Lecture 3 Principles of Toxicology - EES1704H PDF

PRINCIPALS OF TOXICOLOGY EES1704H: ENVIRONMENTAL Ruwan Jayasinghe, MSc, QPRA, DABT RISK ASSESSMENT Senior Principal, Toxicologist & Risk Assessor, WSP Canada Inc.  Toxicology 2  Toxicology is the science of Poisons → “toxic” = poisonous, “ology” =...

PRINCIPALS OF TOXICOLOGY EES1704H: ENVIRONMENTAL Ruwan Jayasinghe, MSc, QPRA, DABT RISK ASSESSMENT Senior Principal, Toxicologist & Risk Assessor, WSP Canada Inc.  Toxicology 2  Toxicology is the science of Poisons → “toxic” = poisonous, “ology” = a field of study  It is the study of the adverse effects of chemicals on living organisms.  Toxicologists are trained to examine the nature of those effects and assess the probability of their occurrence. → Toxicologists are usually specialized to work in one area of toxicology. Toxicology  Industry  Academic  Government  Private  Environmental Toxicology 4 Environmental Health Toxicology → The study of the adverse effects of environmental contaminants on human health Ecotoxicology → The study of the adverse effects of environmental contaminants on ecosystems and its constituents  Toxicological Definitions 5  Poison → Any substance typically at low doses that causes a harmful effect when administered to a living organism  Toxicant → Any chemical, of natural or synthetic origin capable of causing an adverse effect on an organism  Toxin → Toxicant produced by a living organism  Xenobiotic → Any chemical interacting within an organism that does not occur in normal metabolic pathways of that organism  Route of Administration 6 Route and Site of Exposure → Route (pathways) by which toxic agents gain access to the body ◼ Gastrointestinal tract (oral) ◼ Lungs (inhalation) ◼ Skin (topical, subcutaneous, or dermal) ◼ Intravenous (direct to bloodstream) Approximate descending order of effectiveness ◼ Intravenous ◼ Inhalation ◼ Intraperitoneal ◼ Subcutaneous ◼ Intramuscular ◼ Intradermal ◼ Oral ◼ Dermal  Duration and Frequency of Exposure 7 Acute exposure to a chemical less than 24 hours, typically single administration Subacute repeated exposure to a chemical for 1 month or less Subchronic repeated exposure to a chemical for 1 to 3 months Chronic repeated exposure to a chemical for > 3 months  Duration and Frequency of Exposure 8  For many substances acute and chronic toxicities are quite different Benzene Acute – CNS depression Chronic – leukemia  Acute exposure to agents that are rapidly absorbed is likely to produce immediate toxic effects but may also result in delayed toxicity that may or may not be similar to long-term, low-level, or chronic effects.  Spectrum of Toxic Dose 9 LD50 is the dosage (mg/kg body weight) causing death in 50% of the exposed animal population Agent LD50 (mg/kg) Ethyl alcohol 10,000 Salt (sodium chloride) 4,000 Iron (Ferrous sulphate) 1,500 Morphine sulphate 900 Aspirin 250 DDT 250 Strychnine sulphate 2 Nicotine 1 Tetrodotoxin (from fish) 0.1 Dioxin (TCDD) 0.001 Botulinum Toxin 0.00001  Spectrum of Undesired Effects of 10 Chemicals  Allergic reactions  Idiosyncratic reactions  Immediate versus delayed toxicity  Reversible versus irreversible toxic effects  Local versus systemic toxicity  Allergic Reactions 11 Chemical allergy is an immunologically mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one.  Idiosyncratic Reactions 12 Chemical idiosyncrasy - genetically determined abnormal reactivity to a chemical/drug  Some people get nausea after taking an antibiotic  Some people get flush and intoxicated quickly after drinking alcohol Source: http://www.gbhealthwatch.com/Trait-Asian-Flush.php  Immediate Versus Delayed Toxicity 13  Immediate - rapidly after single exposure  Most common  Delayed - long lapse of time after exposure  Example: Cancer 20-30 years (humans) after exposure  DES (diethylstilbestrol) - prevent miscarriage, daughters developed vaginal cancer as young women  Delayed neurotoxic effect from triorthocresylphosphate (TCOP), effects observed after several days  Reversible versus Irreversible Toxic 14 Effects  Some toxic effects are reversible while others are not – dependent on target organ’s ability to regenerate  Liver - most injuries reversible as it has a high ability to regenerate  Central Nervous System (CNS) - largely irreversible because differentiated cells of the CNS cannot divide and be replaced.  Teratogenic effects are irreversible.  Local versus Systemic Toxicity 15 Local effects - usually site of first contact → Skin → Gastrointestinal tract → Respiratory tract Example: chlorine gas – inhalation exposure lungs! → can cause severe pulmonary edema and death with almost no detectable concentration in blood  Systemic Toxicity 16  Systemic toxicity requires absorption, distribution, etc.  Target organ of toxicity - depends on blood flow/mass and specific predisposition with unique biochemical process  Most chemicals that produce systemic toxicity do not cause a similar degree of toxicity in all organs – target organs → CNS most often → Circulatory system → Blood and hematopoietic system → Visceral organs, e.g., liver, kidney, lung → Skin → Muscle and bone, least often  Interactions of Chemicals 17  Additive / Cumulative Effect  occurs when the combined effect of two chemicals is equal to the sum of the effects of each agent given alone ◼ i.e. 2+2=4  Synergistic Effect  occurs when the combined effects of two chemicals are much greater than the sum of the effects of each agent given alone ◼ i.e. 2+2=20  Antagonistic Effect  occurs when the combined effects of two chemicals produce a less toxic product ◼ i.e. 2+2=0  Questions? 18 DOSE RESPONSE  Dose Response Relationships 20  Mathematical relation describing the response of a population of test organisms to a given dose over a specific time period  General Assumptions: → Response caused by substance → Change in response directly related to change in dose → Response measured and observed correctly → Population of test organisms is representative of total population of test organisms → Important consideration in selection of number used  Dose Response Relationships 21  A threshold for toxic effects occurs at the point where the body's ability to detoxify a xenobiotic or repair toxic injury has been exceeded.  For most organs there is a reserve capacity so that loss of some organ function does not cause decreased performance.  LOAEL / NOAEL 22  No Observed Adverse Effect Level (NOAEL) and Low Observed Adverse Effect Level (LOAEL).  They are the actual data points from human clinical or experimental animal studies.  Terminology (Potency and Efficacy) 23  ED – effective dose → Desired response, can also be therapeutic dose  TD – toxic dose → Dose at which toxicity is observed  Lethal Dose → Dose resulting in death  Threshold vs. No Threshold 24  Carcinogens are believed to have no threshold for toxicological response → i.e. any concentration will result in some probability of developing cancer Noncarcinogenic carcinogen  Extrapolation of Rodents to Humans 25  “Experimental results in animals, when properly qualified, are applicable to humans” ~ Basic tenet of toxicology  However, not always the case and we don’t want to gamble with peoples lives…  Modifying Factors & Safety/Uncertainty Factors → Differences between highest level of a chemical that produced a response in an animal and safe level for humans → Use of orders of magnitude  Sensitive Populations 26  Age → Biotransformation and excretion less efficient at early and late stages of life → Infants ◼ Drug metabolizing enzymes are not fully developed until 6- 12 months of age ◼ Ex: chloramphenicol (antibiotic) ◼ Renal function is underdeveloped, can take 2x as long to excrete some compounds (insulin)  Age of Enlightenment 27 All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from the remedy. Paracelsus Philippus Aureolus Theorphrastus Bombstus von Hohenheim-Paracelsus (1493 – 1541)  Disposition 28  Though “dose makes the poison” it is really the concentration of the toxicant at the site of action that determines toxicity  Concentrations may be different in different target organs  Due to disposition of chemical → Absorption → Distribution → Metabolism (Biotransformation) → Excretion Disposition Absorption Excretion  Mechanisms of Action – Reproductive 30  Mutagens  Alter genetic material -can be through adduct formation or other processes  Reproductive toxins  Interfere with various stages of reproductive: sexual maturity, production of gametes, function of gametes, and support processes (semen quality, uterine implantation, etc.) ◼ a. 1 mode of action is via receptor binding ◼ b. Ex of reproductive toxins: metals, insecticides, and volatile organic compounds  Teratogens  Reproductive toxins that interfere with developmental morphogenesis  Depending on the stage of development, effects range from embryonic death to major structural deformities, slowed maturation, and learning disabilities  E.g. fetal alcohol syndrome, thalidomide From Philp, Chap 1  Carcinogenesis 31  Carcinogenesis: Process by which chemicals cause cancer.  Many environmental chemicals/agents are known to cause human cancer: → Tobacco, arsenic, benzene, cadmium, coal tar, cigarette smoke, UV light, X- rays etc → A large number of chemicals are classified as carcinogens based on their ability to induce tumors in animal models.  Chemicals can induce tumors by directly damaging or modifying DNA (genotoxic) or indirectly by suppressing the immune system, changing hormone balance etc  Questions? 32 ORGAN TOXICITY  Neurotoxicity 34  Neurons can not normally regenerate. Thus toxic effects can be permanent.  Neurotoxic chemicals can cross blood brain barrier easily.  Examples: → Lead – children developmental issues → Mercury: In Japan, in 1950s, a chemical plant released large amounts of mercury into the bay. People who ate contaminated fish suffered from severe neurotoxicity. Minamata disease  Hepatotoxicity 35  Liver is highly susceptible to xenobiotic-induced toxicity.  It is the first organ to encounter the xenobiotic when ingested orally.  Carbon tetrachloride is the most widely studied. Cytochrome P450 converts it into a highly reactive free radical which causes toxicity.  Nephrotoxicity 36  Kidneys: Heavy metals are potent nephrotoxins: Cadmium, mercury, lead etc  Effects: Glucosuria, proteinurea, renal necrosis and death.  Pulmonary Toxicity 37  Inhalation of silica causes fibrosis or formation of collagenous tissue.  If large, can impair respiration. Asbestosis: may cause lung cancer.  Cigarette smoke has polycyclic aromatic hydrocarbons such as benzo(a)pyrene which is metabolized by cytochrome P450. The metabolites may trigger cancer.  Reproductive Toxicity 38  A large number of chemicals are toxic to the male or female reproductive system.  Can cause decreased sperm count.  Some environmental chemicals such as dichlorodiphenyltrichloroethane (DDT), DDE etc can mimic human estrogen. They are called “environmental estrogens”.  In wildlife they cause hermaphroditic fish and other reproductive anomalies (sex reversal) in alligators.  Questions? 39