Alternative models developed for estimating acute systemic toxicity generally are evaluated using in vivo LD50 values, but variability in the values makes such assessments challenging. To characterize this variability more fully, NICEATM and collaborators at the Environmental Protection Agency (EPA) National Center for Computational Toxicology compiled a large data set of acute oral LD50 values from several curated databases.
Some chemicals having multiple LD50 values exhibited high variability, with some values ranging across multiple orders of magnitude. Such variability, which confounds hazard categorization, underscores the importance of considering an appropriate margin of uncertainty when using in vivo oral acute toxicity data to assess the performance of alternative methods. The analysis of the full data set will be presented at the 2018 Society of Toxicology meeting, and a manuscript describing the analysis is in preparation for publication in 2018.
NICEATM is working with other National Toxicology Program (NTP) scientists at NIEHS to compile a list of developmental toxicants that cover developmental outcomes ranging from subtle effects such as fetal weight changes through post-implantation loss. Toxicants are selected based on the availability of "high-quality" studies, those appropriately designed and powered with relevant endpoints that cover likely different modes of action.
After further evaluation and assessment, the studies are used to identify and extract data. Identified toxicants are candidates for testing with in vitro assays using primary cells, stem cells, or cell lines and for conducting in vivo assays using lower-order organisms such as zebrafish or roundworm (Caenorhabditis elegans). Test results will be compared to available in vivo mammalian data from rodents, rabbits, and humans. The toxicant list is being constructed with input from experts in industry, academia, and government and is expected to include agrochemicals, pharmaceuticals, and other chemicals.
NICEATM is collaborating with test method developer CertiChem, Inc., to validate an in vitro test method that uses MDA-Kb2 human breast cancer cells to measure androgen receptor agonist and antagonist activity. Testing of 67 coded reference chemicals in agonist and antagonist modes to characterize method reliability and relevance is anticipated to be completed in early FY 2018. Then, 30 additional consumer products will be tested to evaluate the method’s applicability for more than single chemicals.
NICEATM and ICCVAM scientists developed integrated testing strategies that use non-animal data to predict skin sensitization hazard. Three manuscripts published in FY 2016 and FY 2017 describe strategies for using non-animal data to predict outcomes of animal skin sensitization tests, human skin sensitization tests, and human or animal tests for skin sensitization potency classification.
The NTP Toxicology Branch is testing over 200 chemicals nominated by ICCVAM agencies using three in vitro test methods to expand the applicability of a defined approach for identifying skin sensitizers. Mouse local lymph node assay data are available for the nominated chemicals, which include pesticides, formulations, industrial chemicals, and other chemicals of interest to ICCVAM agencies. The three in vitro test methods are the LuSens method, the direct peptide reactivity assay, and the human cell line activation test. NICEATM is coordinating the testing, which began in 2016 and is scheduled for completion in early 2019. The study data will enable NICEATM and ICCVAM to evaluate the appropriateness of a defined approach using these three in vitro methods for various regulatory applications.
NICEATM collaborated with the Cosmetics Europe Skin Tolerance Task Force to evaluate integrated testing and assessment approaches for skin sensitization submitted to the Organisation for Economic Co-operation and Development. NICEATM evaluated six defined approaches with a set of previously untested chemicals having in vitro and in silico data provided by Cosmetics Europe. Manuscripts describing the data sets and the outcome of the analyses have been submitted for publication.
NICEATM and the PETA International Science Consortium are proposing a joint study to evaluate the utility and limitations of a group of in vitro test methods to identify the ocular irritation and corrosion potential of agrochemicals. Coded pesticide formulations donated by agrochemical companies will be tested to describe each method’s performance characteristics and determine which methods could be combined with in vitro defined approaches to assign hazard classification and labeling for eye irritation potential. Although the focus of this study will be on EPA hazard classification, study results also will be evaluated for classification and labeling under the United Nations Globally Harmonized System of Classification and Labelling of Chemicals. Testing will begin in 2018.
Successful computational toxicology projects depend on freely available, high-quality data that are formatted for use in computational workflows. The NICEATM Integrated Chemical Environment (ICE) resource, launched in March 2017, provides high-quality, curated data from NICEATM, its partners, and other resources and tools to facilitate chemical safety assessment. At the end of FY 2017, ICE included data from animal and non-animal tests that assessed regulatory endpoints such as acute oral toxicity, skin and eye irritation, skin sensitization, and endocrine activity. It also included curated high-throughput screening data from Tox21 and physicochemical property data on chemicals such as solubility, melting point, and molecular weight. The site offers downloadable workflows for predicting physicochemical properties, skin sensitization potency, and adverse outcome pathway mapping. ICE is open to all users, with no registration needed.
Updates to ICE in FY 2018 will add formulation data and allow users to compare labeling categories from EPA "six-pack" studies with the performance of the formulation’s active ingredients in non-animal methods. Additional updates will expand the offered in silico prediction models and computational workflows to include in vitro-to-in vivo extrapolation and characterization of chemicals from the ICE website and through downloadable workflows.