Toxicological Sciences, Vol 51, 153-160, Copyright © 1999 by Society of Toxicology
DJ Caldwell, SR Eldridge, AW Lington and RH McKee
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.
ARTICLES
Retrospective evaluation of alpha 2u-globulin accumulation in male rat kidneys following high doses of diisononyl phthalate
Exxon Biomedical Sciences, Inc., East Millstone, NJ 08875-2350, USA. djcaldw@fpe.erenj.com
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