Nongenotoxic

On the basis of these differences in species response it was concluded that phthalates do not pose a significant health hazard to humans. This view is home out by the EU Commission decision of July 25, 1990 which states that DEHP shall not be classified or labeled as a carcinogenic or an irritant substance (42). This has been reaffirmed in a comprehensive review (43) which concludes that "peroxisome proliferators constitute a discrete class of nongenotoxic rodent hepatocarcinogens and that the relevance of thek hepatocarcinogenic effects for human hazard assessment is considered to be negligible."... 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Bakale G, McCreary RD. 1990. Response of the ke test to NCI/NTP-screened chemicals. I. Nongenotoxic carcinogens and genotoxic noncarcinogens. Carcinogenesis 11 1811-1818. 

Metofluthrin (I) The committee determined that the new data were sufficient to support a mitogenic mode of action for the development of liver tumors in rats exposed to metofluthrin in the carcinogenicity study. The report summarized mode of action study data that characterized effects such as increased P450 enzyme levels, increased smooth endoplasmic reticulum, hepatocellular hypertrophy, hepatocellular proliferation, and inhibition of intracellular communication, which were described as steps leading to tumor development via a nongenotoxic mechanism (i.e., mitogenicity). Some of these studies used sodium phenobarbital as a positive control,... 

TABLE 6.3. Tissues Sensitive to Genotoxic and/or Nongenotoxic Carcinogens... 

Butterworth, B.E. and Slaga, T.J. (1987). Nongenotoxic Mechanisms in Carcinogenesis. Banbury Report No. 25. Cold Spring Harbor Laboratory, NY. 

Miyagawa M, Takasawa H, Sugiyama A, et al. 1995. The in vivo-in vitro replicative DNA synthesis (RDS) test with hepatocytes prepared from male B6C3F, mice as an early prediction assay for putative nongenotoxic (Ames-negative) mouse hepatocarcinogens. Mutat Res 343 157-183. 

There are three transgenic models that are primarily used. The p53 model is used exclusively for compounds that have been shown to be positive in one or more mutagenicity studies and are considered to be genotoxic. The Hras2 model is used for nongenotoxic... 

W. N. Choy, Genotoxic and nongenotoxic mechanisms of carcinogenesis, in Genetic Toxicology and Cancer Risk Assessment, ed. W. N. Choy, Marcel Dekker, New York, 2001, pp. 47-71. 

Accumulating evidence suggests that aldrin is not a likely human carcinogen and that it acts as a species-specific hepatocarcinogen in mice through nongenotoxic mechanisms. ... 

The lARC has determined that there is sufficient evidence for the carcinogenicity of amitrole to experimental animals and inadequate evidence for carcinogenicity to humans. It was noted that amitrole produces thyroid tumors in rodents by a nongenotoxic mechanism that involves interference with the functioning of the thyroid peroxidase, resulting in a reduction in circulating thyroid hormone concentration and an increase secretion of thyroid-stimulating hormone. Amitrole would not be expected to produce thyroid cancer in humans exposed to concentrations that do not alter thyroid hormone homeostasis. 

A 2-year feeding study with mice and rats yielded no evidence of carcinogenic effects. Recent extensive reviews have concluded that bisphenol A is nongenotoxic in vivo ... 

Witt, K.L., Livanos, E Kissling, G.E., Torous, D.K., Caspary, W Tice, R.R. and Recio, L. (2008) Comparison of flow cytometry- and microscopy-based methods for measuring micronucleated reticulocyte frequencies in rodents treated with nongenotoxic and genotoxic chemicals. Mutation Research, 649, 101-113. 

Costa M. 1995. Model for the epigenetic mechanism of action of nongenotoxic carcinogens. Am J Clin Nutr 61(suppl) 666S-669S. 

Lake, B.G (1995a) Peroxisome proliferation current mechanisms relating to nongenotoxic carcinogenesis. Toxicol. Lett., 82-83, 673-681... 

Peters, J.M., Cattley, R.C. Gonzalez, F.J. (1997a) Role of PPAR a in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. 

Keyhanfar, F. Caldwell, J. (1996) Factors affecting the metabolism of ciimamyl anthranilate in the rat and mouse. Food chem. Toxicol., 34, 241-249 Lake, B.G (1995a) Peroxisome proliferation current mechanisms relating to nongenotoxic carcinogenesis. Toxicol. Lett., 82183, 673-681... 

Unfortunately, there has been an uncritical acceptance of the notion that a positive result in a rodent bioassay automatically implies a carcinogenic risk for humans. While this may well be the case for genotoxic agents, for nongenotoxic substances there will be exceptions, especially if the proliferative response occurs only at high doses" (Cohen and Ellwein 1991, 903). 

---