On the 12th of May scientists joined to share their work at the CAAT 21st century toxicology webinar via Zoom. Representatives from the EPA, NCATS, FDA, JaCVAM and so many more presented an update of their current work, publications in the pipeline, new assay methods showing promise, new software on their websites that may be of use to others, and policies regarding animal-free new approach methods (NAM) in the process of being updated.
The work presented at this meeting was not only refreshing from a scientific point of view but also for the general public, as they estimate by the year 2026 all drug development testing will be done on in vitro models removing animals from the equation. Current statistics presented showed a very encouraging uptake of NAMs in the UK pharmaceutical sector (a drop in use of animals by 75%) but they are yet to see this uptake in the biomedical industry and university labs. The current testing regime in place is very restrictive, so much so, that if it had been in place years ago we wouldn’t have access to aspirin, as it would have failed in preclinical animal screening.
The first to present was Maureen Gwinn of the EPA. Since the last TT21C meeting in 2019, they have worked on a retrofit in vitro assay that was published in December of 2020, the paper can be found here. This used both the ToxCast and Tox21 platforms to assess endocrine active substances. They incorporated current high-throughput screening (HTS) methods with hepatic metabolism to create the AIME platform. To test this platform they used 15 reference and 48 test chemicals on estrogen receptor transactivation. It proved useful for the identification of both human risk, based on metabolites generated, and false-positive/false-negative test effects.
They also had a paper published in March of that same year that dealt with disruptions to the secretion and production of thyroid hormone caused by some chemicals. The paper can be found here. They developed a medium-throughput assay using a thyroid microtissue culture to estimate these effects. To verify the results they tested the assay on both 2D and 3D cultures using reference chemicals. They found that by growing the thyroid tissue in 3D it restored the secretion of the hormone which was not seen in 2D cultures.
At the moment, they are working on a tiered testing system to help identify the mode of action for risk assessment. The first tier in this approach is HTS including cell painting. Also, they are not working exclusively on human health but are also looking at ecological species. From looking at cross-species differences in ligand interactions and species sensitivity detected for ligands in ecology they identified that human cell lines may not be useful in this context. In addition, they are looking at ways to incorporate data to filter based on exposure, sensitivity, risk, etc. to allow the sorting of chemicals. This may help to identify information gaps and create flexible and sustainable processes that can adapt to scientific advances and continual generation of new safety-related info. They also plan to release a new ComTox Chemicals dashboard later this year. With >900,000 chemicals.
Another publication in the pipeline includes the use of a multi-species assay (multiplexed in vitro bioassay) for nuclear receptor-ligand interactions. It incorporates 5 species intended to capture maximum variability in PPAR𝛾, PPAR𝛼, RXR𝛽 and GR. Screening of additional chemicals may provide new insights into predicting cross-species sensitivity based on amino acid sequence conversion.
They are also looking for new committee members for NAS, see NAM workplay if interested.
Next up was Anton Simenov of NCATS who discussed the Tox21 platform. The goal of NCATS is to assess a diverse set of chemicals against in vitro tests to generate high quality bioactivity data which will be assembled into a big dataset/platform. This in turn will allow the development of models with better translatability for human biology. It includes over 70 screening campaigns with approximately 10,000 chemicals including both approved and rejected drugs, pesticides and industrial chemicals. The creation of this platform has led to the publication of over 100 papers and the production of a very extensive, 100 million data point, database for toxicology. In the pipeline they have an upcoming paper on the storage effects of chemicals over a 4 month period. This was done through extensive quality control surveillance throughout the study.
The platform is also being used to crowdsource model building and expand the platform with the use of artificial intelligence methods, specifically machine learning. The use of this programme has the ability to increase predicitivity. Within this the use of 3D bioprinting machinery for the production of model organisms using cells and hydrogel has been developed. They are currently bioprinting models to replicate blood cell walls and skin (through reconstruction of the epidermis for testing irritants). Bioprinters are filled with cells. Resources are being put towards specifically stem cells, due to how easy they are to source and maintain. The study is specifically on minimising their stress to allow for upscaling of this process. For example, some success has been seen in a 4-molecule cocktail that improves survival of hPSCs and facilitates cell cloning, passaging etc.
Finally the last study mentioned was the development of lung and neuronal models for both COVID and pain prediction in relation to the opioid crisis, respectively. Through these models they are testing the wild type system of toxicological drug effects and effects of the virus on their respective organs.
The director of NCATS, Chris Austin, is moving on to the private sector so there is an opening. They predict selection of a new director will take up to a year, for now the deputy director, Joni Rutten, has stepped up.
Suzanne Fitzpatrick of the FDA then took over to tell us what developments the FDA have made in relation to the use of non-animal models. Along with the creation of a website section dedicated to the resources and developments in non-animal testing, they would like their regulators to be aware of new technologies and methods in drug development before being faced with applications using them. This is especially apparent as the founder of Genoskin mentioned in an interview with Pharm Exec that his team had been invited by the FDA to train their reviewers in how his ex vivo skin model works and its benefits over animal models (https://www.pharmexec.com/view/accelerating-human-data-in-drug-development-dr-pascal-descargues).
They have created a working group under the office of the chief scientist called the alternative methods working group (AMWG) who meet to talk about the alternative methods for toxicology and efficacy assessment under way at the FDA. The aim of this working group is to continue the promise of the FDA to encourage the development and review of new methods and techniques to better translate human and animal biology. This is supplemented with the alternative methods report which aims to provide a snapshot of their ongoing work and global meeting notes to ensure both the public and scientists are kept up to date. Along with this, they also host a monthly webinar series for alternative methods and provide a space for discussion of new methods before submission for approval, this allows the FDA to work with researchers to enable streamlined applications.
At present they have several organ-on-chip (OOC) models being tested in their labs and along with testing they are developing a working definition of microphysiological systems (MPS) to help researchers. OOCs were their first alternative test case which started up the program in 2011 and helped to identify good reference compounds for their validation. The material required for the selection of NAMs are:
- Description of new methodology
- Description of intended use of purpose
- Description of proposed context of use
- Description of gap this method fills/what it is fixing and intended impact
- Any data or publications from use of the method
The final point mentioned was the update to their validation plans from one model for one model approach to the context of use qualification method. Validation includes how you show relevance to humans and how the end points are measured. Results should be reliable to be applied in product development and regulatory decision making.
The EPA then had a second speaker, Louis Scarano, who introduced the work of TSCA. A reform of section 4H of TSCA saw the reduction of vertebrates in testing, encouraging consideration of already available data and use of replacement methods before using vertebrates. Likewise, they are implementing NAMs under TSCA on both new and existing chemicals while also reviewing skin sensitisation papers to help finalise actions towards passing a policy for the reduced use of animals.
Aside from this they have also developed a model for screening both indoor and outdoor air conditions for the exposure of the drug of interest, this is of particular interest when performing drug release experiments. They have big plans in relation to NAMs, with one of their aims being the production of a tiered system that can substitute rats in inhalation studies. During testing of this system they focused on lung overload, lung liquid inhalation and solubility, from these, and the many other studies performed on this system, they see no need for the continued use of rats in respiratory testing.
They have also created a revolutionary platform, OncoLogic, which can be used to predict the carcinogenicity of chemicals. OncoLogic is a downloadable piece of software that works on Windows, the EPA are providing free access to it for everyone but with the note for the general public that they should consult someone who can interpret the data for them such as a chemist. In 2021 they updated the platform to also include more than 52 organic chemicals, the older version was for fibers, metals and polymers.
They are using NAMs to identify existing chemicals and low-priority chemicals that do not require risk identification studies. They plan to advance NAMs for the study of lung effects with the use of surfactants and poorly soluble low toxicity polymers. Evidence integration of chemicals that fit within their established boundaries is being implemented. A new law for NAMs requires the compilation of a list of all approved methods for use in TSCA.
Lastly, they have formed a new group upon office reorganisation who are working mainly on prioritisation efforts for risk evaluation of existing chemicals.
Fifth up was Nicole Kleinstreuer of NICEATM, who presented the work of ICCVAM and NICEATM. Both of whom are advocating for the replacement of endpoints. Their defined approach guideline for skin sensitisation is near completion. She then brought our attention to the biennial progress report which summarises all of the NAM work done across the US. At present they are in the process of rewriting the validation process for ICCVAM and working in collaboration with the UK NC3Rs, NIAID (who were previously animal based), NCATS and others for a global working group, MPSCoRe, for MPS for COVID-19 research. Within the working group they have already established a lung-on-chip model and have created a COVID-19 disease portal in the MPS database.
Outside of the working group, current focus is on acute ‘6-pack’ testing alternatives of pesticide active ingredients. Encouraging results are being seen for dermal lethality whose tests have switched to non-animal models under a waiver of guidance and skin sensitisation non-animal tests have been verbally accepted; they are just waiting on written confirmation. The other 4 tests are currently being evaluated.
Other studies of theirs include developing in silico approaches for oral lethality of chemicals and evaluation of 3D models for inhalation lethality building an LC50 database for in silico model development. A study of ways to replace in vivo LD50 tests is also gaining much interest.
In drawing things to a close she mentioned the additional software available publicly on their website. This included ICE, which is a large list of chemicals with data from both in vivo and in vitro models, cHTS, which includes chemical quality control information, Curve Surfer, which allows the investigation of the curve produced by data from the mechanistic target, and physiologically based pharmacokinetics (PBPK), which allows the estimation of concentrations of chemicals and allows the inclusion of own data for comparison. It allows you to view chemical curves and overall distribution in different tissues. A chemical characterization tool is also featured to allow for search of chemical lists.
Next to speak was Bob Van de Water from Leiden University, who spoke about the EU-ToxRisk programme, which is funded by the EU’s Horizon 2020 research and innovation programme. This programme aims at shifting the process of toxicological testing from animal-based models to human cell response testing methods. The audience heard of the progress of the EU ToxRisk so far, which includes 150 test method descriptions uploaded to their Knowledge Platform, >1000 datasets uploaded to the BioStudies database, 14 case studies and acknowledgement of the project by over 140 scientific publications and many more. Dr. Van de Water’s team is involved in establishing tools and case studies on how NAMs may be applied, with 5 read-across case studies officially reported to the OECD Integrated Approaches to Testing and Assessment (IATA) working group and subsequently published.
One such study mentioned involved the use of high throughput transcriptomic approaches to identify response at the gene level, to help identify modes of action of different complexes and included genes for CYP enzymes, TUBB2B, NCAM1 (CD56) and LHX2. The aim was to identify differences in gene expression biomarkers in order to identify chemicals which presented with strong responses and therefore may be suitable for therapeutic targets. You can view the case study here. There was also mention of many other ongoing studies, involving multi-target organs, high concerning toxicity profile screening, cross-liver system testing, multi organ metabolism and more. All of which can be viewed on their website here.
Van de Water proved that the team at EU-ToxRisk are keeping busy, as they have nearly finalised an ADME competent 4-organ chip made with iPSC and liver organoids and are also looking at CRISPR knock-in fluorophores to make reporter iPSC lines and adverse outcome pathways (AOPs). The ongoing project sustainability work taking place with the Horizon2020 RISK-HUNT3R Project was also discussed, which aims to achieve risk assessment in non-animal models via ab initio safety evaluation, and to move from hazard identification to full risk assessment. Testing strategies and the toolbox used for each were briefly described, including strategies of external to internal exposure, metabolism/toxicokinetics, effect identification, adversity qualification and integrated next generation risk assessment (NGRA). It was proved that there are multiple systems in place to maintain human safety, with the help of their 37 EU partners.
The presentation was signed off with a brief reference to the EU-ToxRisk newsletters, which are released twice a year, and detail the most up-to-date progress of the EU-ToxRisk team, and can be found here on their website.
Following Van de Water was Hajime Kojima of the Japanese Centre for Validating Alternative Methods (JaCVAM), who is working to develop NAMs for systemic toxicology in Japan. There was a focus on the ‘3Rs’, meaning reduction, refinement and replacement of animal testing models for the assessement of chemical safety, along with other materials. Multiple current projects were mentioned, including:
- The development of NAMs for reproductive toxicity for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) under S5.
- Detailed review papers on stem cell assays for reproductive toxicity and in vitro immunotoxicity for the OECD test guidelines.
- Ongoing projects involving the microphysiological system for PBPK modeling and the AI system for repeat dose toxicity testing.
There was a particular focus on the latter project, with reference to pharmacology and toxicology-based tests involving human iPS cells, derived from cardiomyocytes. You can read more about the project here. Dr. Kojima explained that this cardiotoxicity screening uses an impedance-based assay in an effort to measure the impedance of the cardiomyocytes, cardiomyocyte contraction and viability, using their OOC model. This model, created through mounting iPS/stem cell derived liver, kidney, small intestine and blood-brain barrier cells onto a chip, and other devices, is believed to be useful during evaluations as part of the drug discovery process. The aim of the project is the industrialization of regenerative medicine, through application in drug safety and pharmacokinetic evaluations.
They are also working on the Ministry of Economy, Trade and Industry (METI) consignment project, also known as AI-SHIPS, meaning the AI-based Substances Hazardous Integrated Prediction System project. Which, as briefly explained by Kojima, involves the development of an in silico hazard prediction system using AI technology. Find out more here. The basic concept for this project involves the evaluation of the toxicity development mechanism through the use of the PBPK model, translational research, and their newly developed AI/in silico technology – it proves to be an exciting time for all involved.
Up next was Thomas Hartung from John Hopkins University and director at CAAT, who spoke about the ongoing activities within the Center. Hartung began his presentation by making a point of CAATs aim to focus their work towards the overall improval of science rather than the eradication of animal models. He then continued to highlight the success of the online courses at CAAT, with a 3 fold increase in total learners per week, as he praised everyone for their continuous work efforts throughout the Covid-19 pandemic. With plans to develop more online workshops, this area is sure to be a continuous success for the CAAT team.
Hartung also informed the group that CAAT is working toward an MPS world summit in June of 2022, with up to 35 organizations participating on the scientific advisory board, as well as an upcoming international society and conference series.
Continuing on, there was an update on the ongoing work with Developmental Immunotoxicity Testing (DIT) alternatives, a project which works to establish NAMs as a critical element of OECD guidelines and introduce more transparency, consistency and evidence-based methodology into the industry. CAAT has now formed a new working group to focus on alternatives to in vivo DIT testing. The focus then shifted to the developments in Developmental Neurotoxicity Testing (DNT) alternatives, where they are testing the readiness criteria for DNT and working towards reporting standards in an effort to make in vitro assays reproducible. Testing methods consist of using bioengineering techniques to transform the original cell model into a MPS, often a clump of young brain cells derived from adult stem cells, on which a series of toxicology assays can be performed. This involves entering risk genes into the cell model and observing the data, in combination with risk assessment data of the drug, in order to observe the synergy between them. For more reading on the most recent work involving this project, please click here.
As a final point, Hartung touched on the recent developments in AI, such as the recent EU funding of the ONTOX project, an ontology-based AI toxicity testing project, and making sense of ‘-omics data’ as the basis for a pathway-based technology. In regard to the latter, many exciting scientific reports were mentioned, with a heavy focus on the women at the forefront of this development, with the likes of Emily Golden (please see here and here), Vy Tran (see here) and Alexandra Maertens (see here) all receiving honorable mentions.
Also from John Hopkins University was Katya Tsaioun, who spoke about the Evidence-based Toxicology Collaboration (EBTC), of which she is the director. The EBTC is passionate about the integration of scientific evidence into regulatory, environmental and public health decision-making, as well as obtaining better evidence with less wasted research. They hope to achieve this by promoting and improving access to high quality and high impact research through fair and open science, in their effort to raise research standards across the globe. Tsaioun started by giving a brief overview of the work that the EBTC does, such as:
- Applying systematic methods to develop AOPs (see here).
- Developing a series of recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER) for good practice in toxicology systematic reviews (see here).
- Using a systematic review to evaluate non-animal tests for drug-induced liver injuries (see here).
Also in the works is an updated definition for “biological plausibility” for modern systematic reviews, which is expected soon. A key project mentioned was the current progress with the Zebrafish Embryotoxicity Systematic Review (see here), where the working group are in the final stages of removing Zebrafish from validly being used in research, which is noted as a great success for the team.
Some new and upcoming projects from 2020, where new methodologies are being developed were also mentioned, including:
- NASEM committee on TSCA SR methodology
- WHO Systematic review on EMF and oxidative stress
- Certainty in AOPs
- AOP framework for Covid-19 mechanisms with CIAO project (Modelling the pathogenesis of Covid-19 using the Adverse Outcome Pathway framework).
- The quality of Systematic Reviews in EH.
Tsaioun then continued on to talk about the Tox21 platform, where she explained the EBTC are working on three different streams of evidence; in vivo and human data from systematic literature reviews, tox21 and real world pharmacovigilance – all of which are being used to evaluate the accuracy of preclinical research in predicting human drug-induced liver injury (DILI). You can find the full study here.
In their study for evidence stream 1, the working group focused on two drugs that have already been in the market; Troglitazone (recalled) and Rosiglitazone. Of the 42 studies included in the references, none reported a high level of certainty in findings, with an overall failure to detect or report strong liver injury warning by many of these studies. Also during review, they identified some general limitations, in three main areas of publication bias, quality and standard. Many examples were mentioned, one being a lack of regulatory preclinical and clinical studies being published, lack of human randomised control trials (RCTs) published, lack of regulated animal toxicology studies, insufficient data in the methods section and a noticeable trend of abstracts which lack a substantial synopsis of all elements present within the paper.
Next up was stream 2, involving ToxCast in vitro data, which provides insight into activated biological pathways which may have toxicological significance or shed light on any possible mechanisms for toxicity. Upon review of the ToxCast results, the main findings were based on the in vitro tests, where Troglitazone was twice as active as Rosiglitazone. This would indicate a high possibility of more off-target effects. Despite the potential benefits, it was noted that the ToxCast dataset does have it’s limitations, including missing data as not all compounds were thoroughly tested, complexity of data processing steps and a lack of several key tests important for liver injury.
Stream 3 consisted of a review of the human adverse effects reported, where there was a significant difference in reported adverse events, including those related to the liver, between both drugs. There were also 8 times more fatalities reported with Troglitazone over Rosiglitazone. The limitations were identified as a major lack of data, on prescription numbers, doses and potential bias, which seemed particularly significant due to the use of highly observational, non-randomized studies.
The main take-away point from the Tox21 project was the need for new developments in literature review technology, such as machine learning and AI, in order to improve the standard or current research data. Tsaioun noted that regulatory agencies must find more innovative ways to work with sponsors to ensure the transparency of any submitted data.
As a final point, Tsaioun mentioned the relevance of the CIAO project in relevance to the Covid-19 pandemic. The EBTC is working with over 75 scientists, clinicians, AOP developers and toxicologists to train and supervise individuals in literature review and documentation of a systematic scoping review of the neurological effects of Covid-19.
Next up was Kate Willett, Senior Director of the Humane Society International (HSI), who spoke about the Animal-Free Safety Assessment (AFSA) Collaboration, which is coordinated by the HSI. This project works towards the adoption of a modern, species-relevant approach to safety assessments in replacement of animal testing. They have four current projects; cosmetics, tox21, chemicals and vaccines.
In terms of cosmetics, there are ongoing developments in advancing the animal-free cosmetics policy and safety assessment, including policy alignment on animal testing and sales restrictions, as well as education and training for animal free safety assessment. With regard to education and training, the AFSA is passionate about supporting innovation without new animal testing. This has led to the development of a new training program in NGRA, which is based on well established principles and processes such as the 9 principles of the International Cooperation on Cosmetics Regulation (ICCR) and the 3-tiered assessment process of the SEURAT workflow. These are risk based mechanisms and identified the sharing of experiences between shareholders as beneficial. The overall goal is that this will help to address the needs of regulatory and regulated communities and support the long-term acceptance and implementation of legislative matters.
Finally, Willet also revealed that the AFSA team is also devising an educational program which is divided into modules that cover the whole risk assessment process, with specific expertise for each. It is a collaborative effort between scientists who source the content information and relevant examples, educators who devise a plan for the delivery of the material and graphic designers who make it user friendly and easy to read. Currently, they are at the point of collecting initial feedback on the drafts tested, with the aim being an online course which includes information on how to use in vitro data to make decisions and predictive chemistry (in silico).
Last but certainly not least was Daniel Krewski of the University of Ottawa and former Chair of the National Research Council’s Committee on Toxicity Testing and Assessment of Environmental Agents, who’s final report initiated the annual CAAT 21st century toxicology meeting. Krewski spoke about the development of a series of workshops using new data based on evidence integration in risk assessment, the last of this series is to be in person as the case studies are to be interactive. From these workshops a framework for evidence integration has been developed and from this they expect 3 reports, including case studies. He also spoke of his recent work with the EPA to develop a Value-of-Information framework of NAMs, with toxicity strategies, uncertainty, time, cost, public health risks and benefits. The conclusion from this, which is not yet published, is that the timeline of information is more important than precision as less precise data available earlier is more beneficial for public health. Krewski highlighted Covid-19 as a good example of this, as although there are a few issues with the vaccines in terms of populations, they affect far fewer people than Covid itself would. Krewski, along with his collaborators, is also looking at key characteristics of human carcinogens and reproductive toxicants which can help to better our understanding of human risk. The presentation was wrapped up with a brief summary of the ongoing research being conducted at the McLaughlin Centre for Population Health Risk Assessment, where Krewski is based. The research themes consisted of implementing TT21C, evidence integration in risk assessment including integration of NAMs and case studies and other previously mentioned projects.
The webinar was then opened up for commentary, where many great points were discussed amongst audience members and speakers. There was a great sense of hope and excitement for the future of drug testing and development and research in general. People seem to notice that leaders in the industry do not favour animal models due to high risk, use of time and cost and are hoping for the acceptance of more alternative methods soon. They also seem to agree that this should be encouraged by regulatory bodies and guidelines should be developed. A note was made of the tremendous progress made in the last 14 years since the CAAT seminar began, and people expressed their delight at the emergence of real world applications in recent times. Covid-19 seemed a fitting example for many, as the unprecedented development, acceptance and roll-out of not one, but multiple vaccines in the past 15 months or more, was only made possible by largely skipping animal-based experiments. This proves that in some cases, such shortcuts are not only possible but sometimes necessary. This has also paved the way for the first Covid-19 lung-on-a-chip model, which would not have been possible in animal testing as organ manifestations do not correlate with human models.
Overall, it proved to be yet another successful year at the CAAT 21st century toxicology meeting, despite the restrictions of the Covid-19 pandemic preventing the usual in-person activities.
ADME – Absorption, Distribution, Metabolism and Excretion
AFSA – Animal-Free Safety Assessment
AI – Artificial Intelligence
AIME – Alginate Immobilisation of Metabolic Enzymes platform
AI-SHIPS – AI-based Substances Hazardous Integrated Prediction System project.
AMWG – Alternative Methods Working Group
AOPs – Adverse Outcome Pathways
CAAT – Centre for Alternatives to Animal Testing
cHTS – curated High Throughput Screening data
CIAO – Modelling the pathogenesis of Covid-19 using the Adverse Outcome Pathway framework
COSTER – Conduct of Systematic reviews in Toxicology and Environmental health Research
CYP – Cytochrome p450s
DILI – Drug-Induced Liver Injury
DIT – Developmental Immunotoxicity Testing
DNT – Developmental Neurotoxicity Testing
EBTC – Evidence-based Toxicology Collaboration
EPA – US Environmental Protection Agency
FDA – US Food and Drug Administration
GR – Glucocorticoid Receptor
hPSCs – human Pluripotent Stem Cells
HSI – Humane Society International
HTS – High Throughput Screening
IATA – Integrated Approaches to Testing and Assessment
ICCR – International Cooperation on Cosmetics Regulation
ICCVAM – the Interagency Coordinating Committee on the Validation of Alternative Methods
ICE – Integrated Chemical Environment
ICH – International Council for Harmonisation of technical requirements for pharmaceuticals for human use
iPSCs – induced Pluripotent Stem Cells
JaCVAM – Japanese Centre for Validating Alternative Methods
METI – the Ministry of Economy, Trade and Industry
MPS – MicroPhysiological Systems
NAM – New Approach Methods
NAS – National Academy of Science
NCATS – National Centre for Advancing Translational Science
NC3Rs – National Centre for the Replacement, Refinement and Reduction of animals in research
NGRA – Next Generation Risk Assessment
NIAID – National Institute of Allergy and Infectious Diseases
NICEATM – the National Toxicology Program (NTP) Interagency Centre for the Evaluation of Alternative Toxicological Methods
OECD – Organisation for Economic Co-operation and Development
OOC – Organ-On-Chip
PBPK – Physiologically Based PharmacoKinetic model
PPAR – Peroxisome Proliferator-Activated Receptor
RCT – Randomised Control Trial
RXR – Retinoid X Receptor
TSCA – Toxic Substances Control Act
TT21C – Toxicity Testing in the 21st Century
Report written by Ellen Towey and Saoirse Foley.