Comparison of percutaneous absorption and metabolism of di-n-butylphthalate in various species

Beydon, Dominique; Payan, Jean-Paul; Grandclaude, Marie-Christine

doi:10.1016/j.tiv.2009.08.032

Cited by 24 publications

(16 citation statements)

References 25 publications

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“…However, these older studies used non-viable skin, which might explain the differences observed. More recent phthalate skin permeation studies (Beydon et al, 2010) have shown similar results to ours, namely that phthalates do permeate human skin but not as the parent compound but rather as metabolites.…”

Section: Discussionsupporting

confidence: 89%

Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)

et al. 2014

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Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances. Surgically removed skin from patients undergoing abdominoplasty was immediately dermatomed (800 μm) and mounted on flow-through diffusion cells (1.77 cm(2)) operating at 32°C with cell culture media (aqueous solution) as the reservoir liquid. The cells were dosed either with neat DEHP or emulsified in aqueous solution (166 μg/ml). Samples were analysed by HPLC-MS/MS. DEHP permeated human viable skin only as the metabolite MEHP (100%) after 8h of exposure. Human skin was able to further oxidize MEHP to 5-oxo-MEHP. Neat DEHP applied to the skin hardly permeated skin while the aqueous solution readily permeated skin measured in both cases as concentration of MEHP in the receptor liquid. DEHP pass through human skin, detected as MEHP only when emulsified in aqueous solution, and to a far lesser degree when applied neat to the skin. Using results from older in vitro skin permeation studies with non-viable skin may underestimate skin exposures. Our results are in overall agreement with newer phthalate skin permeation studies.

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Section: Discussionsupporting

confidence: 89%

Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)

et al. 2014

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“…However, experimental results by Beydon et al. () showed that the esterase activity in the epidermis is only 4% of that in the entire human skin, and DnBP concentrations in the epidermis are much larger than MnBP concentrations. The influence of metabolism on phthalates for which the relative resistance in the viable epidermis is smaller than DnBP (e.g.…”

Section: Resultsmentioning

confidence: 98%

“…More specifically, esterases are among the enzymes active in skin; hence, esters absorbed in skin may be extensively hydrolyzed (Beydon et al, 2010;WHO, 2006). In vitro studies in both human and rat skin show that di(n-butyl) phthalate (DnBP) is metabolized in skin to monobutyl phthalate (MnBP), which permeates skin much faster than DnBP (Beydon et al, 2010;Payan et al, 2001). However, experimental results by Beydon et al (2010) showed that the esterase activity in the epidermis is only 4% of that in the entire human skin, and DnBP concentrations in the epidermis are much larger than MnBP concentrations.…”

Section: Limitations Of the Modelmentioning

confidence: 99%

“…In vitro studies in both human and rat skin show that di(n-butyl) phthalate (DnBP) is metabolized in skin to monobutyl phthalate (MnBP), which permeates skin much faster than DnBP (Beydon et al, 2010;Payan et al, 2001). However, experimental results by Beydon et al (2010) showed that the esterase activity in the epidermis is only 4% of that in the entire human skin, and DnBP concentrations in the epidermis are much larger than MnBP concentrations. The influence of metabolism on phthalates for which the relative resistance in the viable epidermis is smaller than DnBP (e.g.…”

Section: Limitations Of the Modelmentioning

confidence: 99%

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Predicting dermal absorption of gas-phase chemicals: transient model development, evaluation, and application

2013

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Dermal absorption from air has often been overlooked in exposure assessments. However, our transient model suggests that dermal intake of certain gas-phase phthalate esters is comparable to, or larger than, inhalation intake under commonly occurring indoor conditions. This may also be the case for other organic chemicals that have physicochemical properties that favor dermal absorption directly from air. Consequently, this pathway should be included in aggregate exposure and risk assessments. Furthermore, under conditions where the exposure concentrations are changing or there is insufficient time to achieve steady-state, the transient model presented in this study is more appropriate for estimating dermal absorption than is a steady-state model.

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“…(96,98−105) In vitro studies have shown that inducing cutaneous drug-metabolizing enzymes can substantially increase in vitro permeation (e.g., of benzo(a)pyrene metabolized by cytochrome P450), and that inhibiting dermal enzymes can eliminate nearly all dermal uptake (e.g., of dibutyl phthalate metabolized by carboxylesterase). (95,105) Such in vitro studies clearly demonstrate that dermal metabolic clearance can tightly control the effective epidermal concentration of a chemical that first penetrates overlying SC, and therefore also the total rate at which that chemical is dermally absorbed. These effects may be even be more pronounced in vivo, but are more difficult to study.…”

Section: Pk/pbpk-biosample Analysismentioning

confidence: 99%

Dermal Uptake of 18 Dilute Aqueous Chemicals: In Vivo Disappearance‐Method Measures Greatly Exceed In Vitro‐Based Predictions

Bogen

2012

Risk Analysis

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Average rates of total dermal uptake (Kup ) from short-term (e.g., bathing) contact with dilute aqueous organic chemicals (DAOCs) are typically estimated from steady-state in vitro diffusion-cell measures of chemical permeability (Kp ) through skin into receptor solution. Widely used ("PCR-vitro") methods estimate Kup by applying diffusion theory to increase Kp predictions made by a physico-chemical regression (PCR) model that was fit to a large set of Kp measures. Here, Kup predictions for 18 DAOCs made by three PCR-vitro models (EPA, NIOSH, and MH) were compared to previous in vivo measures obtained by methods unlikely to underestimate Kup . A new PCR model fit to all 18 measures is accurate to within approximately threefold (r = 0.91, p < 10(-5) ), but the PCR-vitro predictions (r > 0.63) all tend to underestimate the Kup measures by mean factors (UF, and p value for testing UF = 1) of 10 (EPA, p < 10(-6) ), 11 (NIOSH, p < 10(-8) ), and 6.2 (MH, p = 0.018). For all three PCR-vitro models, log(UF) correlates negatively with molecular weight (r(2) = 0.31 to 0.84, p = 0.017 to < 10(-6) ) but not with log(vapor pressure) as an additional predictor (p > 0.05), so vapor pressure appears not to explain the significant in vivo/PCR-vitro discrepancy. Until this discrepancy is explained, careful in vivo measures of Kup should be obtained for more chemicals, the expanded in vivo database should be compared to in vitro-based predictions, and in vivo data should be considered in assessing aqueous dermal exposure and its uncertainty.

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Comparison of percutaneous absorption and metabolism of di-n-butylphthalate in various species

Cited by 24 publications

References 25 publications

Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)

Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)

Predicting dermal absorption of gas-phase chemicals: transient model development, evaluation, and application

Dermal Uptake of 18 Dilute Aqueous Chemicals: In Vivo Disappearance‐Method Measures Greatly Exceed In Vitro‐Based Predictions

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