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.

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.

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.

In vitro percutaneous absorption of [14C] ethylene glycol.

The objective of this study was to determine the percutaneous absorption of ethylene glycol through human skin in vitro. The in vitro diffusion cells were of the flow-through design with 1 cm2 surface area. Three separate donor skin samples, taken from the thighs of white males, 16, 37, and 57 years old, were used and three replicates were performed for each experiment. Phosphate buffered saline, at a flow rate of three ml per hour, served as the receptor fluid. The human cadaver skin samples were dermatomed to 500 microns. [14C]-labeled ethylene glycol was applied to the skin surface in acetone vehicle at a dose of 8 micrograms/cm2. After 24-hr dermal exposure, 18.28 +/- 11.66% of the applied dose was recovered in the receptor fluid, 8.29 +/- 5.02% in the skin and 12.53 +/- 6.77% in the skin surface wash (total accountability was 39.11 +/- 7.23%). Individual difference existed (P < 0.05) for the three human skin sources. The combined skin and receptor fluid partitioning resulted in a potential absorbed dose of 26.57% relative to the 8 micrograms/cm2 applied dose for a 24-hr exposure duration. This represents a flux of approximately 2 micrograms/cm2/24 hr or 0.09 micrograms/cm2/hr for ethylene glycol. The maximum flux observed was 2.82%/hr/cm2 or 0.25 micrograms/cm2/hr.

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.

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)

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%.

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)

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)

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)

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.

Percutaneous absorption of [14C]DDT and [14C]benzo[a]pyrene from soil.

The objective was to determine percutaneous absorption of DDT and benzo[a]pyrene in vitro and in vivo from soil into and through skin. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with [14C]-labeled chemical at 10 ppm. Acetone solutions at 10 ppm 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 24-hr skin application time. With acetone vehicle, DDT (18.1 +/- 13.4%) readily penetrated into human skin. Significantly less DDT (1.0 +/- 0.7%) penetrated into human skin from soil. DDT would not partition from human skin into human plasma in the receptor phase (less than 0.1%). With acetone vehicle, benzo[a]pyrene (23.7 +/- 9.7%) readily penetrated into human skin. Significantly less benzo[a]pyrene (1.4 +/- 0.9%) penetrated into human skin from soil. Benzo[a]pyrene would not partition from human skin into human plasma in the receptor phase (less than 0.1%). Substantivity (skin retention) was investigated by applying 14C-labeled chemical to human skin in vitro for only 25 min. After soap and water wash, 16.7 +/- 13.2% of DDT applied in acetone remained absorbed to skin. With soil only 0.25 +/- 0.11% of DDT remained absorbed to skin. After soap and water wash 5.1 +/- 2.1% of benzo[a]pyrene applied in acetone remained absorbed to skin. With soil only 0.14 +/- 0.13% of benzo[a]pyrene remained absorbed to skin.(ABSTRACT TRUNCATED AT 250 WORDS)