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Lagarde F.,French Agency for Food | Beausoleil C.,French Agency for Food | Belcher S.M.,University of Cincinnati | Belzunces L.P.,French National Institute for Agricultural Research | And 3 more authors.
Environmental Health: A Global Access Science Source | Year: 2015

Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a "moderate" to "high" level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A. © 2015 Lagarde et al.; licensee BioMed Central. Source


Emond C.,BioSimulation Consulting Inc. | Emond C.,University of Montreal
Journal of Physics: Conference Series | Year: 2011

Nanotoxicokinetics is a subsection of the toxicology field that involves the study of kinetic displacement of nanoparticles (NPs) in an organism. Four different steps, namely absorption, distribution, metabolism and elimination (ADME), are involved in nanotoxicokinetics. However, only ADE will be covert in this mini review. Because of their size, NPs react differently than particulate matter larger than the nanometre unit in diameter. In the organism, a closer interaction between NPs and biological matrices, called nanotoxicodynamics, might increase the health effects. (Animals are usually in studies to evaluate the global interaction of NPs and biological matrices and to control and reduce the bias.) Understanding the different steps of kinetics is very important to increase the confidence of the amount of NP delivery in the target organ and to assess the level of risk. The objective of this work was to review the behaviour of the NPs interacting with the biological kinetic steps of the ADME and their limitations and constraints. Specifically, it was reviewed the impact of each of the four steps of nanotoxicokinetics, from exposure to elimination in the organism. Recent publications have provided some information on this issue, allowing for a better understanding on how the NPs behave across physiology; however, information is still lacking. We also systematically reviewed the ADME process, and supported our review with examples from the literature. We reviewed the two major factors that influence the absorption of NPs: enumerated biotransformation and elimination limitations. One of the focuses of this study was the interaction between NPs and biological matrices because the morphology and chemical properties may drive the potential for exposure. This paper present different examples of interactions find from literature. To study these interactions, we used a classical pharmacokinetic approach employed in the pharmaceutical industry and compared it to a dynamic predictive tool called the physiologically based pharmacokinetic model. This review would allow us to better interpret the behaviour of NPs. This review would also provide a better insight about the intake, site, and the disposition of NPs and would help identify the major consequences of the interaction of NPs with biological matrices. These interactions might have reversible or irreversible consequences for the integrity of the organism. Source


Li D.,University of Michigan | Emond C.,BioSimulation Consulting Inc. | Johanson G.,Karolinska Institutet | Jolliet O.,University of Michigan
Journal of Physics: Conference Series | Year: 2013

The studies on potential health risks possessed by engineered nanoparticles (NPs) have been growing rapidly. However, detailed and systemic knowledge on the uptake and biodistribution of NPs in body is still limited. Moreover, there is a need to characterize the relation between the characteristics of NPs (size, surface modifications, etc.) and their behaviours in the body. The aim of this study is to explore how these characteristics will influence the NPs uptake and biodistribution. We have successfully developed a Physiologically Based Pharmacokinetic (PBPK) model for the biodistribution of polyethylene glycol-coated polyacrylamide NPs in rats, modelling the capture and removal of NPs by phagocytizing cells. Based on this PBPK model, the behaviours of other nanoparticles (polymeric, quantum dot, silver, titanium oxide and cerium oxide NPs) are investigated, based on data from several experiments published in the literature. Size is one of the important properties to consider. Our model parameterization suggests that the uptake rate by phagocytizing cells will decrease as the size of nanoparticles increases when the removal rates for these nanoparticles are similar. This could indicate that the phagocytizing cells are saturated by the number of NPs rather than absolute mass. Nevertheless, surface modification, such as polyethylene glycol coating, may reduce the uptake rate by phagocytizing cells. With phagocytizing cells serving as a deposit of NPs, these influences of different characteristics of NPs to the behavior of phagocytizing cells could affect the fate of NPs in the body not only during the initial uptake within the first hour but also in long-term at the kinetic and dynamic levels. © IOP Publishing Ltd 2013. Source


Emond C.,BioSimulation Consulting Inc. | Emond C.,University of Montreal | Kouassi S.,University of Montreal | Schuster F.,CEA Saclay Nuclear Research Center
Journal of Physics: Conference Series | Year: 2013

Nanomaterials are widely present in many industrial sectors (e.g., chemical, biomedical, environment), and their application is expected to significantly expand in the coming years. However, nanomaterial use raises many questions about the potential risks to human health and the environment and, more specifically, to occupational health. The available literature supports the ability of the lung, gastrointestinal tract, and skin to act as significant barriers against systemic exposure to many nanomaterials. However, because a potential risk issue exists about the toxicity of nanomaterials to the biological material, tools need to be developed for improving the risk management of the regulators. The goal is to develop a tool that examines the current knowledge base regarding the health risks posed by engineered nanoparticles to improve nanotechnology safety prior to the marketing phase. The approach proposed during this work was to establish a safety assessment constructed on a decision-control pathway regarding nanomaterial production and consumer's product to integrate different aspects. These aspects include: (1) primarily research and identification of the nanomaterial base of physicochemical properties, toxicity, and application; (2) the occupational exposure risk during the manufacturing process; (3) and the engineered nanomaterial upon the consumer product. This approach provides important parameters to reduce the uncertainty related to the production of nanomaterials prior their commercialization, reduce the reluctance from the industry, and provide a certification tool of sanitary control for the regulators. This work provides a better understanding of a critical issue of nanomaterials and consumer safety. © IOP Publishing Ltd 2013. Source


Li D.,University of Michigan | Johanson G.,Karolinska Institutet | Emond C.,BioSimulation Consulting Inc. | Carlander U.,Karolinska Institutet | And 2 more authors.
Nanotoxicology | Year: 2014

Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats. The model explains 97% of the observed variation in nanoparticles amounts across organs. According to the model, phagocytizing cells quickly capture nanoparticles until their saturation and thereby constitute a major reservoir in richly perfused organs (spleen, liver, bone marrow, lungs, heart and kidneys), storing 83% of the nanoparticles found in these organs 120 h after injection. Key determinants of the nanoparticles biodistribution are the uptake capacities of phagocytizing cells in organs, the partitioning between tissue and blood, and the permeability between capillary blood and tissues. This framework can be extended to other types of nanoparticles by adapting these determinants. © 2014 Informa UK Ltd. All rights reserved. Source

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