BioSimulation Consulting Inc.

Newark, DE, United States

BioSimulation Consulting Inc.

Newark, DE, United States
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La Merrill M.,Mount Sinai School of Medicine | Emond C.,BioSimulation Consulting Inc | Emond C.,University of Montréal | Kim M.J.,French Institute of Health and Medical Research | And 10 more authors.
Environmental Health Perspectives | Year: 2013

Background: A dipose tissue (AT) is involved in several physiological functions, including metabolic regulation, energy storage, and endocrine functions. Objectives: In this review we examined the evidence that an additional function of AT is to modulate persistent organic pollutant (POP) toxicity through several mechanisms. Methods: We reviewed the literature on the interaction of AT with POPs to provide a comprehensive model for this additional function of AT. discussion: As a storage compartment for lipophilic POPs, AT plays a critical role in the toxico-kinetics of a variety of drugs and pollutants, in particular, POPs. By sequestering POPs, AT can protect other organs and tissues from POPs overload. However, this protective function could prove to be a threat in the long run. Te accumulation of lipophilic POPs will increase total body burden. These accumulated POPs are slowly released into the bloodstream, and more so during weight loss. Thus, AT constitutes a continual source of internal exposure to POPs. In addition to its buffering function, AT is also a target of POPs and may mediate part of their metabolic effects. This is particularly relevant because many POPs induce obesogenic effects that may lead to quantitative and qualitative alterations of AT. Some POPs also induce a proinflammatory state in AT, which may lead to detrimental metabolic effects. Conclusion: AT appears to play diverse functions both as a modulator and as a target of POPs toxicity.


PubMed | Agency for Toxic Substances and Disease Registry and BioSimulation Consulting Inc
Type: | Journal: Toxicology and applied pharmacology | Year: 2016

Chlorinated dibenzo-p-dioxins (CDDs) are a series of mono- to octa-chlorinated homologous chemicals commonly referred to as polychlorinated dioxins. One of the most potent, well-known, and persistent member of this family is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of translational research to make computerized models accessible to health risk assessors, we present a Berkeley Madonna recoded version of the human physiologically based pharmacokinetic (PBPK) model used by the U.S. Environmental Protection Agency (EPA) in the recent dioxin assessment. This model incorporates CYP1A2 induction, which is an important metabolic vector that drives dioxin distribution in the human body, and it uses a variable elimination half-life that is body burden dependent. To evaluate the model accuracy, the recoded model predictions were compared with those of the original published model. The simulations performed with the recoded model matched well with those of the original model. The recoded model was then applied to available data sets of real life exposure studies. The recoded model can describe acute and chronic exposures and can be useful for interpreting human biomonitoring data as part of an overall dioxin and/or dioxin-like compounds risk assessment.


Emond C.,University of Montréal | Emond C.,BioSimulation Consulting Inc. | Britos T.N.,University of Rennes 1
Journal of Physics: Conference Series | Year: 2015

Scientific literature suggests that exposure to nanoparticles (NPs) might be associated with adverse health effects. A well-developed human risk assessment (HRA) that applies to NPs has never been established and optimized-until now. Furthermore, no government regulations are in place that establish what is considered to be an adequate and secure level of exposure and supported by a strong scientific approach for nanotechnology. It is important to implement the HRA to ensure that workers producing NPs, users of NPs and the general population are protected from deleterious issues related to NPs. In this work, a methodology is described based on the HRA. An effort is required during synthesis before the commercialization phase to evaluate the results of a systematic and rigorous assessment because this could significantly reduce the health risks of those exposed to NPs, including workers and the population. © Published under licence by IOP Publishing Ltd.


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.


Li D.,University of Michigan | Morishita M.,University of Michigan | Wagner J.G.,Michigan State University | Fatouraie M.,University of Michigan | And 6 more authors.
Particle and Fibre Toxicology | Year: 2016

Background: Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health. Methods: A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles. Results: Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces. Conclusions: The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells. © 2016 The Author(s).


Carlander U.,Karolinska Institutet | Li D.,University of Michigan | Jolliet O.,University of Michigan | Emond C.,Biosimulation consulting Inc | And 2 more authors.
International Journal of Nanomedicine | Year: 2016

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP- dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight. © 2016 Carlander et al.


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.


PubMed | University of Michigan, Michigan State University, BioSimulation Consulting Inc. and Karolinska Institutet
Type: Journal Article | Journal: Particle and fibre toxicology | Year: 2016

Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health.A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15min, 24h, and 7days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles.Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4% to the recovery rate at 24h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces.The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells.


Emond C.,BioSimulation Consulting Inc. | Emond C.,University of Montréal
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.


Emond C.,BioSimulation Consulting Inc. | Emond C.,University of Montréal | Kouassi S.,University of Montréal | 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.

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