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.

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.

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.

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.

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.

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.

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 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 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.

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)

Dermal absorption of the phenoxy herbicide 2,4-D dimethylamine in humans: effect of DEET and anatomic site.

Percutaneous absorption of the 14C-ring-labeled phenoxy herbicide 2,4-D-amine (2,4-dichlorophenoxyacetic acid dimethylamine) was examined following topical applications of the herbicide to the palm and forearm of human volunteers. The effect of two vehicles (water and acetone) and the mosquito repellent DEET (N,N-diethyl-m-toluamide) on dermal absorption of 2,4-D-amine also was investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries and was not corrected for nonurinary excretion. The data revealed 14 +/- 4.5% (standard deviation) and 10 +/- 11.5% palmar absorption of 2,4-D-amine applied in water, with and without DEET, respectively, and 7 +/- 6.2% and 13 +/- 5.0% forearm absorption of the herbicide applied in water or acetone, respectively. Soap-and-water skin washes conducted at 24 h posttreatment removed up to 34% of the applied dose. Successive tape strips of skin taken at 24 h posttreatment demonstrated generally decreasing herbicide levels in the outer layers. The data bring into question the complete validity of the rhesus monkey model to predict human dermal absorption.

In vivo percutaneous absorption and skin decontamination of alachlor in rhesus monkey.

The objectives of this study were to determine the percutaneous absorption of alachlor relative to formulation dilution with water, and to determine the ability of soap and water, and of water only, to remove alachlor from skin, relative to time. Alachlor is a preemergence herbicide. The in vivo percutaneous absorption of alachlor in rhesus monkeys was 17.3 +/- 3.3, 15.3 +/- 3.9, and 21.4 +/- 14.2% for 24-h skin exposure to Lasso formulation diluted 1:20, 1:40, and 1:80, respectively. In vivo, there was no support for increased alachlor skin absorption with water dilution, as previously reported for in vitro absorption. The average in vivo absorption of 18% applied dose over 24 h (0.75%/h) was similar to the maximum in vitro rate of 0.8%/h using human skin and human plasma as receptor fluid. Dose accountability in vivo was 80.6-95.2%. [14C]Alachlor in Lasso diluted 1:20 with water was placed on rhesus monkeys at concentrations of 23 micrograms/10 microliters/cm2. Skin decontamination at 0 h with soap and water (50% Ivory liquid 1:1 v/v with water) removed 73 +/- 15.8% (n = 4) of the applied dose with the first wash; this increased to a total of 82.3 +/- 14.8% with two additional washes. Decontamination after 1 h removed 87.5 +/- 12.4% with three successive washes. After 3 h decontamination ability decreased, and after 24 h only 51.9 +/- 12.2% could be recovered with three successive washes. Using water only, at 0 h 36.6 +/- 12.3% alachlor was removed with the first wash and the total increased to 56.0 +/- 14.0% with two additional washes. At 24 h the total amount decreased to 28.7 +/- 12.2% for three successive washes. Alachlor as Lasso in field-use rate (11 micrograms/cm2) and undiluted (217 and 300 micrograms/cm2) proportions were left on rhesus monkey skin for 12 h and decontaminated with soap and water (10% Ivory liquid v/v with water). Continual successive washes (6-8 in sequence) recovered 80-90% of the skin-applied alachlor. These results suggest that simple washing with soap and water is appropriate for removing some chemicals from skin. Decontamination with only water was less effective than with soap and water.

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.

Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy.

Skin absorption of benzoyl peroxide from a topical lotion containing freely dispersed drug was compared with that from the same lotion in which the drug was entrapped in a controlled-release styrene-divinylbenzene polymer system. In an in vitro diffusion system, statistically significant (p = 0.01) differences were found in the content of benzoyl peroxide in excised human skin and in percutaneous absorption. In vivo, significantly (p = 0.002) less benzoyl peroxide was absorbed through rhesus monkey skin from the polymeric system. This controlled release of benzoyl peroxide to skin can alter the dose relation that exists between efficacy and skin irritation. Corresponding studies showed reduced skin irritation in cumulative irritancy studies in rabbits and human beings, whereas in vivo human antimicrobial efficacy studies showed that application of the formulations containing entrapped benzoyl peroxide significantly reduced counts of Propionibacterium acnes (p less than 0.001) and aerobic bacteria (p less than 0.001) and the free fatty acid/triglyceride ratio in skin lipids. These findings support the hypothesis that, at least for this drug, controlled topical delivery can enhance safety without sacrificing efficacy.

Glyphosate skin binding, absorption, residual tissue distribution, and skin decontamination.

Glyphosate is a broad-spectrum postemergence translocated herbicide. Its interactions with skin and potential systemic availability through percutaneous absorption was studied by skin binding, skin absorption, residual tissue distribution, and skin decontamination. Glyphosate in a final formulation (Roundup) undiluted and diluted with water 1:20 and 1:32, would not partition into powdered human stratum corneum (less than 1%). In vitro percutaneous absorption through human skin into human plasma as receptor fluid was no more than 2% over a concentration range of 0.5-154 micrograms/cm2 and a topical volume range of 0.014-0.14 ml/cm2. Disposition of glyphosate following iv administration of 93 and 9 micrograms doses to rhesus monkeys was mainly through urine excretion, 95 +/- 8 and 99 +/- 4% in 7 days, respectively. Percutaneous absorption in vivo in rhesus monkey was 0.8 +/- 0.6% for the low dose (25 micrograms/cm2) and 2.2 +/- 0.8% for the high dose (270 micrograms/cm2). No residual 14C was found in organs of the monkeys euthanized 7 days after the topical application. Washing the skin application site with soap and water removed 90 +/- 4% of applied dose, and washing with water only removed 84 +/- 3% of applied dose. Both soap and water and water only were equal in ability to remove glyphosate from skin over a 24 hr skin application period. About 50% of the initially applied dose could be recovered after 24 hr. Glyphosate is very soluble in water and insoluble in most organics (octanol/water log P = -1.70) and therefore not compatible with the lipid-laden stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)

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)