A random walk model of skin permeation.

A new mathematical model for permeability of chemicals in aqueous vehicle through skin is presented. The rationale for this model is to represent diffusion by its fundamental molecular mechanism, i.e., random thermal motion. Diffusion is modeled as a two-dimensional random walk through the biphasic (lipid and corneocyte) stratum corneum (SC). This approach permits calculations of diffusion phenomena in a morphologically realistic SC structure. Two concepts are key in the application of the model to the prediction of steady-state skin permeability coefficients: "effective diffusivity" and "effective path length," meaning the diffusivity and thickness of a homogeneous membrane having identical permeation properties as the stratum corneum. Algebraic expressions for these two variables are developed as functions of the molecular weight and octanol-water partition coefficient of the diffusing substance. Combining these with expressions for membrane-vehicle partition coefficient and permeability of the aqueous epidermis enables the calculation of steady-state skin permeability coefficients. The resulting four-parameter algebraic model was regressed against the "Flynn data base" with excellent results (R2 = 0.84: SE = 0.0076; F = 154; N = 94). The model provides insight into the contributions of stratum corneum diffusivity and effective path lengths to overall skin permeability and may prove useful in the prediction of non-steady-state diffusion phenomena.     

Estimating Dermal Uptake of Nonionic Organic Chemicals from Water and Soil: I. Unified Fugacity-Based Models for Risk Assessments

Contamination of water and soil that might eventually contact human skin makes it imperative to include the dermal uptake route in efforts to assess potential environmental health risks. Direct measurements of dermal uptake from either water or soil are only available for a small number of the thousands of chemicals likely to be found in the environment. We propose here a mass-transfer model for estimating skin permeability and dermal uptake for organic chemicals that contaminate soil and water. Statistical relationships between measured permeabilities and chemical properties reveal that permeability varies primarily with the octanol-water partition coefficient (Kow) and secondarily with the molecular weight. From these results, we derive a fugacity-based model for skin permeability that addresses the inherent permeability of the skin, the interaction of the skin with the environmental medium on skin (water or soil), and retains a relatively simple algebraic form. Model predictions are compared to measured human skin permeabilities for some 50 compounds in water and four compounds in soil. The model is adjusted to account for dermal uptake during both short-term (10-20 min) and long-term (several hour) exposures. This model is recommended for compounds with molecular weight less than or equal to 280 g.     

Time- and Loading-Dependence in the McKone Model for Dermal Uptake of Organic Chemicals from a Soil Matrix

McKone has recently proposed an innovative two-layer model for dermal uptake of organic chemicals from a soil matrix that explicitly includes variables for properties of the chemical, the soil, the skin, and the exposure. In this note, we investigate the joint time- and loading-dependencies implicit in the model by using MATHEMATICA to find and plot a closed-form function for the uptake fraction for six aromatic hydrocarbons.     

A Compartmental Model for the Prediction of Breath Concentration and Absorbed Dose of Chloroform After Exposure While Showering

In order to predict the exhaled breath concentration of chloroform in individuals exposed to chloroform while showering, an existing physiologically based pharmacokinetic (PB-PK) model was modified to include a multicompartment, PB-PK model for the skin and a completely mixed shower exposure model. The PB-PK model of the skin included the stratum corneum as the principal resistance to absorption and a viable epidermis which is in dynamic equilibrium with the skin microcirculation. This model was calibrated with measured exhaled breath concentrations of chloroform in individuals exposed while showering with and without dermal absorption. The calibration effort indicated that the expected value of skin-blood partitioning coefficient would be 1.2 when the degree of transfer of chloroform from shower water into shower air was 61%. The stratum corneum permeability coefficient for chloroform was estimated to be within the range of 0.16-0.36 cm/hr and the expected value was 0.2 cm/hr. The estimated ratio of the dermally and inhaled absorbed doses ranged between 0.6 and 2.2 and the expected value was 0.75. These results indicate that for the purposes of risk assessment for dermal exposure to chloroform, a simple steady-state model can be used to predict the degree of dermal absorption and that a reasonable value of skin permeability coefficient for chloroform used in this model would be 0.2 cm/hr. Further research should be conducted to compare the elimination of chloroform via exhaled breath when different exposure routes are being compared. The model results from this study suggest that multiple measurements of exhaled breath concentrations after exposure may be necessary when making comparisons of breath concentrations that involve different exposure routes.     

Estimating Contaminant Dose for Intermittent Dermal Contact: Model Development, Testing, and Application

Assessments of aggregate exposure to pesticides and other surface contamination in residential environments are often driven by assumptions about dermal contacts. Accurately predicting cumulative doses from realistic skin contact scenarios requires characterization of exposure scenarios, skin surface loading and unloading rates, and contaminant movement through the epidermis. In this article we (1) develop and test a finite-difference model of contaminant transport through the epidermis; (2) develop archetypal exposure scenarios based on behavioral data to estimate characteristic loading and unloading rates; and (3) quantify 24-hour accumulation below the epidermis by applying a Monte Carlo simulation of these archetypal exposure scenarios. The numerical model, called Transient Transport through the epiDERMis (TTDERM), allows us to account for variable exposure times and time between exposures, temporal and spatial variations in skin and compound properties, and uncertainty in model parameters. Using TTDERM we investigate the use of a macro-activity parameter (cumulative contact time) for predicting daily (24-hour) integrated uptake of pesticides during complex exposure scenarios. For characteristic child behaviors and hand loading and unloading rates, we find that a power law represents the relationship between cumulative contact time and cumulative mass transport through the skin. With almost no loss of reliability, this simple relationship can be used in place of the more complex micro-activity simulations that require activity data on one- to five-minute intervals. The methods developed in this study can be used to guide dermal exposure model refinements and exposure measurement study design.     

Advances on a Decision Analytic Approach to Exposure-Based Chemical Prioritization

The volume and variety of manufactured chemicals is increasing, although little is known about the risks associated with the frequency and extent of human exposure to most chemicals. The EPA and the recent signing of the Lautenberg Act have both signaled the need for high-throughput methods to characterize and screen chemicals based on exposure potential, such that more comprehensive toxicity research can be informed. Prior work of Mitchell et al. using multicriteria decision analysis tools to prioritize chemicals for further research is enhanced here, resulting in a high-level chemical prioritization tool for risk-based screening. Reliable exposure information is a key gap in currently available engineering analytics to support predictive environmental and health risk assessments. An elicitation with 32 experts informed relative prioritization of risks from chemical properties and human use factors, and the values for each chemical associated with each metric were approximated with data from EPA's CP_CAT database. Three different versions of the model were evaluated using distinct weight profiles, resulting in three different ranked chemical prioritizations with only a small degree of variation across weight profiles. Future work will aim to include greater input from human factors experts and better define qualitative metrics.     

Water Adherence Factors for Human Skin

On incidental dermal exposure to chemicals in water, a key exposure factor is the amount of water adhering to skin. Although soil adherence factors have been developed for risk assessment, measurements of water adherence on human skin have not been described. In the Environmental Protection Agency's (EPA's) dermal risk assessment guidance, dermal dose from environmental exposures is based upon the flux rate across the skin, which assumes that an unlimited amount of chemical is available for absorption. This assumption is applicable to certain exposure scenarios such as swimming and bathing. However, exposures to contaminated water frequently involve scenarios where the available chemical is limited by the amount of water adhering to the skin, for example, during accidental splashes. We conducted studies in human volunteers to investigate water adherence per unit area of skin after brief contact with water. In two sets of experiments, either water was applied with a micropipette to 10‐cm² areas of the lower leg, foot, and hand, or the foot and hand were briefly immersed in water. In males, using a micropipette, water adherence ranged from 1.93 (foot) to 7.13 μL/cm² (lower leg). In females, it ranged from 1.10 (lower leg) to 4.83 μL/cm² (hand). Hand and foot immersion resulted in relatively higher values of 6.89 and 5.17 μL/cm², respectively, in males, and 5.40 and 6.39 μL/cm² in females. Water adherence was affected by amount of body hair and type of exposure. Water adherence factors can be used to calculate the applied dose per unit area for exposures involving intermittent water contact.     

Uptake of Chloroform by Skin During Short Exposures to Contaminated Water

Uptake of chloroform into hairless rat stratum corneum from dilute aqueous solutions was studied using tape-stripping to determine amounts deposited in the skin under various environmental exposure scenarios. The length of exposure of sedated animals to the chloroform-containing medium, the frequency and duration of tape-stripping, and the number of tape-strips per location were varied to map the stratum corneum substantivity of chloroform. Eight minutes immersion of the rat within a well-stirred solution at 36°C was found to be adequate time for the gradient to be established fully across the stratum corneum. Penetration was progressively deeper as the exposure time increased. Substantial evaporative loss of chloroform from the aqueous medium of application seem to be responsible for lower cumulative amounts taken up when the same solution was held on the rat's skin within a stainless steel template of fixed area. Of the total uptake (29 mg) from a dilute stirred solution of chloroform (0.44 mg/ml) at 36°C, about 95% was systematically absorbed after a 30 min exposure as determined by residuals (measurement of bath concentrations).     

Intake fraction for multimedia pollutants: a tool for life cycle analysis and comparative risk assessment.

We employ the intake fraction (iF) as an effective tool for expressing the source-to-intake relationship for pollutant emissions in life cycle analysis (LCA) or comparative risk assessment. Intake fraction is the fraction of chemical mass emitted into the environment that eventually passes into a member of the population through inhalation, ingestion, or dermal exposure. To date, this concept has been primarily applied to pollutants whose primary route of exposure is inhalation. Here we extend the use of iF to multimedia pollutants with multiple exposure pathways. We use a level III multimedia model to calculate iF for TCDD and compare the result to one calculated from measured levels of dioxin toxic equivalents in the environment. We calculate iF for emissions to air and surface water for 308 chemicals. We correlate the primary exposure route with the magnitudes of the octanol-water partition coefficient, Kow, and of the air-water partitioning coefficient (dimensionless Henry constant), Kaw. This results in value ranges of Kow and Kaw where the chemical exposure route can be classified with limited input data requirements as primarily inhalation, primarily ingestion, or multipathway. For the inhalation and ingestion dominant pollutants, we also define empirical relationships based on chemical properties for quantifying the intake fraction. The empirical relationships facilitate rapid evaluation of many chemicals in terms of the intake. By defining a theoretical upper limit for iF in a multimedia environment we find that iF calculations provide insight into the multimedia model algorithms and help identify unusual patterns of exposure and questionable exposure model results.     

Chemical Spill Exposure Assessment

POSSM, the PCB On-Site Spill Model, is a contaminant transport model developed to predict environmental concentrations associated with a chemical spill. The model predicts daily changes in chemical concentrations on a spill site (e.g., in soil and on vegetation) and losses of chemical due to volatilization, surface runoff/soil erosion, and leaching to groundwater. Spill areas consisting of soil/vegetation and/or an impervious surface (e.g., asphalt and concrete) can be analyzed, as can different spill cleanup practices. POSSM is used to analyze exposure levels associated with a hypothetical capacitor spill. While the model was developed for PCB spills, it is generally applicable to a number of organic compounds.     

Assessment of Health Risk from Exposure to Contaminated Soil

The risk to human health posed by contaminated soil in a residential area depends on the potential extent of exposure to soil and on the toxic properties of the contaminants. A detailed soil exposure analysis is presented for young children, older children, and adults living in a house surrounded by contaminated soil. From this analysis, a lifetime exposure model is derived and used to assess chronic health risks.     

Assessing Health Risks Associated with DDT Residues in Soils in California: A Proposition 65 Case Study

Population growth in California has increased the pressure to convert agricultural land to commercial, industrial, or residential uses. In the ensuing property transactions, buyers and sellers must address the presence of toxic materials in soils such as pesticides, several of which are known to the State of California to cause cancer under Proposition 65. While this statute does not specifically address soil contaminants, the potential scope of its enforcement is sufficiently broad that owners of former agricultural properties may be obliged to provide warning of exposure to potential buyers, occupants, or construction workers about exposure to residues in soil from pesticide applications. However, Proposition 65 provides no guidance on how to assess exposures to chemicals in soil. The U.S. EPA Risk Assessment Guidance for Superfund (RAGS) provides a method for assessing soil-related exposure pathways that is consistent with the intent of Proposition 65. Using this approach, we have calculated the lifetime average concentrations of DDT in soil corresponding to the no-significant-risk level stipulated under Proposition 65 (1 × 10⁻⁵) for a hypothetical residential exposure scenario. The concentration of DDT in soil corresponding to a no-significant-risk ranges from 7.9-18.8 mg/kg, depending upon which exposure pathways are deemed to be complete for residential land use. It is argued that Proposition 65 forces the assessment and possible cleanup of such a situation through the threat of creating a health risk perception that could affect the market value of a property.     

Chronic Health Risks from Aggregate Exposures to Ionizing Radiation and Chemicals: Scientific Basis for an Assessment Framework

Very little quantitative analysis is currently available on the cumulative effects of exposure to multiple hazardous agents that have either similar or different mechanisms of action. Over the past several years, efforts have been made to develop the methodologies for risk assessment of chemical mixtures, but mixed exposures to two or more dissimilar agents such as radiation and one or more chemical agents have not yet been addressed in any substantive way. This article reviews the current understanding of the health risks arising from mixed exposures to ionizing radiation and specific chemicals. Specifically discussed is how mixed radiation/chemical exposures, when evaluated in aggregation, were linked to chronic health endpoints such as cancer and intermediate health outcomes such as chromosomal aberrations. Also considered is the extent to which the current practices are consistent with the scientific understanding of the health risks associated with mixed-agent exposures. From this the discussion moves to the research needs for assessing the cumulative health risks from aggregate exposures to ionizing radiation and chemicals. The evaluation indicates that essentially no guidance has been provided for conducting risk assessment for two agents with different mechanisms of action (i.e., energy deposition from ionizing radiation versus DNA interactions with chemicals) but similar biological endpoints (i.e., chromosomal aberrations, mutations, and cancer). The literature review also reveals the problems caused by the absence of both the basic science and an appropriate evaluation framework for the combined effects of mixed-agent exposures. This makes it difficult to determine whether there is truly no interaction or somehow the interaction is masked by the scale of effect observation or inappropriate dose-response assumptions.     

Joint Models for Toxicology Studies with Dose-Dependent Number of Implantations

Many chemicals interfere with the natural reproductive processes in mammals. The chemicals may prevent the fertilization of an egg or keep a zygote from implanting in the uterine wall. For this reason, toxicology studies with pre-implantation exposure often exhibit a dose-related trend in the number of observed implantations per litter. Standard methods for analyzing developmental toxicology studies are conditioned on the number of implantations in the litter and therefore cannot estimate this effect of the chemical on the reproductive process. This article presents a joint modeling approach to estimating risk in toxicology studies with pre-implantation exposure. In the joint modeling approach, both the number of implanted fetuses and the outcome of each implanted fetus is modeled. Using this approach we show how to estimate the overall risk of a chemical that incorporates the risk of lost implantation due to pre-implantation exposure. Our approach has several distinct advantages over previous methods: (1) it is based on fitting a model for the observed data and, therefore, diagnostics of model fit and selection apply; (2) all assumptions are explicitly stated; and (3) it can be fit using standard software packages We illustrate our approach by analyzing a dominant lethal assay data set (Luning et al., 1966, Mutation Research, 3, 444-451) and compare ourresults with those of Rai and Van Ryzin (1985, Biometrics, 41,1-9) and Dunson (1998, Biometrics, 54, 558-569). In a simulation study, our approach has smaller bias and variance than the multiple imputation procedure of Dunson.     

Assessments of Direct Human Exposure—The Approach of EU Risk Assessments Compared to Scenario-Based Risk Assessment

The awareness of potential risks emerging from the use of chemicals in all parts of daily life has increased the need for risk assessments that are able to cover a high number of exposure situations and thereby ensure the safety of workers and consumers. In the European Union (EU), the practice of risk assessments for chemicals is laid down in a Technical Guidance Document; it is designed to consider environmental and human occupational and residential exposure. Almost 70 EU risk assessment reports (RARs) have been finalized for high-production-volume chemicals during the last decade. In the present study, we analyze the assessment of occupational and consumer exposure to trichloroethylene and phthalates presented in six EU RARs. Exposure scenarios in these six RARs were compared to scenarios used in applications of the scenario-based risk assessment approach to the same set of chemicals. We find that scenarios used in the selected EU RARs to represent typical exposure situations in occupational or private use of chemicals and products do not necessarily represent worst-case conditions. This can be due to the use of outdated information on technical equipment and conditions in workplaces or omission of pathways that can cause consumer exposure. Considering the need for exposure and risk assessments under the new chemicals legislation of the EU, we suggest that a transparent process of collecting data on exposure situations and of generating representative exposure scenarios is implemented to improve the accuracy of risk assessments. Also, the data sets used to assess human exposure should be harmonized, summarized in a transparent fashion, and made accessible for all risk assessors and the public.     

Parameter Uncertainty and Variability In Evaluative Fate and Exposure Models

The human toxicity potential, a weighting scheme used to evaluate toxic emissions for life cycle assessment and toxics release inventories, is based on potential dose calculations and toxicity factors. This paper evaluates the variance in potential dose calculations that can be attributed to the uncertainty in chemical-specific input parameters as well as the variability in exposure factors and landscape parameters. A knowledge of the uncertainty allows us to assess the robustness of a decision based on the toxicity potential; a knowledge of the sources of uncertainty allows us to focus our resources if we want to reduce the uncertainty. The potential dose of 236 chemicals was assessed. The chemicals were grouped by dominant exposure route, and a Monte Carlo analysis was conducted for one representative chemical in each group. The variance is typically one to two orders of magnitude. For comparison, the point estimates in potential dose for 236 chemicals span ten orders of magnitude. Most of the variance in the potential dose is due to chemical-specific input parameters, especially half-lives, although exposure factors such as fish intake and the source of drinking water can be important for chemicals whose dominant exposure is through indirect routes. Landscape characteristics are generally of minor importance.     

Equation reliability of soil ingestion estimates in mass-balance soil ingestion studies

Exposure to chemicals from ingestion of contaminated soil may be an important pathway with potential health consequences for children. A key parameter used in assessing this exposure is the quantity of soil ingested, with estimates based on four short longitudinal mass-balance soil ingestion studies among children. The estimates use trace elements in the soil with low bioavailability that are minimally present in food. Soil ingestion corresponds to the excess trace element amounts excreted, after subtracting trace element amounts ingested from food and medications, expressed as an equivalent quantity of soil. The short duration of mass-balance studies, different concentrations of trace elements in food and soil, and potential for trace elements to be ingested from other nonsoil, nonfood sources contribute to variability and bias in the estimates. We develop a stochastic model for a soil ingestion estimator based on a trace element that accounts for critical features of the mass-balance equation. Using results from four mass-balance soil ingestion studies, we estimate the accuracy of soil ingestion estimators for different trace elements, and identify subjects where the difference between Al and Si estimates is larger (>3 RMSE) than expected. Such large differences occur in fewer than 12% of subjects in each of the four studies. We recommend the use of such criteria to flag and exclude subjects from soil ingestion analyses.     

Major Sources of Exposure to Benzene and Other Volatile Organic Chemicals1,2

The major sources of human exposure to about a dozen volatile organic chemicals (VOCs) have recently been identified.¹ For nearly every chemical, the major sources of exposure are completely different from the major sources of emissions. This finding implies that current environmental regulations and control strategies are misdirected. Important sources of exposure are typically not regulated in any way, whereas unimportant sources are heavily regulated. Vast sums of money are spent on problems involving little risk (e.g., hazardous waste sites), whereas few resources are expended on problems involving higher risk (e.g., indoor air pollution). The following paper summarizes recent findings regarding major sources of exposure to several VOCs. Benzene is selected as a case study. Brief discussions of tetrachloroethylene and paradichlorobenzene are also included.     

Chemical Leasing Business Models—A Contribution to the Effective Risk Management of Chemical Substances

Chemicals indisputably contribute greatly to the well-being of modern societies. Apart from such benefits, however, chemicals often pose serious threats to human health and the environment when improperly handled. Therefore, the European Commission has proposed a regulatory framework for the Registration, Evaluation and Authorization of Chemicals (REACH) that requires companies using chemicals to gather pertinent information on the properties of these substances. In this article, we argue that the crucial aspect of this information management may be the honesty and accuracy of the transfer of relevant knowledge from the producer of a chemical to its user. This may be particularly true if the application of potentially hazardous chemicals is not part of the user's core competency. Against this background, we maintain that the traditional sales concept provides no incentives for transferring this knowledge. The reason is that increased user knowledge of a chemical's properties may raise the efficiency of its application. That is, excessive and unnecessary usage will be eliminated. This, in turn, would lower the amount of chemicals sold and in competitive markets directly decrease profits of the producer. Through the introduction of chemical leasing business models, we attempt to present a strategy to overcome the incentive structure of classical sales models, which is counterproductive for the transfer of knowledge. By introducing two models (a Model A that differs least and a Model B that differs most from traditional sales concepts), we demonstrate that chemical leasing business models are capable of accomplishing the goal of Registration, Evaluation and Authorization of Chemicals: to effectively manage the risk of chemicals by reducing the total quantity of chemicals used, either by a transfer of applicable knowledge from the lessor to the lessee (Model A) or by efficient application of the chemical by the lessor him/herself (Model B).     

A Probabilistic Arsenic Exposure Assessment for Children Who Contact Chromated Copper Arsenate (CCA)-Treated Playsets and Decks, Part 2: Sensitivity and Uncertainty Analyses

A probabilistic model (SHEDS-Wood) was developed to examine children's exposure and dose to chromated copper arsenate (CCA)-treated wood, as described in Part 1 of this two-part article. This Part 2 article discusses sensitivity and uncertainty analyses conducted to assess the key model inputs and areas of needed research for children's exposure to CCA-treated playsets and decks. The following types of analyses were conducted: (1) sensitivity analyses using a percentile scaling approach and multiple stepwise regression; and (2) uncertainty analyses using the bootstrap and two-stage Monte Carlo techniques. The five most important variables, based on both sensitivity and uncertainty analyses, were: wood surface residue-to-skin transfer efficiency; wood surface residue levels; fraction of hand surface area mouthed per mouthing event; average fraction of nonresidential outdoor time a child plays on/around CCA-treated public playsets; and frequency of hand washing. In general, there was a factor of 8 for the 5th and 95th percentiles and a factor of 4 for the 50th percentile in the uncertainty of predicted population dose estimates due to parameter uncertainty. Data were available for most of the key model inputs identified with sensitivity and uncertainty analyses; however, there were few or no data for some key inputs. To evaluate and improve the accuracy of model results, future measurement studies should obtain longitudinal time-activity diary information on children, spatial and temporal measurements of residue and soil concentrations on or near CCA-treated playsets and decks, and key exposure factors. Future studies should also address other sources of uncertainty in addition to parameter uncertainty, such as scenario and model uncertainty.