Comparative in vivo hepatic effects of di-isononyl phthalate (DINP) and related C-7-C-11 dialkyl phthalates on gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat and mouse liver

The short-term hepatic effects of DINP (CAS 68515-48-0, designated DINP-1) in rats and mice were evaluated at tumorigenic and nontumorigenic doses fro m previous chronic studies. Groups of male F344 rats were fed diets with DI NP-1 at concentrations of 0, 1000, or 12,000 ppm and male B6C3F1 mice at 0, 500, or 6000 ppm DINP-1. After 2 or 4 weeks of treatment, changes in liver weight, gap junctional intercellular communication (GJIC), peroxisomal bet a-oxidation (PBOX), and replicative DNA synthesis were examined. In additio n, hepatic and serum concentrations of the parent compound and major metabo lites were determined, Relative to controls in both species, increased live r weight and PBOX at the high dose of DINP-1 were consistent with peroxisom al proliferation. Hepatic GJIC was inhibited and DNA synthesis was increase d at the high dose of DINP-1, which is also consistent with the tumorigenic response in rats and mice reported in other chronic studies at these doses . These hepatic effects were not observed at the low doses of DINP-1. At co mparable low doses of DINP-1 in other chronic studies, no liver tumors were observed in rats and mice. The monoester metabolite (MINP-1) was detected in the liver at greater concentrations in mice than rats, This result is al so consistent with the dose-response observations in rat and mouse chronic studies. Additionally, other structurally similar dialkyl phthalate esters ranging from C-7 to C-11 were evaluated using a similar protocol for compar ison to DINP-1; these included an alternative isomeric form of DINP (DINP-A ), di-isodecyl phthalate (DIDP), di-isoheptyl phthalate (DIHP), di-heptyl, nonyl undecyl phthalate (D711P), and di-n-octyl phthalate (DNOP), Collectiv ely, these data indicate that in rats and mice, DINP-1 and other C7-C11 pht halates exhibit a threshold for inducing hepatic cellular events. Further, where previous chronic data were available for these compounds, these phtha lates elicited hepatic effects at doses that correlated with the tumorigeni c response. Overall, these studies suggest a good correlation between the i nhibition of GJIC when compared with the data on production of liver tumors in chronic studies.