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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. [ABSTRACT FROM AUTHOR]

The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose–response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [14C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [14C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose–response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT equivalents from different routes of exposure in the rat. [ABSTRACT FROM AUTHOR]

Decreasing renal glomerular filtration rate (GFR) in association with increasing blood cadmium levels was reported in epidemiological studies of general populations. Dependence of cadmium clearance on GFR has implications for interpreting causation in these studies. Associations between cadmium clearance and creatinine clearance, a metric of GFR, were evaluated in a sample of the U.S. population. Blood to urine cadmium clearance and serum creatinine clearance were estimated in approximately 6000 individuals included in the National Health and Nutrition Examination Survey (NHANES 2009–2016). Linear regression models explained approximately 45% of variance in cadmium clearance in adults, with 74% of the explained variance attributed to creatinine clearance and 25% explained by age. In adolescents (12–<20 years), linear regression models explained 55% of variance in cadmium clearance with >99% of the explained variance attributed to creatinine clearance. The models predicted that halving creatinine clearance would result in a 40% decrease in cadmium clearance and a 20% rise in blood cadmium. Dependence of cadmium clearance on GFR has implications for assigning causation to studies in which increasing blood cadmium levels have been associated with increasing risk of low GFR. Statistical associations between blood cadmium and low GFR, such as elevated odds ratios in upper percentile strata of populations, may be partially a consequence of lower cadmium clearance in association with low GFR that is reverse causation. [ABSTRACT FROM AUTHOR]

Blood lead (Pb) clearance (CbPb) and serum creatinine clearance (CsCr), a metric of glomerular filtration rate (GFR), were estimated in approximately 7,600 subjects from the NHANES (2009–2016). Median CbPb in adults was 0.04 L/day (5th-95th percentile range: 0.01–0.12). Linear regression models explained approximately 68% of variance in CbPb in adults, with >98% of explained variance attributed to CsCr. These results provide an improved quantitative understanding of the possible effects of reverse causality in the interpretation of studies of associations between blood Pb and decrements in GFR. [ABSTRACT FROM AUTHOR]

The broad-spectrum antimicrobial zinc pyrithione (ZnPT) is used in numerous products ranging from in-can preservative/mildicide in paints to antidandruff shampoo. Although products containing ZnPT have a long history of safe use, regulatory agencies routinely set limits of exposure based upon toxicological considerations. The objective of this study was to create a physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose-response analysis of ZnPT-induced toxicity, reversible hindlimb weakness, the endpoint that has been used as the basis for ZnPT risk assessments. A rat oral PBPK model was developed that includes compartments for plasma, liver, kidneys, muscle, brain, and rapidly and slowly perfused tissues. Pyrithione metabolism to 2-(methylsulfonyl)pyridine (MSP) and glucuronide conjugates was incorporated into the model. The model was parameterized and optimized based upon data from single-dose intravenous (iv) and oral gavage pharmacokinetic studies of radiolabeled pyrithione ([14C]PT) administered as zinc [14C]-pyrithione (Zn-[14C]PT) to adult female rats. It was further evaluated and refined using data from repeated, multidose oral gavage and dietary studies of Zn[14C]PT in the adult female rat that included measurements of plasma PT concentration, the putative toxic species. The model replicated the observed short-term elimination kinetics of PT in plasma and [14C]PT in whole blood following single doses and longer term temporal patterns of plasma and blood concentrations during repeated dosing schedules. The model also accounted for production and rapid elimination ofS-glucuronide conjugates (SG) of 2-pyridinethiol and 2-pyridinethiol-1-oxide in urine, as well as production and slower elimination of MSP, the major [14C]PT species in blood within several hours following administration of ZnPT. The model provided internal dosimetry predictions for a benchmark dose (BMD) analysis of hindlimb weakness in rats, and was used to combine gavage and dietary studies into a single internal dose-response model with area under the curve (AUC) for plasma PT as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT from different routes of exposure in the rat. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 0.4Mglycine 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 (R2= .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. [ABSTRACT FROM PUBLISHER]

A mouse assay for measuring the relative bioavailability (RBA) of arsenic (As) in soil was developed. In this study, results are presented of RBA assays of 16 soils, including multiple assays of the same soils, which provide a quantitative assessment of reproducibility of mouse assay results, as well as a comparison of results from the mouse assay with results from a swine and monkey assay applied to the same test soils. The mouse assay is highly reproducible; three repeated assays on the same soils yielded RBA estimates that ranged from 1 to 3% of the group mean. The mouse, monkey, and swine models yielded similar results for some, but not all, test materials. RBA estimates for identical soils (nine test soils and three standard reference materials [SRM]) assayed in mice and swine were significantly correlated (r = 0.70). Swine RBA estimates for 6 of the 12 test materials were higher than those from the mouse assay. RBA estimates for three standard reference materials (SRM) were not statistically different (mouse/swine ratio ranged from 0.86–1). When four test soils from the same orchard were assessed in the mouse, monkey, and swine assays, the mean soil As RBA were not statistically different. Mouse and swine models predicted similar steady state urinary excretion fractions (UEF) for As of 62 and 74%, respectively, during repeated ingestion doses of sodium arsenate, the water-soluble As form used as the reference in the calculation of RBA. In the mouse assay, the UEF for water soluble AsV(sodium arsenate) and AsIII(sodium [meta] arsenite) were 62% and 66%, respectively, suggesting similar absolute bioavailabilities for the two As species. The mouse assay can serve as a highly cost-effective alternative or supplement to monkey and swine assays for improving As risk assessments by providing site-specific assessments of RBA of As in soils. [ABSTRACT FROM PUBLISHER]

An analysis of epidemiological studies of associations between exposure to cadmium and kidney toxicity was conducted. Dose-response functions relating low-molecular-weight (LMW) proteinuria to various indices of cadmium dose (dietary cadmium intake, urinary cadmium excretion, or tissue cadmium burden) were obtained from 15 studies of diverse exposures (occupational, general environmental, environmental contamination). Estimates of the dose corresponding to probabilities of LMW proteinuria of 0.1, 0.15, or 0.2 were transformed from the reported dose units into corresponding estimates of target organ dose (µg Cd/g renal cortex, RC) by simulation using a pharmacokinetics (PK) model. The median RC associated with a 0.1 probability (RC[sub 10M]) of LMW proteinuria was predicted to be 153 µg Cd/g cortex (95% confidence interval [CI]: 84-263). The lower confidence limit on the RC[sub 10M] (RC[sub 10L], 84 µg/g cortex) was predicted to be attained with a constant chronic intake of 1 µg/kg/d in females or 2.2 µg/kg/d in males. The RC[sub 10L] was 2.5-5 times higher than the median RCs predicted to result from dietary cadmium intake in U.S. nonsmokers (µg Cd/g cortex: 33, females; 17, males) and 1.6-3 times higher than the corresponding 95th percentile RCs (53, females; 27, males). Additional exposure from smoking cigarettes (approximately 20 cigarettes/d, 3 µg Cd inhaled/d) was predicted to increase the median RC (µg/g cortex) by approximately 45-70% (48, females; 29, males); however, predicted 95th percentile RCs for smokers (66, females; 38, males) were lower than the RC[sub 10L]. These results indicate that, for most of the U.S. population, dietary-derived risks are likely to be negligible, in the absence of exposures from other sources. [ABSTRACT FROM AUTHOR]

Lead intervention at Superfund sites typically seeks to reduce pediatric blood lead levels by disrupting the surface-to-hand-to-mouth pathway. This article presents the results of a survey of the publicly available literature on the effectiveness of lead intervention on pediatric blood lead levels at hazardous waste sites. The survey includes six hazardous waste sites located in Canada, Australia, and the United States at which intervention activities were conducted and pediatric blood lead levels were sampled both pre- and post-intervention. Evaluation of the effectiveness of intervention on pediatric blood lead levels is often complicated due to confounding variables and statistical limitations. Nevertheless, the outcomes of the intervention studies reviewed in this report suggest that various approaches to the intervention of the dust ingestion pathway, alone or in combination, contributed to declines in blood lead levels in children living in areas heavily contaminated with lead. [ABSTRACT FROM AUTHOR]

The Cadmium Dietary Exposure Model (CDEM) utilizes national survey data on food cadmium concentrations and food consumption patterns to estimate dietary intakes in the U.S. population. The CDEM has been linked to a modification of the cadmium biokinetic model of Kjellström and Nordberg (KNM) to derive predictions of kidney and urinary cadmium that reflect U.S. dietary cadmium intake and related variability. Variability in dietary cadmium intake was propagated through the KNM using a Monte Carlo approach. The model predicts a mean peak kidney cadmium burden of approximately 3.5 mg and a 5th-95th percentile range of 2.2-5.1 mg in males. The corresponding peak renal cortex cadmium concentration in males is 15 µg/g wet cortex (10-22, 5th-95th percentile). Predicted kidney cadmium levels in females were higher than males: 5.1 (3.3-7.6) mg total kidney, 29 (19-43) µg/g wet cortex. Predicted urinary cadmium in males and females agreed with empirical estimates based on the NHANES III, with females predicted and observed to excrete approximately twice the amount of cadmium in urine than males. An explanation for the higher urinary cadmium excretion in females is proposed that is consistent with the NHANES III data as well as experimental studies in humans and animals. Females may absorb a larger fraction of ingested dietary cadmium than males, and this difference may be the result of lower iron body stores in females compared to males. This would suggest that females may be at greater risk of developing cadmium toxicity than males. The predicted 5th–95th percentile values for peak kidney cadmium burden are approximately 60% of the peak kidney burden (8–11 mg) predicted for a chronic intake at the U.S. Environmental Protection Agency (EPA) chronic reference dose of 1 µg/kg-d. [ABSTRACT FROM AUTHOR]