1. Occupational lung disorders due to metals
Prof Tony Cantrell
National Institute for Occupational Health &
University of the Witwatersrand
Johannesburg
South Africa

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 microg Hg/litre.
Acute chemical pneumonitis, but died of kidney failure
Hard Metal Disease
Beryllium Disease

6. Lifetime [50 year] cumulative whole body dose of 1 sievert.
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 :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
Engineered nanoparticle 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. NIOH nickel case study: not known as IDLH till now
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] and lung 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, ] 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