Current and Emerging Current and Emerging Paradigms Paradigms

in in Environmental ToxicologyEnvironmental Toxicology

Lecture 2Lecture 2

Understanding the three basic functions Understanding the three basic functions in environmental toxicologyin environmental toxicology

1.1. Interaction of toxicant (xenobiotic) with the environmentInteraction of toxicant (xenobiotic) with the environment Determines amount (dose) of toxicant available to living organismsDetermines amount (dose) of toxicant available to living organisms Time componentTime component

2.2. Interaction of toxicant with site of actionInteraction of toxicant with site of action Usually receptor on/in a cellUsually receptor on/in a cell Receptor often a cell proteinReceptor often a cell protein

3.3. Interaction of toxicant at the molecular level, leading to all Interaction of toxicant at the molecular level, leading to all higher level ecological effectshigher level ecological effects

Line from molecular to ecological effects is poorly understoodLine from molecular to ecological effects is poorly understood

Note: see Figure 2.1Note: see Figure 2.1Note: f(letter) = function of process indicated by letterNote: f(letter) = function of process indicated by letter

Classification of toxicological effectsClassification of toxicological effects

Chemical/physical-chemical characteristicsChemical/physical-chemical characteristics Bioaccumulation/biotransformation/biodegradationBioaccumulation/biotransformation/biodegradation Site of actionSite of action Biochemical monitoringBiochemical monitoring Physiological and behavioral effectsPhysiological and behavioral effects Population parametersPopulation parameters Community parametersCommunity parameters Ecosystem effectsEcosystem effects

Chemical/Physical-Chemical Chemical/Physical-Chemical CharacteristicsCharacteristics

Interactions of xenobiotic compound with Interactions of xenobiotic compound with biological compounds determines toxicitybiological compounds determines toxicity

The degree of effect that is due to the The degree of effect that is due to the physico-chemical characteristics of the physico-chemical characteristics of the compound is called the Structure-Activity compound is called the Structure-Activity Relationship (QSAR).Relationship (QSAR).

Has potential for allowing prediction of Has potential for allowing prediction of toxic effects based only on structure of toxic effects based only on structure of xenobiotic.xenobiotic.

Could save lots of time, money, effort Could save lots of time, money, effort while allowing a greater degree of while allowing a greater degree of protectionprotection

Bioaccumulation/BiotransformationBioaccumulation/Biotransformation/Biodegradation/Biodegradation

Many things can happen to chemical between Many things can happen to chemical between release to environment and arrival at the biological release to environment and arrival at the biological site of actionsite of action

1.1. BioaccumulationBioaccumulation – increase in concentration of – increase in concentration of chemical in tissue relative to concentration in chemical in tissue relative to concentration in environmentenvironment

More likely in lipid solubule/lipophilicsMore likely in lipid solubule/lipophilics

2.2. BiotransformationBiotransformation – chemical change in toxicant caused – chemical change in toxicant caused by biological tissue by biological tissue

May decrease [usually] or increase toxicityMay decrease [usually] or increase toxicity

3.3. BiodegradationBiodegradation – breakdown of a xenobiotic into a – breakdown of a xenobiotic into a simpler chemical formsimpler chemical form

Could be the result of biotransformationCould be the result of biotransformation All above processes dependent on site specific All above processes dependent on site specific

conditions so direction and degree hard to predict conditions so direction and degree hard to predict

Receptor (site) and Mode of ActionReceptor (site) and Mode of Action

Active site extremely important on Active site extremely important on determining mode of actiondetermining mode of action May cause very specific or very general effectMay cause very specific or very general effect

Active site may be on specific nucleic acids, Active site may be on specific nucleic acids, enzymes, cell membranes or non-specificenzymes, cell membranes or non-specific

Covered much more in Xenobiotic Covered much more in Xenobiotic Metabolism part of courseMetabolism part of course

Biochemical/Molecular EffectsBiochemical/Molecular Effects

Broad range of possible effectsBroad range of possible effects

Could be general (ex. general effect on DNA) Could be general (ex. general effect on DNA) or specific (ex. effect of specific portion of or specific (ex. effect of specific portion of DNA)DNA)

Includes effects on chromosomes, enzyme Includes effects on chromosomes, enzyme systems, immunological system, etc.systems, immunological system, etc.

Physiological and BehavioralPhysiological and Behavioral

Biochemical/molecular effects manifested at higher Biochemical/molecular effects manifested at higher organismal levelorganismal level

Classical means by which population health is Classical means by which population health is assessedassessed

Major drawback Major drawback extrapolation from individual extrapolation from individual effect to population and ultimately ecosystem effecteffect to population and ultimately ecosystem effect

Can include pathology, oncogenesis, reproduction, Can include pathology, oncogenesis, reproduction, mortalitymortality, osmo- and ionoregulation, behaviors (fish , osmo- and ionoregulation, behaviors (fish respiration, cough response), temperature preference, respiration, cough response), temperature preference, predator avoidance or prey detectionpredator avoidance or prey detection

Population effectsPopulation effects

Suitable for both field and laboratory Suitable for both field and laboratory evaluationsevaluations

Well-developed protocolsWell-developed protocols Population size, density, age-structure, Population size, density, age-structure,

cycling, growth rate, geneticscycling, growth rate, genetics

Community effectsCommunity effects Evaluation of community structure extensively used in field Evaluation of community structure extensively used in field

studiesstudies Many indices developed to quantify species compositionMany indices developed to quantify species composition Most widely used Most widely used species diversity (biodiversity) species diversity (biodiversity)

Most dramatic impact that can be observedMost dramatic impact that can be observed Decrease in species diversity usually = impact but sometimes reverse is Decrease in species diversity usually = impact but sometimes reverse is

truetrue Diversity can be misleading Diversity can be misleading can have same diversity after exposure can have same diversity after exposure

but be the result of a completely different set of speciesbut be the result of a completely different set of species

Note: most of what we call communities are really assemblages Note: most of what we call communities are really assemblages because we do not understand most of the interactions among because we do not understand most of the interactions among populations in a “community”populations in a “community”

Ecosystem effectsEcosystem effects

Most ecosystem-level changes indicate a Most ecosystem-level changes indicate a serious problemserious problem

Variables measured can include metabolism Variables measured can include metabolism (energy capture, flow, loss), net productivity (energy capture, flow, loss), net productivity (gross productivity – respiration), biomass (gross productivity – respiration), biomass accumulation, rate of detrital breakdown, accumulation, rate of detrital breakdown, landscape alteration, species distribution, landscape alteration, species distribution, chemistrychemistry

Evaluation of effects must be Evaluation of effects must be system-specificsystem-specific

Ecosystem effectsEcosystem effects

Most environmental regulations aimed at Most environmental regulations aimed at protecting ecosystem structure and function protecting ecosystem structure and function but these are rarely measured when but these are rarely measured when determining compliancedetermining compliance

Complexity theoryComplexity theory Alternative to previous “classical) approach to Alternative to previous “classical) approach to

environmental toxicologyenvironmental toxicology Based on differences between organisms and Based on differences between organisms and

ecosystemsecosystems Organisms – genetic structure is retained in all cells Organisms – genetic structure is retained in all cells

(redundant) and designed to maintain homeostasis --> most (redundant) and designed to maintain homeostasis --> most impacts not passed on to future generationsimpacts not passed on to future generations

Ecosystems – no central repository of information like Ecosystems – no central repository of information like genomegenome

History of past events written into ecosystem structure and History of past events written into ecosystem structure and function, nature of interactions function, nature of interactions high complexity and high complexity and non-linear relationshipsnon-linear relationships

Properties of Complex, Non-linear Properties of Complex, Non-linear StructuresStructures

Exhibit both deterministic and stochastic propertiesExhibit both deterministic and stochastic properties Causes and effects of events experienced by systems Causes and effects of events experienced by systems

are not proportionalare not proportional Different parts are linked and affect one another Different parts are linked and affect one another

synergisticallysynergistically Can undergo irreversible processes (because no Can undergo irreversible processes (because no

system “memory”)system “memory”) Dynamic (not in equilibrium)Dynamic (not in equilibrium) Note: above properties may be useful in extrapolating Note: above properties may be useful in extrapolating

toxicity test results on to highly variable ecosystemstoxicity test results on to highly variable ecosystems

Spatial and Temporal ScalesSpatial and Temporal Scales

All previous functions vary over spatial and temporal All previous functions vary over spatial and temporal scalesscales

May appear disconnected but never areMay appear disconnected but never are Usually smaller spatial scale operates at a shorter Usually smaller spatial scale operates at a shorter

temporal scale because of inherent differences when temporal scale because of inherent differences when considering atom-level effects to ecosystem level considering atom-level effects to ecosystem level effects (see Figure 2.4)effects (see Figure 2.4)

Type of environmental problem will be a function of Type of environmental problem will be a function of spatial and temporal scale (see Figure 2.5)spatial and temporal scale (see Figure 2.5)

Wednesday – Intro to toxicity testingWednesday – Intro to toxicity testing