M3 Pharm.pdf

Toxicology Definition and Measures of Toxicity - - - - - - - Toxicity of chemicals is determined in the laboratory by exposing them to test animals, this can be through o Ingestion o Application to the skin o Inhalation o Placing the test material in the water or air of the test animals’ environment...

Toxicology Definition and Measures of Toxicity - - - - - - - Toxicity of chemicals is determined in the laboratory by exposing them to test animals, this can be through o Ingestion o Application to the skin o Inhalation o Placing the test material in the water or air of the test animals’ environment Endpoints of toxicity (ability to cause…) o Mortality (death) o Teratogenicity (birth defects) o Carcinogenicity (cancer) o Mutagenicity (heritable changes in DNA) Median Lethal Dose o Measure of toxicity, dose of chemical causing death in 50% of a test population (LD50) o Normally expressed as mg/kg (milligrams of substance per kilogram of animal body weight) Poison o Pesticide with an LD50 of 50mg/kg or less o Must have the words DANGER or POISON and show skull and crossbones Relative Toxicity of insecticides o TCDD (Dioxin): 0.1 mg/kg o Nicotine 50 mg/kg Heavy Metals o Elements with a specific gravity that is at least 5 times the specific gravity of water ▪ Arsenic, Lead, Mercury o Physical properties: reflectivity, conductivity, easily traced Absorption o Respiratory absorption: inhaled metals as vapor or aerosol into the alveolar space (gas exchange) which can then be absorbed into the blood ▪ Also be large particles in the upper respiratory tract that transported to the pharynx and swallowed - - - o Gastrointestinal absorption: through food and water affected by solubility and physiological state ▪ Metal is absorbed into cells lining the GI tract facilitated by diffusion (passive or facilitated) and pinocytosis ▪ Physiological state of exposed person (Vitamin D enhances the absorption of lead Excretion o Kidney is the main route of excretion o Metals in blood are bound to plasma proteins and amino acids ▪ Those bound to low molecular weight proteins and amino acids can be filtered in gl;omerulus into fluis of the renal tubule ▪ Metals like cadmium and zinc can be reabsorbed by tubular epithelia before reaching the urinary bladder (where little absorption happens) o Some absorbed metal may also be excreted into the intestinal tract in bile, pancreatic secretions or saliva (enterohepatic circulation) o Minor pathways of metal excretion include: Nails and Saliva, Hair (Zinc and copper) Acute versus Chronic toxicity o Acute ▪ Affected organs are those involved in absorption and elimination ▪ Due to high concentration of metal unable to detoxify or be eliminated ▪ Treatments of acute metal toxixcity are designed to Enhance elimination through neutralization Prevent irreversible damage to organs and tissue Treat symptoms o Chronic ▪ Longterm health effects with a long duration between exposure and the onset of signs and symptoms (months to years) ▪ Difficult to diagnose but are diagnosed through presence of excessive metals in blood and urine ▪ Organs not involved in absorption or elimination may be affected like the immune system or hematopoetic Lead and Mercury Contamination o Lead ▪ Sources: Paint (lead containing pigments are still used for bright colours) and soil ▪ Absorption: lungs (size dependent), GI (adults 20-30% and 50% in children, higher lead levels are associated with inadequate iron, ▪ ▪ ▪ ▪ calcium and calories) and skin (only organic lead is well absorbed not inorganic) Lead is carried through the blood stream bound on RBCs Distribution Throughout tissues bone and brain Bones carry out continued toxicity after exposure Crosses the BBB and placenta Excreted through kidney and feces Clinical Manifestations: Acute: acute encephalopathy and renal failure Chronic: Heme synthesis and steroid metabolism (Pb is toxic to zinc dependent enzyme systems due to high SH affinity) Pb has the ability to substitute bivalent cations Ca2+ Mg2+ for monovalent ones Na+ o Mercury ▪ Three forms: Elemental o Clinical Manifestations ▪ At high concentration: acute necrotizing bronchitis (vapor inhalation) and death ▪ Longterm exposure: affects CNS; insomnia, tremors (late), excess sweating, memory impairment. ▪ Dental analgrams are NOT a risk ▪ ▪ ▪ ▪ Inorganic o Affects the kidney mainly tubular damage Organic o Long-term exposure ▪ generalized weakness, visual and hearing impairment o Teratogen with large chronic exposure ▪ Asymptomatic mothers with severely affected infants ▪ Infants appear normal at birth but blindness, psychomotor retardation and deafness develop over time o Effects ▪ CNS: Metabolism disruption and sensorimotor fo organic Hg ( tremor and incoordination) Sources: Mining, Smelting, thermometers and lightbulbs. Mercury in water can be converted to organic mercury (more toxic) in fish Mercuy levels increase as you go up the food chain in fish because the small fish eat the mercury and they get eaten by bigger fish and so on Other effects: gingivitis and excessive salivation Diagnosis and Treatment: - Dx: based on history, physical exam and lab analysis; inorganic mercury can be measured in 24 hour urine samples, and organic in blood samples Treatment: identifying source and ending exposure Drugs: Chelating agents (enhance inorganic mercury elimination) and dimercaprol (increase mercury conc in brain) Artificial Sweeteners o Saccharin is 300X more sweet than sucrose ▪ Non-carb sweetener, Sweet N Low, Sugar Twin ▪ Discovered by a chemist spilling chemical on his hand and noticing a sweetness when eating ▪ Was used by diabetics ▪ NOT metabolized in body for energy ▪ Safety controversy Findings of bladder tumors in rats o Epigenetic promoter o Specific to the rats species bc of unique protein o High doses for long exposure cause cell proliferation Went through periods of being banned and unbanned More than 30 human studies say its safe o Aspartame is 180X more sweet than sucrose ▪ Non-carb swwetener, equal and nutrasweet ▪ Gradual increase in use of soft drinks ▪ Products containing aspartame: Breath Mints, Iced Tea Powder, and Chewing gum Aspartame products do not satisfy craving as well as sugar products Metabolized into methanol, phenylalanine and aspartic acid Phenylalanine is an essential amino acid that synthesizes tyrosine and neurotransmitters, excess is broken down into fumarate and acetoacetate ▪ Safety concerns: Formaldehyde poisoning Methanol converts into formaldehyde in the body, causes damage to neurological and immune system at low doses o Acesulfame postassium ▪ 200x sweeter than sucrose ▪ Used as a flavor enhancer or preserve sweetness of foods ▪ Most being are unanware that this artificial sweetener is being used in food and beverages ▪ Problems: improper testing and no long term studies ▪ Safety: Acesulfame K contains carcinogen methylene chloride Can cause headaches, nausea, depression, and cancer o Sucralose (Spenda) ▪ No calories and not fully absorbed ▪ Not carcinogenic, and does not cause reproductive or neurological risk to humans ▪ Misleading name because its nothing like sucrose (table sugar) ▪ Chlorine presence is the most dangerous component in sucralose Carcinogenic GI problems (bloating) Skin irritation ▪ No long term studies so we have to learn things as we go ▪ Found to affect medication absorption in rats and reduce the microbiota in the gut ▪ ▪ Environmental Toxicity - Lecture by Amanda Copp Toxic Metals - Lead Cadmium Arsenic Mercury Chromium - - - - - - o These metals are useful due to malleability, density, resistance to corrosion Sources of contamination o Lead ▪ Food and old paint o Cadmium ▪ Forest fires and volcanic eruption (natural sources) ▪ Batteries and Industrial Waste (anthropogenic sources) Routes of Exposure o Lead/Cadmium absorption: ▪ Skin – very low ▪ Inhalation – lower since ban on leaded gas but still significant ▪ Ingestion – majority of exposure today o Amount of absorption depends on ▪ Age: increased absorption if younger ▪ Meal status- more absorption on an empty stomach ▪ Nutrition levels – calcium, zinc, or iron deficiencies increase absorption Drinking water o Accepetable level of lead/cadmium is 5ug/L but the issue is that water is not monitored after it leaves treatment facilities so homeowners need to test their own water due to contamination from old pipes Food o Lead and cadmium are not permitted to be added to food but are contaminated by soil, water and air o Canadian diet has an estimated 100ng/kg/day of lead ▪ Frozen dinners and herbs and spices are examples of food with lead and cadmium Blood levels o No known safe level of exposure just keep it as low as possible ▪ Lead in blood is dynamic and dependent on 35 days ½ life, breasfeeding, aging, diet and disease o There are acceptable blood levels that were lowered in 2021 because eof evidence that levels of lead