Abstract  Phthalates are commonly used as plasticizers in the manufacturing of flexible polyvinyl chloride products. Large production volumes of phthalates and their widespread use in common consumer, medical, building, and personal care products lead to ubiquitous human exposure via oral ingestion, inhalation, and dermal contact. Recently, several phthalates have been classified as reproductive toxicants and endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormone signaling. Therefore, exposure to phthalates represents a public health concern. Currently, the effects of phthalates on male reproduction are better understood than the effects on female reproduction. This is of concern because women are often exposed to higher levels of phthalates than men through their extensive use of personal care and cosmetic products. In the female, a primary regulator of reproductive and endocrine function is the ovary. Specifically, the ovary is responsible for folliculogenesis, the proper maturation of gametes for fertilization, and steroidogenesis, and the synthesis of necessary sex steroid hormones. Any defect in the regulation of these processes can cause complications for reproductive and non-reproductive health. For instance, phthalate-induced defects in folliculogenesis and steroidogenesis can cause infertility, premature ovarian failure, and non-reproductive disorders. Presently, there is a paucity of knowledge on the effects of phthalates on normal ovarian function; however, recent work has established the ovary as a target of phthalate toxicity. This review summarizes what is currently known about the effects of phthalates on the ovary and the mechanisms by which phthalates exert ovarian toxicity, with a particular focus on the effects on folliculogenesis and steroidogenesis. Further, this review outlines future directions, including the necessity of examining the effects of phthalates at doses that mimic human exposure.

Abstract  Human exposure to chemicals commonly encountered in our environment, like phthalates, is routinely assessed through urinary measurement of their metabolites. A particular attention is given to the specific population groups, such as obese, for which the dietary intake of environmental chemicals is higher. To evaluate the exposure to phthalates, nine phthalate metabolites (PMs) were analyzed in urine collected from obese individuals and a control population. Obese individuals lost weight through either bariatric surgery or a conservative weight loss program with dietary and lifestyle counseling. Urine samples were also collected from the obese individuals after 3, 6 and 12months of weight loss. Individual daily intakes of the corresponding phthalate diesters were estimated based on the urinary PM concentrations. A high variability was recorded for the levels of each PM in both obese and control urine samples showing the exposure to high levels of PMs in specific subgroups. The most important PM metabolite as percentage contribution to the total PM levels was mono-ethyl phthalate followed by the metabolites of di-butyl phthalate and di 2-ethyl-hexyl phthalate (DEHP). No differences in the PM levels and profiles between obese entering the program and controls were observed. Although paralleled by a significant decrease of their weight, an increase in the urinary PM levels after 3 to 6months loss was seen. Constant figures for the estimated phthalates daily intake were observed over the studied period, suggesting that besides food consumption, other human exposure sources to phthalates (e.g. air, dust) might be also important. The weight loss treatment method followed by obese individuals influenced the correlations between PM levels, suggesting a change of the intake sources with time. Except for few gender differences recorded between the urinary DEHP metabolites correlations, no other differences were observed for the urinary PM levels as a function of age, body mass index or waist circumference. Linear regression analysis showed almost no significance of the relationship between measured urinary PMs and serum free thyroxine, thyroid-stimulating hormone (TSH) for all obese individuals participating to the study, while for the control samples, several PMs were significantly associated with the serum TSH levels.

Abstract  Diundecyl phthalate (DUP) is a high production volume chemical used as a plasticizer in polyvinyl chloride and other plastics. Specific biomarkers of DUP would be useful for human exposure assessment. To identify such biomarkers, we investigated the in vitro metabolism of DUP with human liver microsomes using online solid phase extraction coupled to HPLC-mass spectrometry. Using high resolution mass spectrometry, we conclusively confirmed the structures of four DUP specific metabolites: monoundecyl phthalate (MUP), mono-hydroxyundecyl phthalate (MHUP), mono-oxoundecyl phthalate (MOUP), and mono-carboxydecyl phthalate (MCDP). We also used high resolution mass spectrometry to isolate MCDP and MHUP from co-eluting isobaric metabolites of diisononyl phthalate (i.e., monocarboxyisononyl phthalate) and diisododecyl phthalate (i.e., monohydroxyisododecyl phthalate), respectively, that could not be separated with low resolution tandem mass spectrometry. To evaluate the potential usefulness of the newly identified DUP metabolites as exposure biomarkers, we analyzed 36 human urine samples by high resolution mass spectrometry. We detected MHUP and MCDP in >83% of the samples; median concentrations were 0.21ng/mL and 0.36ng/mL, respectively. MOUP was detected only in 14% of the samples analyzed, and MUP was not detected. All three metabolites eluted as peak clusters likely because of the presence of multiple oxidation sites and multiple isomers in DUP technical mixtures. Taken together, these findings suggest that with the appropriate mass spectrometry quantification techniques, MHUP and MCDP may serve as suitable biomarkers for assessing background exposure to DUP.

Abstract  Phthalates are used in building materials, medical devices, and personal care products. Most studies on phthalates have focused on single phthalates, but it is important to study mixtures of phthalates because humans are exposed to such mixtures daily. We tested the hypothesis that phthalate mixture exposure decreases antral follicle growth, compromises steroidogenic capacity, and induces atresia. Antral follicles from adult CD-1 mice were cultured with vehicle control or phthalate mixture (1–500 µg/ml) for 96 h. The mixture was made of 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. During culture, antral follicle diameters were measured every 24 h to monitor growth. After culture, media were subjected to measurements of sex steroid hormones and follicles were subjected to evaluation of gene expression and atresia. The phthalate mixture (100 and 500 µg/ml) decreased antral follicle growth starting at 24 h compared to controls. The mixture at 10, 100, and 500 µg/ml also decreased androstenedione, testosterone, estrone, and estradiol levels compared to control. The mixture (10, 100, and 500 µg/ml) reduced atresia rating, but it induced more oocyte fragmentation compared to control. The phthalate mixture at different doses adversely affected cell cycle regulators, antioxidant enzymes, apoptotic factors, steroidogenic enzymes, and receptors. Collectively, these data indicate that exposure to an environmentally relevant phthalate mixture reduces antral follicle growth, induces oocyte fragmentation, and decreases hormone production by adversely affecting the expression of cell cycle regulators, apoptotic factors, steroidogenic enzymes, and receptors.

Abstract  Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian brain important for behavioural consequences of stress and energy metabolism. We have addressed possible effects of the phthalate DiNP on NPY expression in human SH-SY5Y cells, a neuronal in vitro differentiation model. Pico- to nanomolar doses of DiNP and its metabolite MiNP resulted in decreased NPY mRNA and peptide expression in retinoid-differentiated cells. Thus, dys-regulated NPY may be an adverse outcome for exposure to low doses of DiNP in human beings. This article is protected by copyright.

Abstract  Determining plasticizers and other additives migrated from plastic materials becomes a hard task when these substances are already present in the laboratory environment. This work dealt with this drawback in the multiresidue determination of four plasticizers (2,6-di-tert-butyl-4-methyl-phenol (BHT), diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) and a UV stabilizer (benzophenone (BP)) by gas chromatography/mass spectrometry (GC/MS) using DiBP-d4 as internal standard. The ubiquity of DiBP by a non-constant leaching process in the laboratory was detected, which could not guarantee the achievement of a trustworthy quantification. To handle this, the assessment of the level of DiBP in solvent blanks having fixed the probabilities of false non-compliance (α) and false compliance (β) at 0.01 was performed. On the other hand, another special case was that of DiNP, in whose chromatogram finger peaks appear because of an array of possible C9 isomers. PARAFAC, used for the identification and quantification of all the substances, is a useful chemometric tool that enabled a more reliable determination of this analyte since no peak areas were considered but chromatographic and spectral loadings. Since phthalates may migrate from rubber latex items, an evaluation of the existence of matrix effects on the determination of the five analytes was conducted prior to an extraction with hexane from a dummy for infants. As matrix effects were present, the quantification of the compounds under study was performed following the standard addition method using PARAFAC sample loadings as response variable. As a result, the presence of BHT was confirmed, being its concentration equal to 37.87μgL(-1). Calibrations based on PARAFAC yielded the following values for the decision limit (CCα): 1.16μgL(-1) for BHT, 1.34μgL(-1) for BP, 1.84μgL(-1) for DEHA and 51.42μgL(-1) for DiNP(for α=0.05 and two replicates).

Abstract  This chapter describes phthalates (phthalic acid testers), which are used as plasticizers that impart flexibility and durability to polyvinylchloride (PVC) products. They are also used in solvents, lubricating oils, fixatives and as detergents in personal care products. Advances in materials sciences and engineering during the last decades have led to a widespread use of phthalates in a wide range of industrial products. When incorporated into PVC, phthalates are not covalently bound and are therefore easily released to the surroundings, leading to contamination of the external environment. Phthalates are detected in several media including food, water, house dust and air. Phthalate esters are suggested to have endocrine-disrupting properties and exposures to high concentrations were shown to induce fetal death, cancer, malformations, liver and kidney injury and reproductive toxicity in animals. Reduced testosterone and adverse male reproductive system development are extensively documented in rodents and the adverse effects observed in animals raise concerns as to whether phthalates represent a potential health risk to humans Therefore, the use of the phthalates DEHP, DBP and BBP is forbidden in toys, cosmetics and food contact materials. Reports have been published which also associate exposure to phthalates with increasing incidence of other human diseases such as obesity, insulin resistance and type 2 diabetes, asthma and allergies and neurological disorders such as ADHD and autism. Due to the fact that there are substantial gaps in knowledge in both phthalate levels of exposure and consequent health effects in humans, additional research is warranted.

Abstract  Phthalates adversely affect the male reproductive system in animals, inducing hypospadias, cryptorchidism, reduced testosterone production and decreased sperm counts. Phthalate effects are much more severe after in utero than adult exposure. Little is known about human health effects. This study discusses two recent studies on perinatal phthalate exposure, which indicated that human testicular development might be susceptible to phthalates. One study analysed phthalate monoesters in breast milk and reproductive hormone levels in infants. Five of six phthalates [monoethyl-(MEP), monobutyl- (MBP), monomethyl- (MMP), mono-2-ethylhexyl- (MEHP) and mono-isononyl phthalate (MiNP)] showed correlation with hormone levels in healthy boys, which were indicative of lower androgen activity and reduced Leydig cell function. MEP and MBP were positively correlated with serum sex hormone-binding globulin (SHBG) levels. MMP, MEP, MBP, MEHP and MiNP were positively correlated with the LH/testosterone ratio. Another study found a reduction of the anogenital index (AGI) in infant boys with increasing levels of MBP, MEP, monobenzyl- and mono-isobutyl phthalate in maternal urine samples during late-pregnancy. Boys with small AGI showed a high prevalence of cryptorchidism and small genital size. Taken together these studies suggest an antivirilizing effect of phthalates in infants. Most of these findings are in line with animal observations. However, the possible effects of MEP appear to be limited to humans. This may be due to differences in exposure routes (inhalation and dermal absorption which circumvents liver detoxification in addition to oral) and metabolism, or this association could be spurious. As phthalates are produced as bulk chemicals worldwide, these new findings raise concern about the safety of phthalate exposure for pregnant women and infants.

Abstract  Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in consumer and medical products that can cross the placenta, disrupt steroid hormone synthesis, and activate peroxisome proliferator-activated receptor gamma. The authors examined DEHP exposure in relation to the timing of labor in a pregnancy cohort study of 283 women recruited in 4 US states (California, Iowa, Minnesota, and Missouri) between 2000 and 2004. The authors estimated associations between concentrations of DEHP metabolites and gestational age at delivery using linear regression models and associations between DEHP metabolites and clinical outcomes using logistic regression models. After covariate adjustment, women at the 75th percentile of DEHP metabolite concentrations had a 2-day-longer mean length of gestation than women at the 25th percentile (95% confidence interval: 1.4, 3.3). Log-unit increases in mono-2-ethylhexyl phthalate and mono-2-ethyl-5-oxohexyl phthalate concentrations were associated with increased odds of cesarean section delivery (30% and 50% increased odds, respectively), increased odds of delivering at 41 weeks or later (100% and 120% increased odds), and reduced odds of preterm delivery (50% and 60% decreased odds). These data suggest that DEHP may interfere with signaling related to the timing of parturition.

Abstract  BACKGROUND: Concern over phthalates has emerged because of their potential toxicity to humans. OBJECTIVE: We investigated the relationship between the urinary concentrations of phthalate metabolites and children's intellectual functioning. METHODS: This study enrolled 667 children at nine elementary schools in five South Korean cities. A cross-sectional examination of urine phthalate concentrations was performed, and scores on neuropsychological tests were obtained from both the children and their mothers. RESULTS: We measured mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), both metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-n-butyl phthalate (MBP), a metabolite of dibutyl phthalate (DBP), in urine samples. The geometric mean (ln) concentrations of MEHP, MEOHP, and MBP were 21.3 microg/L [geometric SD (GSD) = 2.2 microg/L; range, 0.5-445.4], 18.0 microg/L (GSD = 2.4; range, 0.07-291.1), and 48.9 microg/L (GSD = 2.2; range, 2.1-1645.5), respectively. After adjusting for demographic and developmental covariates, the Full Scale IQ and Verbal IQ scores were negatively associated with DEHP metabolites but not with DBP metabolites. We also found a significant negative relationship between the urine concentrations of the metabolites of DEHP and DBP and children's vocabulary subscores. After controlling for maternal IQ, a significant inverse relationship between DEHP metabolites and vocabulary subscale score remained. Among boys, we found a negative association between increasing MEHP phthalate concentrations and the sum of DEHP metabolite concentrations and Wechsler Intelligence Scale for Children vocabulary score; however, among girls, we found no significant association between these variables. CONCLUSION: Controlling for maternal IQ and other covariates, the results show an inverse relationship between phthalate metabolites and IQ scores; however, given the limitations in cross-sectional epidemiology, prospective studies are needed to fully explore these associations.

Abstract  BACKGROUND: Although diet and activity are key factors in the obesity epidemic, laboratory studies suggest that endocrine disrupting chemicals may also affect obesity. METHODS: We analyzed associations between six phthalate metabolites measured in urine and body mass index (BMI) and waist circumference (WC) in National Health and Nutrition Examination Survey (NHANES) participants aged 6-80. We included 4369 participants from NHANES 1999-2002, with data on mono-ethyl (MEP), mono-2-ethylhexyl (MEHP), mono-n-butyl (MBP), and mono-benzyl (MBzP) phthalate; 2286 also had data on mono-2-ethyl-5-hydroxyhexyl (MEHHP) and mono-2-ethyl-5-oxohexyl (MEOHP) phthalate (2001-2002). Using multiple regression, we computed mean BMI and WC within phthalate quartiles in eight age/gender specific models. RESULTS: The most consistent associations were in males aged 20-59; BMI and WC increased across quartiles of MBzP (adjusted mean BMI = 26.7, 27.2, 28.4, 29.0, p-trend = 0.0002), and positive associations were also found for MEOHP, MEHHP, MEP, and MBP. In females, BMI and WC increased with MEP quartile in adolescent girls (adjusted mean BMI = 22.9, 23.8, 24.1, 24.7, p-trend = 0.03), and a similar but less strong pattern was seen in 20-59 year olds. In contrast, MEHP was inversely related to BMI in adolescent girls (adjusted mean BMI = 25.4, 23.8, 23.4, 22.9, p-trend = 0.02) and females aged 20-59 (adjusted mean BMI = 29.9, 29.9, 27.9, 27.6, p-trend = 0.02). There were no important associations among children, but several inverse associations among 60-80 year olds. CONCLUSION: This exploratory, cross-sectional analysis revealed a number of interesting associations with different phthalate metabolites and obesity outcomes, including notable differences by gender and age subgroups. Effects of endocrine disruptors, such as phthalates, may depend upon endogenous hormone levels, which vary dramatically by age and gender. Individual phthalates also have different biologic and hormonal effects. Although our study has limitations, both of these factors could explain some of the variation in the observed associations. These preliminary data support the need for prospective studies in populations at risk for obesity.

Abstract  Exposure to phthalates is widespread because of their use in plastics, cosmetics, and other consumer products. Phthalate exposure has been associated with adverse respiratory outcomes in children. With urinary phthalate measures, we assessed the association between phthalate exposure and four pulmonary function parameters [forced vital capacity (FVC), forced expiratory volume at 1 sec (FEV1), peak expiratory flow (PEF), and maximum mid-expiratory flow] among the 240 adult Third National Health and Nutrition Examination Survey (NHANES III) participants with urinary phthalate data. Linear regression models controlled for race, age, age squared, standing height, body mass index, cumulative smoking, and current smoking. Monobutyl phthalate (MBP) was significantly associated with decrements in three measures of pulmonary function (FVC, FEV1, PEF) in males but not in females. For a change from the 25th to the 75th percentile in MBP level among men, FEV1 decreased 112 mL (SE = 51, p = 0.03). Monoethyl phthalate (MEP) was associated with lower FVC and FEV1 values in men. Monoethylhexyl phthalate (MEHP), the metabolite of the plasticizer commonly used in medical tubing, was not adversely associated with any of the pulmonary function parameters evaluated. Our results suggest that MBP and MEP, but not MEHP, may influence pulmonary function among adult males.

Abstract  BACKGROUND: Hormonally active environmental agents may alter the course of pubertal development in girls, which is controlled by steroids and gonadotropins. OBJECTIVES: We investigated associations of concurrent exposures from three chemical classes (phenols, phthalates, and phytoestrogens) with pubertal stages in a multiethnic longitudinal study of 1,151 girls from New York City, New York, greater Cincinnati, Ohio, and northern California who were 6-8 years of age at enrollment (2004-2007). METHODS: We measured urinary exposure biomarkers at visit 1 and examined associations with breast and pubic hair development (present or absent, assessed 1 year later) using multivariate adjusted prevalence ratios (PR) and 95% confidence intervals (CIs). Modification of biomarker associations by age-specific body mass index percentile (BMI%) was investigated, because adipose tissue is a source of peripubertal hormones. RESULTS: Breast development was present in 30% of girls, and 22% had pubic hair. High-molecular-weight phthalate (high MWP) metabolites were weakly associated with pubic hair development [adjusted PR, 0.94 (95% CI, 0.88-1.00), fifth vs. first quintile]. Small inverse associations were seen for daidzein with breast stage and for triclosan and high MWP with pubic hair stage; a positive trend was observed for low-molecular-weight phthalate biomarkers with breast and pubic hair development. Enterolactone attenuated BMI associations with breast development. In the first enterolactone quintile, for the association of high BMI with any development, the PR was 1.34 (95% CI, 1.23-1.45 vs. low BMI). There was no BMI association in the fifth, highest quintile of enterolactone. CONCLUSIONS: Weak hormonally active xenobiotic agents investigated in this study had small associations with pubertal development, mainly among those agents detected at highest concentrations.

Abstract  Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (PPARs), and the monoesters appear to be the active metabolites that function as ligands of PPARs. There is evidence that PPARs exhibit significant species differences in response to ligand activation. In this study, the activation of mouse and human PPARalpha, PPARbeta, and PPARgamma by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARalpha target gene expression, and a PPARgamma-mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARalpha, with the mouse PPARalpha generally being activated at lower concentrations and exhibiting a greater response than human PPARalpha. Similarly, a range in the trans-activation of mouse PPARbeta by phthalate monoesters was also observed, but this effect was not found with human PPARbeta. A number of phthalate monoesters activated both mouse and human PPARgamma, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARalpha and PPARgamma increase with increasing side-chain length. These studies also show that mouse PPARalpha and PPARbeta are generally activated at lower concentrations of phthalate monoesters than human PPARalpha and PPARbeta, and that both mouse and human PPARgamma exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARalpha and PPARgamma, and the relative induction of PPARalpha target gene mRNA and PPARgamma-mediated adipocyte differentiation, respectively.

Abstract  The plasticizer di(2-ethylhexyl)phthalate (DEHP) exhibits antiandrogenic effects in perinatally exposed male rats. Di(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DINP) are currently being evaluated as potential substitutes for DEHP, but similarities in structure and metabolism of DEHP with DEHA and DINP have led to the hypothesis that similarities in action may also exist. Pregnant Wistar rats were gavaged during gestation and lactation with vehicle, DEHP (300 or 750 mg/kg bodyweight per day), DINP (750 mg/kg bodyweight per day), DEHP (750 mg/kg bodyweight per day) in combination with DEHA (400 mg/kg bodyweight per day), or DEHP (300 mg/kg bodyweight per day) in combination with DINP (750 mg/kg bodyweight per day). DINP and DEHP were both shown to reduce testicular testosterone production ex vivo and testosterone levels in testes and plasma of male fetuses at gestation day 21, indicating a similar mechanism of action for DINP and DEHP. Additionally, plasma LH levels in male fetuses were elevated. Neonatal anogenital distance was reduced and the number of nipples at postnatal day 13 increased in DEHP-exposed male offspring. Serum inhibin B levels were significantly reduced in DEHP-exposed prepubertal male offspring, and in a few adult males. No modulating effects of DEHA on the endocrine effects of DEHP were detected, but a tendency towards an accumulating effect of DEHP and DINP in combination on suppression of testosterone synthesis was seen.

Abstract  Diesters of 1,2-benzenedicarboxylic acid are a family of industrial compounds called "phthalates." The physical and chemical properties of these diesters, and therefore their potential uses, depend on the structure of the dialkyl or alkyl/aryl side chain. The urinary concentrations of phthalate monoesters, which are metabolites, have been used as biomarkers of human exposure to specific phthalates. However, several phthalates, particularly those with side chains of eight or more carbon atoms, are complex mixtures of isomers. For these, the phthalate metabolites to be used as biomarkers of exposure have not been unequivocally identified. We developed a method for assessing total exposure to phthalates, including the isomeric mixtures of high molecular weight phthalates, by measuring the concentration of phthalic acid (PA) in human urine after acid hydrolysis of the phthalate metabolites to PA. The present method accurately assesses total exposure to phthalates without noticeable contamination from the ubiquitous phthalates in the environment, but it gives no information about the parent phthalate.

Abstract  Di-isodecyl phthalate (DiDP), primarily used as a plasticiser, is a mixture of isomers with predominantly ten-carbon branched side chains. Assessment of DiDP exposure has not been conducted before because adequate biomarkers were lacking. In 129 adult volunteers with no known exposure to DiDP, the urinary concentrations of three oxidative metabolites of DiDP: monocarboxyisononyl phthalate (MCiNP), monooxoisodecyl phthalate (MOiDP) and monohydroxyisodecyl phthalate (MHiDP), previously identified in DiDP-dosed rats, were estimated by solid-phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) using the respective oxidative metabolites of di(2-ethylhexyl)phthalate since authentic standards of the DiDP oxidative metabolites were unavailable. Interestingly, the hydrolytic monoester of DiDP, monoisodecyl phthalate (MiDP), was not detected in any of the samples, while MCiNP, MHiDP and MOiDP were detected in 98%, 96% and 85%, respectively, of the samples tested. MCiNP was excreted predominantly in its free form, whereas MOiDP was excreted as its glucuronide. MCiNP, MHiDP and MOiDP eluted as clusters of multiple peaks from the HPLC column probably due to the presence of numerous structurally similar isomers present in commercial DiDP formulations. The urinary concentrations of these oxidative metabolites correlated significantly (p < 0.0001) with each other, thus confirming a common precursor. The urinary concentrations of these DiDP oxidative metabolites also correlated significantly (p < 0.0001) with oxidative metabolites of di-isononyl phthalate (DiNP) suggesting the potential presence of DiNP isomers in commercial DiDP or simultaneous use of DiDP and DiNP in consumer products. The concentrations presented are semiquantitative estimates and should be interpreted cautiously. Nevertheless, the higher frequency of detection and higher urinary concentrations of MCiNP, MHiDP and MOiDP than of MiDP suggest that these oxidative metabolites are better biomarkers for DiDP exposure assessment than MiDP. These data also suggest that unless oxidative metabolites are measured, the prevalence of exposure to DiDP will probably be underestimated.

Abstract  Dibutyl-, di(2-ethylhexyl)-, di(3, 3, 5-trimethylhexyl)- and didecylphthalate (DBP, DEHP, TMHP, DDP) all caused an increase in the amount of hepatic cytochrome P=450, when administered intragastrically to rats. No statistically significant increase could be detected in the catalytic activities dependent on cytochrome P-450 (Benzo(a)pyrene hydroxylation, ethoxycoumarin deethylation). Dibutylphthalate inhibited these reactions, when added to the incubation in vitro. Phthalates caused an increase in the activities of epoxide hydratase, and glutathione-S-transferase. Conjugation of 0-aminophenol and 4-methylumbelliferone with glucuronic acid was increased after phthalate administration.

Abstract  The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June, 1998. The purpose of the Center is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction, including development, caused by agents to which humans may be exposed. The following seven phthalate esters were selected for the initial evaluation by the Center: butyl benzyl phthalate, di(2-ethylhexyl) phthalate, di-isodecyl phthalate, di-isononyl phthalate, di-n-butyl phthalate, di-n- hexyl phthalate, and di-n-octyl phthalate. Phthalate esters are used as plasticizers in a wide range of polyvinyl chloride-based consumer products. These chemicals were selected for the initial evaluation by the CERHR based on their high production volume, extent of human exposures, use in children's products, published evidence of reproductive or developmental toxicity, and public concern.

Abstract  Prepared in cooperation with American Petroleum Inst., Washington, DC.. This document presents a list of ongoing studies being conducted for Exxon Chemical Americas: (1) Diisononyl phthalate (CASRN 68515-48-0)-Pharmacokenetics study-expected completion year-end 1982; (2) Diisononyl phthalate (CASRN 68515-48-0)-Subacute (1 week) oral toxicity-expected completion year-end 1982; and (3) Diisononyl phthalate (CASRN 68515-48-0)-Sub-acute (90 day) oral toxicity-expected completion end 1Q83.

Abstract  Exposure to antiandrogens during the critical developmental window (i.e. sexual differentiation) can permanently demasculinize the male phenotype. Here we have investigated the effects of developmental exposure to di-isononylphthalate (DINP) (250 and 750 mg/kg) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) (50 and 100mg/kg) on 19.5-day-old fetal Sprague-Dawley rat testicular and adrenal steroidogenesis. Maternal exposure to DINP or p,p'-DDE on embryonic days (EDs) 13.5-17.5 did not down-regulate the activity of steroidogenesis in ED 19.5 male rat fetus. Protein expression levels of testicular and adrenal StAR, P450scc, 3beta-HSD and androgen receptor (AR) did not show any changes. However, p,p'-DDE caused clear abnormalities in the ultrastructure of steroidogenic cells in ED 19.5 rat testis and adrenal. These structural alterations can disturb the development and function of fetal testis and adrenal that may become evident later in life.