Incorporation of a recirculating mobile lipid pool description into the cyclic volatile siloxane (cVMS) PBPK model captures terminal clearance of D4 after repeated inhalation exposure in F344 and SD Rats.

The most recent version of the octamethylcyclotetrasiloxane (D4) physiologically based pharmacokinetic (model) was developed using the available kinetic studies in male and female F344 rats. Additional data, which had not been included in the D4 model development, allowed for a more detailed assessment of the loss of D4 following long-term exposure in both SD and F344 rats. This new data demonstrated a deficiency in the published PBPK model predictions of terminal concentrations of D4 in plasma and fat 14 days after the end of exposures for 28-days, 6 h/day, where the model predictions were an order of magnitude lower than the data. To capture this time-point without altering the end-of-exposure peak concentrations in blood and fat required conversion of the one-way (liver to fat) mobile lipoprotein pool (MLP) into a bi-directional pool between liver and fat. Simulation of the D4 pharmacokinetics in the SD rat, as opposed to the F344 rat, also required a reduction of both fold induction of liver metabolism (KMAX: 5- to 2-fold) and maximal rate of metabolism (VMAXC: 5.0-1.54 mg/kg0.75). The revised MLP description was extended to the human D4 model using a parallelogram approach between rat and human MLP parameters to establish the parameters for the current model in the absence of similar long-term clearance data in the human. The revised human D4 model provided good fits to the human inhalation and dermal exposure studies while not appreciably altering cross-species dose metrics based on the free concentration of D4 in blood.

Assessment of blood lead level declines in an area of historical mining with a holistic remediation and abatement program.

UNLABELLED: Lead exposure and blood lead levels (BLLs) in the United States have declined dramatically since the 1970s as many widespread lead uses have been discontinued. Large scale mining and mineral processing represents an additional localized source of potential lead exposure in many historical mining communities, such as Butte, Montana. After 25 years of ongoing remediation efforts and a residential metals abatement program that includes blood lead monitoring of Butte children, examination of blood lead trends offers a unique opportunity to assess the effectiveness of Butte's lead source and exposure reduction measures. This study examined BLL trends in Butte children ages 1-5 (n= 2796) from 2003-2010 as compared to a reference dataset matched for similar demographic characteristics over the same period. Blood lead differences across Butte during the same period are also examined. Findings are interpreted with respect to effectiveness of remediation and other factors potentially contributing to ongoing exposure concerns. REFERENCE POPULATION COMPARISON: BLLs from Butte were compared with a reference dataset (n=2937) derived from the National Health and Nutrition Examination Survey. The reference dataset was initially matched for child age and sample dates. Additional demographic factors associated with higher BLLs were then evaluated. Weights were applied to make the reference dataset more consistent with the Butte dataset for the three factors that were most disparate (poverty-to-income ratio, house age, and race/ethnicity). A weighted linear mixed regression model showed Butte geometric mean BLLs were higher than reference BLLs for 2003-2004 (3.48vs. 2.05µg/dL), 2005-2006 (2.65vs. 1.80µg/dL), and 2007-2008 (2.2vs. 1.72µg/dL), but comparable for 2009-2010 (1.53vs. 1.51µg/dL). This trend suggests that, over time, the impact of other factors that may be associated with Butte BLLs has been reduced. COMPARISON ACROSS BUTTE: Neighborhood differences were examined by dividing the Butte dataset into the older area called "Uptown", located at higher elevation atop historical mine workings, and "the Flats", at lower elevation and more recently developed. Significant declines in BLLs were observed over time in both areas, though Uptown had slightly higher BLLs than the Flats (2003-2004: 3.57vs. 3.45µg/dL, p=0.7; 2005-2006: 2.84vs. 2.52µg/dL, p=0.1; 2007-2008: 2.58vs. 1.99µg/dL, p=0.001; 2009-2010: 1.71vs. 1.44µg/dL, p=0.02). BLLs were higher when tested in summer/fall than in winter/spring for both neighborhoods, and statistically higher BLLs were found for children in Uptown living in properties built before 1940. Neighborhood differences and the persistence of a greater percentage of high BLLs (>5µg/dL) in Butte vs. the reference dataset support continuation of the home lead abatement program. CONCLUSIONS: Butte BLL declines likely reflect the cumulative effectiveness of screening efforts, community-wide remediation, and the ongoing metals abatement program in Butte in addition to other factors not accounted for by this study. As evidenced in Butte, abatement programs that include home evaluations and assistance in addressing multiple sources of lead exposure can be an important complement to community-wide soil remediation activities.