Dibutyl phthalate (DBP) is one of several phthalate esters with extensive use in the plastics industry with the potential for considerable human exposure. Nominated for testing to the NTP by the EPA from both the Superfund and Clean Air Act lists of priority chemicals, dibutyl phthalate is a known rodent peroxisome proliferator. As a class, peroxisome proliferators are often rodent hepatic, testicular or pancreatic carcinogens and are thought to act through a cell proliferative, promotional and/or oxidative stress mechanism(s). The recent identification of PPAR, an orphan receptor with activity specific to these chemicals and homology to similar gene products in humans has encouraged additional investigations of the class. In addition, dibutyl phthalate is a known male and female reproductive toxicant. Thus, dibutyl phthalate is expected to be useful in addressing a variety of mechanistic endpoints which have been hypothesized to be of importance in chemical carcinogenesis and reproductive toxicology. The research efforts by the NIEHS/NTP are numerous and highly coordinated within the ETP, other NIEHS investigators, and outside researchers. The central issue for the peroxisome proliferating chemicals is the induction of rodent neoplasia and the relevance of this response to humans. Interspecies comparisons utilizing sensitive (rats, mice) and insensitive (hamsters) species will be used to identify risk factors predictive of rodent carcinogenicity. This information may lead to the identification of biomarkers useful for mechanistic-based extrapolations to humans. Chemicals currently being evaluated in the class of peroxisome proliferators include dibutyl phthalate, 2,4-dichlorophenoxyacetic acid, gemfibrozil and Wy-14-643. Evaluation of peroxisomal enzyme kinetics, cell replication, and hormonal imbalances are among the research endpoints being coordinated. Induction or inhibition of apoptosis by several peroxisome proliferators is to be investigated. Tissues are being saved from current NTP prechronic studies for the purpose of evaluating mRNA levels as internal dosimeters and potential biomarkers. These tissues may be available to investigators for further study. The NTP studies with the peroxisome proliferators have been specifically designed to facilitate biologically based cell growth (cancer) modeling, using software currently available and used previously by investigators at the NIEHS. Through the use of the RO3 grant program, 6 grants have been awarded to examine in greater detail molecular and biochemical mechanisms relevant to the carcinogenesis of peroxisome proliferators. These grants will utilize NTP archival tissue collected during the 90-day prechronic toxicity study of these four chemicals. Funded studies include evaluation of oxidative products of tissue macromolecules following exposure to peroxisome proliferators, differential gene expression, expression of growth factors, and levels of cellular antioxidants. - dibutyl phthalate, plastics, peroxisome proliferator, cell proliferation
