title: In vitro genotoxicity test approaches with better predictivity: summary of an IWGT workshop.
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 objectives of the working group (WG) were to make recommendations on the use of cell types or lines, if possible, and to provide evaluations of promising new approaches. Results obtained in rodent cell lines with impaired p53 function (L5178Y, 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 cells used without decreasing the sensitivity of the assays. Therefore, the WG suggested using p53- competent - preferably human - cells in in vitro micronucleus or chromosomal aberration tests. The use of the hepatoma cell line HepaRG for genotoxicity testing was considered 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. For dermally applied compounds, the WG agreed that in vitro reconstructed skin models, once validated, will be useful to follow up on positive results from standard in vitro assays as 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.
authors.affiliation: The Procter and Gamble Co., Miami Valley Innovation Center, 11810 East Miami River Road, Cincinnati, OH 45252, USA. spfuhker@pg.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfuhler
authors.forename: Mick
authors.initials: M
authors.lastname: Fellows
authors.forename: Jan
authors.initials: J
authors.lastname: van Benthem
authors.forename: Raffaella
authors.initials: R
authors.lastname: Corvi
authors.forename: Rodger
authors.initials: R
authors.lastname: Curren
authors.forename: Kerry
authors.initials: K
authors.lastname: Dearfield
authors.forename: Paul
authors.initials: P
authors.lastname: Fowler
authors.forename: Roland
authors.initials: R
authors.lastname: Frötschl
authors.forename: Azeddine
authors.initials: A
authors.lastname: Elhajouji
authors.forename: Ludovic
authors.initials: L
authors.lastname: Le Hégarat
authors.forename: Toshio
authors.initials: T
authors.lastname: Kasamatsu
authors.forename: Hajime
authors.initials: H
authors.lastname: Kojima
authors.forename: Gladys
authors.initials: G
authors.lastname: Ouédraogo
authors.forename: Andrew
authors.initials: A
authors.lastname: Scott
authors.forename: Günter
authors.initials: G
authors.lastname: Speit
mesh_terms: D000818:Animals; D002460:Cell Line; D002869:Chromosome Aberrations; D017408:Guidelines as Topic; D006801:Humans; D015162:Micronucleus Tests / Q000379:methods; D009152:Mutagenicity Tests / Q000379:methods* / Q000639:trends*; D011237:Predictive Value of Tests