Investigate and quantify effects of toxicants on individual organisms By definition is the amount of a substance administered at one time 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.

1. BISC 312
Environmental Toxicology I
Instructor: Onkar Bains
INTRODUCTION

2. Mark Breakdown
 Midterm 1 (Monday, October 4th) – 20%
 Midterm 2 (Monday, November 8th ) – 20%
 Final Exam (December 14th) – 45%
 Cumulative with emphasis on material following Midterm 2
 Group Presentation – 15%
 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

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

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

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

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

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

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

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

10. BISC 312
Environmental Toxicology I
ENVIRONMENTAL
TOXICOLOGY, DOSE, DOSE-
RESPONSE

11. What is Environmental Toxicology?
 traditional definition of toxicology is
“________________________________________”
 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“

12. Terminology
 Toxic substances are not usually referred to as poisons
 Xenobiotic:
 Toxicant:
 Toxin:

13. Terminology
 Pollutant:
 Contaminant:

14. Environmental Toxicology
incorporates…
 Biology
 Chemistry
 and more !

15. Ultimate Goals of Environmental
Toxicology
 Investigate and quantify effects of toxicants on
individual organisms
 Identify ecological consequences, i.e. make link
between _____________________ and
__________________ in organisms
 Predict _______________________________

16. Paracelsus
From http://www2.bren.ucsb.edu/~keller/courses/esm202/ESM202Lecture11_2004.pdf.pdf

18. Dose
 By definition is the amount of a substance administered at one
time
 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.
 For example:
 Usual dosage unit is __________________

19. Dose
 Numerous types of doses, for example:

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

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

22. INTERPRETING DOSE-
RESPONSE CURVES

23. Threshold
 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/ToxTutor/Tox1/a22.htm

24. NOAEL and LOAEL
 NOAEL
 “no observed adverse
effect level”
 LOAEL
 “lowest observed adverse
effect level” From http://www.sis.nlm.nih.gov/ToxTutor/Tox1/a25.htm

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

26. STEEP
SLOPE
FLATTER
SLOPE

27. Effective, Toxic and Lethal Doses
 Effective represented “E”
 Toxic represented “T”
 Lethality represented “L”

28. Dose versus Concentration
 LD represents the_____________
 LC represents the ______________________
 Concentration is used when working with
__________________ or when the toxicant is
in the _________

29. Definitions of Percentages
 EC10:
 LD10:
 EC25:

30. Potency
 When comparing 2 or more toxicants, the one with the
smaller ED, LD or TD (EC, LC or TC) is considered to
be __________________
 Valid comparisons between dose response data are
those with same _______________________
 Example:
 Comparing LD50 of Toxicant A with an LD50 of Toxicant B
 Not comparing LD50 of Toxicant A with an LD10 of Toxicant B

31. Potency
 Example:
 Toxicant A LD50 = 23 mg/kg
 Toxicant B LD50 = 38 mg/kg
 Toxicant C LD50 = 67 mg/kg

32. Efficacy
 Toxicant is said to have high efficacy when dose-
response relationship
_____________________________________
_____________________________________

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

34. Therapeutic Index
 For example, if LD50 is 200 and ED50 is 20
mg, the TI would be ____ (____/____)
 The larger the therapeutic index, the _______
the drug.
 Some drugs have a low therapeutic index, e.g.,
Digoxin
 Others have a high therapeutic index, e.g., Naloxone

36. Therapeutic Index & Margin of
Safety
 Use of the ED50 and LD50 doses to derive the TI may be
misleading as to safety, depending on slope of dose-response
curves for therapeutic and lethal effects
 To overcome this deficiency, toxicologists often use another term
to denote safety of drug—Margin of Safety (MOS)
 MOS = ratio of dose that is just within the lethal range (LD01)
to the dose that is 99% effective (ED99)
 MOS = LD01/ED99
 Physician must use caution in prescribing a drug in which MOS
is < 1

37. BISC 312
Environmental Toxicology I
TOXICITY AND TOXICITY
TESTING

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

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

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

41. Innate Chemical Activity
 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:
 nicotine binds to cholinergic receptors in the CNS altering
nerve conduction and inducing gradual onset of paralysis

42. Age
 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:

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

44. Metabolism
 Metabolism, also known as biotransformation, is a major factor
in determining toxicity
 The products of metabolism are known as ______________
 There are two types of metabolism - detoxification and
bioactivation:
 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
____________________________________.

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

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

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

48. Antagonism
 Occurs when one chemical inhibits the action of
another
 2+2=1
 Antidotes
 Example:
 NaNO2 used to treat NaCN poisoning
 Dimercaprol (BAL) chelates metal ions (e.g.,
mercury, arsenic, lead)

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

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

51. Presence of other Chemicals
 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: