SYSTEMIC UPTAKE AND CUTANEOUS DISPOSITION OF PENTACHLOROPHENOL IN A SEQUENTIAL EXPOSURE SCENARIO: EFFECTS OF SKIN PREEXPOSURE TO BENZO[a]PYRENE

Characterizing interactions caused by sequential skin exposures to various environmental toxicants can be critical for a meaningful risk assessment. To assess sequential chemical exposure effect on chemical cutaneous disposition and systemic uptake of a toxicant, [ 14 C]pentachlorophenol (PCP) was topically administered in three porcine skin models (in vivo, ex vivo, and in vitro) at 40 µg/cm 2 with or without skin preexposure to benzo[a]pyrene (BaP), a known human carcinogen and cutaneous cytochrome P-450 (CYP450) inducer. In the mass balance studies, BaP skin preexposure was found to enhance 14 C absorption in all three models with detectable in vivo effect during the first several days. Total 8-h absorption was tripled by skin preexposure to BaP in the ex vivo (1.1 to 3.2%) and in vitro (0.20 to 0.66%) systems. As seen in the extended in vivo studies, total absorption was 50-57% regardless of exposure conditions, suggesting the prolonged observation period may conceal existing impact of potentially modified disposition processes, such as cutaneous metabolism, on systemic absorption. Skin preexposure to the skin CYP450 inducer BaP largely changed label penetration depth and distribution pattern in cutaneous tissues and decreased 14 C concentration in skin and fat. Additionally, BaP preexposure altered 14 C systemic tissue disposition, suggesting that altered cutaneous PCP disposition may eventually change the toxicity profile (cutaneous vs. systemic risk). The preliminary tissue distribution and systemic absorption data suggested that skin preexposure to BaP may considerably modify cutaneous biotransformation rate and thus deserves further investigation. The dermal model-dependent impacts of expected skin biotransformation manipulation by preexposure to chemicals such as BaP on cutaneous disposition and systemic uptake of environmental toxicants such as PCP need to be considered in risk assessment.     

Systemic uptake and cutaneous disposition of pentachlorophenol in a sequential exposure scenario: effects of skin preexposure to benzo[a]pyrene

Characterizing interactions caused by sequential skin exposures to various environmental toxicants can be critical for a meaningful risk assessment. To assess sequential chemical exposure effect on chemical cutaneous disposition and systemic uptake of a toxicant, [(14)C]pentachlorophenol (PCP) was topically administered in three porcine skin models (in vivo, ex vivo, and in vitro) at 40 micro g/cm(2) with or without skin preexposure to benzo[a]pyrene (BaP), a known human carcinogen and cutaneous cytochrome P-450 (CYP450) inducer. In the mass balance studies, BaP skin preexposure was found to enhance (14)C absorption in all three models with detectable in vivo effect during the first several days. Total 8-h absorption was tripled by skin preexposure to BaP in the ex vivo (1.1 to 3.2%) and in vitro (0.20 to 0.66%) systems. As seen in the extended in vivo studies, total absorption was 50-57% regardless of exposure conditions, suggesting the prolonged observation period may conceal existing impact of potentially modified disposition processes, such as cutaneous metabolism, on systemic absorption. Skin preexposure to the skin CYP450 inducer BaP largely changed label penetration depth and distribution pattern in cutaneous tissues and decreased (14)C concentration in skin and fat. Additionally, BaP preexposure altered (14)C systemic tissue disposition, suggesting that altered cutaneous PCP disposition may eventually change the toxicity profile (cutaneous vs. systemic risk). The preliminary tissue distribution and systemic absorption data suggested that skin preexposure to BaP may considerably modify cutaneous biotransformation rate and thus deserves further investigation. The dermal model-dependent impacts of expected skin biotransformation manipulation by preexposure to chemicals such as BaP on cutaneous disposition and systemic uptake of environmental toxicants such as PCP need to be considered in risk assessment.     

3-Hydroxybenzo(a)pyrene as a biomarker of dermal exposure to benzo(a)pyrene

The aim of this study was to determine the percutaneous absorption flux of BaP (20 μg/cm² in ethanol) and the usefulness of urinary 3-OHBaP as a bio-indicator of dermal exposure to BaP. The percutaneous absorbed dose and absorption flux were estimated by comparison with intravenous administration of BaP (0.01 and 0.05 mg/kg in Cremophor^®) as reference way. A percutaneous absorption flux of 0.37 μg/cm²/h was determined by killing groups of rats, following exposure time of 4.5 and 24 h. [¹⁴C] skin content was 3.1 μg/cm², after 24 h exposure to BaP. Total urinary 3-OHBaP accounted for 0.4% of the real absorbed dose, which was fourfold higher than the percentage of an intravenous dose excreted as 3-OHBaP. This finding reveals that percutaneous absorption of BaP, based on the ratio of urinary excretion of 3-OHBaP following percutaneous exposure compared to percutaneous absorption following intravenous administration of BaP, is overestimated in the rat. In vitro, BaP was intensively metabolised by rat skin. Unchanged BaP and 3-OHBaP in receptor fluid accounted for 50 and 30% of the total radioactivity. This percutaneous first past effect of BaP in rats could, in part, explain the higher urinary excretion ratio of 3-OHBaP compared to the value based on intravenous administration of BaP. Conversely, BaP was largely lower metabolised as 3-OHBaP during percutaneous absorption by humans, so BaP absorption flux should be overestimated to a lesser extent in humans than in rats.     

In vitro and in vivo percutaneous absorption of catechol.

The Cosmetic Ingredient Review Expert Panel found insufficient data to conclude that catechol could be used safely in permanent hair dye products. Information was lacking on the extent of oxidation and skin absorption of remaining catechol. In vitro percutaneous absorption studies were conducted in human and rat skin using a consumer permanent hair dye spiked with 0.6% catechol. A 30-min application demonstrated 0.4% of the applied dose was absorbed through human skin and 0.2% through rat skin. The minimal absorption observed was due to the short exposure time and to partial oxidation of catechol by the dye developer. The fate of catechol remaining in rat skin after exposure in vitro and in vivo was investigated with additional absorption studies using catechol in ethanol. At 72 h, 24-h application of 4% catechol resulted in skin absorption of 81% of the applied dose in vitro and 53% in vivo. Skin levels measured at 24 h remained unchanged after 72 h. Therefore the skin reservoir did not contribute to the estimated systemic absorption. A deconvolution technique employed to predict skin absorption using plasma levels from intravenous and dermal administration overestimated in vivo skin absorption due to volatility of catechol in an ethanolic vehicle.     

Dermal absorption in rhesus monkeys of polychlorinated biphenyls from soil contaminated with Aroclor 1260

Human health risk assessments involving contaminated soil include dermal absorption as a potential pathway contributing to the total exposure burden. For PCB-contaminated soil, the U.S. Environmental Protection Agency uses a dermal absorption factor of 14%, based on a 1993 study of dermal absorption in rhesus monkeys. The current study examined several parameters that can influence the dermal absorption of lipophilic hydrocarbons, including soil organic content, particle size, skin residence time, and contaminant "aging" in the soil. Four groups of four female rhesus monkeys each were exposed to radiolabeled Aroclor 1260 either intravenously (100% absorption) or dermally with PCB-spiked soil. Groups exposed for 12 or 24 h to PCBs aged in soil exhibited percutaneous absorption values of 3.43 +/- 0.35 and 4.26 +/- 0.52%, respectively, while a group exposed for 24 h to soil freshly spiked with PCBs exhibited a dermal absorption value of 4.07 +/- 0.46%. Evidence strongly suggests that the factor most responsible for modulating the percutaneous absorption of highly lipophilic compounds from soil is its organic content. The base soil used in the current study with Aroclor 1260 had an organic content of 5-6% (< or =2 mm particle fraction), a value typical for U.S. soil. The organic content of the soil applied to the skin was 8.7% (<150 microm particle fraction), a value that contrasts sharply with the soil containing 0.9% organics used in the 1993 study with Aroclors 1242 and 1254 that produced a dermal absorption value of 14% for PCBs.     

In vitro and in vivo percutaneous absorption of retinol from cosmetic formulations: significance of the skin reservoir and prediction of systemic absorption

The percutaneous absorption of retinol (Vitamin A) from cosmetic formulations was studied to predict systemic absorption and to understand the significance of the skin reservoir in in vitro absorption studies. Viable skin from fuzzy rat or human subjects was assembled in flow-through diffusion cells for in vitro absorption studies. In vivo absorption studies using fuzzy rats were performed in glass metabolism cages for collection of urine, feces, and body content. Retinol (0.3%) formulations (hydroalcoholic gel and oil-in-water emulsion) containing (3)H-retinol were applied and absorption was measured at 24 or 72 h. All percentages reported are % of applied dose. In vitro studies using human skin and the gel and emulsion vehicles found 0.3 and 1.3% retinol, respectively, in receptor fluid at 24 h. Levels of absorption in the receptor fluid increased over 72 h with the gel and emulsion vehicles. Using the gel vehicle, in vitro rat skin studies found 23% in skin and 6% in receptor fluid at 24 h, while 72-h studies found 18% in skin and 13% in receptor fluid. Thus, significant amounts of retinol remained in rat skin at 24 h and decreased over 72 h, with proportional increases in receptor fluid. In vivo rat studies with the gel found 4% systemic absorption of retinol after 24 h and systemic absorption did not increase at 72 h. Retinol remaining in rat skin after in vivo application was 18% and 13% of the applied dermal dose after 24 and 72 h, respectively. Similar observations were made with the oil-in water emulsion vehicle in the rat. Retinol formed a reservoir in rat skin both in vivo and in vitro. Little additional retinol was bioavailable after 24 h. Comparison of these in vitro and in vivo results for absorption through rat skin indicates that the 24-h in vitro receptor fluid value accurately estimated 24-h in vivo systemic absorption. Therefore, the best single estimate of retinol systemic absorption from in vitro human skin studies is the 24-h receptor fluid value. However, the receptor fluid value from the 72-h extended study may be used in a worst-case exposure estimate. In conclusion, in vivo skin absorption studies can be useful in determining whether to include material in the in vitro skin reservoir as absorbable material in estimates of systemic absorption.     

A novel "by difference" method for assessing dermal absorption of polycyclic aromatic hydrocarbons from soil at federal contaminated sites

A highly precautionary cost-effective method for estimating dermal absorption using data from 24-h skin soap washes from in vitro dermal absorption tests in Bronaugh flow-through diffusion cells with human skin is reported. Skin was dosed with 16 U.S. Environmental Protection (EPA) priority polycyclic aromatic hydrocarbons (PAH) applied in mixture each at 2 μg/ml (ppm) in acetone without soil. Concurrent tests were conducted with an unspiked aqueous suspension of PAH-contaminated soil obtained from a Canadian federal contaminated site. Percentage dermal absorption was estimated "by difference" from the applied dose and that detected by high-performance liquid chromatography (HPLC) in 24-h skin soap washes. The dermal absorption for 11 PAH ranged from 71 to 88.3% without and with soil, respectively. Lower absorption was found for 5 PAH in soil, in the range of 26.4 to 60.8%. Data could not be corrected for evaporative loss due to inconsistent data from Tenax adsorbent. Corroboratory gas chromatography/mass spectroscopy (GC/MS) tests are needed. Previously published in vitro data from the authors' laboratory supported use of the "by difference" method.     

Earthworm metabolomic responses after exposure to aged PCB contaminated soils

(1)H NMR metabolomics was used to measure earthworm sub-lethal responses to polychlorinated biphenyls (PCBs) in historically contaminated (>30?years) soils (91-280?mg/kg Aroclor 1254/1260) after two and 14?days of exposure. Although our previous research detected a distinct earthworm metabolic response to PCBs in freshly spiked soil at lower concentrations (0.5-25?mg/kg Aroclor 1254), the results of this study suggest only weak or non-significant relationships between earthworm metabolic profiles and soil PCB concentrations. This concurs with the expectation that decades of contaminant aging have likely decreased PCB bioavailability and toxicity in the field. Instead of being influenced by soil contaminant concentration, earthworm metabolic profiles were more closely correlated to soil properties such as total soil carbon and soil inorganic carbon. Overall, these results suggested that (1)H NMR metabolomics may be capable of detecting both site specific responses and decreased contaminant bioavailability to earthworms after only two days of exposure, whereas traditional toxicity tests require much more time (e.g. 14?days for acute toxicity and >50?days for reproduction tests). Therefore, there is significant opportunity to develop earthworm metabolomics as a sensitive tool for rapid assessment of the toxicity associated with contaminated field soils.     

In vitro dermal absorption of methyl salicylate, ethyl parathion, and malathion: first responder safety

In vitro tests with fresh dermatomed (0.3 to 0.4 mm thick) female breast skin and one leg skin specimen were conducted in Bronaugh flow-through Teflon diffusion cells with three chemicals used to simulate chemical warfare agents: 14C-radiolabeled methyl salicylate (MES), ethyl parathion (PT), and malathion (MT), at three dose levels (2, 20, and 200 mM). Tests were conducted at a skin temperature of 29 degrees C using a brief 30-min exposure to the chemical and a 6.5-h receivor collection period. Rapid absorption of all three chemicals was observed, with MES absorbed about 10-fold faster than PT and MT. For MES, PT, and MT, respectively, there was 32%, 7%, and 12% absorption into the receivor solution (Hank's HEPES buffered saline with 4% bovine serum albumin [BSA], pH 7.4) at the low dose (2 mM), 17%, 2%, and 3% at the medium dose (20 mM), and 11%, 1%, and 1% at the high dose (200 mM) levels. Including the skin depot for MES, PT, and MT, respectively, there was 40%, 41%, and 21% (low dose), 26%, 16%, and 8% (medium dose), and 13%, 19%, and 10% (high does) absorption. Efficacy of skin soap washing conducted at the 30 min exposure time ranged from 31% to 86%, varying by chemical and dose level. Skin depot levels were highest for the relatively lipophilic PT. "Pseudo" skin permeability coefficient (K(p)) data declined with dose level, suggesting skin saturation had occurred. An in-depth comparison with literature data was conducted and risk assessment of first responder exposure was briefly considered.     

Oral bioavailability of cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats

Cyclotrimethylenetrinitramine (RDX), a commonly used military explosive, was detected as a contaminant of soil and water at Army facilities and ranges. This study was conducted to determine the relative oral bioavailability of RDX in contaminated soil and to develop a method to derive bioavailability adjustments for risk assessments using rodents. Adult male Sprague-Dawley rats preimplanted with femoral artery catheters were dosed orally with gelatin capsules containing either pure RDX or an equivalent amount of RDX in contaminated soils from Louisiana Army Ammunition Plant (LAAP) (2300 microg/g of soil) or Fort Meade (FM) (670 microg/g of soil). After dosing rats, blood samples were collected from catheters at 2-h intervals (2, 4, 6, 8, 10, and 12) and at 24 and 48 h. RDX levels in the blood were determined by gas chromatography. The results show that the peak absorption of RDX in blood was 6 h for neat RDX (1.24 mg/kg) and for RDX from contaminated soil (1.24 mg/kg) of LAAP. Rats dosed with RDX-contaminated FM soil (0.2 mg/kg) showed peak levels of RDX in blood at 6 h, whereas their counterparts that received an identical dose (0.2 mg/kg) of neat RDX showed peak absorption at 4 h. The blood levels of absorbed RDX from LAAP soil were about 25% less than for neat RDX, whereas the bioavailability of RDX from FM soils was about 15% less than that seen in rats treated with neat RDX (0.2 mg/kg). The oral bioavailability in rats fed RDX in LAAP soil and the FM soil was reduced with the neat compound but decrease in bioavailability varied with the soil type.     

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 theremainder 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 directcontact with skin. PCP is the most ubiquitous compound foundwhen 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 PCPfrom soil and from the control vehicle acetone. In vivo in theRhesus monkey, percutaneous absorption of PCP was 24.4±6.4%of applied dose from soil and 29.2±5.8% of applied dosefrom acetone vehicle for a 24-hr exposure period. This amountof absorption makes PCP one of the more extensively absorbedcompounds to date. Additionally, the ¹⁴C half-life was 4.5 daysfollowing both intravenous and skin administration of [¹⁴C]PCP.These data suggest high bioavailability and an extended biologicalinteraction period with the long half-life. In vitro percutaneousabsorption with human cadaver skin and human plasma receptorfluid underestimated the in vivo absorption. Receptor fluidaccumulation was 0.6±0.09% and 1.5±0.2% for twoskin 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. Overallaccountability for in vitro dose ranged from 81 to 96%.     

Experimental methods for determining permethrin dermal absorption

The objectives of this study were to (1) determine the percutaneous absorption of radiolabeled permethrin and piperonyl butoxide (PBO) in vivo in rats and in vitro to permit a calculation of the ratio of in vitro to in vivo values, and (2) test a method of estimating in vivo human absorption. Carbon-14 labeled permethrin in ethanol solution was applied to the clipped skin of rats in vivo at doses of 2.25, 20, or 200 μg/cm2. As a reference compound, 14C-labeled PBO in isopropanol solution was applied to rat skin in vivo at a dose of 100 μg/cm2. All applications were washed at 24 h postapplication, and rats were sacrificed either at 24 h for permethrin or 5 d for both compounds. The radiolabel recovered from carcass, urine including cage wash, and feces was summed to determine percent absorption. For the 24-h time point, at doses of 2.25, 20, and 200 μg/cm2 of permethrin, values of 22, 22, and 28%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). For the 5-d time point, at doses of 2.25, 20, and 200 μg/cm2 of permethrin, values of 38, 38, and 30%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). The 5-d percutaneous absorption of 14C-PBO at 100 μg/cm2 was determined to be 42% (n=6). Dose and test duration did not exert a statistically significant effect on percutaneous absorption of permethrin in the rat in vivo. For in vitro absorption determination, 14C-permethrin in ethanol solution was applied to freshly excised human skin in an in vitro test system predictive of skin absorption in humans. Twenty-four hours after application, the radiolabel recovered from dermis and receptor fluid was summed to determine percent absorption. At doses of approximately 2.25, 20, and 200 μg/cm2 permethrin, values of 1, 3, and 2%, respectively, were obtained for percutaneous absorption (n=9 per dose). Excised human skin absorption of 14C-PBO at 100 μg/cm2 was determined to be 7% (n=9). Excised rat skin absorptions of permethrin at 2.25, 20, and 200 μg/cm2 were found to be 20, 18, and 24%, respectively (n=6 per dose), approximately 10-fold higher than human skin absorption. Excised rat skin absorption of PBO was also higher (35%) than the value obtained for human skin by a factor of about 5.     

Interaction of hydration, aging, and carbon content of soil on the evaporation and skin bioavailability of munition contaminants

Water plays a key role in enhancing the permeability of human skin to many substances. To further understand its ability to potentially increase the bioavailability of soil contaminants, artificial sweat was applied to excised pig skin prior to dosing with munition-contaminated soils. Skin was mounted in chambers to allow simultaneous measurement of evaporation and penetration and to control air flow, which changed the dwell time of skin surface water within a l-h period post application of test materials. Additional variables included type of compound, aging of spiked soil samples, and carbon content of soil. To this end, the evaporation and skin penetration of C-14 labeled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,6-dinitrotoluene (26DNT), and 2,4,6-trinitrotoluene (TNT) were determined from two soil types, Yolo, having 1.2% carbon, and Tinker, having 9.5% carbon. RDX soil samples aged 27 mo and 62 mo were compared to freshly spiked soils samples. Similarly, 26DNT samples aged 35-36 mo and TNT samples aged 18 mo were compared to freshly spiked samples. Approximately 10 microg/cm(2) of radiolabeled compound was applied in 10 mg/cm(2) of soil. Radiolabel recovered from the dermis and tissue culture media (receptor fluid) was summed to determine percent absorption from the soils. Radiolabel recovered from vapor traps determined evaporation. Mean skin absorption of all compounds was higher for low-carbon soil, regardless of soil age and skin surface water as affected by air flow conditions. For 26DNT, a simultaneous increase in evaporation and penetration with conditions that favored enhanced soil hydration of freshly prepared samples was consistent with a mechanism that involved water displacement of 26DNT from its binding sites. A mean penetration of 17.5 +/- 3.6% was observed for 26DNT in low-carbon soil, which approached the value previously reported for acetone vehicle (24 +/- 6%). 26DNT penetration was reduced to 0.35% under dryer conditions and to 0.08% when no sweat was applied. When soil hydration conditions were not varied from cell to cell, air flow that favored a longer water dwell time increased penetration, but not evaporation, consistent with a mechanism of enhanced skin permeability from a higher hydration state of the stratum corneum. Profiles of 26DNT penetration versus air flow conditions were exponential for freshly prepared soil samples, suggesting strong and weak binding sites; corresponding profiles of 26DNT penetration from aged samples were linear, suggesting a conversion of weak to strong binding sites. Absorption and evaporation was less than 5% for TNT and less than 1% for RDX, regardless of soil type and age. Fresh preparations of RDX in Tinker soil and aged samples of TNT in Yolo soil showed a significant decrease in skin absorption with loss of surface moisture. The penetration rate of radiolabel into the receptor fluid was highest during the 1-2 h interval after dosing with 26DNT or TNT. High-performance liquid chromatography (HPLC) analysis of 26DNT in receptor fluid at maximum flux indicated no metabolism or breakdown. For TNT, however, extensive conversion to monoamino derivatives and other metabolites was observed. Relatively little radioactivity was found in the dermis after 26DNT and TNT applications, and dermal extracts were therefore not analyzed by HPLC. RDX was not sufficiently absorbed from soils to allow HPLC analysis. This study has practical significance, as the use of water for dust control at remediation sites may have the unintended effect of increasing volatilization and subsequent absorption of soil contaminants. Soil in contact with sweaty skin may give the same result. Skin absorption of 26DNT from soil was over 50-fold higher than the value for dryer skin and over 200-fold higher than the value obtained when there was no sweat application. While the hydration effect was less dramatic for RDX and TNT, soil contaminants more closely matching the physical properties of 26DNT may be similarly affected by hydration.     

Dermal absorption of the insect repellent DEET (N,N-diethyl-m-toluamide) in rats and monkeys: effect of anatomical site and multiple exposure

The dermal absorption of 14C-ring-labeled DEET (N,N-diethyl-m-toluamide) applied in acetone to the skin of Sprague-Dawley rats and rhesus monkeys for 24 h was determined. Absorption in rats dosed middorsally was 36 +/- 8% with a urinary excretion half-life (t1/2) of 20 h. Both the extent and rate of absorption in monkeys were highly dependent on anatomic site, with 14 +/- 5% (t1/2 = 4 h) penetrating the forearm, 33 +/- 11% (t1/2 = 6 h) the forehead, 27 +/- 3% (t1/2 = 7 h) the dorsal forepaw, and 68 +/- 9% (t1/2 = 8 h) the ventral forepaw. Since DEET is commonly applied frequently by the same individual, the effect of multiple exposure was investigated. No significant difference (p greater than or equal to .3) was obtained either between the total percentage absorbed dermally with single (36 +/- 8%; t1/2 = 20 h) as compared with three (31 +/- 5%; t1/2 = 16 h) DEET applications at 2-h intervals to rats, or between single (14 +/- 5%; t1/2 = 4 h) as compared with three (12 +/- 1%; t1/2 = 4 h) applications at 0.5-h intervals to monkey forearm. A DEET metabolite detected in urine 4 h following topical exposure in humans was extractable following either acid (HCl) hydrolysis or urine treatment with beta-glucuronidase and was identified as ethyltoluamide (parent ion 163; base ion 119) following HPLC purification and characterization by GC/MS.     

Relative oral bioavailability of arsenic from contaminated soils measured in the cynomolgus monkey.

A number of studies have found that gastrointestinal absorption of arsenic from soil is limited, indicating that a relative oral bioavailability (RBA) adjustment is warranted when calculating risks from exposure to arsenic-contaminated soil. However, few studies of arsenic bioavailability from soil have been conducted in animal models with phylogenetic similarity to humans, such as nonhuman primates. We report here the results of a study in which the RBA of arsenic in soil from a variety of types of contaminated sites was measured in male cynomolgus monkeys. A single oral dose of each contaminated soil was administered to five adult male cynomolgus monkeys by gavage, and the extent of oral absorption was evaluated through measurement of arsenic recovery in urine and feces. Urinary recovery of arsenic following doses of contaminated soil was compared with urinary recovery following oral administration of sodium arsenate in water in order to determine the RBA of each soil. RBA of arsenic in 14 soil samples from 12 different sites ranged from 0.05 to 0.31 (5-31%), with most RBA values in the 0.1-0.2 (10-20%) range. The RBA values were found to be inversely related to the amount of arsenic present with iron sulfate. No other significant correlations were observed between RBA and arsenic mineralogic phases in the test soils. The lack of clear relationships between arsenic mineralogy and RBA measured in vivo suggests that gastrointestinal absorption of arsenic from soil may be more complex than originally thought, and subject to factors other than simple dissolution behavior.     

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.     

Polychlorinated biphenyls (PCBs): dermal absorption, systemic elimination, and dermal wash efficiency

The objectives of this study were to determine the dermal absorption, systemic elimination, and dermal wash efficiency for polychlorinated biphenyls (PCBs). 14C-Labeled 42% PCB and 14C-labeled 54% PCB were topically and parenterally administered to rhesus monkeys and guinea pigs. Dermal absorption, determined by 14C urinary excretion, was extensive. In guinea pigs, 33% of the applied 14C-labeled 42% PCB dose and 56% of the 14C-labeled 54% PCB dose were absorbed. In rhesus monkeys, 15-34% of the labeled 42% PCB was dermally absorbed, depending on the magnitude of the applied dose. 14C-labeled 42% PCB applied to guinea pig skin was immediately washed with water and acetone. Only 59% of the applied dose was removed from the skin. A post-24-h washing removed only 1% of applied labeled 42% PCB and 20% of applied labeled 54% PCB. Postcontamination washing cannot be assumed to remove all contaminated PCB from skin. The body elimination of 14C was continuous and slow, with elimination half-lives on the order of 2-3 d in the guinea pig and 4-7 d in the monkey. Only 50-65% of an intramuscular dose could be accounted for in urine and feces for up to 28 d excretion. The elimination half-lives following topical administration were not much greater than that following intramuscular administration. This suggests that PCBs are rapidly and extensively absorbed through the skin, and that they are then probably generally distributed throughout the body, and then slowly eliminated.     

Effects of skin preapplication treatments and postapplication cleansing agents on dermal absorption of 2,4-dichlorophenoxyacetic acid dimethylamine by Fischer 344 rats

Various methods of preparing dermal application sites in Fischer 344 rats prior to exposure to 2,4-dichlorophenoxyacetic acid dimethylamine salt (2,4-D amine) and the effect of various cleansing agents following exposure were examined by measuring recoveries of 14C-labeled 2,4-D amine in skin, postapplication cleansing solution, blood, and urine. The middorsal area of the rat was the site of application for four treatments tested: (1) hair clipping only, (2) hair clipping followed by an epilatory cream, (3) hair clipping plus shaving with an electrical razor, and (4) as in treatment 3 followed by washing with soap and water. A last preparation was the rat's tail thoroughly brushed with soap and water. The results indicated that the tail retained greater than 75% of the material, thus preventing its absorption into the blood stream and subsequent removal by cleansing. With treatment 1 the dense short hair remaining after clipping impaired the absorption of 2,4-D as evidenced by considerably lower blood and urinary levels than treatments 2-4. With preparations 1-4, 45-61% of the dose was removed with the 7-h postapplication cleansing and a further 5-6% with the subsequent 23-h cleansing. In other studies using preparation 3 above, the following cleansing agents were tested: soap and water, water, isopropanol, acetone, and Rad-Con, a foam-producing cleanser. Rad-Con removed more 2,4-D from the skin than other cleansing agents after 7 h of exposure and more than soap and water after 23 h. The percentages of 2,4-D left on the skin following either 7- or 23-h cleansing with Rad-Con were 8-12%, nearly half those following the other cleansing agents. Cleansing agents other than Rad-Con presented little advantage over soap and water. With all cleansing agents, delaying cleansing from 7 to 23 h after exposure resulted in higher blood and urinary levels of 2,4-D measured 24 h after application.     

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.