Comparative in Vivo Hepatic Effects of Di-Isononyl Phthalate (DINP) and Related C7-C11 Dialkyl Phthalates on Gap Junctional Intercellular Communication (GJIC), Peroxisomal Beta-Oxidation (PBOX), and DNA Synthesis in Rat and Mouse Liver

Abstract

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 from previous chronic studies. Groups of male F344 rats were fed diets with DINP-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 beta-oxidation (PBOX), and replicative DNA synthesis were examined. In addition, hepatic and serum concentrations of the parent compound and major metabolites were determined. Relative to controls in both species, increased liver weight and PBOX at the high dose of DINP-1 were consistent with peroxisomal proliferation. Hepatic GJIC was inhibited and DNA synthesis was increased 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 comparable 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 also consistent with the dose-response observations in rat and mouse chronic studies. Additionally, other structurally similar dialkyl phthalate esters ranging from C7 to C11 were evaluated using a similar protocol for comparison 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). Collectively, these data indicate that in rats and mice, DINP-1 and other C7-C11 phthalates exhibit a threshold for inducing hepatic cellular events. Further, where previous chronic data were available for these compounds, these phthalates elicited hepatic effects at doses that correlated with the tumorigenic response. Overall, these studies suggest a good correlation between the inhibition of GJIC when compared with the data on production of liver tumors in chronic studies.

Risk assessment of oral exposure to diisononyl phthalate from children’s products

“…Hepatomegaly is an early observable effect of DINP exposure in rodents. Increases in absolute and relative liver weights have been reported following as little as 1 week of exposure in mice and 2-4 weeks in F344 rats (Barber et al, 1987;BIBRA, 1985;Smith et al, 2000). Increased kidney weights were reported in rats following as little as 3 weeks of exposure (BIBRA, 1985).…”

“…In rats, 14 C-DINP was rapidly absorbed and eliminated following single or multiple oral doses Smith et al, 2000). Roughly half of the oral dose was eliminated in urine within 24 h, and the remainder in feces within 96 h. It is estimated that 75-90% of the oral dose is absorbed.…”

“…Palmitoyl-CoA oxidase activity was elevated at the high dose in both sexes (lower doses were not tested). DINP induces peroxisome proliferation in rats ( Barber et al, 1987;Moore, 1998a;Smith et al, 2000) and mice (Kaufmann et al, 2002;Moore, 1998b;Smith et al, 2000), as determined by peroxisomal b-oxidation activity or electron microscopy. Hepatocellular proliferation and palmitoyl-CoA oxidase activity were induced in wild-type mice, but not in mice deficient in the peroxisome proliferator-activated receptor a (PPARa) (Valles et al, 2003).…”

Epigenetic Effects of Endocrine Disrupting Chemicals: Phthalates: Review

“…71 Örneğin, fare ve sıçanların karaciğerinde DEHP, diizononil ftalat [diisononyl phthalate (DINP)] ve diğer bazı peroksizom proliferatörlerinin gap birleşme iletişimini inhibe ettiği gösterilmiştir. 72 DEHP uygulaması kesildiğinde bile bu inhibisyonun devam ettiği gö-rülmüştür. 73 Ayrıca, maddenin uygulama dozu ve sıklığının da hücreler arası iletişimin değişmesinde rolü vardır ve değişim, peroksizom proliferatörle-rinin genotoksik olmayan karsinogenik etki potansiyellerinin değerlendirilmesinde iyi bir göstergedir.…”

Urinary metabolites of diisodecyl phthalate in rats

“…Oral exposure to DiDP was found to cause liver enlargement in the rat (CERHR, 2000;Kaufmann et al, 2002;Kavlock et al, 2002;Smith et al, 2000). It appears that liver and kidney tumors induced by DiDP are the result of non-genotoxic processes (McKee et al, 2000).…”