Induction of LacZ mutations in Muta Mouse can distinguish carcinogenic from non-carcinogenic analogues of diaminotoluenes and nitronaphthalenes.
2,4-Diaminotoluene (2,4-DAT) is a liver carcinogen in rats and mice whereas 2,6-DAT is not. Both are genotoxic in vitro. Tests for mutations in transgenic mice, unscheduled DNA synthesis (UDS), DNA damage and enhancement of initiated foci in vivo have shown some discrimination between these two analogues, but only after oral administration. 1- and 2-nitronaphthalene (1- and 2-NNT) are also both genotoxic in vitro, although, unlike 2,4- and 2,6-DAT, they do not require metabolic activation. There is some evidence that 2-NNT may be able to induce liver and bladder tumours, and there is some evidence that 1-NNT is not carcinogenic to rats or mice, but none of the data are convincing. When tested for induction of LacZ mutations in Muta Mouse after topical exposure (human occupational exposure route) at their maximum tolerated doses, 2,4-DAT induced a positive response in liver and a marginal response in kidney, whereas 2,6-DAT was negative. 2-NNT also induced a positive mutagenic response in liver, and a marginal response in bladder, whereas 1-NNT was negative. Neither 2,4- nor 2,6-DAT induced mutations at the site of application (skin) as might be expected for chemicals requiring activation by liver enzymes. 2-NNT, which is a direct-acting mutagen in vitro, gave a marginal response for induced mutation at the site of application, but 1-NNT was negative. This study shows that investigation of induction of LacZ mutations after topical application in vivo can provide useful data to help discriminate potentially carcinogenic from non-carcinogenic chemicals that are mutagenic in vitro. Robust carcinogenicity data are needed to determine whether 2-NNT can induce tumours in the liver and bladder.
Kirkland
David
D
Covance Laboratories Ltd., Otley Road, Harrogate HG3 1PY, United Kingdom. david.kirkland@covance.com
Beevers
Carol
C
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D007763:Lac Operon; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D009281:Naphthalenes / Q000008:administration & dosage / Q000633:toxicity*; D010655:Phenylenediamines / Q000008:administration & dosage / Q000633:toxicity*; D012867:Skin / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D002273:Carcinogens; D009153:Mutagens; D009281:Naphthalenes; D010655:Phenylenediamines; C016614:1-nitronaphthalene; C025235:2,6-diaminotoluene; C010914:2,4-diaminotoluene; C048317:2-nitronaphthalene