The genetic toxicity of the peroxisome proliferator class of rodent hepatocarcinogen.
Peroxisome proliferators comprise a structurally diverse class of chemicals. Some of the members of this class show evidence of genetic toxicity (most evidently the in vitro clastogen Wyeth 14,643, WY), while others do not (most evidently methyl clofenapate, MCP). When attempting to understand the mechanism of rodent hepatocarcinogenesis of this class of chemicals the possible role of genetic toxicity should be assessed on a class-wide basis, i.e., if just one peroxisome proliferator is shown to be unequivocally inactive as a genetic toxin, genetic toxicity cannot be implicated in the carcinogenic activity of peroxisome proliferators as a class. In an earlier paper, we established MCP as inactive in a range of in vitro and in vivo genetic toxicity assays. However, the top dose level of MCP that could be tested for induction of chromosome aberrations (clastogenicity) in human lymphocytes and CHO cells was limited by the relative insolubility of the test agent in the assay medium. Methyl clofenapate was not toxic up to a dose that produced precipitate, so cannot be directly compared with WY, which induced aberrations only at toxic dose levels. In the present paper, we have evaluated the clastogenicity of the carcinogenic peroxisome proliferator nafenopin (NAF) at dose levels up to those that are toxic to CHO cells, and found no evidence of chromosome aberration induction. These data isolate further the genetic toxicity of WY from other peroxisome proliferators, and increase confidence in the proposal that genetic toxicity does not play a critical role in the hepatocarcinogenicity of peroxisome proliferators.
Galloway
S M
SM
Merck Research Laboratories, Merck, W 45-3, Sumneytown Pike, West Point, PA 19486, USA. sheila_galloway@merck.com
Johnson
T E
TE
Armstrong
M J
MJ
Ashby
J
J
D000818:Animals; D016466:CHO Cells; D002992:Clofenapate / Q000737:chemistry / Q000633:toxicity; D006224:Cricetinae; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000633:toxicity; D006801:Humans; D015394:Molecular Structure; D009255:Nafenopin / Q000737:chemistry / Q000633:toxicity*; D020025:Peroxisome Proliferators / Q000737:chemistry / Q000633:toxicity*; D011743:Pyrimidines / Q000737:chemistry / Q000633:toxicity
D020025:Peroxisome Proliferators; D011743:Pyrimidines; D009255:Nafenopin; D002992:Clofenapate; C006253:pirinixic acid; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate