In Vivo Percutaneous Absorption of Arsenic from Water and CCA-Treated Wood Residue

Ronald C. Wester*,1, Xiaoying Hui{dagger}, Sherry Barbadillo{dagger}, Howard I. Maibach{dagger}, Yvette W. Lowney{ddagger}, Rosalind A. Schoof§, Stewart E. Holm and Michael V. Ruby{ddagger}

* University of California, San Francisco, Dermatology Department, PO Box 0989, San Francisco, California 94143-0989; {dagger} University of California,San Francisco, California 94143-0989; {ddagger} Exponent, Boulder, Colorado 80301; § Integral Consulting, Inc., Mercer Island, Washington; and Georgia-Pacific Corporation, Atlanta, Georgia 30303-1847

Received September 30, 2003; accepted February 5, 2004


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study was conducted to evaluate the dermal absorption of arsenic from residues present on the surface of wood preserved with chromated copper arsenate (CCA). The research reported herein used methods parallel to those of earlier research on the dermal absorption of radiolabeled arsenic (R. C. Wester et al., 1993Go, Fund. Appl. Toxicol. 20, 336–340), with modifications to allow use of environmental matrices that are not radiolabeled. These modifications include the surface area of application and dietary intake of arsenic, thus maximizing the potential for detection of dermally absorbed arsenic in exposed animals above diet-associated background levels of exposure. Two forms of arsenic were administered in this work. The first, arsenic in solution, was applied to the skin of monkeys to calibrate the model against prior absorption research and to serve as the basis of comparison for absorption of arsenic from CCA-treated wood residues. The second substrate was residue that resides on the surface of CCA-treated wood. Results from this research indicate that this study methodology can be used to evaluate dermally absorbed arsenic without the use of a radiolabel. Urinary excretion of arsenic above background levels can be measured following application of soluble arsenic, and absorption rates (0.6–4.4% absorption) are consistent with prior research using the more sensitive, radiolabeled technique. Additionally, the results show that arsenic is poorly absorbed from CCA-treated wood residues (i.e., does not result in urinary arsenic excretion above background levels).

Key Words: dermal arsenic absorption; CCA; arsenic exposure; environmental arsenic.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prior research on the dermal absorption of soluble arsenic administered in water, and soluble arsenic mixed with soil, in Rhesus monkeys (Wester et al., 1993Go) produced mean dermal absorption rates for soluble arsenic in the range of 2.0–6.4% of the applied dose. Percent absorption did not vary across five orders of magnitude in the applied dose. Also, in Wester et al. (1993)Go, the absorption rates for arsenic from the test soil fell within the range of the rates for percutaneous absorption of the arsenic administered in water. The research method was based on dermal application and subsequent urinary excretion of radiolabeled arsenic (As73), thereby permitting detection of very small amounts of absorbed arsenic in the urine. Subsequent to this research, questions arose as to whether the data on dermal absorption of soluble arsenic mixed with soil immediately prior to dermal application are representative of arsenic absorption from environmental media (U.S. EPA, 2001aGo). Specifically, this issue affects the ongoing discussion of dermal absorption of arsenic from wood treated with chromated copper arsenate (CCA). Currently, the U.S. EPA is evaluating whether children who repeatedly contact playground equipment or decks made from CCA-treated wood may face increased risks from the associated arsenic exposures (U.S. EPA 2001aGo, 2003Go). The U.S. EPA assessment currently relies on dermal arsenic absorption data generated for soluble arsenic and soluble arsenic mixed with soil, and may not be representative of exposures associated with contact with CCA-treated wood. This paper used a methodology similar to that used by Wester et al. (1993)Go to assess dermal arsenic absorption from the residues that would adhere to an individual's skin after contacting the surface of CCA-treated wood.

Among several challenges associated with studying exposure to arsenic from environmental media is the large degree of exposure to background levels of arsenic from the diet (Schoof, 1999aGo,bGo; Yost et al., 2004Go). Typical daily urinary arsenic excretion for Rhesus monkeys consuming the standard diet of Purina monkey chow is 5–15 µg As/day. In the Wester et al. (1993)Go research, the use of a radiolabeled arsenic source circumvented the confounding effects of concomitant dietary exposures and associated difficulties in data interpretation. For study of environmental samples (e.g., contaminated soils or treated wood), it is not practicable to use a radiolabeled source. Therefore, a new research protocol was designed, incorporating a low-arsenic diet. Urine samples were analyzed using inductively coupled plasma/mass spectrometry, which provided an adequately low detection limit for total arsenic in urine. This alteration in the study design allows for a sensitive evaluation of dermal arsenic absorption from natural environmental media.

The research reported herein describes the use of the Rhesus monkey model to measure the dermal absorption of arsenic from water and from residues collected from the surface of CCA-treated wood. The Rhesus monkey is a relevant animal model for in vivo human percutaneous absorption (Wester and Maibach, 1975Go, 1989Go).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Formulations and dosing rates.
An open crossover design was used, in which each animal is dosed in each of the trials (soluble arsenic in solution applied to the skin, CCA residue applied to the skin, and iv injection), with a washout period of at least 14 days between each dose. This design allows for each animal to serve as its own internal control.

The iv dose (1060 µg arsenic/monkey) was administered as a solution of sodium arsenate heptahydrate in deionized (DI) water (2120 mg/l arsenic). For the iv dose, each monkey received 0.5 ml of the dosing solution injected into the saphenous vein. The iv dose was given while the monkeys were in their metabolic cages, so the monkeys did not spend any time in the metabolic restraint chairs, as they did with the topical doses.

For the soluble arsenic dose, arsenic was administered in water onto the monkey's skin at an application rate of 5 µl/cm2 evenly applied across 100 cm2 of skin, to achieve a total dermal dose of 1430 µg arsenic (Table 1). The solution was prepared from sodium arsenate heptahydrate in DI water, which was acidified with 1% nitric acid (trace-metal grade). The soluble arsenic dose was designed to match the arsenic dose applied in the CCA-treated wood residue.


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TABLE 1 Arsenic Doses Given during This Study and Earlier Dermal Absorption Studies

 
The CCA residue used in this study is the easily dislodgeable material present on the surface of CCA-treated wood, and was collected from the surface of CCA-treated wood that had been weathered in the environment. This represents the material that a human might contact during play or use of a CCA-treated wooden structure. Consideration was given to using an actual piece of CCA-treated wood in this research, but we elected to use the "collected residue" for the following reasons:

The residue, in the form of a fine particulate, was supplied by the American Chemistry Council (ACC, 2003Go), and represents the material present on the surface of CCA-treated wood, which an individual might contact during use of, or play on, structures made of treated wood. In collecting the "residue" from the surface of the wood, efforts were made to collect the material on the surface of the wood that might be dislodged during direct human contact with the wood. Specifically, CCA-treated boards consisting of either Southern Yellow Pine or Ponderosa Pine were removed from in-service residential decks in Michigan and Georgia. Deck structures ranged from one to four years of age and had no coatings applied. Aged structures were selected, because they were believed to best represent the material that an individual might contact over time. As described below, recent chemical characterization work indicates that the chemical structure of the arsenic in the residue collected from the surface of decks is indistinguishable from the form of arsenic in newly treated or aged CCA-treated wood structures. A total of 1456 board sections (each 2 ft. long) were collected and shipped to Michigan State University, where the residue was collected as a single composite from multiple boards. The residue was collected by wiping the boards with a soft-bristle test-tube brush while rinsing with DI water. The rinsate and residue collected in this manner were filtered through glass wool, concentrated by rotary evaporation under vacuum at 46°C, and then air dried in a fume hood at 22°C and 65% humidity. The dried residue was irradiated using Cobalt-60 irradiation for 3 h, to eliminate possible microbial contamination of the sample.

Duplicate aliquots of the residue material used in the dermal dosing studies were analyzed for arsenic, chromium, copper, iron, and manganese concentrations, which involved digestion in refluxing nitric acid and analysis by inductively coupled plasma mass spectroscopy (ICP-MS; EPA Method 6010B; U.S. EPA, 1997Go). This analytical method was used to ensure adequate sensitivity for all metals of interest. As a means of comparing the composition of the CCA residue with the composition of treated wood, samples (a 1-cm2 wood chip from the top 0.2 cm of wood surface) of newly treated wood and a sample of weathered wood from a five-year-old CCA-treated residential deck were subjected to identical digestion and analyses.

For very fine soil (i.e., silty clay), a loading of 5.4 mg/cm2 of skin results in a monolayer (U.S. EPA, 2001bGo). Because the residue appears similar in particle size distribution to silty clay, and a loading rate of 4 mg/cm2 of the residue provides complete coverage on a flat surface, a loading rate of 4 mg/cm2 was selected for this study. Application of 4 mg/cm2 on 100 cm2 of skin area resulted in a total dose of 1422 µg arsenic (Table 1). The residue was applied as a dry powder, and spread in an even layer across the exposure area.

In Vivo Model.
Female Rhesus monkeys were selected for this research because of their ability to duplicate the biodynamics of percutaneous absorption in humans, and because previous studies of percutaneous arsenic absorption have used this same model. Prior research indicates that percutaneous absorption in the Rhesus monkey is similar to absorption in humans across a variety of chemicals and range of dermal penetration characteristics (Wester and Maibach, 1975Go). This research indicates that measurements from the monkey are just slightly higher than their counterparts in the human. Results from other species (pig, rat, rabbit) are not nearly as close to the values measured in humans, and indicate that, of the species tested, absorption in the monkey is closest to that in the human.

The monkeys were approximately 20 years old, which is the same approximate age as the monkeys used in the previous dermal arsenic absorption research (Wester et al., 1993Go). The animals reside within the monkey colony maintained by the University of California, San Francisco, and have not been used for active research for 18 months. Prior to the beginning of the current series of studies, no topical doses had been applied to the skin of these animals for more than four years.

Each topical dose was applied to a pre-measured 100-cm area of abdominal skin of three monkeys. The dosing area was demarked by "masking" the boundaries with a single layer of Tegaderm (a water-vapor-permeable adhesive membrane available from 3M Health Care, St. Paul, MN) and then was dosed by spreading the fluid (5 µl/cm2) or residue (4 mg/cm2) evenly across the 100-cm2 dosing area. The dosing area was then covered with a layer of Tegaderm to ensure that the material remained in contact with the skin. The Tegaderm patch over the dosing area extended well beyond the boundaries of the exposure area. In addition to the Tegaderm patch, the abdomen of each monkey was wrapped with Spandage Instant Stretch Bandage (MEDI-TECH International Corp., Brooklyn, NY) to ensure that the applied dose was kept in direct contact with the skin throughout the dosing period. This bandage is of a web construction; most of the Tegaderm was exposed to the open air for moisture and air exchange. Following application of the topical doses, the monkeys were placed in metabolic restraint chairs for the duration of the eight-h dosing period. The eight-h dosing period was selected to represent an upper bound of time that an individual might remain in contact with residues, and is also the upper limit of time that the monkey can remain in the metabolic restraint chair. During this time, the monkeys had free access to water, but were restricted from touching their abdominal area. Researchers remained in the room and interacted with the monkeys, and the monkeys were hand fed bananas and liquid diet during this stage.

Urine was collected during the 8-h dosing period in a pan under the metabolic chair. After 8 h, the monkeys were removed from the chairs, the Spandage bandage and Tegaderm patch were removed, and the applied doses were removed using a soap and water wash (50/50 v/v, soap and water, followed by water, soap, and two final water washes). The monkeys were then transferred to metabolic cages for continued urine collection over the following seven days.

As with humans, significant exposure to arsenic occurs from the normal diet (Schoof, 1999aGo,bGo; Yost, 2004Go). Urinary excretion of total arsenic for Rhesus monkeys on the standard diet of Purina Monkey Chow falls in the range of 5 to 15 µg/day—levels that would obscure accurate detection of the arsenic that might be absorbed following topical application of arsenic. Therefore, the monkeys were provided a low-arsenic diet (Primate Liquidiet from BioServe, Inc.) for seven days prior to each dose. The powdered Liquidiet formulation also was prepared into meal bars, which were provided ad libitum to the monkeys during the research period (seven days prior to dosing through seven days after dosing). The diet was supplemented with pieces of banana and apple, which are both known to be low in total arsenic (Schoof et al., 1999aGo). DI water was provided ad libitum. The liquid diet was provided as both liquid and solid forms. Preference was for the solid form. The monkeys maintained their body weight during the study.

The monkey urine samples were preserved with nitric acid (2%) at the time of collection, and shipped to Battelle Pacific Northwest Laboratories in Sequim, Washington, for analysis. At Battelle, the urine samples were acidified with an additional 2% (by volume) of concentrated nitric acid and analyzed for total arsenic by ICP/MS (Method 1638, U.S. EPA, 2002Go). This method provides a method detection limit (MDL) of approximately 0.1 µg/l arsenic in monkey urine. Quality assurance and quality control (QA/QC) samples included a method blank, duplicates, matrix spikes, and a laboratory control sample at a 5% frequency of analysis.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Total metals concentrations of arsenic, chromium, and copper in the residue are presented in Table 2, along with corresponding data for a sample of newly treated wood (recently purchased from a local retailer), and a sample of weathered wood from a five-year-old residential deck. The relative concentrations of these three metals are similar for all three samples, indicating that the residue contains a proportion of the CCA metals that is similar to both freshly treated and aged wood. As expected, concentrations of all three metals are somewhat lower in the wood-chip samples than in residue. Although the residue is largely composed of decayed wood from the wood surface, larger wood fragments were removed from the sample during preparation of the residue, when the residue is filtered through glass wool. In contrast, the wood-chip samples contained a larger proportion of wood matter. More instructive is the ratio of the different metals from these analyses, which are similar across the samples.


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TABLE 2 Metal Concentrations in CCA Residue and Wood

 
Data for the mass of urinary arsenic excreted by the monkeys following dermal dosing are presented in Table 3 (soluble arsenic), Table 4 (CCA residue), and Table 5 (iv dose). Data on the background arsenic excretion for each monkey for the days prior to the dosing period are included. The value reported for the 0- to 24-h period is the combined arsenic mass from the urine collected during the 8-h dosing period, a wash of the urine collection pan, and the urine collected from 8 h to 24 h after the monkeys were returned to their cages. The right-most column in each of these tables presents the mass of arsenic excreted for each 24-h period, corrected for background levels of arsenic in urine by subtracting out the median of the eight background data points for each monkey, on a monkey-specific basis. (In other words, the eight background values for each monkey were compiled, and the median was calculated for each monkey. The median values of 6.09, 5.48, and 3.41 µg arsenic/24-h period for monkeys 1, 2, and 3, respectively, were subtracted out of the 24-h urine value to yield "background-corrected" values.) The median value was selected because it is the best representation of the central tendency of background urinary arsenic excretion over time, and is less sensitive to potential outlier effects (Fig. 1). This correction was applied to the data to reduce the influence of dietary arsenic on the excreted arsenic mass. The mass of arsenic excreted that is associated with the dermally applied dose is calculated by adding the mass excreted from the time of dosing through 96 h after dosing. After 96 h, the arsenic excretion has returned to background levels.


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TABLE 3 Urinary Arsenic Data following Dermal Application of Arsenic in Soluble Dose

 

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TABLE 4 Urinary Arsenic Data following Dermal Application of Arsenic in CCA Residue

 

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TABLE 5 Urinary Arsenic Data following Intravenous Arsenic Dose

 


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FIG. 1. Background urinary arsenic mass excretion in comparison to excretion following dosing with CCA residue.

 
Prior research indicates that for female Rhesus monkeys, urinary excretion of an iv dose of arsenic was 80 ± 6.7% of the administered dose (Wester et al., 1993Go). The iv dose given during this study resulted in 82.1 ± 2.2% of the administered arsenic dose excreted in urine (Table 5). The average urinary arsenic excretion value from this study (82.1%) was used to adjust the assumed total mass of arsenic excreted over the 96-h collection period, by dividing the calculated mass excreted by 0.821. This correction is intended to account for the fraction of arsenic that might be retained within the body or excreted by other routes (e.g., feces). This calculated mass excreted was then divided by the applied dose to calculate the percent of the applied dose that was absorbed for each animal and each dosing substrate. The percent absorption of arsenic was calculated in the following manner:

(1)

For the soluble dose, absorption rates were 3.4, 0.62, and 4.4% for the three monkeys in the study (Table 3). Dosing levels used in our earlier research on the dermal absorption of arsenic are compared to those used in this study in Table 1. Despite the nearly seven-fold difference in the dermal loading rate between the two studies, the average absorption rate for the group dosed with soluble arsenic (2.8%) is consistent with results from Wester et al. (1993)Go (Table 6). These results are consistent with the previous study, wherein absorption rates were relatively consistent (range of 2–6.4%) despite a five-orders-of-magnitude change in the dose levels (i.e., an applied dose range of 0.000024 to 2.1 µg/cm2). These data strongly support the suggestion that the difference in the measured absorption rates in the Wester et al. (1993)Go research reflects experimental variability rather than dose-related differences in absorption (U.S. EPA, 2001bGo). This is consistent with our understanding of individual variability in percutaneous absorption in humans and animals (Wester and Maibach, 1991Go, 1997Go).


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TABLE 6 Summary of Dermal Arsenic Absorption Values from Various Dosing Substrates

 
Converse to the results for soluble arsenic, data from dermal application of CCA residue indicate virtually no absorption. Absorption rates following dermal application of residue are presented in Table 4. These data show that urinary excretion of arsenic following dermal application of the CCA residue does not cause a detectable increase in urinary arsenic excretion, despite the fact that equivalent doses of arsenic were applied for both soluble arsenic and residue.

The time profiles for urinary arsenic excretion by each monkey are provided in Figure 2. These charts show a consistent time course for the three monkeys; peak excretion of arsenic occurs within 24 h of the dermal application of the soluble dose, with a rapid return to near-background levels of excretion within 48 to 72 h. Peak 24-h urinary arsenic excretion following the soluble dose ranged up to a maximum value of 41.6 µg. The time profile for arsenic excretion following dermal application of the CCA residue is also consistent across all three monkeys. Figure 2 depicts that, following application of the CCA residue, there is no increase in urinary arsenic excretion, followed out through time.



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FIG. 2. Urinary arsenic mass excretion in 24-h increments.

 
Because the number of animals that can be used in primate research is constrained, the crossover study design—wherein each individual animal is dosed in each dose group, and data from each individual monkey can be used as its own "comparison control"—was specifically selected for use in this research. This study design optimizes the potential to observe statistically significant results despite the small sample size. It does necessitate, however, use of specific statistical approaches that are consistent with the study design. To determine whether the difference in the results for the two dermal exposure groups was statistically different from background or from each other, an ANOVA analysis followed by a Tukey's multiple comparison test was conducted. In a study with a small number of animals, the variability between animals could be greater than the differences in absorption for different treatment groups; thus, statistical differences should be assessed after accounting for overall differences between monkeys. Because of the sequential nature of the data generated (i.e., at specified time points after dosing), analyses must also account for any time-dependent patterns present over the sampling period evaluated (e.g., comparing data within a given timepoint). The ANOVA model used to evaluate these data included factors for monkey, time, and treatment group. The factor for monkey controls for inter-monkey differences in mass excreted, allowing each monkey to serve as its own control. Monkey number was included as a random factor, because the monkeys tested were not specifically of interest but rather a random selection of monkeys. In order to incorporate the sampling order, time period was included in the ANOVA model as an ordered factor. After accounting for monkey and time period differences, the treatment factor (i.e., soluble or residue dose group) was assessed for significance and followed by Tukey's multiple comparison test to identify which treatments are different from one another, using an overall significance level of 0.05 or 95% confidence. Results indicate that the urinary arsenic excretion levels in the animals exposed to the CCA residue are not statistically greater than background. This is also depicted in Figure 1, which shows a scatter plot of the daily urinary excretion values for each monkey, including background urinary excretion for each animal (i.e., prior to dosing trials), in comparison to the daily urinary excretion following exposure to the CCA residue. This figure demonstrates that the range of daily urinary excretion following exposure to CCA residue falls well within the range of background urinary arsenic excretion. Conversely, the urinary arsenic excretion in the animals exposed to soluble arsenic in solution is significantly greater than background, and significantly greater than the residue exposure group.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The results from this research indicate that the methodology described above can be used to evaluate dermally absorbed arsenic from environmental samples. The development of this method was challenging because of the high degree of background arsenic exposure from the diet, and the potential for that background exposure to obscure any signal from a dermally applied dose. Use of the low-arsenic diet resulted in an approximately four-fold decrease in urinary arsenic excretion relative to the standard primate diet, and allowed for detection above background of a dermally applied dose of arsenic.

Although the results indicate that the urinary arsenic levels following topical administration of arsenic in CCA residues are not distinguishable from background, the non-zero values for background urinary arsenic excretion, and the variability of the measured background values, impose some limits regarding the sensitivity of the model to detect an absorbed dose. A statistical evaluation using a comparison of means (t-test) for our data indicates that the absorbed dose would need to be in the range of 0.10 to 0.16% of the applied dose, at the dosing levels used in this study, for daily arsenic excretion levels to be detectable above background. Thus, while these data suggest that there may not be any dermal absorption of arsenic from CCA residue (no monkey demonstrated urinary arsenic excretion that was statistically different from background), the uncertainty associated with this research model tells us that dermal absorption of arsenic from CCA residues is at least an order of magnitude lower than absorption of soluble arsenic from solution.

Extensive chemical analyses indicate that the arsenic present in the CCA residue used in this study is structurally and chemically identical to the arsenic present on the surface of newly treated or aged CCA-treated wood (Nico et al., 2003Go), thus making it an appropriate study substrate for understanding the potential dermal absorption of arsenic following contact with CCA-treated wood. The negligible absorption of arsenic from the CCA residues derives from the fact that this arsenic is chemically bound with other metals (particularly chromium) and ultimately to the wood structure (Bull, 2001Go; Nico et al., 2003Go). The physico-chemical conditions on the surface of the skin do not result in the liberation of arsenic from the residue, thus precluding absorption. These results indicate that percutaneous absorption of arsenic from environmental media can be significantly different from soluble arsenic or even soluble arsenic mixed with environmental media (Table 6). Therefore, it is not appropriate to apply generic assumptions regarding dermal absorption to these unique matrices, and medium-specific analysis may be required to understand the dermal absorption from them (and potential associated risks). This appears to be true for arsenic, and may be true for other metals that form similarly stable complexes in the environment. The latter point should not be overgeneralized until additional metals have been thoroughly studied.


    ACKNOWLEDGMENTS
 
The authors appreciate the help received from the American Chemistry Council, who provided the collected residue that was used in this research, as well as partial funding for the study. We also appreciate the support of Eric Crecelius and his staff at Battelle Marine Sciences Labs for their assistance and technical expertise in evaluating arsenic in urine. Finally, we acknowledge Georgia-Pacific Corporation for the funding they provided.


    NOTES
 

1 To whom correspondence should be addressed. Fax: (415) 753-5304. E-mail: rcwgx{at}itsa.ucsf.edu


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
American Chemistry Council (ACC) (2003). Dislodgeable material collection procedure. CCA-Treated Wood Work Group. May 12.

Bull, D. C. (2001). The chemistry of chromated copper arsenate. II. Preservative-wood interactions. Wood Sci. Technol. 34, 459–466.[CrossRef][ISI]

Nico, P. S., Fendorf, S. E., Lowney, Y. W., Holm, S. E., and Ruby, M. V. (2003). Chemical structure of arsenic and chromium in CCA-treated wood: Implications of environmental weathering. Environ. Sci. Technol. (in press)

Schoof, R. A., Yost, L. J., Eickhoff, J., Crecelius, E. A., Cragin, D. W., Meacher, D. M., and Menzel, D. B. (1999). A market basket survey of inorganic arsenic in food. Food Chem. Toxicol. 37, 839–846.[CrossRef][ISI][Medline]

Schoof, R. A., Eickhoff, J., Yost, L. J,, Crecelius, E. A., Cragin, D. W., Meacher, D. M., and Menzel, D. B. (1999). Dietary exposure to inorganic arsenic. In Proc. Third International Conference on Arsenic Exposure and Health Effects. W. R. Chappell, C. O. Abernathy, and R. L. Calderon (eds). pp. 81–88. Elsevier Science Ltd.

U.S. Environmental Protection Agency (EPA) (1997). Test methods for evaluating solid waste-physical/chemical methods, SW-846. Revised methods. Version 2. Integrated Manual/Update III. Washington, DC.

U.S. Environmental Protection Agency (EPA) (2001a). A set of scientific issues being considered by the Environmental Protection Agency regarding: Preliminary evaluation of the non-dietary hazards and exposure to children from contact with chromated copper arsenate (CCA)-treated wood playground structures and CCA-contaminated soil. FIFRA Scientific Advisory Panel (SAP) Meeting, October 23–25, 2001, Arlington, VA. SAP Report No. 2001-12, December 12.

U.S. Environmental Protection Agency (EPA) (2001b). Risk assessment guidance for Superfund. Volume I: Human health evaluation manual (Part E, Supplemental guidance for dermal risk assessment), Interim Draft, September. Office of Emergency and Remedial Response. Washington, DC.

U.S. Environmental Protection Agency (EPA) (2002). Analysis of multi-media, multi-concentration samples for metals by 200-Series metals methods and 1600-series trace metals methods. Office of Water, Washington, DC.

U.S. Environmental Protection Agency (EPA) (2003). A probabilistic risk assessment for children who contact CCA-treated playsets and decks. Draft final report. Office of Pesticide Programs, Antimicrobials Division. November 10.

Wester, R. C., and Maibach H. I. (1975). Percutaneous absorption in the rhesus monkey compared to man. Tox. Appl. Pharmacol. 32, 394–398.[ISI][Medline]

Wester, R. C., and Maibach, H. I. (1989). In vivo animal models for percutaneous absorption. In Percutaneous Absorption, 2nd ed. (R. Brouaugh and H. Maibach, Eds.), pp. 221–238. Marcel Dekker, New York.

Wester, R. C., and Maibach, H. I. (1991). Individual and regional variation with in vitro percutaneous absorption. In In Vitro Percutaneous Absorption (R. Brouaugh and H. Maibach, Eds.), pp. 25–30. CRC Press, Boca Raton, FL.

Wester, R. C., and Maibach, H. I. (1997). Toxicokinetics: Dermal exposure and absorption of toxicants. In Comprehensive Toxicology, Vol. 1, General Principles (J. Bond, Ed.), pp. 99–114. Elsevier Science, Oxford, U.K.

Wester, R. C., Maibach, H. I., Sedik, L., Melendres, J., and Wade, M. (1993). In vivo and in vitro percutaneous absorption and skin decontamination of arsenic from water and soil. Fund. Appl. Toxicol. 20, 336–340.[CrossRef][ISI][Medline]

Yost, L. J., Tao, S. H., Egan, S. K., Barraj, L. M., Smith, K. M., Tsuji, J. S., Lowney, Y. W., Schoof, R. A., and Rachman, N. J. (2004). Estimation of dietary intake of inorganic arsenic in U.S. children. Human and Ecological Risk Assessment. (in press)