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.

Urinary cadmium clearance, its relationship to glomerular filtration rate and implications for cadmium epidemiology.

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.

Estimates of urinary blood lead clearance and its relationship to glomerular filtration rate based on a large population survey.

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.

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.

Mouse assay for determination of arsenic bioavailability in contaminated soils.

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 As(V) (sodium arsenate) and As(III) (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.

Evaluation of the integrated exposure uptake biokinetic (IEUBK) model for lead in children.

BACKGROUND: The Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK model) was developed by the U.S. Environmental Protection Agency to support assessments of health risks to children from exposures to lead (Pb). OBJECTIVE: This study evaluated performance of IEUBK model (v2.0) as it would be typically applied at Superfund sites to predict blood Pb levels (BLLs) in populations of children. METHODS: The model was evaluated by comparing model predictions of BLLs to 1144 observed BLLs in a population of children at the Bunker Hill Superfund Site for which there were paired estimates of environmental Pb concentrations. RESULTS: Predicted population geometric mean (GM) BLLs (GM: 3.4 µg/dL, 95% CI: 3.3, 3.5) were within 0.3 µg/dL of observed (GM: 3.6 µg/dL, 95% CI: 3.5, 3.8). The model predicted the observed age trend in GM BLLs and explained ~90% of the variance in the observed age-stratified GM BLLs. The mean predicted probability of exceeding 5 µg/dL (P5) was 27% (95% CI: 24, 29) and observed P5 was 32% (95% CI: 29, 35), a difference of 5%. Differences between geographic area stratified mean P5 (predicted minus observed) ranged from -11 to 14% (mean difference: 2.3%). SIGNIFICANCE: Although the more general applicability of these findings to other populations remains to be determined in future studies, our results support applications of the IEUBK model (v2.0) for informing risk-based decisions regarding remediation of soils and mitigation of exposures at Superfund sites where the majority of the exposure unit GM BLLs are expected to be ≤5 µg/dL and where it is desired to limit the predicted probability of exceeding 5 µg/dL to <5%.

Pharmacokinetics/pharmacodynamics (PK/PD) modeling of risks of kidney toxicity from exposure to cadmium: estimates of dietary risks in the U.S. population.

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 (microgram Cd/g renal cortex, RC) by simulation using a pharmacokinetics (PK) model. The median RC associated with a 0.1 probability (RC10M) of LMW proteinuria was predicted to be 153 micrograms Cd/g cortex (95% confidence interval [CI]: 84-263). The lower confidence limit on the RC10M (RC10L, 84 micrograms/g cortex) was predicted to be attained with a constant chronic intake of 1 microgram/kg/d in females or 2.2 micrograms/kg/d in males. The RC10L was 2.5-5 times higher than the median RCs predicted to result from dietary cadmium intake in U.S. nonsmokers (microgram 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 micrograms Cd inhaled/d) was predicted to increase the median RC (microgram/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 RC10L. 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.

Application of geostatistics to risk assessment.

Geostatistics offers two fundamental contributions to environmental contaminant exposure assessment: (1) a group of methods to quantitatively describe the spatial distribution of a pollutant and (2) the ability to improve estimates of the exposure point concentration by exploiting the geospatial information present in the data. The second contribution is particularly valuable when exposure estimates must be derived from small data sets, which is often the case in environmental risk assessment. This article addresses two topics related to the use of geostatistics in human and ecological risk assessments performed at hazardous waste sites: (1) the importance of assessing model assumptions when using geostatistics and (2) the use of geostatistics to improve estimates of the exposure point concentration (EPC) in the limited data scenario. The latter topic is approached here by comparing design-based estimators that are familiar to environmental risk assessors (e.g., Land's method) with geostatistics, a model-based estimator. In this report, we summarize the basics of spatial weighting of sample data, kriging, and geostatistical simulation. We then explore the two topics identified above in a case study, using soil lead concentration data from a Superfund site (a skeet and trap range). We also describe several areas where research is needed to advance the use of geostatistics in environmental risk assessment.