SeminarSub: Medical Biotechnology (4MBT 04)

Under guidance of, Lecturer in-charge Dr. Beena Vinod Department of BIOTECHNOLOGY3/15/2012 Salman Khan CMRIMS Bangalore

SALMAN KHAN M.Sc IV Semester (bt) Reg no: 10204015

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Salman Khan CMRIMS Bangalore

ToxicologyWhat is toxicology? The study of the effects of poisons. Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins

Toxicant - the specific poisonous chemical. Xenobiotic - man-made substance and/or produced by but not normally found in the body. Khan CMRIMS Bangalore 3/15/2012 Salman

History2700 B.C. 1900-1200 B.C. Chinese journals: plant and fish poisons Egyptian documents that had directions for collection, preparation, and administration of more than 800 medicinal and poisonous recipes. Hindu medicine includes notes on poisons and antidotes. Greek physicians classified over 600 plant, animal, and mineral poisons. Romans used poisons for executions and assassinations. Avicenna Islamic authority on poisons and antidotes. Spanish rabbi Maimonides writes first-aid book for poisonings, Poisons and Their Antidotes

800 B.C. - India 50-100 A.D. 50- 400 A.D. (A.D. 980-1036) 1200 A.D. -

Swiss physician Paracelsus (1493-1541) credited with being the father of modern toxicology. All substances are poisons: there is none which is not a poison. 3/15/2012 Salman Khan CMRIMS Bangalore The right dose differentiates a poison from a remedy

Paracelsus (1493-1541)3/15/2012 Salman Khan CMRIMS Bangalore

Units Used to Measure Chemicals in the EnvironmentPPM Parts per million = 1 inch in 16 miles, 1 minute in two years PPB Parts per billion = 1 inch in 16,000 miles, 1 second in 32 years PPT Parts per trillion = 1 inch in 16 million miles,1 second in 320 centuries Toxicity of chemicals is determined in the laboratory The normal procedure is to expose test animals By ingestion, application to the skin, by inhalation, gavage, or some other method which introduces the material into the body, or By placing the test material in the water or air of the test animals environment Toxicity is measured as clinical endpoints which include Mortality (death) Teratogenicity (ability to cause birth defects) Carcinogenicity (ability to cause cancer), and, Mutagenicity (ability to cause heritable change in the DNA) Commonly used, 2 measures of mortality the LD50 The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a variety of methods, and the LC50 The concentration of a chemical in an environment (generally air or water) which produces death in 50% of an exposed population of test animals in a specified time frame 3/15/2012 Salman Khan CMRIMS Bangalore

Caution reflects the lowest degree of relative toxicity All pesticides with an LD50 of greater than 500 mg/kg must display this word on their label Actually includes two groups of pesticides those classed by the EPA as Relatively nontoxic (>5,000 mg/kg) and those classed as slightly toxic (500 5,000 mg/kg) Warning reflects an intermediate degree of relative toxicity All pesticides with an LD50 of greater than 50 and less than 500 mg/kg must display this word on their label Pesticides in this category are classed as moderately toxic Danger reflects the highest degree of relative toxicity All pesticides with an LD50 of less than 50 mg/kg must display this word on their label Pesticides here are classed as highly toxic Poison Legally defined term not just anything you don t like Any pesticide with an LD50 of 50 mg/kg or less Labels must reflect this classification Label must have the signal word DANGER plus the word POISON 3/15/2012 Salman Khan CMRIMS Bangalore Label also must display the skull and crossbones icon

Relative Toxicity: Comparative informationHighly toxic chemicals 0 50 mg/kg range (tasting to 1 teaspoonful) mg/kg Botulinus toxin 0.00001 Dioxin 0.1 Parathion 13.0 Strychnine 30.0 Nicotine 50.0 Moderately toxic chemicals 50- - 500 mg/kg range (teaspoonful to 1 ounce) mg/kg Paraquat 95 Caffeine 200 Carbaryl 270 Malathion 370 2,4-D 375

Organisms can t differentiate between natural and synthetic chemicals. Chemicals must be evaluated in their biological context of behavior in organisms Mode of action, not source, is the concern of toxicologists and informed users of 3/15/2012 Salman Khan CMRIMS Bangalore pesticides

Aquatic Toxicology Ecotoxicology Chemical Toxicology Forensic Toxicology Descriptive Toxicology Regulatory Toxicology Nanotoxicology Environmental Toxicology Medical Toxicology3/15/2012 Salman Khan CMRIMS Bangalore

What is environmental toxicology ? Definition: study of impacts of pollutants on the structure and function of ecosystems manmade poisonous chemicals and their effect on the environment does not include the study of naturally occurring toxins, for example cholera toxin, or brevitoxin Environmental toxicology is a new discipline that grew out of studies on the environmental fate and transport of pesticides in the 1940s and 1950s The discipline toxicology is as old as medicine many toxic plant chemicals are used as therapeutic agents in medicine. The term ecotoxicology appeared in the literature in 1969 Field was pioneered by Rachel Carson3/15/2012 Salman Khan CMRIMS Bangalore

1907-1964

Marine Biologist from Pennsylvania MA from Johns Hopkins U. Author of Silent Spring Received much attention, because she wrote and presented scientific facts well She was disturbed by the widespread and indiscriminate use of pesticides Many of these pesticides were known to affect wildlife e.g. kill birds She lobbied very hard to control and ban certain highly toxic chemicals Testified before congress in 1963 and called for new policies with respect to human health and the environment

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Salman Khan CMRIMS Bangalore

Routes of Environmental Exposure

Ingestion (water and food) Absorption (through skin) Injection (bite, puncture, or cut)

Inhalation (air)3/15/2012 Salman Khan CMRIMS Bangalore

Environmental toxicology is highly interdisciplinary field

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Environmental toxicology is driven by legislationNational Environmental Policy Act Clean Air Act Federal Environmental Pesticide Control Act Federal Water Pollution Control Act Safe Drinking Water Act Toxic Substances Control Act Resource Conservation and Recovery Act Comprehensive Environmental Response, Compensation and Liabilities Act Clean Water Act3/15/2012 Salman Khan CMRIMS Bangalore

Environmental toxicology depends on Lab work Effects of toxicants on biochemistry and physiology

Field work Field observations of reproduction and survival in polluted vs. nonpolluted sites

Modeling of fate and transport of toxicants in the environment i.e. exposure and risk assessment Static models Strategic models Testable models3/15/2012

: short term modeling of ecosystems : model of a specific aspect of a system : model makes predictions that can be tested in the field or laboratorySalman Khan CMRIMS Bangalore

Purpose/function of environmental toxicology is to Identify the mode / site of action of a xenobiotic FATE and TRANSPORT / interaction of a xenobiotic with the biosphere (including specific organisms) after it is released / pollution occurs identify the effect the xenoboitic has on an ecosystems / higher level organisation e.g. loss of fertility of Alligators in Lake Apopca

site of action Introduction of xenobiotic

physiology behavior

community parameters

Ecosystem effect

biotransformation3/15/2012

biochemistry

population dynamics Salman Khan CMRIMS Bangalore

How do we measure these effect ? Physio-chemical characteristics: QSAR (quantitative structure activity relationship)O N CH2 CH NH O CH S CH3 COOH CH3

COOH CH2 O N HC O HN CH CH S S CH3 CH3 N COOH CH3 CH3

Estimate the contribution of portions of the molecule to physio-chemical characteristicsIonic interactions Hydrophobic interactions Van der Vaals forces Salman Khan CMRIMS Bangalore Hydrogen bonding

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Abiotic environmental fate Partitioning Adsorption Transport/advection PCB vs. Benzene

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Biotic environmental fate The interaction of a xenobiotic at the site of action in an organism is often molecular happenstance i.e. xenobiotic mimic compounds which are naturally found in species that they affect hormone mimics

Bioaccumulation The storage of a compound in fatty tissue of an animal Result of food chain / trophic levels

Biotransformation Metabolic processes, mainly by environmental bacteria, that alter the structure and toxicity of a compound

Biodegradation Breakdown of a xenobiotic to CO2 and water3/15/2012 Salman Khan CMRIMS Bangalore

Biotic mode of action (Receptors) Chemicals that interfere with biochemical receptor sites Signaling proteins in membranes Replication Protein synthesis

Chemicals that damage biochemical or molecular targets DNA damage Strange breakage Chromosome abnormalities Cancer Non-genotoxic effects such as immunosuppression

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Physiological and behavioral effects Standard tool for assessing toxicological effects on populations Tissue lesions Tumors Reproductive success

Population success Population age structure xenobiotics often exert a stronger effect on juveniles => a shift in age structure might indicate that a population is not doing well, because it is affected by a xenobiotic Shift in bacterial communities contamination reduces bacterial diversity; bacterial numbers often increase because the contaminant is food for some while it is toxic for others

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Community effects Species diversity Abundance Distribution

Ecosystem effects Productivity Trophic level structure Stability

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MEDICAL TOXICOLOGY

Generic Name: methylphenidate Ritalin-SR 20 mg. Ritalin-SR is used in the treatment of narcolepsy and belongs to the drug class CNS stimulants. Risk cannot be ruled out during pregnancy. 3/15/2012 Salman Khan CMRIMS Bangalore

Medical toxicology, is a medical subspecialty focusing on the diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins, and biological agents. Medical toxicologists are involved in the assessment and treatment of acute or chronic poisoning, adverse drug reactions (ADR), overdoses, envenomation, and substance abuse, and other chemical exposures.3/15/2012 Salman Khan CMRIMS Bangalore

Clinical EvaluationThe types of patients evaluated by physicians who specialize in medical toxicology include: Unintentional and intentional overdoses of prescription and nonprescription medications Drugs of abuse Exposure to industrial chemical products and environmental hazards Envenomations and other natural toxins

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Salman Khan CMRIMS Bangalore

Part I: Approach to the poisoned patient History: find out information, Physical Examination Vital signs: Pulse, Temperature, Blood pressure, Respiration rate, Physical: Neurologic exam, Pupils, Dermatological exam, Odors... Epidemiology of Toxicology. Lab tests/Diagnostics. Imaging Management (GI decontamination and antidotes).3/15/2012 Salman Khan CMRIMS Bangalore

Part II: Case male presents in police custody complaining of chest pain. He studies Mr. XYZ, a 28 year oldhas no other past medical history. No history of cardiac disease. Patient further states that his chest pain began tonight about one to two hours after he was arrested by police. No history of trauma. Social history=Smokes 1 pack/day. Occasional alcoholic. Family History= No cardiac deaths. Physical exam Differential diagnosis (if required) For Instance How should this person s cocaine related chest pain be managed (This person ingested bags of cocaine. What is the best method of GI decontamination?) The patient's chest pain and hypertension eventually resolve with large doses of nitroglycerin and benzodiazepines. The patient is administered activated charcoal and polyethylene glycol solution by the ICU physician. Because of the ST segment elevations, the cardiologist elects to give thrombolytics. Since thrombolytics were "on board" the general surgeon refuses to take the patient to the OR for exploratory laparotomy and removal of the cocaine packets. The patient is transferred to the ICU, where he eventually recovers and is discharged Salman Khan CMRIMS Bangalore with3/15/2012 ejection fraction a 10%

Afshari CA, Hamadeh HK (2004). Toxicogenomics: principles and applications. New York: Wiley-Liss. ISBN 0-471-43417-5. Nelson, Lewis S.; Lewin Neal; Howland Mary Ann; Hoffman, Robert S.; Goldfrank, Lewis R.; Flomenbaum, Neal; (2010). Goldfrank's Toxicologic Emergencies, 9th Edition.. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-143763-0. Dart, Richard C. (2003). Medical Toxicology. Phila: Lippincott, Williams & Wilkins. ISBN 07817-2845-2 Ernest Hodgson (2010). "A Textbook of Modern Toxicology". John Wiley and Sons. p.10. ISBN 047046206X Toxicology Mechanisms and Methods (Journal) ISSN 1537-6516, Publisher Informa Pharmaceutical science (UK) Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R.; Hoffman, Robert Louis; Howland, Mary Deems; Neal A. Lewin (2006).Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-143763-0. Olson, Kent C. (2004). Poisoning & drug overdose. New York: Lange Medical Mooks/McGraw-Hill. ISBN 0-8385-8172-2. Web sites. http://www.dmoz.org/Science/Biology/Toxicology/ http://sis.nlm.nih.gov/enviro/toxtutor.html http://ctdbase.org/ 3/15/2012 Salman Khan CMRIMS Bangalore http://www.toxicogenomics.nl/

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