Toxicokinetic models are useful tools to better understand the fate of contaminants in the human body and to establish biological guidance values to interpret biomonitoring data in human populations. This research aimed to develop a biologically-based toxicokinetic model for four rare earth elements (REEs), cerium (Ce), praseodymium (Pr), neodymium (Nd) and yttrium (Y), and to establish biomonitoring equivalents (BE) serving as biological guidance values. The model was constructed using physiological data taken from the literature as well as new experimental kinetic data. These new data indicated that REEs readily disappeared from blood and accumulated mostly in the liver; excretion occurred mainly through feces although a small fraction was eliminated in urine. To properly reproduce the observed kinetics, the model was represented as 19 compartments, which include main tissues and their components (such as retention by macrophages) supplied by blood, as well as routes of excretion. The transfer coefficients between compartments were determined numerically by adjustments to experimental data. Simulations gave good fits to available experimental kinetic data and confirmed that the same model structure is applicable to the four elements. BEs of 0.3 µg/L of Pr and Nd were derived from the provisional RfD of 0.5 mg/kg bw/day established by the U.S. EPA. These BEs can be updated according to new reference dose values (RfD). Overall, the model can contribute to a better understanding of the significance of biological measurements and to the inference of exposure levels; it can also be used for the modeling of other REEs. The BEs will further allow rapid screening of different populations using biological measurements in order to guide risk assessments.
Human biomonitoring represents an important tool for health risk assessment, supporting the characterization of contaminant exposure and nutrient status. In communities where country foods (locally harvested foods: land animals, fish, birds, plants) are integrated in the daily diet, as is the case in remote northern regions where food security is a challenge, such foods can potentially be a significant route of contaminant exposure. To assess this issue, a biomonitoring project was implemented among Dene/Métis communities of the Dehcho region of the Northwest Territories, Canada.Participants completed dietary surveys (i.e., a food frequency questionnaire and 24-h recall) to estimate food consumption patterns as well as a Health Messages Survey to evaluate the awareness and perception of contaminants and consumption notices. Biological sampling of hair, urine and blood was conducted. Toxic metals (e.g., mercury, lead, cadmium), essential metals (e.g., copper, nickel, zinc), fatty acids, and persistent organic pollutants (POPs) were measured in samples.The levels of contaminants in blood, hair and urine for the majority of participants were below the available guidance values for mercury, cadmium, lead and uranium. However, from the 279 participants, approximately 2% were invited to provide follow up samples, mainly for elevated mercury level. Also, at the population level, blood lead (GM: 11 μg/L) and blood cadmium (GM: 0.53 μg/L) were slightly above the Canadian Health Measures Survey data. Therefore, although country foods occasionally contain elevated levels of particular contaminants, human exposures to these metals remained similar to those seen in the Canadian general population. In addition, dietary data showed the importance and diversity of country foods across participating communities, with the consumption of an average of 5.1% of total calories from wild-harvested country foods.This project completed in the Mackenzie Valley of the Northwest Territories fills a data gap across other biomonitoring studies in Canada as it integrates community results, will support stakeholders in the development of public health strategies, and will inform environmental health issue prioritization.
High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.
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