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|Title:||In vitro genotoxicity test approaches with better predictivity: Summary of an IWGT workshop|
|Authors:||PFUHLER Stefan; FELLOWS Mick; VAN BENTHEM Jan; CORVI Raffaella; CURREN Rodger; DEARFIELD Kerry; FOWLER Paul; FRÖTSCHL Roland; ELHAJOUJI Azeddine; LE HÉGARAT Ludovic; KASAMATSU Toshio; KOJIMA H; OUÉDRAOGO Gladys; SCOTT Andrew; SPEIT Guenter|
|Citation:||MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS vol. 723 no. 2 p. 101-107|
|Publisher:||ELSEVIER SCIENCE BV|
|Type:||Articles in Journals|
|Abstract:||Improving current in vitro genotoxicity tests is an ongoing task for genetic toxicologists. Further, the question on how to deal with positive in vitro results that are demonstrated to not predict genotoxicity or carcinogenicity potential in rodents or humans is a challenge. These two aspects were addressed at the 5th International Workshop on Genotoxicity Testing (IWGT) held in Basel, Switzerland, on August 17 ¿ 19, 2009. The first objective of the working group was to review data on the response of the cell lines commonly used for mammalian cell tests, and to consider whether it was possible to make recommendations on the use of any particular cell line. The second objective of the working group was to provide evaluations on promising new approaches. Results obtained in rodent cell lines with impaired p53 function (V79, CHL and CHO cells) and human p53-competent cells (peripheral blood lymphocytes, TK6 and HepG2 cells) suggest that a reduction in the percentage of non-relevant positive results for carcinogenicity prediction can be achieved by careful selection of the mammalian cells used without decreasing the sensitivity of the assays. These findings were confirmed in other laboratories. Therefore, this IWGT working group suggests using p53-competent- preferably human - cells in in vitro MN- or CA-tests. It was further suggested that the use of the hepatoma cell line HepaRG for genotoxicity testing is promising since these cells possess better phase I and II metabolizing potential compared to cell lines commonly used in this area and may overcome the need for the addition of S9. The IWGT working group further recommends adherence to good cell culture practice, characterization of all new cells, checking regularly for genetic drift, and working with low passage stocks. It was emphasized that a genotoxicity cell bank with fully characterized stocks of all commonly used cells would be very valuable. Regarding promising new approaches, the IWGT working group agreed that in vitro reconstructed skin models, once validated, will be useful to follow up on positive results from standard in vitro assays for dermally applied compounds since they resemble the properties of human skin (barrier function, metabolism). While the reconstructed skin micronucleus assay has been shown to be further advanced, there was also consensus that the Comet assay should be further evaluated due to its independence from cell proliferation and coverage of a wider spectrum of DNA damage. Finally, the IWGT working group recommends evaluating further the metabolic capacity of the reconstructed skin models.|
|JRC Institute:||Institute for Health and Consumer Protection|
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