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Updates from the Center for Alternatives to Animal Testing (CAAT)
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CAATwalk
February 1, 2019

News and Updates from CAAT

   Contents:


Thomas Hartung Cited in Nature Lab Animal

Excerpt:

“There's a trend for making more and more such data available,” said Thomas Hartung, chair for evidence-based toxicology at Johns Hopkins University. 

One particularly rich source of information developed after Europe enacted the REACH (Registration, Evaluation, Authorisation, and Restriction of Chemicals) regulations in 2006, which required publication of toxicological tests for all candidate chemicals (https:// www.echemportal.org/echemportal/ propertysearch/index.action). Hartung and his group tapped this source to create a massive chemical topography that can be used to map a new chemical and estimate its toxicological properties.

Using 10 million representative molecules (out of about 140 million known), they created a map of the known chemical universe that placed structurally similar molecules close to one another. To determine structural proximity, their model/algorithm had to compare each molecule to every other molecule in the database. That added up to 50 trillion comparisons of individual chemical pairs, which demanded about two days of calculations on an Amazon cloud service. The researchers then pooled chemicals by 74 labels of available toxicological data, under 19 categories like acute toxicity, reproductive toxicity, or skin irritation. Any modern computer can run a comparison of a novel chemical against one of those data sets to see where it fits in the chemical space, and then examine the data of the chemical’s closest structural relatives. “If it’s negative all around, we can say it’s extremely unlikely that something will suddenly be positive,” said Hartung. An analysis where 190,000 chemicals with known classification as toxic or not were compared to the respective prediction showed that the model was 87% accurate. By contrast, when an animal study is repeated using the identical molecule, the same result occurs only 81% of the time3. “Our computational approaches outperform the reproducibility of the animal tests,” said Hartung. 

Hartung’s work is looking for regulatory acceptance, which he hopes will be forthcoming in the United States as his group works to get the method validated through The Interagency Coordinating Committee on the Validation of Alternative Methods, a group established in 2000 that includes 16 US regulatory and research agencies.

Full Article: Toxicology Testing Steps Towards Computers (Nature Lab Animal)
 



CAAT Satellite Meeting at Society of Toxicology 
Updates on Activities Related to 21st Century Toxicology: Invited Presentations and Open Microphone

 

A Society of Toxicology (SOT) Satellite Meeting
Organized by CAAT and the Human Toxicology Project Consortium (HTPC)

Thursday, March 14, 2019
12:30-4pm
Hilton Hotel
Baltimore, MD

If you’re planning to attend the Society of Toxicology conference in Baltimore this March, please join CAAT and the Human Toxicology Project Consortium (HTPC) for our annual satellite meeting on advancing 21st century toxicology activities. The satellite meeting provides an informal setting in which interested stakeholders can update each other on this important topic. 
 
The meeting will feature a number of invited presentations but also leave time for an open microphone segment in which participants are welcome to make announcements or to comment on germane topics, with or without a few slides.
 
The preliminary program is as follows:
 
12:30 Box lunch (for pre-registered participants) and welcome, Martin Stephens (Johns Hopkins University)
 
13:00 Invited updates (10-minute talks each followed by up to 5 minutes of discussion)

  • ToxCast - Russell Thomas (EPA)
  • Tox21 - Rick Paules (NIEHS)
  • EU Tox-Risk - Bob van de Water (Leiden University)
  • ICCVAM - Nicole Kleinstreuer (NICEATM)
  • Organ-on-a-chip & Predictive Toxicology Roadmap - Suzanne Fitzpatrick (FDA)
  • Progress in implementing NAMs under TSCA - Gino Scarano (EPA)
  • Canadian Centre for Alternatives to Animal Methods - Charu Chandrasekera (University of Windsor)
  • Evidence-based data analytics predict human DILI using ToxCast data - Katya Tsaioun (Johns Hopkins)
  • Human Toxicology Project Consortium - Catherine Willett (Humane Society Int’l)
  • CAAT’s In Silico Prediction Tool - Thomas Hartung (Johns Hopkins) 

15:30 Open microphone for comments, announcements, and discussion

16:00 Adjourn
 
Please email Camila Januario to register. Box lunches will be available to those who have pre-registered.

Details 
 



Video: Thomas Hartung in Science. Facts. Fate. The World of Tomorrow (Frontiers)

Science. Facts. Fate. The World of Tomorrow

Thomas Hartung appears at 4:30 and 10:30 minute marks.
 


New Publications


Beger, R. D., Dunn, W. B., Bandukwala, A., Bethan, B., Broadhurst, D., Clish, C. B., et al. (2019). Towards quality assurance and quality control in untargeted metabolomics studies. Metabolomics, 15(1), 4. http://doi.org/10.1007/s11306-018-1460-7
 
Following up our workshop:
Quality assurance of metabolomics 
Bouhifd M, Beger R, Flynn T, Guo L, Harris G, Hogberg H, Kaddurah-Daouk R, Kamp H, Kleensang A, Maertens A, Odwin-DaCosta S, Pamies D, Robertson D, Smirnova L, Sun J, Zhao L, and Hartung T.
ALTEX. 2015;32(4):319-26. PubMed PMID: 26536290; NIHMSID: NIHMS895385; PubMed Central PMCID: PMC5578451.

Abreu CM, Gama L, Krasemann S, Chesnut M, Odwin-Dacosta S, Hogberg H, Hartung and Pamies D. Microglia increase inflammatory responses in iPSC-dervied human BrainSpheres. Frontiers Microbiology 2018, Front Microbiol. 2018; 9: 2766. doi: 10.3389/fmicb.2018.02766.
 


New Book (with Correction)


Alternatives to Animal Testing: Proceedings of Asian Congress 2016

Hajime Kojima, Troy Seidle, Horst Spielmann, (Editors)

Springer Nature Singapore Pte Ltd., Singapore 2019; 130 pages, 15 chapters
ISBN 978-981-13-2446-8, 2019

The book is based on the First Asian Congress 2016 on Alternatives and Animal Use in the Life Sciences, which was held on November 16-18, 2016, in Fukuoka, Japan. You can download the fully open-source in its entirety here

The editors were incorrectly listed in the previous issue of CAATwalk. We regret the error. 
 
 

Request for Information (RFI): Input on Assays and Approaches for Evaluating Chemical Effects on Cancer Pathways 

RFI response period ending March 31, 2019

The National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIH) is seeking input on assays and approaches for evaluating chemical effects on cancer pathways, specifically, pathways that map to the hallmarks of cancer and key characteristics of carcinogens.  

Cancer is a leading cause of mortality worldwide. While the defining feature of cancer is uncontrolled division of abnormal cells, it is a complex disease with varied presentations (i.e., different etiologies and target tissues) that involves dysregulation of multiple interconnected signaling pathways. Diverse environmental factors have been associated with the development and progression of various cancer types. A critical question in the field of environmental health is how to harness what is known about cancer biology and associated environmental exposures to improve public health outcomes. This Request for Information is in support of the Converging on Cancer Workshop, which is aimed at providing a clear path forward for evaluating the interactions between environmental exposures and cancer biology using the latest tools in toxicology and identifying knowledge gaps that require research attention. Potential applications of this understanding include building a framework for incorporating mechanistic data into cancer risk assessment, developing efficient and reliable screening tools to detect the carcinogenic potential of environmental chemicals (including mixtures), engineering safer products, and designing more effective multi-target therapeutics.  

The hallmarks of cancer (1) and key characteristics of carcinogens (2) offer two paradigms for organizing information to better understand the interactions between environmental exposures and biological systems that lead to cancer. The hallmarks of cancer represent the biological traits of tumors that allow for the unchecked growth of cancer, while the key characteristics framework begins with known human carcinogens and identifies their defining properties. It is clear from biomonitoring studies that we are constantly exposed to numerous structurally-diverse chemicals. A recent nomination to NTP was for development of a testing strategy to better understand how environmental chemicals might interact with multiple cancer-relevant biological pathways to elicit mixture effects that would not be expected based on single chemical considerations. This RFI is intended to generate input that will facilitate new testing approaches designed to evaluate these hypotheses in a cancer context. Responses to the RFI should provide information on technologies targeting cancer-specific pathways and mechanisms, including organotypic and/or mechanistically insightful tools, preferred animal models, and in silico/computational approaches to link relevant pathways, as well as cancer types for use in evaluating hypotheses regarding the joint action of chemicals that target cancer pathways.

Information Requested
The NTP requests information regarding assays and approaches to measure the key biological mechanisms/pathways associated with chemical carcinogenesis. Responses to any or all of the questions below are invited from interested individuals/groups, including, but not limited to, the environmental health research community, health professionals, educators, policy makers, industry, and the public.
  • Systematic review approaches to transparently identify and evaluate mechanistic information on the carcinogenic properties of chemicals and chemical mixtures.
  • Assays associated with the biological mechanisms/pathways described by the hallmarks of cancer and the key characteristics of carcinogens.
  • Assays that integrate across multiple cancer-related pathways (e.g., organotypic microphysiological systems, mechanistic animal models).
  • Modeling approaches to assess the joint effects of multiple chemicals on carcinogenic potential.
  • Feedback on critical pathways and mechanisms to target when developing novel carcinogenicity testing strategies.
  • Feedback on cancer types conducive to exploring chemical interaction hypotheses.
  • Environmental chemicals known to affect key biological mechanisms/pathways leading to cancer and which key biological mechanisms/pathways are affected by these chemicals.
  • Types of scientific data (e.g., mechanistic, epidemiological) needed to address underlying knowledge gaps of chemical exposures leading to carcinogenesis.
  • New technologies and innovative research approaches that could be leveraged to address these underlying knowledge gaps.

All responses to information requested in this RFI are voluntary. Please submit your responses to:
Cynthia V. Rider, Ph.D.
Toxicologist
530 Davis Dr
Durham, NC 27713
cynthia.rider@nih.gov
 



Advances in Cell and Tissue Culture 2019: Call for Papers Submission Deadline: February 28th, 2019


Would you like to present your research at ACTC 2019 Cardiff on June 4-5, 2019? Our first call for papers is now open for both oral and poster presentations—all presenters benefit from 20% off of already low registration prices. 

Details and Registration: https://theactc.com
 



More information: http://wc11maastricht.org/

 

Best wishes from all of us,

The CAAT Team
     
hand holding centrifuge tubes
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