Introduction to Toxicology

• Course 1 introduces the study of toxicology

Introduction to Toxicology

• Toxicology studies the adverse effects of xenobiotics.
• Exogenous agents' adverse effects are studied using toxicants as tools in molecular biology.
• Study of endogenous compound mechanisms focuses on oxygen radicals and reactive intermediates.
• This discipline assesses safety and evaluates risks
• Toxicologists investigate chemical action and exposure mechanisms in biomedicine.
• Physiologic and pharmacologic phenomena are understood using toxic chemicals.
• Recognizing, identifying, and quantifying hazards comes from occupational chemical exposure.
• It looks at the public health aspects of chemicals in air, water, environment, food, and drugs
• Toxicology contributes to the discovery and development of new drugs, additives, and pesticides.
• Standards and regulations are developed to safeguard health and the environment from chemicals.
• Environmental toxicologists study chemical effects on flora and fauna, expanding toxicology's scope.
• Molecular toxicologists research how toxicants affect cell growth and differentiation at the gene level.
• Clinical toxicologists create antidotes and treatments for xenobiotic poisonings.
• Toxicology blends science and art.
• Toxicology's science involves observation and data accumulation; its art uses data to predict exposure outcomes in humans and animals.

History of Toxicology

• First usage of animal venoms and plant extracts for hunting, warfare, and assassination.
• The Ebers papyrus (circa 1500 BC) documents information about various recognized poisons.
• Mention of digitalis- and belladonna alkaloid-containing plants.
• Hippocrates added poisons and clinical toxicology principles (bioavailability in therapy/overdose, ~400 BC).
• Dioscorides first tried to classify poisons with descriptions and drawings.
• Plant and animal toxin poisoning was common.
• Rome saw epidemics of poisoning in the BC fourth century.
• Maimonides wrote that milk, butter, cream could delay intestinal absorption regarding bioavailability.
• Toffana, an infamous figure, sold prepared arsenic-containing cosmetics like Agua Toffana.
• A club of young, wealthy, married women evolved into a club of eligible, wealthy widows.
• Arsenic-containing cosmetics caused deaths into the 20th century.
• Catherine de Medici exported her skills from Italy to France, targeting women's husbands.
• Paracelsus stated all substances are poisons, the dose differentiates the poison.
• Paracelsus, a physician-alchemist, created revolutionary views for toxicology, pharmacology, and therapeutics.
• He emphasized the "toxicon" as the main toxic agent as a chemical entity
• Experimentation is essential in examining chemical responses.
• Therapeutic vs. toxic properties of chemicals were now being distinguished.
• Paracelsus introduced mercury for syphilis until his famous trial, surviving 300 years.
• Occupational hazards of metalworking were known by the fifteenth century.
• Benzene's toxicity was discovered around 1900.
• Orfila, Spanish physician, initiated forensic toxicology with autopsies/chemical analysis as legal poisoning proof.
• Forensic toxicology (Orfila, 1818) was systematically being studied.
• World War II greatly increased the production of drugs, pesticides, synthetics, and chemicals.
• Ether, chloroform, and carbonic acid led to several iatrogenic deaths.
• Benzene was used as leukemia drug in the early 1900s.
• Becquerel and the Curies discovered "radioactivity".
• Arsenicals treated acute and chronic diseases.
• Methanol and lead discoveries during alcoholic beverage prohibition in the US began neurotoxicology.
• Sulfanilamide combatted bacterial illnesses, leading to ethylene glycol deaths; glycol was metabolized into oxalic and glycolic acid.
• World War II, organophosphate cholinesterase inhibitors were also discovered.
• "Detoxication Mechanisms," authored by R. T. Williams, was published in 1947.
• President signed additives amendments to the Food, Drug and Cosmetic Act, not allowing carcinogenic chemicals.
• The thalidomide tragedy led to thousands of birth defects.
• The impact of chemicals on embryos, fetuses, and the environment because an important part of the era.
• Analytical tools were developed for toxin detection in tissues and substrates.
• Toxicology developed cellular/molecular sub-disciplines, with toxicological investigations focusing on risk assessment.

Toxiciology Definitions

• Toxicology is the study of chemical/physical agents' adverse effects on organisms.
• Toxicological research investigates cellular, biochemical, and molecular actions.
• Relating exposure (dose) to the response is required.
• Risk assessment quantitatively estimates potential health/environmental effects from chemical exposures (pesticide residues in food/water).

Types of Toxicology

• A mechanistic toxicologist identifies and knows how chemicals exert toxic effects at the cellular, biochemical, and molecular levels.
• Safer chemicals are designed using mechanistic data.
• The new fields of pharmacogenomics, toxicogenomics, provide exciting futures mechanistic toxicologists to protect/identify genetically susceptible individuals and customize therapies for efficacy and toxicity minimization.
• A descriptive toxicologist is concerned directly with toxicity testing, which provides information for safety evaluation and regulatory requirements.
• Experimental animals or cell systems are toxicity tested to evaluate risks to humans.
• "Omics" (genomics, transcriptomics, proteomics, metabonomics) form the basis of the emerging sub-discipline of toxicogenomics.
• A regulatory toxicologist uses descriptive/mechanistic toxicology data to determine if chemicals pose low enough risk for stated marketing.
• Forensic toxicology blends analytic chemistry with toxicological principles.
• Concerned primarily with the medicolegal aspects of the harmful effects of chemicals on humans and animals.
• The expertise of forensic toxicologists is invoked to discover the causes of death post-mortem.
• Clinical toxicologists are physicians with toxicology/emergency medicine training.
• Intervene in treating patients poisoned with drugs/chemicals and creating new methods.
• Environmental toxicology studies chemical pollutants' impacts on biological organisms in the environment.
• Ecotoxicology studies how toxic substances affect population dynamics in ecosystems.

Toxic Response Types

• Poison: Any agent seriously injuries function or produces death.
• All chemicals can harm or kill if present in enough doses.
• Some chemicals are poisonous at micrograms.
• Large doses of other chemicals may remain harmless.
• Low-toxicity chemicals may cause cancer, teratogenesis, or neurobehavioral effects without acute toxicity signs.
• Genetic factors affect toxin susceptibility.
• Toxin: Toxic substances produced by plants, fauna, fungi, or bacteria.
• Toxicant: Toxic substances from anthropogenic activities.
• Also classify toxic agents by physical state (gas, dust, liquid).
• Chemical stability/reactivity (explosive, flammable, oxidizer).
• General chemical structure (aromatic amine, halogenated hydrocarbon).
• Poisoning potential (extremely toxic, very toxic, slightly toxic, etc.).
• Biochemical action mechanisms (alkylating agent, cholinesterase inhibitor, methemoglobin producer).
• Chemical allergy: Immunologically mediated adverse reactions to chemicals from previous sensitization or similar structures.
• Hypersensitivity defines this allergic state.
• Once sensitization occurs, very low chemical doses can cause allergic reactions.
• Allergic reactions are dose-related to pollen concentration in sensitized individuals.
• Human skin (dermatitis, urticaria, itching) and eye (conjunctivitis) are most commonly involved.
• Bronchiole constriction characterizes chemically induced asthma.
• Chemical idiosyncrasy: Genetically determined abnormal reactivity to chemicals.
• Prolonged muscular relaxation/apnea follows succinylcholine in Idiosyncratic reactions.
• Succinylcholine usually produces muscle relaxation of short duration because of rapid metabolic degradation by plasma butyryl-cholinesterase.
• Genetic polymorphism in enzyme butyrylcholinesterase limits succinylcholine breakdown.
• Abnormally nitrite-sensitive people can oxidize hemoglobin iron to methemoglobin -recessive autosomal trait due to diminished NADH-cytochrome b5 reductase.
• Serine codon 127 changes with proline single nucleotides.
• Immediate toxic effects occur rapidly after substance administration.
• Delayed effects occur later.
• Chemicals might cause cancer after 20-30 years post-exposure.
• Delayed neurotoxicity follows exposure to organophosphorus insecticides covalently modifying neuropathy target esterase(NTE), with neuronal serine esterase.
• Long axon degeneration in central/peripheral nervous system begins when certain organophosphates (OP) bind NTE.
• Some chemical toxic effects reverse; others do not.
• Tissue regeneration determines reversible-irreversible injury.
• Most liver injuries reverse because the liver regenerates well.
• CNS injuries rarely reverse because differentiated cells cannot regenerate.
• Chemicals' carcinogenic/teratogenic effects are considered irreversible.
• Local effects occur at biological system-toxicant contact, such as ingesting caustics/inhaling irritants.
• Chlorine gas damages and swells lung tissue, potentially fatally.
• Systemic effects require absorption/distribution from entry to distant sites.
• Tetraethyl lead on skin absorbs then causes typical central nervous system damage.
• Marked local effects can cause systemic impacts; kidney damage from severe acid burn reflects indirect effect with no toxicant kidney access.
• Select organs which are targets of toxicity.
• The most prominent organ involved with toxicity usually the most frequent.
• Because of the large number of chemicals an individual may come in contact with at any given time- spectrum of responses.
• Chemical are known to interact by altering protein binding, biotransformation and absorption.
• The toxicological response depends on the site of action.
• Additive effect: Combined chemical effect equals the sum of individual agent effects (2 + 3 = 5).
• For example, Organophosphate insecticides inhibit cholinesterase additively.
• Synergistic effect: Combined effect is much greater than a sum of individual agents (2 + 2 = 20).
• Carbon tetrachloride and ethanol both can cause liver damage, together they have a potentiated risk of liver injury than separate.
• Potentiation: One substance lacks toxicity to organ/system but makes toxic chemical much more toxic (0 + 2 = 10).
• Example: Isopropanol may not affect the liver, but when combined with carbon tetrachloride, the toxicity of carbon tetrachloride greatly increases.
• Antagonism occurs when two chemicals administered together interfere with other’s actions.
• Functional antagonism: Two chemicals counterbalance each other by producing opposite effects on the same.
• Chemicals at toxic doses cause convulsions controlled with anticonvulsants such as benzodiazepines.
• Chemical antagonism/inactivation is toxic product reduced by chemical reaction between two compounds.
• Dimercaprol chelates arsenic, mercury, and lead as British anti-lewisite (BAL), reducing toxicity; antitoxins treat animal toxins.
• Dispositional antagonism results from altered chemical absorption, distribution, biotransformation, or excretion, changing concentration and/or duration at target organ.
• Activated charcoal prevents toxicant absorption, and increased chemical excretion results from osmotic diuretics/urine pH adjustment.
• Receptor antagonism occurs when chemicals binding the same receptor cause less effect together than separate or one chemical counteracts another.
• Receptor antagonist naloxone treats depressive effects of morphine/morphine-like competitive binding.
• Tolerance: Decreased responsiveness to chemical's toxicity.
• Less toxicant reaches site where its effect happens (dispositional tolerance).
• A tissue becomes less responsive to chemicals.
• Carbon tetrachloride causes tolerance by reducing reactive metabolite formation.
• Cadmium tolerance is explained by metallothionein induction metal-binding protein.
• Toxicity is influenced by biotransformation, like metabolic breakdown.
• Relatively non-toxic chemicals convert to intermediate forms interfering with normal cellular biochemistry/physiology when enzymes act.
• Exposure route and duration are the two major factors influencing toxicity.
• Gastrointestinal tract (ingestion), Lungs (inhalation), Skin (topical, percutaneous, or dermal), Parenteral routes are sites for exposure.
• Fastest route into bloodstream is intravenously.
• Other routes, ranked by effectiveness are inhalation, intraperitoneal, subcutaneous, intramuscular, intradermal, oral, and dermal.
• Chemical dissolution/formulation influence absorption following ingestion, inhalation, or topical contact.
• An agent acting on the CNS is less toxic orally than by inhalation if liver detoxifies
• Influenced by agent concentration, vehicle volume, vehicle properties; toxic results by exposure route.
• Local (non-specific)- toxic action doesn't require site/receptor to cause effects (acids/alkalis).
• Remote (systemic)- poison affects organ remote from its portal of entry.
• Systematically and locally, poisons act simultaneously.
• Direct: the poison causes toxic effects- corrosives.
• Indirect actions results from interaction with biological activity
• Binding to cell membrane to change function/structure- affecting normality;
• Interfering with enzymatic actions;
• Forming harmful metabolites;
• Effects on DNA.
• Classified by target organ (hepatotoxic, nephrotoxic).
• Classified by use (food additive, drug, pesticide).
• Classified by source, animal, plant.
• Classified by effect, carcinogen, mutagen.
• Classified by physical state, gas, liquid, solid.
• Classified by chemistry, amine, hydrocarbon.
• Classified by poisoning potentiality, extremely toxic, slight.
• Biochemical mechanism of action-alkylating agent, AChE inhibitor.
• Increase severity with increased dose
• Gaseous states more toxic than liqiud staes, and solid form the least toxic.
• Purity.
• Individual: Age, Sensitivity, Health.
• Exposure: Inhalation, IV, Ingestion, Touch.
• Environment- Temperature, Pressure, and Humidity.
• Exposure duration and frequency categorized as acute, subacute, subchronic, and chronic.
• Acute exposure: Chemical exposure lasts below 24 h, usually in a single event.
• Acute exposure by inhalation is exposure for <= 24 h, generally up to 4 h.
• Subacute exposure is for 1 month.
• Subchronic between 1 to 3 months.
• Dose-response relationships show more severe response with higher dose.
• Response dose relatedness involves alteration to certain biochemical process.
• Adverse ecological effects caused by stress termed 'response' (toxic reaction).
• Response: Molecular, individual, population, community, and ecosystem levels.
• Stressor which may not cause the response by itself, in the presence of other potentiate response (0+2=4).
• One component may cause a toxic affect because of other much greater effects are known (Synergism).
• Tobacco smoke+asbestos dust=lung cancer.
• Combined chemical affect equals sum of individual chemicals (2+2=4).
• A dose of drug a at 25% is combined with dose a drug B at 50%, then overall 75% of the maximum response is produced.
• This possible whent the stressors are similar.
• Diazinon and chlorpyrifos = additive toxicity in present together.
• Selective toxicity produces harm to a specific organism even existing with intimacy.
• Specificity through diverse mechanisms results from variable distribution, biotransformation, or excretion.
• Variation major reason some chemicals damage tissues but not others attributed to the concentration of ultimate toxic compound.
• Differential ability to mobilize is how the variability is possible
• Selectivity arises from distinct biochemistry in distinct cells
• Estimate intrinsic substance toxicity, often lethal dose (LD50).
• Provides about target organs, clinical manifestations of toxicity.
• Identify susceptible, varied species.
• Reverse toxic answer.
• LD50
• LC50
• Mutagenicity: Chemicals altering nucleus's genetic cell makeup allowing changes to pass on to later generations.
• Mutations appear across two cell: Consequences vary greatly.
• Germinal mutations damage DNA in sperm and egg cells that can undergo meiotic division, therefore may cause transmissions of future generations.
• Initial embryo unaffected may cause the fetus to have death during latest stage development results in abortion.
• Mutations: Congenital abnormalities can result.
• Genetic abnormalities are visible with a microscope.
• Normal growth is incompatible certain mutations.
• Mutagenicity tests show compound chemical is carcinogenic, frequent oncogenic potential.
• The first change is the cell's toxic substance gene.
• Critical toxicology challenge is that transcriptional regulation is dynamic, affecting gene expression with both dose and time.

Toxicity and the Target Molecule

• Intensity of toxic impact: Concentration ultimate at action site.
• Ultimate toxicant: Acts using a macromolecule changing biology resulting in toxicity.
• Often the original compound is what cause toxic affects (parent compound).
• Sometimes its made up metabolites, a reactive gas that toxifies
• The best toxicity absorption, distribution to work site, metabolic activation.
• The highest level amount absorption to work site, metabolic activation.
• Opposing Pre-system elimination is distribution from work site, remove toxin work.
• Chemicals may transfer into cells to the systemic following absorbtion.
• Plasma allows chemicals to flow through capillary wall.
• Lipid-soluble move across cells for diffusion.
• Highly ionic and those that take water may enter into cell with transportation systems.
• Reach site for toxicity with distribution.
• Arsenite = Aquaglyceroporin influx
• Amiodarone, amitriptyline, fluoxetine= Lysosomal accumulates.
• Lysosomal enzyme prevents toxicant removal.
• Microvascular hepatic lesions cause liver damage with mitochondrial abnormalities.
• Distributes toxins to particular site.
• Cell organelles, Intracellular binding, Special cell, and special membrane.
• High protein cannot release diffusion, where this is only needed for some xenobiotics enter cell.
• Aqueous has little tight function, where blood barriers dont allow aqueous from reaching except the transporters.

Specialized Barriers

• Reproduction cell has limit access, and sertolic is only allows to pass the testicals.
• The placenta limits hydrophilic molecules.
• Highly lipophilic accumulate.
• The body removes with xenobiotics from circulation from external, and biotransformation is the chemic removal.
• Structure of Excretion: The major excretory are glomeru, and hepacotyes.
• The speed is greatly increase properties from physicochemical
• Highly hydrophilic compounds can efficiently remove.
• transcellular dissolves.
• Halogenated biphenyls don't allow this.
• Vapor release, the non chemical vapors diffuse through lung, and exit.
• Absorbtion occurs in tubule where toxicant can diffuse, and is dependent on solubility.
• Anions can result, and are ph depended.
• Acid is removed though alkalinizations, and acids.
• Can transverse thought the mucosal lining because of diffusion.

Toxication

• When xenobiotic is the toxin while other are harmful, its a toxication.
• Oxidation can allow ethylene glycol to become oxalate, an active inhibitor.
• When cephalosporin binds and release, vitamin K will bind and become inactive.
• Fragaments posses one paired electrons in the outer space.
• Accept extra electron to molecular, one electone.
• The biotransformation causes toxification while others remove the toxicant.

Detoxicaiton

• Sometime enzymes become very saturate, and dont have depletion of cellular anti oxidants.
• Free radicals are potentially causes harmful products.
• This is done through.
• Toxicity comes through with target , typically is linked with ultimate toxicant, its a dysfunction.
• The most affect targets are proteins and DNA.
• When cell have lipid can easily bind.
• Binding allows to pass, and be able for the toxic.
• It goes though dysfuctions, and distruction, which can cause antigen.
• This can occur on several type of target
• For cell to function at the site for it to bind, where the process are block by toxicants.
• Xenobiotic-neuro is ligand and can activate receptor cell through an activator.
• The electrolyte have is activate with toxicity.
• Many cell are with the nervous system through choline where these will alter receptor through atrophine

Harmful Mechanism of cells

• The mechanisms will come with mitochondrial in cell destruction.
• This is caused through ATP destruction or dysfunction.
• When hydrogen delivery to the electron transport chain, it causes damage.
• Harm occurs can result from low expose but high can lead with issues.
• Toxic can cause is high atp can dictate, because toxin react through cysteine causing caspase inactivation.