Week 1 PDF

Section A: Introduction to Toxicology and Environmental Health Principles of Toxicology 1) Environmental toxicology: the study of harmful e0ects of various chemical, biological, and physical agents on living organisms in the ecosystems including humans...

Section A: Introduction to Toxicology and Environmental Health Principles of Toxicology 1) Environmental toxicology: the study of harmful e0ects of various chemical, biological, and physical agents on living organisms in the ecosystems including humans § Occupies connection between toxicology, environmental health, and public policy § describes chemical transport, fate, persistence and bioaccumulation of substances and their e0ects at the population/community levels à Causes of Death: 1) Chronic obstructive pulmonary disease (lung) 2) Asthma 3) Cardiovascular 4) Cancer 5) Congenital (disease present from birth) Xenobiotic à Exposure à Toxicokinetics à Toxicodynamics 2) Xenobiotic: substance that is foreign to the body or the ecological system 3) Exposure: how xenobiotic comes into contact with body 4) Toxicokinetics (exposure assessment): describes what happens to xenobiotic in the body § Absorption: this is the entry of toxicants through external membrane barriers into circulation Skin, lungs, GI tract § Distribution: movement of toxicants through circulatory fluids to organs and tissues Blood plasma, tissue § Metabolism/Biotransformation: the biochemical process that converts the original toxicant to various metabolic products § Excretion/Elimination: the removal of the toxicant or its metabolites from the body Kidneys, liver à lungs, saliva, sweat, breast milk  5) Toxicodynamics (risk assessment): describes what the xenobiotic does to the body § Processes: Oxidative stress; Electrophilic Attack, DNA Damage, Endocrine Disruption, etc. 6) Toxicology: the study of poisons § Toxicology provides vital information to permit us to assess potential health risks. § Study of capacity of chemical to cause injury § Study of adverse e0ects of chemical, physical or biological agents on living organisms and the ecosystem, including the prevention and improvement of adverse e0ects § Study of harmful e0ects of drugs, environmental contaminants, and naturally occurring substances found in food, water, air, and soil § Study of adverse e0ects of chemicals on biological systems, includes humans, animals and ecosystem § Deals with identification, analysis, e0ects and treatment of the e0ects of poisons History of Toxicology 1) Human exposure to toxic substances in the past § Approximately 100,000 chemicals currently in use worldwide, 500 new chemicals enter the marketplace annually. There are  approximately 23,000 chemicals on Canada’s Domestic Substances List § Most exposure of humans to chemicals = diet from food plants 2) Poison Recipes § Greeks used hemlock as the state poison § Romans used arsenic § Chinese used opium both as a therapeutic agent and poison § South American tribes used and continue to use curare in hunting § States in the US use lethal injection (pentothal, pancuronium bromide and potassium chloride), cyanide gas 3) Advent (arrival) of toxicology § Paracelsus – “Dose makes the poison” § Mathieu Orfila – “father of toxicology” 4 Primary factors that determine adverse eOects from toxicology: Intrinsic Toxicity, Dose, Exposure conditions, Individual susceptibility 1) Intrinsic toxicity: natural harmful e0ects a substance can have on living organisms, regardless of amount or exposure § Depends on variety of physical-chemical properties of toxicant: Molecular structure and functional groups; soluble/Insoluble The stability or reactivity the volatility: how easily chemical vapors chemical species/ form: group of chemicals § toxicants may/may not have threshold: Threshold - substances have a level of exposure (the threshold) below which no adverse eOects occur. o For example, cadmium and bisphenol A (BPA) may have safe exposure limits. Non-threshold - these substances, any level of exposure can potentially cause harmful eOects, regardless of how small. o Examples include hexachlorobenzene, vinyl chloride, and lead. Various measures used to assess toxicity of substances: o NOAEL (no observed adverse e0ect level) - highest dose at which no harmful e0ects are observed, helps determine safe exposure levels.  o LOAEL (lowest observed adverse e0ect level) - adverse e0ects are observed at the lowest dose, useful for understanding the onset of toxicity. § Toxicological Reference Values (TRVs), which are used for risk assessment. o The more hazardous the non-threshold toxicant, the lower the Exposure Limit o The more hazardous the genotoxic carcinogen, the higher the Cancer Slope Factor § Classifying Toxic E0ects o Toxic e0ects are generally categorized according to the site of toxicity and mechanism of action § Sometimes the e0ect(s) only occur in one location of the body. This site is referred to as the target organ A single toxicant can have multiple target organs that are each a0ected at di0erent levels of exposure. The specific target organ of one toxicant may di0er with age/sex/ethnicity § Mechanisms of toxicity may be similar among organs/tissues § The typical types of organ- or tissue-specific toxicity include: Blood/cardiovascular toxicity Dermal/ocular toxicity Hepatotoxicity Immunotoxicity Nephrotoxicity Neurotoxicity Reproductive toxicity Respiratory toxicity § The severity of toxic responses depends upon the duration and frequency of exposures: Acute: less than 24 hours, usually a single dose Subacute: repeated exposure for up to one month duration  Subchronic: repeated exposure for one to three months Chronic: repeated exposure for greater than three months up to a lifetime § Haber’s Law: As exposure duration increases, it takes less of a toxicant to result in an adverse e0ect Chronic toxicity occurs when: o A toxicant accumulates o the rate of absorption exceeds the rate of elimination o each dose of toxicant causes irreversible toxicity o there is an insu0icient time for recovery between doses § Mechanisms of Toxicity include: Endocrine disruption Developmental toxicity Oxidative stress Carcinogenicity Genetic toxicity Enzyme inhibition 2) Dose: amount of substance taken into body § Determines toxicological eOect in an organism § Usually standardized by body weight and time § Measures of dose are quantified through exposure assessments. These measures/estimates may reflect: External dose o For example: The amount of toxicant swallowed from drinking water o Bioavailability adjustments: extent a substance/drug becomes completely available to its intended biological destination o Dose reconstructions: past exposures to toxicants o Comparison against exposure limits: External doses compared to exposure limits to understand if there is a health hazard o Details on Drivers of exposure Internal dose o For example: the amount of toxicant that is absorbed into the blood o Bioavailability o Measurement: body samples § Blood, blood plasma, urine hair, fingernails § “Gold-standard” – concentration of toxicant – of exposure assessment o Few Health Based Guidance Values for risk assessment o Aggregates all sources of exposure § Exposure Conditions: o Magnitude o Route (Ingestion (Oral), Inhalation (lung), Dermal (skin)) o Duration (Acute, sub-chronic, chronic) o Frequency (# of times exposed, time between exposure) § Exposure routes o Route influences the distribution and metabolism of the toxicant o The route of exposure may be important if there are tissue- specific toxic responses. § Individual Susceptibility Same toxicant brings di0erent e0ects on di0erent individuals o Susceptibility and sensitivity is the same thing factors like sex, age, nutrition, medical history, environmental exposures, genetic background, and species di0erences § Susceptible Life-stage: In utero exposures o Thalidomide § 1956 introduce as a sedative and anti-nauseant during pregnancy § Withdrawn in 1961 § Human teratogen causing missing limbs or limb malformations § Over 10,000 infants a0ected globally, and only 50% survived § The negative e0ects of thalidomide led to the development of more structured drug regulations and control over drug use and development § Still in use for specific treatments