Transcript W507 – Basic human biology and target organs

W507 – Basic human biology
and target organs
Respiratory System
• Structure
• The lung as a route of entry
• The lung as a target organ
– Particles
– Gases
• Occupational lung disease
Respiratory System Structure
Naso-pharynx (head airways)
Nose, Mouth, Pharynx (throat)
Tracheobronchial region
Conducting airways in chest
(trachea, bronchi, bronchioles)
Alveolar region (deep lung)
Gaseous exchange with blood
(respiratory bronchioles, alveoli)
Source: Tranter 1999 – reproduced with permission
Naso-pharynx / head airways
• Nose/Nasal Cavity (Turbinates)
- Warms, moistens & filters air as inhaled.
- Large, moist, ciliated surface, large blood
supply
• Mouth breathing
– bypasses nasal filter
• Pharynx (throat)
Tracheo-bronchial region
Structure:
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Trachea (1)
Main Bronchi (2) (Left & Right Lung)
Bronchi (15 divisions)
Bronchioles (10 divisions)
Terminal Bronchioles
With each division the total cross-sectional area increases
– trachea 2cm2
– terminal bronchioles 80 cm2
• Flow rate decreases
Lining of airway:
• Lined with mucous membranes which are lined with cilia (small hairs)
that can sweep trapped particles up to the throat (Mucociliary escalator)
Alveolar Region
Gas exchange occurs across the thin walls (one or two
cell thickness) of the alveoli and respiratory
bronchioles
Alveoli
• Air sacs surrounded by blood capillaries
• Approximately 300-600 million alveoli with total surface
area 100-200m2
• No cilia, so particles may remain within alveoli for long
periods (months or even years)
• Phagocytes (macrophage cells) travel throughout alveoli
and may engulf and digest deposited particles
Alveolar region – gas exchange
• Thin barrier between air in alveoli and blood in
pulmonary capillary (0.5um)
• Allows rapid diffusion of:
– O2 (alveoli to blood)
– CO2 (blood to alveoli)
• O2 is bound to haemoglobin inside red blood cell
• Oedema (accumulation of fluid) increases thickness of
barrier and impairs diffusion
Particle deposition in the
respiratory system
• A particles ability to reach the deep lung depends
on chemical and physical structure, including size,
density and shape
• Diameter is generally the most important factor
that affects whether (and where) a particle will
deposit in the respiratory system
• Strictly speaking it is the ‘aerodynamic diameter’
rather than the diameter that is important
Deposition Mechanisms: Particles
• Interception: head airways
Large particles (10-100 µm aerodynamic diameter)
too large to penetrate the passages between the
nasal hairs or the nasal turbinates
• Impaction: head airways and divisions of large
bronchi
Large particles (5-30µm) fail to negotiate branches
in airways and impact at speed on the airway wall
Deposition Mechanisms: Particles
• Sedimentation: small bronchioles and alveoli
Smaller particles (1-5µm) follow the air stream, but
eventually settle (sediment) out under their own weight
due to gravity
• Diffusion: alveoli
Small particles (<1µ) remain suspended in the air stream
and are often exhaled. Diffusion occurs in the alveoli
where the airflow is negligible. Particles move at random
(Brownian Motion) until they collide with the alveolar
membranes
Particle Clearance
• Irritant receptors (nose & bifurcation of large bronchi) reflex
sneezing, coughing, constriction of bronchi to limit further
penetration
• Mucociliary escalator (nasal passage and tracheobronchial tree)
Particles trapped in mucous lining the airway. Moved by cilia to
pharynx (throat) for swallowing
• Macrophage (deep lung) Particles either engulfed and digested
by macrophage then transported by lymphatic system to blood;
Or, particles destroy macrophage – particles remain in lungs and
bound in connective tissue
ISO 7708: 1993 Curves
• Inhalable fraction:
% of particles that can enter the nose or mouth during breathing
and is therefore liable to deposition anywhere in the respiratory
tract. In practical terms maximum particle size is about 100 µm.
• Respirable fraction:
% of particles that can reach the deep lung (the alveolar region).
Particle sizes of respirable dust generally up to 10 µm.
• Alveolar deposition:
Increases as particle size decreases; however, then decreases
because a significant % of very small particles are exhaled
immediately.
Particle penetration & deposition:
ISO 7708: 1993 curve
Gases and vapours - lung as route
of entry
• Main risk from lipid soluble gases and vapours
– pass through alveoli into blood
– E.g. CO, H2S, mercury, organic vapours
What features of the lung facilitate absorption?
What effect does work rate have?
Lung penetration by gases
• Highly water soluble gases (e.g. ammonia, formaldehyde)
only reach the upper respiratory tract – readily dissolve /
absorb into moist mucous membranes
• Penetration to deep lung increases if:
– Exposure is high
– Gas molecules are adsorbed onto particles
• e.g. SO2 on soot particles
• Less water soluble gases (e.g. phosgene) will tend to reach
the deep lung
The lung as a target organ
• Irritation / Inflammation
- Upper respiratory tract (URT)
- Deep lung
• Pneumoconioses
- Fibrotic
- Benign
• Emphysema
• Lung cancer
• Respiratory sensitisation
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Rhinitis
Occupational asthma
Extrinsic allergic alveolitis
Byssinosis
Acute Irritation / Inflammation
• Upper Respiratory Tract
- Coughing, irritation of mucous membranes – high exposures
can cause release of fluid (oedema)
- Irritant mists, fumes, dusts (e.g. chromium acid mists, metal
oxide fumes, MMMF)
- Highly water soluble gases (e.g. ammonia, hydrogen chloride)
• Deep lung
- Irritation of mucous membranes and pulmonary oedema
- High exposure to many metal fumes (e.g. cadmium oxide
which can cause an acute chemical pneumonitis)
- Low water soluble gases (e.g. phosgene, nitrogen dioxide)
Fibrotic pneumoconiosis
Macrophage system
• Very effective in removing most dust particles from lungs.
• However in some situations macrophages are unable to engulf or
remove the particle.
• In these situations chemicals released from the macrophage can cause
scarring (or fibrosis) which if widespread may be fatal.
Examples include
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Coal worker’s pneumoconiosis (coal dust)
Silicosis (crystalline silica)
Asbestosis (asbestos)
Hard metal disease (cobalt, tungsten)
Benign pneumoconiosis
• Non-fibrotic disease
• Changes may be seen on X-Ray, but
breathing not usually impaired.
• Insoluble deposits including:
- Iron oxide
- Tin oxide
- Barium sulphate
Emphysema and bronchitis
Emphysema
• progressive destruction of the alveoli walls causing merging of
alveoli
• fewer, larger alveoli, leading to less surface area
• breathlessness, cough
• chronic condition – can be caused by cadmium oxide, smoking
Chronic Bronchitis
• excess mucous, chronic infection of the bronchioles
• often secondary to other disease
Lung cancer
• Abnormal growth of cells in the lungs
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Asbestos
Rubber fume
Chromium (VI)
Arsenic
Smoking etc
• Usually a tumour develops in the bronchi
– Symptoms include coughing, pain and breathing obstruction
– Cells from the cancer may spread to other parts of the body
– Often fatal
Respiratory sensitisation
• Allergic Rhinitis
– Rapid allergic reaction affecting nose, throat and
eyes
– Nose can become ‘blocked’ or excessively runny
– Eyes become swollen, red, itchy and watery
– Can be caused by a wide range of substances
including pollen, organic dusts and some
chemicals
Respiratory sensitisation
• Occupational asthma
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Inflammation and allergic constriction of bronchi
Narrowing of airways and increased mucus production
Tight chest, breathlessness, wheezing, difficulty breathing out
Allergic reaction often occurs after repeated exposure after
which the person becomes sensitised to very low exposure levels
• Respiratory sensitisers include
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Isocyanates
Solder fumes
Some metals (e.g. platinum, cobalt)
Organic materials such as latex, animal proteins, vegetable dust
Detergents
Enzymes
Respiratory sensitisation
• Extrinsic allergic alveolitis
– Inflammation of the terminal bronchioles and alveoli
• Acute effects
– Delayed flu-like symptoms lasting 48 hours
– Fever, headache, muscle pain, cough
• Chronic effects
– Fibrosis, weight loss, breathlessness on exertion, disabling
• Causes
– Inhalation of respirable fungal spores, dried animal proteins
– There are a number of industry specific terms including ‘Farmers
Lung’ (Mouldy grain, hay).
Respiratory sensitisation
Byssinosis
• Caused by exposure to dust produced during
machine spinning and weaving of cotton and other
vegetable fibres such as flax and hemp.
• Symptoms develop after many years of exposure
and include tight chest, breathlessness, cough. In
chronic cases breathing difficulty due to irreversible
airway obstruction which can be disabling.
Skin
• Structure & function
• Skin as a route of entry
• Skin as a target organ
- dermatitis
- other skin conditions
Skin Structure
Source: Tranter 1999 – Reproduced with permisssion
Skin Structure and Function
• Epidermis – can be divided into 3 cell layers
- cornified
- granular
- germinative
• Dermis - connective and elastic tissue which also contains:
-hair follicles
-blood vessels
-sweat glands
-nerve fibres
-sebaceous glands
• Subcutaneous layer
- contains fat cells - insulates, cushions
Skin as a route of entry
• Properties of toxins
- solubility: lipid soluble agents permeate better than water soluble
e.g. phenol, solvents, organo-phosphate pesticides
• Properties of skin which increase permeation
- warm, moist skin: prolonged sweating, skin folds
- damaged skin: pre-existing disease, physical damage, defatting
• Exposure
- chemical trapping: under gloves or clothing
Skin as Target Organ
Dermatitis = Any inflammatory disease of the skin
• Symptoms: reddening of skin (erythema), scaling
and cracking – may also become swollen and itchy
and sometimes blistered
• Dermatitis is very common and difficult to treat
successfully
• Can be divided into two categories
– Irritant contact dermatitis
– Allergic contact dermatitis
Irritant Contact Dermatitis
• About 70% of occupational skin disease
• All workers exposed may be affected, provided exposure is
repeated and prolonged
• Typical skin irritants
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Detergents
Alkalis (lime, cement, caustic)
Acids
Organic solvents
Oxidising and reducing agents
Some plants
Dermatitis
Allergic Contact Dermatitis
• About 20% of occupational skin disease
– Only sensitised workers affected – once sensitised
symptoms occur even on very low exposures
• Examples include:
– Nickel (‘nickel itch’) – electroplating, jewellery
– Epoxy resins (adhesives)
– Latex (gloves etc)
• Causative agent often confirmed by patch testing
Other skin conditions
Folliculitis
– Pores blocked by oils, greases, waxes
– Causes acne like lesions
• Chloracne – type of folliculitis caused by
chlorinated hydrocarbons.
Pigmentation Disturbances
• De-pigmentation
- some phenols
• Hyper-pigmentation
- tar and some insecticides - can cause reddening and
darkening of skin
- silver salts – can cause blue-grey discolouration
Ulceration of skin
• Ulceration of skin is a well documented effect of
exposure to hexavalent acid
– Chromic acid in electroplating industry
– Also some cements that contain hexavalent chromium
– Other examples include:
• Antimony
• Mercury fulminate
Skin Cancer
• Malignant tumour
– UV exposure
• Most common cause – associated with production
of melanomas (cancer of melanin producing cells in
the skin)
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Polycyclic aromatic hydrocarbons (PAH)
Coal tar, asphalt
Soot
Arsenic
Nervous System
• Structure and function
• Nervous system as a target organ
– Structural damage to neuron
– Functional damage to the nerves
Nervous System
• Controls the activities and functioning of the body
– Also responds to external stimuli in a precise, rapid
manner
• Anatomical Divisions:
– Central Nervous System (CNS)
• brain & spinal cord
– Peripheral Nervous System (PNS)
• all other nerves
Nervous system
• Nervous system can also be divided into two
functional divisions
• Motor nerves – control movement (muscles)
– somatic control voluntary movement
– autonomic control involuntary movement (e.g. heart beat,
breathing)
• Sensory nerves – involved in the sensation of touch,
pain, temperature, vibration, sight, sound, balance
Nerve cell (neuron): functional
unit
(Source: Multiple Sclerosis Trust – reproduced with permission)
• Cell Body: makes proteins
for all parts of neurone with
central nucleus
• Axons: long projections
along which nerve impulses
travel rapidly
• Myelin
sheath:
fatty
substance that insulates the
axons
and
speeds
up
conduction
• Post-synaptic membrane:
nerve or muscle cell
Transmission of nerve impulse
(signal)
• Nerve impulses transmitted along axon as electrical
signals
– Signal caused by rapid polarisation and depolarisation of
the axon which changes the balance of sodium and
potassium ions between the axon and the outside
– Signal reaches the end of the axon (the synaptic knob)
which is located close to the target cell
– Gap between the synaptic knob and the target cell is called
the synapse or synaptic gap
Normal synaptic transmission
• Arrival of nerve impulse triggers release of
chemical neurotransmitters (e.g. acetylcholine) into
synaptic gap.
• Acetylcholine travels across gap to the target cell
or neuron. This triggers a response in the target
cell
• Enzyme (acetylcholinesterase) destroys the
acetylcholine to prevent continued stimulation of
the target cell
Nervous system as a target organ
Structural damage to neuron
• Lead – damages myelin sheath slowing nerve
impulse transmissions
• Mild symptoms – tiredness
• Severe cases – peripheral neuropathy producing
muscle weakness, often showing as ‘wrist drop’ or
‘foot drop’
• n-Hexane – causes swelling of axon and
degeneration of axon and myelin sheath
• Symptoms include muscular weakness and sensory
motor loss particularly to hands and feet
Nervous system as a target organ
• Structural damage to neuron
– Manganese – damages axon
• Symptoms resemble Parkinson’s disease with tremor and
difficulty in walking and speaking
– Mercury – damages the sensory nerves
• Symptoms include hearing, speech and vision problems.
Also tremors and shaking and psychiatric disturbances
– Organo-metallics (e.g. methyl mercury and tetra
ethyl lead) – can readily reach the brain
• Symptoms include irritability, memory loss, convulsions
and psychiatric disturbances
Blood Brain barrier
• Selective barrier which protects most of brain against water
soluble toxins
• but permeable to lipid soluble toxins (e.g. organometals, solvents)
• Matures 6 months after birth (consequence?)
Most tissues
Blood brain barrier
Nervous system as a target organ
• Functional damage to nerve
– Organic solvents – act as CNS depressants
• High affinity for lipid rich tissues (e.g. myelin sheath) and absorb
into it causing swelling and impairing nerve impulse transmission
• Acute narcotic and anaesthetic effects: drowsiness, loss of feeling,
unconsciousness, death
• Chronic effects: possible long-term damage to neurons
Nervous system as a target organ
• Functional damage to nerve
– Organo-chlorine pesticides – polarisation and depolarisation
of axon is prolonged
• Symptoms include tremors caused by nerves becoming hyper-excitable
– Organo-phosphorous pesticides – interfere with chemical
transmission across the synapse
• Acetylcholine not hydrolysed by target cell enzymes leading to
reactivation of target cell
• Symptoms include excessive muscle contractions, convulsions and
paralysis
Circulatory system
• Components and function
• Blood as a target organ
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Haemolysis
Carboxyhaemoglobin formation
Methaemoglobin formation
Anaemia
Leukaemia
Circulatory system
• Main components of cardiovascular or circulatory
system are the heart, the blood and the blood vessels
• Blood vessels
– Arteries – bring oxygenated blood pumped from the heart
to the tissues
– Veins – bring de-oxygenated blood back to the heart
– Blood passes from arteries to veins through capillaries –
the thinnest and most numerous of the blood vessels
Blood composition and function
Main function is transport
O2 from lungs to tissues, CO2 from tissues to lungs
Also transports nutrients, heat, waste, toxins.
55% Plasma
- fluid component (water, electrolytes, proteins)
Thrombocytes (platelets)
- blood clotting
Leucocytes (white blood cells)
- defence (phagocytic cells and cells involved in immunity)
44% Erythrocytes (red blood cells)
- transport O2 and CO2 bound to haemoglobin
Red blood cell (erythrocytes)
• Responsible for transport of oxygen
– Main component is haemoglobin (Hb) – large complex
molecule composed of protein (globin) and pigment
(haem) that contains ferrous iron
– Produced from stem cells in blood marrow (together with
white blood cells and platelets)
– Lifespan 120 days
– Normal forms of Hb are
• Oxyhaemoglobin (HbO2)
• Carbaminohaemoglobin (HbCO2)
White blood cell (leucocytes)
• Main function is to protect the body against
infection from invading organisms
• Two main types
– Phagocytic cells – scavenger cells – physically engulf
and destroy foreign bodies and bacteria
– Immunocytic cells – complex mechanism – produce
antibodies that directly attack specific organisms such as
viruses
Blood as a target organ
• Haemolysis (breakdown of red blood cells)
– Occurs when cell membrane is damaged and cell destroyed
– Breakdown products reach the kidney and may damage or
overload kidney function
– Characterised by appearance of blood breakdown products
in urine which turns red
– Causes: arsine (arsenic trihydride) and stibine (antimony
hydride)
Blood as a target organ
• Carboxyhaemoglobin formation
– Oxygen transported by haemoglobin as oxyhaemoglobin
• However, carbon monoxide binds strongly to haemoglobin forming
carboxyhaemoglobin which prevents uptake of oxygen
• As levels of carboxyhaemoglobin increase, ability of blood to
transport oxygen decreases
– Symptoms: headache, lethargy, dizziness, unconsciousness,
death
– Sources: Incomplete combustion, engine and boiler
exhausts, metal smelting and processing
• Note: exposure to dichloromethane can also lead to elevated
carboxyhaemoglobin levels as carbon monoxide is produced as a
breakdown product of dichloromethane metabolism
Blood as a target organ
• Methaemoglobin formation
– Methaemoglobin is an oxidation product of
haemoglobin that has no oxygen-carrying
capacity
• Iron in the red blood cells is converted from the
ferrous (II) state to the ferric (III) state
• Methaemoglobin can be produced after exposure to
some aromatic amines such as aniline
Blood as a target organ
• Anaemia
– Condition when amount of haemoglobin in blood is
reduced
– May be caused by substances that affect normal
production of haemoglobin in the bone marrow
– Can be caused by inorganic lead and benzene
• Leukaemia
– Group of blood disorders where abnormal white blood
cells are produced in large quantities which replace or
crowd out normal white blood cells
– Can be caused by benzene
Liver – structure and function
• One of the largest organs in the body
• Main functions
– Metabolism of fats, carbohydrates & proteins
– Biotransformation of alcohol, hormones and organic
chemicals to increase water solubility for excretion by
kidneys
– Production of bile to aid fat digestion in small intestine
– Storage of iron and some vitamins
– Production of plasma proteins
Position in circulation
Position in circulation
• Receives high flow of oxygenated blood from hepatic
artery and
• Partially deoxygenated blood from small intestine via
hepatic portal vein
• Blood returns to circulation via hepatic vein
• Liver is first organ to receive blood from digestive tract
and is therefore liable to be exposed to high
concentrations
of
substances
absorbed
from
gastrointestinal tract
Liver – structure and function
• Liver is main site for biotransformation
– Metabolic changes detoxify (or in some cases produce metabolites
that are more toxic)
– In either case the liver may be at risk
• Liver lobules
– Groups of cells that lie between the hepatic artery and portal vein
and the hepatic vein
– Blood that may contain toxins passes over these cells which contain
enzymes that are involved in the biotransformation process
– Detoxified blood passes into the central vein for return to the
circulatory system
The liver as target organ
• Fat accumulation in liver as product of biotransformation
– Causes – exposure to chlorinated hydrocarbons, excessive
consumption of alcohol
• Cirrhosis – build up of fibrous tissues
– Causes – exposure to many organic solvents, excessive
consumption of alcohol
– May be a pre-cursor of liver cancer
• Note: for above effects there may be synergistic effects
from alcohol and solvents
The liver as target organ
• Liver cancers
– In addition to cancers linked to fibrous changes (e.g.
cirrhosis) of the liver, there are a few specific examples
of substances that can cause liver cancer
– Arsenic
– Vinyl chloride monomer – exposure has been linked to
angiosarcoma (a rare liver cancer)
Structure and function of the
kidneys
Range of functions
– Excretory functions
• Filtration of normal metabolic waste products from the blood
• Excretion of water-soluble toxins and metabolites and excess
salts from urine
– Regulatory functions
• Regulation of sodium, potassium and other salt levels
• pH (acidity) of blood
• Body water and blood fluid levels
– Specialised functions
• Production of some hormones and vitamin D
Nephron function
• The kidney plays a crucial role in regulating
electrolytes in the human blood (e.g. sodium,
potassium, calcium).
• pH balance is regulated by the removal of excess
hydrogen ions (H+) from blood.
• Kidneys remove urea from the body, a nitrogenous
waste product from the metabolism of proteins.
Kidneys as a target organ
• Vulnerability
– route of excretion for water soluble toxins & their
metabolites
– reabsorption of water concentrates toxins in tubules
– high blood flow
• Kidneys damaged by wide range of substance
– those that:
– interfere with oxygen supply
– damage the glomeruli
– block / damage tubules or interfere with tubular
reabsorption
Kidneys as a target organ
• Acute renal failure (renal shutdown)
– Urine production decreases allowing urea and
other waste products to accumulate in blood
– Examples of substances that can cause acute renal
failure include:
• Arsine and stibine - can cause breakdown of red blood
cells which can block the tubules. Appearance of
haemoglobin in urine can cause it to turn red.
Kidneys as a target organ
• Chronic kidney damage or renal failure
– Can occur when a significant number of nephrons are
damaged or die
– Remaining nephrons are overloaded. Proteins and
glucose are found in urine
– Heavy metals e.g. cadmium, mercury and lead
• Characteristic low-molecular weight proteins are found in
the urine as result of kidney damage by cadmium
– Halogenated hydrocarbons e.g. carbon tetrachloride
and chloroform
• Biotransformation of these substances in the liver produces a
metabolite that damages kidney tissue
Reproductive system
• Exposure to some substances may affect ability to
produce offspring
• Males
– Reduced sperm count or sperm motility
• Causes: some pesticides, oestrogen (pharmaceutical manufacture),
some glycol ethers, lead
• Females
– Menstrual disorders
• Causes: carbon disulphide, inorganic mercury
– Increased risk of miscarriage
• Some glycol ethers, lead, some anaesthetic gases
Reproductive system
• Exposure to some substances may affect the development of
the unborn child
– Termed developmental toxicants or teratogens that can affect the
embryo or foetus
– Often relatively non-toxic to the mother
– Organic mercury – can affect development of brain cells leading to
CNS defects
– Thalidomide – caused upper and lower limb defects
– Lead – can cross the placental barrier and can cause severe swelling of
the brain and destruction of neurons. It can also cause spontaneous
abortion or premature birth