DNA damage and repair tests for the detection of genotoxic agents

Abstract

In vitro tests for DNA reactivity of chemicals serve several important purposes. Genotoxins can cause toxicity, teratogenicity, mutagenicity and carcinogenicity. Positive results in reliable tests are highly predictive of potential carcinogenicity. Among available tests the hepatocyte primary culture/DNA repair test, including its modifications to provide multispecies and bacterial metabolism, has been demonstrated to be a very sensitive test. Assessment of DNA reactivity of known carcinogens also provides information on their possible mechanisms of action.

Scientific Opinion on Flavouring Group Evaluation 77, Revision 2 (FGE.77Rev2): Consideration of Pyridine, Pyrrole and Quinoline Derivatives evaluated by JECFA (63rd meeting) structurally related to Pyridine, Pyrrole, Indole and Quinoline Derivatives evalu

“…14.001,14.004,14.007,14.030,14.038,14.039,14.041,14.045,14.046,14.047,14.058,14.059,14.060,14.061,14.065,14.066,14.068,14.071,14.072 and 14.164] the Panel agrees with the JECFA conclusion "no safety concern at estimated levels of intake as flavouring substances" based on the MSDI approach. (Nagao et al, 1977) Reverse mutation S. typhimurium TA98 and TA100 10,000 -20,000 µg/ml Negative d (Epler et al, 1979) Mutation E. coli B/r HCR+ 50 µg/ml Negative d (Sideropoulos and Specht, 1984) Unscheduled DNA synthesis Rat hepatocytes NR Negative (Williams, 1984)…”

“…There was no evidence of increased unscheduled DNA synthesis when freshly isolated rat liver cells were incubated with pyrrole or isoquinoline (concentrations not specified) (Williams, 1984). Single-strand DNA breaks and inhibition of growth were reported when undeuterated or deuterated (at C2 or C3 positions) 3-methylindole (skatole) at 10 µmol/l to 1 mmol/l (1.31 to 131.18 µg/ml) was incubated with isolated cultured bovine kidney cells.…”

“…10,000 -20,000 µg/ml Negative d (Epler et al, 1979) Mutation E. coli B/r HCR+ 50 µg/ml Negative d (Sideropoulos and Specht, 1984) Unscheduled DNA synthesis Rat hepatocytes NR Negative (Williams, 1984) 14.004 1304 (Florin et al, 1980) Reverse mutation S. typhimurium TA98 and TA100 NR Negative c (Kim et al, 1989) Reverse mutation S. typhimurium TA98 and TA100 (Florin et al, 1980) Reverse mutation S. typhimurium TA98 and TA100 NR Negative d (Lee et al, 1994) Unscheduled DNA synthesis Rat hepatocytes NR Negative (Williams, 1984) 14.061 1315 …”

Scientific Opinion on Flavouring Group Evaluation 77, Revision 1 (FGE.77Rev1): Consideration of Pyridine, Pyrrole and Quinoline Derivatives evaluated by JECFA (63rd meeting) structurally related to Pyridine, Pyrrole, Indole and Quinoline Derivatives evaluated by EFSA in FGE.24Rev2 (2013)

“…There was no evidence of increased unscheduled DNA synthesis when freshly isolated rat liver cells were incubated with pyrrole or isoquinoline (concentrations not specified) (Williams, 1984). Single-strand DNA breaks and inhibition of growth were reported when undeuterated or deuterated (at C2 or C3 positions) 3-methylindole (skatole) at 10 µmol/l to 1 mmol/l (1.31 to 131.18 μg/ml) was incubated with isolated cultured bovine kidney cells.…”

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

“…Safrole was shown to increase UDS in primary rat hepatocytes and HeLa cells at concentrations of 0.000 162-1620 μg/ml (Michalopoulos et al, 1978;Althaus et al, 1982;Williams, 1984;Barrett, 1985;Glauert et al, 1985;Martin & Campbell, 1985;Williams et al, 1985;Howes et al, 1990b). It should be noted that at concentrations greater than 162 μg/ml, safrole is highly cytotoxic (Burkey et al, 2000).…”