Risk assessment of endocrine disrupting phthalates and hormonal alterations in children and adolescents.

Risk assessment and hormone evaluation were carried out for di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), endocrine disrupting chemicals (EDCs), in 302 Korean children (n = 223) and adolescents (n = 79) (< age 19). Urinary and serum concentrations of DEHP, MEHP (mono(2-ethylhexyl) phthalate), DBP, MBP (monobutyl phthalate), and PA (phthalic acid, a common final metabolite of phthalates) were detected in children and adolescents. Daily exposure levels were estimated to be 16.45 ± 36.50 µg/kg b.w./day for DEHP, which is one-third of the tolerable daily intake (TDI) value (50 µg/kg b.w./day), but 14 out of 302 participants had a hazard index (HI = intake/TDI) value >1. The mean daily exposure level of DBP was 1.23 ± 1.45 µg/kg b.w./day, which is one-eighth of the TDI value (10 µg/kg b.w./day), but 1 out of 302 participants had a HI value > 1. Positive correlations were observed between serum DBP or MEHP, and serum estradiol (E2) and/or luteinizing hormone (LH) in prepubescent children. In addition, serum MBP levels were found to be negatively correlated with serum triiodothyronine (T3) or thyroxine (T4) in male participants, and serum DEHP levels with serum thyroid stimulating hormone (TSH) in female adolescents. Low-density lipoprotein (LDL) levels were positively correlated with serum PA levels in children and adolescents. DEHP, DBP or its metabolites may be associated with altered hormone levels in children and adolescents. Data suggest that exposure levels of DEHP and DBP in Korean children need to be reduced to levels below TDI to protect them from EDC-mediated toxicities. Abbreviations: DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; E2: estradiol; EDC: endocrine disrupting chemical; EFSA: European Food Safety Authority; FSH: follicle stimulating hormone; HDL: high density lipoprotein; HI: hazard index; LDL: low density lipoprotein; LH: luteinizing hormone; MEHP: mono(2-ethylhexyl) phthalate; MBP: monobutyl phthalate; PA: phthalic acid; PPAR: peroxisome proliferator-activated receptor gamma; PVC: polyvinyl chloride; T3: triiodothyronine; T4: thyroxine; TDI: tolerable daily intake; TG: triglyceride; TSH: thyroid stimulating hormone; UPLC/MS/MS: Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry; WWF: World Wildlife Fund.

Comparison of embryotoxicity of ESBO and phthalate esters using an in vitro battery system.

Epoxidized soy bean oil (ESBO) and phthalate esters have been used as a plasticizer in polyvinyl chloride products. In this study, the embryotoxicity of ESBO and phthalate esters, namely, diethyl hexyl phthalate (DEHP), butylbenzyl phthalate (BBP) and dibutyl phthalate (DBP) was evaluated using short-term in vitro battery system, such as the whole embryo, midbrain and limb bud culture systems. Whole embryos at gestation day 9.5 were cultured for 48 h and the morphological scoring was measured. The cytotoxic effect and differentiation for mid-brain (MB) and limb bud (LB) cell were assessed by 50% inhibition concentration (IC(50)) with neutral red uptake and hematoxylin-stained foci (MB) or Alcian Blue staining (LB), respectively. In the whole embryo culture assay, ESBO (83, 250 and 750 microg/ml) exerted no toxic effect on growth and development of the embryo, whereas phthalate esters (1, 10, 100 microg/ml for DEHP, 10, 100, 1,000 microg/ml for BBP and DBP) inhibited growth and development dose dependently. In mid-brain and limb bud culture, the IC(50) of differentiation and cytotoxicity in BBP was 412.24 and 231. 76 microg/ml for mid-brain, and 40.13 and 182.38 microg/ml for limb bud, respectively. The IC(50) of differentiation and cytotoxicity in DBP was 27.47 and 44.53 microg/ml for mid-brain, and 21.21 and 25.54 microg/ml for limb bud cells, respectively. The lower IC(50) in both cells was obtained from DBP when compared to BBP. From these results, limb bud cells responded more sensitively to BBP and DBP than mid-brain cells. The IC(50) of limb bud cell differentiation and cytotoxicity in DBP is 1.9 and 7.1 less than that of BBP. However, any alteration in cytotoxicity and differentiation was observed with ESBO treatment. These studies suggested that ESBO is not embryotoxic; however, DEHP, BBP and DBP exhibit embryotoxic potential at high concentration.

Induction of apoptosis and CYP4A1 expression in Sprague-Dawley rats exposed to low doses of perfluorooctane sulfonate.

In previous studies, perfluorooctane sulfonate (PFOS), an environmental organic compound, was reported to cause hepatotoxicity and hypolipidemia in rodents. However, the low dose toxicity of PFOS and the toxic mechanisms involved remain to be determined. To clarify the low dose toxicity and action mechanism in the target organ toxicity, Sprague-Dawley (SD) rats were orally administered with PFOS at the doses of 0, 1.25, 5, 10 mg/kg/day for 28 days. As a result, no death or abnormal symptoms were observed in all groups. The significant loss of mean body weight was observed in female rats treated with 10 mg/kg PFOS and the relative liver weight of 10 mg/kg PFOS-treated group was significantly greater compared to control. Histopathological examination revealed that fatty change was evident in the liver of male rats treated with PFOS (5 and 10 mg/kg) and hypertrophy and cellular swellings in females at the dose of 10 mg/kg, which showed different pattern of pathological lesions. In addition, we demonstrated the expression induction of hepatic caspase-3 and cytochrome P450 4A1 (CYP4A1) related with apoptosis and lipid metabolism, respectively. This study suggested that no-observed-adverse-effect level (NOAEL) of PFOS was 1.25 mg/kg in 28-day repeated toxicity study and, however, the toxic response showed gender differences. The possible toxic mechanism of PFOS was the induction of apoptosis and altering lipid metabolism which resulted in hepatotoxicity.