Endocrine disruptor (ED) assessment in the EU

From ‘conceptual framework’ to reality

Session description

The OECD ‘Conceptual Framework’ has now come of age with Endocrine Disruptor assessment deadlines for

applicants to submit additional data for AS submissions coming into force in 2018 for Biocidal Products and Plant

Protection Products

In vitro assays - OECD CF Level 2

+ Historical development of ED testing capabilities at ENVIGO

+ Contrast development and divergence of testing strategies between the EU and US

+ ENVIGO membership of EU-NETVAL validation program for development of in vitro ED assays

Endocrine disruptor endpoints - OECD CF Level 4 and Level 5

+ In vivo ED capabilities and Mass Spectrometry analytical support for ED endpoints

Regulatory framework and support - OECD CF Level 1

+ Envigo Regulatory Consulting Group - OECD ‘Conceptual Framework’ revised guidance document OECD 150

and implications for AS submissions for Biocidal Products and Plant Protection Products

Introduction

JC

1996 – OECD set up EDTA+ Endocrine Disruptor Testing and Assessment advisory group – origin of the Conceptual Framework

1996 – US Congress Food Quality/Safe Water Acts+ Requiring EPA to implement an endocrine disruptor screening program

2002 – OECD First draft of the Conceptual Framework (CF) adopted

+ Testing and Assessment of Endocrine Disruptors

2009 – EPA List 1 test orders issued for 67 chemicals + EDSP Tier 1 screening battery: 5 in vitro assays, 6 in vivo assays

2011 – EPA vision: EDSP21 + Replace Tier 1 screening battery with in silico + HTS assays

2012 – OECD Revised draft Conceptual Framework

+ Guidance document No. 150: Standardized test guidelines for evaluating chemicals for Endocrine Disruption

20+ years of progress…

2012 – 6th SETAC Europe Special Science Symposium on Endocrine Disruptors+ ‘CRO EXPERIENCE: Validation, conduct and reporting of EDSP assays (J.Carter)

2014 – FIFRA SAP meeting+ Aim - to advise EPA on future direction of EDSP program ….IBER: HTS + ToxCastTM

2014 – ‘EU-NETVAL’ - Envigo 1st UK member

+ Envigo selected to conduct first EUNETVAL in vitro ED validation project

2018 – OECD Revised Guidance Document 150+ Issued September 2018

EU announce deadlines for AS renewals in 2018

2019 – SOT Baltimore+ Envigo Exhibitor Hosted Session – ED assessment in the EU

20+ years of progress… (continued)

OECD Conceptual Framework

OECD Test Guidelines supporting the CF

Test Guidelines Number and Name

Level of

Conceptual

Framework

TG 493: In Vitro Oestrogen Receptor Binding Assay 2

TG 455: In Vitro Oestrogen Receptor Transactivation Assay 2

TG 458: In Vitro Androgen Receptor Transactivation Assay 2

TG 456: H295R Steroidogenesis Assay 2

TG 440: Uterotrophic Bioassay 3

TG 441: Hershberger Bioassay 3

TG 229: Fish Short-Term Reproduction Test 3

TG 230: Fish Screening Assay 3

TG 231: Amphibian Metamorphosis Assay 3

TG 407: 28-day Repeated Dose Toxicity Study in Rodents 4

TG 408: 90-day Repeated Dose Toxicity Study in Rodents 4

TG 313: Prenatal Developmental Toxicity Study 4

TG 421: Reproduction/Developmental Toxicity Screening Test 4

TG 422: Combined Repeated Dose Reproduction/Developmental Toxicity Screening 4

TG 426: Developmental Neurotoxicity Study 4

TG 451-3: Combined Chronic Toxicity/Carcinogenicity Study 4

TG 234: Fish Sexual Development Test 4

TG 241: Larval Amphibian Growth and Development Assay 4

TG 443: Extended One-Generation Reproductive Toxicity Study 5

TG 240: Medaka Extended One-Generation Reproductive Toxicity Study 5

TG 416: Two Generation Reproduction Toxicity Study 5

OECD WORK ON ENDOCRINE DISRUPTING

CHEMICALS - March 2018www.oecd-ilibrary.org/content/book/9789264221413-en

OECD Revised Guidance Document 150…

….lists 35 OECD TG’s plus 7 draft TG’s

OECD CF Level 2

OECD CF Level 2

In vitro assays providing data about selected

endocrine mechanism(s)/pathway(s)

(mammalian and non-mammalian methods)

+ Estrogen Receptor binding affinity (OECD TG 493)

+ Androgen Receptor binding affinity (US EPA TG OPPTS 890.1150)

+ Yeast Estrogen/Androgen Screen (ISO 19040-1 & 2)

+ Estrogen Receptor transactivation (OECD TG 455)

+ Androgen Receptor transactivation (OECD TG 458)

+ Steroidogenesis in vitro (OECD TG 456)

+ Aromatase assay (US EPA TG OPPTS 89- 1200)

+ Thyroid disruption assays

+ Retinoid receptor transactivation assays

+ Other hormone receptors assays as appropriate

+ High Throughput Screens (HTS)

Yeast estrogen/

androgen screen+ Routledge E.J. and

Sumpter J.P., Env.

Toxicology and

Chemistry (1996)

ISO 19040-1&2

…OECD TG in future

GM Saccharomyces

cerevisiae - GSK

Turning the clock back to 1996…

2009 – EPA List 1 test orders issued for 67 chemicals

+ EDSP Tier 1 screening battery: 5 in vitro assays, 4 in

vivo mammalian assays

EPA Tier 1 EDSP battery

2012 – 6th SETAC Europe Special Science

Symposium on Endocrine Disruptors

+ ‘CRO EXPERIENCE: Validation, conduct

and reporting of EDSP assays (John Carter)

+ Challenges meeting acceptance criteria for multiple

endpoints in the in vitro assays

+ High cost to industry, lack of laboratory capacity to perform

the high volume testing requirements envisaged in future

t4 Workshop (2013) conclusions from performance of the EDSP Tier 1 screening assays:

Future direction must have…

+ Greater emphasis placed on using fewer animals in line with the vision embodied in Tox21

+ Change direction to develop in vitro HTS and computational models to support a ‘bioactivity’ and ‘exposure’

risk based approach

FIFRA SAP meeting 2014 - to advise EPA on future direction

+ Strategic approach: IBER prioritization based on identifying overlap of

bioactivity predicted/measured using ToxCast* model and exposure potential

predicted using ExpoCast HTE tool. (* includes QSAR models and 18 in vitro

HTS for ER and AR bioactivity, Ref EDSP21 dashboard)

IBER: Integrated Bioactivity Exposure Ranking

Steven Knott (US EPA, 2015) – IBER explained

Joshua Harrill (US EPA NCCT, Dec 2018)

+ Presented on HTTr (transcriptomics) at the UK NC3Rs in London, describing

TempO-Seq human whole transcriptome assay in MCF-7 cells for determining

chemical bioactivity thresholds in human derived in vitro models

US EPA divergence from OECD CF assays

Original EDSP Tier 1 screening assays Current OECD CF assaysUS EPA High throughput screening and in

silico model alternatives

In vitro

ER Transactivation US-EPA OCSPP 890.1300 OECD 455 ToxCast ER model

ER Binding US-EPA OCSPP 890.1250 OECD 493 ToxCast ER model

AR Binding US EPA TG OPPTS 890.1150 US EPA TG OPPTS 890.1150 AR model (future)

Steroidogenesis US-EPA OCSPP 890.1550 OECD 456 STR Model (future)

Aromatase US EPA TG OPPTS 89- 1200 US EPA TG OPPTS 89- 1200 STR Model (future)

In vivo mammalian

Uterotrophic US-EPA OCSPP 890.1600 OECD 440 ToxCast ER model

Hershberger US-EPA OCSPP 890.1400 OECD 441 AR model (future)

Pubertal Male US-EPA OCSPP 890.1500 US-EPA OCSPP 890.1500 ER, STR and THY models (future)

Pubertal Female US-EPA OCSPP 890.1450 US-EPA OCSPP 890.1450 ER, STR and THY models (future)

+ EU-NETVAL - European Union Network of Validation Laboratories for Alternative Methods

+ Established in 2014 by EURL ECVAM and tasked with prioritizing development of in vitro Endocrine Disruptor assays

+ 2014 – Envigo was invited to join EU-NETVAL - the only lab from the UK at that time - attended the inaugural meeting at the

EC Joint Research Centre based at Ispra (Italy) in June 2014.

+ 2015: First EU-NETVAL validation project - call for 3 member labs to validate a new in vitro assay for Androgen Receptor

Transactivation to support the OECD TG 458 - AR-CALUX® Assay

+ ENVIGO selected – criteria based on established in vitro validation track record - previously took part in ECVAM validation

programs for in vitro eye irritation (BCOP assay), for skin corrosivity (Epiderm assay) and for EPA list 1 EDSP submissions

EU-NETVAL Background

+ AR-CALUX® uses a genetically modified human cell

line that induces luciferase production when exposed

to androgenic chemicals. The test is able to

distinguish between agonist (androgenic) and

antagonist (anti-androgenic) responses.

+ The agonist reference chemical, 5α-Androstan-17β-

ol-3-one (DHT) and the antagonist reference

chemical, Flutamide, are assayed along side the test

chemicals.

+ The assay end-point is assessed by adding Promega

Steady Glo® Luciferase Assay System to the cell

monolayer of AR-CALUX® cells and measuring the

resulting luminescence using a luminometer plate

reader.

EU-NETVAL - AR-CALUX® assay

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Androstan – agonist response

Flutamide – antagonist response

+ EURL ECVAM SOP for AR-CALUX® – very prescriptive methodologies

+ Envigo adapted assay to more common practice – white plates,

steadyGLO luciferase and achieved the ECVAM SOP acceptance criteria

+ EU-NETVAL dispatched a ‘swat team’ to investigate the Envigo deviations

+ The EU-NETVAL team accepted our modifications and JRC-ECVAM

amended the validation SOP

EU-NETVAL - progress of first validation project

AR-CALUX® project schedule:

+ 2016 - Method transfer phase

+ 2017 – GLP validation: 20 proficiency chemicals

+ 2018 - Reported

OECD TG adoption schedule:

+ 2019 - A series of reviews (ESAC, WNT and VMG-NA)

+ 2020 –revised TG publication

Oct 2017 – Leslie Akhurst attended the

annual EU-NETVAL members meeting

in ISPRA to present the Envigo results

from the AR-CALUX® validation

+ 2014: EU-NETVAL is tasked with prioritizing development of in vitro ED assays - specifically,

the lack of in vitro assays for assessing Thyroid disruptors was identified

+ 2016: OECD Expert Working Group identified 17 TH assays with potential for EU-NETVAL validation

+ 2018: 13 EU-NETVAL laboratories from member countries are supporting the TH assay validation

project with scientific, technical and legal interactions ongoing between EUNETVAL, the commercial

method developers and the participating validation laboratories to kick start practical work

EU-NETVAL ‘Project 2’ – In vitro methods for Thyroid Disruptors

Central Regulation

+ TRH receptor activation

+ TSH receptor mediated activation

TH synthesis

+ Thyroperoxidase inhibition assay

+ Tyrosine iodination inhibition assay

+ Tyrosine iodination assay

+ Sodium iodide uptake assay

Secretion and transport

+ TTR/TBG ANSA fluorescence

displacement assay

+ T4-FITC displacement assay

Metabolism and excretion

+ Deiodinase activity (D1,D2, D3) assay

+ Glucuronidation assay (LC/MS)

+ TH sulfonation inhibition

+ Sodium iodide uptake assay

Local cellular concentrations

+ T3/T4 cellular uptake assay

Cellular responses

+ Human TR reporter gene assay

+ TRβ CALUX model

Multiple MOA assays

+ Zebra fish Eleutheroembryo thyroid assay

Integrative cellular assays

+ T-screen assay using GH3-cell line

+ Human neural progenitor cells assay

Endocrine disruptor endpoints on OECD CF Level 4

and Level 5 studies

David Myers

Senior Toxicologist, Envigo

OECD 407 – 28 day repeat dose oral study (rats)

+ Endpoints – no change in TG since 2007

+ Standard histopathology and organ weights

(reproductive/endocrine)

+ Optional endpoints - Hormone assays: T3, T4

,TSH serum levels

+ However the OECD 407 study can be conducted

as part of the OECD 422 study and this TG has

already changed to include T3, T4 and TSH

analysis as mandatory

+ Anticipate that the OECD 407 will be updated in

the near future

OECD CF Level 4 – In vivo mammalian toxicity

OECD 408 – 90 day repeat dose oral study (rats)

+ TG updated 25 June 2018

+ Mandatory endpoints now include:

+ Hormone assays: serum levels of T3, T4 and

TSH

OECD 414 - Pre natal developmental toxicity study in rats

+ TG updated 25 June 2018 with new ED endpoints added for rat studies only (not for rabbit study)

+ Serum T4, T3 and TSH concentrations to be measured for all dams.

+ Thyroids to be weighed and examined microscopically for all dams.

+ Ano-genital distance to be measured for all live fetuses.

+ Envigo are now rapidly amassing historical control data to support study data interpretation from

new studies being performed to the 25 June 2018 revised guideline.

OECD CF Level 4 – In vivo mammalian toxicity

OECD 421/422 Reproduction/Developmental toxicity screening tests

+ TGs updated in 2015/2016 with the following new endpoints now mandatory:

+ Oestrus cycles are monitored for 2 weeks before treatment starts and only females showing regular cycles are

included on study.

+ Oestrus cycles are also monitored from the start of treatment until mating.

+ Ano-genital distance of all pups is measured between PND 0-4.

+ Serum T4 concentrations are analysed for F0 males and male and female offspring at PND 13 - T4 levels in

F0 dams and Day 4 pups may be analysed if triggered as may TSH levels.

+ Substantial volumes of historical control data now exist to support study data interpretation having performed

60+ studies over 2017/18.

OECD CF Level 4 – In vivo mammalian toxicity

OECD 416 - Two-Generation Reproduction Toxicity study - Endpoints – no change in TG

OECD CF level 5 In vivo mammalian reproduction toxicity

OECD 443 – Extended One Generation Reproduction Toxicity study (EOGTRS)

+ Endpoints – no substantial changes in TG updated in June 2018

+ A range of specific endpoints required for EOGTRS study (not for 2-Gen), including as follows:

+ T4 and TSH levels in serum measured in F0 and F1A animals (10 M/10 F per group)

+ T4 and TSH assayed in serum of unselected F1 weanlings (10 pooled samples per sex per group)

+ Envigo has performed a historical control data study in both Sprague Dawley and Han Wistar rats to support

data interpretation on customer studies.

The T4 and T3 hormone endpoints required for the OECD CF Level 4 and Level 5 studies are fully supported at

Envigo by the Department of BioAnalysis using LC MS/MS. Envigo was the first analytical lab to be able to

validate these assays and was invited by the EPA to join round table discussions on this subject at SOT 2017 to

share details of the analytical methods. The next slides cover how our Envigo analytical team achieved this.

T3 and T4 Analysis by Liquid Chromatography

Coupled to Tandem Mass Spectrometry

Detector (LC-MS/MS)

Sunetha Diaram BBA MSc MRSC

Head of Department, Bioanalysis (LC-MS/MS), Envigo

Failure of standard T3/T4 analysis to meet new

OECD regulatory requirements

+ Regulatory expectation for analysis of circulating levels of thyroid hormones in rats

(pup and adult) on OECD 414, 421, 422 and 443 studies; fetal hormone levels

assayed on studies required for US EPA

+ Currently published immunoassay and LC MS/MS techniques are sufficient for the

determination of T3 and T4 levels in adult rats

+ But are generally not sufficient for T3 and T4 determination in fetuses and juveniles on

reproductive toxicology studies due to:

+ lack of sensitivity, low selectivity and large sample volume requirements

Envigo performed a Positive Control Pre and Post Natal Developmental Thyroid Study in Sprague-

Dawley Rats by Oral Administration of PTU (Propylthiouracil)

+ Quantifiable levels of total T3 and T4 hormones were detected in pregnant and

lactating females and weanlings

+ However the validated immunoassay technique was unable to detect T3 and T4 in

fetuses or in F1 offspring at Days 4 and 13 of age

Modification and validation of new method required

Modifications to the LC MS-MS method were developed and validated to achieve:

+ Improved detection of hormone levels in control samples (fetuses in particular) and more sensitive detection of

test item related increases or reductions in hormone levels

+ Reduced incidence of repeat analysis arising from high concentration samples.

+ Increased accuracy/sensitivity using small volume samples (~165 µL serum to allow for 50µL analysis volume)

GLP Validation focus:

Challenges and Best Practice

Integrity of Method - Selectivity

+ Check for chromatographic selectivity from [the

isobaric] Reverse T3

+ rT3 is believed to be metabolically inactive, whilst T3

is an active thyroid hormone

+ They have the same mass transitions and therefore

imperative that they are chromatographically

separated using isotopically labeled standards

Challenges and Best Practice

Different collection tubes

+ Observation: Two different collection tubes were

frequently used for the clotting process to generate

the serum sample

+ plain plastic tubes or tubes containing clot

activator

+ Measured trend: Serum samples obtained using

plain tubes for the clotting process resulted in loss of

data due to suppressed analytical instrument

responses

+ Solution: Use of appropriate isotope stable, labelled

internal standards in clot activator tubes to safeguard

data points where low pg/mL T3 and T4 levels are

present in the samples - particularly prevalent in fetus

and Day 4 age pups

+ Conclusion - Tubes containing clot activator

produced cleaner samples….

+ Successfully demonstrated that tubes containing

clot activator plus isotope stable, labelled internal

standards can be used for accurate, sensitive and

stable T3 and T4 sampling

+ The CV (precision) and RE (accuracy) for both T3

and T4, across quality control samples (generated

from collection tube types were within acceptance

criteria of ≤20%

+ No adverse impact from using clot activator tubes

with a 30 minute clotting period compared to plain

tubes with a 1 hour clotting period

Challenges and Best Practice

Triggered thyroid hormone analysis – stability requirements

+ Adult male and Day 13 of age male and female

offspring samples are analyzed for T4 on OECD

421/422 studies

+ There needs to be a clear pattern in the data indicating

a dose related decrease or increase in thyroid

hormones which is assessed via statistical calculations

+ If further analysis is required, this can be long after the

sample collection period after adult and Day 13 samples

have been analyzed

+ Often further time delays occur following review by Tox

SD and Sponsor regarding decision for triggered

analysis

+ Therefore establishing stability for the serum samples

is critical

Historical control data is steadily being generated

Conclusion

+ An LC-MS/MS method was validated at Envigo to be:

+ Selective , Sufficiently sensitive, Accurate

+ Robust irrespective of sample collection method (plain vs clot activator tubes)

+ Successful in establishing sufficient stability of T3 and T4 in serum samples

+ The range validated for total T3 and T4 only utilizes 50 μL sample

+ Achieved the required detection/quantification in control samples for fetuses

+ The validated method allows for more efficient sampling times within the animal unit (30 min clotting period

instead of traditional 1 hour for plain tubes)

+ Test item related increases or reductions in hormone levels were quantifiable in the range validated whilst

minimizing the need to perform repeat analysis arising from high concentration samples

Regulatory framework and support

Dr. Asta Ruzgyte Frère, Dr. Peter Stoldt

Legal - updates to EU Regulations and Guidance

COMMISSION DELEGATED REGULATION (EU) 2018/605 (complementing BPR)

COMMISSION IMPLEMENTING REGULATION (EU) 2018/1569 (amending PPPR)

Guidance for the identification of endocrine disruptors in the context

of Regulations (EU) No 528/2012 and (EC) No 1107/2009

ECHA and EFSA with the technical support of the JRC EFSA Journal 2018;16(6):5311

In accordance with “OECD 2018 Revised Guidance Document 150 on

Standardised Test Guidelines for Evaluating Chemicals for Endocrine

Disruption”

OECD Publishing, Paris, https://doi.org/10.1787/9789264304741-en

Active substance

Co-formulant

Active substance

Safener

Synergist

Applicability of BPR and PPP regulations

BPR (Biocidal Product Regulation)

(EU) No 528/2012PPP (Plant Protection Product)

Regulation (EC) No 1107/2009

A substance of concern under the European BP or PPP legislation is to be

regarded as having ED properties, as long as it is not demonstrated that the

substance is not an endocrine active substance

‘GUILTY’ until proven ‘INNOCENT’

Three conditions stipulated in ED assessment criteria based on WHO definition of an Endocrine Disruptor:

ED Assessment Criteria

Adversity

change in

▪ Morphology

▪ Physiology

▪ Growth

▪ Development

▪ Reproduction

▪ Life span

- Individual organism

- Or it’s progeny

▪ Or in populations

Endocrine activity

The capacity to alter the

function(s) of the endocrine

system modalities

Biological plausible link between adversity an endocrine activity

OECD Conceptual Framework

Regulatory expertise required to build Weight of Evidence (WoE) approach

ENVIGO REGULATORY CONSULTING GROUP

+ 45 staff – Diverse team comprising SMEs in Toxicology, Ecotox, Chemistry, Environmental fate…. with

extensive accumulated knowledge of in silico modelling and dossier submissions

+ Understand your molecule, use accurate information for modelling

+ Understand your data – interpret in context of ED assessment criteria

+ Identify gaps in your data – to build a complete safety profile

+ Understand what to do with your data – includes decisions not to perform studies that you don’t need

+ Understand the legal guidance - understand (and sometimes challenge) what regulators are asking for

OECD CF Level 1: Workflow

Compilation of new data

Gathering of all relevant information and evaluation of data quality

Analyse/conclude/advise on the sufficiency of the dataset and identify data gaps

Assessing data in context of ED criteria and establising lines of WoE

1

2

3

4

Workflow – Task 1

Gathering of all relevant information and evaluation of data quality

+ Understanding your molecule – establish accurate information

for use in modelling and decision making

+ Physical and chemical properties,

eg, MW, reactivity, volatility, biodegradability

+ All available read across, chemical categories, existing

information from (Q)SARs and other in silico tools (eg ToxCast,

EDKB)

+ All available toxicological and ecotoxicological data eg. from

standaradized CF Level 4 and Level 5 studies or from

non-standardized tests.

1

11

2

Workflow – Task 2

Compilation of new ‘predictive’ data:

+ (Q)SAR predictions of endocrine disruption potential using the

following models :

Model E.A.T.S

DEREK Nexus 6.0.1 EAS

VEGA NIC 1.1.4 E

OECD QSAR Toolbox 4.2 E

Endocrine Disruptome EATS

Danish QSAR Database EAT

1

23

Workflow – Task 3

Assembling, assessing and reporting the lines of evidence:

+ Understand your data – expert judgement to interpret in

context of the ED assessment criteria

+ Empirical evaluation of data is based on dose/concentration-

responses, consistent findings across study types and

repeatability.

+ Reporting and organisation of your assembled data is focused

on whether the lines of evidence contribute to adverse effects

mediated by endocrine (EATS) activity and this can also be

informed by information from other non-EATS modalities

1

23

4

Workflow – Task 4

Analysis of the sufficiency of the dataset

+ EATS-mediated adversity

+ to support conclusion on absence of EATS-mediated

adversity

+ EATS-related endocrine activity

+ to support conclusion on absence of EATS-related

endocrine activity

+ Considerations on the generation of further data

EU Deadlines for AS renewals/applications

Endocrine Disrupter Criteria applicable from:

7 June 2018 (Biocidal Products) - ECHA 10 November 2018 (PPP) - EFSA

Commission Delegated Regulation (EU) 2017/2100 Commission Implementing Regulation (EU) 2018/1659

Applies to any AS and co-formulant within a BP, where the

evaluation period was not completed by 7 June 2018.

Previously approved AS will require an assessment at renewal

For applicants, additional information requests to only

exceed 180 days in exceptional circumstances

For Member States evaluation, current evaluation

procedures should be adhered to

For ECHA evaluation: 270 days for a full evaluation and 90

days if the Competent Authority evaluation is not a full one

Applies to any application, including pending renewals of

substances submitted before 10 November 2018

For applicants, a deadline for the submission of extra data,

not exceeding 30 months

For evaluation Member States, 90 days to assess

information

For EFSA evaluation , 120 days to assess and conclude

Envigo ED Team

Regulatory Experts in

Toxicology and Ecotoxicology

and in silico modelling

Levels 1/2/3/4/5

Operational Toxicology

In vitro - Level 2

Operational Toxicology

In vivo

Levels 3/4/5

Operational

Ecotoxicology

Level 3/4/5

Coordination:

Marketing / Proposals / Sales / Project

Management

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