Скачать 0.54 Mb.
Silver Jubilee Year Celebrations of Society of Toxicology (STOX) India|
International Conference on Toxicology, Environmental and Occupational Health
14-17th Nov., 2005
Industrial Toxicology Research Centre, Lucknow, India
CONTINUING EDUCATION COURSES
CEC- 01 : Toxicogenomics and Metabonomics
Dr. JM Arif
K F Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
Dr. VM Shingatgeri
Drug Safety Evaluation, Ranbaxy Laboratories Ltd, Gurgaon, Haryana, India
TOXICOGENOMICS - A NEW PARADIGM OF TOXICOLOGY
Centre For Biological Safety and Research, Notational Institute of Health Sciences, 1-18-1 Kamiyoha, Setagayaku, Tokyo-158-8501, Japan.
The micro-array and gene chip technologies applied in toxicology are called "toxicogenomics" ("toxicological transcriptomics") . Toxicogenomics provides deterministic genetic information on one hand, and non-deterministic epigenetic information on the other hand. Although the collection of genotoxicity data and other short-term testing data link to the former, the sub-chronic and the long-term testing data represent both. Toxicogenomics has bilateral uses, such as in the elucidation of the toxicologic mechanism of gene expression (inductive toxicogenomics) or in the prediction of toxicologic phenotypes on the basis of the categorization of gene expression profiling (deductive toxicogenomics). Since the latter is based on a shortness of informational component in genomics rather than on phenotypic uncountable information, the predictability of the latter may be limited, however, the power of such predictability is of interest, because the latter is based on whole "finite information" from global genomic expressions. One of sample applications introduced presently is toxicogenomics based on systems biology, such as applied hemopoietic stem cell biology . The toxicogenomics data analyses by computational biology can also elucidate new toxicologic paradigms; classic "principal component analysis (PCA)", i.e., automatic component analysis delivered solely by genomic expression, can elucidate mechanistic toxicologic contribution of unknown functional genes after chemical and xenobiotic exposure.
1. Inoue, T, Introduction: Toxicogenomics - a New Paradigm of Toxicology, in Toxicogenomics, T. Inoue and W.D. Pennie, Editors. 2003, Springer- Verlag Tokyo: Tokyo. p. 3-11.
2. Hirabayashi Y and Inoue T: Chapter 24. Toxicogenomics Applied to Hematotoxicology. In: Handbook of Toxicoge-nomics, J. Borlak (ed), Wiley- VCH, Verlag GmbH, Weinheim, 2005, pp. 583-608.
GENE EXPRESSION PROFILING IN THE LOWER EUKARYOTE MODEL, SACCHAROMYCES CEREVISIAE, FOR STUDYING TOXIC AGENTS
Pillai B and Ramchandran S
Institute of Genomics and Integrative Biology, Delhi University, Mall Road, New Delhi-110 007, India. e-mail: firstname.lastname@example.org
Traditionally, toxicologists have been using bioassays based on rodent models to evaluate the toxic effects of chemical compounds and to study the mechanism of action of toxicants. There is a growing need to develop high- throughput assays for rapid screening of large numbers of toxicants. Baker's yeast or Saccharomyces cerevisiae can be a promising model for such assays due to its amenability to genetic studies and the vast amount of genomics knowledge and resources associated with this unicellular fungus. The response of cells to an aqueous extract of cigarette smoke was studied by genome wide expression profiling using the yeast Saccharomyces cerevisiae as a model. Exposure to cigarette smoke extract inhibits yeast growth and results in global changes in gene expression. The transcription profile revealed that exposure to cigarette smoke could result in changes in gene expression spanning many functional classes of genes. Genes involved in response to oxidative stress and DNA repair are upregulated after a brief exposure to cigarette smoke extract. The effects of cigarette smoke extract on yeast growth can be reversed by treatment with anti-oxidants. Knockout mutants lacking superoxide dismutase (sod1) gene were seen to be hypersensitive to cigarette smoke exposure. YAP1 is a central transcriptional regulator of oxidative stress in yeast. Its target promoters were induced rapidly after exposure to cigarette smoke extract. Promoter reporter assays based on YAP1 dependent expression of beta-galactosidase offer a convenient and potentially high-throughput assay for monitoring the toxic effects of cigarette smoke. The overall agreement between our observations and the recently reported effects of cigarette smoke on gene expression in rodent and human cells suggests that yeast can be used as a model system in toxicogenomics studies for monitoring of toxic agents and for studying the cellular and molecular consequences of exposure to potentially toxic agents. We have also developed software tools that support the experimenter in various stages of microarray technology. Array D is a universally applicable, freely available software that offers various design solutions for micro-arrays using a specific set of user-defined requirements.
TOXICOGENOMICS AND REGULATORY PERSPECTIVE
Shingatgeri VM, Udupa V and Rajaram SM
Drug Safety Evaluation, Ranbaxy Laboratories Ltd, Plot 20, Sector 18, Gurgaon, Haryana, India. e-mail: vyasmadhavrao.shingatgeri@ ranbaxy.com
Early identification of safety of a drug candidate is critical to an efficient drug discovery and development process. Toxicogenomics is an interface of the diverse disciplines like toxicology and genomics and is based on application of genomic technologies to define globally the changes in gene expressions (both mRNA and proteins) as a consequence to the exposure to chemicals, drugs, environmental agents and stressors. It combines information from studies of genomic-scale mRNA profiling, cell or tissue-wide protein profiling, genetic susceptibility and computational models to understand the roles of gene-environment interactions in disease, improves the prediction of toxicities at an earlier stage with complimentary data, unravel the molecular mechanisms of toxicity, identification of biomarkers of exposure and assess adverse drug reactions of marketed products in humans or new drug candidates. The challenge in toxicogenomics is to validate the experiment, analyze and correctly interpret the large micro-array data sets in relation to existing information (e.g., screening of a drug-induced gene expression fingerprint against a database containing drug-related gene expression toxicity profiles). It is critical that interdisciplinary information (chemistry, biochemistry, genetics, genomics, clinical) be integrated into the same data warehouse. Because of the potential of gene expression profiling to improve the safety assessment of new chemical entities, FDA has recently issued a draft "Guidance for Industry: Pharmacogenomic Data Submissions" (FDA 2003)" in an attempt to clarify FDA policy on the use of pharmacogenomic data in the drug application review process (http: //www. fda.gov/cder/guidance). In addition, the FDA is embarking on a new guidance initiative for the co-development of pharmacogenomics-based drugs and biologic products and the diagnostic tests necessary for therapeutic decision making. It is anticipated to see the base of pharmacogenomics knowledge grow and expand, and being used in the drug discovery and regulatory evaluation processes in advancing public health.
TOXICOGENOMICS: PRINCIPLES AND APPLICATIONS
Industrial Toxicology Research Centre, Mahatma Gandhi Marg, Lucknow-226001, India
'Toxicogenomics', in brief, is the study of interactions between the 'toxicants' and the 'genome'. In functional terms, it includes two aspects. One, how toxicants influence the expression of different genes in a tissue [now studied by microarray based transcription profiling or transcriptomics, and analysis of the total proteins i.e. proteomics], and second, how changes in the genome (e.g. single nucleotide polymorphism; SNPs) of different genes) leads to differences in the response of individuals to a toxicant. These studies were almost unthinkable till a few years ago, but has now become possible because of a few landmark developments viz. availability of entire human genome sequence, and development of 'Microarray technology' and a whole host of proteomic tools. In microarray-analysis, expression of all the genes of an individual at a given situation can now be studied. Briefly, it includes, i) arraying of all the genes (around 30,000 from human genome) on a solid matrix as tiny spots; ii) Isolation of mRNA molecules from a cell-type and hybridization with the arrayed gene-spots; and iii) scanning of the hybridized molecules. In a typical microarray-experiment, we expect to see many genes that do not hybridize to any of the mRNAs, suggesting that their expression is shut-off at this time. Amongst the expressed genes, we expect to see low, moderate or high signal, depending on their expression in these cells. A comparison of such genome-wide transcription analysis (transcriptomics) amongst individuals in a population will identify the genes whose levels are altered after exposure to the pollutant. The information will be helpful in delineation of the mechanism of action of this pollutant, and identification of biomarkers for toxic response. Likewise, all the proteins that are present in a tissue at a given time can be analyzed by 2D-gel electrophoresis, or other such techniques. This protein display, when compared with the corresponding display from a toxicant exposed sample, will identify the specific proteins that are associated with the toxicant-exposure. While the genomes of different individuals are >99.9% identical, we still differ from each other in many ways. One of the major reasons for this is 'single nucleotide changes' that occur in the genome. These 'Single nucleotide polymorphisms; SNPs' are now being identified, and their association with differential toxic response is being understood. In the presentation, the principals, methodology, and applications of Toxicogenomics in various real-life situations will be discussed.
CEC- 02: Good Laboratory Practice
Mr. Saha R
Head, National GLP Compliance Monitoring Authority, DST, New Delhi
Dr. S Srivastava
Central Drug Research Institute, Mahatma Gandhi Marg, Lucknow, India
QUALITY ASSURANCE AND GOOD LABORATORY PRACTICES
Advanced Facility for Safety Evaluation of GM-Drugs, Industrial Toxicology Research Centre, Mahatma Gandhi Marg, Lucknow-226001, India. e-mail: email@example.com
Quality Assurance Programme in Good Laboratory Practices (GLP) is referred as a defined system established to assure Test Facility Management of compliance with the Principles of GLP. It should be documented and implemented by appropriately trained individuals, designated by and directly responsible to the Management. QA-personnel should not be involved in the conduct of studies being assured but be familiar with their procedures. The responsibilities of QA include, but are not limited to (1) maintaining copies of all Study Plans and Standard Operating Procedures (SOPs) in use at the test facility, reviewing/verifying that they contain all information required for GLP compliance and identifying critical phases for Inspection; (2) accessing an up-to-date copy of the Master Schedule for planning QA activities, assessing QA workload and evaluating extent of overlap between regulatory and non-regulatory studies through sharing common work areas and facilities; (3) conducting inspections (study-based, process-based and facility-based) and promptly reporting the observations to the Study Director and Management for corrective actions if any; (4) auditing Final Reports for accuracy and completeness; and (5) annexing a signed QA-statement in the final report specifying the type of inspection with dates and phases of study and dates of reporting the inspection results to the Management and Study Director, supporting Study Director's claim of GLP compliance and management confirmation that the report reflects the raw data. QA should develop its own SOPs, inspection checklists, plans of activity, documents and records, etc to effectively discharge its responsibilities and for the Management to verify their efficiency and effectiveness. Special provisions exist for QA-activity pertaining to short-term and in-vitro studies, field-studies, multi-site studies, computerized systems and non-regulatory studies. At small test facilities, QA functions may be performed by individuals working in different departments/studies or by out-side agency, however, it is prudent to have at least one individual exclusively for co-ordination of QA-function.
GLP COMPLIANCE OF FACILITIES
Division of Toxicology, Central Drug Research Institute, Mahatma Gandhi Marg, Lucknow-226001, India
In GLP parlance, everything a Study Director, Principal Investigator or Study Personnel needs for the performance of a study comes under the purview of FACILITIES. The norms of GLP require that the Facilities should be well suited for the total number and the different types of studies being performed at a test laboratory. They also enjoin that the Management is ultimately responsible for providing adequately sufficient Facilities for proper conduct of the studies. Thus, proper acquisition, maintenance and methodical use of suitable Facilities are essential components of GLP compliance, and the overall onus of ensuring all this lies with the Management of a Test facility. Range of things included under Facilities fall into the following categories:
4. Well Characterized Test Item
5. Well Characterized Test System
6. Waste Disposal
· It should be clearly evident that the building (laboratory areas, animal facility, test item handling and dose preparation area and archives) and their support systems (electricity, water, environmental control, waste disposal) are designed and maintained in such a way that there is no environmental stress, confusion, cross-mixing or mishandling of materials, animals, samples and raw data.
· The equipment should be of demonstrably good quality and capacity. It should be appropriately located, well serviced, calibrated and used as per written procedures. All records of its installation, use, standardization as well as preventive and curative maintenance should be easily traceable and available.
· Procedures for control of quality of supplies (chemicals, reagents, stains, animal feed, nutrients, water and bedding husk) should be available and be practiced. Management should ensure that all aspects, including purchase, storage, monitoring, use and disposal, are being looked after and also being properly recorded in accordance with written procedures.
· Proper characterization, handling, storage and care of test items and test systems are absolutely essential for reproducibility of results. There should be enough provisions and precautions to ensure high quality, proper control and maintenance of desirable characteristics of these two things.
· In the end, it cannot be overemphasized that procedures for handling the breakdowns in any of the above components of Facilities should be available and practiced so as to preserve the sanctity and authenticity of the studies.
During this presentation, an effort will be made to understand how the above conditions of GLP compliance of FACILITIES can be met in a convincing manner.
ROLE OF STUDY PLAN, STANDARD OPERATING PROCEDURES (SOP'S) AND DOCUMENTATION IN GLP COMPLIANCE
|Cellular Toxicology is the third tutorial on toxicology produced by the Toxicology and Environmental Health Information Program of the National Library of||Toxicology Tutor II is the second of three toxicology tutorials being produced by the Toxicology and Environmental Health Information Program of the National|
|Engineered nanomaterials: a review of the toxicology and health hazards||International Board of Clinical Metal Toxicology|
|* Ecology Ecotoxicology Aquatic Toxicology Environmental analytical chemistry of organic compounds Environmental Chemistry (Fates of trace substances in aquatic ecosystems) *||Nutraceuticals, nutrigenomics, Public Health Nutrition, Clinical and Therapeutic Nutrition, Institutional Food Administration, Food Science, Food Safety, Food Toxicology and Quality Control|
|International Society for Environmental Ethics||Within a year, with the rush underway, the world began to learn about the rich silver deposits at Leadville. By 1879, the silver was pouring out. About that|
|Mammalian toxicology||International Conference of the Utopian Studies Society (Europe)|