Occupational lung disorders due to metals

1. Occupationallung disorders due to metals Prof Tony Cantrell National Institute for Occupational Health & University of the Witwatersrand Johannesburg South Africa tony.cantrell@nioh.nhls.ac.za

2. I hope that this talk will steer us away from the rigid way of thinking about toxic metals to new approaches for old problems. Dealing with some aspects from existing wisdom and also looking at what the future may come up with. This presentation is not meant to form a mini reference file on the subject of metals and lung disease, but should rather help us develop an approach to understanding what happens when we insult our lungs with metals at work and in the environment.

4. Non-specific metal toxicity • Metals are generally toxic in the human body, even if some are essential to our wellbeing in trace amounts • As soluble divalent cations, or in other chemical forms, they interact with susceptible sites on enzymes, proteins, active receptors, DNA, membranes etc • Who are exposed? workers – children – hobbyists – the general population • Gradually the environmental background of non-degradable toxins is building up as industrial volumes accelerate

5. Some specific disease entities involving the lungs include: • Irritation of the lungs, asthma, chronic bronchitis, COPD, cancers • Metal Fume Fever – cutting, smelting, galvanizing • Cadmium fume causes pneumonitis distinct from Metal Fume Fever • Acute chemical pneumonitis - gold amalgum retorters inhale mercury vapour • The ACGIH BEI for elemental mercury in urine is 35 microg Hg/litre. • The patient was measured as excreting 11 000 microg Hg/litre. • Acute chemical pneumonitis, but died of kidney failure • Hard Metal Disease • Beryllium Disease

6. Uranium induced malignancies - Slimes dams and old milled dust in air Concern was old cyanide! Lifetime [50 year] cumulative whole body dose of 1 sievert. An additional statistical risk of developing lung cancer = 5%

7. Chromiun, Nickel, Vanadium Well known to cause variety of occupational asthma and lung cancers, and other occupational diseases Chromium: lung not the only target site septal defects, rodent ulcers, carcinoma of the tongue etc. Mechanism assumed to be via chronic irritant action [hexavalent ion] Nickel: Respiratory sensitizer, probable lung carcinogen Vanadium: Respiratory irritant in association with SOx and ammonia

8. Metal Fume Fever • Caused by the inhalation of finely divided fume [<1 micron] of some non-ferrous metals • Frequently encountered • Self limiting without intervention • Symptoms • Flu-like illness of short duration, metallic taste in mouth, throat irritation and dry cough , tight chest, cold shivers • Onset: 3-10 hours post exposure, resolving on its own within 48 hours • Follwing an attack, a temporary period of tolerance for 1 or 2 days

9. Metal Fume Fever • Caused by heavy exposure to finely divided ZnO dust and fume during dip galvanizing of hot corrugated iron sheets, casting molten metal, flame cutting and welding • Copper and magnesium fume have similar effects. Brass ‘Foundrymans Ague’

10. Cadmium pneumonitis • Acute exposure at low concentrations > symptoms = MFF. Occupational history is critical for the differential Dx • Irritation of the URT with cough, irritation of the throat, metallic taste, dyspnea, chest pain • Onset may be delayed for 4-8 hours • At higher exposure: pulmonary oedema, chemical pneumonitis, GIT and fluid balance problems • Exposure for as little as a shift can lead to wheezing, chest pain, persistent cough and respiratory failure 3-7 days later • Higher exposures may lead to progressive pulmonary fibrosis and impaired lung function. At this stage multiple organ systems will also be affected

11. Hard Metal Disease • This is a chronic interstitial lung disease caused by cobalt fume and dust • aka - Giant cell interstitial pneumonitis • Affects workers exposed to cobalt fume/dust while making or using tungsten/carbide hardened tools • Latency of 6-48 months • Present with dyspnea on exertion, cough , fatigue • Show lung infiltrates and possibly restrictve lung function defect

12. Hard Metal Disease • Symptoms & Findings • Chest tightness, cough • Clubbing • Diffuse, interstitial infiltrates • Exertional dyspnea • Inspiratory rales • Restrictive defect • Sputum production • Weight loss • If cobalt exposure continues, progressive fibrosis with respiratory failure may develop • Cobalt may also > occupational asthma, bronchitis, bronchiolitis obliterans, and acute chemical pneumonitis at high cobalt exposure

13. Welding exposes the worker to metal fumes of variable composition • Millions worldwide use the process • High temperatures up to 4000 oC produce hazardous fumes and gases • An Antonini et al revue examined the effect of welding fume on respiratory health [Am J Resp Hlth 2003 43:350] • Full-time welders exhibit • Metal fume fever • Airway irritation • Lung function changes • Susceptibility to lung infection • Possible increase in incidence of lung cancer • But mechanisms are not clear, and further work is needed

14. Exposures associated with welding What causes Welders’ Lung? Iron siderosis, deposits in the lung Manganese respiratory irritant, neurotoxic Cr & Ni lung cancers,, septal defects, skin ulcers Cu & Zn metal fume fever Cd brown CdO fume, lung irritation, kidney, Ca prostate? Lead divalent ion [Pb2+] effects, lung cancers? Fluoride URT irritation, chronic bone disease, fluorosis Ozone irritant, lung fibrosis NOx acute & chronic effects on lungs + the effects of PPE, radiation, very hot air and high work rate Mixed exposure at its worst!

15. Does lead cause lung disease? • Not the usual target organ [marrow, kidneys, CNS, sperm] • Not a classical carcinogen • Yet the lung are the main portal of entry to the body. Non-specific divalent toxicity must have some negative effects! • The IARC have classified Pb and its compounds as probable human carcinogens based on increased prevalence of lung, kidney and bladder tumors in workers occupationally exposed to lead. • 1 of 6 cohort studies on smelter workers showed a significant 2-fold increase in lung cancer. • Is this playing with numbers? • Confounders to consider include conditions in the industry, trace contaminants [alloys, recycling] and other factors

16. The role of nanoparticles in the lungs • Engineerednanoparticle technology is developing fast, with the attendant production and analytical skills • This has generated new interest in ultrafine particles created in industrial processes and which can be inhaled • Their small size will affect retention, dwell time and fate in the lungs • May not necessarily damage the lung itself, but small size allows them to penetrate what is normally a defensive barrier. Affects toxicity, alters possible target organs. Affects a spectrum of exposure diseases.

17. Nanoparticles II • Some Swedish workers postulate that very small Mn particles may track up nerve fibres into the brain. But this is only one form of exposure. Normal miners also develop Mn toxicity from exposure to much larger particles. • Metallic nanoparticles in the workplace are generated at very high temperature, such as encountered in welding. This could include second stage fume formation from larger dust particles. • Exposure to this type of vapour has been shown to result in increased heart rate, increased autonomic control in workers. • American and Swedish laboratories are working on characterizing high temperature process aerosols for distribution in the URT. • Need for new measurement methods for conceptual understanding of NP technology and its attendant hazards • Need for different methods of hygiene, control and PPE • NIOH nickel case study: not known as IDLH till now

18. Into the future with beryllium • Beryllium is the second lightest metal which makes excellent alloys for components in a variety of aerospace, defense and other applications [Be/Cu] • But inhalation of beryllium dust or fumes causes chronic beryllium disease [CBD]andlung cancer • CBD is a rare disease characterized by diffuse interstitial pulmonary granulomatosis. Presents with dyspnea and dry cough • CXR show fine granular shadows throughout the lungs • Compromised lung function and blood gases • Accumulation of CD4(+) T cells • Mimics sarcoidosis and must be considered in the differential Dx

19. Recent work in the Netherlands and in the USA has shown that only 5-15 % of exposed workers get interstitial disease! The use of genomic analysis may explain why genetic and/or susceptibility variation may predispose certain individuals to CBeDisease Silver & Sharp [Occup Env Med (2006) 48:4, 434-43] have reported that the predictive value of the HLA-DPB1-Glu69 marker for susceptibility to beryllium disease is 12%. Not yet at the stage of clinical application, such techniques are assisting occupational medicine to enter the 21st Century in style. The challenge to us is to keep abreast with modern technology!

20. A genomic micro-array showing up and down regulated genes from a typical analysis