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Principles of Toxicology: Part B
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Topics for Principles of Toxicology: Part B
Endocrine Toxicity Carcinogenicity Neurotoxicity Persistence and Bioaccumulation The topics for “Part C” (what we could not cover) Summary
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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.
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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.”
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Endocrine Disrupting Compounds
Raging Hormones Endocrine Disrupting Compounds
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Endocrine System The 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”
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Introduction - EDC 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 Colborn T, vom Saal FS, Soto AM (EHP, 101(5) October 1993).
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Hormones are chemical signals
which regulate almost every biological process: Growth and development Mental development, mood, memory Sexual maturation Immune function
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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
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Many studies link EDCs to:
Reproductive disorders Immune system dysfunction Certain cancers, especially of reproductive organs Birth defects of the penis and falling sperm counts Neurological effects Attention deficit disorder and poor memory Low IQ
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EDCs have many names Environmental estrogens Hormone mimic
Xenoestrogens Anti-androgens Phytoestrogens Endocrine-disruptors Endocrine-active compounds Generically, Endocrine Disrupting Chemicals (EDCs)
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Hormones and Function – I
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Hormones and Function – II
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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.
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Disruption of the ES The 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.
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Hormones are released by the glands
And 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
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Endocrine Disrupting Chemicals
Are natural or man-made compounds Which fit into hormone receptors Blocking the normal hormone, or Acting instead of the normal hormone, in an irregular manner
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Early development is crucial
A particular signal blocked during early pregnancy can affect both children and adults
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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.
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Known sources of EDCs Ordinary 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 metals Arsenic Lead Cadmium Mercury
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Chemicals - EDCs Hormones (natural & synthetic) Plant constituents
Pesticides compounds used in the plastics industry and in consumer products other industrial by-products and pollutants
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Hormone Systems We Know Can Be Affected
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Endocrine Disruptors: Phytoestrogens
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Thyroid Thyroid controls metabolism; the gas pedal of physiology
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Thyroid disease Hyperthyroid Hypothyroid Perchlorate toxicity Thin Hot
Graves disease Hypothyroid Weight gain and lethargy Perchlorate toxicity Competes with iodine for uptake in the thyroid
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You’ve got Some Nerve
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The Structure of Nerves
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Mechanism of Action
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Clinical Features (Acute Toxicity)
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Neurotoxicity Neuropathy Axonopathy Myelinopathies
Loss of a neuron is irreversible Ethanol, lead, Mn, As, Hg Axonopathy Specific to axon and myelin Hexane dione, acrylamide, Au Myelinopathies Lead Neurotransmitter Interference Amphetamines, nicotine muscarine, domoic acid
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OP poisoning
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Alternate sites for antidotes
Protect AChE Supply AChE Reduce ACh Protect ACh Receptor Reduce OP Load Multiple Mechanisms
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What if you give too much Atropine
Anticholinergic Syndrome: Hot as hell Blind as a bat Red as a beet Dry as a bone Mad as a hatter A sensitive indicator for ingestion, but poor predictor for toxicity. Full syndrome is rare
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Solvents Large class of volatile, lipophilic compounds
Uses 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 solvents Now more than 350
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Toxicity of Solvents Quite complex and can span the spectrum of adverse effects Determined by structure and route of exposure Well absorbed by all routes, primarily lung Most solvents must be metabolized to act Narcosis is the exception Exposure to most often to a mixture of solvents additives synergistic antagonistic
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Green solvents Less volatile Less toxic Less global concern
Focus on volatile-heavy industries Automotive Paint Cosmetics Example-Sherwin Williams Soy bean oil and recycled PET
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Carcinogenesis The Process of Cancer
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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 growth Can be benign or malignant
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Definitions Benign Malignant Non invasive Rare mitoses Slow growth
No metastsis Malignant Invasive Common mitosis\rapid growth metastasis
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Definitions Mutagenesis: the process is fundamentally changing DNA
Germ cells (egg/sperm) : heritable change Somatic cells no heritable change Mutagen: causes an increase in the rate of mutagenesis Mitogenesis : induction of mitosis Metastasis: spreading to distant site Clastogenesis: breaking or rearranging of chromsomes
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Background rates Approximately .22 – .33 from no discernable cause (natural background) Exogenous cancer rate: unknown Vulnerable periods In utero Early life stages (development) Industrial setting
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The Cell Cycle
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Stages of Carcinogenesis
Initiation Act directly or indirectly at the level of DNA Electrophilic species Do not induce carcinogenesis alone Irreversible Requires interaction w/promotors for carcinogenesis Fate Remain static Deleted through apoptosis High enough dose may allow for complete carcinogenesis
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Stages of Carcinogenesis
Promotion Do not induce cancer alone Reversible Clonal expansion Requires repeated exposures Tumor promotors are generally organ specific
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Stages of Carcinogenesis
Progression Ill defined stages from benign to malignant tumors Likely a multi-step process involving Oncogene activation Chromosomal aberration Estimates range from 3 to 7 steps or “hits” Conversion of preneoplastic cells to neoplatic cells
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Co-Carcinogens Are the agents that enhance the overall process of carcinogenesis to genotoxic agents Possible mechanisms Increased uptake or availability of a xenobiotic
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Known or suspected cancer mechanisms
Hormone production or function Compound that interfere with the production or function of the endocrine system EDCs affect early puberty and estrogen dependent cancers Inflammation DNA damage (genotoxic) Radiation Chemical Damage to repair systems Epigenetic Do not act at the level of DNA Immune System deficits
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Types of carcinogen mechanisms
Genotoxic Epigenetic Damages DNA Directly ( no metab req.) Indirectly (metab req.) Radiation and oxicdation Inorganic chemicals Do not alter DNA After the expression of certain genes that regulate Proliferation Differentiation apoptosis
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DNA Repair mechanisms Base excision repair Nucleotide excision repair
Removes bases with large bulky groups Recombinatorial repair Mismatch repair Repairs mistakes on both strands of DNA
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Oncogenes Genes that stimulate the transformation of normal cells into cancer cells Tumor suppression genes Inhibition causes expression and proliferation of cell growth
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Summary Cancer is a complex disease involving biology and chemistry
Excellent example of systems biology Carcinogens can be classified in several ways Organ affected Chemical class (PAH, electrophiles, metals nitrosamines or state (physical, chemical or biological) Many processes must act together, in the correct order
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Know When to Leave the Party
Persistence and Bioaccumulation
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Persistence Is a measure of the stability of a compound, either in the environment and/or in nature Measured using half lives and other chemodynamic parameters Pseudopersistence: when input is constant; for example sewage outfalls and PPCPs
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Chemical kinetics Describes the rates of reactions
Rates are determined by Frequency of collisions Concentration Time Pressure The likelihood that the collision will result in a product Rates are often complex RDS
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First order reactions Most common in organisms and environmental conditions Rate is dependent upon the number of particles present Represented by the Rate Constant, k Determined experimentally Half Life T ½ = 0.693/k
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Influences of Persistence
Molecular structure and size Hydrophobicity Lipophilicity Presence of microorganisms
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Processes of persistence
Hydrolysis Photolysis Volatilization Dissociation Redox Biotic Aerobic and anaerobic degradation
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Biodegradation Is microbially mediated
Is an essential component of all environmental cycles Ultimately results in CO2 and H20 (mineralization Important in treatment systems
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Regulatory use of persistence
PBT criteria Environmental half-lives are determined Persistence – 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 Treatment Pesticide application and permitting Risk Assessment
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Example: Parathion
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Bioaccumulation I’ve had enough!
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Bioaccumulation When organisms take up and store xenobiotics at a greater rate than they excrete them, then bioaccumulation occurs If the only source is water, then the same phenomenon is termed bioconcentration Must characterize Nature of exposure Route Bioavailability Nature of kinetic processes
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The process of bioaccumulation
Are generally thermodynamic processes that are diffusion driven Lipophilicity is the primary factor in most bioaccumulative processes K = concentration in lipid/concentration in water Usually the organic is n-octanol Kow is used as the equilibrium constant
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Examples of the range of Kow for organic compounds
Chemical/Class Kow PAHs Halogenated aliphatic hydrocarbons Chlorinated ethers 103 – 104 Organic pesticides PCDD/PCDF (dioxins and furans) Methyl mercury 2
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Biomagnification
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Organ-specific toxicity
Liver Kidney Lung Heart Immune system Skin Eye
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Non-organ specific toxicity
Blood and lymph Membranes Genetic toxicity Developmental toxicity
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Ecological Toxicology
Aquatic toxicology Avian Toxicology Wildlife Toxicology Phytotoxicity
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Venoms and poisons Snakes and other reptiles Arthropods Plants
Usually proteins Arthropods Scorpions and spiders, etc.. Plants Dermatitis (poison Ivy) Systemic effects Ricin form castor beans; cardiac glycosides Nicotine
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Radioactivity Special mechanisms of toxicity
Involves energy changes to living systems
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Summary of Part B Toxicology draws on a number of fundamental and allied scientific disciplines The complexity of life is revealed in studying and discovering its secrets Toxicology informs other disciplines; medicine, physiology, biochemistry Toxicology is an evolving science becoming more thrilling each day.
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