The time line of exposure and responses may also differ. Tools that make it possible to address these issues e. Toxicogenomics can provides a library of generic expression profiles for different classes of toxicity that allows the characterization of an unknown compound based upon the profiles with which it fits. While genomics is used on a large scale for pathway analysis and marker identification, this concept has not yet been fully implemented in toxicity testing strategies and risk assessment.
Carcinogenicity testing is in this respect an interesting case study.
The use of toxicogenomics for identifying the mechanisms of action of genotoxic and non-genotoxic carcinogens has been increasing over the past few years and there are now training sets for carcinogens and non-hepatotoxic non-carcinogens. The learnings of this case study should be also implemented on other toxicological endpoints Johnson et al. It can be anticipated that the integration of genomics, proteomics, and metabonomics data obtained from exposed and unexposed cellular or animal models, and clinical samples, will improve our understanding of the mechanisms of action of a test compound significantly Hanahan and Weinberg, Furthermore, these data will help to establish relevant associations using newly developed computational technologies e.
It is anticipated that a more in-depth understanding of the relation between toxicity and biological pathways will make it possible to prevent animal testing by using a combination of tests that individually represent key events of the mechanisms of action of toxicity and that allow for assessment of the potential of a test compound to affect these key events.
In vitro and in silico methods can be used to accomplish this. If sufficient scientific justification is provided it may be possible to waive an animal test. When selecting the battery of in vitro and in silico methods addressing key steps in the relevant biological pathways, it is important to employ standardized and internationally accepted tests. Each block should be producing data that are reliable, robust, and relevant the alternative 3R elements for assessing the specific aspect e.
Implementing toxicity testing in the 21st century
If they comply with these elements they can be used in integrated testing strategies. To date there are no existing procedures and guidelines for putting together and validating such strategies. Obviously, this constitutes a hurdle for the implementation by regulatory agencies Kinsner-Ovaskainen et al. It is important to keep in mind that in vitro tests do not have fewer limitations than in vivo tests.
Therefore, proof is needed that a new method is equal to or better than an existing in vivo traditional model. An added challenge is that since science is moving very quickly it is difficult to decide when a test is good enough to be a final test for risk assessment. There is a need to incorporate new thinking into risk assessment.
Regulators are receptive to new technologies but concrete data e. Data documentation should be comprehensive, traceable, and make it possible for other investigators to retrieve information as well as reliably repeat the studies in question regardless of whether the original work was performed to Good Laboratory Praxis GLP standards.
It is important to address in a systematic way the factors that are critical for assay reproducibility and reliability. An issue often faced while performing cell-based tests is intra- and inter-laboratory variability in spite of rigorous compliance with the Standard Operation Procedure SOP. The reasons for this variability are often undefined but it is generally accepted that the causes include the cell cultures, analytical processing, technical error, and differences in qualitative judgment.
Therefore, these parameters should be carefully addressed and standardized. Retrospective weight of evidence would be one tool for harmonizing how people perform specific tests and to assure good quality of the data. This would help to identify flaws in the analytical processes, technical error, and qualitative judgment.
The exploitation by the in vitro testing community of emerging nano-biotechnologies facilitating the real time monitoring of cellular activity and processes reflecting the quality of the cell culture would provide objective tools for eliminating variations in the performance of cell-based tests.
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Gohlke, J.
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Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling. Carcinogenesis 25, — Keywords: in vitro toxicology, human-specific methods, pathways of toxicity, markers of toxicity, adverse responses. Citation: Roggen EL In vitro toxicity testing in the twenty-first century.
This is an open-access article subject to an exclusive license agreement between the authors and Frontiers Media SA, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited. Toggle navigation.
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