Introduction to Toxicology

• Toxicology is derived from the Greek words "toxicon" (poison) and "logos" (study).
• Toxicology is the science of poisons and their effects on living organisms.
• Toxicology integrates biology, chemistry, pharmacology, and environmental sciences.
• Toxicology examines how toxicants interact with biological systems providing insights into risk assessment, safety measures, and therapeutic interventions.
• Toxicology is an interdisciplinary field encompassing biology, chemistry, anatomy, pharmacology, and more.
• Toxicology evaluates harmful effects caused by chemical, biological, physical, and genetic agents.
• An example is the study of lead toxicity.
• Focus areas include dose-response relationships, exposure durations, and quantitative/qualitative assessments of adverse effects.

Subdisciplines of Toxicology

• Biochemical Toxicology studies biochemical mechanisms of toxicity (e.g., enzyme inhibition by organophosphates).
• Reproductive and Developmental Toxicology examines effects on reproduction and offspring (e.g., thalidomide causing birth defects).
• Clinical Toxicology focuses on poisoning diagnosis and treatment (e.g., use of N-acetylcysteine for acetaminophen overdose).
• Forensic Toxicology investigates poisoning in legal cases (e.g., arsenic in homicide investigations).
• Environmental Toxicology evaluates pollutant effects on ecosystems (e.g., DDT's impact on bird populations).
• Regulatory Toxicology develops safety standards for chemicals (e.g., permissible levels of benzene in drinking water).
• Mechanistic Toxicology explores cellular and molecular mechanisms (e.g., cyanide binding to cytochrome c oxidase).
• Occupational Toxicology studies workplace exposures (e.g., asbestos causing mesothelioma).
• Food Toxicology examines contaminants and additives (e.g., aflatoxins in nuts and grains).

Historical Background

• Paracelsus (1493-1541) introduced the dose-response principle: "All substances are poisons; the right dose differentiates a poison from a remedy."
• Mathieu Orfila (1787-1853) is the Father of forensic toxicology, who established toxicology as a distinct discipline.

Key Milestones

• Friedrich Serturner isolated morphine in 1817.
• Rachel Carson's "Silent Spring" (1962) initiated environmental toxicology.
• Development of antidotes like British Anti-Lewisite (BAL) for arsenic poisoning (1945).
• Socrates' death by hemlock poisoning illustrates historical toxicology.

Types of Toxicants

• Xenobiotics are foreign substances biologically active but not metabolized for energy (e.g., pesticides like glyphosate).
• Poisons are harmful substances at small doses (e.g., botulinum toxin).
• Toxicants are synonymous with poisons and classified as biotoxins, endotoxins, exotoxins, and venoms (e.g., snake venom containing neurotoxins).
• Systemic Toxicants affect the entire body (e.g., cyanide inhibiting cellular respiration).
• Organ-Specific Toxicants target specific tissues (e.g., benzene affecting blood-forming tissues).

Classification of Toxic Agents

• Classified based on physical state as solid (e.g., lead dust), liquid (e.g., methanol), or gaseous (e.g., carbon monoxide).
• Classification based on chemical properties as stability, reactivity (e.g., organophosphates inhibiting acetylcholinesterase).
• Classification by target organs such as liver (e.g., carbon tetrachloride), kidneys (e.g., mercury), or lungs (e.g., silica dust).
• Classification by symptoms as corrosive (e.g., sulfuric acid), irritant (e.g., ammonia), systemic poisons (e.g., arsenic).

Toxicity Ratings and Dose-Response

• Super toxic (e.g., botulinum toxin).
• Moderately toxic (e.g., caffeine).
• Practically nontoxic (e.g., water).

Toxicity Ratings

• 6 (super toxic) - General dose, mg/kg: <5. Lethal dose for a 70-kg man: A few drops.
• 5 (extremely toxic) - General dose, mg/kg: 5-50 Lethal dose for a 70-kg man: A pinch to 1 teaspoon.
• 4 (very toxic) - General dose, mg/kg: 51-500 Lethal dose for a 70-kg man: 1 teaspoon to 2 tablespoons.
• 3 (moderately toxic) - General dose, mg/kg: 501 mg/kg to 5 g/kg. Lethal dose for a 70-kg man: 1 ounce to 1 pint (1 pound).
• 2 (slightly toxic) - General dose, mg/kg: 5.1 g/kg to 15 g/kg. Lethal dose for a 70-kg man: 1 pint to 1 quart (2 pounds).
• 1 (practically nontoxic) - General dose, mg/kg: >15 g/kg. Lethal dose for a 70-kg man: More than 2 pounds.

Dose-Response Principle

• Dose determines whether a substance is therapeutic or toxic.
• Aspirin is safe at low doses but can cause gastric ulcers and toxicity at high doses.
• Iron is essential but toxic at high levels, causing oxidative damage.

Sources of Poisoning

• Accidental Poisoning can be caused by contaminated food or water (e.g., aflatoxin contamination in peanuts).
• Malicious Poisoning is criminal or intentional use of toxicants (e.g., polonium-210 in poisoning cases).
• Occupational Exposure to chemicals is due to industrialization (e.g., benzene exposure in factories).
• Environmental Exposure to pollutants is from air, water, and soil contamination (e.g., lead in Flint water crisis).

Mechanisms of Toxicity

• The toxicity cascade involves exposure (e.g., ingestion of pesticides).
• The toxicity cascade involves distribution within the body (e.g., arsenic accumulating in the liver).
• The toxicity cascade involves metabolism by enzymes (e.g., conversion of acetaminophen to toxic NAPQI).
• The toxicity cascade involves interaction with cellular macromolecules (e.g., cyanide binding to cytochrome c oxidase).
• The toxicity cascade involves expression of toxic effects (e.g., cell death or organ damage).

Types of Toxicity

• Acute Toxicity involves effects from single or short-term exposure (e.g., cyanide poisoning causing rapid death).
• Chronic Toxicity results from long-term exposure (e.g., vinyl chloride causing liver cancer).
• Reversible Toxicity is temporary (e.g., narcosis from solvents).
• Irreversible Toxicity is permanent (e.g., lung fibrosis from silica dust).
• Cumulative Toxicity is incremental damage from repeated exposures (e.g., alcohol-induced liver cirrhosis).
• Immediate Toxicity shows symptoms that appear shortly after exposure (e.g., acute pesticide poisoning).
• Delayed Toxicity: Symptoms emerge after prolonged exposure (e.g., peripheral neuropathy from organophosphates).

Key Toxicological Metrics

• Dose is the quantity of substance administered to achieve a toxicological effect.
• Lethal Dose (LD) is the lowest dose causing death in test animals.
• LD50 is the dose lethal to 50% of test subjects. The LD50 of nicotine in humans is approximately 0.8 mg/kg.
• NOEL (No Observed Effect Level) is the highest dose causing no adverse effects.
• Lethal Concentration (LC) is the concentration in an environmental medium causing death.
• LC50 is lethal to 50% of the population.
• Acceptable Daily Intake (ADI) is a safe daily intake level for humans over a lifetime (e.g., ADI for glyphosate).

Applications of Toxicology

• Regulatory Toxicology develops safety guidelines and exposure limits for chemicals (e.g., maximum allowable lead levels in drinking water).
• Forensic Toxicology investigates poisoning in legal cases (e.g., carbon monoxide in accidental deaths).
• Clinical Toxicology diagnoses and treats poisonings, utilizing antidotes (e.g., naloxone for opioid overdoses).
• Environmental Toxicology evaluates pollutant effects on ecosystems (e.g., mercury's impact on aquatic life).
• Occupational Toxicology ensures worker safety in chemical environments (e.g., silica dust exposure in construction).
• Toxicogenomics uses genomics to assess individual susceptibility to toxicants (e.g., genetic variations affecting acetaminophen metabolism).

Modern Challenges and Future Directions

• Emerging Pollutants: New chemical threats require advanced toxicological methods (e.g., microplastics in marine environments).
• Toxicogenomics: Personalized approaches to predict and mitigate toxicity (e.g., identifying genes linked to pesticide sensitivity).
• Advances in Testing: Development of biomarkers and high-throughput screening techniques (e.g., using CRISPR for toxicity research).
• Global Collaboration: Harmonizing regulations and research efforts to address toxicological challenges worldwide.

Factors Affecting the Toxic Response

• Toxic responses to xenobiotics are influenced by various environmental, host, and chemical factors.
• These responses modulate the extent and nature of toxic effects in exposed populations.

Host Factors

• Age significantly determines chemical toxicity.
• Younger Individuals have a higher susceptibility due to underdeveloped metabolic and excretory pathways,
• Deficient Glucuronyl Transferase in neonates can lead to increased bilirubin levels, causing neonatal jaundice. Treatment often involves phototherapy to convert bilirubin into excretable forms.
• Immature Blood-Brain Barrier facilitates easier CNS penetration of toxins such as lead, which can cause severe neurological damage in children.
• Elderly have reduced renal clearance of drugs like aminoglycosides increasing nephrotoxicity risk.
• Altered hepatic metabolism can enhance the effects of benzodiazepines.

Species and Strains

• Toxicity varies by species due to differing metabolic pathways.
• Endosulfan is highly toxic to aquatic species like fish but less toxic to mammals due to differing detoxification mechanisms.
• Atropa belladonna is metabolized efficiently via atropine esterase by rabbits, unlike humans, for whom it can cause severe anticholinergic toxicity.
• Strain differences within species affects responses. Certain inbred mouse strains (e.g., BALB/c) exhibit higher susceptibility to cyclophosphamide toxicity.

Sex

• Hormonal influences modify toxicity.
• Male mice are more susceptible to chloroform-induced nephrotoxicity.
• Estrogen or castration mitigates toxicity.
• Females may exhibit enhanced hepatoxicity to substances like acetaminophen due to sex-based differences in CYP450 enzyme expression.
• Pregnant females require special caution due to teratogenic effects, such as isotretinoin causing craniofacial abnormalities in fetuses.

Size or Weight

• Larger individuals tolerate higher doses due to proportional metabolic capacity.
• Acceptable daily intakes (ADIs) are adjusted per body weight.
• Pediatric dosing of antibiotics like amoxicillin is calculated in mg/kg.

Nutrition

• Diet composition impacts xenobiotic metabolism.
• High-fat diets increase chloroform hepatotoxicity by altering hepatic enzyme activity.
• Vitamin C deficiency reduces drug metabolism in guinea pigs, making them more susceptible to oxidative damage from xenobiotics.

Habitual Drug Use

• Chronic consumption of substances like caffeine, nicotine, or alcohol alters xenobiotic sensitivity.
• Chronic alcohol use induces hepatic enzymes, enhancing acetaminophen metabolism to toxic intermediates.
• Smokers metabolize theophylline faster due to enzyme induction by polycyclic aromatic hydrocarbons in tobacco.

Factors Related to Toxicants

• Physical and Chemical Properties like solubility and particle size influence absorption and toxicity.
• Fine particles (e.g., zinc phosphide) are absorbed more readily than coarse ones.
• Trichlorphon converts to more toxic dichlorvos in alkaline solutions, posing higher risks during agricultural use.

Route and Rate of Administration

• Toxicity is highest when compounds rapidly enter the bloodstream.
• Parenteral routes ensure faster bioavailability than oral administration.
• Intravenous administration of potassium chloride can cause cardiac arrest, whereas oral intake is less toxic due to slower absorption.
• Pyrethroids are detoxified via gut hydrolysis in mammals but remain toxic to fish due to a lack of this pathway.

Drug Interactions

• Co-administration of xenobiotics can lead to additive, antagonistic, or synergistic effects.
• Enzyme inducers like rifampin enhance drug metabolism, potentially reducing efficacy.
• Enzyme inhibitors like ketoconazole reduce xenobiotic clearance, increasing toxicity risks.

Tolerance

• Repeated exposures modify responses.
• Enzyme induction (e.g., hepatic CYP450 enzymes) increases detoxification.
• Chronic use of barbiturates reduces sedative effects due to enzyme induction.
• Chlorpromazine reduces CNS sensitivity upon repeated use, illustrating tolerance development.

Environmental Factors

• Temperature extremes influence chemical toxicity.
• High temperatures enhance chlorophenol toxicity via mitochondrial disruption.
• Low temperatures potentiate hypothermia induced by a-chloralose in cats.
• Stress, physical activity, and hormonal states also modulate toxic responses.

Toxicokinetics of Xenobiotics

• Toxicokinetics studies the absorption, distribution, metabolism, and excretion (ADME) of toxicants, influencing their effects at target sites.

Absorption

• Absorption is defined as the movement of xenobiotics into the bloodstream from exposure sites.
• Factors affecting absorption include solubility, concentration, and site-specific properties.
• Weak acids (e.g., aspirin) are absorbed in the stomach due to non-ionized states.
• Basic compounds (e.g., codeine) are absorbed in the intestines, facilitated by alkaline pH.
• Lipophilic compounds like pesticides (malathion) penetrate intact skin, causing systemic effects.
• Abrasions increase permeability to chemicals, as seen in occupational exposures to solvents like dimethyl sulfoxide (DMSO).
• Small particles (<1 µm) reach alveoli, causing systemic effects.
• Asbestos fibers penetrate lung tissue, leading to mesothelioma.
• Larger particles (≥10 µm) are trapped in the nasal cavity or pharynx.

Distribution

• Once absorbed, toxicants are transported via blood to target tissues.
• Lipid-soluble compounds accumulate in fatty tissues (e.g., DDT).
• The blood-brain barrier restricts hydrophilic molecules like penicillin but allows lipophilic agents like nicotine.
• Protein Binding: Drugs like warfarin, which bind extensively to plasma proteins, have limited tissue distribution.

Metabolism

• Biotransformation converts lipophilic toxicants into hydrophilic metabolites for excretion.
• Phase I: Oxidation, reduction, hydrolysis (e.g., CYP450 enzymes converting benzene into phenol).
• Phase II: Conjugation reactions (e.g., glucuronidation of bilirubin).
• Metabolites can be detoxified (e.g., paracetamol sulfate) or bioactivated (e.g., benzopyrene to carcinogenic intermediates).

Excretion

• Xenobiotics are eliminated via renal, hepatic, pulmonary, or lactational routes.
• Polar compounds (e.g., aminoglycosides) are excreted in urine (Renal Excretion).
• Lipophilic compounds undergo enterohepatic circulation (e.g., DDT) through Biliary Excretion.
• Volatile compounds like benzene are exhaled during Pulmonary Excretion.
• Lipophilic compounds (e.g., DDT, tetracycline) can pass to offspring, potentially causing developmental toxicity via Milk.