Principles of Toxicology: Part B

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 Disrupting Compounds

Raging Hormones

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)

Hormones and Function – I

Hormones and Function – II

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

Hormone Systems We KnowCan Be Affected

Endocrine Disruptors: Phytoestrogens

ThyroidThyroid controls metabolism; the gas pedal

of physiology

Thyroid diseaseHyperthyroid

ThinHotGraves disease

HypothyroidWeight gain and lethargy

Perchlorate toxicityCompetes with iodine for uptake in the

thyroid

You’ve got Some Nerve

The Structure of Nerves

Mechanism of Action

Clinical Features (Acute Toxicity)

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

OP poisoning

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

The Process of Cancer

Carcinogenesis

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

The Cell Cycle

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

Persistence and Bioaccumulation

Know When to Leave the Party

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

Example: Parathion

Bioaccumulation

I’ve had enough!

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

Biomagnification

Organ-specific toxicityLiverKidneyLungHeartImmune system SkinEye

Non-organ specific toxicityBlood and lymphMembranesGenetic toxicityDevelopmental toxicity

Ecological ToxicologyAquatic toxicologyAvian ToxicologyWildlife ToxicologyPhytotoxicity

Venoms and poisonsSnakes and other reptiles

Usually proteinsArthropods

Scorpions and spiders, etc..Plants

Dermatitis (poison Ivy)Systemic effects

Ricin form castor beans; cardiac glycosidesNicotine

RadioactivitySpecial mechanisms of toxicityInvolves energy changes to living systems

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.