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  • An-Najah National University

    College of Medicine and Health Sciences 

    Department of Medicine

     First Semester 2014-2015

     

     

    Course Name: Toxicology

    Course Num.: 105447

    Introduction to Toxicology

    Design Semester: First Semester 2013-2014

     

    Instructor:

    • Name, Title:          Basma Damiri, PHD

    • Office Address:     173020

    • Email:                     bdamiri@najah.edu

     

    Course Description:

    This course is structured to provide the learners with the fundamental concepts of toxicology and its various fields with emphasis
on 
principles 
and 
applications 
of
toxicology
 and 
the 
responses 
of
 organ 
systems 
to 
toxicants. The course is designed to provide the basic principles of toxicology including quantitation of toxicity, toxicokinetics, toxicodynamics, biochemical action of poisons and environmental toxicology; acute and chronic effects of various classes of poisons at cellular and systemic levels in relation to typical routes of exposure and regulatory testing methods. This will be obtained through studying the history of the science of toxicology; toxicant type (poisons, pesticides, drugs, metals, industrial pollutants, solvents, oils, estrogen, estrogen mimics, triclosan, carcinogens, teratogens, natural toxins and other pollutants); dose-response relationships, absorption of toxicants, adsorption, distribution and storage of toxicants, metabolism, biotransformation and biological elimination, sequestration, and remediation; Mammalian systems with emphasis on target organ toxicity, detoxification and adverse effects; Teratogenesis, mutagenesis, carcinogenesis, Risk assessment; risk management, and risk communication, General Toxicology and drug development: Acute and repeated dose studies; Rodent vs. non-rodent designs; and Toxicology endpoints, No or Low Observed Effect Concentration (NOEC and LOEC), and LC50.

     

    Course Objectives:

    At the end of this course, the learner should be able to:

    1. Distinguish between the different fields of toxicology.

    2. Recognize the basic principles methods of toxicology and toxicology testing.

    3. Define the basic concepts of toxicokinetics and toxicodynamics.

    4. Explain dose-response relationship and NOEC, LOEC, and LC50 concepts.

    5. Define the acute and chronic toxicities of common drugs, industrial and household products and natural chemicals from animals and plants in humans.

    6. Describe what a toxic syndrome is.

    7. Explain systemic toxicology.

    8. Apply basic concepts of laboratory testing principles.

    9. Develop approaches for prevention, diagnosis and treatment of adverse effects.

        

    Textbook:

    Course content will be presented through textbook readings and lectures. All lecture materials will be posted to An-Najah National University website.

    • Casarett, Louis (2007): Casarett & Doull's Toxicology: The Basic Science of Poisons, Seventh Edition (Casarett & Doull Toxicology), McGraw Hill.

    •  Williams, Philip and James, Robert and Roberts, Stephen (2003): Principles Toxicology, Environmental and Industrial Applications. 2nd Edition, John Wiley & Sons.

    • Tembrell, John (2002): Introduction to Toxicology  2^nd Edition, Taylor & Francis.

     

     

    To see the full course outline .. Click Here

• Topic 1

  Chapter One: Toxicology

  • Introduction:

    Toxicology: is the study of the adverse effects of chemicals on living organisms?  Toxicologist is a person dealing with those adverse effects.

     

    Objectives:

    Upon successful completion of this chapter, you will be able to:

    1. Define toxicology,

    2. Identify the six applied areas of toxicology,

    3. Explain ways, in which Toxicology is relevant to our daily life,

    4. Outline the basic principles of toxicology,

    5. Define dose and contrast the types of dose measures,

    6. Distinguish how each type of dose is measured,

    7. Explain the concept of dose- response,

    8. Describe the concept of dose-effect.

     

    Study Plan:

    1- Find the attachments
    

     

  • 

    File

    Chapter 1: Introduction File
  • 

    File

    Introduction File
  •  

    2- The following videos show one of the disasters that occurred due to mercury toxicity. Watch the following video about Minimata disease.

    
    

  •  

    3- Participate in the following forum about minimata

  • 

    Forum

    Forum 1 : Minimata
  •  

    4- Answer the following activity

  • 

    Assignment

    Chemical Interaction Assignment

• Topic 2

  Chapter Two: Toxicokinetics ADME

  • 

    Introduction:

    The deposition of a chemical or a xenobiotic is defined as the composite action of its absorption, distribution, biotransformation, and elimination.  This chapter will focus on the contribution of absorption, distribution, biotransformation, and elimination to xenobiotic toxicity. 

    
    

    ADME stands for:

    Absorption,

    Distribution,

    Metabolism, and

    Excretion. 

     

    Objectives : 

    Upon finishing this chapter, you should be able to:

    1. Recognize the fundamental principles of toxicology.

    2. Explain the broad principles that govern transfer of molecules across the membrane.

    3. Explain the factors that influence absorption of foreign compounds from the GI tract and the lungs, and across the skin.

    4. Illustrate the simple kinetic models that describes disposition (distribution and elimination) of toxicants.

    5. Recognize the mechanism of elimination (biotransformation and excretion).

     

    Plan: 

    1- Study chapter 2 form the book Principles of Toxicology and study the following files:

  • 

    File

    ADME File
  • 

    File

    Chapter 2 - ADME File
  • 

    File

    Absorption- distribution- excretion File

    Absorption- distribution- excretion

  •  

    2- Please watch the following videos!

    
    

  •  

    3- Answer the following activity

  • 

    Assignment

    Glyceryl Trinitrate Assignment
  •  

    4- Participate in the following forums

  • 

    Forum

    Application: ventilation vs flow limited compounds Forum
  • 

    Forum

    Think about it ! Forum
  • 

    File

    ADME File
  • 

    File

    ADME 2 File
  • 

    File

    ADME 3 File
  • Do you know  that in GI tract, 

    Cd--> decreases the absorption of Cu and Zn
    Ca --> decreases the absorption of Cd
    Mg --> decreases the absorption of F

    Grapefruit juice --> increases the absorption of Ca-channel blockers and cholesterol lowering agents.

    Grapefruit juice through the action of naringin and flavonoids --> inhibits P450 3A activity and alters the function of P-gp

• Topic 3

  Chapter Three: Biotransformation; A Balance between Bioactivation and Detoxification.

  • 

    Introduction :

    This chapter will talk about Metabolism:

    • Phase I
    • Phase II

     

    Objectives : 

    At the end of this chapter learner will be able to:

    1. Explain how xenobiotics enter, circulate, and leave the body.

    2. Recognize the sites of the metabolism of xenobiotics in the body.

    3. Recognize the chemistry and the enzymology of xenobiotic metabolism.

    4. Explain the mechanism of bioactivation as well as the inactivation of xenobiotics during metabolism.

    5. Explain the variation in xenobiotic metabolism resulting from prior or contaminant exposure to xenobiotics and from physiological factors.

     

    Plan: 

    1- Study chapter 3 form the book Principles of Toxicology and study the following files:

  • 

    File

    Chapter 3: Phase I File
  • 

    File

    Elimination of Toxicants File
  •  

    2- Watch the following video about first pass metabolism

    
    

  •  

    3- Watch the following video about phase I metabolism

     

  •  

    4- Watch the following video about phase II metabolism

     

  • Elimination

    

  • 
    

    

    
    

    The metabolism of a toxicant can

    1. Reduce the half-life of a chemical or a xenobiotic,
    2. .............................................................................,
    3. .............................................................................,
    4. ............................................................................,
    5. ..............................................................................

     

    Factors influence toxicants metabolizing capability are

    1. Gender,
    2. ………...................................................................,
    3. ………...................................................................,
    4. ………...................................................................,
    5. ………...................................................................,
    6. ………....................................................................
  • 
    

    

    Drug Toxocity

     

    What is the connection between Grapefruit, furanocoumarins , flavonoids, and CYP3A, benzodiazepines, (such as diazepam), cisapride (Propulsid), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor)?

  •  

    4- Answer the following activity

  • 

    Assignment

    Assignment 3.1: ADME
  • 
    

    Clinical Toxicology

  • MPTP Metabolism and Toxicity

    

    

    

• Topic 4

  Chapter Six : Hepatotoxicity

  
  

  •  

    

    Introduction:

     

    This chapter will familiarize the students with the basis of liver injury, normal liver function, the role the liver plays in certain chemical-induced toxicities, types of liver injury, evaluation of liver injury, and finally, specific chemicals that are hepatotoxic.

    
    

    
    

    Objectives :

    At the end of this chapter, you will be able to:

    1. Recognize the function of the liver.

    2. Recognize why the liver is a target organ for toxicity.

    3. Recognize why liver is so important in toxicology.

    4. Know the effect of toxic chemicals on liver.

    5. Differentiate between different types of liver injury

     

    Plan :

    1- Study the following file about Hepatotoxicity

  • 

    File

    Hepatotoxicity file

• Topic 5

  Chapter Five : Nephrotoxicity

  •  

     

     

    Introduction: 

    Nephrotoxicity, may also be referred to as renal toxicity, is one of the most common kidney problems and occurs when the body is exposed to a drug or toxin that causes damage to the kidneys. Nephrotoxicity can be temporary with a temporary elevation of lab values (BUN and/or creatinine).  If these levels are elevated, these may be due to a temporary condition such as dehydration or you may be developing renal (kidney failure). If the cause of the increased BUN and/or creatinine levels is determined early, and your healthcare provider implements the appropriate intervention, permanent kidney problems may be avoided.

    
    

    Objectives :

    At the end of this chapter, you should be able to:

    1. Recognize why kidney is a target organ for toxicity.

    2. Know chemicals or toxicants that cause damage to the renal tubule.

    3. Identify important kidney functions seldom considered as toxic endpoints.

    4. Recognize causes and mechanism of bladder toxicity.

    5. Understand the mechanism of heavy metals toxicity in the kidney.

    6. Know the adverse effects of chemicals on the kidney.

    7. Identify nephrocarcinogenicity

     

    Plan :

    1- Study the following files about nephrotoxicity

  • 

    File

    Nephrotoxicity File
  • 

    File

    Nephrotoxicity File
  •  

    2- Upload a video from youtube talking about renal toxicity.

  • 

    Assignment

    Assignment 5.1 : Video

• Topic 6

  Toxic Animals and Plants in Palestine

  • Introdcution:

    In this week, it  will  do home study in order to learn about toxic animals and plants found in Palestine.

     

    Objectives:

    At the end of this topic, learner will be able to:

    1. Recognize toxic animals and plants in Palestine,

    2. Recognize the most toxic animals and plants in the world. 

  •  

    2- Watch the following two videos

     

  •  

    3- Answer the following Feedback

  • 

    Feedback

    Feedback
  • 

    Assignment

    Toxic animals and plants in Palestine Assignment

• Topic 7

  Chapter Four : Hematotoxicity

  •  

    

    Introduction:

    This chapter describes the toxicants that affect the blood and common occupational and environmental chemicals and drugs that affect blood formation and function.

     

    Objectives:

    At the end of this chapter learner should be able to:

    1- Identify toxicants that affect formation of RBC, WBC, platelets and (Bone marrow suppression).

    2- Explain different neurological and cardiovascular toxicities caused by interference with oxygen utilization (i.e. H2S and cyanide).

    4- List and evaluate clinical tests used to evaluate hematotoxicity

    5-Explain the interference with O2 transport by drugs and chemicals

     

    

     

    Plan:

    1- Study the following file about Hematotoxicity

  • 

    File

    Hematotoxicology File
  •   

    2- Watch the following video about blood toxity

     

  •  

    3- Watch the following video about hydrogen sulfide 

     

  •  

    4- Answer the following activity about hematotoxicants

  • 

    Assignment

    Assignment 4.1: Hematotoxicants
  • 

    File

    Hematotoxicity File

• Second exam
  • 

    Assignment

    Presentation Assignment

• Topic 9

  Chapter Seven : Neurotoxicity

  •  

    

     

    Intoduction: 

    
    

    Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, certain drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods.

    
    

    Objectives: 

    
    

    At the end of this chapter you should:

    1. Recognize ways in which neurotoxic chemicals may impair nervous system function.

    2. Identify targets of neurtoxicants.

    3. Identify the anatomical and the physiological features that makes the axon a particular target for toxicants.

    4. Recognize the chemicals that act on the neuron and cause disruption for it?

    5. list the peripheral neurotoxicants and how do they affect neurons?

    6. Describe in details the function of blood brain barrier in brain toxicity?

    7. Demonestrate the relationship between the nervous system and the respiratory system (rule of anoxia in neurotoxicity)?

    8. Demonestrate the site effect of nicotine on the nervous system (neurotoxicity)?

    
    Plan :

     
    1- See this chapter from the book, then read this file 

  •  

    2- Answer the following real case 

  •  

    3- Watch the following two videos

     

  • 

    File

    Neurotoxicity File
  • Toxic response of the neural system -Chapter 16  (Casarett & Doull’s)

    The principal basis of blood brain barrier is the specialized endothelial cells ( with tight junction) in the microvasculature, aided, at least in part, by interaction via glia.

    In addition to this interface with blood, the brain, the spinal cord, and peripheral nerves are also completely covered with continuous lining of specialized cells that limits the entry of molecules from adjacent tissue.  In the brain and the spinal cord, this is the meningeal surface; in the peripheral nerves, each facial of nerve is surrounded by perineurial cells.

     

    The toxicant must pass through the endothelial cells rather than between them as they do in other tissue.

    BBB contains also transporters such as multidrug- resistant proteinà active transport.

    If not actively transported into the brainà the penetration of the toxicant is largely depends on its lipid solubility.

    Exceptions:

    Mature nervous system, spinal and autonomic ganglia have small number of other sites within the brain called cirumventricular organs à the specialized endothelial tight junction is not protected by blood- tissue barriers.

    A somewhat less tight barrier is provided by several layer s of overlapping astrocytic foot processes.

• Topic 10

  Chapter Eight : Dermal and Ocular Toxicity

  •  

    

    Objectives :

    At the end of this chapter learner should:

    1. Recognize the factors influence the diffusions of chemicals across stratum corneum (SC).
    2. Differentiate between types of contact dermatitis

    • a) Irritant  ( not immunity- related disease)

    • b) Allergic contact dermatitis

    • c) Ulcer

    • d) Skin cancer

    3.Recognize different types of chemicals and toxicants that cause the different types of contact dermatitis .

     

    Plan :

    1- Study the following powerpoint presentation about dermal toxicity

  • 

    File

    Dermal Toxicity File
  •  

    2- Upload a picture for dermal or occular toxicity!

  • 

    Assignment

    Assignment 8.1 : Picture
  • 

    File

    Immune Toxicology File

• Topic 11

  Chapter Nine : Pulmonary Toxicity

  •  

    

     

    Introduction:

    
    

    In this chapter the anatomy and physiology of the lung will be related to the most prevalent mechanisms
    of lung toxicity resulting from exposure to commonly encountered industrial toxins. Specifically, the
    chapter will discuss
    • Lung anatomy and physiology
    • Defense mechanisms of the lung
    • Different classes of chemicals that are known to damage the lung
    • Four basic mechanisms by which industrial chemicals exert toxic effects on the lung
    • Clinical evaluation of occupational lung injuries
    When considering toxicology and the lung, it is important to note that the lung is both a target organ
    for many toxins and a major port of entry into the body, providing toxins the opportunity to exert toxic
    effects in other organs.

    
    

    Objectives :

    At the end of this chapter, you should :

    A. Explain general principles of lung pathogenesis:

    1. Oxidative stress

    2. Clearance of particles

    3. Toxicity of vapors and gases

    4. Expalin metabolism of toxicants:

    • ROS –oxidative damage

    • O2 and air pollutants are capable of forming oxygen radicals, ozone, NOx, SOx, tobacco, and smoke.

    B. Recognize gas exchange region and the different types of cells and their function.

    C. Identify general diseases as a result of lung toxicity

     

    Plan : 

    1- Read the following powerpoint presentation about pulmonary toxicity

  • 

    File

    Pulmonary Toxicity File
  •  

    2- Watch the following video about Asthma

     

• Topic 12

  Developmental and Reproductive Toxicology

  Second exam 6/4/2014

  • 

    Part 1: Male Reproductive Toxicity

    
    

    Intoduction: 

    
    This chapter will review the established toxic responses of the human male and female reproductive systems and of human fetal development. The focus will be on potential human health effects from occupational and/or environmental exposure and examples will be drawn from this area. However, there is much additional mechanistic information from experimental systems and many more chemicalsfor which there are experimental indications of potential reproductive toxicity. In evaluating the importance of such chemicals or mechanisms with regard to human exposure, two basic tenets oftoxicology must be considered: 1) what are the characteristics of a likely exposure, and 2) what could be a relevant dose. Understanding how reproductive processes respond to chemical challenges is the key to addressing these issues.

    
    Topics to be covered include
    • Male reproduction and the susceptibility of rapidly dividing germ cells
    • Female reproduction and the regulation of endocrine status as a potential target for toxic
    responses
    • Fetal development—the major opportunities for toxic responses during development and
    the established causes of developmental defects
    • Current research concerns—hot, timely topics

    
    

    Objectives:

    1. To identify toxicants that affect male and female reproductive systems,

    2. Determine the characteristics and the dose of these toxicants that may cause adverse effect on male and female reproductive systems,

    3. Explain why reproductive processes respond to chemical challenges is the key to addressing these issues.

    
    

    (y)  Do you know that human diet may contain large amounts of phytoestrogens such as lignans and isoflavones.

    Estrogen-blocking effects have been demonstrated in women who ate isoflavones rich diet. 

     

    However, most phytoestrogens are metabolized and excreted in urine in the same way as endogenous estrogens and therefore do not accumulate in the body. 

    The opposite holds true, however, for some other xenoestrogens, including polychlorinated biphenyl (PCBs), dioxins, and furans. Exposure to some PCBs congeners has been correlated with reduced serum motility and density. Furthermore, after in utero exposure, increased fetal loss, reduced birth weight, and behavioral and developmental effects were reported after sever poisoning accidents in Japan and Taiwan.

    Occupational exposure to estrogenic compounds like Kepone has also resulted in decreased sperm count and motility and abnormal sperm morphology.

    Other xenoestrogens to which human can be exposed are alkylphenols, phthalate, esters, and biphenyl-A.

    Considerable concern about these compounds have been raised because they are so pervasive in the environment. In particular, intake of phthalates, which may amount to several hundreds of µg/kg/day, mainly by consumption of food, may result in estrogenic effect.

    The most obvious exposure to xenoestrogens is, of course, the direct administration of synthetic hormones, such as diethystibesterol (DES), the effect of which is well documented in women who took it. In some countries, the same hormones may be present in meat and dairy products.

    DDT is xenoestrogen and is used as a pesticide.

    Now think about some foods that have liganin and isflavones?

     

    What are DDT, Kepone, phthalate, and biphenyl-A?

     

    DDT is insecticide 
    

  • 1- Study the following powerpoint presentation 

  • 

    File

    Male Reproductive Toxicology File
  •  

    2- Watch the following video about male reproductive toxicology

     

• Topic 14

  Chapter Ten : Mutagenesis and Genetic Toxicology

  •  

    Introduction:

    
    

    Genetic toxicology combines the study of physically or chemically induced changes in the hereditary
    material (deoxyribonucleic acid or DNA) with the prediction and the prevention of potential adverse
    effects. Modification of the human genetic material by chemical agents or physical agents (e.g.,
    radiation) represents one of the most serious potential consequences of exposure to toxicants in the
    environment or the workplace. Nevertheless, despite increasing research interest in this area, the
    number of agents or processes that are known to cause such changes is quite limited. This chapter
    presents information regarding the following areas:
    • Types and characteristics of genetic alteration
    • Common research methods for the assessment of genetic change
    • Practical significance of test results from animal and human studies in the identification of
    potential mutagens
    • Theoretical relationships between mutagenesis and carcinogenesis

    
    

    Objectives :

    At the end of this chapter, you should be able to:

    1. Identify different types of teratogens.

    2. Recognize critical periods of susceptibility.

    3. Explain mechanism of teratogenicity.

    4. Identify the factors influence teratogenicigy.

     

    Plan:

    1- Study the file below about teratogenicity

  • 

    File

    Teratogenicity File
  •  

    2- Look at the following pictures

  •  

    

  •  

    

     

    

     

  •  

    3- Watch the following video 

     

• Topic 15

  Chapter Eleven : Carcinogenicity

  •  

    Introduction:

    
    

    At the most fundamental level, cancer is caused by abnormal gene expression. This abnormal gene expression occurs through a number of mechanisms, including direct damage to the DNA and inappropriate transcription and translation of cellular genes. Carcinogenesis has been shown to be induced or at least accelerated by exposure to certain types of chemicals. These chemicals are known as carcinogens. In the pages that follow, we will discuss the carcinogenic process and how chemicals can contribute to that process.

    
    This chapter will discuss:
    • Tumor classification and nomenclature
    • Properties of carcinogenic chemicals
    • An overview of the molecular basis of carcinogenesis
    • Methods for testing chemicals for carcinogenic activity
    • Chemicals identified as human carcinogens
    • Risks associated with occupational carcinogens
    • Factors that modulate carcinogenic risk
    
    

    
    

    
    

    Objectives :

    At the end of this chapter, you should:

    1. Explain multi step process: Three “ hit” hypothesis.
       

    2. Recognize different types of carcinogenes and their mechanisms.

    3. Identify molecular target of carcinogenic agents.

     

    Plan :

    1- Study the following file about carcinogenicity

  • 

    File

    Carcinogenicity File
  •  

    An oncogene is a gene that has the potential to cause cancer

    Look at the following pictures 

  •  

    

     

    

  •  

    3- Watch the following video that shows top ten cancer-fighting food

     

• Topic 16

  Final Exam !!!!