Bioavailable soil Pb minimized by in situ transformation to plumbojarosite.

Exposure to lead (Pb) during early life has persistent adverse health effects. During childhood, ingestion of bioavailable Pb in contaminated soils can be a major route of Pb absorption. Remediation to alter physiochemical properties of soil-borne Pb can reduce Pb bioavailability. Our laboratory-based approach for soil Pb remediation uses addition of iron (Fe) sulfate and application of heat to promote formation of plumbojarosite (PLJ), a sparingly soluble Pb-Fe hydroxysulfate mineral. We treated two soils with anthropogenic Pb contamination and samples of clean topsoil spiked with various Pb compounds (i.e., carbonate, chloride, phosphate [P], or sulfate) to convert native Pb species to PLJ and used a mouse assay to assess relative bioavailability (RBA) of Pb in untreated (U) and remediated soils. Bone and blood Pb levels were significantly lower (P < 0.001, Student's t test) in mice that consumed diets amended with remediated soils than with U soils. Estimated RBA for Pb in both remediated natural soils and Pb-mineral spiked soils were reduced by >90% relative to Pb RBA for U soils, which is substantially more effective than other soil amendments, including P. X-ray absorption spectroscopy showed that >90% of all Pb species in remediated soils were converted to PLJ, and ingested PLJ was not chemically transformed during gastrointestinal tract transit. Post treatment neutralization of soil pH did not affect PLJ stability, indicating the feasibility in field conditions. These results suggest that formation of PLJ in contaminated soils can reduce the RBA of Pb and minimize this medium's role as a source of Pb exposure for young children.

Dietary lead modulates the mouse intestinal microbiome: Subacute exposure to lead acetate and lead contaminated soil.

The effect of dietary lead on the intestinal microbiome has not been fully elucidated. To determine if there was an association between microflora modulation, predicted functional genes, and Pb exposure, mice were provided diets amended with increasing concentrations of a single lead compound, lead acetate, or a well characterized complex reference soil containing lead, i.e. 6.25-25 mg/kg Pb acetate (PbOAc) or 7.5-30 mg/kg Pb in reference soil SRM 2710a having 0.552 % Pb among other heavy metals such as Cd. Feces and ceca were collected following 9 days of treatment and the microbiome analyzed by 16 S rRNA gene sequencing. Treatment effects on the microbiome were observed in both feces and ceca of mice. Changes in the cecal microbiomes of mice fed Pb as Pb acetate or as a constituent in SRM 2710a were statistically different except for a few exceptions regardless of dietary source. This was accompanied by increased average abundance of functional genes associated with metal resistance, including those related to siderophore synthesis and arsenic and/or mercury detoxification. Akkermansia, a common gut bacterium, was the highest ranked species in control microbiomes whereas Lactobacillus ranked highest in treated mice. Firmicutes/Bacteroidetes ratios in the ceca of SRM 2710a treated mice increased more than with PbOAc, suggestive of changes in gut microbiome metabolism that promotes obesity. Predicted functional gene average abundance related to carbohydrate, lipid, and/or fatty acid biosynthesis and degradation were greater in the cecal microbiome of SRM 2710a treated mice. Bacilli/Clostridia increased in the ceca of PbOAc treated mice and may be indicative of increased risk of host sepsis. Family Deferribacteraceae also was modulated by PbOAc or SRM 2710a possibly impacting inflammatory response. Understanding the relationship between microbiome composition, predicted functional genes, and Pb concentration, especially in soil, may provide new insights into the utility of various remediation methodologies that minimize dysbiosis and modulate health effects, thus assisting in the selection of an optimal treatment for contaminated sites.

Evaluating the mouse model for estimation of arsenic bioavailability: Comparison of estimates of absolute bioavailability of inorganic arsenic in mouse, humans, and other species.

Accurate assessment of adverse health effects attributable to ingestion of inorganic arsenic (As) present in contaminated soils requires determination of the internal dose of metal provided by ingested soil. This calculation requires estimation of the oral bioavailability of soil-borne (As). Animal models to assess the bioavailability of soil (As) are frequently used as surrogates for determination of this variable in humans. A mouse assay has been widely applied to estimate the bioavailability of As in soils at sites impacted by mining, smelting, and pesticides. In the mouse assay, the relative bioavailability (RBA) of soil (As) is determined as the ratio of the fraction of the ingested arsenic dose excreted in urine after consumption of diets containing a test soil or the soluble reference compound, sodium arsenate. The aim of the current study was to compare (As) bioavailability measured in the mouse assay with reported estimates in humans. Here, a pharmacokinetic model based on excretion of arsenic in urine and feces was used to estimate the absolute bioavailability (ABA) of As in mice that received an oral dose of sodium arsenate. Based upon this analysis, in mice that consumed diet amended with sodium arsenate, the ABA was 85%. This estimate of arsenic ABA for the mouse is comparable to estimates in humans who consumed (As) in drinking water and diet, and to estimates of ABA in monkeys and swine exposed to sodium arsenate. The concordance of estimates for ABA in mice and humans provides further support for use of the mouse model in human health risk assessment. Sodium arsenate ABA also provides a basis for estimating soil arsenic ABA from RBA estimates obtained in the mouse model.

Improving the predictive value of bioaccessibility assays and their use to provide mechanistic insights into bioavailability for toxic metals/metalloids - A research prospectus.

Widespread contamination of soil, dust, and food with toxic metal(loid)s pose a significant public health concern. Only a portion of orally ingested metal(loid) contaminants are bioavailable, which is defined as the fraction of ingested metal(loid)s absorbed across the gastrointestinal barrier and into systemic circulation. Bioaccessibility tools are a class of in vitro assays used as a surrogate to estimate risk of oral exposure and bioavailability. Although development and use of bioaccessibility tools have contributed to our understanding of the factors influencing oral bioavailability of metal(loid)s, some of these assays may lack data that support their use in decisions concerning adverse health risks and soil remediation. This review discusses the factors known to influence bioaccessibility of metal(loid) contaminants and evaluates experimental approaches and key findings of SW-846 Test Method 1340, Unified BARGE Method, Simulated Human Intestinal Microbial Ecosystem, Solubility Bioaccessibility Research Consortium assay, In Vitro Gastrointestinal model, TNO-Gastrointestinal Model, and Dutch National Institute for Public Health and the Environment bioaccessibility models which are used to assess oral absolute bioavailability and relative bioavailability in solid matrices. The aim of this review was to identify emerging knowledge gaps and research needs with an emphasis on research required to evaluate these models on (1) standardization of assay techniques and methodology, and (2) use of common criteria for assessing the performance of bioaccessibility models.

Plumbojarosite Remediation of Soil Affects Lead Speciation and Elemental Interactions in Soil and in Mice Tissues.

Lead (Pb) contamination of soils is of global concern due to the devastating impacts of Pb exposure in children. Because early-life exposure to Pb has long-lasting health effects, reducing exposure in children is a critical public health goal that has intensified research on the conversion of soil Pb to low bioavailability phases. Recently, plumbojarosite (PLJ) conversion of highly available soil Pb was found to decrease Pb relative bioavailability (RBA <10%). However, there is sparse information concerning interactions between Pb and other elements when contaminated soil, pre- and post-remediation, is ingested and moves through the gastrointestinal tract (GIT). Addressing this may inform drivers of effective chemical remediation strategies. Here, we utilize bulk and micro-focused Pb X-ray absorption spectroscopy to probe elemental interactions and Pb speciation in mouse diet, cecum, and feces samples following ingestion of contaminated soils pre- and post-PLJ treatment. RBA of treated soils was less than 1% with PLJ phases transiting the GIT with little absorption. In contrast, Pb associated with organics was predominantly found in the cecum. These results are consistent with transit of insoluble PLJ to feces following ingestion. The expanded understanding of Pb interactions during GIT transit complements our knowledge of elemental interactions with Pb that occur at higher levels of biological organization.

High Lead Bioavailability of Indoor Dust Contaminated with Paint Lead Species.

House dust and soils can be major sources of lead (Pb) exposure for children. The American Healthy Homes Survey (AHHS) was developed to estimate Pb exposure from house dust and soil, in addition to other potential household contaminants and allergens. We have combined X-ray absorption spectroscopic (XAS) fingerprinting and in vivo mouse relative bioavailability (RBA) measurements for a subset of house dust and residential soils collected in the AHHS, with the primary objective of gaining a better understanding of determinants of house dust Pb bioavailability. Lead speciation was well related to variations in RBA results and revealed that highly bioavailable Pb (hydroxy)carbonate (indicative of Pb-based paint) was the major Pb species present in house dusts. Measured Pb RBA was up to 100% and is likely driven by paint Pb. To our knowledge, this is the first report of in vivo Pb RBA for U.S. house dust contaminated in situ with paint Pb and corroborates results from a previous study that demonstrated high RBA of paint Pb added to soil. We also report a relatively low RBA (23%) in a residential soil where the major Pb species was found to be plumbojarosite, consistent with a previous report that plumbojarosite lowers Pb RBA in soils.

Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects.

The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAsIII and DMAsIII in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAsIII and DMAsIII in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAsIII and DMAsIII formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.

Using mathematical modeling to infer the valence state of arsenicals in tissues: A PBPK model for dimethylarsinic acid (DMAV) and dimethylarsinous acid (DMAIII) in mice.

Chronic exposure to inorganic arsenic (iAs), a contaminant of water and food supplies, is associated with many adverse health effects. A notable feature of iAs metabolism is sequential methylation reactions which produce mono- and di-methylated arsenicals that can contain arsenic in either the trivalent (III) or pentavalent (V) valence states. Because methylated arsenicals containing trivalent arsenic are more potent toxicants than their pentavalent counterparts, the ability to distinguish between the +3 and +5 valence states is a crucial property for physiologically based pharmacokinetic (PBPK) models of arsenicals to possess if they are to be of use in risk assessment. Unfortunately, current analytic techniques for quantifying arsenicals in tissues disrupt the valence state; hence, pharmacokinetic studies in animals, used for model calibration, only reliably provide data on the sum of the +3 and +5 valence forms of a given metabolite. In this paper we show how mathematical modeling can be used to overcome this obstacle and present a PBPK model for the dimethylated metabolite of iAs, which exists as either dimethylarsinous acid, (CH3)2AsIIIOH (abbreviated DMAIII) or dimethylarsinic acid, (CH3)2AsV(O)OH (abbreviated DMAV). The model distinguishes these two forms and sets a lower bound on how much of an organ's DMA burden is present in the more reactive and toxic trivalent valence state. We conjoin the PBPK model to a simple model for DMAIII-induced oxidative stress in liver and use this extended model to predict cytotoxicity in liver in response to the high oral dose of DMAV. The model incorporates mechanistic details derived from in vitro studies and is iteratively calibrated with lumped-valence-state PK data for intravenous or oral dosing with DMAV. Model formulation leads us to predict that orally administered DMAV undergoes extensive reduction in the gastrointestinal (GI) tract to the more toxic trivalent DMAIII.

Dietary Lead and Phosphate Interactions Affect Oral Bioavailability of Soil Lead in the Mouse.

Effects of dietary P level on the oral bioavailability of Pb present in soil were examined in a mouse model. Adult female C57BL/6 mice had free access to AIN-93G purified rodent diet amended with Pb as a soluble salt, Pb acetate, or in a soil matrix (NIST SRM 2710a). In these studies, the basal diet contained P at a nutritionally sufficient level (0.3% w/w) and the modified diets contained P at a lower (0.15%) or a higher (1.2%) level. For either dietary Pb source (Pb acetate or NIST SRM 2710a), low dietary P level markedly increased accumulation of Pb in bone, blood, and kidney. Tissue Pb levels in mice fed a high P in diet were not different from mice fed the basal P diet. Dietary P and Pb interacted to affect body weight change and feed efficiency in mice. The relative contribution of different Pb species in diet and feces was also affected by dietary P level. Differences in Pb species between diet and feces indicated that transformation of Pb species can occur during gastrointestinal tract transit. These interactions between Pb and P that alter Pb speciation may be important determinants of the bioavailability of Pb ingested in soil.

Dose and Diet - Sources of Arsenic Intake in Mouse in Utero Exposure Scenarios.

In humans, early life exposure to inorganic arsenic is associated with adverse health effects. Inorganic arsenic in utero or in early postnatal life also produces adverse health effects in offspring of pregnant mice that consumed drinking water containing low part per billion levels of inorganic arsenic. Because aggregate exposure of pregnant mice to inorganic arsenic from both drinking water and food has not been fully evaluated in experimental studies, quantifying arsenic exposure of the developing mouse is problematic. Here, we determined levels of total arsenic and arsenic species in natural ingredient rodent diets that are composed of many plant and animal-derived foodstuffs and in a purified ingredient rodent diet that is composed of a more restricted mixture of foodstuffs. In natural ingredient diets, total arsenic levels ranged from ∼60 to ∼400 parts per billion, and in the purified ingredient diet, total arsenic level was 13 parts per billion. Inorganic arsenic was the predominant arsenic species in trifluoroacetic acid extracts of each diet. Various exposure scenarios were evaluated using information on inorganic arsenic levels in diet and drinking water and on daily food and water consumption of pregnant mice. In a scenario in which pregnant mice consumed drinking water with 10 parts per billion of inorganic arsenic and a natural ingredient diet containing 89 parts per billion of inorganic arsenic, drinking water contributed only ∼20% of inorganic arsenic intake. Quantitation of arsenic species in diets used in studies in which drinking water is the nominal source of arsenic exposure provides more accurate dosimetry and improves understanding of dose-response relations. Use of purified ingredient diets will minimize the discrepancy between the target dosage level and the actual dosage level attained in utero exposure studies designed to evaluate effects of low level exposure to inorganic arsenic.

In vivo and in vitro methods for evaluating soil arsenic bioavailability: relevant to human health risk assessment.

Arsenic (As) is the most frequently occurring contaminant on the priority list of hazardous substances, which lists substances of greatest public health concern to people living at or near U.S. National Priorities List site. Accurate assessment of human health risks from exposure to As-contaminated soils depends on estimating its bioavailability, defined as the fraction of ingested As absorbed across the gastrointestinal barrier and available for systemic distribution and metabolism. Arsenic bioavailability varies among soils and is influenced by site-specific soil physical and chemical characteristics and internal biological factors. This review describes the state-of-the science that supports our understanding of oral bioavailability of soil As, the methods that are currently being explored for estimating soil As relative bioavailability (RBA), and future research areas that could improve our prediction of the oral RBA of soil As in humans. The following topics are addressed: (1) As soil geochemistry; (2) As toxicology; (3) in vivo models for estimating As RBA; (4) in vitro bioaccessibility methods; and (5) conclusions and research needs.

Long-Term in Situ Reduction in Soil Lead Bioavailability Measured in a Mouse Model.

Effects of different treatments on the bioavailability of lead (Pb) in soil from a smelter emission contaminated site in Joplin, Missouri, were evaluated in a mouse model. Similar estimates of relative bioavailability for Pb in untreated or treated soil were obtained in mice and in the well-established juvenile swine model. In the mouse model, treatments that used phosphate (phosphoric acid or triple superphosphate) combined with iron oxide or biosolids compost significantly reduced soil Pb bioavailability. Notably, effects of these remediation procedures were persistent, given that up to 16 years had elapsed between soil treatment and sample collection. Remediation of soils was associated with changes in Pb species present in soil. Differences in Pb species in ingested soil and in feces from treated mice indicated that changes in Pb speciation occurred during transit through the gastrointestinal tract. Use of the mouse model facilitates evaluation of remediation procedures and allows monitoring of the performance of procedures under laboratory and field conditions.

Relating soil geochemical properties to arsenic bioaccessibility through hierarchical modeling.

Interest in improved understanding of relationships among soil properties and arsenic (As) bioaccessibility has motivated the use of regression models for As bioaccessibility prediction. However, limits in the numbers and types of soils included in previous studies restrict the usefulness of these models beyond the range of soil conditions evaluated, as evidenced by reduced predictive performance when applied to new data. In response, hierarchical models that consider variability in relationships among soil properties and As bioaccessibility across geographic locations and contaminant sources were developed to predict As bioaccessibility in 139 soils on both a mass fraction (mg/kg) and % basis. The hierarchical approach improved the estimation of As bioaccessibility in studied soils. In addition, the number of soil elements identified as statistically significant explanatory variables increased when compared to previous investigations. Specifically, total soil Fe, P, Ca, Co, and V were significant explanatory variables in both models, while total As, Cd, Cu, Ni, and Zn were also significant in the mass fraction model and Mg was significant in the % model. This developed hierarchical approach provides a novel tool to (1) explore relationships between soil properties and As bioaccessibility across a broad range of soil types and As contaminant sources encountered in the environment and (2) identify areas of future mechanistic research to better understand the complexity of interactions between soil properties and As bioaccessibility.

Relationship Between Total and Bioaccessible Lead on Children's Blood Lead Levels in Urban Residential Philadelphia Soils.

Relationships between total soil or bioaccessible lead (Pb), measured using an in vitro bioaccessibility assay, and children's blood lead levels (BLL) were investigated in an urban neighborhood in Philadelphia, PA, with a history of soil Pb contamination. Soil samples from 38 homes were analyzed to determine whether accounting for the bioaccessible Pb fraction improves statistical relationships with children's BLLs. Total soil Pb concentration ranged from 58 to 2821 mg/kg; the bioaccessible Pb concentration ranged from 47 to 2567 mg/kg. Children's BLLs ranged from 0.3 to 9.8 µg/dL. Hierarchical models were used to compare relationships between total or bioaccessible Pb in soil and children's BLLs. Total soil Pb concentration as the predictor accounted for 23% of the variability in child BLL; bioaccessible soil Pb concentration as the predictor accounted for 26% of BLL variability. A bootstrapping analysis confirmed a significant increase in R2 for the model using bioaccessible soil Pb concentration as the predictor with 99.0% of bootstraps showing a positive increase. Estimated increases of 1.3 µg/dL and 1.5 µg/dL in BLL per 1000 mg/kg Pb in soil were observed for this study area using total and bioaccessible Pb concentrations, respectively. Children's age did not contribute significantly to the prediction of BLLs.

Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population.

BACKGROUND: Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual's capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. METHODS: A total of 904 older adults (≥45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 µg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. RESULTS: Relative contributions of inorganic, mono-, and di-methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. CONCLUSIONS: These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models.

Estimating relative bioavailability of soil lead in the mouse.

Lead (Pb) in soil is an important exposure source for children. Thus, determining bioavailability of Pb in soil is critical in evaluating risk and selecting appropriate strategies to minimize exposure. A mouse model was developed to estimate relative bioavailability of Pb in NIST SRM 2710a (Montana 1 Soil). Based on Pb levels in tissues, the mean relative bioavailability of this metal in this soil was 0.5. Estimates of relative bioavailabilities derived from mouse compared favorably with those obtained in juvenile swine. The mouse model is thus an efficient and inexpensive method to obtain estimates of relative bioavailability of soil Pb.

Predicting oral relative bioavailability of arsenic in soil from in vitro bioaccessibility.

Several investigations have been conducted to develop in vitro bioaccessibility (IVBA) assays that reliably predict in vivo oral relative bioavailability (RBA) of arsenic (As). This study describes a meta-regression model relating soil As RBA and IVBA that is based upon data combined from previous investigations that examined the relationship between As IVBA and RBA when IVBA was determined using an extraction of soil in 0.4 M glycine at pH 1.5. Data used to develop the model included paired IVBA and RBA estimates for 83 soils from various types of sites such as mining, smelting, and pesticide or herbicide application. The following linear regression model accounted for 87% of the observed variance in RBA (R(2) = .87): RBA(%) = 0.79 × IVBA(%) + 3. This regression model is more robust than previously reported models because it includes a larger number of soil samples, and also accounts for variability in RBA and IVBA measurements made on samples collected from sites contaminated with different As sources and conducted in different labs that have utilized different experimental models for estimating RBA.

Role of complex organic arsenicals in food in aggregate exposure to arsenic.

For much of the world's population, food is the major source of exposure to arsenic. Exposure to this non-essential metalloid at relatively low levels may be linked to a wide range of adverse health effects. Thus, evaluating foods as sources of exposure to arsenic is important in assessing risk and developing strategies that protect public health. Although most emphasis has been placed on inorganic arsenic as human carcinogen and toxicant, an array of arsenic-containing species are found in plants and animals used as foods. Here, we 2evaluate the contribution of complex organic arsenicals (arsenosugars, arsenolipids, and trimethylarsonium compounds) that are found in foods and consider their origins, metabolism, and potential toxicity. Commonalities in the metabolism of arsenosugars and arsenolipids lead to the production of di-methylated arsenicals which are known to exert many toxic effects. Evaluating foods as sources of exposure to these complex organic arsenicals and understanding the formation of reactive metabolites may be critical in assessing their contribution to aggregate exposure to arsenic.

Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals.

Although inorganic arsenic has long been recognized as a potent toxicant and carcinogen in humans, recent evidence shows that at least some of its effects are mediated by methylated metabolites. Elucidating the conversion of inorganic arsenic to mono-, di-, and trimethylated species has provided insights into the enzymology of this pathway and identified genetic and environmental factors that influence the susceptibility of individuals to this metalloid's adverse health effects. Notably, almost all work on the formation, fate, and effects of methylated arsenicals has focused on oxoarsenicals in which arsenic is bound to one or more oxygen atoms. However, thioarsenicals are a class of arsenicals in which a sulfur atom has replaced one or more oxygens that are bound to arsenic. Thioarsenicals have been identified as urinary metabolites in humans and other animals following exposure to inorganic arsenic. Studies find that methylated thioarsenicals exhibit kinetic behavior and toxicological properties that distinguish them from methylated oxoarsenicals. This perspective considers that formation, fate, and effects of methylated thioarsenicals with an emphasis on examining the linkages between the molecular processes that underlie both methylation and thiolation reactions. Integrating this information will provide a more comprehensive view of the relationship between the metabolism of arsenic and the risk posed by chronic exposure to this environmental contaminant.

Independent data validation of an in vitro method for the prediction of the relative bioavailability of arsenic in contaminated soils.

In vitro bioaccessibility (IVBA) assays estimate arsenic (As) relative bioavailability (RBA) in contaminated soils to improve accuracy in human exposure assessments. Previous studies correlating soil As IVBA with RBA have been limited by the use of few soil types and sources of As, and the predictive value of As IVBA has not been validated using an independent set of As-contaminated soils. In this study, a robust linear model was developed to predict As RBA in mice using IVBA, and the predictive capability of the model was independently validated using a unique set of As-contaminated soils. Forty As-contaminated soils varying in soil type and contaminant source were included in this study, with 31 soils used for initial model development and nine soils used for independent model validation. The initial model reliably predicted As RBA values in the independent data set, with a mean As RBA prediction error of 5.4%. Following validation, 40 soils were used for final model development, resulting in a linear model with the equation RBA = 0.65 × IVBA + 7.8 and an R(2) of 0.81. The in vivo-in vitro correlation and independent data validation presented provide critical verification necessary for regulatory acceptance in human health risk assessment.