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My commentary on the case…….

Renal carcinoma. Renal cell carcinoma is the commonest primary renal tumour, but the renal collecting system is lined with transitional epithelium, so that the pathology and aetiology of transitional cell carcinomas (TCC) in this area is to all intents and purposes identical to those described for bladder TCC.

Bladder cancer

Bladder cancer is the eighth most common malignancy in men, and accounts for about 5% of all cancers world wide, being more prevalent in industrial societies so that environmental agents are suspect in its causation. A number of etiologic factors are associated with the development of TCC. The major occupational cause, occupational exposure to arylamines, has been recognized for 4 decades. The first cases of occupational bladder cancer were described by Rehn in 1895, in workers who were making aniline based synthetic dyes. The agents responsible were identified as benzidine 2-Napthylamine and 4-aminobiphenyl. Other dyestuff carcinogens include -toluidine, 3,3’-dichlorobenzidine and o-dianisidine..

The rubber tyre industry was also implicated in the 1930s because antioxidants, particularly an ICI product called Nonox ‘S’, were contaminated with 2-Napthylamine.

More recently, smoking has also been associated in the causation of TCC. The mechanism for smoking and bladder cancer is not known with certainty, but it is likely that cigarette smoke also contains low levels of the carcinogenic arylamines which induce bladder cancer in occupational settings. These arylamines undergo metabolic transformation within the body, and then form DNA adducts, a probable essential step in the carcinogenic process.

Chemicals in the printing industry. I have edited the relevant sections from the OSH publication “Health and safety in the printing industry” to produce some sections of this report. Printing ink contains pigments, additives (such as plasticisers) and solvents.

Toxicity of pigments Pigments are added to paint and printing ink formulations primarily to provide colour to the product but also to give opacity and body. They are usually light-stable and non-reactive with the medium. Extender pigments are usually white or off-white in colour, but add little in colour or opacity when incorporated in coatings. There is a large variety of other pigment materials which are both organic and inorganic in nature. Typical inorganic pigments include titanium dioxide, zinc oxide, lithopone, and antimony oxide (white); chromic oxide (green) ultramarine blue (a form of aluminium silicate); brown or yellow oxides of iron (known as ochres); ferric oxide (red); lead oxide (red); carbon black; cadmium compounds (yellows and oranges); and lead chromes which are complex lead chromate salts and which, depending on their exact formulation, give rise to a wide range of colours varying from lemon through yellow and orange to pink and scarlet. Types of organic pigment materials include the highly stable phthalocyanines (blue and green); quinacridones (red); benzidine-based substances (yellow); lakes, of various colours, obtained by precipitation from dyestuffs, often by using a metallic hydroxide; and azo-based pigments, again of many different colours. Pigments are generally finely powdered solids. The principal routes of entry into the body are by ingestion (swallowing) of pigment dust from contaminated hands or food, and inhalation of line dust into the lungs. For many pigment materials, particularly those which are organic-based, details of toxicity are unknown. Although it is sometimes possible to infer the approximate degree of toxicity from a knowledge of the toxic properties of the parent molecule, this does not make it safe to assume a low toxicity for all derivatives of a particular pigment class where the parent molecular unit is itself known to be of low toxicity. Where reliable information is not available on the toxicity of a pigment material, it must be assumed to be toxic and appropriate precautions as noted below observed. Specific materials well known to present toxic hazards include lead-based pigments, and cadmium compounds. Lead chromes and lead oxide may give rise to problems of excessive lead absorption in employees if handled incorrectly. The inhaled or ingested dust from these materials will be absorbed into the blood stream and contribute to an increased body burden of lead. If these levels become high, as measured by the quantity of lead in the red blood cells, the employee will begin to suffer the symptoms associated with lead poisoning. Lead chromate and related compounds are also under suspicion as possible cancer-causing agents. For provisions relating to personal hygiene when working with lead compounds, the regulations should be consulted. Cadmium compounds used as pigments must be handled with caution as these substances can be very toxic. Exposure to ingested cadmium causes injuries to kidneys and livers and stomach upsets resembling food poisoning, while inhalation of the dust of cadmium compounds may result in chest pains, coughing and tightness in the chest, and eventually cadmium emphysema.

Additive toxicity. Additives in printing inks account for only a small percentage of the total formulation but their inclusion is critical to the performance of many products. Thus: (a) Dryers are added as oxidation catalysts for the drying of oil inks. The most usual drier additives are cobalt naphthenate, lead acetate, and manganese linoleate. (b) Slip compounds such as waxes are added to improve the scull resistance of inks, particularly those used in packaging. (c) Wetting agents are added in very low concentrations, and they are generally detergent-related materials of low toxicity. The hazard potential of most additives is low; however, cobalt naphthenate and lead acetate may each present certain problems. Cobalt naphthenate is very easily ignited by an external source of ignition. Storage and handling of cobalt naphthenate must take due account of its highly combustible nature. Cobalt naphthenate iscommonly used in solution in mineral turpentine. Lead acetate can be inhaled or ingested into the body in the same manner as for any finely divided solid lead compound. Raised lead-in-blood levels will result, and if the absorption continues the symptoms of lead poisoning may become apparent

Solvents in the printing industry. As Mr Monkwood describes in his report, solvents are frequently used within the printing industry, both in the formulation of inks (which also contain alcohols, ketones acids and esters), but more importantly in “cleaning up”. A variety of solvents are used, all of them being various “cuts” obtained during the fractionation of petroleum. They therefore contain aliphatic, polycyclic and aromatic compounds. The effect of the non-substituted aliphatic and aromatic compounds (those with only carbon and hydrogen) is primarily on the nervous and hepatic systems. In the nervous system, the syndrome known as solvent induced neurotoxicity is a common outcome. The main symptoms are headache, irritability and forgetfulness. Some cuts of solvent also contain cyclohexane, which has been known to cause a peripheral neuropathy. This produces abnormalities of sensation in the peripheral nerves. The hepatic problems include potentiation of liver enzymes, and liver failure with prolonged or heavy exposure. If the hydrocarbons are chlorinated, the toxicity is increased. Solvents such as tetrachloroethylene are very hepatotoxic, and also cause renal damage. The renal damage is usually a proximal tubular necrosis, or more widespread ischaemic damage. Chlorinated organic solvents have also been associated with cancer in (for example) dry cleaners, but this is renal cell carcinoma, a primary tumour of the kidney and not a transitional cell tumour.

Solvent exposure in the industry. I had the chance to make a workplace assessment at Speedyprint Press, during which time I was able to examine some of the machines which Mr Monkwood would have used. I am familiar with the broad outline of the printing process, but the visit served to refresh my memory.

The process at Speedyprint is based on lithography, which uses the properties of dissimilar materials. The ink absorbs onto a solvent receptive area, and the water receptive area forms the background. The image is transferred from the printing cylinder to a “blanket” before transfer to the paper, hence the term offset printing.

The printer is involved in all aspects of running the printing machine.

Exposure to inks (containing pigments) takes place while installing the printing cylinders. This job can be fiddly, and gloves are supposed to be worn, but this seems not always to be possible. as a result, the hands become fairly liberally coated with wet ink at times. Absorption would therefore mainly be through the skin.

Ink is loaded into the machine (often at three places with colour machines). The ink comes in the form of a viscous paste. This is transferred to the inking unit with a spatula or knife. Once again, there is the possibility of skin contamination.

Cleaning up is the process where most solvents are used. “Wash ups” are the process whereby the inking units are cleaned. With some newer units, the process is semi automatic, but on older machines the unit required to be disassembled and cleaned manually. The insides of the printing units can be liberally coated with ink, and also require cleaning.

Special mention must be made of blankets which were stuck on to the printing cylinder with adhesive. These required the use of special solvents, probably containing cyclohexane/cyclohexanone.

I observed solvent use at the press. It is held in plastic “squeezy” bottles, with a small cut-out in the lid. For cleaning up purposes it is either applied direct to the part to be cleaned, or applied by a rag. By either route, both inhalation and skin exposure is possible. The exposure has been higher in the past, when more open vessels were used for solvent storage and use, and is still probably quite high at present.

Opinion. 1. The diagnosis is Transitional Cell Carcinoma of the Bladder.

2. As regards work-relatedness, section 33 of the act requires that the personal injury must be caused by an environment that has a particular property or characteristic that causes or contributes to the personal injury. In this case, there was heavy exposure to organic solvents, mostly of a non-chlorinated nature, in many employment tasks. Mr Monkwood frequently seems to have suffered from the symptoms of solvent toxicity, and is understandably worried that the solvents may also have caused his renal cancer. In these cases, a search must of course be instigated for possible aetiological agents. As far as I can ascertain, there is however no link between bladder or renal TCC and exposure to non-chlorinated organic solvents. There have been suggestions that chlorinated solvents may cause renal cancer, however the link here seems to be related to renal cell carcinoma, a different disease. On the basis of the major exposure, there is no aetiological link.

3. The main agent in printing which has been associated with TCC is in the dyestuffs associated with printing, particularly the benzidine based yellow substances. Exposure to these agents within the dyestuff industry (and some sections of the printing industry) may be by ingestion of the substance in powder form, for example during mixing of agents in screen printing. Exposures would therefore be high. In lithography, such dyes are part of a liquid formulation, and though skin absorption could possibly take place, exposure would be very much less under these circumstances, from the point of view of both frequency and intensity of exposure.

4. Section 33(2)(c) requires that the risk is significantly greater for persons who work in that environment than for persons who do not work in it. The epidemiological evidence for TCC of the bladder can best be described as equivocal. There are a number of studies which have shown an increased risk for printers, but there is an almost equal number of reports which show no association. I attach a list of such studies which I have briefly reviewed for the purposes of making this report. The occupations implicated are many: apart from the occupations with an established risk (such as rubber and dye workers) engineers, agricultural workers, hairdressers, meat workers, painters and truck drivers all feature. The problem with many of these occupations is that the exposure is ill defined. Many of the reports (such as those which I have listed) are case-control studies, which are based on job titles. The job title reported in these studies does not necessarily reflect a specific exposure, for example letterpress, gravure, lithographic and screen printers may all report the occupation “printer” whereas the exposures are all very different. Note particularly that the larger studies do not show an increase of risk, the most recent of these being a study of 803 urothelial cancer patients from the West Midlands by Sorahan et al. These authors state specifically that “there was no excess risk for the printing industry, and this estimate was in keeping with a pooled estimate of Relative Risk (1.10, 95% CI 0.88-1.39) derived by the present authors from those nine published cohort studies reviewed by a working group from the International Agency for Research on Cancer to evaluate cancer risks associated with printing processes and printing inks”. This must be regarded as the most definitive evidence to date.

5. Section 33(b)(ii) is also important in this case. The particular property or characteristic must not be found to any material extent in the non-employment activities or environment of the insured. In this case, Mr Monkwood smoked. This has been shown to be a definite risk factor for bladder cancer, with most studies showing a relative risk between 1.5 and 5 for smokers v referents. In this case, I think that this is the most likely cause of the condition: the mechanism has been reasonably well defined, and the epidemiological evidence is coherent.

I therefore conclude that the most likely cause of Mr Monkwoods TCC was his smoking. His occupational exposure, on the basis of the present evidence, is most unlikely to be material.

I realise that you may wish to clarify this report. If so, please do not hesitate to get in touch.

Yours faithfully

David McBride Specialist Occupational Physician