Twenty absorbing years.
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Administration, Topical↗
Biomedical subjects
R C Wester
Publications and source records attributed to R C Wester.
Percutaneous absorption of azone following single and multiple doses to human volunteers.
Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 microCi of [14C]Azone. The skin application site was washed with soap and water after each 24-h dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The [14C]Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was > 98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-h skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p < 0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.
Aged↗
Time-response necessary in validation for extraction of pesticides from cloth patches used in field exposure studies.
Environmental exposure in field studies is generally monitored by the cloth patch technique. Many investigators question the accuracy of the technique, in part due to lack of validation. The objective was to examine extraction of chemicals from cloth patches for potential technique validation. Chemicals studied were glyphosate, atrazine, malathion, alachlor and 2,4-dichlorophenoxy acetic acid (2,4-D), a selection of hydrophilic (glyphosate) and varying lipophilic compounds. The 14C-radiolabeled chemical was applied to a cotton patch (two types used) and solvent extracted over a 48-h time period. The chemical was soluble in the application solvent and in the extraction solvent. Extraction was near 100% at time 0 h, but statistically (P < 0.05 or greater) decreased to levels of 20-50% by 48 h. The missing chemical was detected in cloth residue and accountability was always excellent. The chemicals exhibited a time-response by incorporating into the cotton patch and not being available for extraction. Thus, validation of the cloth patch technique must include the time-period from the start of a field trial until laboratory analysis, a process which can take several days. This may account in part for differences noted between cloth patch technique and biological monitoring. It was subsequently shown that sonication loosens chemicals incorporated in the cloth patch, making the chemicals available for extraction. That sonication dislodged the chemicals suggests that the chemicals were not chemically bonded within the fabric but were probably sequestered within the fabric away from the solvent.
Environmental Monitoring↗
Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide.
In order to determine the human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide, a commercial formulation containing either [14C]pyrethrin (3.8 mCi/mmol) or [14C]piperonyl butoxide (3.4 mCi/mmol) was applied to the ventral forearm of six human volunteers. The formulation contained 0.3% pyrethrin and 3.0% piperonyl butoxide. Spreadability studies showed that concentrations of 5.5 micrograms pyrethrin/cm2 and 75.8 micrograms piperonyl butoxide/cm2 (used in this study) would be consistent with levels found in actual use. The forearms were thoroughly cleansed with soap and water 30 min after application (as recommended for actual use). Percutaneous absorption was determined by urinary cumulative excretion following dose application. With a 7-day urinary accumulation, 1.9 +/- 1.2% (SD) of the dose of pyrethrin and 2.1 +/- 0.6% of the dose of piperonyl butoxide applied was absorbed through the forearm skin. 1 hr after application blood samples contained no detectable radioactivity. The percutaneous absorption of pyrethrin and piperonyl butoxide from the scalp was calculated to be 7.5% of the applied dose for pyrethrin and 8.3% for piperonyl butoxide. The calculated half-life of 14C excretion was 50 hr for pyrethrin and 32 hr for piperonyl butoxide. The data should be of relevance to appropriate risk assessment in extrapolating animal data to humans.
Administration, Cutaneous↗
Metabolism of 3-indolylacetic acid during percutaneous absorption in human skin.
This study assessed the in vitro percutaneous absorption and metabolism of 3-indolylacetic acid after topical dosing to human skin from four sources. The metabolism of the compound during percutaneous absorption was assessed. The absorbed and metabolized chemicals were analyzed by radioactive scintillation counting and thin-layer chromatography: 1.2% +/- 0.04%, 1.4% +/- 0.07%, 3.0% +/- 1.0%, and 0.1% +/- 0.02% of the applied doses permeated through human skin samples from sources A to D, respectively, whereas 3.4% +/- 0.5% to 20.0% +/- 0.2% of the applied doses were retained by the skin. Of the absorbed dose, 2.1% +/- 1.0% to 12.1% +/- 3.5% was present as metabolites in the receptor fluid, and 2.2% +/- 0.5% to 5.2% +/- 0.1% was present as metabolites retained in the skin. Microsomal fractions were prepared from the skin samples, and the actions of these preparations on 3-indolylacetic acid were estimated. 5'-Hydroxyl-3-indolylacetic acid, 5',6'-dihydroxy-3-indolylacetic acid, and 5,6-dihydroxyindole were formed both during percutaneous absorption and by skin microsomal preparations. In addition, the skin samples biotransformed the acid to metabolic indican (3-indoxylsulfuric acid) and to the glucuronide conjugate of indole. The possible functional significance of the metabolism is discussed.
Administration, Cutaneous↗
Metabolism of propranolol during percutaneous absorption in human skin.
This in vitro study evaluated the extent of the absorption and metabolism of propranolol in human skin from four sources. Between 10.4 +/- 3.1 and 36.6 +/- 2.6% of the applied dose was absorbed; however, only a small portion (between 4.1 +/- 0.9 and 16.1 +/- 1.3%) of the dose permeated through the skin. Naphthoxyacetic acid formed during percutaneous absorption was located in the skin supernate. 4'-Hydroxypropranol was formed during percutaneous absorption and by skin microsomes. In addition, the microsomes biotransformed propranolol to norpropranolol. The retention of some of the absorbed drug and metabolites in the skin could explain the low plasma concentration and irritation observed following topical application of propranolol.
Adult↗
Percutaneous absorption of pentachlorophenol from soil.
Pentachlorophenol (PCP) is one of the most heavily used pesticides. About 80% of PCP is used for wood preservation, whereas the remainder is used as an herbicide, fungicide, and disinfectant. PCP is a probable human carcinogen, based on animal studies. Illness and death have been reported where PCP is in direct contact with skin. PCP is the most ubiquitous compound found when the general population is screened for pesticide residue. PCP is found in soil as well as other environmental sources. Our objective was to determine the skin bioavailability of PCP from soil and from the control vehicle acetone. In vivo in the Rhesus monkey, percutaneous absorption of PCP was 24.4 +/- 6.4% of applied dose from soil and 29.2 +/- 5.8% of applied dose from acetone vehicle for a 24-hr exposure period. This amount of absorption makes PCP one of the more extensively absorbed compounds to date. Additionally, the 14C half-life was 4.5 days following both intravenous and skin administration of [14C]PCP. These data suggest high bioavailability and an extended biological interaction period with the long half-life. In vitro percutaneous absorption with human cadaver skin and human plasma receptor fluid underestimated the in vivo absorption. Receptor fluid accumulation was 0.6 +/- 0.09% and 1.5 +/- 0.2% for two skin sources for PCP in acetone vehicle and 0.01 +/- 0.00% and 0.00 +/- 0.08% for two skin sources with soil vehicle. Skin content after skin surface wash ranged from 2.6 to 3.7% for acetone vehicle and 0.07-0.11% for soil vehicle. Overall accountability for in vitro dose ranged from 81 to 96%.
Acetone↗
In vivo and in vitro percutaneous absorption and skin decontamination of arsenic from water and soil.
The objective was to determine the percutaneous absorption of arsenic-73 as H3ASO4 from water and soil. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive arsenic-73 at a low (trace) level of 0.0004 microgram/cm2 (micrograms arsenic per square centimeter skin surface area) and a higher dose of 0.6 micrograms/cm2. Water solutions of arsenic-73 at a low (trace) level of 0.000024 micrograms/cm2 and a higher dose of 2.1 micrograms/cm2 were prepared for comparative analysis. In vivo in Rhesus monkey a total of 80.1 +/- 6.7% (SD) intravenous arsenic-73 dose was recovered in urine over 7 days; the majority of the dose was excreted in the first day. With topical administration for 24 hr, absorption of the low dose from water was 6.4 +/- 3.9% and 2.0 +/- 1.2% from the high dose. In vitro percutaneous absorption of the low dose from water with human skin resulted in 24-hr receptor fluid (phosphate-buffered saline) accumulation of 0.93 +/- 1.1% dose and skin concentration (after washing) of 0.98 +/- 0.96%. Combining receptor fluid accumulation and skin concentration gave a combined amount of 1.9%, a value less than that in vivo (6.4%) in the Rhesus monkey. From soil, receptor fluid accumulation was 0.43 +/- 0.54% and skin concentration was 0.33 +/- 0.25%. Combining receptor fluid plus skin concentrations gave an absorption value of 0.8%, an amount less than that with in vivo absorption (4.5%) in the Rhesus. These absorption values did not match current EPA default assumptions.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
Absorption and metabolism of 2-chloro-2,6-diethyl-N-(butoxymethyl)acetanilide (butachlor) in human skin in vitro.
Studies have demonstrated that several chemicals are absorbed and metabolized during skin permeation. We investigated the absorption and metabolism of the pesticide butachlor. Radiolabeled butachlor was measured in human (n = 5) skin and the unchanged compound and metabolites were quantified by high-pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC). Following a 24-hr exposure, an average butachlor quantity of approximately 5.00% of the applied dose (1.01 micrograms) was absorbed by the skin. The mean peak penetration rate was 0.7% of the applied dose per hour. The skin retained 1.40 to 8.10% of the applied butachlor. The retention of 1.4 to 8.1% of the pesticide by the skin suggests the importance of monitoring human skin following topical exposure. Of the dose recovered in the skin, 0.9% was metabolized to 4-hydroxybutachlor, while 1.8% of the dose in the receptor fluid was recovered as polar conjugates (cysteine, 0.29% dose; glutathione, 0.1% dose; unidentified metabolites, 1.4% dose); 2.8 and 6.8% of the dose absorbed by the skin (approximately 5.0%) were recovered as metabolites in the receptor fluids and skin homogenates, respectively. Similar to metabolism during percutaneous absorption, butachlor was metabolized to its conjugated and hydroxyl derivatives by skin fractions. The rate of butachlor glutathione and butachlor cysteine formation using skin cytosolic fractions were 12.0 +/- 1.5 and 48.0 +/- 3.6 pmol/min/mg protein +/- SD, respectively. When human skin microsomes were incubated with butachlor, 4-hydroxybutachlor was formed at the rate of 55.0 +/- 15.0 pmol/min/mg protein +/- SD. 4-Hydroxybutachlor formation was totally dependent on the presence of NADPH. The biotransformation of butachlor using skin fractions indicates the metabolic capacity of the tissue. The biological significance of these metabolites in the disposition of butachlor requires further investigation.
Acetanilides↗
Racial differences in the in vivo percutaneous absorption of some organic compounds: a comparison between black, Caucasian and Asian subjects.
Individual differences exist between patients, and, for topical therapy, differences in skin due to race may be a consideration. Pharmacological response depends upon the percutaneous absorption and the inherent activity of the chemical once absorbed into the biological system. Our objective was to determine the in vivo percutaneous absorption of three test chemicals in human subjects with Asian (A), black (B) and Caucasian (C) ethnic skin. Following a 30 min topical application on the upper outer arm of 1 mumol/cm2 14C-labeled chemical, percutaneous absorption was determined by both urinary excretion and the stripping technique. Amounts absorbed were: for benzoic acid 1.43 +/- 0.27% (SD) (A), 1.07 +/- 0.18% (B), 1.2 +/- 0.19% (C); for caffeine 1.06 +/- 0.17% (A), 1.01 +/- 0.19% (B) and 0.96 +/- 0.12% (C); for acetylsalicylic acid 1.8 +/- 0.31% (A), 1.59 +/- 0.31% (B) and 2.12 +/- 0.36% (C). No statistical difference (P > 0.05) was found in percutaneous absorption of benzoic acid, caffeine or acetylsalicylic acid between Asian, black and Caucasian subjects.
Adult↗
In vitro percutaneous absorption and metabolism in man of 2-chloro-4-ethylamino-6-isopropylamine-s-triazine (atrazine).
Atrazine is an extensively used herbicide in the USA. Our objective was to determine the absorption and metabolism (detoxification) of atrazine in human skin. Percutaneous absorption of atrazine in human skin from four sources was examined utilizing a flow-through in-vitro diffusion system. About 16.4% of the applied dose was absorbed by the skin. Radioactivity in the receptor fluid at 20 h was less than 5% of the administered dose. The highest concentration of the applied dose was found in the skin supernates, where 12.0% of the dose (68 nmol) was recovered. Some metabolites of atrazine were identified by thin layer and high pressure liquid chromatography after extraction of receptor fluid and the skin supernates. Two metabolites of atrazine [2-chloro-4-ethylamino-6-amino-s-triazine (desisopropylatrazine) and 2-chloro-4,6-diamino-s-triazine] were found in the receptor fluid and the skin supernates. An additional metabolite (2-chloro-4-amino-6-isopropylamino-s-triazine) was found in the skin supernates. Since desisopropylatrazine represented about 50% of the total metabolites formed during percutaneous absorption, cleavage of the N-isopropyl to the amino product was a key step in the metabolism of atrazine. Further metabolism may proceed by cleavage of the N-deethyl group to give totally dealkylated atrazine. The biotransformation of atrazine was studied in skin microsomal fraction supplemented with an NADPH-generating system. In analogy to metabolism during percutaneous absorption, atrazine was metabolized to its deisopropyl and deethylpropyl derivatives. In addition, 2-hydroxy derivatives of atrazine were formed by the skin microsomal fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
Percutaneous absorption of diazinon in humans.
Diazinon is an organophosphorus insecticide which, through general use, comes into contact with human skin. To investigate its percutaneous absorption, human volunteers were exposed for 24 hr to 14C-labelled diazinon applied in acetone solution (2 micrograms/cm2) to the forearm or abdomen, or in lanolin wool grease (1.47 micrograms/cm2) to the abdomen. Complete void urine samples were collected daily for 7 days. Percutaneous absorption ranged from 2.87 +/- 1.16% (mean +/- SD, n = 6) to 3.85 +/- 2.16% of the applied dose, and there were no statistically significant differences with regard to site or vehicle of application. In rhesus monkeys, over the 7 days after iv dosing (2.1 microCi [14C]diazinon, 31.8 micrograms) a total of 55.8 +/- 6.8% (n = 4) of the dose was excreted in the urine, and 22.6 +/- 5.2% was eliminated in the faeces (78.4% total accountability). In in vitro percutaneous absorption studies with human abdominal skin, 14.1 +/- 9.2% of the applied dose accumulated in the receptor fluid over 24 hr of exposure to 0.25 microgram/cm2 (acetone vehicle). The calculated mass absorbed was the same (0.035 microgram/cm2) for both in vitro and in vivo absorption through human skin.
Administration, Cutaneous↗
Percutaneous absorption of PCBs from soil: in vivo rhesus monkey, in vitro human skin, and binding to powdered human stratum corneum.
Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental pollutants. The major resident site for these PCBs is the soil, and human skin is frequently in contact with soil. Our objective was to determine the percutaneous absorption of the PCBs Aroclor 1242 and Aroclor 1254 from soil. PCB-contaminated soil was prepared at levels of 44 ppm Aroclor 1242 and 23 ppm Aroclor 1254. PCB concentrations on skin were 1.75 micrograms/cm2 for Aroclor 1242 and 0.91 microgram/cm2 for Aroclor 1254. In vivo percutaneous absorption in the rhesus monkey was determined by urinary and fecal [14C]-PCB excretion for a 5-wk period following topical dosing. Absorption of Aroclor 1242 was determined in vitro with human skin for comparative purposes. In vivo in the rhesus monkey the percutaneous absorption of Aroclor 1242 was 13.8 +/- 2.7 (SD)% of the dose and the absorption of Aroclor 1254 was 14.1 +/- 1.0%. These absorption amounts are similar to the absorption of Aroclor 1242 and 1254 from other vehicles (mineral oil, trichlorobenzene, acetone). With in vitro percutaneous absorption through human skin, most of the Aroclor 1242 and Aroclor 1254 resided in the skin and the amounts were dependent upon dosing vehicle (water > mineral oil > soil). Both PCBs readily partitioned from water into soil and human powdered stratum corneum. By difference the partitioning favored both PCBs going from soil into stratum corneum. These data emphasize the role of soil in percutaneous absorption and provide information for appropriate risk assessment.
Administration, Topical↗
Percutaneous absorption of topical corticosteroids.
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Absorption↗
In vitro percutaneous absorption of cadmium from water and soil into human skin.
The objective was to determine percutaneous absorption of cadmium as the chloride salt from water and soil into and through human skin. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive cadmium-109 at 13 ppb. Water solutions of cadmium-109 at 116 ppb were prepared for comparative analysis. Human cadaver skin was dermatomed to 500-microns, and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 16-hr skin application time. Cadmium in water (5 microliters/cm2) penetrated skin to concentrations of 8.8 +/- 0.6 and 12.7 +/- 11.7% of the applied dose from two human skin sources. Percentage doses absorbed into plasma were 0.5 +/- 0.2 and 0.6 +/- 0.6%, respectively. Cadmium from soil (0.04 g soil/cm2) penetrated skin at concentrations of 0.06 +/- 0.02 and 0.13 +/- 0.05% for the two human skin sources. Amounts absorbed into plasma were 0.01 +/- 0.01 and 0.07 +/- 0.03%. Most of the nonabsorbed cadmium was recovered in the soap and water skin surface wash. Binding of cadmium from water to soil was greater than binding from water to powdered human stratum corneum, supporting the lower absorption from soil than from water. Short-term exposure of cadmium in water to human skin for 30 min (bath or swim) resulted in skin uptake, which upon further perfusion (48 hr), absorbed into the plasma receptor fluid (systemic). Cadmium in soil was increased from 6.5 to 65 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
In vivo and in vitro percutaneous absorption and skin evaporation of isofenphos in man.
Studies were done to determine the percutaneous absorption of isofenphos in human volunteers from whom informed consent had been obtained. In vivo absorption in man was 3.6 +/- 3.6% of applied dose for 24-hr exposure and 3.6 +/- 0.5% for 72-hr exposure. Skin wash recovery data show that isofenphos evaporates from in vivo skin during the absorption process; the surface dose is minimal (< 1%) by 24 hr. Skin stripping showed no residual isofenphos in stratum corneum. This explains the similar absorption for 24 and 72-hr dose prewash exposures. Skin surface recovery in vivo with soap and water was 61.4 +/- 10.4 for the first dosing time (15 min). Time-recovery response declined with time to 0.5 +/- 0.2% at 24 hr. In vitro absorption utilizing flow-through diffusion methodology with human cadaver skin and human plasma receptor fluid gave 2.5 +/- 2.0% dose absorbed, an amount similar to in vivo studies. An additional 6.5 +/- 24% was recovered in the skin samples (total of 9%). Skin surface wash at 24 hr recovered 79.7 +/- 2.2% and skin content was 6.5 +/- 2.4% (total dose accountability of 88.7 +/- 4.6%). Thus, isofenphos was available for absorption during the whole dosing period. Neither in vitro absorption nor in vitro evaporation studies predicted the potential skin evaporation of isofenphos. Published dermal studies in the rat had predicted isofenphos absorption at 47% of applied dose (12-fold greater than actual in man). Subsequent toxicokinetic modeling predicted possible concern with the use of isofenphos.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
In vivo percutaneous absorption of hydrocortisone: multiple-application dosing in man.
Percutaneous absorption of hydrocortisone was measured in six healthy adult men from whom informed consent had been obtained. The study compared a single topical dose to multiple-topical dose treatments (one vs three applications) on the same day. 14C-Labeled hydrocortisone in acetone was applied to 2.5 cm2 of ventral forearm skin and protected with a nonocclusive polypropylene chamber. The amount of 14C measured in urine collected over 7 days was used to determine hydrocortisone absorption. The treatments, performed 2 to 3 weeks apart, each utilized adjacent sites on the same individuals. A single dose of 13.33 micrograms/cm2 delivered 0.056 microgram/cm2 of hydrocortisone through the skin. When the single dose was tripled to 40 micrograms/cm2, the amount delivered through the skin increased by nearly three times, from 0.056 to 0.140 micrograms/cm2; the expected delivery was 3 x 0.056 micrograms/cm2 = 0.168 microgram/cm2. Three serial doses of 13.33 micrograms/cm2 (total, 40 micrograms/cm2) were also expected to deliver 0.168 micrograms/cm2 with or without soap and water washing between doses, but the observed amount of hydrocortisone delivered through the skin significantly exceeded our expectations. This indicates that multiple-dosing treatments resulted in a significant increase in bioavailability. It is postulated that increased vehicle application and washing dissolved and mobilized previously dosed hydrocortisone and increased bioavailability.
Administration, Cutaneous↗
Percutaneous absorption of [14C]chlordane from soil.
The objective was to determine percutaneous absorption of chlordane in vitro and in vivo from soil into and through skin. The data are needed to calculate the absorbed dose of chlordane from soil, which is then used to assess the toxicity risk. Chlordane, an insecticide for which residues exist in soil, is restricted currently to use for termite control. Chlordane is highly lipophilic with little or no movement out of soil. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt, 0.9% organic) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with 14C-labeled chemical at 67 ppm. Acetone solutions were prepared for comparative analysis. Human cadaver skin was dermatomed to 500 microns and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/h flow rate) for a 24-h skin application time. Chlordane concentration within skin from in vitro studies was 0.34 +/- 0.31% from soil and 10.8 +/- 8.2% from acetone vehicle (p less than .01). Individual variation from human skin sources was evident (p less than .008). Chlordane accumulation in human plasma receptor fluid was the same for soil (0.04 +/- 0.05%) and acetone (0.07% +/- 0.06%) formulations. Most of the remaining chlordane was recovered in the soap and water skin surface wash. In contrast, in vivo percutaneous absorption of chlordane in the rhesus monkey was the same for soil (4.2 +/- 1.8%) and acetone (6.0 +/- 2.8%) formulations (p = .29, nonsignificant). Multiple soap and water washings were necessary to remove chlordane from skin, suggesting that a single wash may not adequately remove all the chlordane.
Administration, Topical↗