Steady-State Human Pharmacokinetics of Monobutyl Phthalate Predicted by Physiologically Based Pharmacokinetic Modeling Using Single-Dose Data from Humanized-Liver Mice Orally Administered with Dibutyl Phthalate.

Dibutyl phthalate (DBP) was widely used as a plasticizer but it has been recently replaced with other kinds of phthalates such as di(2-ethylhexyl)phthalate and diisononyl phthalate because of its toxicity. To evaluate the human risk of DBP, forward and reverse dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling based on in vivo experimental pharmacokinetic data in humanized-liver mice (HL-mice) obtained after an oral dose of 100 mg/kg. Absorbed DBP was converted to monobutyl phthalate (MBP) and its glucuronide extensively in vivo. HL-mice had higher concentrations of MBP glucuronide in plasma than did the control mice. Concentrations of MBP glucuronide in 0-7 h accumulated urine samples from HL-mice were significantly higher than those in control mice. Similarly, in vitro MBP glucuronidation rates mediated by pooled microsomes from rat or mouse livers were lower than those mediated by human liver microsomes. Liver damage by MBP to humanized liver was detected by measuring human albumin mRNA in HL-mouse plasma. By simple PBPK modeling, in silico concentration curves in plasma, liver, or urine following virtual oral administration of DBP were created for rats, control mice, and HL-mice. A human PBPK model for MBP was established based on the HL-mouse PBPK model using allometric scaling without consideration of interspecies factors in terms of liver metabolism. Human PBPK models were used to estimate urinary and plasma concentrations of MBP and its glucuronide throughout 14 days of oral DBP administration (1.2 and 13 µg/kg/day). Reverse dosimetry PBPK modeling found that reported 50th and 95th percentile MBP urine and plasma concentrations of the general population could potentially imply exposures similar to or exceeding tolerable daily intake levels (5-10 µg/kg/day) recommended by the European and Japanese authorities. Further in-depth assessment of DBP is needed to assess the validity of assumptions made based on human biomonitoring data.

Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP).

In a published controlled dosing experiment, a single individual consumed 5mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models - their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific "best-fit" intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5µg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.

A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development.

Male rat sexual development was evaluated after dietary administration of 0, 760, 3800, 11,400 ppm diisononyl phthalate (DiNP) and 7600 ppm dibutyl phthalate (DBP) from gestation day (GD) 12 to postnatal day (PND) 14. Maternal weight was reduced on GD 20, PND 2 and 14 at 11,400 ppm DiNP. Pup weight was reduced on PND 2 and 14 at 11,400 and 3800 ppm DiNP. DBP induced multinucleated germ cells (MNGs) and Leydig cell aggregates (LCAs) in PND 2 testes. 7600 ppm DBP reduced anogenital distance (AGD) on PND 2 and 14, and increased nipple retention and reproductive tract malformations on PND 49. DiNP induced MNGs (3800 ppm) and LCAs (11,400 ppm) on PND 2, and reduced AGD (11,400 ppm) on PND 14. DiNP did not alter AGD, nipple retention or reproductive tract malformations on PND 49. Global endpoint analysis showed no evidence of a rat "phthalate syndrome" on PND 49 with DiNP administration.

[The effects of di-n-butyl phthalate on the somatic cells of laboratory mice]. / Wplyw ftalanu di-n-butylu (DBP) na komórki somatyczne myszy laboratoryjnych.

Phthalates are widely used as a plasticizers in manufacture of synthetic materials and as solvents in sanitary products, cosmetics and pharmaceutical products. Dibutylphthalate (DBP) is used as a plasticizers and as a textile lubricating agent and as solvent in printing ink. The study aimed the evaluation of the magnitude of DNA damage in liver and bone marrow cells and estimation of dibutyl phthalate (DBP) concentration in peripheral blood following prolonged exposure to DBP. Experiments were conducted an the Pzh:Sfis male mice. Animals were exposed 8 weeks, 3 days per week per os to DBP suspension in oil in doses of 500 mg/kg bw (1/16 LD50) and 2000 mg/kg bw (1/4 LD50). Following groups of mice were sacrificed 4 and 8 weeks after the start of exposure and 4 weeks after the end of exposure. Decreased body weight of mice and statistically significant decreased liver and relative liver weights were observed following 8-weeks exposure to 2000 mg/kg bw DBP. In the same time higher however not statistically significant level of DNA damage measured by Comet assay in liver cells were noted. DBP did not induce enhanced frequency of DNA damage in bone marrow cells. Following 8-weeks exposure to the dose of 2000 mg/kg bw DBP the increased level of DBP in peripheral blood was observed. Enhanced levels of DBP were still noted 4 weeks after the termination of exposure. Results confirmed that DBP acts as a weak mutagen for DNA of somatic cells. However, following prolonged exposure this compound seems to undergo slower metabolism and was reaching temporarily higher levels in peripheral blood.

[Dectective of serum di-n-butyl phthalate and di-2-ethylhexyl phthalate level in normal children].

OBJECTIVE: To study on the level of serum di-n-butyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP) in normal children by using gas chromatography. METHODS: Gas chromatography method was established. DBP, DEHP in normal children were detected, and their reference level was calculated, DBP and DEHP level in different age and genders were analysed. RESULTS: DBP could be detected in 110 serum samples from total 310 samples, and DEHP could be detected in 118 serum samples from the total 310 samples. The detected contrations of DBP range from non detectable to 0.98 ng/ml, P75 was 0.68 ng/ml, P95 was 0.75 ng/ml. There was no difference in the detection ratios between females and males, while baby group detection ratios was lower than other groups. The detected contrations of DEHP range from non detectable to 0.94 ng/ml, P75 was 0.67 ng/ml, P95 was 0.74 ng/ml. There was no difference in the detection ratios between females and males. While there was difference among age groups. CONCLUSION: The study domonstrated that DBP and DEHP concentrations in normal children are very low. The refrence level of DBP was suggested as lower than 0.75 ng/ml, DHEP was suggested as lower than 0.74 ng/ml.

[Determine and parallel analysis of three kinds of PAEs in serum for obese children].

OBJECTIVE: To study the serum contents of the PAEs of obese children at the ages of 10 to 12 years, in order to estimate the harm of PAEs on obese children. METHODS: The contents of three kinds PAEs(DEP, DBP and DEHP) in the serum for two groups of children, including 36 obese children and 36 normal weight children, were determined by the reversed phase high performance liquid chromatography (RP-HPLC) method And the average measure value of three kind PAEs between two groups of children were analysed. RESULTS: The median serum levels of PAEs were 0.0032 (DEP), 0.1649 (DBP) and 0.1680 (DEHP) in obese children. And the serum levels of PAEs were 0.0026 (DEP), 0.0359 (DBP) and 0.1063 (DEHP) in normal weight children. The differences of average measure value of DBP and DEHP in three kind PAEs between two groups of children were significant (P < 0.01). The amounts of obese children in high level were more than those of normal weight children, and the constitution ratios in three kinds of PAEs of obese children were higher than those of normal weight children. The differences between two groups of children were significant (P < 0.01). CONCLUSION: The average levels of DBP and DEHP in serum of obese children were more than those of serum of normal weight children. The amounts of obese children were higher than those of normal weight children in high level content of three kinds of PAEs.

Analysis of di-n-butyl phthalate and other organic pollutants in Chongqing women undergoing parturition.

In this study, 40 healthy women from Chongqing undergoing parturition were recruited and samples of venous blood, umbilical cord blood, breast milk and urine were collected for analysis of organic pollutants by GC/MS. A total of 292 different organic pollutants were detected, including 156 in venous blood, 139 in umbilical cord blood, 176 in breast milk and 138 in urine. Nine different PAEs were detectable in the samples: di-n-butyl phthalate (DBP), bis(2-methylpropyl) phthalate, butyl-8-methyl-nonyl phthalate, di-ethyl phthalate, butyl-2-methylpropyl phthalate, butyloctyl phthalate, di-dodecyl phthalate, di-isodecyl phthalate, and di-tridecyl phthalate. DBP was one of the chemicals detected at the highest frequency (48.82%). DBP concentrations were 84.75+/-33.52, 52.23+/-32.50, 57.78+/-35.42 and 24.93+/-18.67 microg/l in venous blood, umbilical cord blood, breast milk and urine, respectively. This study represents the first investigation of organic pollutants in a Chongqing population.

Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans.

In vitro and animal studies have reported endocrine-disrupting activity of chemicals used commonly as additives in cosmetics and skin care products. We investigated whether diethyl phthalate (DEP), dibutyl phthalate (DBP), and butyl paraben (BP) were systemically absorbed and influenced endogenous reproductive and thyroid hormone levels in humans after topical application. In a two-week single-blinded study, 26 healthy young male volunteers were assigned to daily whole-body topical application of 2 mg/cm2 basic cream formulation each without (week one) and with (week two) the three 2% (w/w) compounds. The concentrations of BP and the main phthalate metabolites monoethyl (MEP) and monobutyl phthalate (MBP) were measured in serum together with the following reproductive hormones: follicle stimulating hormone (FSH), lutenising hormone (LH), testosterone, estradiol, and inhibin B and thyroid hormones (thyroid stimulating hormone (TSH), free thyroxine (FT4), total triiodothyroxine (T3), and total thyroxine (T4)). MEP, MBP, and BP peaked in serum a few hours after application, reaching mean +/- SEM levels of 1001 +/- 81 microg/L, 51 +/- 6 microg/ L, and 135 +/- 11 microg/L, respectively. Only MEP was detectable in serum before treatment. Minor differences in inhibin B, LH, estradiol, T4, FT4, and TSH were observed between the two weeks, but these were not related to exposure. We demonstrated for the first time that DEP, DBP, and BP could be systemically absorbed in man after topical application. The systemic absorption of these compounds did not seem to have any short-term influence on the levels of reproductive and thyroid hormones in the examined young men.

[Study on the di-n-butyl phthalate and di-2-ethylhexyl phthalate level of girl serum related with precocious puberty in Shanghai].

OBJECTIVE: To determine the levels of the di-n-butyl phthalate and di-2-ethylhexyl phthalate in the serum of precocious girls in Shanghai, and study the development relationship between DBP, DEHP and precocious girls. METHODS: The concentrations of two phthalates (di-n-butyl phthalate, DBP, di-2-ethylhexyl phthalate, DEHP) in serum of 110 precocious girls and 100 normal children were measured by using gas chromatography, in the same time, the volumes of the uteruses and ovaries for precocious girls and normal children were measured by B-ultrasound and then did correlation analysis between the concentrations of DBP, DEHP and the volumes of uteruses and ovaries of precocious girls. RESULTS: DBP and DEHP were detected for 27.3% and 22.7% in precocious girls respectively, DBP and DEHP were detected for only 4% and 3% in normal children respectively. From the ratio of DBP and DEHP in serum of precocious girls were higher than normal children. Precocious girls uteruses and ovaries volume were higher than those of normal children respectively (P < 0.05, P < 0.05). DBP in serum of precocious girls had positive correlation with the volumes of the uteruses (r = 0.456, P < 0.05), and had positive correlation with volumes of the ovaries (r = 0.378, P < 0.01). DEHP in serum of precocious puberty had positive correlation with the volumes of uteruses (r = 0.382, P < 0.05), and had positive correlation with volumes of ovaries (r = 0.689, P < 0.01). CONCLUSION: Precocious girls could be contaminated more severely than normal girls, and DBP, DEHP could influence the volumes of the uteruses and ovaries.

Gas chromatographic--mass spectrometric detection of circulating plasticizers in surgical patients.

Gas chromatographic and gas chromatographic--mass spectrometric analytical techniques were employed to quantitate and confirm levels of circulating organic plasticizers in critically ill surgical patients. Two plasticizers, dibutyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP), have been identified. DEHP can be found in many plastic medical devices. The DEHP levels were significant soon after transfusion or in the presence of renal dysfunction. The source of DBP is not clear at present and requires further study. The prevention of this contamination and the toxicity of these plasticizers should be investigated to ensure the safe use of plastic medical devices.