Chemical carcinogens can be classified into two categories (i.e. mutagenic and non-mutagenic) on the basis of positive or negative evidence of DNA In 1971, the International Agency for Research on Cancer (IARC), initiated a program for the evaluation of the carcinogenic risk of chemicals to humans based on the epidemiological evidence and evidence of carcinogenicity studies in animals (1). Recently, the IARC attempted to evaluate data from numerous short term tests for additional evidence of carcinogenicity (1). The foregoing is based on the observation that more than 80% of the carcinogens tested were mutagenic in the Salmonella/microsome assay (2-4). The end-points interpreted as positive in the short-term test systems are based on the hypothesis that damage to DNA is possibly a central event in the initiation of carcinogenesis and the neoplastic transformation of mammalian cells (2, [5][6][7][8][9][10][11][12] Carcinogens With and Without Mutagenic ActivityA positive correlation between positivity in short-term mutagenic assays and carcinogenicity has been established (2-5, 13) for a variety of chemicals, which are both carcinogens and mutagens. However, certain chemicals, which are carcinogenic in traditional animal bioassay studies, do not appear to yield positive results in the presently available short-term tests (3, 5, 6, 13-15). Accordingly, carcinogens can be classified into t w o broad types: mutagenic, when there is sufficient evidence for such activity in short term assays, and non-mutagenic, when there is no evidence for activity in mutagenesis assays. The IARC Working Group considered a minimum of three positive results obtained in two of three test systems measuring DNA damage, mutagenicity or chromosomal effects (1) as sufficient evidence for mutagenic activity in short-term tests. Although the IARC Group did not define the criteria for "negative" evidence, we feel that at least three negative results in three test systems measuring DNA damage, mutagenicity or chromosomal aberrations are necessary be-

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors, and it is assumed that the biological effects of these receptors depend on interactions with recently identified coactivators, including steroid receptor coactivator-1 (SRC-1). We assessed the in vivo function of SRC-1 on the PPARalpha-regulated gene expression in liver by generating mice in which the SRC-1 gene was inactivated by gene targeting. The homozygous (SRC-1(-/-)) mice were viable and fertile and exhibited no detectable gross phenotypic defects. When challenged with a PPARalpha ligand, such as ciprofibrate or Wy-14,643, the SRC-1(-/-) mice displayed typical pleiotropic responses, including hepatomegaly, peroxisome proliferation in hepatocytes, and increased mRNA and protein levels of genes that are regulated by PPARalpha. These alterations were indistinguishable from those exhibited by SRC-1(+/+) wild-type mice fed either ciprofibrate- or Wy-14, 643-containing diets. These results indicate that SRC-1 is not essential for PPARalpha-mediated transcriptional activation in vivo and suggest redundancy in nuclear receptor coactivators.

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Several studies with two-dimensional gel electrophoresis (2-DE) have shown that the abundance of numerous mouse liver proteins is altered in response to treatment with chemicals known to cause peroxisome proliferation. The peptide masses from tryptic digests of two liver proteins showing dramatic decreases in abundance in response to numerous peroxisome proliferators were used to search sequence databases. The selenium-binding protein 2 (SBP2 formerly 56 kDa acetaminophen-binding protein, AP 56) and selenium-binding protein 1 (SBP1 formerly 56 kDa selenium-binding protein, SP 56) in mouse liver, proteins with a high degree of sequence similarity, were the highest ranked identities obtained. Identity with SBP2 was subsequently confirmed by immunodetection with specific antiserum. Treatment of mice with 0.025% ciprofibrate resulted in the more basic of this pair of proteins being decreased to 30% of control abundance while the acidic protein was decreased to 7% of the control amount. Dexamethasone treatment, in contrast, caused increases of 80% and 20% in the abundance of the acidic and basic forms, respectively. Administration of dexamethasone to mice in combination with ciprofibrate produced expression of the acidic SBP2 at 23% of the control level and the basic SBP2 at 36%, a slightly moderated reduction compared with the decrease that occurred with ciprofibrate alone. These data suggest that peroxisome proliferators such as ciprofibrate cause a decrease in the abundance of the SBP2, which leads to increased cell proliferation, even in the presence of an inhibitor such as dexamethasone. Such a decrease in SBP, thought to serve as cell growth regulation factors, could be central to the nongenotoxic carcinogenicity of the peroxisome proliferators observed in rodents.

The carcinogenic potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in Syrian golden hamsters, at different dose levels. Twenty-one percent of the hamsters that received a total of 600 micrograms/kg body weight of TCDD either by the s.c. or i.p. route developed squamous cell carcinomas of the skin of facial region within 12-13 months from the beginning of the experiment. Neoplasms were not observed in any other organs. These studies suggest that TCDD may be a complete carcinogen in hamsters, the species most resistant to the toxic effect of this compound.