[PPT] - LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS THE NEED FOR PowerPoint Presentation

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LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS

THE NEED FOR AUGMENTATION OF REGULATORY PATH

2019-01-17 1

Abhay Deshpande, Ph.D. Director -Global Innovation & Strategy -JRF Global

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22 February 2019 2

Contents and flow of thoughts

What is bothering the regulators?
Replace / Reduce Animals!!
Use alternative methods….in vitro! Use read-across!
History of Guidelines are updates & revisions
Consolidate the guidelines….more data while using the animals
EOGRTS
Hormone analysis in OECD 407/408
AoPs, applied in the vitro studies mammalian/fish etc.
Conclusion

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 3

Regulatory Trends in the EU & the US

European Union
REACH, Biocides & Crop care products
Weight of evidence
QSAR models
In vitro methods
Grouping of substances and read-across
US
EPA for TSCA & FiFRA (Federal Insecticide, Fungicide, and Rodenticide Act)

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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Horizon is constantly moving

The EU regulators are insisting on use of for all the future registration

needs;

Read across for Acute oral and dermal toxicity
in vitro tests for skin irritation/corrosion, eye irritation as well as

skin sensitization

Inhalation toxicity still remains in vivo, but the new guidelines

based on Toxic Class criteria use reduced animals.

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22 February 2019 5

Options?? Alternative methods….in silico/in vitro!

Grouping & Read-across
Weight of Evidence/WoE
QSAR
Non-animal methods

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/weight-of-evidence

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 6

Grouping & Read Across

Use relevant information from analogous substances to predict the properties
f the ‘target' substances.
Eliminate experimental (animal) testing by using the concept……justifications

must establish adequacy and appropriateness of the document.

Must be Key data based on identifiable with appropriate references to

IUCLID(*) substance dataset would be necessary.

Prediction must be based on structural similarity / dissimilarity.
A read-across approach can be used to defend a conclusion for a property using

a weight-of-evidence approach. (* International Uniform Chemical Information Database)

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/grouping-of-substances-and-read-across

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 7

Read-Across Assessment Framework (RAAF)

Process:

Check the robustness of read-across adaptation.
Hypothesize the justification for using the data from one substance

structurally related substance to the other, for each property.

Search for experimental data for contradictions against the proposed

hypothesis if any.

Provide credible supporting information.
Impurities and potentially different substance compositions must but be

highlighted

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 8

Weight of Evidence (WoE) Weight of Evidence must be based on;

Published literature
Data from existing studies
Epidemiological data/human experience.

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/weight-of-evidence

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 9

Weight of evidence :

Includes, as a minimum, two separate study /text book values records

for a certain property, single value from a secondary data source is not sufficient

Domain expert to assess the reliability, relevance, adequacy of the available

data to assess combined evidence is adequate to avoid a test

The expert judgement should be transparent and understandable

appropriately supported by delineating the process of arriving at conclusion and providing the references.

Weight of Evidence (WoE)

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 10

QSAR

Mathematical models (generated based published research data)
Predict the physicochemical, biological and environmental fate properties
f compounds, based on their chemical structure.
Limitations: Currently (Q)SARs have limitations in accurately predicting

complex toxicological properties, not deemed fit for purpose for classification and labelling or risk assessment.

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/qsar-models

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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Documented format: IULID
To be used only when the test results, are not available
Consider using additional parameters and link potential interactions

between them.

(Q)SARs may be coupled with other data and used in a weight of evidence

approach.

One study record for each chemical structure for (Q)SAR prediction.

QSAR

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 12

in vitro methods in vitro methods

Test system is alive, but outside of a living organism
Usually involves isolated cells/immortalized/reconstructed cell lines,

rarely tissues or organs

They could be used for supporting part / full replacement of animal tests.
Use of sufficiently well-developed methods in compliance with

internationally agreed test development criteria (ECVAM*).

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/in-vitro-methods

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

* European Centre for the Validation of Alternative Methods

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22 February 2019 13

2016 onwards, the EU mandates in vitro test methods the default for

certain toxicological properties.

No Acute dermal and eye irritation and sensitization tests will be

accepted.

Sensitization could be done using LLNA assay but GPS is a “No-No”!
Regulator may accept an in vitro assay data, which hasn’t been

internationally validated, as dossier or support of WoE.

in vitro methods

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 14

Efforts aimed at achieving maximal data by adding additional endpoints in the existing animal testing guidelines

OECD 443-EOGRTS- The Extended One Generation Reproduction Toxicity

Test

Developmental Tox guideline with immuno and neurotox cohorts
OECD 407/408
Hormone analysis (T3, T4, TSH & Testosterone estimation mandatory
On horizon: Plasma concentration for establishing limit of exposure!

Consolidate the guidelines….

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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22 February 2019 15

Guideline updating….OECD test guidelines

Year No of Guidelines revised % revised Revision per year 2018 15 20.8% 20.8% 2017 4 5.6% 5.6% 2016 14 19.4% 19.4% 2015 8 11.1% 11.1% 2008–2014 11 15.3% 2.2% 1998-2007 8 11.1% 1.1% 1981-1997 12 16.7% 1.0% 72

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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The Guideline Horizon @ OECD is constantly changing!

77 changes in the past 10 years
30 of the 72 OECD test guidelines, have been released focused on in vitro

methods aimed at animal study replacement!

15 of the 30 have been released during 2016 till date!
EU regulators: completely stopped acceptance of Guinea Pig

Maximization test for Skin sensitization w.e.f. October 11, 2016!!

Rest of the changes aimed at bring in options to reduce animals/reduce

pain/discomfort/achieve more from the existing guidelines with

additional biomarkers chipped in!

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2019-01-17 17

AOPs are on horizon…

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

NC3Rs Pathways-based approaches resource: Issue 6: August 2018 DPRA OECD 442 C KeratinoSens/ LuSens OECD 442 D hCLAT OECD 442 E Kinetic DPRA on its way….

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Should & Can the Animal testing be avoided?

Tests effectively Eliminated;

Rodent Acute Oral /Dermal toxicity, Skin and eye irritation, skin sensitization ,

New product Development:

LD50/LC50/metabolism based tests using specific cell system using human

primary/immortalized/iPSC derived differentiated cells

Zebra fish embryo

Regulatory Accepted

Skin & Eye Irritation / corrosion tests
Skin sensitization using battery of tests driven by AoPs

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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2019-01-17 19

Should & Can the Animal testing be avoided?

Animal testing be best avoided,

NC3Rs: wherever, the test unequivocally establishes that the

expected safety assessment needs should be met with by the alternative tests!

Antithesis:
Animal testing is still the best way to find new treatments

for patients Garattini S, Grignaschi G, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.11.013

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

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Our take @ JRF:

Equilibrium is the law of the universe!
It ensures steady state and stability!
Wide pendulum swings are anti-stability!

Rational thinking is the need of the hour!!!

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

For Animal testing Against Animal testing

Animal testing is still the best

way…….there are several researchers who openly / in private conversation, support this view. Avoid animal testing….there are possibly equal number of

pinion-leaders who support

this view.

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2019-01-17 21

Thanks to XIVth ASC & Dr. Mayee for this opportunity

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS - Abhay Deshpande, JRF Global

LATEST TRENDS IN SAFETY EVALUATION OF AGROCHEMICALS

THE NEED FOR AUGMENTATION OF REGULATORY PATH

Abhay Deshpande, Ph.D. Director -Global Innovation & Strategy -JRF Global

Contents and flow of thoughts

Regulatory Trends in the EU & the US

Horizon is constantly moving

needs;

skin sensitization

based on Toxic Class criteria use reduced animals.

Options?? Alternative methods….in silico/in vitro!

Grouping & Read Across

must establish adequacy and appropriateness of the document.

IUCLID(*) substance dataset would be necessary.

a weight-of-evidence approach. (* International Uniform Chemical Information Database)

Read-Across Assessment Framework (RAAF)

Process:

structurally related substance to the other, for each property.

hypothesis if any.

highlighted

Weight of Evidence (WoE) Weight of Evidence must be based on;

Weight of evidence :

for a certain property, single value from a secondary data source is not sufficient

data to assess combined evidence is adequate to avoid a test

appropriately supported by delineating the process of arriving at conclusion and providing the references.

Weight of Evidence (WoE)

QSAR

complex toxicological properties, not deemed fit for purpose for classification and labelling or risk assessment.

between them.

approach.

QSAR

in vitro methods in vitro methods

rarely tissues or organs

internationally agreed test development criteria (ECVAM*).

certain toxicological properties.

accepted.

internationally validated, as dossier or support of WoE.

in vitro methods

Efforts aimed at achieving maximal data by adding additional endpoints in the existing animal testing guidelines

Test

Consolidate the guidelines….

Guideline updating….OECD test guidelines

Year No of Guidelines revised % revised Revision per year 2018 15 20.8% 20.8% 2017 4 5.6% 5.6% 2016 14 19.4% 19.4% 2015 8 11.1% 11.1% 2008–2014 11 15.3% 2.2% 1998-2007 8 11.1% 1.1% 1981-1997 12 16.7% 1.0% 72

The Guideline Horizon @ OECD is constantly changing!

methods aimed at animal study replacement!

Maximization test for Skin sensitization w.e.f. October 11, 2016!!

pain/discomfort/achieve more from the existing guidelines with

additional biomarkers chipped in!

AOPs are on horizon…

Should & Can the Animal testing be avoided?

Tests effectively Eliminated;

New product Development:

primary/immortalized/iPSC derived differentiated cells

Regulatory Accepted

Should & Can the Animal testing be avoided?

Animal testing be best avoided,

expected safety assessment needs should be met with by the alternative tests!

for patients Garattini S, Grignaschi G, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.11.013

Our take @ JRF:

Rational thinking is the need of the hour!!!

For Animal testing Against Animal testing

way…….there are several researchers who openly / in private conversation, support this view. Avoid animal testing….there are possibly equal number of

this view.

Thanks to XIVth ASC & Dr. Mayee for this opportunity

Thank you so much Audience.