Occupational Toxicology – Part 3

Occupational toxicology – Part 3

DR MELISSA YSSEL, MBCHB (PRET), FC PATH (SA) CHEM, DOHM (PRET), INDUSTRIAL TOXICOLOGY CENTRE – LANCET LABORATORIES, PO BOX 7001, PRETORIA, 0001 TEL: 012 483 0272, FAX: 012 483 0187, e-mail: [email protected] www.lancet.co.za

Occupational toxicology will be presented as a five-part series.

SITE SPECIFIC TOXICITIES H. Reproductive toxicity A. Immunotoxicity I. Dermatotoxicity B. Haematotoxicity C. PULMONOTOXICITY PULMONOTOXICITY D. Cardiotoxicity The respiratory tract, with its limited defence mechanisms and high E. Hepatotoxicity degree of exposure to the environment, is one of the most vulnerable F. Nephrotoxicity organ systems to chemical pollutants. G. Neurotoxicity

SITE OF RESPIRATORY TRACT DEPOSITION

Water solubility Examples of sources Site of injury High Ammonia, formaldehyde Upper airways Moderate Chlorine, sulphur dioxide Lower airways Low Nitrogen oxides, phosgene Lung parenchyma Particle size (aerodynamic diameter) Examples of sources Site of injury >10 µm Dust from earth’s crust Upper airways 2,5–6 µm Some fire smoke particles Lower airways <2,5 µm Metal fumes, asbestos fibres Lung parenchyma

POTENTIAL EFFECTS OF INHALED IRRITANTS Site of injury Acute effects Chronic effects Eyes, nose, sinuses, oropharynx Irritation, inflammation Corneal scarring, nasal polyps Upper airways Laryngeal edema, upper airway obstruction Laryngeal polyps Lower airways Tracheobronchitis, decreased mucociliary clearance Asthma, bronchiectasis Lung parenchyma Pulmonary fibrosis, bronchiolitis obliterans

UPPER RESPIRATORY TRACT rhinorrhea and nasal congestion. Upper airways: nares to larynx Workplace allergens producing allergic rhino-conjunctivitis may Functions: Air conditioning; filtering; ‘scrubbing’ mechanism for water- either be commonly encountered allergens, exposure to which may soluble air pollutants; microbial defence – lysozyme and be incidental to the work environment (grass pollen exposure in a lactoferrin; sensation – odour and irritant perception; and phonation. landscaper), or it may be unusual agents encountered only in industrial setting (trimellitic anhydride exposure in plastic workers). Initial Acute response mechanisms of upper airways sensitization may occur either in the workplace or outside, thus it 1. Allergy. may be either work-related or work-exacerbated. 2. Neurogenic reflexes. Symptoms: sneezing, itching, rhinorrhea and congestion, with or with- • Stimulation of trigeminal nerve afferents – low pH, endogenous in- out eye and chest symptoms. Non-occupational symptoms occur flammatory mediators (bradikinins) and chemical irritants. during a portion of the year (typically from pollens) = ‘seasonal allergic • Two major responses: parasympathetic reflex (‘gustatory rhinitis’ rhinitis’, in contrast to ‘perennial allergic rhinitis’ (year round symptoms) e.g. with ingestion of spicy food) and the axon reflex (theoretical in response to indoor allergens (dust mites, cockroach, mould spores). more than proven). Occupational allergic rhinitis may exhibit either of the above tem- poral features, although perennial is somewhat more common: Mechanisms Systemic eosinophylia; increased total IgE; increased RAST/ELISA Irritant stimulus antigen-specific IgE; and positive skin prick tests. 1. Mast cell degranulation. 2. Central (autonomic) reflexes – cranial nerve V–VII. Agents associated with occupational allergic rhinitis 3. Local (axon) reflex – cranial nerve V. High molecular weight compounds (proteins) Mediator release • Animal antigens (animal handlers, farmers, veterinarians). 1. Glandular secretion – rhinorrhea. • Green coffee bean and castor bean (dock workers). 2. Plasma transudation – rhinorrhea/nasal congestion. • Proteolytic enzymes (detergent workers, cosmetologists). 3. Vasodilatation – nasal congestion. • Grains/contaminants (bakers, farmers, grain handlers). 4. Chemotaxis – inflammation. • Insect antigens (various occupations). • Gum Arabic/gum acacia (printers). OCCUPATIONAL ALLERGIC RHINITIS • Psyllium (health care workers). Twenty percent of the population suffers from allergic rhinitis. Five • Natural rubber latex (health care workers). percent of the population suffers from nonallergic rhinitis. Typically these individuals experience either seasonal pollinosis or, if allergic Low molecular weight compounds to common indoor allergens, perennial symptoms of sneezing, • Diisocyanates (polyurethanes – painters, boat builders).

OOCCUPATIONALCCUPATIONAL HHEALTHEALTH SSOUTHERNOUTHERN AAFRICAFRICA MMAYAY/J/JUNEUNE 20062006 1111 • Acid anhydrides (plastics – painters, fabricators). Most commonly reported symptoms in the work environment. • Colophony (rosin core solder – electronics workers). Symptoms: Predominantly irritant symptoms (nasal congestion and • Antibiotics (heath care workers). rhinorrhea) rather than itching or sneezing, high symptom prevalence rate among co-workers and dramatic improvement at night and over OCCUPATIONAL IRRITANT RHINITIS weekends. Erythema of the mucous membranes (punctate erosions The eyes, nose and throat are sensitive to chemical irritants (gases, of nasal mucosa) supports an irritant process. Lack of systemic vapours, dusts and smokes) resulting in mucous membrane irritation. eosinophylia. Normal total IgE.

Water solubility Initial level of impact Compounds High Eyes Aldehydes Nose Ammonia Pharynx Chlorine Larynx Sulphur dioxide Medium Trachea Ozone Bronchi Low Bronchioles Nitrogen dioxide Alveoli Phosgene

OCCUPATIONAL ‘VASOMOTOR’ RHINITIS Gasoline, diesel oil, ? mineral oil. An augmented nasal reactivity to nonspecific physical stimuli. Leather and textile workers. Subcategory of non-allergic rhinitis. Machining fluids. Symptoms of rhinorrhea predominate. SENSORY (OLFACTORY) ALTERATIONS Relevant physical stimuli: Temporary/permanent. • Low humidity; temperature extremes; rapid temperature changes; Temporary threshold shift (recovered olfactory acuity within 2 hours and excessive air motion. of cessation of exposure) – due to adaptation = odours lose their intensity during continuous exposure. NON-OCCUPATIONAL (OTHER) RHINITIS SYNDROMES For the sake of completeness: Differential diagnosis: head trauma, endocrine disorders, chronic na- • Non-allergic rhinitis with eosinophylia syndrome (NARES). sal obstruction, post-infectious inflammation, neurodegenerative dis- • Endocrine rhinitis. orders, neoplasms, congenital defects e.g. Kallmann’s syndrome, psy- • Wegener’s granulomatosis. chiatric conditions. • Nasal polyposis. • Immotile cilia/Katagener’s syndrome. Quantitative defects: hyposnosmia (reduced odour acuity) and anos- • Cystic fibrosis. mia (absent odour perception). Qualitative defects: olfactory agnosmia (decreased ability to identify PARANASAL SINUS DISEASE odours) and various dysosmias (distorted odour perception) e.g. Active smokers at higher risk for developing acute/chronic sinusitis. aliosmia (unpleasant sensations from normally pleasant odorants) Inflammation of the upper and lower respiratory tracts appears to and parosmias (phantom odours). be linked, in that active sinusitis apparently augments nonspecific bronchial reactivity in asthmatics. Causes • Cadmium/nickel exposure – alkaline battery workers, braziers. Pathophysiology of occupationally-induced (or exacerbated) sinusitis • Hydrocarbon exposure – tank cleaners. 1. Initial allergic or irritant rhinitis. • Solvent +/- acrylic acid exposure – paint formulators. 2. Ciliastasis (with impaired clearance of pathogenic organisms). • Ammonia and sulphuric acid exposure – chemical plant workers. 3. Mucous membrane swelling (with occlusion of sinus ostia and im- • Mercaptans, hydrogen sulphide exposure: acute, reversible ‘olfactory paired drainage), and finally: paralysis’. 4. Infection.

Postulated mechanisms LOWER RESPIRATORY TRACT/LUNGS • Up-regulation of neurogenic responses. Lower airways: tracheo-bronchial tree to the lungs • Aspiration of biochemical-mediator laden nasal secretions into the Cell types lower respiratory tract. Ciliated epithelial cells Type I alveolar cells – gas exchange. Agents/processes associated with sino-nasal cancer: Type II alveolar cells – surfactant. Wood dust; leather dust; nickel refining; chrome refining and plating (Chromates (Cr6+)); cigarette smoking; mustard gas manufacturing; Susceptibility to damage due to: Isopropanol manufacturing (strong acid method); welding, flame cut- • Large surface area. ting and ? brazing; ? Formaldehyde; and Radium dial painting. • Sensitive mucosal tissues.

LARYNGEAL PATHOLOGY TOXIC INHALATION INJURY Symptoms: ‘hoarseness’ • Short-term exposures to high concentrations of noxious gases, fumes Exposure/overuse (noise). or mists. Squamous cell carcinoma of the larynx. • Generally due to industrial or transportation accidents or fires. Laryngeal strictures. • Site of injury depends on the physical and chemical properties of Laryngeal papillomatosis. the inhaled agent. • Site of deposition is determined primarily by water solubility. Agents/processes associated with laryngeal cancer: • Other factors: duration of exposure and minute ventilation of victim. Asbestos. • Effects are usually transient but can range from mild irritation of the Cigarette smoking. mucous membranes of the upper airways to fatal adult respiratory Ethanol consumption. distress syndrome (ARDS).

12 MAYAY/J/JUNE 20062006 OCCUPATIONAL HHEALTHEALTH SSOUTHERN AAFRICAFRICA • Adverse effects depend on the concentration of the inhaled sub- Agents causing inhalation fevers stance. • Metal fume fever (zinc, copper, magnesium). • Polymer fume fever (Teflon pyrolysis products – Long-term sequelae: bronchiectasis, bronchiolitis obliterans and per- polytetrafluoroethylene). sistent asthma. • Humidifier fever (contaminated water). • Organic dust toxic syndrome (ODTS) (mouldy silage, compost, wood OCCUPATIONAL ASTHMA chips, sewage sludge). Asthma is characterized by reversible airway obstruction, airway in- • Mill fever (cotton, hemp, jute, flax dust). flammation and increased airway responsiveness to a variety of stimuli. • Grain fever (grain dust).

Major types of occupational asthma METAL-INDUCED LUNG DISEASE 1. Sensitizer-induced asthma: variable time during which ‘sensitization’ • Hard-metal (cemented alloy of tungsten carbide with cobalt) – ex- to an agent present in the work site takes place. posed workers develop interstitial lung disease = ‘hard-metal disease’ 2. Irritant-induced asthma: occurs without a latent period after sub- and occupational asthma. stantial exposure to an irritating dust, mist, vapour or fume. • Putative cause of both processes: cobalt. • Beryllium – ceramics, electronics, aerospace, nuclear weapons/ Reactive airways dysfunction syndrome (RADS) = irritant induced power industries. asthma caused by a short-term, high-intensity exposure. • Chronic beryllium disease = granulomatous inflammatory disorder similar to sarcoidosis. Agents causing occupational asthma • Other metals: cadmium, chromium, or nickel fumes, mercury va- Without ‘sensitization’: pour, antimony, barium, iron, and tin dust, titanium, tantalum, molyb- • Anticholinesterase effect – organophosphate pesticides (agriculture). denum. • Endotoxin effect – cotton dust (textiles). • Airway inflammation – acids, ammonia, chlorine (custodial workers, PNEUMOCONIOSIS paper manufacturing). 1. Silicosis (exposure to silicon dioxide, silica). • Airway irritation – dusts, fumes, mists, vapours, cold (construction, Three disease patterns: chemical workers). a. Chronic simple silicosis (>10 years exposure). b. Subacute/accelerated silicosis (short, heavy exposure i.e. 2–5 With ‘sensitization’: years). High molecular weight agents: IgE-mediated (complete allergens) – c. Acute silicosis (intense exposure over several months). animal/plant proteins (laboratory workers, bakers). 2. Asbestosis (asbestos – chrysolite, amosite, crocidolite, anthophyllite, tremolite and actinolite). Low molecular weight agents: 3. Coal worker’s pneumoconiosis (coal dust). • IgE-mediated (haptens) – antibiotics, metals (pharmaceutical indus- 4. Other pneumoconioses: graphite (disease similar to coal worker’s try, metal plating). pneumoconiosis), kaolin and diatomaceous earth (silicosis-like dis- • Mechanism unknown – acid anhydrides, diisocyanates, plicatic acid ease), talc and mica (disease with features of both silicosis and as- (epoxy plastics and paints), polyurethane foams and paints, western bestosis), aluminium oxide. red cedar products. CHRONIC BRONCHITIS HYPERSENSITIVITY PNEUMONITIS • Inflammation of the bronchial tree. • ‘Extrinsic allergic alveolitis’. • Persistent cough, production of sputum, for most days, for at least 3 • Immunologically-mediated inflammatory disease of the lung paren- months of the year, for at least 2 successive years. chyma that is induced by inhalation of organic dusts that contain a variety of etiologic agents. Agents causing chronic bronchitis • Initial lymphocytic alveolitis and granulomatous pneumonitis – im- 1. Minerals: coal, oil mist, silica, silicates, man-made vitreous fibres, provement or complete resolution if antigen exposure is terminated Portland cement. early. 2. Metals: osmium, vanadium, welding fumes. • Continued antigen exposure – progressive interstitial fibrosis. 3. Organic dusts: cotton, grain, wood. 4. Smoke: tobacco smoke, fire smoke, engine exhaust. Agents causing hypersensitivity pneumonitis: 1. Bacteria: mouldy hay – farmer’s lung, mouldy grain – grain work- PLEURAL DISORDERS er’s lung, compost – mushroom worker’s lung, mouldy sugar cane • Visceral pleura (lungs). fibres – bagassosis, heated water reservoirs – humidifier lung, deter- • Parietal pleura (mediastinum, diaphragm, rib cage). gent – detergent worker’s lung. • Asbestos exposure (also talc, mica). 2. Fungi: mouldy malt – malt worker’s lung, mouldy cheese – cheese • Benign pleural effusions. worker’s lung, mouldy cork dust – suberosis, mouldy maple bark – • Pleural plaques. maple bark stripper’s lung, mouldy red wood dust – sequoiosis. • Malignant mesothelioma – 80% asbestos-related (crocidolite, 3. Amoebae: contaminated water – humidifier lung. amosite). 4. Animal proteins: bird droppings/feathers – bird breeder’s lung, ro- dent urine/sera/pelts – animal handler’s lung, infested flour – wheat LUNG CANCER weevil lung. Known: asbestos, arsenic, chloromethyl ethers, chromium 5. Chemicals: toluene diisocyanate, hexamethylene diisocyanate (hexavalent), nickel, radon, environmental tobacco smoke, mustard (paintings, coatings), diphenylmethane diisocyanate (polyurethane gas, polyaromatic hydrocarbons e.g. benzopyrene. foam) – isocyanate lung, trimellitic anhydride (epoxy resins, paints) – TMA pulmonary haemorrhage-anaemia syndrome. Suspected: acrylonitrile, beryllium, cadmium, formaldehyde, silica, man-made vitreous fibres, vinyl chloride monomers. INHALATION FEVERS Consist of several syndromes that are characterized by short-term, but debilitating, flu-like symptoms after exposure to organic dusts, REFERENCE polymer fumes and metal fumes. Attack rate high i.e. most people La Dou J. Occupational & Environmental Medicine. 2nd ed. United States of will experience symptoms as a result of high-level exposure to the America: McGraw-Hill; 1997. etiologic agent.

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