Application of a multi-route physiologically based pharmacokinetic model for manganese to evaluate dose-dependent neurological effects in monkeys.
نویسندگان
چکیده
Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594-605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal.
منابع مشابه
Physiologically Based Pharmacokinetic (PBPK) model for biodistribution of radiolabeled peptides in patients with neuroendocrine tumours
Objective(s): The objectives of this work was to assess the benefits of the application of Physiologically Based Pharmacokinetic (PBPK) models in patients with different neuroendocrine tumours (NET) who were treatedwith Lu-177 DOTATATE. The model utilises clinical data on biodistribution of radiolabeled peptides (RLPs) obtained by whole body scintigraphy (WBS) of the patients.Methods: The blood...
متن کاملManganese exposure, essentiality & toxicity.
Manganese (Mn) is an essential element present in all living organisms and is naturally present in rocks, soil, water, and food. Exposure to high oral, parenteral, or ambient air concentrations of Mn can result in elevations in Mn tissue levels and neurological effects. However, current understanding of the impact of Mn exposure on the nervous system leads to the hypothesis that there should be...
متن کاملAnalysis of manganese tracer kinetics and target tissue dosimetry in monkeys and humans with multi-route physiologically based pharmacokinetic models.
Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models conta...
متن کاملUpdate on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment
Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features...
متن کاملA Model of Time-dependent Biodistribution of 153Sm-Maltolate Complex and Free 153Sm Cation Using Compartmental Analysis
Introduction Compartmental analysis allows the mathematical separation of tissues and organs to determine activity concentration in each point of interest. Biodistribution studies on humans are costly and complicated, whereas such assessments can be easily performed on rodents. In this study, we aimed to develop a pharmacokinetic model of 153Sm-maltolate complex as a novel therapeutic agent and...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Toxicological sciences : an official journal of the Society of Toxicology
دوره 129 2 شماره
صفحات -
تاریخ انتشار 2012