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The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61y) who ingested a single dose (645±20μg/kg body weight) of ring-deuterated DEHP (DEHP-D(4)). Concentrations of DEHP-D(4), of free ring-deuterated MEHP (MEHP-D(4)), and the sum of free and glucuronidated MEHP-D(4) were measured in blood for up to 24h; amounts of the monoesters MEHP-D(4), ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46h after ingestion. The bioavailability of DEHP-D(4) was surprisingly high with an area under the concentration-time curve until 24h (AUC) amounting to 50% of that of free MEHP-D(4). The AUC of free MEHP-D(4) normalized to DEHP-D(4) dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D(4) even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D(4) in blood, the parameter regarded as relevant for risk assessment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A comparison of the dose-dependent blood burden of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP) in pregnant and nonpregnant rats and marmosets is presented. Sprague-Dawley rats and marmosets were treated orally with 30 or 500 mg DEHP/kg per day, nonpregnant animals on 7 (rats) and 29 (marmosets) consecutive days, pregnant animals on gestation days 14-19 (rats) and 96-124 (marmosets). In addition, rats received a single dose of 1000 mg DEHP/kg. Blood was collected up to 48 h after dosing. Concentrations of DEHP and MEHP in blood were determined by GC/MS. In rats, normalized areas under the concentration-time curves (AUCs) of DEHP were two orders of magnitude smaller than the normalized AUCs of the first metabolite MEHP. Metabolism of MEHP was saturable. Repeated DEHP treatment and pregnancy had only little influence on the normalized AUC of MEHP. In marmosets, most of MEHP concentration-time courses oscillated. Normalized AUCs of DEHP were at least one order of magnitude smaller than those of MEHP. In pregnant marmosets, normalized AUCs of MEHP were similar to those in nonpregnant animals with the exception that at 500 mg DEHP/kg per day, the normalized AUCs determined on gestation days 103, 117, and 124 were distinctly smaller. The maximum concentrations of MEHP in blood of marmosets were up to 7.5 times and the normalized AUCs up to 16 times lower than in rats receiving the same daily oral DEHP dose per kilogram of body weight. From this toxicokinetic comparison, DEHP can be expected to be several times less effective in the offspring of marmosets than in that of rats if the blood burden by MEHP in dams can be regarded as a dose surrogate for the MEHP burden in their fetuses.

The main purpose of the study was to establish the relation between exposure dose of propylene oxide (PO) and dose in various tissues of male F344 rats exposed to the compound by inhalation. The animals were exposed to 0, 5, 25, 50, 300, or 500 ppm PO in the air for 3 days (6 h/day) or 4 weeks (6 h/day, 5 days/week). Blood, nasal respiratory epithelium, lung, and liver were collected. 2-Hydroxypropylvaline (HPVal) in hemoglobin was quantified using the N-alkyl Edman method and gas chromatography/tandem mass spectrometry. 7-(2-Hydroxypropyl)guanine (7-HPG) in DNA was quantified using (32)P postlabeling. The levels of 7-HPG in DNA of nasal respiratory epithelium and lung increased linearly with concentration as measured both after 3 days and 4 weeks of exposure. Similarly, 7-HPG in liver DNA and HPVal in hemoglobin showed a linear increase with PO concentration in the 3-day exposure group, whereas a deviation from linearity was observed above 300 ppm in the 4-week exposure group. The new results confirm previous observations of a dose difference between tissues with the highest dose present in the nasal respiratory epithelium. The measured adduct levels were used for calculation of adduct increments and corresponding tissue doses per unit of external exposure dose. For this purpose, the buildup of adducts was modeled considering the different kinetics of formation and elimination of adducts with DNA and hemoglobin, respectively, and also considering the increasing body weight of the animals. The half-life of 7-HPG in vivo, as well as tissue doses, could be solved from DNA adduct data at the 3rd and 26th days. Within the range of concentrations where the dose-response curves for adduct formation are linear, the relationship between exposure dose and resulting tissue doses could be based equally well on adduct data from the short-term exposure as on adduct data from the prolonged exposure.

Kinetics of the metabolic inactivation of 1,2-epoxypropane (propylene oxide; PO) catalyzed by glutathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degrees C in cytosol and microsomes of liver and lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfactory nasal mucosa of F344 rats. In all of these tissues, GST and EH activities were detected. GST activity for PO was found in cytosolic fractions exclusively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, representing 1-3% of the corresponding GST activity. For GST, the ratio of the maximum metabolic rate (V(max)) to the apparent Michaelis constant (K(m)) could be quantified for all tissues. In liver and lung, these ratios ranged from 12 (human liver) to 106 microl/min/mg protein (mouse lung). Corresponding values for EH ranged from 4.4 (mouse liver) to 46 (human lung). The lowest V(max) value for EH was found in mouse lung (7.1 nmol/min/mg protein); the highest was found in human liver (80 nmol/min/mg protein). K(m) values for EH-mediated PO hydrolysis in liver and lung ranged from 0.83 (human lung) to 3.7 mmol/L (mouse liver). With respect to liver and lung, the highest V(max)/K(m) ratios were obtained for GST in mouse and for EH in human tissues. GST activities were higher in lung than in liver of mouse and human and were alike in both rat tissues. Species-specific EH activities in lung were similar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver., (Copyright 2001 Academic Press.)

A physiological toxicokinetic (PT) model was developed for inhaled propylene gas (PE) in mouse, rat, and human. Metabolism was simulated to occur in the liver (90%) and in the richly perfused tissue group (10%). The partition coefficients tissue:air were determined in vitro using tissues of mice, rats, and humans. Most of the tissues have partition coefficients of around 0.5. Only adipose tissue displays a 10 times higher value. The partition coefficient blood:air in human is 0.44, about half of that in rodents. PE can accumulate in the organism only barely. For male B6C3F1 mice and male Fischer 344/N rats, parameters of PE metabolism were obtained from gas uptake experiments. Maximum rates of metabolism (V(maxmo)) were 110 micromol/h/kg in mice and 50.4 micromol/h/kg in rats. V(maxmo)/2 was reached in mice at 270 ppm and in rats at 400 ppm of atmospheric PE. Pretreatment of the animals with sodium diethyldithiocarbamate resulted in an almost complete inhibition of PE metabolism in both species. Preliminary toxicokinetic data on PE metabolism in humans were obtained in one volunteer who was exposed up to 4.5 h to constant concentrations of 5 and 25 ppm PE. The PT model was used to calculate PE blood concentrations at steady state. At 25 ppm, the blood values were comparable across species, with 0.19, 0.32, and 0.34 micromol/L for mouse, rat, and human, respectively. However, the corresponding rates of PE metabolism differed dramatically, being 8.3, 2.1, and 0.29 micromol/h/kg in mouse, rat, and human. For a repeated human exposure to 25 ppm PE in air (8 h/day, 5 days/week), PE concentrations in venous blood were simulated. The prediction demonstrates that PE is eliminated so rapidly that it cannot accumulate in the organism. For low exposure concentrations, it became obvious that the rate of uptake into blood by inhalation is limited by the blood flow through the lung and the rate of metabolism is limited by the blood flow through the metabolizing organs., (Copyright 2000 Academic Press.)

Ethylene (ET) is a gaseous olefin of considerable industrial importance. It is also ubiquitous in the environment and is produced in plants, mammals, and humans. Uptake of exogenous ET occurs via inhalation. ET is biotransformed to ethylene oxide (EO), which is also an important volatile industrial chemical. This epoxide forms hydroxyethyl adducts with macromolecules such as hemoglobin and DNA and is mutagenic in vivo and in vitro and carcinogenic in experimental animals. It is metabolically eliminated by epoxide hydrolase and glutathione S-transferase and a small fraction is exhaled unchanged. To estimate the body burden of EO in rodents and human resulting from exposures to EO and ET, we developed a physiological toxicokinetic model. It describes uptake of ET and EO following inhalation and intraperitoneal administration, endogenous production of ET, enzyme-mediated oxidation of ET to EO, bioavailability of EO, EO metabolism, and formation of 2-hydroxyethyl adducts of hemoglobin and DNA. The model includes compartments representing arterial, venous, and pulmonary blood, liver, muscle, fat, and richly perfused tissues. Partition coefficients and metabolic parameters were derived from experimental data or published values. Model simulations were compared with a series of data collected in rodents or humans. The model describes well the uptake, elimination, and endogenous production of ET in all three species. Simulations of EO concentrations in blood and exhaled air of rodents and humans exposed to EO or ET were in good agreement with measured data. Using published rate constants for the formation of 2-hydroxyethyl adducts with hemoglobin and DNA, adduct levels were predicted and compared with values reported. In humans, predicted hemoglobin adducts resulting from exposure to EO or ET are in agreement with measured values. In rodents, simulated and measured DNA adduct levels agreed generally well, but hemoglobin adducts were underpredicted by a factor of 2 to 3. Obviously, there are inconsistencies between measured DNA and hemoglobin adduct levels., (Copyright 2000 Academic Press.)