1

BISC 312BISC 312Environmental Toxicology IEnvironmental Toxicology I

Instructor: Instructor: OnkarOnkar BainsBainsINTRODUCTIONINTRODUCTION

Mark BreakdownMark Breakdown

Midterm 1 Midterm 1 (Monday, October 4(Monday, October 4thth) ) –– 20%20%

Midterm 2 Midterm 2 (Monday, November 8(Monday, November 8thth ) ) –– 20%20%

Final Exam Final Exam (December 14(December 14thth) ) –– 45%45% Cumulative with emphasis on material following Midterm 2Cumulative with emphasis on material following Midterm 2

Group Presentation Group Presentation –– 15%15% Around 10 people per groupAround 10 people per group 15 - 20 minutes to present15 - 20 minutes to present Q&AQ&A Taking place mid November and onTaking place mid November and on Material discussed will be on final !!Material discussed will be on final !! 9% based on presentation; 6% based on your group mark9% based on presentation; 6% based on your group mark

2

Instructor InfoInstructor Info

Email addressEmail address –– obains@sfu.caobains@sfu.ca

OfficeOffice –– SSB 6125 SSB 6125

Office HoursOffice Hours –– Mondays from 1:00pm to Mondays from 1:00pm to2:00pm or by appointment (not Tuesdays or2:00pm or by appointment (not Tuesdays orThursdays)Thursdays)

Topics to be coveredTopics to be covered What is Environmental Toxicology?What is Environmental Toxicology?

Dose, Dose ResponseDose, Dose Response

Toxicity and Toxicity TestingToxicity and Toxicity Testing

Uptake, Distribution, Biotransformation, EliminationUptake, Distribution, Biotransformation, Elimination

TeratogenesisTeratogenesis, Mutagenesis, Carcinogenesis, Mutagenesis, Carcinogenesis

3

Topics to be coveredTopics to be covered

Environmental Pollutants:Environmental Pollutants:

PAHsPAHs

PCBsPCBs

Dioxins/furansDioxins/furans

PesticidesPesticides

Heavy metalsHeavy metals

Endocrine disruptorsEndocrine disruptors

Biological toxinsBiological toxins

Topics to be coveredTopics to be covered

Multixenobiotic/MultidrugMultixenobiotic/Multidrug resistance resistance

Oil spills and bioremediationOil spills and bioremediation

Atmospheric pollution and Greenhouse effectAtmospheric pollution and Greenhouse effect

Acid rainAcid rain

Biomarkers and Biomarkers and BioindicatorsBioindicators

Group presentation topicsGroup presentation topics

4

Group Presentation TopicsGroup Presentation Topics

Waste water treatmentWaste water treatment

AsbestosAsbestos

Pulp and paper mill effluentPulp and paper mill effluent

ArsenicArsenic

Free radical toxicityFree radical toxicity

PhthalatesPhthalates

EutrophicationEutrophication

TributyltinTributyltin

CFCCFC’’s (maybe)s (maybe)

Guest SpeakersGuest Speakers

Mr. Rick LeeMr. Rick Lee Cancer and CarcinogenesisCancer and Carcinogenesis

Ms. Vicki FlemingMs. Vicki Fleming M.E.T. project based on oral cancer and smokingM.E.T. project based on oral cancer and smoking

Mr. Mr. JasenJasen Nelson Nelson Endocrine disruptorsEndocrine disruptors

5

Guest SpeakersGuest Speakers

Mr. Keith Tierney and Ms. Amber TaylorMr. Keith Tierney and Ms. Amber Taylor Pesticides and olfactionPesticides and olfaction

Ms. Michelle Ms. Michelle StockwellStockwell Pesticides and fish farmingPesticides and fish farming

Mrs. Helena Mrs. Helena DaudtDaudt CadmiumCadmium

BISC 312BISC 312Environmental Toxicology IEnvironmental Toxicology I

ENVIRONMENTALENVIRONMENTALTOXICOLOGY, DOSE, DOSE-TOXICOLOGY, DOSE, DOSE-

RESPONSERESPONSE

6

What is Environmental Toxicology?What is Environmental Toxicology?

traditional definition oftraditional definition of toxicology istoxicology is““________________________________________________________________________________”” Poison = Poison = a substance that can cause damage or disturbancea substance that can cause damage or disturbance

to the function of organisms or ecosystemsto the function of organisms or ecosystems

"the study of the _________ effects of chemicals or"the study of the _________ effects of chemicals or______________ on living organisms______________ on living organisms““

TerminologyTerminology

ToxicToxic substances are not usually referred to as poisons substances are not usually referred to as poisons

XenobioticXenobiotic::

Toxicant:Toxicant:

Toxin:Toxin:

7

TerminologyTerminology

Pollutant:Pollutant:

Contaminant:Contaminant:

Environmental ToxicologyEnvironmental Toxicologyincorporatesincorporates……

BiologyBiology ChemistryChemistry

and more !and more !

8

Ultimate Goals of EnvironmentalUltimate Goals of EnvironmentalToxicologyToxicology

Investigate and quantify effects of toxicants onInvestigate and quantify effects of toxicants onindividual organismsindividual organisms

Identify ecological consequences, i.e. make linkIdentify ecological consequences, i.e. make linkbetween _____________________ andbetween _____________________ and__________________ in organisms__________________ in organisms

Predict _______________________________Predict _______________________________

ParacelsusParacelsus

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

9

DoseDose

By definition is the amount of a substance administered at oneBy definition is the amount of a substance administered at onetimetime

However, other parameters are needed to characterize theHowever, other parameters are needed to characterize theexposure to exposure to xenobioticsxenobiotics..   The most important are the number of The most important are the number ofdoses, frequency, and total time period of the treatment.doses, frequency, and total time period of the treatment.

For example:For example:

Usual dosage unit is __________________Usual dosage unit is __________________

10

DoseDose

Numerous types of doses, for example:Numerous types of doses, for example:

Dose-Response CurveDose-Response Curve

X axisX axis——DOSEDOSE

Y axisY axis——RESPONSERESPONSE

A higher dose or concentration causes a more intense effect (response)

11

Significance of Dose-ResponseSignificance of Dose-Response

Knowledge of the dose-response relationship:Knowledge of the dose-response relationship:

establishes causality that the chemical has in fact induced theestablishes causality that the chemical has in fact induced theobserved effectsobserved effects

establishes the lowest dose where an induced effect occurs -establishes the lowest dose where an induced effect occurs -the threshold effectthe threshold effect

determines the rate at which injury builds up - the slope fordetermines the rate at which injury builds up - the slope forthe dose responsethe dose response

INTERPRETING DOSE-INTERPRETING DOSE-RESPONSE CURVESRESPONSE CURVES

12

ThresholdThreshold Point at which toxicity first appears is known as thePoint at which toxicity first appears is known as the

______________________________________________ A thresholdA threshold for toxic effects occurs at pointfor toxic effects occurs at point

where______________________________________where____________________________________________________________________________________________________________________________

From http://www.sis.nlm.nih.gov/ToxTutor/Tox1/a22.htm

NOAEL and LOAELNOAEL and LOAEL

NOAELNOAEL ““no observed adverseno observed adverse

effect leveleffect level””

LOAELLOAEL ““lowest observed adverselowest observed adverse

effect leveleffect level”” From http://www.sis.nlm.nih.gov/ToxTutor/Tox1/a25.htm

13

What does the slope of a doseWhat does the slope of a doseresponse curve tell us?response curve tell us?

A steep slope indicates that a small change inA steep slope indicates that a small change indose will result indose will result in____________________________________________________________________________________________________________________________________________________

A flat slope indicates a large change in dose isA flat slope indicates a large change in dose isrequired before a significant change in responserequired before a significant change in responsewill be observedwill be observed

STEEPSLOPE

FLATTERSLOPE

14

Effective, Toxic and Lethal DosesEffective, Toxic and Lethal Doses

EffectiveEffective represented represented ““EE””

ToxicToxic represented represented ““TT””

LethalityLethality represented represented ““LL””

Dose versus ConcentrationDose versus Concentration

LDLD represents the_____________ represents the_____________

LCLC represents the ______________________ represents the ______________________

ConcentrationConcentration is used when working with is used when working with__________________ or when the toxicant is__________________ or when the toxicant isin the _________in the _________

15

Definitions of PercentagesDefinitions of Percentages

ECEC1100::

LDLD1100::

ECEC2525::

PotencyPotency

When comparing 2 or more toxicants, the one with theWhen comparing 2 or more toxicants, the one with thesmallersmaller ED, LD or TD (EC, LC or TC) is considered ED, LD or TD (EC, LC or TC) is consideredto be __________________to be __________________

Valid comparisons between dose response data areValid comparisons between dose response data arethose with same _______________________those with same _______________________ Example:Example:

Comparing Comparing LDLD5050 of Toxicant A with an of Toxicant A with an LDLD5050 of Toxicant B of Toxicant B NotNot comparing comparing LDLD5050 of Toxicant A with an of Toxicant A with an LDLD1010 of Toxicant B of Toxicant B

16

PotencyPotency

Example:Example: Toxicant A LDToxicant A LD5050 = 23 mg/kg = 23 mg/kg Toxicant B LDToxicant B LD5050 = 38 mg/kg = 38 mg/kg Toxicant C LDToxicant C LD5050 = 67 mg/kg = 67 mg/kg

EfficacyEfficacy

Toxicant is said to have high efficacy whenToxicant is said to have high efficacy whendose-response relationshipdose-response relationship____________________________________________________________________________________________________________________________________________________

17

Therapeutic IndexTherapeutic Index Used to compare the therapeutically ___________ toUsed to compare the therapeutically ___________ to

the _______________the _______________

Statement of relative safety of a drugStatement of relative safety of a drug

Ratio of dose producing toxicity to dose needed toRatio of dose producing toxicity to dose needed toproduce desired therapeutic responseproduce desired therapeutic response

__________________________________________________________

Common method used to derive TI is to use ____Common method used to derive TI is to use ____%%dose-response pointsdose-response points  

Therapeutic IndexTherapeutic Index

For example, if LD50 is 200 and ED50 is 20 mg,For example, if LD50 is 200 and ED50 is 20 mg,the TI would be ____ the TI would be ____ (____/____)(____/____)

The larger the therapeutic index, the _______The larger the therapeutic index, the _______the drug.the drug. Some drugs have a low therapeutic index, e.g.,Some drugs have a low therapeutic index, e.g.,

DigoxinDigoxin Others have a high therapeutic index, e.g., Others have a high therapeutic index, e.g., NaloxoneNaloxone

18

Therapeutic Index & Margin ofTherapeutic Index & Margin ofSafetySafety

Use of the EDUse of the ED5050 and LD and LD5050 doses to derive the doses to derive the TI TI may bemay bemisleading as to safety, depending on slope of dose-responsemisleading as to safety, depending on slope of dose-responsecurves for therapeutic and lethal effectscurves for therapeutic and lethal effects

To overcome this deficiency, toxicologists often use anotherTo overcome this deficiency, toxicologists often use anotherterm to denote safety of drugterm to denote safety of drug——MarginMargin of Safetyof Safety (MOS)(MOS)

MOSMOS = ratio of dose that is just within the lethal range (LD= ratio of dose that is just within the lethal range (LD0101) to) tothe dose that is 99% effective (EDthe dose that is 99% effective (ED9999)) MOS =MOS =   LD LD0101/ED/ED9999

Physician must use caution in prescribing a drug in which MOSPhysician must use caution in prescribing a drug in which MOSis < 1is < 1

19

BISC 312BISC 312Environmental Toxicology IEnvironmental Toxicology I

TOXICITY AND TOXICITYTOXICITY AND TOXICITYTESTINGTESTING

Toxic EffectsToxic Effects

Toxicity can result from adverse cellular, biochemical, orToxicity can result from adverse cellular, biochemical, ormacromolecular changes.macromolecular changes.   Examples are: Examples are:

cell replacement, such as fibrosiscell replacement, such as fibrosis

damage to an enzyme systemdamage to an enzyme system

disruption of protein synthesisdisruption of protein synthesis

production of reactive chemicals in cellsproduction of reactive chemicals in cells

DNA damageDNA damage

interference with nutritioninterference with nutrition

20

Toxicity Depends UponToxicity Depends Upon…… The toxicity of a substance depends on the following:The toxicity of a substance depends on the following:

form and innate chemical activityform and innate chemical activity

dosage, especially dose-time relationshipdosage, especially dose-time relationship

exposure routeexposure route

speciesspecies

ageage

sexsex

metabolismmetabolism

ability to be absorbedability to be absorbed

excretionexcretion

distribution within the bodydistribution within the body

presence of other chemicalspresence of other chemicals

FormForm The formThe form of a substance may have a profoundof a substance may have a profound

impact on its toxicity especially for metallicimpact on its toxicity especially for metallicelements.elements.   For example: For example:

21

Innate Chemical ActivityInnate Chemical Activity

Innate chemical activityInnate chemical activity of substances also variesof substances also variesgreatly.greatly.   Some can quickly damage cells causing Some can quickly damage cells causingimmediate cell death.immediate cell death.   Others slowly interfere only with Others slowly interfere only witha cell's function.a cell's function.   For example: For example:

nicotine binds to cholinergic receptors in the CNS alteringnicotine binds to cholinergic receptors in the CNS alteringnerve conduction and inducing gradual onset of paralysisnerve conduction and inducing gradual onset of paralysis

AgeAge

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

22

SexSex

Although uncommon, toxic responses can varyAlthough uncommon, toxic responses can varydepending on sex.depending on sex.   Examples are: Examples are:

MetabolismMetabolism

Metabolism, also known as biotransformation, is a major factorMetabolism, also known as biotransformation, is a major factorin determining toxicityin determining toxicity

The products of metabolism are known as ______________The products of metabolism are known as ______________  

There are two types of metabolism - detoxification andThere are two types of metabolism - detoxification andbioactivationbioactivation::   DetoxificationDetoxification——process by which process by which xenobioticxenobiotic is converted to is converted to

__________________.__________________.   This is a natural defense mechanism of the This is a natural defense mechanism of theorganism.organism.   Generally the detoxification process converts lipid-soluble Generally the detoxification process converts lipid-solublecompounds to polar compounds.compounds to polar compounds.  

BioactivationBioactivation——process by which a process by which a xenobioticxenobiotic may be converted to may be converted to____________________________________.____________________________________.

23

ExcretionExcretion Site and rate of excretionSite and rate of excretion is another major factor affecting theis another major factor affecting the

toxicity of a toxicity of a xenobioticxenobiotic  

Kidney is the primary excretory organ, followed by theKidney is the primary excretory organ, followed by thegastrointestinal tract, and the lungs gastrointestinal tract, and the lungs (for gases)(for gases)  

XenobioticsXenobiotics may also be excreted in sweat, tears and milk may also be excreted in sweat, tears and milk

Lipid-soluble toxicants are reabsorbed and concentrated inLipid-soluble toxicants are reabsorbed and concentrated inkidney cellskidney cells

Impaired kidney function causes slower elimination of toxicantsImpaired kidney function causes slower elimination of toxicantsand increases their toxic potentialand increases their toxic potential

Presence of other ChemicalsPresence of other Chemicals

Presence of other chemicals may decrease, addPresence of other chemicals may decrease, addto or increase toxicityto or increase toxicity of some of some xenobioticsxenobiotics  

There are four basic types of interactions:There are four basic types of interactions:  

24

AdditivityAdditivity

Toxicity of the mixture will be approximatelyToxicity of the mixture will be approximatelythe summation of the toxicity of the individualthe summation of the toxicity of the individualtoxicantstoxicants

Toxicants that share a common mechanismToxicants that share a common mechanism 1+1=21+1=2 Example:Example:

AntagonismAntagonism

Occurs when one chemical inhibits the action ofOccurs when one chemical inhibits the action ofanotheranother

2+2=12+2=1 AntidotesAntidotes Example:Example:

NaNONaNO22 used to treat used to treat NaCNNaCN poisoning poisoning DimercaprolDimercaprol (BAL) (BAL) chelateschelates metal ions (e.g., metal ions (e.g.,

mercury, arsenic, lead)mercury, arsenic, lead)

25

PotentiationPotentiation

Occurs when one substance does have a toxicOccurs when one substance does have a toxiceffect but when mixed with another chemicaleffect but when mixed with another chemicalmakes that chemical much more toxicmakes that chemical much more toxic

0+2=200+2=20 Example:Example:

SynergismSynergism

Occurs when the combined effect of 2Occurs when the combined effect of 2chemicals is much greater than the sum ofchemicals is much greater than the sum ofeffects of each chemical aloneeffects of each chemical alone

2+2=202+2=20 Example:Example:

26

Presence of other ChemicalsPresence of other Chemicals

This table quantitatively illustrates the percent of the population affected byThis table quantitatively illustrates the percent of the population affected byindividual exposure to chemical A and chemical B as well as exposure to theindividual exposure to chemical A and chemical B as well as exposure to thecombination of chemical A and chemical B.combination of chemical A and chemical B.   It also gives the specific type of It also gives the specific type ofinteraction:interaction: