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CARLSBAD, CA, United States

Nel A.E.,University of California at Los Angeles | Nel A.E.,Predictive Biology
Journal of Internal Medicine | Year: 2013

Nanotechnology introduces a new field that requires novel approaches and methods for hazard and risk assessment. For an appropriate scientific platform for safety assessment, nanoscale properties and functions of engineered nanomaterials (ENMs), including how the physicochemical properties of the materials relate to mechanisms of injury at the nano-bio interface, must be considered. Moreover, this rapidly advancing new field requires novel test strategies that allow multiple toxicants to be screened in robust, mechanism-based assays in which the bulk of the investigation can be carried out at the cellular and biomolecular level whilst maintaining limited animal use and is based on the contribution of toxicological pathways to the pathophysiology of disease. First, a predictive toxicological approach for the safety assessment of ENMs will be discussed against the background of a '21st-century vision' for using alternative test strategies (ATSs) to perform toxicological assessment of large numbers of untested chemicals, thereby reducing a backlog that could otherwise become a problem for nanotechnology. An ATS is defined here as an alternative to animal experiments or refinement/reduction alternative to traditional animal testing. Secondly, the approach of selecting pathways of toxicity to screen for the pulmonary hazard potential of carbon nanotubes and metal oxides will be discussed, as well as how to use these pathways to perform high-content or high-throughput testing and how the data can be used for hazard ranking, risk assessment, regulatory decision-making and 'safer-by-design' strategies. Finally, the utility and disadvantages of this predictive toxicological approach to ENM safety assessment, and how it can assist the 21st-century vision, will be addressed. © 2013 The Association for the Publication of the Journal of Internal Medicine.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 438.91K | Year: 2012

DESCRIPTION (provided by applicant): Strain background can strongly influence the outcome of toxicity tests in animals. Time and cost constraints preclude in vivo approaches to longstanding concerns about the lack of genetic diversity in animal models. Anin vitro platform is vastly more efficient for understanding the role of genetic background in toxicology testing, and sacrifices no animals. In this project we propose to build a large panel of genetically diverse ES cells from the Diversity Outcross line of mice. The DO mice are an advanced intercross of the 8 founder strains used for the Collaborative Cross. The DO strains capture almost all the sequence variants in laboratory strains, and harbor hundreds to thousands more recombinational breakpoints than F2 mice. They ideally suited for facilitate complex trait mapping. ES cells offer tremendous flexibility and is also ideal for an in vitro genetics platform. DO ES cell lines immortalize DO genomes, creating a renewable resource. In principle, ES cellscan provide access to almost any cell type by directed differentiation. In this way, the DO ES panel is extremely versatile as a permanent, renewable resource. In Phase I, we will establish feasibility by deriving 90 independent, validated DO ES lines andestimate the genetic component of cytotoxicity observed for 15 model toxicant compounds in the Phase I panel. In Phase II we will complete the 600 ES line panel, identify compounds with a significant genetic component to cytotoxic response using a 1400 reference compound set, and map the loci mediating that genetic component in the identified compounds. PUBLIC HEALTH RELEVANCE: There is a longstanding interest in how genetics impacts toxicology, but cost effective, highly scalable tools to investigate this relationship were not available. This project will improve human health and reduce the risk of environmental toxicants by developing a high throughput in vitro platform for investigating the genetic basis of variable response to toxicant exposure.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.94K | Year: 2007

DESCRIPTION (provided by applicant): Determining the reproductive toxicity risk of compounds is vitally important to ensure the health of the general population. It is a difficult and complex task involving testing in animals. While it is well known that mouse strain background can have a profound effect on phenotype, understanding the role of strain background in toxicity testing remains a tremendous challenge. An in vitro genetic testing system contributes toward this end by offering the advantages of lower cost, higher throughput and no sacrifice of animals in testing. An in vitro genetic system can be a "first tier" testing platform, directing in vivo testing to mouse strains that maximize informativeness and minimize animal use. We propose to develop an in vitro, ES cell based system to assess the impact of genetic background in toxicity testing. ES cells are particularly attractive for this purpose since they can be propagated indefinitely in their pluropotent state while retaining the ability to contribute to all tissues of an animal [3]. In Phase I we will determine the feasibility of this system by establishing ES cell lines from a small number of genetically distinct mouse strains and evaluating them in the Embryonic Stem Cell Test (EST) with a reference compound. In Phase II, additional ES lines will be established and tested with a larger panel of reference compounds, toward the development of a system to define the genetic components of toxicity in the EST. This system will lead to more predictive reproductive toxicity testing by providing a platform to investigate the role of genetic background on toxicity risk. The testing platform will be made commercially available to the pharmaceutical and chemical industries, as well as to academic institutions. We propose to develop a system that can help elucidate the role of genetics in reproductive toxicity testing. The broad and varied genetic backgrounds in the proposed testing system better reflects the genetic diversity of the US population, and may lead to more predictive testing that reduces environmental health risk to the population.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 990.71K | Year: 2015

DESCRIPTION provided by applicant We are interested in the genetic basis of drug induced cardiotoxicity and how these genetic factors may underlie serious adverse drug reactions that affect a small but significant fraction of individuals therapeutic circumstances o both We will conduct genomewide screens for factors affecting cardiomyocyte contractile deficit or arrhythmia caused by anthracycline and tyrosine kinase inhibitor induced contractile deficit or arrhythmia The ultimate research goal of this project is to discover novel mechanisms targets and chemical structures underlying variability in drug induced cardiotoxicity The proposed two stage approach is to first conduct high throughput genomewide association studies in vitro using genetically diverse mouse ES derived cardiomyocytes The genes found in those studies will be functionally validated in human IPS derived cardiomyocytes by reducing their expression via gene knockdown This approach takes advantage of the mapping power of mouse genetics with the biological relevance of human cell responses PUBLIC HEALTH RELEVANCE We are developing a high throughput platform for understanding how genes and drugs can interact to damage the heart This research will ultimately improve treatment of many diseases by reducing the likelihood of unexpected drug induced heart damage


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 943.21K | Year: 2009

DESCRIPTION (provided by applicant): Determining the reproductive toxicity risk of compounds is vitally important to ensure the health of the general population. It is a difficult and complex task involving testing in animals. While it is well known that mouse strain background can have a profound effect on phenotype, understanding the role of strain background in toxicity testing remains a tremendous challenge. An in vitro genetic testing system contributes toward this end by offering the advantages of lower cost, higher throughput and no sacrifice of animals in testing. An in vitro genetic system can be a first tier testing platform, directing in vivo testing to mouse strains that maximize informativeness and minimize animal use. We propose to develop an in vitro, ES cell based system to assess the impact of genetic background in toxicity testing. ES cells are particularly attractive for this purpose since they can be propagated indefinitely in their pluripotent state while retaining the ability to contribute to all tissues of an animal. In Phase I we demonstrated the feasibility of this system by establishing ES cell lines from six genetically distinct mouse strains and showing that a measurable and significant variability due to genetic background can be measured in response to exposure to a reference compound, retinoic acid. In Phase II, a panel of approximately 100 genetically distinct ES lines will be established and tested with a larger panel of reference compounds, toward the development of a system to define, map and identify the genetic components of cellular response to environmental burden. This system will lead to more predictive reproductive toxicity testing by providing a platform to investigate the role of genetic background on toxicity risk. The testing platform will be made commercially available to the pharmaceutical and chemical industries, as well as to academic institutions. PUBLIC HEALTH RELEVANCE: We propose to develop a system that can help elucidate the role of genetics in reproductive toxicity testing. The broad and varied genetic backgrounds in the proposed testing system better reflects the genetic diversity of the US population, and may lead to more predictive testing that reduces environmental health risk to the population.

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