Post on 29-Dec-2015
Topics for Principles of Toxicology: Part BEndocrine ToxicityCarcinogenicityNeurotoxicityPersistence and BioaccumulationThe topics for “Part C” (what we could not
cover)Summary
The systemic problem“Many compounds introduced into the
environment by human activity are capable of disrupting the endocrine
system of animals, including fish, wildlife, and humans. The
consequences of such disruption can be profound. . .”
- From the consensus statement of the inter-disciplinary scientists who met at
Wingspread Conference in July 1991.
Rachel Carson – Silent Spring (1962)
“As crude a weapon as a cave man’s club, the chemical barrage has been hurled against the fabric of life.”
“The “control of nature” is a phrase conceived in arrogance, born of the Neanderthal age of biology and the convenience of man.”
Endocrine SystemThe endocrine system is the body’s
chemical communication system, using the blood vessels to move chemicals throughout the body to communicate will different cells of the body. The endocrine system regulates metabolism, growth, development and puberty, and organ function.
An endocrine disruptor is “an exogenous agent that interferes with the synthesis, secretion, transport, metabolism, binding or elimination of hormones that are responsible for homeostasis, reproduction and developmental processes”
Introduction - EDC 1991 - endocrine disruptor first used
at a conference at the Wingspread Conference Center in Racine, Wisconsin. This conference was chaired by Theo Colburn,
The term was introduced into the scientific literature in 1993. Colborn T, vom Saal FS, Soto AM (EHP, 101(5) October 1993).
Hormones are chemical signals which regulate almost every biological
process:Growth and developmentMental development, mood, memorySexual maturationImmune function
Health Effects - EDCs reproductive issues reduced fertility male and female reproductive tract
abnormalities skewed male/female sex ratios
changes in hormone levels early puberty brain and behavior problems impaired immune functions various cancers
Many studies link EDCs to:Reproductive disordersImmune system dysfunctionCertain cancers, especially of reproductive
organsBirth defects of the penis and falling sperm
countsNeurological effectsAttention deficit disorder and poor memoryLow IQ
EDCs have many namesEnvironmental
estrogensHormone mimicXenoestrogensAnti-androgens
Phytoestrogens Endocrine-
disruptorsEndocrine-active
compoundsGenerically,
Endocrine Disrupting Chemicals (EDCs)
Receptors Cell surface receptors (membrane receptors,
transmembrane receptors) are specialized integral membrane proteins that take part in communication between the cell and the outside world. Extracellular signaling molecules (usually hormones, neurotransmitters, cytokines, growth factors or cell recognition molecules) attach to the receptor, triggering changes in the function of the cell.
Disruption of the ESThe Endocrine System may be
disrupted in one of three ways:
A substance may imitate a natural hormone and lock onto a receptor within the cell.
A substance can bind to a receptor within a cell and
thus prevent the correct hormone from binding.
The disruptors can interfere or block the way natural hormones and receptors are made or controlled.
Hormones are released by the glandsAnd travel through
the blood until they reach their particular receptor cell
Where they fit, like a key in a lock, to turn on or off functions
Endocrine Disrupting Chemicals Are natural or man-
made compoundsWhich fit into
hormone receptors Blocking the
normal hormone, orActing instead of
the normal hormone, in an irregular manner
Early development is crucial A particular signal blocked during early pregnancy can
affect both children and adults
Known sources of EDCs Pesticides, herbicides, insecticides, fungicides, persistent and
non-persistent, new and old, from DDT to tributyltin (TBT) Leaching from most plastic products, especially the phthalates
used to make plastics and stabilize them so they do not break down in sunlight
Drugs such as birth control pills, DES, and cimetidine, especially in sewage water
DES, diethylibestrol, given to mothers to prevent morning sickness, caused genital cancers in their children 20 years later.
Known sources of EDCsOrdinary household products, such as the
nonylphenols added to detergents and soaps Commercial cleaners
Added to pesticides and detergents as a “surfactant” to make the chemical work better in water, NP is one of the agents suspected of changing the
sex of fish in rivers around the world.Industrial chemicals such as polychlorinated
biphenyls (PCBs), dioxins, and polyaromatic hydrocarbons (PAHs).
Heavy metalsArsenicLead Cadmium Mercury
Chemicals - EDCs Hormones (natural & synthetic) Plant constituents Pesticides compounds used in the plastics
industry and in consumer products other industrial by-products and
pollutants
Thyroid diseaseHyperthyroid
ThinHotGraves disease
HypothyroidWeight gain and lethargy
Perchlorate toxicityCompetes with iodine for uptake in the
thyroid
NeurotoxicityNeuropathy
Loss of a neuron is irreversibleEthanol, lead, Mn, As, Hg
AxonopathySpecific to axon and myelinHexane dione, acrylamide, Au
MyelinopathiesLead
Neurotransmitter InterferenceAmphetamines, nicotine muscarine, domoic
acid
Alternate sites for antidotes• Protect AChE• Supply AChE• Reduce ACh • Protect ACh Receptor• Reduce OP Load• Multiple Mechanisms
What if you give too much AtropineAnticholinergic Syndrome:
Hot as hellBlind as a batRed as a beetDry as a boneMad as a hatter
A sensitive indicator for ingestion, but poor predictor for toxicity.
Full syndrome is rare
SolventsLarge class of volatile, lipophilic compoundsUses in paints, glues and adhesives, nail
polish and other cosmetics, chemical synthesis and analytical chemistry
Many solvents are part of complex mixtures (fuels)Early 20th C-12 solventsNow more than 350
Toxicity of SolventsQuite complex and can span the spectrum
of adverse effectsDetermined by structure and route of
exposureWell absorbed by all routes, primarily lungMost solvents must be metabolized to act
Narcosis is the exception
Exposure to most often to a mixture of solventsadditives synergisticantagonistic
Green solventsLess volatileLess toxicLess global concernFocus on volatile-heavy industries
AutomotivePaintCosmetics
Example-Sherwin WilliamsSoy bean oil and recycled PET
Definitions
Carcinogenesis the process of increased cancer incidence or decrease in time to tumor. Most cancers are monoclonal (derived from one cell)
Cancer: a subset of lesions that increase neoplasia
Neoplasm: a new growth; can be benign or malignant
Tumor: Space occupying growthCan be benign or malignant
Definitions
BenignNon invasiveRare mitosesSlow growthNo metastsis
MalignantInvasiveCommon mitosis\
rapid growthmetastasis
DefinitionsMutagenesis: the process is fundamentally
changing DNAGerm cells (egg/sperm) : heritable changeSomatic cells no heritable change
Mutagen: causes an increase in the rate of mutagenesis
Mitogenesis : induction of mitosisMetastasis: spreading to distant siteClastogenesis: breaking or rearranging of
chromsomes
Background ratesApproximately .22 – .33 from no
discernable cause (natural background)Exogenous cancer rate: unknownVulnerable periods
In uteroEarly life stages (development)Industrial setting
Stages of CarcinogenesisInitiation
Act directly or indirectly at the level of DNAElectrophilic species
Do not induce carcinogenesis alone IrreversibleRequires interaction w/promotors for
carcinogenesisFate
o Remain statico Deleted through apoptosiso High enough dose may allow for complete
carcinogenesis
Stages of CarcinogenesisPromotion
Do not induce cancer alone ReversibleClonal expansionRequires repeated exposuresTumor promotors are generally organ specific
Stages of CarcinogenesisProgression
Ill defined stages from benign to malignant tumors
Likely a multi-step process involvingOncogene activationChromosomal aberration
Estimates range from 3 to 7 steps or “hits”Conversion of preneoplastic cells to neoplatic
cells
Co-CarcinogensAre the agents that enhance the overall
process of carcinogenesis to genotoxic agents
Possible mechanismsIncreased uptake or availability of a
xenobiotic
Known or suspected cancer mechanismsHormone production or function
Compound that interfere with the production or function of the endocrine systemEDCs affect early puberty and estrogen dependent cancers
InflammationDNA damage (genotoxic)
RadiationChemical
Damage to repair systems
EpigeneticDo not act at the level of DNA
Immune System deficits
Types of carcinogen mechanisms
Genotoxic Epigenetic
Damages DNADirectly ( no metab
req.)Indirectly (metab
req.)Radiation and
oxicdationInorganic
chemicals
Do not alter DNAAfter the
expression of certain genes that regulateProliferationDifferentiationapoptosis
DNA Repair mechanismsBase excision repairNucleotide excision repair
Removes bases with large bulky groups
Recombinatorial repairMismatch repair
Repairs mistakes on both strands of DNA
OncogenesGenes that stimulate the transformation of
normal cells into cancer cellsTumor suppression genes
Inhibition causes expression and proliferation of cell growth
SummaryCancer is a complex disease involving
biology and chemistryExcellent example of systems biology
Carcinogens can be classified in several waysOrgan affectedChemical class (PAH, electrophiles, metals
nitrosaminesor state (physical, chemical or biological)
Many processes must act together, in the correct order
PersistenceIs a measure of the stability of a compound,
either in the environment and/or in natureMeasured using half lives and other
chemodynamic parametersPseudopersistence: when input is constant;
for example sewage outfalls and PPCPs
Chemical kineticsDescribes the rates of reactionsRates are determined by
Frequency of collisionsConcentrationTimePressure
The likelihood that the collision will result in a product
Rates are often complexRDS
First order reactionsMost common in organisms and
environmental conditionsRate is dependent upon the number of
particles presentRepresented by the Rate Constant, k
Determined experimentallyHalf Life
T ½ = 0.693/k
Influences of PersistenceMolecular structure and sizeHydrophobicityLipophilicityPresence of microorganisms
Processes of persistenceHydrolysisPhotolysisVolatilizationDissociationRedoxBiotic
Aerobic and anaerobic degradation
BiodegradationIs microbially mediatedIs an essential component of all
environmental cyclesUltimately results in CO2 and H20
(mineralizationImportant in treatment systems
Regulatory use of persistencePBT criteria
Environmental half-lives are determinedPersistence
– the half-life in marine water is higher than 60 days, or– the half-life in fresh- or estuarine water is higher than 40 days, or – the half-life in marine sediment is higher than 180 days, or– the half-life in fresh- or estuarine water sediment is higher than 120 days, or– the half-life in soil is higher than 120 days.
Wastewater TreatmentPesticide application and permittingRisk Assessment
BioaccumulationWhen organisms take up and store
xenobiotics at a greater rate than they excrete them, then bioaccumulation occursIf the only source is water, then the same
phenomenon is termed bioconcentrationMust characterize
Nature of exposureRouteBioavailability
Nature of kinetic processes
The process of bioaccumulationAre generally thermodynamic processes
that are diffusion drivenLipophilicity is the primary factor in most
bioaccumulative processesK = concentration in lipid/concentration in
waterUsually the organic is n-octanol
Kow is used as the equilibrium constant
Examples of the range of Kow for organic compoundsChemical/Class Kow
PAHs 103 - 107
Halogenated aliphatic hydrocarbons
101 - 103
Chlorinated ethers 103 – 104
Organic pesticides 100 - 1010
PCDD/PCDF (dioxins and furans) 10 6 - 10 10
Methyl mercury 2
Venoms and poisonsSnakes and other reptiles
Usually proteinsArthropods
Scorpions and spiders, etc..Plants
Dermatitis (poison Ivy)Systemic effects
Ricin form castor beans; cardiac glycosidesNicotine
Summary of Part BToxicology draws on a number of
fundamental and allied scientific disciplinesThe complexity of life is revealed in
studying and discovering its secretsToxicology informs other disciplines;
medicine, physiology, biochemistryToxicology is an evolving science becoming
more thrilling each day.