Comparative Pharmacokinetics and Subacute Toxicity of Di(2-Ethylhexyl) Phthalate (DEHP) in Rats and Marmosets: Extrapolation of Effects in Rodents to Man

Abstract

Certain phthalate esters and hypolipidemic agents are known to induce morphological and biochemical changes in the liver of rodents, which have been associated with an increased incidence of hepatocellular tumors in these species. There is evidence that hypolipidemic agents do not induce these effects in either subhuman primates or man. The oral and intraperitoneal administration of di(2-ethylhexyl) phthalate (DEHP) to the marmoset monkey at doses up to 5 mmole DEHP/kg body weight/day for 14 days did not induce morphological or biochemical changes in the liver or testis comparable with those obtained in rats given the same amount of DEHP. In the marmoset, the excretion profile of [14C]-DEHP following oral, IP, and IV administration and the lower tissue levels of radioactivity demonstrated a considerably reduced absorption in this species compared to the rat.The urinary metabolite pattern in the marmoset was in many respects qualitatively similar to but quantitatively different from that in the rat; the marmoset excreted principally conjugated metabolites derived from w -1 oxidation. The pharmacokinetic differences between these two species indicate that the tissues of the marmoset are exposed to a level of DEHP metabolites equivalent to the complete absorption of a dose of Ca. 0.1 to 0.25 mmole DEHP/kg body weight/day without significant toxicological effects. These exposure levels are at least 100-fold greater than the worst estimates of incidental human exposure (ca. 0.0015 mmole/ kg/day). They are comparable with the human therapeutic dose of many hypolipidemic drugs (ca. 0.15 mmole/ kg/day), a dose at which it is claimed that there is an absence of morphological or biochemical changes to human or subhuman primate liver. The evidence suggests that in some nonrodent species the hepatocellular and testicular response to DEHP is considerably less than that in rodents and is dose-dependent.

Plasticizer concentration in cord blood cryopreserved with DMSO

“…Distribution studies in rodents indicate that DEHP is widely distributed in the tissues without evidence of accumulation (Daniel and Bratt and Butterworth 1974, Gaunt 1982, Pollack et al 1985. Similar distribution patterns have been found between rats and marmosets after oral administration even though in marmosets absorption from the gut was lower (Rhodes et al 1986). DEHP and its metabolites may be secreted into the milk of lactating rats (Dostal et al 1987, Parmar et al 1985 and also pass into human milk (Bruns-Weller and Pfjordt 2000, , Gruber et al 1998, Mortensen et al 2005, Zhu et al 2006.…”

Response to ‘Dr Raymond David, BASF Corporation’

“…Distribution studies in rodents indicate that DEHP is widely distributed in the tissues without evidence of accumulation (Daniel and Bratt 1974, Gaunt and Butterworth 1982, Pollack et al 1985a. After oral administration of 14 C-DEHP rats and marmosets showed qualitatively similar distribution patterns (liver>kidney>testes) (Rhodes et al 1986). DEHP and its metabolites may be secreted into the milk of lactating rats (Dostal et al 1987, Parmar et al 1985 and also pass into human milk (Bruns-Weller and Pfjordt 2000, Gruber et al 1998, Mortensen et al 2005, Zhu et al 2006.…”

“…For male reproductive toxicity caused by DEHP there is a difference in sensitivity between various animal species, rodents being more susceptible than non human primates (Rhodes et al 1986). The same dose (2000 mg/kg for 14 days orally) induced testis atrophy and liver enlargement in rats, but failed to do so in marmosets (Rhodes et al 1986).…”

“…In contrast to rodents there may be a dose-limited absorption at higher doses (2000 mg/kg per day for 14 days) in non-human primates (Rhodes et al 1983, Rhodes et al 1986). Koch et al (2004bKoch et al ( , 2005a found that urinary excretion in human followed at least a twophase elimination model.…”

“…The same dose (2000 mg/kg for 14 days orally) induced testis atrophy and liver enlargement in rats, but failed to do so in marmosets (Rhodes et al 1986). Also in another study, adult male marmosets treated up to 2500 mg/kg DEHP for 13 weeks failed to show evidence of testicular toxicity (Kurata et al 1998).…”