Biomedical subjects

R C Wester

Publications and source records attributed to R C Wester.

At least 19 recordsLinked to original sources

PubMed2000

Predicted chemical warfare agent VX toxicity to uniformed soldier using parathion in vitro human skin exposure and absorption.

Chemical warfare agents (CWA) are easily and inexpensively produced and are a significant threat to military forces and the public. Most well-known CWAs are organophosphorus compounds, a number or which are used as pesticides, including parathion. This study determined the in vitro percutaneous absorption of parathion as a CWA simulant through naked human skin and uniformed skin (dry and sweated). Parathion percentage dose absorbed through naked skin (1.78 +/- 0. 41) was greater than dry uniformed skin (0.29 +/- 0.17; p = 0.000) and sweated uniformed skin (0.65 +/- 0.16; p = 0.000). Sweated and dry uniformed skin absorption were also different (p = 0.007). These relative dry and sweated uniformed skin absorptions were then applied to VX skin permeability for naked skin (head, neck, arms, and hands) and the remaining uniformed skin over the various regions of the human body. Risk assessment shows VX 50% lethality within the first hour for a soldier wearing a sweated uniform. By 8 h postexposure to naked skin plus trunk area predicted lethality for both dry and sweated uniform, and, at 96 h postexposure, all body regions individually exposed would produce lethality. Military uniform and public clothing provide some immediate protection but absorption through cloth and skin does occur. Immediate safety response to skin and clothing is required.

Administration, Cutaneous↗

PubMed2000

Utility of real time breath analysis and physiologically based pharmacokinetic modeling to determine the percutaneous absorption of methyl chloroform in rats and humans.

Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/MS system, was assessed using a PBPK model with a dermal compartment to determine the percutaneous absorption of methyl chloroform (MC) in rats and humans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper-shaved area on their back. The soil exposure cell was covered with a charcoal patch to capture volatilized MC and prevent contamination of exhaled breath. This technique allowed the determination of MC dermal absorption kinetics under realistic, non-occluded conditions. Human exposures were conducted by immersing one hand in 0.1% MC in water, or 0.75% MC in soil. The dermal PBPK model was used to estimate skin permeability (Kp) based on the fit of the exhaled breath data. Rat skin K(p)s were estimated to be 0.25 and 0.15 cm/h for MC in water and soil matrices, respectively. In comparison, human permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent Kp, nearly twice as much MC was absorbed from the occluded water (61.3%) compared to the non-occluded soil (32.5%) system in the rat. The PBPK model was used to simulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate that neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposures under realistic conditions.

Administration, Topical↗

PubMed2000

Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling.

The development and validation of noninvasive techniques for estimating the dermal bioavailability of solvents in contaminated soil and water can facilitate the overall understanding of human health risk. To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored in real time using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concentration was quantified for 3-5 h postdosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (K(P)) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concentrations. Rat skin was significantly more permeable than human skin. Estimates for K(P) in a water matrix were 0.31 +/- 0.01 cm/h and 0.015 +/- 0.003 cm/h in rats and humans, respectively. K(P) estimates were more than three times higher from water than soil matrices in both species. K(P) values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, K(P) values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration.

Administration, Cutaneous↗

PubMed1999

HPLC-accelerator MS measurement of atrazine metabolites in human urine after dermal exposure.

Metabolites of atrazine were measured in human urine after dermal exposure using HPLC to separate and identify metabolites and accelerator mass spectrometry (AMS) to quantify them. Ring-labeled [14C]atrazine was applied for 24 h with a dermal patch to human volunteers at low (0.167 mg, 6.45 muCi) and high (1.98 mg, 24.7 muCi) doses. Urine was collected for 7 days. The urine was centrifuged to remove solids, and the supernatant was measured by liquid scintillation counting prior to injection on the HPLC to ensure that < 0.17 Bq (4.5 pCi) was injected on the column. A reversed-phase gradient of 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile became less polar with increasing time and separated the parent compound and major atrazine metabolites over 31 min on an octadecylsilane column. Peaks were identified by coelution with known standards. Elution fractions were collected in 1-min increments; half of each fraction was analyzed by AMS to obtain limits of quantitation of 14 amol. Mercapturate metabolites of atrazine and dealkylated atrazine dominated the early metabolic time points, accounting for approximately 90% of the 14C in the urine. No parent compound was detected. The excreted atrazine metabolites became more polar with increasing time, and an unidentified polar metabolite that was present in all samples became as prevalent as any of the known ring metabolites several days after the dose was delivered. Knowledge of metabolite dynamics is crucial to developing useful assays for monitoring atrazine exposure in agricultural workers.

Administration, Cutaneous↗

PubMed1999

In vivo skin decontamination of methylene bisphenyl isocyanate (MDI): soap and water ineffective compared to polypropylene glycol, polyglycol-based cleanser, and corn oil.

In the home and workplace, decontamination of a chemical from skin is traditionally done with a soap-and-water wash, although some workplaces may have emergency showers. It has been assumed that these procedures are effective, yet workplace illness and even death occur from chemical contamination. Water, or soap and water, may not be the most effective means of skin decontamination, particularly for fat-soluble materials. This study was undertaken to help determine whether there are more effective means of removing methylene bisphenyl isocyanate (MDI), a potent contact sensitizer, from the skin. MDI is an industrial chemical for which skin decontamination, using traditional soap and water and nontraditional polypropylene glycol, a polyglycol-based cleanser (PG-C), and corn oil were all tried in vivo on the rhesus monkey, over 8 h. Water, alone and with soap (5% and 50% soap), were partially effective in the first h after exposure, removing 51-69% of the applied dose. However, decontamination fell to 40-52% at 4 h and 29-46% by 8 h. Thus, the majority of MDI was not removed by the traditional soap-and-water wash; skin tape stripping after washing confirmed that MDI was still on the skin. In contrast, polypropylene glycol, PG-C, and corn oil all removed 68-86% of the MDI in the first h, 74-79% at 4 h, and 72-86% at 8 h. Statistically, polypropylene glycol, PG-C, and corn oil were all better (p < 0.05) than soap and water at 4 and 8 h after dose application. These results indicate that a traditional soap-and-water wash and the emergency water shower are relatively ineffective at removing MDI from the skin. More effective decontamination procedures, as shown here, are available. These procedures are consistent with the partial miscibility of MDI in corn oil and polyglycols.

Administration, Topical↗

PubMed1998

Analytical performance of accelerator mass spectrometry and liquid scintillation counting for detection of 14C-labeled atrazine metabolites in human urine.

Accelerator mass spectrometry (AMS) has been applied to the detection of 14C-labeled urinary metabolites of the triazine herbicide, atrazine, and the analytical performance of AMS has been directly compared to that of liquid scintillation counting (LSC). Ten human subjects were given a dermal dose of 14C-labeled atrazine over 24 h, and urine from the subjects was collected over a 7-day period. Concentrations of 14C in the samples have been determined by AMS and LSC and range from 1.8 fmol/mL to 4.3 pmol/mL. Data from these two methods have a correlation coefficient of 0.998 for a linear plot of the entire sample set. Accelerator mass spectrometry provides superior concentration (2.2 vs 27 fmol/mL) and mass (5.5 vs 54,000 amol) detection limits relative to those of LSC for these samples. The precision of the data provided by AMS for low-level samples is 1.7%, and the day-to-day reproducibility of the AMS measurements is 3.9%. Factors limiting AMS detection limits for these samples and ways in which these can be improved are examined.

Adult↗

PubMed1998

Human in vivo and in vitro hydroquinone topical bioavailability, metabolism, and disposition.

Hydroquinone is a ubiquitous chemical readily available as monographed in cosmetic and nonprescription forms for skin lightening, and is an important industrial chemical. The in vivo bioavailability for 24-h application in humans was 45.3+/-11.2% of dose from a 2% cream formulation containing [14C]hydroquinone, with the majority of radioactivity excreted in the first 24 h. Timed skin wash and skin tape-stripping sequences showed a rapid and continuous movement of hydroquinone into the stratum corneum of human volunteers. Plasma levels taken both ipsilateral and contralateral to the topical dosing site contained radioactivity at the first 0.5-h sampling time. Peak plasma radioactivity was at 4 h in the 8-h blood sampling period. In vitro percutaneous absorption with fresh viable human skin gave a bioavailability of 43.3% of dose, and flux was calculated at 2.85 microg/cm2/h. In vitro, some of the skin samples were pretreated with the metabolic inhibitor sodium azide, which had no effect on percutaneous absorption. Receptor fluid accumulations and 24-h skin samples were extracted and the extracts subjected to thin-layer chromatography (TLC). Control [14C]hydroquinone extraction and TLC had one radioactivity peak, hydroquinone. Receptor fluid and skin extraction had a second peak with the same Rf as benzoquinone, which was decreased with azide treatment. No other peaks were found. Ethyl acetate extraction of urine from the in vivo study showed all radioactivity to be only water-soluble, free hydroquinone released following glucuronidase treatment. Risk assessment should not only involve the bioavailability of intact topical hydroquinone, but also consider phase I and phase II metabolism in both humans and any animal for which toxicity potential was assessed.

Administration, Topical↗

PubMed1998

Percutaneous absorption of salicylic acid, theophylline, 2, 4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man in vivo.

Human risk assessment for topical exposure requires percutaneous absorption data to link environmental contamination to potential systemic dose. Human absorption data are not readily available, so absorption models are used. In vitro diffusion systems are easy to use but have proved to be somewhat unreliable and are not validated to man. This study compares percutaneous absorption in the isolated perfused porcine skin flap (IPPSF) system with that in man in vivo. The study design utilized the same compounds and the same dose concentration and vehicle in both systems. Methodology for each system was that which is routinely used ineach system. The skin surface was not protected during the absorption dosing period. Percutaneous absorption values were, for man and the IPPSF system, respectively: salicylic acid (6.5 +/- 5.0%; 7.5 +/- 2.6%), theophylline (16.9 +/- 11.3%; 11.8 +/- 3.8%), 2,4-dimethylamine (1.1 +/- 0.3%; 3.8 +/- 0.6%), diethyl hexyl phthalic acid (1.8 +/- 0.5%; 3.9 +/- 2.4%), and p-aminobenzoic acid (11.5 +/- 6.3%; 5.9 +/- 3.7%) (correlation coefficient was 0.78; p < 0.04). The skin surface wash recovery postapplication was similar for salicylic acid in man (53.4 +/- 6.3%) and the IPPSF system (48.2 +/- 4.9%). With the other compounds the majority of surface chemical was recovered in the surface wash and skin tape strip in the IPPSF system. With man, other than salicylic acid, only a few percent applied dose was recovered with surface washing and tape stripping. Since the wash procedure was effective with pig skin, we can assume that these chemicals in man were lost to adsorption to any clothing or bedding with the volunteers. The absorption in man was not less than that in the IPPSF. Assuming the dose was lost in man, it seems plausible that whatever compound was to penetrate human skin in solvent vehicle did so in the period of time before the chemical was removed. The IPPSF system appears to be a good model for predicting percutaneous absorption relative to man. This study design should be used to validate other systems to humans in vivo.

4-Aminobenzoic Acid↗

PubMed1998

In vivo percutaneous absorption of boric acid, borax, and disodium octaborate tetrahydrate in humans compared to in vitro absorption in human skin from infinite and finite doses.

Literature from the first half of this century report concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax, and disodium octaborate tetrahydrate (DOT) in biological matrices. This made it possible, in the presence of comparatively large natural dietary boron intakes for the in vivo segment of this study, to quantify the boron passing through skin. Human volunteers were dosed with 10B-enriched boric acid, 5.0%, borax, 5.0%, or disodium octaborate tetrahydrate, 10%, in aqueous solutions. Urinalysis, for boron and changes in boron isotope ratios, was used to measure absorption. Boric acid in vivo percutaneous absorption was 0.226 (SD = 0.125) mean percentage dose, with flux and permeability constant (Kp) calculated at 0.009 microgram/cm2/h and 1.9 x 10(-7) cm/h, respectively. Borax absorption was 0.210 (SD = 0.194) mean percentage of dose, with flux and Kp calculated at 0.009 microgram/cm2/h and 1.8 x 10(-7) cm/h, respectively. DOT absorption was 0.122 (SD = 0.108) mean percentage, with flux and Kp calculated at 0.01 microgram/cm2/h and 1.0 x 10(-7) cm/h, respectively. Pretreatment with the potential skin irritant 2% sodium lauryl sulfate had no effect on boron skin absorption. In vitro human skin percentage of doses of boric acid absorbed were 1.2 for a 0.05% solution, 0.28 for a 0.5% solution, and 0.70 for a 5.0% solution. These absorption amounts translated into flux values of, respectively, 0.25, 0.58, and 14.58 micrograms/cm2/h and permeability constants (Kp) of 5.0 x 10(-4), 1.2 x 10(-4), and 2.9 x 10(-4) cm/h for the 0.05, 0.5, and 5.0% solutions. The above in vitro doses were at infinite, 1000 microliters/cm2 volume. At 2 microliters/cm2 (the in vivo dosing volume), flux decreased some 200-fold to 0.07 microgram/cm2/h and Kp of 1.4 x 10(-6) cm/h, while percentage of dose absorbed was 1.75%. Borax dosed at 5.0%/1000 microliters/cm2 had 0.41% dose absorbed, flux at 8.5 micrograms/cm2/h, and Kp was 1.7 x 10(-4) cm/h. Disodium octaborate tetrahydrate (DOT) dosed at 10%/1000 microliters/cm2 was 0.19% dose absorbed, flux at 7.9 micrograms/cm2/h, and Kp was 0.8 x 10(-4) cm/h. These in vitro results from infinite doses (1000 microliters/cm2) were 1000-fold greater than those obtained in the companion in vivo study. The results from the finite (2 microliters/cm2) dosing were closer (10-fold difference) to the in vivo results. General application of infinite dose percutaneous absorption values for risk assessment is questioned by these results. These in vivo results show that percutaneous absorption of boron, as boric acid, borax, and disodium octaborate tetrahydrate, through intact human skin, is low and is significantly less than the average daily dietary intake. This very low boron skin absorption makes it apparent that, for the borates tested, the use of gloves to prevent systemic uptake is unnecessary. These findings do not apply to abraded or otherwise damaged skin.

Adult↗

PubMed1998

In vivo percutaneous absorption of boron as boric acid, borax, and disodium octaborate tetrahydrate in humans: a summary.

Literature from the first half of this century reports concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry, which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax, and disodium octaborate tetrahydrate (DOT) in biological matrices. This made it possible, in the presence of comparatively large natural dietary boron intakes for the in vivo segment of this study, to quantify the boron passing through skin. Human volunteers were dosed with 10B-enriched boric acid, 5.0%, borax, 5.0%, or disodium octaborate tetrahydrate, 10% in aqueous solutions. Urinalysis, for boron and changes in boron isotope ratios, was used to measure absorption. Boric acid in vivo percutaneous absorption was 0.226 (SD = 0.125) mean percent dose, with flux and permeability constant (Kp) calculated at 0.009 microg/cm2/h and 1.9 x 10(-7) cm/h, respectively. Borax absorption was 0.210 (SD = 0.194) mean percent dose, with flux and Kp calculated at 0.009 microg/cm2/h and 1.8 x 10(-7) cm/h, respectively. DOT absorption was 0.122 (SD = 0.108) mean percent, with flux and Kp calculated at 0.01 microg/cm2/h and 1.0 x 10(-7) cm/h, respectively. Pretreatment with the potential skin irritant 2% sodium lauryl sulfate had no effect on boron skin absorption. These in vivo results show that percutaneous absorption of boron, as boric acid, borax, and disodium octaborate tetrahydrate, through intact human skin is low and is significantly less than the average daily dietary intake. This very low boron skin absorption makes it apparent that, for the borates tested, the use of gloves to prevent systemic uptake is unnecessary. These findings do not apply to abraded or otherwise damaged skin.

Administration, Topical↗

PubMed1998

In vitro percutaneous absorption of boron as boric acid, borax, and disodium octaborate tetrahydrate in human skin: a summary.

Literature from the first half of this century reports concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax and disodium octaborate tetrahydrate (DOT) in biological matrices. In vitro human skin percent doses of boric acid absorbed were 1.2 for a 0.05% solution, 0.28 for a 0.5% solution, and 0.70 for a 5.0% solution. These absorption amounts translated into flux values of, respectively, 0.25, 0.58, and 14.58 microg/cm2/h, and permeability constants (Kp) of 5.0 x 10(-4), 1.2 x 10(-4), and 2.9 x 10(-4) cm/h for the 0.05%, 0.5%, and 5.0% solutions. The above in vitro doses were at infinite, 1000 microL/cm2 volume. At 2 microL/cm2 (the in vivo dosing volume), flux decreased some 200-fold to 0.07 microg/cm2/h and Kp of 1.4 x 10(-6) cm/h, while percent dose absorbed was 1.75%. Borax dosed at 5.0%/1000 microL/cm2 had 0.41 percent dose absorbed, flux at 8.5 microg/cm2/h, and Kp was 1.7 x 10(-4) cm/h. Disodium octaborate tetrahydrate (DOT) dosed at 10%/1000 microL/cm2 was 0.19 percent dose absorbed, flux at 7.9 microg/cm2/h, and Kp was 0.8 x 10(-4) cm/h. These in vitro results from infinite doses (1000 microL/cm2) were a 1000-fold greater than those obtained in the companion in vivo study. The results from the finite (2 microL/cm2) dosing were closer (10-fold difference) to the in vivo results. General application of infinite dose percutaneous absorption values for risk assessment is questioned by these results.

Adult↗

PubMed1998

Human cadaver skin viability for in vitro percutaneous absorption: storage and detrimental effects of heat-separation and freezing.

PURPOSE: For decades, human cadaver skin has been banked and utilized by hospitals for burn wounds and to study percutaneous absorption and transdermal delivery. Skin storage maintenance and confirmation of skin viability is important for both uses, especially for the absorption process where the in vivo situation is simulated. METHODS: Our system uses dermatomed human cadaver skin immediately placed in Eagles MEM-BSS, and refrigerated after donor death, then transferred to the laboratory and placed in Eagles MEM-BSS with 50 micrograms/ml gentamicin at 4 degrees C for storage. RESULTS: Skin viability, determined by anaerobic metabolism where glucose is converted to lactose, was highest (p < 0.000) during the 18 hours of the first day after donor death, decreased some 3-fold by day 2 (p < 0.000), but then maintained steady-state viability through day 8. Viability then decreased by approximately one-half by day 13. Thus, using the above criteria, human skin will sustain viability for 8 days following donor death in this system. Heat-treated (60 degrees C water for one minute) and heat-separated epidermis and dermis lose viability. CONCLUSIONS: Human skin viability can be maintained for absorption studies. It is recommended that this system be used, and that heat-separation and skin freezing not be used, in absorption studies where skin viability and metabolism might be contributing factors to the study.

Administration, Cutaneous↗

PubMed1998

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers.

PURPOSE: The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. METHODS: Human volunteers were dosed with topical [14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. RESULTS: Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24-48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 +/- 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4-22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and beta-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3'hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. CONCLUSIONS; There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.

Administration, Topical↗

PubMed1998

In vitro cutaneous disposition of a topical diclofenac lotion in human skin: effect of a multi-dose regimen.

PURPOSE: This study determines comparative bioavailability of diclofenac sodium lotion compared to an aqueous solution after topical application to viable human skin in vitro. In addition, the difference between a single dose and multiple doses (8 times) was also determined. METHODS: An in vitro flow-through diffusion cell system was employed, using radiolabelled diclofenac sodium. RESULTS: Multiple doses of lotion (2 microl/cm2 and 5 microl/cm2) delivered a total of 40.1 +/- 17.6 microg and 85.6 micro 41.4 microg diclofenac, respectively, at 48 h, compared to only 9.4 +/- 2.9 microg and 35.7 +/- 19.0 microg absorbed after topical application of diclofenac as an aqueous solution (P < 0.05). A single dose study showed no statistical difference between diclofenac delivered in lotion or an aqueous solution. Over 48 h the total absorption from lotion was 10.2 +/- 6.7 microg and 26.2 +/- 17.6 microg (2 microl/cm2 and 5 microl/cm2, respectively), compared to 8.3 +/- 1.5 microg and 12.5 +/- 5.7 microg from an aqueous solution. Both single doses of lotion and aqueous diclofenac showed decreased diclofenac absorption into the receptor fluid between 12 and 24 h. However, when applied multiple times, absorption from lotion was continually increasing up to 48 h. The total dose accountability ranged from 76.8 +/- 8.2% to 110.6 +/- 15. 1% of the applied dose. CONCLUSIONS: Diclofenac lotion exhibited enhanced diclofenac percutaneous absorption rate through human skin (mass, flux and partition coefficient) when applied a multiple number of times and this enhanced absorption was maintained over 48 h. This suggests that a constituent of the lotion (DMSO) will enhance human skin absorption of diclofenac when used in a multi-dose regimen, but not after a single dose.

Administration, Topical↗

PubMed1997

Human skin in vitro percutaneous absorption of gaseous ethylene oxide from fabric.

Ethylene oxide, a colourless gas at ordinary room temperature and pressure, is widely used as a fumigant, coming in contact with clothing and human skin. It is genotoxic in somatic and germ cells. [1,2-14C]Ethylene oxide and fabric discs were sealed in a glass container; the fabric discs were then removed and placed on human skin mounted in glass diffusion cells. Percutaneous absorption was 1.3% of the dose when the fabric/skin surface was open to surrounding air, and increased to 46.0% when the surface was occluded with latex glove material. The absorption was rapid, occurring within the first 0-4 hr assay period. Absorbed chemical was confirmed to be unchanged ethylene oxide in the receptor fluid. This study also serves as a model for exposure of fabric/skin to any potentially hazardous gas.

Administration, Cutaneous↗

PubMed1996

In vitro percutaneous absorption of model compounds glyphosate and malathion from cotton fabric into and through human skin.

Chemicals are introduced to fabric at many steps during manufacture and use. Fabrics containing chemicals can cause medical problems such as dermatitis and death. Insecticides impregnated into uniforms worn by "Desert Storm" personnel are implicated in "Gulf War Syndrome'. These chemicals must get from fabric into and through skin to cause toxic effects. The objective of the present study was to determine in vitro percutaneous absorption of model chemicals glyphosate (water soluble) and malathion (relative water insoluble) from cotton fabric into and through human skin. The percutaneous absorption of glyphosate from water solution was 1.42 +/- 0.25% dose. This decreased to 0.74 +/- 0.26% for glyphosate added to cotton sheets and immediately put onto skin. If the cotton sheets were dried for 1 or 2 days, then applied to skin, absorption was 0.08 +/- 0.02% and 0.08 +/- 0.01% respectively. However, wetting the 2-day dried cotton sheet with water to simulate sweating or wet conditions increased absorption to 0.36 +/- 0.07%. Similar results were found for malathion. Absorption of malathion from aqueous ethanol solution was 8.77 +/- 1.43%. This decreased to 3.92 +/- 0.49%, 0.62 +/- 0.11% and 0.60 +/- 0.14% for 0, 1- and 2-day-treated cotton sheets. However, malathion absorption from 2-day treated/dried cotton sheets increased to 7.34 +/- 0.61% when wetted with aqueous ethanol. These results show that chemicals in fabric (clothing, rug, upholstery, etc.) can transfer from fabric into and through human skin to cause toxic effects.

Dose-Response Relationship, Drug↗

PubMed1996

In vivo percutaneous absorption of acetochlor in the rhesus monkey: dose-response and exposure risk assessment.

Percutaneous absorption of three topical dose levels of [14C]acetochlor in the rhesus monkey were determined for exposure risk assessment. The topical doses were 30.7, 0.43 and 0.03 mg acetochlor in 40 microliters commercial formulation and aqueous dilutions thereof, spread over 10 cm3 skin surface area (lower abdominal). The dosing area was not covered. The skin application time was 24 hr. The dosed skin surface area was washed with 50% soap (Ivory Liquid) and water at the end of the 24-hr dosing period. An intravenous dose of 0.43 mg was also administered to determine the excretory kinetics of acetochlor in the rhesus monkey. The same four monkeys were used for all dose administrations. Bioavailability was determined by radioactivity disposition in blood, urine and faeces. Percutaneous absorption was 23.1 +/- 8.7, 17.3 +/- 5.9 and 4.9 +/- 1.4% for 0.03, 0.43 and 30.7 mg doses, respectively. Assuming a constant state of absorption, the hourly exposure flux (microgram/cm2/hr) was 0.03 +/- 0.01 for the 0.03 mg dose (3 micrograms/cm2). Increasing the dose approximately 15-fold to 0.43 mg (43 micrograms/cm2) resulted in a 10-fold increase in flux to 0.3 microgram/cm2/hr. Increasing the dose a further 70-fold to 30.7 mg (3070 micrograms/cm2) resulted in only another 21-fold increase in flux (6.3 +/- 1.8 micrograms/cm2/hr). Thus, the efficiency of absorption (%) decreased with increased topical dose, but the amount (mass/flux) of acetochlor absorbed always increased with increased dose. Plasma levels of topical acetochlor at the high dose were detectable at 1 hr and continued at a relatively steady level through the 24-hr dosing period. After the skin surface wash (24 hr) plasma levels decreased but were still detectable at the last 168-hr sampling period. Acetochlor, recently EPA approved as an herbicide for corn crops, is carcinogenic; however, farmers will use half as much acetochlor/acre as other herbicides. The percutaneous absorption of acetochlor is equal to that of alachlor. Therefore, human exposure based on one-half usage suggests that human risk assessment should be one-half all other factors being equal.

Administration, Topical↗

PubMed1996

Percutaneous absorption of 2,4-dichlorophenoxyacetic acid from soil with respect to soil load and skin contact time: in vivo absorption in rhesus monkey and in vitro absorption in human skin.

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), used for control of weeds in agriculture, forestry, and rights of way, can accumulate as a residual chemical in soil. The objective was to determine percutaneous absorption of 2,4-D from soil, with emphasis on soil load and skin contact time. With control acetone vehicle, in vivo absorption of 2,4-D in the rhesus monkey was 8.6 +/- 2.1% of the dose, which compared closely to published human absorption of 6.0 +/- 2.4%. Percutaneous absorption from soil loads of 1 and 40 mg/cm2 were 9.8 +/- 4.0 and 15.9 +/- 4.7%, respectively, values similar to acetone vehicle. In vitro absorption in human skin calculated from skin contact accumulation over 24 h was 1.8 +/- 1.7, 1.7 +/- 1.3, and 1.4 +/- 1.2% for soil loads of 5, 10, and 40 mg/cm2, respectively. Thus, soil load did not affect 24-h percutaneous absorption. Current Environmental Protection Agency (EPA) recommended calculated reductions due to soil load are not supported by these results with 2,4-D. Percutaneous absorption of 2,4-D from acetone vehicle for 8 h dosing period was 3.2 +/- 1.0%, one-third the value of 8.6 +/- 2.1% over 24 h. With soil vehicle, absorption for 8 h was only 0.03 +/- 0.02% for 40 mg/cm2 soil load and 0.05 +/- 0/.004% for 1 mg/cm2 soil load. Absorption for 16 h was 2.2 +/- 1.2%. Absorption over time was linear for acetone vehicle, where total dose is deposited on skin, but not linear for soil vehicle, which had an 8-h delay (lag time). This equates with a normal 8-h work day where most of the contaminated soil can be washed off the skin. The apparent partition coefficient of 2,4-D between soil and water changed over time. This suggests there is a "mobility" phase for 2,4-D in soil that will change with time. For soil vehicle, percutaneous absorption of 2,4-D was not linear in respect to soil load or to skin contact time. Calculation based on assumed linearity can falsely estimate potential human health hazard. Clearly, the dermatokinetics with soil and skin represent complex interactive forces that require detailed evaluation before overgeneralizing rules for interpretation in terms of risk assessment.

2,4-Dichlorophenoxyacetic Acid↗