Genotoxicity of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat and Drosophila: effects of deuterium substitution.
Formation of 2-bromoacrolein (2BA) from tris(2,3-dibromopropyl)phosphate (Tris-BP) by cytochrome P450 (cyt. P450) activity is most likely responsible for the high mutagenicity of Tris-BP for bacteria in vitro when rat liver microsomes are used for metabolic activation. As yet, it has not been established whether cyt. P450 plays a role in the formation of genotoxic metabolites from Tris-BP in higher organisms in vivo. This was studied by comparing the effects of completely deuterated Tris-BP (D15-Tris-BP) with normal Tris-BP in various in vivo test systems for genotoxicity: deuterium substitution should decrease cyt. P450-dependent bioactivation of Tris-BP. Three test systems in Drosophila were used to measure different types of genetic damage: (I) the ring-X chromosome loss (CL) test to detect clastogenicity, (II) the sex-linked recessive lethal (RL) test to detect forward mutations and deletions and (III) the white/white+ (w/w+) eye mosaic assay to detect predominantly mitotic recombination. Tris-BP was positive in all test systems, while D15-Tris-BP was without effect. The relative clastogenic efficiency of a compound, defined as the ratio of CL over RL, can be used to distinguish monofunctional agents (CL/RL ratio < or = 1) from those having cross-linking potential (CL/RL ratio > 2). The CL/RL ratio of Tris-BP was 2.4, indicating that Tris-BP has cross-linking potential. No CL/RL ratio for D15-Tris-BP could be determined, because it was negative in both tests. The putative Tris-BP metabolite 2BA was also tested in the Drosophila test systems. 2BA was positive in the CL test at a high dose, but it showed no response in the RL test. The relative clastogenic efficiency (the ratio of CL/RL) could not be determined accurately, but the data nevertheless argue in favour of cross-linking properties of 2BA. Further, 2BA was clearly positive in the w/w+ eye mosaic test system, which indicates that it is a recombinagen. Genotoxicity of Tris-BP in rats was determined by the induction of micronuclei in hepatocytes. Tris-BP administered intraperitoneally 17 h after 2/3 partial hepatectomy (PH), induced a high frequency of micronuclei at days 2 and 3 after injection (26% and 22%, respectively). D15-Tris-BP, however did not increase the micronuclei frequency.(ABSTRACT TRUNCATED AT 400 WORDS)
Division of Toxicology, Center for Drug Research, Sylvius Laboratories, Leiden/Amsterdam, The Netherlands.
G J
GJ
van Beerendonk
M J
MJ
Nivard
E W
EW
Vogel
S D
SD
Nelson
J H
JH
Meerman
D000818:Animals; D003903:Deuterium; D004330:Drosophila; D005411:Flame Retardants / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D010755:Organophosphates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D005411:Flame Retardants; D009153:Mutagens; D010755:Organophosphates; C012085:tris(2,3-dibromopropyl)phosphate; D003903:Deuterium