Plasma Di(2-ethylhexyl)phthalate Research Articles

Evaluation of Exposure to Bisphenol A, Bisphenol F, and Phthalates in Patients with Phenylketonuria and Its Differences According to Dietary Status.

Phenylketonuria (PKU) is the most common amino acid metabolism disorder. Patients with blood phenylalanine (Phe) levels of ≥6 mg/dL require treatment, and the most definitive treatment is the Phe-restricted diet. Bisphenols and phthalates are widely used endocrine-disrupting chemicals (EDCs) found in personal care products, baby bottles, and food packaging. In this study, we evaluated the possible routes of exposure to these EDCs in patients diagnosed with PKU (n = 105, 2-6 years of age) and determined the relationship between the plasma levels of bisphenol A (BPA), bisphenol F (BPF), di-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP), mono-(2ethylhexyl) phthalate (MEHP), and dietary regimens. Participant characteristics and exposure routes were evaluated according to their dietary treatment status. Thirty-four of these patients were on a Phe-restricted diet, while the remaining 71 had no dietary restrictions. DBP and DEHP levels were higher in those using plastic tablecloths (p = 0.049 and p = 0.04, respectively). In addition, plasma DBP levels were higher in those who used bottled water (p = 0.01). Being under 4 years of age, using plastic food containers, and using plastic shower curtains were characteristics associated with higher MEHP levels (p = 0.027, p = 0.019, and p = 0.014, respectively). After adjustment for baseline characteristics (Model 1), the odds of having a plasma BPA level in the upper tertile were 3.34 times higher in the free-diet group (95% CI = 1.09-10.25). When we additionally adjusted for plastic exposure (Model 2), the odds ratio was found to be 18.64 (95% CI = 2.09-166.42) for BPA. In the free-diet group, the probability of having plasma DEHP levels in the upper tertile was increased by a relative risk of 3.01 (p = 0.039, 95% CI = 1.06-8.60). Our results indicate that exposure to bisphenols and phthalates varies with dietary treatment. The difference in sources of exposure to EDCs between the diet and non-diet groups indicates that diet plays an important role in EDC exposure.

SAT-724 Endocrine Disruption by Phthalate Exposure in the Pediatric Intensive Care Unit

Aim: Pediatric intensive care relies on plastic indwelling medical devices softened by phthalates. Phthalates leach into the circulation and concerns about toxicity were raised. Exceeding a certain threshold of di(2-ethylhexyl)phthalate (DEHP) exposure in the pediatric intensive care unit (PICU) has been associated with an attention deficit 4 years later (1). Moreover, DEHP and its metabolites have endocrine disrupting properties. Critically ill children reveal the non-thyroidal illness syndrome (2) and unexplained relatively low cortisol (3). Whether DEHP exposure in PICU has endocrine disruptive effects is unknown. We investigated whether DEHP exposure in the PICU, exceeding the previously identified “toxic” threshold for attention, is independently associated with thyroid- and HPA-axis alterations upon PICU discharge. Methods: In this preplanned secondary analysis of the PEPaNIC RCT (N=1440) (4), plasma DEHP metabolite concentrations (MEHP, 5OH-MEHP, 5cx-MEPP, 5oxo-MEHP) were quantified for all patients with a last PICU day sample (N=920). Minimal DEHP exposure was defined as the product of the total DEHP metabolite concentrations on the last PICU day and duration of PICU stay, with 0.551 µmol/L.days identified as “toxic” threshold (1). Serum TSH, total T4, total T3 and rT3 concentrations were quantified for patients with an available last day sample (N=913). For patients with a last day plasma sample and who did not receive corticosteroids (N=391), plasma ACTH, total cortisol, albumin and CBG concentrations were quantified and free cortisol calculated. Multivariable linear regression analyses, adjusted for baseline risk factors and for duration of PICU stay, assessed whether exceeding the previously determined threshold of toxic DEHP exposure was independently associated with the hormone levels on the last PICU day. Main results: Median total DEHP metabolite concentration was 0.101 (IQR 0.049 - 0.279) µmol/L on the last PICU day. Minimal DEHP exposure was 0.337 (IQR 0.161 - 0.880) µmol/l.days, and 328 patients (35.7%) exceeded the toxic threshold. Exceeding this threshold was independently associated with lower total T4 (P=0.002), total T3 (P=0.02) and total cortisol (P=0.001), and higher rT3 (P=0.01) concentrations on the last PICU day, but not with TSH, ACTH or free cortisol. Conclusion: Critically ill children had DHEP metabolites in plasma upon PICU discharge and more than a third were exposed to toxic levels. Toxic DEHP exposure was an independent contributor to the severity of the non-thyroidal illness phenotype and to lower cortisol upon PICU discharge. Future research should assess whether such endocrine-disruptive impact of DHEP exposure in the PICU plays a role in the long-term developmental legacy of critical illness in children. 1 Verstraete et al Intensive Care Med 2016 2 Jacobs et al Thyroid 2019 3 Jacobs et al Intensive Care Med 2019 4 Fivez et al N Engl J Med 2016

Oxidative Stress Parameters, Selenium Levels, DNA Damage, and Phthalate Levels in Plastic Workers.

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate. DEHP is highly used in PVC floorings and PVC windows and carpeting. The objective of this study was to determine sex hormone levels, oxidative stress parameters, selenium levels, DNA damage, and phthalate levels in plastics workers (n = 24, age = 20-58 years) working in the production of rubber mechanical goods and exposed to DEHP in workplace. The control group (n = 29, age = 25-54, all male) was selected from age-matched healthy adults. Antioxidant parameters and DNA damage were determined by spectrophotometry. Selenium levels were determined by atomic absorption spectroscopy. Plasma hormone levels were measured by chemiluminescence microparticle immunoassay. Plasma phthalate levels were determined by high-pressure liquid chromatography. Plastic workers had lower serum testosterone and free T4 levels and higher follicle-stimulating hormone levels vs. controls. Liver enzyme activities were markedly higher in workers vs. controls. There were also increases in plasma glutathione peroxidase levels and marked decreases in plasma selenium and erythrocyte total glutathione levels in plastics workers (P < 0.05 vs. control). Plasma 8-hydroxy-2'-deoxyguanosine levels were 14-fold higher in plastics workers than in controls. Plasma DEHP and mono(2-ethylhexyl)phthalate were also markedly higher in workers vs. controls. The results of this study show that occupational exposure to DEHP may lead to disturbances in sex hormones, increased liver problems, higher oxidative stress and DNA damage levels, and lower trace element concentrations in workers. More comprehensive and mechanistic studies with higher numbers of subjects are needed to show the unwanted effects of occupational exposure to DEHP.

Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort

Environmental phthalate exposure has been associated with attention deficit disorders in children. We hypothesized that in children treated in the pediatric intensive care unit (PICU), circulating phthalates leaching from indwelling medical devices contribute to their long-term attention deficit. Circulating plasma concentrations of di(2-ethylhexyl)phthalate (DEHP) metabolites were quantified in 100 healthy children and 449 children who had been treated in PICU and were neurocognitively tested 4 years later. In a development patient cohort (N = 228), a multivariable bootstrap study identified stable thresholds of exposure to circulating DEHP metabolites above which there was an independent association with worse neurocognitive outcome. Subsequently, in a second patient cohort (N = 221), the observed independent associations were validated. Plasma concentrations of DEHP metabolites, which were virtually undetectable [0.029 (0.027-0.031) µmol/l] in healthy children, were 4.41 (3.76-5.06) µmol/l in critically ill children upon PICU admission (P < 0.001). Plasma DEHP metabolite concentrations decreased rapidly but remained 18 times higher until PICU discharge (P < 0.001). After adjusting for baseline risk factors and duration of PICU stay, and further for PICU complications and treatments, exceeding the potentially harmful threshold for exposure to circulating DEHP metabolites was independently associated with the attention deficit (all P ≤ 0.008) and impaired motor coordination (all P ≤ 0.02). The association with the attention deficit was confirmed in the validation cohort (all P ≤ 0.01). This phthalate exposure effect explained half of the attention deficit in post-PICU patients. Iatrogenic exposure to DEHP metabolites during intensive care was independently and robustly associated with the important attention deficit observed in children 4 years after critical illness. Clinicaltrials.gov identifier: NCT00214916.

Health hazard assessment of occupationally di-(2-ethylhexyl)-phthalate-exposed workers in China

Di-(2-ethylhexyl)-phthalate (DEHP) is a potential hazard to human health. The effects of occupational high level DEHP exposure on human health were evaluated by measuring the plasma cholinesterase, residues, renal and hepatic biochemical markers. The study was conducted in three representative polyvinyl chloride manufacturing facilities from large size (S1), medium side (S2) to small size (S3). Total 456 adult males including 352 exposed workers (occupational) and 104 control workers (background) were selected. The average DEHP concentrations in respirable particulate matter were 233, 291, and 707μgm−3 for S1–S3, respectively, compared with 0.26μgm−3 in the background atmosphere (labeled by S4). The results showed significant decreases in post exposure plasma cholinesterase (PChE) levels (<30%) from the exposed workers as compared to baseline. These exposed workers had been evaluated for plasma DEHP residues. Regression analyses explored that PChE decreased significantly with increasing plasma DEHP residues. Serum aspartate aminotransferase, alanine aminotransferase, creatinine, urea, gamma glutamyltransferase, malondialdehyde, total antioxidant and C-reactive protein were significantly raised as compared to the controls. Of the 352 exposed workers, 116 (33.0%) had a daily DEHP intake 22.7μgkgbw−1d−1 , which is more than 20μgkgbw−1d−1 specified by the US Environmental Protection Agency. The study demonstrated that occupational phthalate exposure produces health hazards.

Celery oil modulates DEHP-induced reproductive toxicity in male rats

The objective of the study was to investigate the protective effect of Apium graveolens (AP) against di-(2-ethylhexyl) phthalate (DEHP)-induced testes injury in rats. Adult rats were divided into nine groups: (1) control group (no treatment); (2) corn oil (60μg/kg body weight – bwt); (3) AP (50μg/kg bwt); (4) 300mg DEHP/kg bwt; (5) 500mg DEHP/kg bwt; (6) 1000mg DEHP/kg bwt; (7) 300mg DEHP/kg bwt+AP; (8) 500mg DEHP/kg bwt+AP; and (9) 1000mg DEHP/kg bwt+AP. Oral administration of treatments was performed daily for 6 weeks. DEHP decreased (p<0.01) body weight, testis weight and serum concentrations of testosterone, cholesterol and total proteins. Moreover, DEHP increased (p<0.001) total antioxidant capacity in the testis and plasma DEHP level. In addition, DEHP decreased mRNA expression of two testicular steroidogenic enzymes: 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. DEHP also caused atrophy, vacuolar degeneration and aspermia of the seminiferous tubules. AP administered concurrently with DEHP effectively alleviated most of the DEHP-induced effects. In conclusion, in male rats, DEHP had adverse effects on the testis including inhibition of androgen production. A concurrent administration of A. graveolens (celery oil) protected the testis against DEHP-induced toxicity.

Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study

We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.

Plasma Phthalate Levels in Pubertal Gynecomastia

Several untoward health effects of phthalates, which are a group of industrial chemicals with many commercial uses including personal-care products and plastic materials, have been defined. The most commonly used, di-(2-ethylhexyl)-phthalate (DEHP), is known to have antiandrogenic or estrogenic effects or both. Mono-(2-ethylhexyl)-phthalate (MEHP) is the main metabolite of DEHP. In this study, we aimed to determine the plasma DEHP and MEHP levels in pubertal gynecomastia cases. The study group comprised 40 newly diagnosed pubertal gynecomastia cases who were admitted to Hacettepe University Ihsan Doğramaci Children's Hospital. The control group comprised 21 age-matched children without gynecomastia or other endocrinologic disorder. Plasma DEHP and MEHP levels were measured by using high-performance liquid chromatography. Serum hormone levels were determined in some pubertal gynecomastia cases according to the physician's evaluation. Plasma DEHP and MEHP levels were found to be statistically significantly higher in the pubertal gynecomastia group compared with the control group (P < .001) (DEHP, 4.66 +/- 1.58 and 3.09 +/- 0.90 microg/mL, respectively [odds ratio: 2.77 (95% confidence interval: 1.48-5.21)]; MEHP, 3.19 +/- 1.41 and 1.37 +/- 0.36 microg/mL [odds ratio: 24.76 (95% confidence interval: 3.5-172.6)]). There was a statistically significant correlation between plasma DEHP and MEHP levels (r: 0.58; P < .001). In the pubertal gynecomastia group, no correlation could be determined between plasma DEHP and MEHP levels and any of the hormone levels. DEHP, which has antiandrogenic or estrogenic effects, may be an etiologic factor in pubertal gynecomastia. These results may pioneer larger-scale studies on the etiologic role of DEHP in pubertal gynecomastia.

Validation of High Performance Liquid Chromatographic Method with UV Detector for the Determination of Di(2-ethylhexyl)Phthalate in Plasma in some Korean Male Workers

2) Objectives: This study was conducted to validate a simple, rapid and sensitive reverse-phase high-per formance liquid chromatographic method with UV detector (HPLC-UV) and present the plasma level of di(2-ethylhexyl)phthalate (DEHP) in some Korean male workers. M e t h o d s: HPLC-UV for quantification of plasma DEHP was validated by the following guideline from the Center for Drug Evaluation and Research (CDER) - calibration/standard curve, precision, accu racy and recovery. Plasma DEHP from 255 healthy Korean male workers aged from 30 to 60 years was analyzed by validated HPLC-UV method. R e s u l t s: The calibration curve over the range 0~150 μg /l for the plasma DEHP standard solution showed linearity(r 2 =0.999). The limit of detection (LOD) and limit of quantificatio n (LOQ) of plasma DEHP were 5.22 μg /l and 15.81 μg /l, respectively. The accuracy and precision for 2.5 μg /l o f DEHP were acceptable in CDER guideline on the second and third day but not first day, and those for 50 μg /l and 150 μg /l of DEHP were acceptable on all three days(Ed-confirm this addition). The distribu tion of plasma DEHP level was skewed to the left and ranged from 0 to 18.9 μg /l. The plasma DEHP level was lower than 10 μg /l for 98 % of subjects and lower than 5 μg /lfor 85 %. The geometric mean and standard deviation of plasma DEHP were 0.4±1.5 μg /l. C o n c l u s i o n s : The HPLC-UV method for quantification of plasma DEHP was acceptable by CDER guideline. The plasma DEHP of 255 Korean male workers ranged from 0 to 18.9 μg /l and the distribu tion was skewed to the left.

High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis.

Emerging evidence suggests a potential role for ubiquitous environmental contaminants in the physiopathology of endometriosis. Di-(2-ethylhexyl)-phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride (PVC) formulations, is a widespread environmental contaminant with potentially adverse effects on fertility in animal models. In the present study, we tested the hypothesis that DEHP and/or and its main metabolite, mono-ethylhexyl phthalate (MEHP), play a role in the pathogenesis of endometriosis. Specimens of blood and peritoneal fluid were collected in a group of women with endometriosis (n = 55), and in age-matched control women (n = 24). Concentrations of DEHP and MEHP were measured in plasma and peritoneal fluid by using high performance liquid chromatography (HPLC). Differences between groups were tested using the Fisher's exact test, Wilcoxon-test, and Kruskal-Wallis analysis of variance. Endometriotic women showed significantly higher plasma DEHP concentrations than controls (median 0.57 micro g/ml, interquartile range: 0.06-1.23; values range: 0-3.24 versus median 0.18 micro g/ml, interquartile range: 0-0.44; values range: 0-1.03; P = 0.0047) and 92.6% of them had detectable DEHP and /or MEHP in the peritoneal fluid. No significant differences in either the DEHP/MEHP plasma concentrations (P >/= 0.31) or DEHP/MEHP peritoneal fluid concentrations (P >/= 0.66) were observed in the endometriotic patients as a function of the disease stage at the time of diagnosis. The present findings showed for the first time an association between DEHP plasma concentrations and endometriosis, suggesting a possible role for phthalate esters in the pathogenesis.

Exposure to Di(2-ethylhexyl)phthalate in Humans during Pregnancy

Background: Di(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer, is a widespread ubiquitous environmental contaminant. The potential health hazards from exposure to DEHP and its main metabolite, mono(2-ethylhexyl)phthalate (MEHP), have been well documented. Exposure to DEHP and MEHP in humans at risk, such as pregnant women and human fetuses, has not been tested. Methods: Plasma DEHP and MEHP concentrations were measured in a total of 24 consecutive mother-infant pairs by high performance liquid chromatography. Associations between DEHP/MEHP and infant characteristics were tested using Fisher’s exact test, unpaired t tests and univariate linear regression analysis. Results: Measurable DEHP and MEHP concentrations were found in 17/24 (70.8%) and 18/24 (75%) maternal plasmas, respectively, and in 11/25 (44%) and 18/25 (72.0%) cord samples, respectively. Either DEHP or MEHP were detectable in 21/24 (87.5%) maternal plasmas and 19/25 (76%) cord samples. The mean DEHP concentrations in maternal and cord plasmas were 1.15 ± 0.81 and 2.05 ± 1.47 µg/ml, respectively. The mean MEHP concentrations were 0.68 ± 0.85 and 0.68 ± 1.03 µg/ml, respectively. No significant correlations were found between maternal and cord blood DEHP, maternal and cord blood MEHP, maternal DEHP and cord blood MEHP, or maternal MEHP and cord blood DEHP plasma concentrations. Conclusion: Although the effects of perinatal exposure to phthalates need further research, our findings: (i) confirm the high frequency of DEHP and/or MEHP exposure in human pregnancies; (ii) indicate that the exposure to these environmental contaminants begins during intrauterine life, and (iii) suggest that fetal exposure is closely related to the maternal exposure.

In vivo Comparative Evaluation of Hemodialysis Tubing Plasticized with DEHP and TEHTM

The migration of plasticizers from blood lines was studied in 11 patients with chronic renal failure on hemodialysis for a period of six months. Di-2-ethylhexylphthalate (DEHP), the conventional plasticizer, was compared with tri-2-ethylhexyltrimellitate (TEHTM). A liquid chromatography method for quantitative determination of DEHP and TEHTM in human blood plasma is described. During treatment with tubing containing DEHP, the plasma level of DEHP rose from 0.10 micrograms/ml (less than 0.05-0.17 n = 11) to 0.70 micrograms/ml (0.30-1.6 n = 11). When the patients were changed to tubing containing TEHTM, the concentration of DEHP was below or close to the detection limit and TEHTM could not be detected. No adverse events of either tubing were found as regards acute toxic effects, performance or applicability.

Liquid chromatographic analysis of di(2-ethylhexyl) phthalate: application to pharmacokinetic studies in the mongrel dog.

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of di(2-ethylhexyl) phthalate (DEHP) in serum or plasma. Plasma DEHP concentrations that were measured by HPLC in specimens obtained from hemodialysis patients were in good agreement with corresponding concentrations that were measured by gas chromatography with selected ion monitoring (GC-SIM) (r2 = 0.996). Plasma DEHP concentrations were measured after intravenous DEHP administration (1.2-4.4 mg DEHP/kg body weight) to determine the effect of bilateral ureteral ligation on DEHP elimination in the mongrel dog. DEHP plasma clearance (approximately 6.3 ml/min/kg), steady-state distribution volume (approximately 0.21/kg), and terminal half-life (approximately 50 min) were unchanged in two dogs following bilateral ureteral ligation. DEHP terminal half-life and steady-state distribution volume were substantially smaller (25- to 70-fold) than reported previously in the rat or dog.

Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats.

The disposition of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and four of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg DEHP/kg body weight. Plasma concentrations of DEHP and metabolites were followed for 24 h after the start of the infusion. The kinetics of the primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) was studied separately. The concentrations of DEHP in plasma were at all times considerably higher than those of MEHP, and the concentrations of MEHP were much higher than those of the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were at most 15% of that of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP and the omega- and (omega-1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. This was partly supported by the observation that the clearance of MEHP was higher than that of DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP.

Disposition of orally administered di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate in the rat.

The disposition of di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) was studied in the rat. Three hours after a single oral dose of DEHP (2.8 g/kg), plasma concentrations of 8.8 +/- 1.7 micrograms/ml DEHP and 63.2 +/- 8.7 micrograms/ml MEHP were reached. MEHP levels declined with a half-life of 5.2 +/- 0.5 h. The ratio of the area under the plasma concentration-time curve of MEHP to that of DEHP was 16.1 +/- 6.1. When 14C-DEHP was administered, 19.3 +/- 3.3% of the radioactivity was excreted in the urine within 72 h, the rest being excreted in the faeces. The urinary excretion rate of total radioactivity declined with a half-life of 7.9 +/- 0.5 h. Single administration of MEHP (0.4 g/kg) resulted in plasma concentrations of 84.1 +/- 14.9 micrograms/ml 3 h after dosing; the half-life of MEHP was 5.5 +/- 1.1 h. Multiple dosing with DEHP (2.8 g/kg/day) for 7 consecutive days produced no accumulation of DEHP or MEHP in plasma.

Toxic Potential of the Plasticizer Di(2-ethylhexyl) Phthalate in the Context of Its Disposition and Metabolism in Primates and Man

Although human toxicity from exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) is unknown, reports of animal toxicity from DEHP have stimulated extensive toxicological studies. In the absence of direct toxicity data, information on the disposition and metabolism of DEHP in primates and man may enhance our assessment of the toxic potential of DEHP in man. Studies of DEHP disposition and metabolism in the African Green monkey and man show that the compound is rapidly and extensively metabolized. It is excreted largely in the urine (greater than 90%) as conjugated (glucuronide) oxidation products of mono(2-ethylhexyl) phthalate; excretion in feces accounts for the other 10% of the administered DEHP. Plasma disappearance of parenterally administered DEHP is equally rapid so that by 24 hr following DEHP administration, plasma DEHP concentrations are virtually undetectable, while greater than 70% of the dose has been excreted in urine and stool. The transience of DEHP in primates and the extent to which it is metabolized and conjugated may play a role in the observed lack of toxicity.

Toxic potential of the plasticizer Di(2-ethylhexyl) phthalate in the context of its disposition and metabolism in primates and man.

Although human toxicity from exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) is unknown, reports of animal toxicity from DEHP have stimulated extensive toxicological studies. In the absence of direct toxicity data, information on the disposition and metabolism of DEHP in primates and man may enhance our assessment of the toxic potential of DEHP in man. Studies of DEHP disposition and metabolism in the African Green monkey and man show that the compound is rapidly and extensively metabolized. It is excreted largely in the urine (greater than 90%) as conjugated (glucuronide) oxidation products of mono(2-ethylhexyl) phthalate; excretion in feces accounts for the other 10% of the administered DEHP. Plasma disappearance of parenterally administered DEHP is equally rapid so that by 24 hr following DEHP administration, plasma DEHP concentrations are virtually undetectable, while greater than 70% of the dose has been excreted in urine and stool. The transience of DEHP in primates and the extent to which it is metabolized and conjugated may play a role in the observed lack of toxicity.

Di‐2‐Ethylhexyl Phthalate (DEHP) and Mono‐2‐Ethylhexyl Phthalate (MEHP) Accumulation in Whole Blood and Red Cell Concentrates

Plasma DEHP concentrations were measured weekly in whole blood and red cell concentrates (RCC) during 21 days of storage in standard CPD within PL-130 blood bags. In addition, DEHP and MEHP accumulation patterns were investigated in blood stored for 42 days in modified CPD with adenine within PL-146 and BB-69 storage containers. Total per-unit plasma DEHP of RCC units was 49 to 71 per cent of the total in plasma of whole blood units (PL-130). From 28 to 42 days, mean DEHP levels were 12 to 19 per cent higher in whole blood stored in PL-146 than in BB-69. Although MEHP was not found in any blood bag plastic, MEHP accumulated in plasma during whole blood storage. MEHP concentrations were 2.8 to 3.8 times higher in plasma stored in BB-69 than in PL-146. It is postulated that MEHP arises from hydrolysis of DEHP by plasma lipase, even in frozen plasma sample, and that the rate of this reaction is influenced by blood bag plastic surface characteristics.

Toxicology of di-2-ethylhexyl phthalate and other phthalic acid ester plasticizers.

The first poly(vinyl chloride) blood bag containing di-2-ethylhexyl phthalate (DEHP) as a plasticizer was introduced in medicine in 1950. Since then, millions of liters of blood collected in plastic have been transfused. Aside from the obvious advantages of plastic over glass containers for the collection, storage and transfusion of blood, plastic containers have made blood component therapy possible; at least six different blood fractions can now be separated aseptically from whole blood and administered individually to the patient as needed. Poly(vinyl chloride) plastics containing DEHP also have been employed in a variety of other biomedical devices, including transfusion and infusion assemblies, administration sets, artificial kidney connecting tubing, bubble-type oxygenators, catheters, enema and urinary drainage bags, etc. Plasticized poly(vinyl chloride) plastics were selected for these medical applications principally because of their unique physical properties, ease of fabrication, low cost, and apparent safety. To provide the necessary flexibility, relatively high levels of plasticizer (up to 40%) must be blended into the plastic formulation. Recent reports have identified milligram-% quantities of DEHP in blood or plasma