Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) / Chapter Skim
Currently Skimming:
5 Application to Hazard Screening
5 Application to Hazard Screening
Pages 73-91
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 73... ...
Toxicogenomic technologies may be incorporated directly into existing, more traditional hazard screening tests; they may be the basis of new tests that substitute for more traditional tests; or they may generate mechanistic insights that enable more basic tests to be conducted for screening compounds, such as receptor binding or other physicochemical assays. This chapter primarily discusses the first two applications of toxicogenomic technologies.
|
From page 74... ...
Another way to describe this quality is that hazard screening tests often accept a higher rate of false-positive results to avoid not detecting a hazard because of a high rate of false-negative results. When the data generated by screening tests are continuous, as is the case with gene and protein expression and metabolite assays, the selection of thresholds for positive and negative results plays a dominant role in determining the
|
From page 75... ...
Aerobic biodegradability Environmental toxicology Acute toxicity to fish Acute toxicity to daphnia Toxicity to algae Chronic toxicity Necessity determined based on physical chemical properties of the chemical. Any new data required should be collected using the most sensitive species (fish, daphnia, or algae)
|
From page 76... ...
. A critical challenge in designing and validating toxicogenomic screening tests is to identify and define a "gold standard" for hazard screening -- the indication of the true state of toxicity against which the sensitivity and specificity of the screening test can be measured.
|
From page 77... ...
STATE OF THE ART Current Practices for Pharmaceutical Hazard Screening With the advent of combinatorial chemistry, pharmaceutical companies are now able to consider thousands of drug candidates at once in the drug development process. Drug companies are seeking a variety of in vitro and in silico methods to screen drug candidates for effectiveness and toxicity before more expensive, and slower, in vivo testing (Johnson and Wolfgang 2000; Ulrich and Friend 2002; van de Waterbeemd and Gifford 2003; Suter et al.
|
From page 78... ...
Most companies applied toxicogenomic technologies in the discovery and preclinical phases, and, whereas most preferred using in vivo assays, several said they were developing in vitro screening tests. Among the principal barriers to broader use and acceptance of toxicogenomic technologies in drug screening were uncertainty about biologic relevance, resource limitations, and regulatory consequences.
|
From page 79... ...
Publicly available information on the application of toxicogenomic technologies for screening environmental chemicals has come from government institutions rather than from industry. EPA and NIHS are conducting two projects of interest.
|
From page 80... ...
The study provides a rare insight into the value of toxicogenomic approaches when investigators have access to a densely populated, high-quality database -- in this case, the Roche toxicogenomic database, which classifies compounds into subcategories based on their histopathologic manifestations. This study used a retrospective approach to determine whether gene expression profiling could have predicted the toxicity of a failed candidate compound before it was evaluated by more time-consuming methodologies of classic toxicology.
|
From page 81... ...
Remarkably, gene expression profiles induced by acutely toxic doses also identified Ro-Cmp-A as a steatotic hepatotoxicant as early as 24 hours after exposure, despite a lack of characteristic histopathology. If specific marker genes with mechanistic links to toxicity were selected, steatotic activity was predicted by expression profiling as soon as 6 hours after an acutely toxic dose.
|
From page 82... ...
Although this moderate degree of sensitivity and specificity is not ideal for a screening test, the authors suggest that the test provides a promising alternative to 28-day in vivo studies with histopathology, which are the only tests now available to screen candidate drugs for nephrotoxicity. Another nonhepatotoxicity example assessed the utility of transcriptome profiling in screening for endocrine disruptors (Daston and Naciff 2005)
|
From page 83... ...
Most efforts to apply toxicogenomic techniques to hazard screening have used gene expression (transcriptome) profiling, but a small number of studies have demonstrated the potential usefulness of proteomic and metabonomic studies to classify putative drugs or other compounds into categories of toxicity or biologic activity.
|
From page 84... ...
However, assays limited in dose range and time course could not be expected to exclude the possibility of differential toxicity within a category and toxicogenomic data would not be expected to be the sole source of information for category validation. As databases grow and the quality of the interpretative methods improves, gene and protein assays may ultimately support quantitative interpolation within categories as well as provide mechanistic insight to inform further testing protocols.
|
From page 85... ...
Additional database development and demonstration of predictive accuracy would be required before true toxicogenomic screens would be useful in this setting. Use of Toxicogenomics to Screen for Hazard in Future Chemical Programs Current toxicogenomic assays are not sufficiently developed to replace more traditional toxicologic screening tests, but there are important opportunities to build the familiarity and databases needed to inform future toxicogenomic screening regimens by adding toxicogenomic tests to existing chemical programs.
|
From page 86... ...
There are several aspects of this generalizability: • Because the screening of environmental chemicals has different requirements than the screening of candidate drugs, algorithms designed for screening candidate drugs will need to be modified and validated for environmental chemicals. • The database of toxicogenomic and traditional toxicologic data used for training and validating screening algorithms must be extensive and comprehensive enough to allow accurate predictions for a wide range of chemicals.
|
From page 87... ...
Importantly, the animal tests would serve as a backup for identifying those toxic candidate drugs that have been missed by the toxicogenomic screens. In contrast, the absence of any statutory requirement for animal testing for industrial chemicals other than pesticides in the United States means that there is no backstop to the screening tests.
|
From page 88... ...
From the industry standpoint, for the screening tests to be economically feasible, they must also be highly specific and avoid falsely identifying benign chemicals as potentially toxic. To be acceptable to public health and industry stakeholders, toxicogenomic screening assays for industrial chemicals need to demonstrate greater accuracy than traditional tests as well as the ability to detect a broader array of outcomes than they currently do.
|
From page 89... ...
For using toxicogenomic assays to screen for a battery of end points, reliable assays and their associated algorithms for a broader set of end points will need to be developed. These end points include those toxicities of greater interest for environmental chemicals (for example, cancer, neurodevelopmental toxicity)
|
From page 90... ...
RECOMMENDATIONS Intermediate 1. Convene an expert panel to provide recommendations for which model compounds, laboratory platforms, and specific data elements are necessary for building toxicogenomic databases for screening applications.
|
From page 91... ...
c. Integrate data relevant to toxicogenomic screening of envi ronmental chemicals into ongoing biomedical initiatives such as the National Institutes of Health Molecular Libraries initia tive.
|
Key Terms
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.