April 26, 2022

Prospective Case Study to assess chemicals, using and developing New Approach Methodologies (NAM)

Overall goal/objectives:

There are industrial chemicals that are produced in large volumes worldwide with limited information for hazard and safety by standard guideline methods. This project aims to leverage our resources in an international context to address these substances, while developing a NAM based approach that would be used and verified for prioritisation and that can ultimately inform conclusive hazard – and risk assessment as well as risk management. Our specific objectives are:

to demonstrate how NAM data and classical toxicological studies can be used to inform the hazard and safety profile of chemicals with limited or unclear toxicological data;
to identify potential shortcomings, and to optimize the NAM battery for various application (from screening, prioritization and first tier assessments, to conclusive hazard characterisation/assessment and risk management);
to build experience and confidence in application of NAMs for hazard characterisation and risk assessment; and
to developed an approach using chemicals of mutual interest and build consensus on application within in an international context.

Case Study Leader:

European Chemicals Agency (Tomasz Sobanski)

Collaborators:

ECHA, US EPA (ORD), Health Canada, NTP, A*STAR, JRC, University of Birmingham

Status: In progress

Data generation for Tier 1 (In vitro and in silico) have been completed, now results are integrated, normalised and analysed by the case study team.
Substance selection for Tier 2 testing (5-day multi-omics assay) has been completed. 20 substances have been nominated using following criteria:
- Low BER, lack of regulatory tox data and hazard of interest;
- Confidence building (PODNAM and PODTRADITIONAL in agreement + NAM informed safety);
- Potential problems (PODNAM and PODTRADITIONAL in disagreement).
Work on manuscript describing Tier 1 outcome is in progress.
Preparations for Tier 2 testing are ongoing at NTP (substance sourcing, approvals, test planning)

Presentations or publications that have been publicly released:

K.P.Friedman: “Integration of New Approach Methodologies for Prospective Selection of Chemicals for Additional Study”, Society of Toxicology 61st Annual Meeting in San Diego, CA
T.Sobanski: “APCRA Prospective Case Study”, EPAA “Deep-dive” workshop: Use of NAMs in regulatory decisions for chemical safety, 23-24 November 2021
T.Sobanski: “APCRA Retrospective and Prospective Case Studies” NORA NAM Workshop, November 2021
T.Sobanski: “Experience of ECHA in applying NAMs in a regulatory context”, BFR International Symposium and Workshop: New Methods, Omics and Novel Concepts in Toxicology, November 2021

Feb 28, 2025

Assessing Quantitative Concordance Between Human and Rodent Toxicity Data

Case Study Leader: US EPA (Chelsea Weitekamp)

Overall goal/objectives: Traditional toxicity testing for environmental chemicals follows the preclinical model of drug safety testing, resting on the assumption that rodents serve as sufficient predictors of adverse health effects that may occur in humans. However, drug development suffers from high attrition rates, in large part due to observations of unexpected toxicity in early phase…

Dec 1, 2022

The Landscape of Exposure NAMs and their Evaluation with Traditional Exposure Data

Case Study Leader: US EPA (Kristin Isaacs)

Overall goal/objectives: There is a need for high-throughput new approach methods (NAMs) for exposure, as data critical to exposure estimation are often limited. The NAM approaches include structure-based machine-learning Quantitative Structure Use Relationship (QSUR) models, non-targeted monitoring of environmental data, high throughput toxicokinetics, rapidly parameterized consumer exposure models, and consensus multi-pathway modeling (CPDat/SHEDS-HT) approaches (e.g.,…

Apr 26, 2022

Transcriptomic analysis of human primary hepatocyte spheroids: Applications for read-across and additivity in risk assessment of emerging perfluorinated alkylated substances (PFAS) and PFAS mixtures

Case Study Leader: Health Canada (Ivy Moffat)

Overall goal/objectives: Per- and polyfluoroalkyl substances (PFAS) are a diverse class of organic chemicals used for various commercial, industrial, and residential applications. These stable chemicals resist degradation, allowing them to accumulate within the environment, posing a potential risk to humans and animals. However, with over 4,000 PFAS in the environment, there is a lack of…

Apr 26, 2022

High Throughput Toxicokinetics for In Vitro-In Vivo Extrapolation

Case Study Leader: US EPA (John Wambaugh)

Overall goal/objectives: New approach methodologies (NAMs) for toxicology have resulted in the availability of in vitro bioactivity data across multiple pathways and endpoints for chemicals that often have no other data. HTTK allows for in vitro-in vivo extrapolation (IVIVE) so that bioactivity data (such as µM concentrations) can be placed in a human exposure context…

Apr 26, 2022

Use of NAMs for assessing the immunotoxic potential of PFASs

Case Study Leader: EFSA (Jose Tarazona/Luisa Ramos Bordajandi)

Overall goal/objectives: The available information has evidenced immunosuppression effects following PFASs exposure, in particular the reduction in the vaccination efficacy and possible increase in the susceptibility to infectious diseases; however the information is insufficient for a comprehensive risk assessment. The aim of the case study is to define and implement a NAM-based IATA protocol for…

Feb 28, 2025

Classifier for endocrine ER/AR activity screening

Case Study Leader: JRC (Effrosyni Katsanou, Stavroula Sampani)

Overall goal/objectives: Designing classifiers for use in different regulatory contexts that indicate a level of concern for the potential of a chemical to cause endocrine disruption in humans Case Study Leader: JRC (Effrosyni Katsanou, Stavroula Sampani) Collaborators: JRC, Health Canada, US EPA Status: In progress Presentations or publications that have been publicly released:

Feb 28, 2025

Incorporation of NAMs into species sensitivity distributions for ecological risk assessment – an evaluation

Case Study Leader: ECCC (Rebecca Dalton), US EPA (Dan Villeneuve)

Overall goal/objectives: The aim of the present case study is to evaluate the benefits and impact of incorporating NAMs-based vertebrate data into the derivation of species sensitivity distributions (SSDs). Species sensitivity distributions represent a probabilistic distribution of the measured sensitivities of different species of organisms to a given substance. They are generally used to identify…

Apr 26, 2022

Transcriptomics-based points of departure for ecotoxicology – investigating the applicability of high throughput transcriptomics data to inform quantitative hazard assessments for ecological species

Case Study Leader: US EPA (Dan Villeneuve)

Overall goal/objectives: The overall goal of this case study is to test the hypothesis that concentration-response modeling of whole organism transcriptomic response following a 24 h exposure to larval fathead minnows (24-48 h post-hatch) can provide point of departure estimates that are protective, but not overly conservative, relative to acute and chronic toxicity measured in…

Feb 28, 2025

Retrospective Case Study Examining the Utility of In Vitro Bioactivity as a Conservative Point of Departure

Case Study Leader: US EPA (Katie Paul Friedman), ECHA (Tomasz Sobanski)

Overall goal/objectives: To elucidate whether a “region of safety” (ROS), i.e. a threshold below which no bioactivity or toxicity would be anticipated, can be identified using NAMs for a list of chemicals with existing human health evaluations. Case Study Leader: US EPA (Katie Paul Friedman), ECHA (Tomasz Sobanski) Collaborators: US EPA (ORD), ECHA, EFSA, A*STAR Status:…

Feb 28, 2025

Use of transcription profiles and primary human liver cells grown as spheroids to address potency and additivity of perfluorinated alkylated substances: Applications for read-across and additivity in risk assessment of emerging PFAS

Case Study Leader: Health Canada (Ella Atlas)

Overall goal/objectives: Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals.…