Considerations of Design and Data When Developing Physiologically Based Pharmacokinetic Models
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
As an example, we consider a recent set of models for the biological effect of perchlorate on thyroid function (16,30,47). Detection of ClO4− in several drinking water sources across the United States has led to public concern over health effects from chronic low-level exposures (48). Perchlorate inhibits thyroid iodide (I−) uptake at the sodium-iodide symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A PBPK model was developed to describe the kinetics and distribution of both radioactive I− and ClO4− in both humans and rats. The model also simulates the subsequent inhibition of thyroid uptake of radioactive I− by ClO4−, as well as the response of the system to upregulate NIS in the presence of sustained levels of perchlorate. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model’s successful prediction of free and bound radioactive I− and perchlorate’s interaction with free radioactive I− provide a basis for extending the structure to address the complex hypothalamic–pituitary–thyroid feedback system and, ultimately, predict the effects of iodide deficiency and perchlorate exposure. This progressive development of the model structure in order to describe greater levels of detail of the biological system is a major advantage of the PBPK/PD approach to data analysis.
Clinical Considerations in Radiotracer Biodistribution Studies
Lelio G. Colombetti in Biological Transport of Radiotracers, 2020
Perchlorate has been used extensively to alter the uptake of pertechnetate in the choroid plexus. The ability of sodium Perchlorate to attenuate or block the uptake of pertechnetate at its usual uptake sites has been advantageous, however, by blocking several secretion routes; concentrations in blood, tumor, and brain are generally increased. These levels decline more slowly and this leads to prolonged tissue concentrations.27 This tissue redistribution of pertechnetate probably results, in part, from release of pertechnetate from plasma into red cells within 2 to 3 min after Perchlorate administration.28 Sodium periodate oxidation of membrane carbohydrates in intact cells seems to affect membrane permeability and induce cellular transformation.8 Perchlorate would be expected to have similar effects on cell membranes.
Environmental Toxins and Chronic Illness
Aruna Bakhru in Nutrition and Integrative Medicine, 2018
Certainly, while EDCs have drawn attention due to their impact on numerous organ systems and physiologic processes, the impact that seems to have created the greatest concern over the last few years is that which deals with reproductive health. Fortunately, Zlatnik (2016) has recently published an excellent review of the literature on the subject, highlights of which will be presented here. As an introduction the author points out that a sampling of pregnant women in the United States showed that virtually every participant in the study had at least 43 different chemicals in her bloodstream. These chemicals included polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phenols, polybrominated diphenyl ethers, phthalates, polycystic aromatic hydrocarbons, and perchlorate. Next, to reiterate what was stated above about the realities of identification and management of environmental toxins in real-life clinical scenarios as opposed to the gross toxicity settings often discussed in published research on the subject consider the following quote: Environmental exposures and their outcomes can be hard to assess. This is multifactorial: exposure to chemicals is typically not documented outside of industrial settings, and different people have different levels of sensitivity (stemming from nutritional status, life stage, metabolism, or genetics). Additionally, the particular chemical involved may not be identifiable, even if an exposure was known to occur. The timing of exposure may be unclear or have occurred in the distant past.
Comparison the sensitivity of amphibian metamorphosis assays with NF 48 stage and NF 51 stage Xenopus laevis tadpoles
Published in Toxicology Mechanisms and Methods, 2019
Yin-Feng Zhang, Hai-Ming Xu, Fei Yu, Hong-Yu Yang, Dong-Dong Jia, Pei-Feng Li
Perchlorate, a common aquatic contaminant, is well known to disrupt homeostasis of the HPT axis by inhibiting TH synthesis via competitive inhibition of the sodium-iodide symporter (Serrano-Nascimento et al. 2018). Perchlorate salts are strong oxidizers and are widely used as components of fireworks, airbags, and currently applied fertilizers (Cole-Dai et al. 2018). In this study, we used the environmentally relevant concentrations of 32–125 μg/L SP to validate the sensitivity and applicability of the optimized AMA (Carr and Patino 2011). This selected concentration of SP is within environmental ranges measured in surface and ground waters of many industrial nations and in bodies of water in which amphibians breed (Carr and Patino 2011; Ruthsatz et al. 2018). The tadpoles at stage 48 or stage 51 from a clutch were exposed to a series of concentrations of SP (32, 63, and 125 µg/L), with the chlorinated tap water as control. The exposure procedure is conducted following the MMI treatment, as described above. The numbers of NF 48 or NF 51 stage X. laevis tadpoles analyzed in SP treatment on day 7 and at the end of the exposure is listed in Table 1.
Benchmark dose (BMD) modeling: current practice, issues, and challenges
Published in Critical Reviews in Toxicology, 2018
Lynne T. Haber, Michael L. Dourson, Bruce C. Allen, Richard C. Hertzberg, Ann Parker, Melissa J. Vincent, Andrew Maier, Alan R. Boobis
Perchlorate is a drug, a rocket fuel ingredient, and a natural part of desert environments. It is also found as an environmental contaminant in the soils of certain areas and in the food and drinking water of several locations. Several groups have established the safe dose for perchlorate, including but not limited to (Strawson et al. 2004) with a value of 0.002 mg/kg/d, the (NRC 2005), and (US EPA 2005) with identical values of 0.0007 mg/kg/d (JECFA 2011) with a value of 0.01 mg/kg/d and (EFSA 2014) with a value of 0.0003 mg/kg/d. These values differ by about 30-fold. Importantly, each of these groups used the same basic information to determine their safe doses.
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