Toxicology Final

Liver functions

Storage, metabolism, biosynthesis

Hepatotoxicity

The liver often the target of chemicals due to its function; Gastrointestinal exposure results in first pass metabolism in the liver; Reactive metabolites may cause local toxicity

Fatty liver disease

Abnormal accumulation of lipids in the liver; many possible mechanisms; interference with protein synthesis; impaired conjugation of triglycerides; decrease synthesis of phospholipids

Necrosis

Degeneration of hepatocytes; accumulation of unsaturated lipids; membrane destruction; disturbance of ionic homeostasis

Apoptosis

Controlled form of cell death; natural process that can be activated by chemicals; or can be suppressed resulting in unwanted cell proliferation

Cholestasis

Suppression or stoppage of bile flow; can result from inflammation or membrane damage

Cirrhosis

Progressive deposition of collagen/fibrous material, restricting blood flow; results from chronic chemical exposure

Hepatitis

Inflammation of liver usually caused by viral infection; can be induced in rare cases by chemicals

Carbon tetrachloride

A hepatotoxicant; solvent used in a number of historical applications; forms reactive metabolites; causes necrosis and membrane damage in liver

Ethanol

A hepatotoxicant; consumed in beer, wine, and spirits; excess consumption known to result in liver damage; interferes with lipid metabolism, caused inflammation and necrosis

Acetaminophen

A hepatotoxicant; over the counter analgesic; CYPs can cause the reactive metabolites; as glutathione is depleted, liver damage results

Kidney function

Elimination of waste products; particularly polar toxicants

Factors affecting the susceptibility of the kidney to toxicants

High renal blood flow; concentration of plasma in the kidneys may increase toxicity; reabsorption and secretion of chemicals; creation of reactive metabolites

Cadmium, Lead, Mercury, Uranium (metals)

Nephrotoxicants; readily taken up in kidneys; may result in mitochondrial toxicity, membrane destruction; can be sequestered by metal binding proteins (metalolothionein), but can be overwhelmed

Chloroform

A nephrotoxicant; a common industrial solvent; forms reactive metabolites; binds cellular proteins, causing necrosis

Aminoglycosides

Antibiotics can be nephrotoxic at high doses (streptomycin, kanamycin, neomycin); are reabsorbed in the proximal tubule and sequestered in lysozymes; when this system becomes overwhelmed the lysozymes burst causing necrosis

Nervous system function

Transmission of information from external or internal environment; integrates the information; coordinates an appropriate response

Demyelination

Myelin acts as an insulator for neurons, aiding in signal transduction; chemicals may directly impact the myelin sheath or cells that produce myelin; results in disruption of nerve conduction

Axonopathy

Axon responsible for conducting signal down the length of neuron; can be disrupted through chemicals that target ATP production and tubulin, as well as axonal swelling; impacts on motor function and sensory function

Neuronopathy

More generalized damage to nerve cell; usually neurotoxicants cause necrosis and activate apoptosis pathways; example: inadvertently activate ion channels for extended periods of time, activating apoptosis

Neurotransmitters responsible for transmitting signals between neurons

Alterations in synaptic function involve…

Direct interactions with neurotransmitter receptors

Targets of many psychotropic drugs; also can be targets of toxins including plant alkaloids

Indirect interactions with neurotransmitter receptors

Acetylcholine esterase inhibitors block the breakdown of neurotransmitters; disruption of neurotransmitter release in presynaptic neuron (botulinum toxin)

Aluminum

Neuropathy; degenerative changes in cortex

Arsenic

Neuropathy; axonal degeneration in PNS

Methylmercury

Neuropathy; neural degeneration

Methanol

Neuropathy; necrosis of putamen, degeneration of retinal ganglion cells

Acrylamide

Axonopathy; axonal degeneration

Hexachlorophene

Myelinopathy; brain swelling, intramyelinic edema in CNS and PNS

Demoic acid

Neurotransmitter-associated injury; neural loss

Tellurium

Myelinopathy; demyelinating neuropathy

Cuprizone

Myelinopathy; edema, gliosis

Lead

Neuropathy; brain swelling, axonal loss

Carbon tetrachloride

Neuropathy; enlarged astrocytes in striatum

Thallium

Neuropathy; brain swelling, axonal degeneration

Endocrine system function

Maintenance of homeostasis; reproductive system; energy production; metabolism; Physiological progression; development, growth, maturation

Endocrine disruptors

Target nuclear receptors and membrane-bound receptors

Hormone receptor agonists

Estrogen receptor, ecdysone receptor; retinoic acid receptor

Hormone receptor antagonists

Estrogen receptor, androgen receptor, glucocorticoid receptor

Inhibition of hormone synthesis

CYP19 responsible for converting testosterone to estradiol; fungicide propiconazole inhibits CYP19, reduced circulating enzymes

Increase hormone clearance

Exposure to organochlorines like dioxins and PCBs induce metabolizing enzymes that can also metabolize hormones

Displacement of hormones from serum-binding proteins

Hormones circulate via serum proteins; chemicals displace hormone on proteins, reducing circulating proteins

Acrylonitrile, aniline

Affects the adrenal medulla whose primary hormones are epinephrine or norepinephrine, responsible for the “fight or flight” reaction

Nicotine, reserpine

Affects the adrenal cortex, whose primary hormone is aldosterone, which acts as a mineralocorticoid-which regulates electrolyte balance; and cortisol, which is a glucocorticoid, which produces a long-term stress response by changing the blood glucose level

Aluminum

Affects the parathyroid gland, whose primary hormone is the parathyroid hormone, responsible for calcium regulation

Thiouracil, sulfonamides

Affects the thyroid gland, whose primary hormone is thyroxine (T3) and triiodothyronine (T4) which plays a large role in metabolism

Prednisolone, valproic aid, ethionine

Affects the pancreas, whose primary hormones are insulin, which promotes cellular uptake of glucose to form glycogen; and glucagon, which promotes the release of glucose from cellular glycogen stores

N-methylnitrosourea

Affects the pituitary gland whose primary hormones are:

• Thyroid-stimulating hormone (TSH) - stimulates the thyroid gland to secrete T3 and T4

• Follicle-stimulating hormone (FSH) - steroidal hormone production

• Luteinizing hormone (LH) - steroidal hormone production

• Prolactin - Milk production

• Growth hormone (HGH) = Growth, cellular reproduction

DDT, lindane, chlordane, benzene, hexane, toulene

Affects the ovaries, whose primary hormones are estrogen, which plays a role in sexual development; and progesterone, which plays a role in pregnancy

Dinitrobenzene, dimethanesulfonate, methyl chloride

Affects the testes, whose primary hormone is testosterone, which plays a role in maturation and muscle development

Aroclor

Affects the pineal gland, whose primary hormone is melatonin, responsible for sleep cycle maintenance

Respiratory system function

Atmospheric gas exchange and protection from inhaled toxicants

Respiratory toxic responses

Irritation, cell necrosis, fibrosis, emphysema, allergic responses, cancer

Respiratory irritation

Causes inflammation which can constrict airways, cause edema, secondary infection

Respiratory fibrosis

Chronic inflammation results in formation of collagenous tissue; permanently restricts gas exchange

Emphysema

Enlargement of air spaces, decreasing surface area for gas exchange

Aluminum dust

Comes from ceramics, paints, fireworks, electrical goods; can cause fibrosis of the lungs

Ammonia

Comes from manufacture of fertilizers, explosives; causes lung irritation

Arsenic

Comes from manufacture of pesticides, glass, pigments, alloys; causes lung cancer and bronchitis

Asbestos

Comes from mining, construction, and shipbuilding; causes asbestosis and lung cancer

Beryllium

Comes from ore extraction, ceramics, and alloys; causes fibrosis and lung cancer

Cadmium chloride

Comes from welding, smelting, manufacture of electronics, alloys and pigments; causes emphysema

Chlorine

Comes from manufacture of pulp and paper, plastics, and chlorinated chemicals; causes lung irritation

Chromium

Comes from manufacture of Cr compounds, paint pigments; causes lung cancer

Coal dust

Comes from coal mining; causes fibrosis

Hydrogen fluoride

Comes from manufacture of chemicals, plastics, photographic film, solvents; causes lung irritation and edema

Iron oxides

Comes from welding, steel manufacturing, mining, and foundry work; causes lung fibrosis

Nickel

Comes from nickel extraction and smelting, electroplating; causes nasal cancer, lung cancer, and edema

Nitrogen oxides

Comes from welding and explosive manufacturing; causes emphysema

Ozone

Comes from welding, bleaching, and deodorizing; causes emphysema

Phosgene

Comes from the production of pesticides and plastics; causes edema

Silica

Comes from mining, quarrying, and farming; causes fibrosis (silicosis)

Sulfur dioxide

Comes from bleaching, refrigeration, fumigation, and coal combustion; causes lung irritation

Talc

Comes from the rubber industry and cosmetics; causes fibrosis

Tetrachloroethylene

Comes from dry cleaning and metal degreasing; causes lung edema

Function of immune system

Defend body against infectious agents; may also react with foreign substances such as dust, pollen, and chemicals, there is innate and acquired responses

Immunosuppression

Interference with immune cell division; suppression of antibody response; disruption of T-cell maturation; surface receptor interference

Type 1 allergic reaction

Anaphylactic response; chemical causes release of inflammatory mediators, causing swelling, vasodilation, etc

Type 2 allergic reaction

Antibody-dependent allergies: antibodies are activated and directed against the body’s own cells

Type 3 allergic reaction

Immune complex disposition: antigen/antibody complex settles in certain tissues, like kidneys and lungs, marking them for destruction by immune system

Type 4 allergic reaction

Cell-mediated allergy: rexposure causes a large reaction because individual has become sensitized to that chemical

Drugs that act as immunosuppressive agents

Cyclosporin A, cyclophosphamide, glucocorticoids (Dexamethazone), azothioprine

Metals that act as immunosuppressive agents

Lead, calcium, methylmercury, organotins

Pesticides that act as immunosuppressive agents

Chlorodane, DDT, Dieldrin

Industrial compounds that act as immunosuppressive agents

2,3,7,8-Tetracholorodibenzo-p-dioxin (TCDD), polychlorinated and polybrominated biphenyls (PCB and PBBs), benzene, poly aromatic hydrocarbons

Addictive substances that act as immunosuppressants

Cocaine, ethanol, opiates, cannabinoids, nicotine

Air pollutants that act as immunosuppressants

Environmental tobacco smoke, ozone, nitrogen dioxide

Microbial toxins that act as immunosuppressants

Aflatoxin, ochratoxin A, trichothecenes T-2 toxin

Radiation that acts as an immunosuppressants

Ionizing, UV

Other substances that act as immunosuppressants

Asbestos, diethylstilbestrol (DES), dimethylnitrosamine

Proteins associated with respiratory allergy

Enzymes, latex, animal dander, dust mites, molds, cockroach, microbial peptides

Low molecular weight (<3000)-haptens associated with respiratory allergies

Toulene diisocyanate, diphenylmethane diisocyanate, phthalic anhydride; trimellitic anhydride, platinum salts, reactive dyes

Adjuvants associated with respiratory allergies

Ozone, nitrogen dioxide, diesel exhaust, residual oil fly ash

Function of reproductive system

Production of gametes and reproduction; controlled by the hypothalamic-pituitary-gonadal axis; xenobiotics can act on signaling or reproductive organs

Endocrine disruption in males

Alterations of hormone binding, synthesis, and/or metabolism; examples include diethylstilbestrol and cimetidine

Germ cell and spermatogenesis with toxicity in males

Disruption of normal maturation of sperm; examples of chemicals causing this include vinyl chloride and ionizing radiation

Sexual behavior response to toxicity in males

Impacts on sex drive and erectile dysfunction; examples of chemicals that cause this include anabolic steroids, antidepressants

Endocrine disruption in females

Alterations of hormone binding, synthesis, and/or metabolism; examples of chemicals that cause this include DDT or methoxychlor

Toxicity in the ovaries and uterus

Premature ovarian failure; premature menopause; examples of chemicals that cause this include tamoxifen and cyclophosphamide

Sexual behavior affected by toxicity in females

Decreased libido; examples of chemicals that cause this include some oral contraceptives and drugs of abuse