Chemical Toxicology for Medical Students PDF 2024/2025 Lecture Notes

Chemical Toxicology for Medical Students 2024/2025 0 Simplified Physiology 0 Toxicology Course Introduction: Clinical Importance of Chemical Toxicology I. Basics II. Toxicokinetics III. Cellular Toxicology...

Chemical Toxicology for Medical Students 2024/2025 0 Simplified Physiology 0 Toxicology Course Introduction: Clinical Importance of Chemical Toxicology I. Basics II. Toxicokinetics III. Cellular Toxicology 0  Major Parts of the Cell All organisms are made up of cells: (eukaryotic, prokaryotic) Cells membrane – regulate entry Cytoplasm – liquid atmosphere of cell Mitochondria – energy production – ATP Nucleus – DNA – genes, cell division Golgi – secretory function Lyzosome – digestive function Cells combine to form tissues which are specialized – connective, nerve, muscle Tissues combine to form organs which can perform complex functions Organs combine to form systems, e.g., respiratory, reproductive, nervous, circulatory system 0  History and Development of Toxicology: o Historical Background: o The concept of toxicology began in ancient times, where doctors tried to understand the effects of certain toxic substances, such as poisonous plants and heavy metals. o Swiss physician Paracelsus (1493-1541) is considered a pioneer of modern toxicology, coining the famous phrase: "The dose makes the poison.“ o Toxicology in Modern Medicine: Toxicology has evolved to encompass a broad range of studies, including environmental toxicology, drug toxicology, and accidental poisoning, providing critical insights into managing toxic substances in daily life and medical settings. 0  The Dose Makes the Poison Chemical Beneficial Dose Toxic Dose Aspirin 300-1000 mg 1000-30,000mg Vitamin A 500 units/d 50,000 units/d Oxygen 20% in air 50-100% in air There are no harmless substances. Only harmless ways of using substances 0  Toxicokinetics and Body Interaction with Toxins Classification of Toxins by Effects: o Local Toxins: Affect only the site of exposure, such as acids causing skin burns. o Systemic Toxins: Spread through the bloodstream and affect body systems, such as cyanide poisoning, which prevents cells from using oxygen. Immune Response to Toxic Exposure: o Inflammation and Immune Stimulation: Some toxins cause an inflammatory response due to the immune system’s reaction. While this response may be part of a defense mechanism, it can also lead to additional tissue damage. o Impact on the Immune System: Certain toxic substances may weaken the immune system, such as chronic exposure to lead, increasing susceptibility to infections and diseases. 0  There are several examples of toxins that stimulate the inflammatory and immune response, which may lead to additional tissue damage. Here are some examples: 1.Endotoxins o Gram-negative bacteria, such as Escherichia coli (E. coli) and Salmonella, produce endotoxins that are released when bacterial cells break down. These toxins can trigger a strong immune response, leading to widespread inflammation that may cause vascular damage and, in severe cases, sepsis. 2.Hepatotoxins o Certain chemicals, such as alcohol and some medications (like high doses of paracetamol), can stimulate the immune system against liver cells, causing inflammation and long-term liver fibrosis. This inflammation can lead to liver tissue deterioration and chronic diseases such as cirrhosis or liver failure. 0  3. Mycotoxins o Toxins like aflatoxins, produced by some fungi such as Aspergillus, can cause chronic inflammation in the liver and increase the risk of liver cancer. Continuous inflammation from exposure to this toxin leads to liver tissue damage. 4. Particulate Matter o Fine particles from air pollution, such as nitrogen dioxide and PM2.5 particles, can enter the lungs and cause an inflammatory response. Chronic inflammation in the lungs leads to long-term conditions such as asthma and chronic obstructive pulmonary disease (COPD) and may increase the risk of lung cancer. 0  5. Heavy Metals o Heavy metals like mercury and lead, when entering the body, can induce inflammation in the nervous system or kidneys. Mercury accumulates in the brain, causing neuroinflammation that leads to nervous tissue damage, while lead affects the kidneys and nervous system, resulting in long-term inflammatory responses. o 6. Smoking o Cigarette smoke contains numerous toxic substances that stimulate the immune response in the lungs. This results in chronic inflammation that can cause lung tissue damage, increasing the risk of diseases such as asthma, COPD, and lung cancer. 0  Effects of Toxicity on Biological Functions of Cells Mechanisms of Toxin Action on Cells: o Enzyme Inhibition: Some toxins, such as cyanide, inhibit cellular enzymes necessary for energy production, disrupting vital cellular processes. o Membrane Damage: Certain toxins destroy or alter cell membrane structure, leading to leakage of cellular contents and loss of cell function. o DNA Damage: Some chemicals can cause mutations or DNA damage, like exposure to carcinogenic substances such as benzene. 0  Symptoms from Cellular Damage: o Oxidative Stress: Accumulation of free radicals from toxic exposure causes oxidative stress, leading to damage of cell membranes, proteins, and DNA, potentially resulting in chronic diseases such as cancer. o Fibrosis: Chronic exposure to toxic substances can lead to fibrosis, such as liver fibrosis due to chronic exposure to toxins like alcohol and heavy metals. 0  Analyzing Routes of Toxic Exposure and Its Effects in Medical Settings Common Exposure Routes: o Inhalation: Inhaling toxic airborne substances, such as chlorine in disinfectants, can cause respiratory issues and irritation of the nose and eyes. o Skin Absorption: While the skin acts as a natural barrier, it can absorb certain chemicals that may be harmful, like chemotherapy drugs. o Ingestion: Inadvertently ingesting toxic substances, such as food contaminated with mycotoxins. 0  Routes of Exposure Breathing Zone Inhalation* Eyes Absorption Ingestion Injection *Most important route of entry 0  Routes of Exposure Ingestion (mouth) – Rare, but contamination can = intake – Stomach GI tract bloodstream – Absorbed - systemic injury – Liver, kidney; Detoxification process Inflammation cirrhosis - fibrotic liver disease malignant tumors – Factors: physical state, duration 0  Routes of Exposure Injection – Directly into bloodstream “sharps”, needles, broken glassware skin puncture or injuries – Bypasses protective mechanisms – Usually rare in workplace primarily associated with blood borne pathogens especially hazardous in health care industry 0  Routes of Exposure Skin absorption – Depends on site of contact temperature (vasodilatation) thickness, blood flow – Depends on skin condition integrity; pH – Time-dependent (duration) – Properties of the toxin concentration reactivity solubility (in fat/water) molecular size 0 Skin Thickness 0  Identifying and Managing Exposure: Exposure Assessment in Clinical Environments: Using environmental assessment tools to measure levels of toxic exposure, such as gas detectors in operating rooms. Protective Measures and Awareness: Training healthcare workers on toxic exposure prevention, such as regular handwashing, avoiding face contact after handling chemicals, and storing toxic materials securely. 0  Dose-Response Impact on Clinical Outcomes - Dosage and Complications Individual Sensitivity to Toxins: o Individual Differences: There may be variations in response to doses among individuals based on genetic factors, age, sex, and lifestyle. Special Cases: Children, the elderly, and individuals with chronic diseases are more vulnerable to toxic effects due to their body’s reduced natural defenses. 0  Short- and Long-Term Effects of Exposure: o Acute Effects: Symptoms like headaches, nausea, and dizziness that may appear immediately after exposure to substances such as alcohol or carbon monoxide. o Chronic Effects: Such as liver failure or cancer, which may result from continuous exposure to low doses of toxins over the long term. 0  Diagnostic Tools in Toxicology and Their Clinical Application Early Diagnosis and Therapeutic Intervention: o Immunoassay Testing: To detect toxin levels in the blood, such as alcohol or industrial toxins. o Imaging Techniques: X-rays, MRI, or ultrasound to identify tissue and organ damage due to toxicity. Treatment of Toxicity Cases and Medical Care Protocols: o Antidote Use: Such as cyanide antidote kits to counteract the toxic effects of cyanide. o Supportive Drug Therapy: Such as using "N- acetylcysteine" to protect the liver in cases of acetaminophen poisoning. 0  Prevention and Occupational Safety for Healthcare Workers Preventive Measures in Hospitals and Clinics: o Adherence to Chemical Safety Protocols: Such as storing chemicals away from heat sources, identifying safe disposal areas for toxic substances. o Minimizing Direct Exposure: Through the use of gloves, protective masks, and goggles when handling toxic substances. Managing Accidental Incidents: o First Aid: For example, rinsing skin with water in case of exposure to caustic substances, or flushing eyes if exposed to acids. o Administrative Protocols: Incident reporting to help improve safety protocols and ensure that first aid supplies are available in work areas. 0  Factors Influencing Toxicity Concentration of toxin Duration and frequency of exposure Route of exposure Environmental factors — temperature, humidity, atmospheric pressure Chemical combinations (difficult and expensive to test) Age Sex and hormonal status Genetic makeup State of health—presence of disease or stress Nutrition Lifestyle Dose-Response Relationship With increasing dose, there is an increase in the number affected and/or an increase in the intensity of the effect: e.g., mortality; cancer; respiratory depression; liver pathology Dose = (Concentration) x (Time) 0  Dose-Response Terms TDlo – Toxic dose low - lowest dose for effect LDlo – Lethal dose low - lowest dose that causes death in 10% of the test population LD50 – Lethal dose 50% - dose that causes death in 50% of the test population TClo – Toxic concentration low - used to express toxic concentration via inhalation LClo – Lethal concentration low –via inhalation LC50 – Lethal concentration 50% - concentration that causes death in 50% of the test population via inhalation 0  Lethal Dose Agent LD50 Ethyl Alcohol 7060 (mg/kg) Sodium Chloride 3000 Naphthalene 1760 Ferrous Sulfate 1500 Aspirin 1000 Formaldehyde 800 Ammonia 350 Dextromethorphan Hydrobromide 350 Caffeine 192 Phenobarbital 150 Chlorpheniramine Maleate 118 DDT 100 Strychnine Sulfate 2 Nicotine 1 Dioxin 0.0001 Botulinus Toxin 0.00001 0 Environmental Health and Safety 0  Services and Resources Training (BBP, Lab Chemical Safety, Hazardous Waste, Radiation Safety) as well as optional training (DOT infectious and biological material shipping, reactive chemicals) Research Registration for Biosafety and Radiation safety – review protocols for safety and health hazards and ensure that you obtain the proper training Perform general and radiation safety Provide hazardous waste removal including chemical, radioactive, and special medical waste Administrate Injury reporting and Workers compensation in the case of an incident 0  Personal Protective Equipment (PPE) Always wear appropriate PPE, which, at a minimum, includes: Gloves when hand contact is expected Protective clothing (laboratory coat) when the potential for splattering body fluids exists Eye protection when the potential for splashes or sprays exist General rules for using PPE: Make sure it fits properly Check for damage before use If damaged during use, remove and replace immediately Do not wear sandals or perforated shoes Remove PPE when leaving the laboratory 0  Toxicology Poisons - the adverse effects of substances on living systems. “All substances are poisons; There is none which is not a poison. The right dose differentiates a poison from a remedy…” – Paracelsus (1493-1541) Chemical Toxicology – The potential adverse effects and control of chemicals in the workplace. 0  Substances that produce adverse biological effects of any nature Toxicants May be chemical or physical in nature Effects may be of various types (acute, chronic, etc.) Specific proteins produced by living organisms Toxins (Mushroom toxin or tetanus toxin) Most exhibit immediate effects Poisons Toxicants that cause immediate death or illness when experienced in very small amounts 0  Basic Concepts Toxicity – capacity to cause injury Hazard – potential harm associated with a specific substance under potential exposure conditions Risk – the likelihood or chance that harm will occur under actual conditions (Toxicity) X (Exposure) = Risk All chemicals have the capacity to be toxic All chemicals act in the body according to the principles of chemistry, physics and biology Natural chemicals are not inherently harmless Synthetic chemicals are not inherently hazardous 0  Chemical Toxicology The study of the effect the chemical has on the body. Pharmacokinetics The study of the effect the body has on the chemical. Toxicity Studies Determine toxic effect – local effect, target organ, systemic effect, acute, chronic effects. Determine toxic dose – identify the dose that will produce a given toxic effect. 0