week 10

Question 1

Systemic toxicity

Answer 1

• Chemicals can cause local toxic effects (at site of contact); but more often, toxic effects are observed at single or multiple sites distant from the entry site
• A striking example are the skin effects seen after an oral or i.v. drug dose.
• In contrast to local effects, systemic effects require both absorption of a toxicant and distribution by the bloodstream from its entry point to a distant site, where the deleterious effects are produced.
• Rates and extent of absorption may also vary greatly depending on the form of the chemical and the route of exposure. E.g.
  o Ethanol is readily absorbed from the G.I. tract but poorly absorbed through the skin.
  o Organometallics, like organic mercury, are readily absorbed from the G.I. tract, while inorganic metallic forms, like lead sulfate, are not.

Question 2

Effects of Systemic toxicity

Answer 2

• A systemic toxicant affects the whole body or acts outside the entry site. Most substances produce systemic effects
• Some materials may exhibit both types of effect, e.g.
  o Fuel additive tetraethyl lead produces skin effects at absorption sites and then transported systemically to produce its typical effects on CNS and other organs.
• Most chemicals that cause systemic toxicity do not affect all organs to the same degree. Major toxicity is typically seen in only 1 or 2 “target organs”
• Target organs don’t necessarily have the highest cocnentratin of chemical, since organs vary in their sensitivity to specific agents, e.g.
  o Lead is concentrated in bone, but its toxicity is exhibited in soft tissues to which it migrates
  o The organochlorine pesticide DDT is concentrated in fatty tissue but produces no known toxic effects in that tissue.

Question 3

The target organ most frequently affected in systemic toxicity is the central nervous system (CNS). Target organs ranked in order of frequency for exhibiting systemic toxicity are:

Answer 3

1. CNS
2. Circulatory system
3. Blood and haematopoietic system
4. Visceral organs, such as the liver, kidney, and lung
5. Skin
6. Muscle + bone

Question 4

Examples of systemic toxicants include:

Answer 4

• Potassium cyanide, a systemic toxicant that affects virtually every cell/organ by interfering with O2 utilization via the mitochondrial transport chain
• The toxic metal leaf, a multi-organ chemical toxicant that damages several types of cells, including kidney cells, nerve cells, and red blood cells.
• Whole body irradiation: physical agent that interacts with cellular water -> produces highly reactive free radicals -> damages cellular components -> causes many effects, from cell malfunction to death; failure of normal cell division (e.g. cancer)

Question 5

Systemic toxicity can be further categorized in a variety of ways:

Answer 5

• Acute toxicity
• Subchronic and chronic (carcinogenicity) toxicity
  Developmental and genetic (somatic) toxicity

Question 6

Overview of cytotoxicity and tissue damage

Answer 6

Cells have many critical structures and processes necessary for normal function and survival
Any compound disrupting one or more important cellular processes may cause cellular dysfunction and may lead to cytotoxicity

Question 7

Toxicity can result from adverse cellular, biochemical, or macromolecular changes, e.g.

Answer 7

• Damage to an enzyme system
• Disruption of protein synthesis
• Production of reactive chemicals in cells
• DNA damage
• Interruption of autophagy (normal degradation of cytoplasmic components via lysosomes)

Question 8

Some xenobiotics may also act directly by:

Answer 8

• Modification of an essential biochemical function
• Interference with nutrition
• Alteration of a physiological mechanism

Question 9

cellular chemicals

Answer 9

Most toxic effects are initiated by chemical interactions, i.e. a foreign chemical or physical agent interferes with or damages normal changes in the body.
This type of interaction results in the body’s chemical being unable to carry out its function in maintaining homeostasis.
There are many ways that this can happen, e.g.
- Interference with absorption or disposition of an essential nutrient
- Interference with nerve transmission, or
- Damage to components of a cell organelle preventing its functioning

Question 10

Cells have many critical structures + processes necessary for normal function and survival, including

Answer 10

• Cell and organelle membranes
• Energy generation in mitochondria
• Protein synthesis (involving RNA and ribosomes) and turnover
• DNA replication
• Peroxisome oxidation
• Lysosomal function
• Cell division and deletion

Any compound that disrupts one or more important cellular process may cause cellular dysfunction, which may lead to cytotoxicity.

Question 11

Cellular adaptations to toxicity

Answer 11

Specific intracellular chemical changes may be manifest as changes in cellular appearance or function. Actual mechanisms leading to cell damage are usually appearance or function.

Question 12

To maintain homeostasis, cells and tissues:

Answer 12

• Constantly adapt to changes in the tissue environment
• Attempt to respond to external stimuli to cope with new demands placed on them
• Are usually capable of an amazing degree of cellular adaptability
  o This adaptability may be beneficial (physiological) or detrimental (pathological)

Question 13

Examples of physiological adaptations are:

Answer 13

• An increase in skeletal muscle cells in athletes due to exercise and increased metabolic demand
• Increased number and size of epithelial cells in breasts of women resulting from endocrine stimulation during pregnancy.

Question 14

This imperfect adaptation is a pathological change – it has 3 basic types:

Answer 14

1. Increase in cell activity
2. Decrease in cell activity
3. Alteration in cell morphology (structure and appearance) or cell function

Question 15

Examples of pathological adaptations are:

Answer 15

• Changes from ciliated columnar epithelium to non – ciliated squamous epithelium in trachea and bronchi of cigarette smokers, to better withstand irritation by smoke -> decreased trachea-bronchial defences from loss of cilia and mucous secretions.
• Replacement of normal liver cells by fibrotic cells (cirrhosis) in chronic alcoholics (ethanol). A severely cirrhotic liver is incapable of
  o Normal metabolism, maintenance of nutrition, and detoxification of xenobiotics.

Question 16

Atrophy

Answer 16

Atrophy (including involution) is a decrease in the size and/or number of cells
Tissue/organ may decrease in size if a sufficient number of cells are involved.
When cells atrophy, they have:
- Reduced oxygen needs
- Reduced protein synthesis
- Decreased number and size of organelles
Common causes of atrophy:
- Reduced use of the cells
- Lack of hormonal or nerve stimulation
- Decease in nutrition
- A reduced blood flow to the tissue
- Natural aging
Example of atrophy: decrease in size of muscles and muscle cells in people with legs that are paralysed, in a cast, or infrequently used (e.g. bed-ridden patients).

Question 17

hypertrophy

Answer 17

Hypertrophy is an increase in size of individual cells
- Frequently results in an increase in size of a tissue or organ
- During hypertrophy, cell components increase in numbers with increased functional capacity to meeting increased cell needs.
- Generally, occurs when the organ or tissue cannot adapt to an increased demand by transformation of more cells – commonly seen in cardiac and skeletal muscle cells, which do not divide to form more cells.
Common causes of hypertrophy:
- Increased work or stress placed on an organ or hormonal stimulation.
- Example of hypertrophy is the compensatory increase in the size of cells in one kidney after the other kidney has been removed or is in a diseased state.

Question 18

hyperplasia

Answer 18

Hyperplasia is an increase n the number of cells in a tissue
- Generally results in enlargement of tissue mass and organ size.
- Occurs only in tissues capable of mitosis (i.e. epithelium of skin, intestine, glands), and not in cells that don’t divide
- Often a compensatory measure to meet an increase in body demands
Examples of hyperplasia:
- A frequent response to tissue damage (wounds or trauma), where hyperplasia of connective tissue (e.g. fibroblasts and blood vessels) contributes to the wound repair
- A frequent response to a number of toxic agents – in many cases, when the toxic stress is removed, the tissue returns to normal
- Form hormonal stimulation, e.g. breast and uterine enlargement due to increased estrogen production during pregnancy

Question 19

metaplasia

Answer 19

Metaplasia: conversion from one mature cell type to another
- This cellular replacement often occurs with chronic irritation and inflammation.
- Tissue becomes more resistant to external stress – replacement cells survive better
- But usually results in a loss of function that was performed by the original cells
Examples of metaplasia:
- Chronic reflux of stomach acid into the oesophagus (Gastroesophageal reflux disease): normal oesophageal cells (squamous epithelium) die
-> replaced with acid-resistant columnar cells of the stomach (Barrett’s syndrome)

• In chronic cigarette smokers: trachea and bronchi cells change from ciliated columnar epithelium to non-ciliated stratified squamous epithelium (reduced function of mucociliary escalator moving particles out of the trachea). Metaplastic sites are frequently sites for neoplastic transformations.
• In chronic alcoholics: normal functional hepatic cells are replaced by nonfunctional fibrous tissue (liver cirrhosis) ->disrupt liver architecture, blood flow, and metabolism.

Question 20

Dysplasia

Answer 20

Dysplasia: abnormal cell changes or deranged cell growth
- Cells are structurally changes in size, shape, and appearance from original cell type; cellular organelles also become abnormal
- Common feature of dysplastic cells: larger nuclei and higher mitotic rate
Causes of dysplasia:
- Chronic irritation and infection – reversible in many cases if the stress is removed; but may be permanent in other cases (a precancerous change)
Examples of dysplasia:
- Atypical cervical cells that precede cervical cancer – viewed in routine screening test of cervical cells (i.e. Papanicolaou test or pap smear)

• Cancer can occur at, e.g. sites of Barrett’s syndrome; bronchi of chronic smokers (bronchogenic squamous cell carcinoma)

Question 21

anaplasia

Answer 21

Anaplasia: appearance of undifferentiated cells with irregular nuceli and cell structure with numerous mitotic figures
- Frequently associated with malignancies (a grading criteria for aggressive cancer)
Example of an anaplastic carcinoma:
- Cell appearance has changed from highly differentiated cell of origin to a cell type lacking normal characteristics of the original cell. Anaplastic cells have generally lost normal cellular controls that regulate cell division and differentiation.

Question 22

neoplasia

Answer 22

Neoplasia: is basically a new growth of tissue; commonly termed a tumour
- Two types of neoplasia: benign and malignant (cancer)

Question 23

To maintain homeostasis in the presence of a toxic event, cells and tissues undergo physiological and pathological adaptations, i.e.

Answer 23

• Atrophy including involution), a decrease in cell size and/or number
• Hypertrophy, an increase in individual cell size
• Hyperplasia, an increase in cell number in a tissue
• Metaplasia, the conversion from one mature cell type to another
• Dysplasia, abnormal cell changes or deranged cell growth
• Anaplasia, the appearance of undifferentiated cells
• Neoplasia, the new growth of tissue (tumour)

Question 24

Cell damage and tissue repair

Answer 24

• Toxic damage to cells can cause individual cell death – if sufficient cells are lost, then tissue or organ failure results, ultimately leading to death of the organism
• The human body is extremely complex: > 200 different cell and tissue types; 1000s of different biochemicals acting alone of in concert to maintain bodily functions.
• Some tissues have a great capacity for repair (i.e. most epithelial tissues, like skin) others have limited or no capacity to regenerate and repair (e.g. nervous tissue)
• Most organs have a functional reserve capacity so they can still continue to perform their function with reduced ability
  o Hypertrophy of one organ (a kidney) to assume the capacity lost when the other kidney has been lost or surgically removed.
  o In partial liver damage, there is sufficient liver regeneration to maintain most of the capacity of the original liver.

Question 25

Toxic damage to cells can be transient and non- lethal; or may cause cell or tissue death in severe situations There are 4 main final endpoints to cellular or biochemical toxicity

Answer 25

- The tissue may be completely repaired and return to normal - The tissue may be incompletely repaired, but is capable of sustaining its function with reduced capacity - Death of the organism, or the complete loss of a tissue or organ (replacement therapy, e.g. insulin or organ transplant). - Neoplasm or cancers may result -> many can cause death, while others may be cured by medical treatment

Question 26

- 2 common reversible cell changes associated with toxic exposures are:

Answer 26

Cellular swelling (associated with hypertrophy): from cellular hypoxia damaging the Na-K membrane pump -> changes in intracellular electrolyte balance -> influx of fluids -> cell swelling Fatty change is more serious and occurs with severe cellular injury (common in liver as most fat is synthesized and metabolized in liver cells) -> inhibits fat metabolism -> small vacuoles (fat droplets) accumulate in cytoplasm.

Question 27

Toxicological significance of tissues:

Answer 27

- Tissues have many critical structures and processes that are necessary for the proper function of the organs they comprise - Any compound that disrupts the structural organization of tissues, or important tissue functions, may cause general organ dysfunction that may lead to organ toxicity.

Question 28

Within organs, there are two basic types of tissues:

Answer 28

- Parenchymal – containing the functional cells (e.g. squamous dermal cells, liver hepatocytes, and pulmonary alveolar cells). - Stromal – supporting connective tissues (e.g. blood vessels, elastc fibres)

Question 29

Repair of injured cells can be accomplished by:

Answer 29

1. Regeneration of parenchymal cells, involving hyperplasia response: - Labile cells routinely divide and replace cells with limited lifespan (e.g. epithelium) - Stable cells usually have a long lifespan with a normally low rate of division, but can rapidly divide upon demand (e.g. hepatocytes) 2. Repair and replacement by the stromal connective tissue, involving metaplasia after damage to: - Permanent cells that never divide, even when stressed or some cells die. (e.g. neurons, skeletal, and cardiac muscle).

Question 30

Important sites of organ specific toxicity are:

Answer 30

- Organs that are major routes of exposure o Skin, G.I. tract, and respiratory systems - Organs that are major sites of metabolism or excretion – liver, kidney - Organs in control systems of the body – nervous system, endocrine system - Organ systems that maintain the body – immune system, blood/CV system - Organ systems for reproduction – female and male reproductive systems (containing germ cells)

Question 31

SKIN

Answer 31

Characteristics related to toxicity: - Major external barrier and important route of absorption – influences toxicokinetics of many chemicals and extent of their toxic responses. - Skin damage will increase permeability to external toxicants and leads to fluid loss. - Most common target for diseases caused by chemicals in the workplace Types of toxicity: dermal toxicity may result from direct or internal distribution to the skin. Effects range from mild irritation to severe changes, i.e. corrosion, hypersensitivity (allergy) and skin cancer. Examples of dermal toxicity: - Irritation from gasoline exposure - Corrosion from acids, or strong alkalis like NaOH - Allergy from poison ivy - Skin cancer from arsenic ingestion or exposure to UV light

Question 32

Sensory Organs

Answer 32

Special senses that detect physical and chemical stimuli from external environ. The eye is our visual sensory organ – contains a cornea, lens, retina, optic nerve. Characteristics related to toxicity: external sensory organs are very vulnerable to direct chemical exposures. Optical and neuronal eye components are all potential targets of toxicity. Types of toxicity: - By direct contact to cornea and conjunctiva (mucous membranes around eye) or internal distribution to the eye. - Conjunctivitis and corneal erosion from occupational exposure to acids, strong alkalis, and many household items. - Circulating chemicals can distribute to eyes and cause corneal opacity, cataracts (corticosteroids), and retinal or optic nerve damage (methanol – wood alcohol). Other sensory organ toxicity: Ototoxicity: ear damage affecting hearing or balance (e.g. permanent deafness from aminoglycoside antibiotics)

Question 33

Gastrointestinal system

Answer 33

G.I. tract – hollow passage from mouth to anus; including oesophagus, stomach, small and large intestine, digestive organs. Characteristics related to toxicity: - Important absorption route for many chemicals - Disruption of this internal barrier from localized toxicity can provide easier entry of ingested chemicals -> increased systemic levels and altered toxicokinetics and may cause systemic toxicity. - Other compounds may gain entry into the body via gut transport pathways. Has significant capacity for biotransformation of chemicals: - Intestinal bacteria – important metabolising functions (producing secondary bile acids, cleaving plant glycosides) - Intestinal mucosa has xenobiotic – metabolising enzymes (P450) Types of toxicity: direct irritation alteration of control systems for: - Absorption and secretion – as digestive factors and secretory processes are under complex control - Gut movement – altered peristaltic processes - Protective functions – stomach acid and mucous lining Examples of G.I. toxicity - NSAIDs, like aspiring, can cause G.I. haemorrhage - Many plant toxins -> gastroenteritis - Arsenic acute poisoning is corrosive -> abdominal pain, vomiting, bleeding - Lead causes severe abdominal pain and cramping

Question 34

respiratory system

Answer 34

Characteristics related to toxicity: - Important absorption route by inhalation of volatile chemicals and particles - Particle size determines the site of deposition within resp. tract, affecting: o Severity of localized tissue damage o Degree of absorption of systemic toxicants o Mechanisms available for particle removal - Local effects produced by inhalation of corrosive substances or irritants with serious consequences. - Also a site of biotransformation -> can result in localized toxicity - Acute or chronic damage to resp. system severely affects general health status and quality of life types of toxicity: - Pulmonary irritation (cigarette smoke) - Asthma/ bronchitis (constriction of airways) - Reactive airway disease (from isocyanates) - Emphysema (form chronic cigarette smoking) - Allergic alveolitis (dried sugar cane dust, fungal spores) - Fibrotic lung disease. (asbestosis, silicosis) - Pneumoconiosis (dust deposits in lung) - Lung cancer (form exposure to cigarette smoke, asbestos, radon gas, industrial chemicals)

Question 35

liver

Answer 35

Hepatocytes perform several metabolic processes: Metabolic function Synthetic function Secretory/excretory Storage function Catabolic function Characteristics related to toxicity: Most metabolically active organ and biotransforming enzymes (P450); 1st major site of metabolism for orally absorbed compounds -> common target organ for toxicity from many compounds and their locally produced metabolites Any compound disrupting one or more important hepatic processes also interferes with transport and/or metabolism of endogenous factors and waste products -> accumulation and potential toxicity. Types of liver toxicity: - Steatosis – lipid accumulation in hepatocytes (ethanol) - Intrahepatic cholestasis – back up of bile salts into liver cells (estrogens) - Cirrhosis – chronic fibrosis, often due to chronic alcohol consumption - Hepatic necrosis – hepatocyte death (paracetamol) - Chemical hepatitis – inflammation and immune cell infiltration after necrosis from toxicants - Hepatic cancer - Hypersensitivity – some chemical metabolites can form neoantigens on hepatocyte surface, prompting immune reactions

Question 36

kidney

Answer 36

Characteristics related to toxicity: - Receives high blood volume (20-25% of cardiac output) – so circulating chemicals are delivered in high amounts where they are filtered and concentrated in tubular fluid and cells – easily reaching toxic concentrations. Any compound that disrupts renal function will also interfere with excretion and elimination of endogenous factors, waste products and other xenobiotics, leading to their accumulation and potential toxicity High urinary conc. Of toxic chemicals can cause bladder toxicity and cancer Types of nephrotoxicity: - Decreased ability to excrete body wastes - Inability to maintain body fluid and electrolyte balance - Decreased synthesis of essential hormones (e.g. erythropoietin) Most common site of renal damage is in 1st part of nephron (proximal tubule) due to selective transport and accumulation of many chemicals Examples of nephrotoxic compounds: - Many drugs, e.g. paracetamol, NSAIDs, antibiotic aminoglycosides and cyclosporine A - Many toxic metals (hg, Cd) binds to protein rich in sulfur-containing amino acids -> accumulate in kidney, interfere with Ca-dependent pathways and/or causing free radical damage - Some industrial halogenated hydrocarbons are initially metabolized in the liver before their glutathione-conjugates are metabolically-activated in the kidney to a reactive metabolite. Others can be activated by renal cytochrome P450 to cause kidney damage.

Question 37

nervous system

Answer 37

Characteristics related to toxicity: - Very susceptible to chemicals that disrupt excitable membranes of nerves, and release/action of neurotransmitters - Exposure to chemicals that cause CNS depression can be life threatening due to interruption of respiration and other vital functions. - Subtle changes to CNS function can modify behaviour, senses and mood. - Changes in endocrine and immune function can also influence the nervous system Types of neurotoxicity: - Neuronopathies – neuron injury and death - Axonopathies – injury to axons - Interference with electrical transmission, by either: o Demethylation, the loss of the axons insulating myelin sheath, slowing electrical conduction along the nerve o Interfering with electrical impulses travelling down the axon to synaptic junction - Interference with chemical neurotransmission, by either: o Altering release of neurotransmitters o Blocking activation of receptors for neurotransmitters, or inhibiting cessation of signal

Question 38

endocrine system

Answer 38

Characteristics related to toxicity: - Disturbances in hormonal levels form chemical exposures may cause: o Decreased hormonal effects leading to specific tissue shrinkage (atrophy) o Increased hormonal effects leading to acceleration tissue growth (tumour) Disturbances in endocrine function will greatly affect target organs of the specific hormone signal Endocrine disturbances can also cause changes in nervous and immune function due ti their close interactions Types of toxicity: Chemicals that interrupt hormonal signalling are called endocrine disruptors. Mechanisms responsible are: - receptor binding by hormone mimics o chemicals that mimic hormonal action or mimic the hormones shape to bind the receptor. Both greatly affect the female reproductive system - altered hormone synthesis or release o some chemicals inhibit hormonal synthesis or stimulate it - altered endocrine tissue pathology o with chemicals causing a tumour in endocrine tissue. Any chemical that causes prolonged decreases in circulating hormones also disrupts the negative feedback control by the hypothalamus and pituitary -> pituitary cells undergo hypertrophy and hyperplasia, overproducing stimulating hormones that can also promote hyperplasia in target organs.

Question 39

immune system

Answer 39

Characteristics related to toxicity: - immune system relies heavily on ability of specific immune cell populations to rapidly proliferate and migrate to sires of disease -> very susceptible to any chemicals that inhibit cellular growth, division, migration and phagocytosis immune system is the body’s last line of defence against tumours and invading organisms, so any compound that disrupts immune function will predispose the organism towards opportunistic diseases, i.e. cancer or infection by viruses, bacteria or parasites. Types of immunotoxicity: Can result from inhibition of immune function or inappropriate enhancement of immune function or proliferation. Examples are: - contact dermatitis due to poison ivy - systemic lupus erythematosus in workers exposed to hydrazine - immunosuppression by cocaine - leukemia induced by benzine

Question 40

cardiovascular system

Answer 40

Characteristics related to toxicity: Chemicals that impair heart function and blood flow can cause acute anoxia and localized necrosis which, depending on the target organ, may quickly result in death. Chemical exposures that cause changes to CV tissues and their processes may also cause both acute and chronic ‘vasculotoxic’ responses in multiple organs. Types of toxicity: blood and CV toxicity results from xenobiotics acting directly on cells in circulating blood, bone marrow, blood vessels, and heart. Examples are: - hypoxia due to CO binding of haemoglobin preventing transport of O2 - disease in circulating RBCs due to haemolysis caused by lead or chromium. - Cardiac arrhythmias or altered heart rate caused by an overdose of any anti-arrhythmic drug or inotropic agent - Arteriosclerosis due to accumulation in arteries and veins of fatty plaques containing lipoproteins and cholesterol, a condition made worse by hypertension, cigarette smoking, and diabetes - Heart attacks from enhanced blood clotting o Specific COX2 inhibitors not only block production of pro-inflammatory prostaglandins by COX2 in arthritic joints, but unfortunately also stop COX2 production of prostacyclin in blood vessels, which is needed to balance pro-clotting effects of thromboxane produced by vascular COX1.

Question 41

reproductive system

Answer 41

Characteristics related to toxicity: - Extremely susceptible to chemicals that affect germ cells (oocytes and spermatozoa), by damaging genetic material or inhibiting cellular proliferation and division - Chemical exposures that affect male and female reproductive systems can alter libido and fertility, and also development of fetus and newborn - Rapid fetal development involves several stages that are very susceptible to the toxic effects of chemical exposure, particularly during organ formation. Response to chemicals causing birth defects (teratogens) depends on nature of toxic agent and specific time of exposure during gestation. - Chemical exposures that affect endocrine or nervous systems, or supporting cells of reproductive system, can also disrupt various reproductive processes. Types of reproductive toxicity: - decreased libido and male impotence - infertility - interrupted pregnancy - infant death, or childhood morbidity - altered sex ration and multiple births - chromosomal abnormalities and birth defects - childhood cancer

Question 42

summary of organ specific toxicity

Answer 42

- organs and organ systems are important sites of specific toxicity with serious consequences for the body. They provide vital functions, including: o major routes of exposure – skin, GI system, rep. system o major sites of metabolism or excretion – liver kidney o control systems of the body – nervous system, endocrine system o organ systems that maintain the body – immune system, blood/cv system o organ systems for reproduction – female and male reproductive systems (containing germ cells) - as organs and organ systems often interact to maintain homeostasis within the body, specific toxicity to one organ can often disrupt the function of other organs and organ systems.