifen acid was shown to have no carcinogenic potential in the 2-year rat and 18-mon mouse assays.

• ADME

• Acute six pack

• Genotoxicity

• 28- and 90-day rat

• Developmental rat and rabbit

• 28-day Dermal

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Bridging Data Strategy

28-Day Halauxifen-methyl vs. Acid Comparison

Doses Conclusions

Halauxifen

Acid

Rat 28-day

10, 50, 250, and

750 mg/kg/day

NOAEL: 250 mkd (♂, ♀)

Target organ: Kidney

Halauxifen-Methyl

Rat 28-day

10, 52, 261, and

782 mg/kg/day

NOAEL: 10 mkd (♂),

52 mkd (♀)

Main target organ: Liver

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7-day Rat Mode of Action Study:Liver Effects

Halauxifen-methyl Halauxifen acid

At 782 mg/kg/day:

Increased liver weight

with hepatocyte

hypertrophy

At 750 mg/kg/day:

No liver effects

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Halauxifen acid

Core Toxicology Package

2 Year Cancer Bioassay

Halauxifen-methyl is AhR activator

• Associated with rodent liver effects

• Prototypical AhR ligands include Dioxin

• Human Relevant MoA

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Prototypical AhR Ligand

• Dioxin

• Metabolically stable– Long t1/2

– Bioaccumulates

• Sustained AhR activation– ↑Cyp1a1 levels

• Hepatic Effects – Hepatic proliferation not until

> 14 weeks of sustained exposure

• Relevant to Humans

Halauxifen-methyl- is it a prototypical AhR ligand?

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How do we evaluate a rodent liver MoA that could be relevant to humans?

Determine exposure of Halauxifen-methyl in liver

- Understand metabolism differences in different matrices

Mode-of-Action (MoA)

-AhR activation (dose response)

-In vitro species differences- rat, mouse and humans

Hepatocellular Proliferation (dose response)

Key

Event 1

Key

Event 2

Key

Event 3

Characterize Liver MoA

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Enters Liver via Portal Vein

“Saturation of Hydrolysis”

Occurs

AhR-mediated Liver Toxicity

Human Relevance:Hydrolysis of Halauxifen-methyl to

Halauxifen acid

Halauxifen

methyl ester

Enters GI

Tract

Absorption

Enters Systemic

Circulation as

Halauxifen acid

Liver Hydrolysis Rate

Humans > Rodents

8 min vs. 30 min

GI Hydrolysis

Rate

Humans >

Rodents

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Prototypical AhR Ligand

• Dioxin

• Metabolically stable– Long t1/2

– Bioaccumulates

• Sustained AhR activation– ↑Cyp1a1 levels

• Hepatic Effects – Hepatic proliferation not until

> 14 weeks of sustained exposure

• Relevant to Humans

Non Prototypical-AhR Ligand• Omeprazole (Prilosec),

Halauxifen-methyl

• Rapid metabolism and clearance from the liver

• Transient AhR Activation

• Cyp1a1 levels at baseline after 4 days of recovery

• Hepatic Effects– Proliferation at 4 weeks

– Reversible

• Relevant to Humans?

Halauxifen methyl- not a prototypical AhR ligand

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Human Relevance:Halauxifen-methyl mediated AhR activation in Rat

and Human Primary Hepatocytes

Rat Human

Cyp1a1

Induction

Primary

Hepatocytes

147-fold2.9 to 34-fold

Average:

11-fold

AhR activation in rat >>>> humans

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•Halauxifen-methyl ester• is NOT a prototypical AhR activator

• rapidly metabolized

• rapidly eliminated

• has a threshold for liver effects in rats • NOAEL of 10 mg/kg/day

• Systemic exposure is to Halauxifen acid - NOT an AhR activator

• Human Relevance: • Liver Toxicokinetics: rat slower metabolism than human

• Toxicodynamics: AhR activation in rat >>> human

•Conservative human dietary exposure estimate• is 0.0001 mg/kg bw/day

• margin of exposure relative to the rat NOAEL >100,000 fold

• data are protective of human health

Halauxifen-methyl MoA

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Cancer Classification

“not likely to be carcinogenic to humans” Halauxifen-acid

“not likely to be carcinogenic to humans at doses that do not induce Cyp1a1 expression (a biomarker for

AhR activation)”

Halauxifen- methyl

No cancer bioassay conducted

Mechanistic Studies

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All Apical Effects Result From Prior Changes At The Molecular Level

Apical Effect

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Transcriptome Profiling and Toxicity

Big Data

Genome-Wide Gene

Expression (15,000

Endpoints)

Toxicological Insight

Ali & Qadir, Big Data for Human Development, 2016

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HESI eSTAR Committee Predictive Chronic/Cancer Projects

1. Carcinogenomics Project

• Being led by scientists from Merck and the US EPA but multisector involvement

• Aim is to develop short-term study transcriptional biomarkers predicting tumor outcome in rats

2. Molecular Point of Departure Project

• Led by scientists from Corteva and NIEHS but multisector involvement

• Aim is to develop a framework to derive an in vivo transcriptome POD for use in chemical risk assessment

that will produce a human health-protective POD without needing to link the transcriptomic change with a

specific adverse effect, mechanism, or mode of action.

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POSTERS

Rethinking Carcinogenicity Assessment for Agrochemicals

(ReCAAP)

Abstract/Poster Board Number: 2200/P558

Date: Tuesday, 17 March

Time: 9–10:45 am

Location: CC Exhibit Hall

Abstract/Poster Board Number: 2231/P612

Date: Tuesday, 17 March

Time: 2:15–4:30 pm

Location: CC Exhibit Hall

WORKSHOP

Human-Relevant Carcinogenicity Testing: Tools for Cancer Assessment in 2020 and Beyond

Date: Tuesday, 17 March

Time: 8–10:45 am

Location: Room 304A

Chair: Nicole Kleinstreuer, NTP NICEATM, US

Co-chair: Gina Hilton, PETA International Science Consortium Ltd.

Upcoming Presentations at SOT 2020

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Colleagues@

• CortevaTM Agriscience

• Dow Toxicology Lab, Midland, MI

• Haskell R&D Center, CortevaTM, Wilmington, DE

ReCAAP team

Thank you for your attention !

Page 35: Rethinking Carcinogenicity Assessment For Agrochemicals ...Class/Read across. Guidance Document with WoE Framework Case Studies ReCAAP Project Overview Regulatory ... Halauxifen acid:

Contact Information

Dr. Warren Casey, PhD, DABTNational Toxicology Program

Acting Chief of Biomolecular Screening Branch

Email: [email protected]

Dr. Sabitha Papineni, DVM, PhDCortevaTM Agriscience

Global Senior Regulatory Toxicologist

Email: [email protected]