Percutaneous Uptake Research Articles

67 Criteria for the assessment of the percutaneous absorption of hazardous substances at the workplace – The German MAK Commission approach

Abstract The uptake of hazardous substances at the workplace through the skin can be one major route of exposure and therefore add to the occupational health risk for employees. More than one third of all substances with a limit value in workplace air in Germany have been designated with ‘H’ by the MAK Commission of the Deutsche Forschungsgemeinschaft (DFG), indicating that the percutaneous absorption under workplace conditions can make a significant contribution to the systemic exposure of an employee. The recommendations of the MAK Commission are one major source for regulatory decisions taken by the German Ministry of Labor and Social Affairs for sustaining health and safety in the work area. This presentation summarizes the general approach of the MAK Commission’s working group on percutaneous absorption, the selection and ranking of data (workplace studies, animal studies, in vitro studies, mathematical models or algorithms) as well as the quantitative criteria for an assignment with ‘H’. For the final assessment, the estimated absorbed amount of a substance is compared with the systemically tolerable amount extrapolated from the no observed adverse effect level (NOAEL). A designation with ‘H’ is recommended if the percutaneous uptake accounts for approximately 25 % or more of the tolerable quantity. Only in the case of genotoxic substances without limit values is the ability of a substance to cross the skin barrier sufficient in itself to recommend designation with an ‘H’. The assessment process as well as its merits and challenges are illustrated by some examples.

Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy.

Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm-2 h-1) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.

Reference intervals for thyroid-stimulating hormone, free thyroxine, and free triiodothyronine in elderly Chinese persons

Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) is a high production volume brominated flame retardant (BFR) used in consumer products, resulting in ubiquitous human exposure. Although the major route of exposure for this chemical is believed to be via ingestion, dermal contact is likely via contaminated dust. Independent trials of a single dose of 100 nmol/cm2 (∼1 μCi [14C]/cm2) of [14C]-radiolabeled TBBPA-BDBPE was applied to whole rat skin (in vivo) or split-thickness human and rat skin (ex vivo) to estimate in vivo human percutaneous uptake. [14C]-radioactivity was quantified to determine dermal absorption (dose retained in dosed skin) and penetrance (dose recovered in receptor fluid [ex vivo] or tissues/excreta [in vivo]) over 24 h. In vivo absorption and penetration for rat skin was 26% and 1%, with a maximum flux of 44 ± 9 pmol/cm2/h. In ex vivo rat skin, absorption and penetration and absorption values were 23% and 0.3% (flux = 26 ± 8 pmol/cm2/h). In ex vivo human skin, 53% was absorbed and penetration was 0.2% with a maximal flux of 16 ± 12 pmol/cm2/h. Computed maximal flux for in vivo human skin was 21 ± 9 pmol/cm2/h with expected total absorption of ∼80% and a penetration of <1%. HPLC-radiometric analyses of samples showed that TBBPA-BDBPE was not metabolized in ex vivo or in vivo studies. These studies indicate that TBBPA-BDBPE is likely to be dermally bioavailable even after washing and dermal contact with this chemical should be considered an important route of exposure.

Dermal disposition of Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) using rat and human skin

Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) is a high production volume brominated flame retardant (BFR) used in consumer products, resulting in ubiquitous human exposure. Although the major route of exposure for this chemical is believed to be via ingestion, dermal contact is likely via contaminated dust. Independent trials of a single dose of 100 nmol/cm2 (∼1 μCi [14C]/cm2) of [14C]-radiolabeled TBBPA-BDBPE was applied to whole rat skin (in vivo) or split-thickness human and rat skin (ex vivo) to estimate in vivo human percutaneous uptake. [14C]-radioactivity was quantified to determine dermal absorption (dose retained in dosed skin) and penetrance (dose recovered in receptor fluid [ex vivo] or tissues/excreta [in vivo]) over 24 h. In vivo absorption and penetration for rat skin was 26% and 1%, with a maximum flux of 44 ± 9 pmol/cm2/h. In ex vivo rat skin, absorption and penetration and absorption values were 23% and 0.3% (flux = 26 ± 8 pmol/cm2/h). In ex vivo human skin, 53% was absorbed and penetration was 0.2% with a maximal flux of 16 ± 12 pmol/cm2/h. Computed maximal flux for in vivo human skin was 21 ± 9 pmol/cm2/h with expected total absorption of ∼80% and a penetration of <1%. HPLC-radiometric analyses of samples showed that TBBPA-BDBPE was not metabolized in ex vivo or in vivo studies. These studies indicate that TBBPA-BDBPE is likely to be dermally bioavailable even after washing and dermal contact with this chemical should be considered an important route of exposure.

Research in practice: the second barrier of the human skin

A major function of human skin is to form an effective barrier between the environment and the inside of the organism. Especially important for this function is the activity of the physical barrier of the skin, which is mainly located in the stratum corneum. To improve this barrier function of the skin, skin protection agents are used. Recent studies have revealed that application of skin protection agents before exposition to xenobiotics does not generally reduce the percutaneous uptake of these compounds. These findings indicate that besides new study designs and improved test systems, there seems to be a need for new therapeutic approaches for more effective skin protection. In this light, new findings regarding a second barrier function of the human skin, the biochemical/toxicological barrier, could be of interest. A crucial part of this barrier function are members of the cytochrome P450 (CYP) family and efflux-transport proteins of the multidrug resistance-related protein family (MRPs), which are mainly expressed by basal layer keratinocytes. Recent studies have revealed that besides the physiological and protective function of these transport proteins and CYP enzymes in skin cells, the same proteins also play a role in the transport of contact allergens and activation of prohaptens to haptens causing contact dermatitis. Inhibition of this metabolism mediated activation of prohaptens and stimulation of the active elimination of contact allergens from skin cells could represent novel mechanisms improving the established tools for skin protection.

Percutaneous absorption of aromatic amines – A contribution for human health risk assessment

Several aromatic amines (AA) are human carcinogens. AA are widely-used, e.g., in the rubber industry. The uptake of AA at the workplace occurs by inhalation and percutaneous absorption. At present there are no risk assessment studies for percutaneous AA absorption using occupationally relevant concentrations. We conducted diffusion cell experiments for aniline (ANI), o-toluidine (OT), 4,4′-methylenedianiline (MDA) and N-phenyl-2-naphthylamine (PBNA). Excised human skin was exposed to different AA concentrations in vehicles containing water and solvents. Recovery for ANI in receptor fluid was about 20–38% and for MDA 15% over 24h. PBNA could not be detected in the receptor fluid. Further data for OT and β-naphthylamine (BNA) were considered from our recent study. A semi-quantitative percutaneous absorption ranking for AA was derived: BNA>OT>ANI>MDA>PBNA. For aqueous ANI solutions up to saturation a linear relationship of exposed dose and penetrated amount was observed. However, a linear extrapolation of the flux of neat compounds, as often recommended for risk assessment policies, underestimates considerably the percutaneous uptake. The in vitro data support our recent findings in rubber industry workers that the percutaneous absorption may significantly contribute to overall exposure of AA.

Human volunteer study on the inhalational and dermal absorption of N-methyl-2-pyrrolidone (NMP) from the vapour phase

N-Methyl-2-pyrrolidone (NMP) is a versatile organic solvent frequently used for surface cleaning such as paint stripping or graffiti removal. Liquid NMP is rapidly absorbed through the skin but dermal vapour phase absorption might also play an important role for the uptake of the solvent. This particular aspect was investigated in an experimental study with 16 volunteers exposed to 80 mg/m(3) NMP for 8 h under either whole-body, i.e. inhalational plus dermal, or dermal-only conditions. Additionally, the influence of moderate physical workload on the uptake of NMP was studied. The urinary concentrations of NMP and its metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) were followed for 48 h and analysed by gas chromatography-mass spectrometry (GC-MS). Percutaneous uptake delayed the elimination peak times and the apparent biological half-lives of NMP and 5-HNMP. Under resting conditions, dermal-only exposure resulted in the elimination of 71 +/- 8 mg NMP equivalents as compared to 169 +/- 15 mg for whole-body exposure. Moderate workload yielded 79 +/- 8 mg NMP (dermal-only) and 238 +/- 18 mg (whole-body). Thus, dermal absorption from the vapour phase may contribute significantly to the total uptake of NMP, e.g. from workplace atmospheres. As the concentration of airborne NMP does not reflect the body dose, biomonitoring should be carried out for surveillance purposes.

On the follicular pathway of percutaneous uptake of nanoparticles: Ion microscopy and autoradiography studies

We report on the visualization of the penetration of sunscreen formulations containing TiO 2 nanoparticles (about 20 nm primary particle size) into hair follicles of both human and porcine skin using the complementary methods of ion microscopy (PIXE, RBS, STIM) and autoradiography. Particles were found as deep as approx. 400 μm in the follicle, obviously introduced mechanically rather than by a diffusive process. No particles were observed in vital tissue nor in sebaceous glands.

Percutaneous absorption of aromatic amines in rubber industry workers: impact of impaired skin and skin barrier creams

Background: Several aromatic amines (AA) could cause bladder cancer and are an occupational hygiene problem in the workplace. However, little is known about the percutaneous absorption of chemicals via impaired...

In vitro Percutaneous Absorption and in vivo Stratum Corneum Distribution of an Organic and a Mineral Sunscreen

Sunscreens, whose main function is to protect the skin against the harmful effects of solar irradiation, should remain at the skin surface or impregnate the first layers of the stratum corneum only and not penetrate into the underlying living tissue. The goal of this work was to assess the penetration of titanium dioxide (TiO₂) and methylene bis-benzotriazoyl tetramethylbutylphenol (MBBT), included in a broad-spectrum sunscreen formulation, into human skin in vivo, using the tape stripping method, and in vitro, using a compartmental approach. An additional objective was to propose an easy and minimally invasive approach to determining the percutaneous uptake of sunscreens following topical application. TiO₂ and MBBT were quantified using colorimetric assay and HPLC analysis, respectively. The transmission electron microscopy and particle-induced X-ray emission techniques were used to localize the TiO₂ in skin sections.More than 90% of both sunscreens was recovered in the first 15 tape strippings. In addition we have shown that the remaining 10% did not penetrate the viable tissue, but was localized in the furrows and in the opened infundibulum. Less than 0.1% of MBBT was detected in the receptor medium, and no TiO₂ was detected in the follicle, viable epidermis or dermis. Thus, this in vivo and in vitro penetration study showed an absence of TiO₂ penetration into the viable skin layers through either transcorneal or transfollicular pathways and negligible transcutaneous absorption of MBBT. However, differences in distribution within the stratum corneum reinforced the need for a complementary approach, using minimally invasive in vivo methodology and in vitro compartmental analysis.This combination represents a well-adapted method for testing the safety of topically applied sunscreen formulations in real-life conditions.

Dermal absorption of aromatic amines in workers with different skin lesions: a report on 4 cases

There are only few studies about the relationship of skin lesions and the percutaneous uptake of hazardous substances in exposed workers. Several aromatic amines are well known carcinogens for humans and/or animals. This case report emphasizes the relevance of dermal absorption of the aromatic amine ortho-toluidine considering four workers with different skin status (healthy, erythematous and burned skin as well as dishydrotic eczema) during the vulcanisation process of rubber products in a components supplier plant for automobile industry. The results of our case report show that dermal absorption of o-toluidine through damaged epidermal barrier is significantly higher than through healthy skin.

Percutaneous Absorption of 4-Cyanophenol from Freshly Contaminated Soil in Vitro: Effects of Soil Loading and Contamination Concentration

Despite the skin's excellent barrier function, dermal exposure to soil contaminated with toxic chemicals can represent a significant health hazard (e.g., via multiple work related contacts in the farming and waste disposal industries). The development of environmental standards or limits for chemical levels in soil has been impeded because quantification of percutaneous uptake from this medium has not been well-defined. The objective of the research described here, therefore, was to better characterize the rate and extent of dermal penetration as a function of soil loading and degree of soil contamination. The absorption of a model compound (4-cyanophenol, CP) across hairless mouse skin in vitro has been determined at four different soil loadings (5, 11, 38 and 148 mg cm-2) and at six levels of soil contamination (concentrations ranging from 0.19 to 38 mg/g soil). Following 8 h of exposure, the amount of CP absorbed was independent of soil loading when CP concentration was constant, implying that the quantity of soil presentwas always sufficientto provide atleast a single layer of tightly packed particles. At the lowest loadings, however, with increasing times of exposure, the CP transport rate fell off due to depletion of chemical from the soil. At constant soil loading (38 mg cm(-2)), CP flux (Jss) across the skin was linearly proportional to the level of contamination (C(o)soil) over the range 0.19 to 23.5 mg of CP per gram of soil: Jss (micorg cm(-2) h(-1)) = (1.1 x 10(-5) g cm(-2) h(-1)) x Csoil (microg/g soil). At the highest CP contamination concentration, however, the transport rate was about an order of magnitude higher than expected, possibly due to the presence of pure CP crystals. In conclusion, these results provide new quantifications of the characteristics of dermal uptake from chemically contaminated soils and important information with which to develop and verify predictive models of dermal absorption.

Levels of exposure from drinking water

The relative exposure from drinking water is generally small, although there is a lack of information on total daily intake of individual organic micropollutants. There are, however, a few exceptions. Materials used in domestic distribution systems (lead, copper and plastics) may cause a deterioration of the water quality, especially in stagnant water. The relative exposure to the related compounds may increase considerably. Monitoring data from the tap (with defined sampling techniques) are needed. Also, disinfection/oxidation by-products (bromate, trihalomethanes) can be present in drinking water in considerable amounts and the relative exposure from drinking water may even approach 100%. Especially for volatile organic micropollutants, exposure routes from drinking water other than ingestion must be taken into account (inhalation, percutaneous uptake). When there is a need for detection of substances at very low levels it is important that the measurements are reliable. International interlaboratory comparisons for organic micropollutants are lacking at the moment.

Development of Skin Barrier Function in Premature Infants

Histologic analysis suggests that epidermal development is complete in utero at approximately 34 wk gestational age. Infants born more prematurely have elevated rates of both transepidermal water loss and transcutaneous heat loss, and have difficulty maintaining homeostasis. The underdeveloped integument is also a portal of entry for infection and the percutaneous uptake of toxins. Previous measurements of transepidermal water loss have suggested that, regardless of gestational age, competent barrier function is attained within 2-4 wk postnatal age. In this study we have utilized another noninvasive biophysical technique, low frequency impedance spectroscopy, to complement transepidermal water loss measurements. We present longitudinal data from infants ranging from 23 to 32 wk gestational age. The results suggest that, for ultra-low birth weight infants (23-25 wk gestational age), the complete development of a fully functional stratum corneum can require significantly longer than 4 wk. In contrast, the data from the older infants suggest that a postnatal existence period of 2-4 wk may not be necessary to attain functional maturity, because infants born at 30 and 32 wk gestational age were found to have barrier function comparable with that of adults.

Bioaccumulation of water soluble aluminium chloride in the hippocampus after transdermal uptake in mice.

Normally, only very small amounts of ingested aluminium are absorbed and accumulated. Despite the percutaneous absorption of many drugs and chemicals, the skin has not been considered as a possible site at which aluminium could enter the body. Application of low aqueous concentrations of aluminium chloride (A1C1(3), 6H20) (0.025-0.1 micrograms/cm2) to healthy shaved Swiss mouse skin for 130 days led to a significant increase in urine, serum and whole brain aluminium, especially in the hippocampus, compared to control animals. This percutaneous uptake and accumulation of aluminium in the brain was greater than that caused by dietary exposure to 2.3 micrograms per day in feed and water. In vitro studies demonstrated the passage of aluminium through viable mouse skin. This study shows for the first time that aluminium is absorbed through the skin of mice in vivo and this contributes to a greater body burden than does oral uptake.

Occupational exposure to organic solvents during paint stripping and painting operations in the aeronautical industry.

The exposure of workers to methylene chloride and phenol in an aeronautical workshop was measured during stripping of paint from a Boeing B 747. Methylene chloride exposure was measured during two work days by personal air sampling, while area sampling was used for phenol. During paint stripping operations, methylene chloride air concentrations ranged from 299.2 mg/m3 (83.1 ppm) to 1888.9 mg/m3 (524.7 ppm). The exposures to methylene chloride calculated for an 8-h work day ranged from 86 mg/m3 (23.9 ppm) to 1239.5 mg/m3 (344.3 ppm). In another aeronautical workshop, exposure to organic solvents, especially ethylene glycol monoethylether acetate (EGEEA), was controlled during the painting of an Airbus A 320. The external exposure to solvents and EGEEA was measured by means of individual air sampling. The estimation of internal exposure to EGEEA was made by measuring its urinary metabolite, ethoxyacetic acid (EAA). Both measurements were made during the course of 3 days. The biological samples were taken pre- and post-shift. During painting operations, methyl ethyl ketone, ethyl acetate, n-butyl alcohol, methyl isobutyl ketone, toluene, n-butyl acetate, ethylbenzene, xylenes and EGEEA were detected in working atmospheres. For these solvents, air concentrations ranged from 0.1 ppm to 69.1 ppm. EGEEA concentrations ranged from 29.2 mg/m3 (5.4 ppm) to 150.1 mg/m3 (27.8 ppm). For biological samples, the average concentrations of EAA were 108.4 mg/g creatinine in pre-shift and 139.4 mg/g creatinine in post-shift samples. Despite the fact that workers wore protective respiratory equipment during paint spraying operations, EEA urinary concentrations are high and suggest that percutaneous uptake is the main route of exposure for EGEEA.(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous uptake, distribution, and excretion of pyrene in rats

Groups of 12 male Wistar rats, of about 400 g body weight, were dosed with 2, 6, or 15 mg/kg of 14C-labeled pyrene, dissolved in acetone, applied to 4 cm2 of a shaved area of the mid back. Three animals in each dose group were killed at 1, 2, 4, and 6 d post-dosing, and their principal organs were removed and analyzed for pyrene and [14C]pyrene equivalents. Urine and feces, as well as the area of skin to which the dose was applied, were also analyzed for [14C]pyrene equivalents. The rate of uptake from the skin was rapid (t1/2 0.5-0.8 d) relative to rate processes for the other organs, and about 50% of the applied dose was excreted over the 6 d of the study. The significant decrease in the fraction of the dose excreted and in the normalized amounts distributed to the various organs and tissues, as the dose increased for all chemical species measured, was strongly suggestive of nonlinear kinetics, as has been observed in previous studies. Levels of pyrene were highest in the liver, kidneys, and fat. Levels of metabolites were also high in the lung. It was evident that the dermal route of uptake was not insignificant for this model polycyclic aromatic hydrocarbon and may represent a significant exposure route for exposed humans.

Percutaneous uptake and kinetics of methyl isobutyl ketone (MIBK) in the guinea-pig

Continuous intravenous infusion of 0.478 μmol min methyl isobutyl ketone (MIBK) was performed for 30 min in pentobarbital-anesthetized guinea-pigs. Epicutaneous exposure for 150 min was carried out 2.5 h later after administration of MIBK to a sealed glass ring on the clipped back of the animals. Arterial blood was analyzed for MIBK by gas chromatography. Blood clearance averaged 201 ml · min −1 · kg −1 body wt. A maximum percutaneous uptake of 1.1 μmol·min −1 · cm −2 was reached 10–45 min after the onset of exposure and decreased to 0.56 μmol · min −1 · cm −2 during the latter part of exposure.

In vitro release of selected nonsteroidal antiinflammatory analgesics [NSAIA] from reservoir-type transdermal formulations

AbstractIndomethacin [I], Ketoprofen [II] and Sulindac [III] were evaluated for in vitro percutaneous uptake from various ointment bases. Three doses for each NSAIA were employed for evaluation. Each reservoir system was evaluated for drug release across composite skin (semipermeable membrane) using a modified FDC assembly over a 12 h period. The drug release profiles were examined for mechanism of drug release and developing recommendations for designing a dermal product for a NSAIA.For all NSAIAs: This study demonstrated that I, II and III can penetrate the composite skin barrier with differing efficiencies. II penetrated with maximal ease while I with minimal ease. The drug release rate increased with increasing drug load. 0/W and water soluble system compositions yielded superior drug release rates when compared to other reservoir systems. The drug release characteristics indicated adherence to diffusional pathways borne out of Q versus square-root-of-time relationship. The Qmax:Drug Load (Dose) ratio...

Use of Percutaneous Absorption Data in Risk Assessment

Assessment of risks to humans associated with the use of chemicals requires knowledge of the hazard (toxicity) of the chemical and level of human exposure. Hazard assessment is often based on animal bioassays and quantitative exposure estimates of dermal exposure obtained from studies monitoring workers. Because human skin is an effective barrier to many chemicals, it cannot be assumed that the deposited dose is equivalent to the systemic dose. However, an estimate of systemic dose may be derived by multiplying the deposited dose by the percentage of percutaneous uptake. This correction can have major impact on the regulatory decision, because the adjusted dose used in the risk calculation may be reduced significantly, especially at high doses, when the uptake is not linearly proportional to the exposure. It is therefore important that the dermal absorption value be accurate. As outlined in this paper, numerous factors can affect percutaneous absorption. Nevertheless, many regulatory agencies will consider the use of percutaneous absorption data derived from in vivo studies to adjust the dermally deposited dose to that delivered systemically. Numerous issues must be resolved before in vitro dermal penetration studies can be used for risk assessment.