Aggregate exposure assessment using cosmetic co-use scenarios: II. Application and validation for phthalates.

Aggregate exposure assessments using co-use scenarios could provide more realistic estimations than single product exposure assessment. Co-use scenarios for cosmetic products were determined from a ranking of the frequency of occurrence of co-use patterns and the number of cosmetics used. We conducted aggregate exposure assessments using the co-use scenarios and validated the new methodology by comparing the results to those of a receptor-based aggregate exposure assessment. The aggregate exposures of di(2-ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DnBP) and diethyl phthalate (DEP) in cosmetics were estimated by co-use scenarios for cosmetics. The co-use scenario-based AED increased with the number of cosmetics in the co-use scenarios, and was higher in female and younger groups. The major contributors in females were facial cream for DEHP, nail polish for DnBP, and shower cologne or perfume for DEP. The major contributors in males were body lotion for DEHP, facial sunscreen for DnBP, and hair styling product for DEP. The distribution of the co-use scenario based AEDs displayed a similar trend to that of the receptor-based AEDs, with the 95th percentiles of the AED slightly underestimated in the co-use scenario. The applied methodology could provide reasonable aggregate exposures with relatively few resources required.

Risk assessment for humans using physiologically based pharmacokinetic model of diethyl phthalate and its major metabolite, monoethyl phthalate.

Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1-10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC-ESI-MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 µg/kg/day (pregnant), 0.193 µg/kg/day (fetus), 1.005-1.253 µg/kg/day (adults), 0.356-0.376 µg/kg/day (adolescents), and 0.595-0.603 µg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure.

Salicylic acid analogues as chemical exchange saturation transfer MRI contrast agents for the assessment of brain perfusion territory and blood-brain barrier opening after intra-arterial infusion.

The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Predicted, focal opening of the BBB through intra-arterial infusion of hyperosmolar mannitol is feasible, but there is a need to facilitate imaging techniques (e.g. MRI) to guide interventional procedures and assess the outcomes. Here, we show that salicylic acid analogues (SAA) can depict the brain territory supplied by the catheter and detect the BBB opening, through chemical exchange saturation transfer (CEST) MRI. Hyperosmolar SAA solutions themselves are also capable of opening the BBB, and, when multiple SAA agents were co-injected, their locoregional perfusion could be differentiated.

Assessment of estrogenic potential of di-n-butyl phthalate and butyl benzyl phthalate in vivo.

Phthalate compounds are widely used industrial chemicals; when incorporated into polyvinyl chloride, they are not covalently bound and released into the surrounding media. Some of them have estrogenic potential in vitro but data on in vivo studies are scanty. For the 3-day uterotrophic assay, di-n-butyl phthalate (DBP;10 and 100 mg/kg), butyl benzyl phthalate (BBP; 20 and 200 mg/kg), and diethylstilbestrol (DES, 40 µg/kg, positive control) were administered orally to immature female rats for three consecutive days from postnatal day (PND) 21. For the 20-day pubertal onset assay, DBP (10 and 20 mg/kg), BBP (20 and 200 mg/kg), and DES (6 µg/kg) were administered orally from PND 21 daily for 20 days. In the uterotrophic assay, in groups treated with higher dose of DBP and BBP, the uterine wet weight significantly decreased in the higher dose, and there were minor variations in the ovary wet weight, while the wet weight of these organs increased significantly in DES-treated group. In the 20-day pubertal assay, the weight of uterus and ovary declined significantly and changes in vaginal weight were nonsignificant in DBP- and BBP-treated groups. However, in DES-treated group nonsignificant elevation in vagina weight was observed. All the DES-treated animals showed the vaginal opening (VO) on day 26.17 ± 0.16. However, VO was not observed in any of the animals in control, vehicle control, BBP-, and DBP-treated groups up to PND 42, except in one animal each in vehicle control and DBP (100 mg/kg)-treated groups. The data indicated that both DBP and BBP were unable to induce elevation in the uterine and ovarian weight. While DES treatment can accelerate the growth of uterus and ovary and alter the onset of puberty and estrous cyclicity in prepubertal rats. These suggest that these compounds may not have estrogenic potential in vivo.

Metabolomics in the assessment of chemical-induced reproductive and developmental outcomes using non-invasive biological fluids: application to the study of butylbenzyl phthalate.

This study was conducted to evaluate the use of metabolomics for improving our ability to draw correlations between early life exposures and reproductive and/or developmental outcomes. Pregnant CD rats were exposed by gavage daily during gestation to vehicle or to butylbenzyl phthalate (BBP) in vehicle at a level known to induce effects in the offspring and at a level previously not shown to induce effects. Urine was collected for 24 h (on dry ice using all glass metabolism chambers) from dams on gestational day 18 (during exposure) and on post natal day (pnd) 21, and from pnd 25 pups. Traditional phenotypic anchors were measured in pups (between pnd 0 and pnd 26). Metabolomics of urine collected from dams exposed to vehicle or BBP exhibited different patterns for endogenous metabolites. Even three weeks after gestational exposure, metabolic profiles of endogenous compounds in urine could differentiate dams that received the vehicle, low dose or high dose of BBP. Metabolic profiles could differentiate male from female pups, pups born to dams receiving the vehicle, low or high BBP dose, and pups with observable adverse reproductive effects from pups with no observed effects. Metabolites significant to the separation of dose groups and their relationship with effects measured in the study were mapped to biochemical pathways for determining mechanistic relevance. The application of metabolomics to understanding the mechanistic link between low levels of environmental exposure and disease/dysfunction holds huge promise, because this technology is ideal for the analysis of biological fluids in human populations.