BISC 312 Environmental Toxicology I Instructor Onkar Bains

BISC 312 Environmental Toxicology I Instructor: Onkar Bains INTRODUCTION

Mark Breakdown n Midterm 1 (Monday, October 4 th) – 20% n Midterm 2 (Monday, November 8 th ) – 20% n Final Exam (December 14 th) – 45% n n Cumulative with emphasis on material following Midterm 2 Group Presentation – 15% n n n Around 10 people per group 15 - 20 minutes to present Q&A Taking place mid November and on Material discussed will be on final !! 9% based on presentation; 6% based on your group mark

Instructor Info n Email address – obains@sfu. ca n Office – SSB 6125 n Office Hours – Mondays from 1: 00 pm to 2: 00 pm or by appointment (not Tuesdays or Thursdays)

Topics to be covered n What is Environmental Toxicology? n Dose, Dose Response n Toxicity and Toxicity Testing n Uptake, Distribution, Biotransformation, Elimination n Teratogenesis, Mutagenesis, Carcinogenesis

Topics to be covered n Environmental Pollutants: n n PAHs n Heavy metals n Endocrine disruptors n Biological toxins PCBs Dioxins/furans Pesticides

Topics to be covered n Multixenobiotic/Multidrug resistance n Oil spills and bioremediation n Atmospheric pollution and Greenhouse effect n Acid rain n Biomarkers and Bioindicators n Group presentation topics

Group Presentation Topics n Waste water treatment n Phthalates n Asbestos n Eutrophication n Pulp and paper mill effluent n Tributyltin n Arsenic n CFC’s (maybe) n Free radical toxicity

Guest Speakers n Mr. Rick Lee n n Ms. Vicki Fleming n n Cancer and Carcinogenesis M. E. T. project based on oral cancer and smoking Mr. Jasen Nelson n Endocrine disruptors

Guest Speakers n Mr. Keith Tierney and Ms. Amber Taylor n n Ms. Michelle Stockwell n n Pesticides and olfaction Pesticides and fish farming Mrs. Helena Daudt n Cadmium

BISC 312 Environmental Toxicology I ENVIRONMENTAL TOXICOLOGY, DOSERESPONSE

What is Environmental Toxicology? n traditional definition of toxicology is “____________________” n n Poison = a substance that can cause damage or disturbance to the function of organisms or ecosystems "the study of the _____ effects of chemicals or _______ on living organisms“

Terminology n Toxic substances are not usually referred to as poisons n Xenobiotic: n Toxicant: n Toxin:

Terminology n Pollutant: n Contaminant:

Environmental Toxicology incorporates… Biology n Chemistry n n and more !

Ultimate Goals of Environmental Toxicology n Investigate and quantify effects of toxicants on individual organisms n Identify ecological consequences, i. e. make link between ___________ and _________ in organisms n Predict ________________

Paracelsus From http: //www 2. bren. ucsb. edu/~keller/courses/esm 202/ESM 202 Lecture 11_2004. pdf

Dose n By definition is the amount of a substance administered at one time n However, other parameters are needed to characterize the exposure to xenobiotics. The most important are the number of doses, frequency, and total time period of the treatment. n For example: n Usual dosage unit is _________

Dose n Numerous types of doses, for example:

Dose-Response Curve n X axis—DOSE n Y axis—RESPONSE A higher dose or concentration causes a more intense effect (response)

Significance of Dose-Response n Knowledge of the dose-response relationship: n establishes causality that the chemical has in fact induced the observed effects n establishes the lowest dose where an induced effect occurs the threshold effect n determines the rate at which injury builds up - the slope for the dose response

INTERPRETING DOSERESPONSE CURVES

Threshold n n Point at which toxicity first appears is known as the ____________ A threshold for toxic effects occurs at point where______________________ From http: //www. sis. nlm. nih. gov/Tox. Tutor/Tox 1/a 22. htm

NOAEL and LOAEL n NOAEL n n “no observed adverse effect level” LOAEL n “lowest observed adverse effect level” From http: //www. sis. nlm. nih. gov/Tox. Tutor/Tox 1/a 25. htm

What does the slope of a dose response curve tell us? A steep slope indicates that a small change in dose will result in _____________________________________ n A flat slope indicates a large change in dose is required before a significant change in response will be observed n

STEEP SLOPE FLATTER SLOPE

Effective, Toxic and Lethal Doses n Effective represented “E” n Toxic represented “T” n Lethality represented “L”

Dose versus Concentration n LD represents the_______ n LC represents the ___________ n Concentration is used when working with _________ or when the toxicant is in the _____

Definitions of Percentages n EC 10: n LD 10: n EC 25:

Potency n When comparing 2 or more toxicants, the one with the smaller ED, LD or TD (EC, LC or TC) is considered to be _________ n Valid comparisons between dose response data are those with same ____________ n Example: n n Comparing LD 50 of Toxicant A with an LD 50 of Toxicant B Not comparing LD 50 of Toxicant A with an LD 10 of Toxicant B

Potency n Example: Toxicant A LD 50 = 23 mg/kg n Toxicant B LD 50 = 38 mg/kg n Toxicant C LD 50 = 67 mg/kg n

Efficacy n Toxicant is said to have high efficacy when dose-response relationship _____________________________________

Therapeutic Index n Used to compare therapeutically ______ to the ________ n Statement of relative safety of a drug n Ratio of dose producing toxicity to dose needed to produce desired therapeutic response n _______________ n Common method used to derive TI is to use ____% dose-response points

Therapeutic Index n For example, if LD 50 is 200 and ED 50 is 20 mg, the TI would be ____ (____/____) n The larger therapeutic index, the _______ the drug. Some drugs have a low therapeutic index, e. g. , Digoxin n Others have a high therapeutic index, e. g. , Naloxone n

Therapeutic Index & Margin of Safety n Use of the ED 50 and LD 50 doses to derive the TI may be misleading as to safety, depending on slope of dose-response curves for therapeutic and lethal effects n To overcome this deficiency, toxicologists often use another term to denote safety of drug—Margin of Safety (MOS) n MOS = ratio of dose that is just within the lethal range (LD 01) to the dose that is 99% effective (ED 99) n n MOS = LD 01/ED 99 Physician must use caution in prescribing a drug in which MOS is < 1

BISC 312 Environmental Toxicology I TOXICITY AND TOXICITY TESTING

Toxic Effects n Toxicity can result from adverse cellular, biochemical, or macromolecular changes. Examples are: n cell replacement, such as fibrosis n damage to an enzyme system n disruption of protein synthesis n production of reactive chemicals in cells n DNA damage n interference with nutrition

Toxicity Depends Upon… n The toxicity of a substance depends on the following: n form and innate chemical activity n dosage, especially dose-time relationship n exposure route n species n age n sex n metabolism n ability to be absorbed n excretion n distribution within the body n presence of other chemicals

Form n The form of a substance may have a profound impact on its toxicity especially for metallic elements. For example:

Innate Chemical Activity n Innate chemical activity of substances also varies greatly. Some can quickly damage cells causing immediate cell death. Others slowly interfere only with a cell's function. For example: n nicotine binds to cholinergic receptors in the CNS altering nerve conduction and inducing gradual onset of paralysis

Age n Age may be important in determining the response to toxicants. Some chemicals are more toxic to infants or older organisms than to young adults. For example:

Sex n Although uncommon, toxic responses can vary depending on sex. Examples are:

Metabolism n Metabolism, also known as biotransformation, is a major factor in determining toxicity n The products of metabolism are known as _______ n There are two types of metabolism - detoxification and bioactivation: n n Detoxification—process by which xenobiotic is converted to _________. This is a natural defense mechanism of the organism. Generally the detoxification process converts lipid-soluble compounds to polar compounds. Bioactivation—process by which a xenobiotic may be converted to __________________.

Excretion n Site and rate of excretion is another major factor affecting the toxicity of a xenobiotic n Kidney is the primary excretory organ, followed by the gastrointestinal tract, and the lungs (for gases) n Xenobiotics may also be excreted in sweat, tears and milk n Lipid-soluble toxicants are reabsorbed and concentrated in kidney cells n Impaired kidney function causes slower elimination of toxicants and increases their toxic potential

Presence of other Chemicals Presence of other chemicals may decrease, add to or increase toxicity of some xenobiotics n There are four basic types of interactions: n

Additivity Toxicity of the mixture will be approximately the summation of the toxicity of the individual toxicants n Toxicants that share a common mechanism n 1+1=2 n Example: n

Antagonism Occurs when one chemical inhibits the action of another n 2+2=1 n Antidotes n Example: n Na. NO 2 used to treat Na. CN poisoning n Dimercaprol (BAL) chelates metal ions (e. g. , mercury, arsenic, lead) n

Potentiation Occurs when one substance does have a toxic effect but when mixed with another chemical makes that chemical much more toxic n 0+2=20 n Example: n

Synergism Occurs when the combined effect of 2 chemicals is much greater than the sum of effects of each chemical alone n 2+2=20 n Example: n

Presence of other Chemicals n This table quantitatively illustrates the percent of the population affected by individual exposure to chemical A and chemical B as well as exposure to the combination of chemical A and chemical B. It also gives the specific type of interaction: