diisononyl-phthalate and Precancerous-Conditions

Diisononyl phthalate (DINP), a widely used plasticizer, has been evaluated in two chronic studies in rats and one in mice. In the early 1980s, Exxon found no carcinogenic potential at the estimated maximum tolerated dose (MTD) of 0.6% (307 mg/kg/ day for male rats) administered in the diet of rats for 2 years. A recent study conducted at dietary levels up to 1.2% DINP (733 mg/kg/d for male rats) reported kidney tumors in male rats at the high treatment level, but not in female rats nor mice of either sex. Because these tumors occurred only in male rats, and only at high doses, the male rat-specific alpha 2u-globulin (alpha2UG) mechanism of action was investigated. Technological advances in immunohistochemical staining and computerized image analysis techniques permitted measuring the accumulation of alpha2UG in archived kidneys from the earlier Exxon study. Using archived tissue obtained at the 12-month interim sacrifice, we identified a dose-dependent accumulation of alpha2UG in specific regions of male rat kidneys only. An increase in cell proliferation was confirmed by immunohistochemical detection of proliferating-cell nuclear antigen (PCNA) and was confined to the areas of alpha2UG accumulation. H and E-stained sections revealed tubular epithelial hypertrophy and regeneration, consistent with the immunohistopathology findings. These findings are consistent with the alpha2UG mechanism of tumorigenesis, which is not regarded as relevant for humans. Thus, exposure to DINP produced a dose-dependent alpha2UG accumulation in male rat kidneys, significant at a dietary level of 0.6% and a likely mechanism for the kidney tumors seen only in male rats administered higher dietary levels of DINP.

Topics: Alpha-Globulins; Animals; Cell Count; Epithelial Cells; Female; Immunoenzyme Techniques; Kidney Diseases; Kidney Tubules; Male; Phthalic Acids; Plasticizers; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; Retrospective Studies; Risk Assessment; Sex Characteristics

Groups of 110 Fischer 344 rats/sex were fed diisononyl phthalate (DINP) at dietary levels of 0, 0.03, 0.3, and 0.6 wt% for periods up to 2 years. Interim sacrifices of 10 predesignated rats/sex/dose were at 6, 12, and 18 months with surviving animals sacrificed at 24 months. At study termination, survival was in excess of 60% for every group. At the mid or high dose, the following biological effects were noted: slight decreases in food consumption and body weight; slight increase in mortality; a dose-related increase in relative organ weights of liver and kidney; and some slight effects on urinalysis, hematologic, and clinical chemistry parameters. No peroxisome induction was observed in livers of treated rats compared with controls. No clear treatment-related nonneoplastic or neoplastic lesions were found. However, mononuclear cell leukemia (MNCL) and changes known to be associated with an increased incidence of MNCL were seen in the mid-dose and high-dose groups. A literature review suggests that MNCL is a common finding in aging F344 rats and that this increased incidence in rats treated with DINP is not relevant to man. A clear no-observed-effect level was demonstrated for all biological end points at a dietary level of 0. 03 wt% or approximately 17 mg/kg/day of DINP.

Topics: Administration, Oral; Adrenal Glands; Animals; Blood Chemical Analysis; Body Weight; Carcinogenicity Tests; Female; Hematologic Tests; Kidney; Leukemia, Experimental; Liver; Male; Microbodies; No-Observed-Adverse-Effect Level; Organ Size; Phthalic Acids; Precancerous Conditions; Rats; Rats, Inbred F344; Spleen; Survival Rate; Testis; Urine