title: Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate.
abstract: Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e.g., liver and testis) in rats and mice can not be ruled out and DEHP was classified as possibly carcinogenic to humans (Group 2B).
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431, USA. Electronic address: iir@unc.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000139:chemically induced; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D020025:Peroxisome Proliferators / Q000633:toxicity; D010968:Plasticizers / Q000633:toxicity*; D051381:Rats; D013736:Testicular Neoplasms / Q000139:chemically induced; D013737:Testis / Q000187:drug effects
chemical_list: D002273:Carcinogens; D020025:Peroxisome Proliferators; D010968:Plasticizers; D004051:Diethylhexyl Phthalate