Despite their lipophilic nature, phthalates are metabolized and excreted in feces and urine within 3 d; consequently, bio-accumulation is not believed to be a problem. Studies measuring urinary monoester metabolite concentrations have revealed higher and more widespread phthalate exposure than had previously been suspected . Notably, several studies have indicated that concentrations of most urinary phthalate metabolites are significantly higher in children than in adults . There is growing evidence that some secondary oxidative metabolites of DEHP, such as mono- phthalate and mono- phthalate , are present in urine in considerably higher concentrations than mono- phthalate . They and other recently identified metabolites may constitute more sensitive biomarkers of exposure to DEHP . Extrapolation of daily phthalate intake from urinary excretion of their metabolites is hampered by several factors. Urinary phthalate metabolite levels have been found to vary with the time of sample collection . Furthermore, substantial within-subject variability has been observed, and researchers have calculated that up to four samples obtained 1 to 3 mo apart may be necessary to classify exposure with a reliability of 80% . Another difficulty in estimating daily phthalate intakes from urinary excretion of their metabolites is the limited availability of fractional excretion data. This is illustrated by the vast differences in the estimates of median daily DEHP intake obtained using the same data but different assumptions of the fractional excretion of MEHP . Note that if the higher estimate were correct, up to 31% of the metabolite values would yield intake estimates exceeding the reference dose of 20 µg/ kg of body weight/d set by the US EPA,cannabis cultivation technology and 12% of intake estimates would exceed the tolerable daily intake value of 37 µg/kg/d set by the corresponding European Union agency.
Table 7 summarizes daily intake estimates for DEHP and other common phthalates. Considerable amounts of phthalates can leach from the bags and tubing used for various medical procedures, such as hemodialysis, and parenteral nutrition . The resulting high levels of exposure experienced by neonates in intensive care have long been of particular concern because the rapid growth and development of neonates, combined with the immaturity of their detoxification enzyme systems, makes them particularly vulnerable. A recent small study of six premature neonates in intensive care units found 22-fold higher mean urinary MEHP concentrations compared to California toddlers and 26-fold higher median MEHP concentrations than were reported for 6- to 11-yr-old children in NHANES III . Daily intake may exceed 4 mg/kg/d in infants receiving exchange transfusions, whereas patients with adult hemodialysis may be exposed to up to 3 mg/kg/d . It was also feared that mouthing of plastic toys would result in significant phthalate exposure in small children, and many American manufacturers voluntarily discontinued the use of DEHP in plastic toys for small children. However, a recent risk assessment, estimated that exposure of children age 12 to 23 mo by this route was an average of 0.08 µg/kg/d and concluded that chewing soft plastic toys was not likely to present a health hazard . Although urinary excretion of phthalate metabolites constitutes a noninvasive method for assessing exposure, the need to correct for dilution and the uncertainty of available fractional excretion data represent serious drawbacks.In serum and breast milk, however, even the measurement of monoester metabolites can yield artificially elevated results because of the presence of lipases capable of mediating the conversion of the parent phthalates into their respective monoesters . This problem may be circumvented by the use of secondary metabolites arising from the oxidative metabolism of the monoester, such as 5-OH-MEHP and 5-oxo-MEHP in the case of DEHP . Unfortunately, conversely to urine, these oxidative metabolites do not constitute the major metabolites in serum and are not as frequently detectable as MEHP .
Animal studies have shown that DEHP, MEHP, and DBP—but not BBzP—have adjuvant properties in terms of IgE and IgG1 production when injected subcutaneously together with OVA . Findings suggestive of enhanced sensitization have also been reported in humans, but the activity pattern of phthalates was quite distinct. Specifically, results from a Swedish case–control study indicated a significant association between physician diagnosed rhinitis or eczema and BBzP in dust from the child’s bedroom, whereas DEHP was associated with physician-diagnosed asthma, and DEP showed no association with either disease . The association of individual phthalates with different symptom outcomes may be a reflection of their different physical properties, including vapor pressures, polarities, and octanol/air partition coefficients. Notably, median concentration of DEHP and BBzP were significantly higher in bedrooms with PVC flooring, and a correlation between PVC flooring and case status was also observed in this study, although it was weaker than the associations observed with DEHP and BBzP. This confirms the results of an earlier case–control study that indicated an association of PVC flooring and other plasticizer-containing surfaces with bronchial obstruction in 2-yr-old children in Oslo . The association was found to be considerably stronger in children from homes with low air exchange rates compared with those with high air exchange rates, suggesting that chemical compounds in the vapor phase or adsorbed to suspended particles were involved in the observed associations. In a previous study by these investigators, DEHP and BBzP concentrations in sedimented dust and suspended PM were highly correlated . Dust has been shown to increase the DEHP emission rate from PVC floors and its deposition on internal surfaces . In addition to PVC floors, the amount of plastic wall materials was found to be associated with persistent wheezing, cough, and phlegm in a cross-sectional study of children age 1 to 7 yr .
An exploratory study examined associations between phthalate exposure as measured by urinary phthalate metabolites and pulmonary function parameters in a sub-sample of 240 adults who participated in NHANES III . There were significant negative associations between mono-n-butyl pthalate and forced vital capacity , forced expiratory volume after 1 s , and peak expiratory flow in males only. The effect on FVC was essentially confined to nonsmoking males. An association between monoethyl phthalate and lower FVC and FEV1 was also observed only in males. Conversely, in nonsmoking women, FEV1 and maximum midexpiratory flow correlated positively with MEHP concentrations. Under alkaline conditions, DEHP is degraded into MEHP and 2-ethyl-1-hexanol, and the latter is reportedly used in Sweden as an indicator of alkaline degradation of DEHP . A geometric mean 2-ethyl-1-hexanol concentration of 2.47 µg/m3 was reported in Finnish homes, and the geometric mean personal exposure was only slightly higher and similar to the geometric mean of 3.0 µg/m3 reported for a German population . Findings suggestive of an association between one or both of the DEHP breakdown products, MEHP and 2-ethyl-1-hexanol, with an increased prevalence of self-reported and objective ocular and nasal symptoms have been reported in workers at four Swedish hospitals . Together, these results suggest that phthalate exposure may play a role in SBS symptoms both directly and indirectly , both of which are associated with higher frequencies of SBS symptom reporting .Under the auspices of the NTP Center for the Evaluation of Risks to Human Reproduction, a panel of experts assembled comprehensive reviews of the literature published through 2000 concerning the reproductive toxicity of phthalates . Of this group of compounds, only gestational exposure to DEHP, BBzP, DBP, and, with far lesser potency, di-isononyl phthalate induced defects of the male reproductive organs in rats, mice, rabbits, and—to a far lesser degree—hamsters. The extent and severity of male reproductive toxicity depended greatly on the dose, timing,indoor grow cannabis and duration of exposure and the route and vehicle of administration. Effects on reproductive parameters have also been observed following administration during prepuberty, whereas adult exposure has resulted in adverse effects on the male reproductive system only at very high doses. Few effects of prenatal or prenatal plus lactational exposure to phthalate esters have been reported in female offspring, but several recent studies indicated that DBP induced isolated instances of reproductive tract malformations , significantly delayed vaginal opening and occurrence of first estrous , decreased pituitary weights, and increased the incidence of hypoplasia of the alveolar buds of the mammary glands . Nonetheless, the male reproductive organs appear to be markedly more sensitive to the effects of phthalates.
Since the aforementioned reviews, the male reproductive toxicity of DEHP, BBzP, and DBP has been confirmed and extended to the demonstration of significant effects, even with markedly lower doses or considerably shorter dosage regimens than had previously been used . Decreases in sperm count and motility and an increased incidence of morphologically abnormal sperm are among the most sensitive indicators of the male reproductive toxicity of phthalates . The defects observed in the male reproductive organs include hypospadias, cryptorchidism, testicular atrophy, underdeveloped or absent epididymis, irreversible degeneration and atrophy of seminiferous tubules, reduced anogenital distance, and retained nipples/areolae. In other words, they involve the testosteronedependent differentiation of the Wolffian ducts into epididymides, vasa deferentia, seminalvesicles, and normal development of fetal testes; acquisition of preputial separation and onset of spermatogenesis; and the dihydrotestosterone -dependent development of male external genitalia and the prostate, regression of nipples/areolae, and anogenital distance. Recent studies have indicated that in addition to testosterone- and DHT-dependent processes, insulin-like hormone 3 -dependent processes are also affected by exposure to phthalates that are toxic to the male reproductive organs. Insl3 is produced by Leydig cells and regulates the development of the gubernaculum, which in turn is critical for testicular descent first into the lower abdomen to the inguinal ring and later into the scrotal sacs. A pronounced reduction of Insl3 messenger RNA was observed in testes of male gestation day 18 fetuses from dams exposed to 1000 mg/kg of DEHP, DBP, or BBzP from GDs 14 to 18; DBP and BBzP were more effective than DEHP . Similarly, Insl3 mRNA levels and immunoreactive Insl3 in interstitial cells in testis collected on GD 19 were significantly reduced in fetuses whose dams were exposed to 500 mg/ kg/d of DBP, although not at lower doses from GD 12 through GD19 . The malformations in androgen-dependent tissues in male rat offspring of mothers treated with DBP or DEHP resemble those induced by well-known anti-androgens, such as vinclozolin or flutamide . However, they do not appear to be mediated by the androgen receptor . Rather, numerous studies have shown that gestational exposure to DEHP , DBP , and BBzP as well as their common metabolite MBP induces a marked decrease in testicular testosterone production and levels of serum testosterone concentrations. In a direct comparison, DBP and BBzP were more effective than DEHP . These decreases do not appear to be permanent when exposure is limited to the gestational period . Developmentally toxic phthalates not only affect Leydig cells but alter the structure and function of Sertoli cells, which have been proposed to be the actual primary target . Whereas some recent research have failed to find direct or indirect evidence of alterations in Sertoli structure and function , cell-specific immuno histochemistry has revealed that maturation of Sertoli cells was incomplete in male fetuses exposed to DBP starting at GD 13 . During fetal development, Sertoli cells secrete paracrine factors that are essential for the differentiation and testosterone production of Leydig cells. Therefore, the immaturity of Sertoli cells and resulting disturbances in Sertoli-Leydig cell signaling could explain the marked reduction in testosterone synthesis by fetal Leydig cells. Such decreased testosterone production is frequently seen in conjunction with Leydig cell hyperplasia . This has been suggested to constitute a compensatory mechanism to maintain testosterone output . Alternatively, the reduced testosterone and Insl3 production after gestational exposure to phthalates could delay Leydig cell maturation and differentiation, thereby prolonging their proliferation and resulting in hyperplasia . Several recent studies have used microarray and reverse transcriptase polymerase chain reaction to investigate changes in the gene expression profile in the testes following in utero exposure to phthalates. In some cases, this was accompanied by immunohistochemical analysis of changes in protein expression. Interestingly, the phthalates known to be reproductive toxicants all induced very similar alterations in gene expression, whereas no significant changes were observed after exposure to the nondevelopmentally toxic phthalates .