of Work: 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. 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 recently completed NTP prechronic studies for the purpose of evaluating mRNA levels as internal dosimeters and potential biomarkers. Immunohistochemistry will be one method used to evaluate the expression of the peroxisome proliferator activated receptor (PPAR) receptor. 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. Future in-house or collaborative experiments being designed include evaluation of oxidative products following exposure to peroxisome proliferators, and investigation of both testicular and ovarian toxicity of dibutyl phthalate (DBP), including the potential role of cell turnover or PPAR in the reproductive toxicity. Chemicals currently being evaluated in the class of peroxisome proliferators include dibutyl phthalate, 2,4-dichlorophenoxyacetic acid, gemfibrozil and Wy-14-643. 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, many other NIEHS investigators, and outside researchers.
