Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense (2015) / Chapter Skim
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6 Lessons Learned and Next Steps
6 Lessons Learned and Next Steps
Pages 96-112
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From page 96... ...
In the present chapter, the committee briefly discusses some current programs that are evaluating or developing modern testing strategies, reviews its suggested tiered testing strategy, and highlights important lessons learned from current testing programs that should be considered by DOD in developing its future testing strategy. The chapter also provides the committee's overall conclusions and identifies several steps that DOD could take in the short term to medium term (3–10 years)
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From page 97... ...
The ACuteTox effort considers in vitro methods that address specific mechanisms of action relevant to acute systemic toxicity (such as assays for neurotoxicity) and includes such computational methods as QSAR modeling and physiologically based biokinetic modeling.
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From page 98... ...
IMPLEMENTATION OF THE COMMITTEE'S CONCEPTUAL MODEL FOR ASSESSMENT OF ACUTE CHEMICAL TOXICITY As discussed in Chapter 2, the committee developed a conceptual framework that links chemical structure, physicochemical properties, biochemical properties, and biological activity to acute toxicity. Implementation of the conceptual framework will require DOD to support development of a suite of databases, assays, models, and tools that are based on in vitro, nonmammalian in vivo, and in silico approaches for predicting acute toxicity.
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From page 99... ...
One goal of the overall approach is to reduce the number of chemicals that progress through each tier in an efficient and cost-effective manner. DEVELOPMENT OF A MODERN TIERED APPROACH FOR PREDICTING ACUTE TOXICITY: INITIAL STEPS There are some initial steps that DOD could take to implement the committee's tiered testing strategy.
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From page 100... ...
A variety of in silico methods have been developed to predict the molecular sites where metabolism could occur and the types of metabolites that could be formed.5 Several available QSAR models use structural properties or physicochemical properties to predict acute oral LD50s. Few such models are available for predicting inhalation LC50s, and the committee was unable to identify models for predicting dermal LD50s.
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From page 101... ...
, adoption of HTS assays in the context of a tiered testing approach as a replacement for in vivo assays appears likely (van der Burg et al.
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From page 102... ...
The study demonstrated that ToxCast in vitro assays per form adequately for prioritizing chemicals for further evaluation of ER activity, and the HTS as says are predictive of the likelihood of a positive or negative finding in more resource-intensive assays. The predictiveness of many HTS assays, however, remains low (< 50%)
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There are several possible reasons why acute systemic toxicity of some chemicals is poorly predicted by basal cytotoxicity assays. First, toxicity might be due to tissue- or organ-specific effects caused by the chemical of interest.
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The ACuteTox project identified several important technical considerations in the design of an in vitro testing strategy (Kopp-Schneider et al.
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Mechanistically Based Assays Another approach that has been used to predict acute chemical toxicity is based on the development of assays that evaluate a mechanism of action known to be critical for a chemical's toxic response. One mechanism-based example explored by the committee uses HTS assays and computational approaches to predict chemical-induced inhibition of AChE activity.
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From page 106... ...
OTHER CONSIDERATIONS The committee has identified several broad technical considerations that are important, such as the use of reference chemicals and development of appropriate data-integration models. 10 OECD provides additional information about developing AOPs at http://www.oecd.org/chemicalsafe ty/testing/listsofprojectsontheaopdevelopmentprogrammeworkplan.htm.
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From page 107... ...
That issue might require DOD to develop distinct tiered approaches for different chemical classes, such as metals. DOD will also need to support the development of HTS assays for mechanisms of actions that are known or suspected to be involved in acute chemical toxicity.
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Recommendation: DOD should initiate pilot studies that evaluate chemical classes of highest concern with well-characterized reference chemicals. The pilot studies will allow it to develop the assays and tools that are needed to predict acute chemical toxicity efficiently and accurately and to evaluate the rate of false negatives and false positives.
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2008. A database of IC50 values and principal component analysis of results from six basal cytotoxicity assays, for use in the modelling of the in vivo and in vitro data of the EU ACuteTox project.
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2013. Selection of test methods to be included in a testing strategy to predict acute oral toxicity: An approach based on statistical analysis of data collected in phase 1 of the ACuteTox project.
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2008. Neutral red uptake cytotoxicity tests for estimat ing starting doses for acute oral toxicity tests.
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2014. Hybrid in silico models for drug-induced liver injury using chemical descriptors and in vitro cell-imaging information J
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