Skip to main content

Currently Skimming:

Summary
Pages 1-17

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.


From page 1...
... It is poised to take advantage of the revolutions in biology and biotechnology. Advances in toxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology could transform toxicity testing from a system based on whole-animal testing to one founded primarily on in vitro methods that evaluate changes in biologic processes using cells, cell lines, or cellular components, preferably of human origin.
From page 2...
... Fresh thinking and the use of emerging methods for understanding how environmental agents affect human health will promote beneficial changes in testing of these agents and in the use of data for decision-making. The envisioned change is expected to generate more robust data on the potential risks to humans posed by exposure to environmental agents and to expand capabilities to test chemicals more efficiently.
From page 3...
... to develop a more robust scientific basis for assessing health effects of environmental agents.1 The committee considered recent scientific advances in defining a new approach to toxicity testing. Substantial progress is being made in the elucidation of cellular-response networks -- interconnected pathways composed of complex biochemical interactions of genes, proteins, and small molecules that maintain normal cellular function, control communication between cells, and allow cells to adapt to changes in their environment.
From page 4...
... at each step and the ability to exit the strategy at any point when sufficient data have been generated for decision-making. The vision emphasizes the generation and use of population-based and human exposure data where possible for interpreting test results and encourages the collection of such data on important chemicals with biomonitoring, surveillance, and epidemiologic studies.
From page 5...
... Chemical Characterization Chemical characterization is meant to provide insights to key questions, including a compound's stability in the environment, the potential for human exposure, the likely routes of exposure, the potential for bioaccumulation, possible routes of metabolism, and the likely toxicity of the compound and possible metabolites based on chemical structure or physical or chemical characteristics. Thus, data would be collected on physical and chemical properties, use, possible environmental concentrations, metabolites and breakdown products, initial molecular interactions of compounds and metabolites with cellular components, and possible toxic properties.
From page 6...
... Targeted testing will serve to complement the assays and support evaluation. Toxicity Pathways Figure S-2 illustrates the activation of a toxicity pathway.
From page 7...
... testing and dose-response modeling. Accordingly, the vision emphasizes the development of suites of predictive, high-throughput assays2 that use cells or cell lines, preferably of human origin, to evaluate relevant perturbations in key toxicity pathways.
From page 8...
... to understand effects of representative prototype compounds from classes of materials, such as nanoparticles, that may activate toxicity pathways not included in a standard suite of assays; (3) to refine a risk estimate when the targeted testing can reduce uncertainty, and a more refined estimate is needed for decision-making; (4)
From page 9...
... An example could involve compounds for which host-susceptibility factors in humans are well understood and human biomonitoring provides good information about tissue or blood concentrations of the compound and other related exposures that affect the toxicity pathway in a human population. Extrapolation modeling estimates the environmental exposures or human intakes that would lead to human tissue concentrations similar to those associated with perturbations of toxicity pathways in vitro and would account for host susceptibility factors.
From page 10...
... Because the vision emphasizes studies conducted in human cells that indicate how environmental agents can affect human biologic responses, the studies will suggest biomarkers (indicators of human exposure, effect, or susceptibility) that can be monitored and studied in human populations.
From page 11...
... Common scenarios, defined by the committee as "risk contexts," for which toxicity testing is used to make decisions include evaluation of potential environmental agents, existing environmental agents, sites of environmental contamination, environmental contributors to a human disease, and the relative risk of different environmental agents. Some risk contexts require rapid screening of tens of thousands of environmental agents; some require highly refined dose-response data, extending down to environmentally relevant exposure concentrations; and some require the ability to test chemical mixtures or to use assays focused on specific mechanisms.
From page 12...
... Phase I would focus on elucidating toxicity pathways; developing a data-storage, -access, and -management system; developing standard protocols for research methods and reporting; and planning a strategy for human surveillance and biomonitoring to support the toxicity-pathway testing approach. Phase II would involve development and validation of toxicity-pathway assays and identification of markers of exposure, effect, and susceptibility for use in surveillance and biomonitoring of human populations.
From page 13...
... Life Stages -- How can the perturbations of toxicity pathways associated with developmental timing or aging be best captured to enable the advancement of high-throughput assays? Effects of Exposure Duration -- How are biologic responses affected by exposures of different duration?
From page 14...
... be missed if the new assays were used alone and will compel the development of assays to address these gaps. Surveillance and biomonitoring of human populations would also begin during Phase III.
From page 15...
... Fifth, existing guidelines focus on concordance between the results of new and existing assays; the difficulty will be to find standards for comparison that can assess the relevance and predictivity of the new assays. Sixth, because virtually all environmental agents will perturb signaling pathways to some degree, a key challenge will be to determine when such perturbations are likely to lead to toxic effects and when they are not.
From page 16...
... Thus, some resistance to the vision proposed by this committee is expected. However, the vision takes full advantage of current and expected scientific advances to enhance our understanding of how environmental agents can affect human health.
From page 17...
... 17 Summary digm shift that will not only improve the current system but transform it into one capable of overcoming current limitations and meeting future challenges.


This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More information on Chapter Skim is available.