W507 – Basic human biology and target organs

1. W507 – Basic human biology and target organs

2. Respiratory System • Structure • The lung as a route of entry • The lung as a target organ • Particles • Gases • Occupational lung disease

3. 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

4. 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)

5. Tracheo-bronchial region Structure: • 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)

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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.

13. Particle penetration & deposition: ISO 7708: 1993 curve

14. 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?

15. 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

16. The lung as a target organ • Irritation / Inflammation • Upper respiratory tract (URT) • Deep lung • Pneumoconioses • Fibrotic • Benign • Emphysema • Lung cancer • Respiratory sensitisation • Rhinitis • Occupational asthma • Extrinsic allergic alveolitis • Byssinosis

17. 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)

18. 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 • Coal worker’s pneumoconiosis (coal dust) • Silicosis (crystalline silica) • Asbestosis (asbestos) • Hard metal disease (cobalt, tungsten)

19. 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

20. 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

21. Lung cancer • Abnormal growth of cells in the lungs • 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

22. 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

23. Respiratory sensitisation • Occupational asthma • 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 • Isocyanates • Solder fumes • Some metals (e.g. platinum, cobalt) • Organic materials such as latex, animal proteins, vegetable dust • Detergents • Enzymes

24. 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).

25. 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.

26. Skin • Structure & function • Skin as a route of entry • Skin as a target organ - dermatitis - other skin conditions

27. Skin Structure Source: Tranter 1999 – Reproduced with permisssion

28. 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

29. 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

30. 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

31. Irritant Contact Dermatitis • About 70% of occupational skin disease • All workers exposed may be affected, provided exposure is repeated and prolonged • Typical skin irritants • Detergents • Alkalis (lime, cement, caustic) • Acids • Organic solvents • Oxidising and reducing agents • Some plants

32. Dermatitis

33. 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

34. Other skin conditions Folliculitis • Pores blocked by oils, greases, waxes • Causes acne like lesions • Chloracne – type of folliculitis caused by chlorinated hydrocarbons.

35. 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

36. 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

37. Skin Cancer • Malignant tumour • UV exposure • Most common cause – associated with production of melanomas (cancer of melanin producing cells in the skin) • Polycyclic aromatic hydrocarbons (PAH) • Coal tar, asphalt • Soot • Arsenic

38. Nervous System • Structure and function • Nervous system as a target organ • Structural damage to neuron • Functional damage to the nerves

39. 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

40. 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

41. (Source: Multiple Sclerosis Trust – reproduced with permission) Nerve cell (neuron): functional unit • 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. Circulatory system • Components and function • Blood as a target organ • Haemolysis • Carboxyhaemoglobin formation • Methaemoglobin formation • Anaemia • Leukaemia

50. 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