Address: International Agency for Research on Cancer, 150, cours Albert-Thomas, F-69372 Lyon
Phone: 33 47 273 8418
Fax: 33 47 273 8319
Past position(s): Director, Department Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health
Areas of interest: Cancer; molecular epidemiology; chemoprevention
Historically, kidney cancer has been used to mean either all malignancies of the renal system (renal cell carcinoma (RCC), ICD-9 189.0; renal pelvis, ICD-9 189.1; and ureter, ICD-9 189.2) or RCC only. This categorization has led to some confusion in epidemiological studies, resulting in a need to scrutinize previously reported data. RCC comprises 75 to 80% of the total, with the remainder being primarily transitional cell carcinomas of the renal pelvis and ureter. Separation of these two cancer types is appropriate since the pathogenesis of RCC and of transitional cell carcinoma is quite different, and epidemiological risk factors are distinct as are the signs and symptoms of the two diseases. This section focuses on RCC.
The major identified risk factor for kidney cancer is tobacco smoking, followed by suspected but poorly defined occupational and environmental risk factors. It is estimated that the elimination of tobacco smoking would decrease the incidence of kidney cancer by 30 to 40% in industrialized countries, but occupational determinants of RCC are not well established. The population attributable risk due to occupational exposures has been estimated to be between zero, based on recognized carcinogenesis, and 21%, based on a multicentric multisite case-control study in the Montreal area of Canada. Early biomarkers of effect in association with biomarkers of exposure should assist in clarifying important risk factors. Several occupations and industries have been found in epidemiological studies to entail an increased risk of renal cancer. However, with the possible exception of agents used in dry cleaning and exposures in petroleum refining, the available evidence is not consistent. Statistical analysis of epidemiological exposure data in relation to biomarkers of susceptibility and effect will clarify additional aetiological causes.
Several epidemiological studies have associated specific industries, occupations and occupational exposures with increased risks of renal cell carcinoma. The pattern that emerges from these studies is not fully consistent. Oil refining, printing, dry cleaning and truck driving are examples of jobs associated with excess risk of kidney cancer. Farmers usually display decreased risk of RCC, but a Danish study linked long-term exposure to insecticides and herbicides with an almost fourfold excess of RCC risk. This finding requires confirmation in independent data, including specification of the possible causal nature of the association. Other products suspected of being associated with RCC include: various hydrocarbon derivatives and solvents; products of oil refining; petroleum, tar and pitch products; gasoline exhaust; jet fuel; jet and diesel engine emissions; arsenic compounds; cadmium; chromium (VI) compounds; inorganic lead compounds; and asbestos. Epidemiological studies have associated occupational gasoline vapour exposure with kidney cancer risk, some in a dose-response fashion, a phenomenon observed in the male rat for unleaded gasoline vapour exposure. These findings gain some potential weight, given the widespread human exposure to gasoline vapours in retail service stations and the recent increase in kidney cancer incidence. Gasoline is a complex mixture of hydrocarbons and additives, including benzene, which is a known human carcinogen.
The risk of kidney cancer is not consistently linked with social class, although increased risk has occasionally been associated with higher socio-economic status. However, in some populations a reverse gradient was observed, and in yet others, no clear pattern emerged. Possibly these variations may be related to lifestyle. Studies with migrant people show modification in RCC risk towards the level of the host country population, suggesting that environmental factors are important in the development of this malignancy.
Except for nephroblastoma (Wilms’ tumour), which is a childhood cancer, kidney cancer usually occurs after 40 years of age. An estimated 127,000 new cases of kidney cancer (including RCC and transitional cell carcinoma (TCC) of the renal pelvis and ureter), corresponding to 1.7% of the world total cancer incidence, occurred globally in 1985. The incidence of kidney cancer varies among populations. High rates have been reported for both men and women in North America, Europe, Australia and New Zealand; low rates in Melanesia, middle and eastern Africa and southeastern and eastern Asia. The incidence of kidney cancer has been increasing in most western countries, but stagnated in a few. Age-standardized incidence of kidney cancer in 1985 was highest in North America and western, northern and eastern Europe, and lowest in Africa, Asia (except in Japanese men) and the Pacific. Kidney cancer is more frequent in men than in women and ranks among the ten most frequent cancers in a number of countries.
Transitional cell carcinoma (TCC) of the renal pelvis is associated with similar aetiological agents as bladder cancer, including chronic infection, stones and phenacetin-containing analgesics. Balkan nephropathy, a slowly progressive, chronic and fatal nephropathy prevalent in the Balkan countries, is associated with high rates of tumours of the renal pelvis and ureter. The causes of Balkan nephropathy are unknown. Excessive exposure to ochratoxin A, which is considered possibly carcinogenic to humans, has been associated with the development of Balkan nephropathy, but the role of other nephrotoxic agents cannot be excluded. Ochratoxin A is a toxin produced by fungi which can be found in many food stuffs, particularly cereals and pork products.
Screening and diagnosis of kidney cancer
The sign and symptom pattern of RCC varies among patients, even up to the stage when metastasis appears. Because of the location of the kidneys and the mobility of contiguous organs to the expanding mass, these tumours are frequently very large at the time of clinical detection. Although haematuria is the primary symptom of RCC, bleeding occurs late compared to transitional cell tumours because of the intra-renal location of RCC. RCC has been considered the “medical doctor’s dream” but the “surgeon’s curse” because of the interesting constellation of symptoms related to paraneoplastic syndromes. Substances that increase the red blood cell count, calcium and factors which mimic abnormal adrenal gland function have been reported, and abdominal mass, weight loss, fatigue, pain, anaemia, abnormal liver function and hypertension have all been observed. Computerized axial tomography (CAT scan) of the abdomen and ultrasound are being ordered by physicians with increased frequency so, consequently, it is estimated that 20% of RCCs are diagnosed serendipitously as a result of evaluation for other medical problems.
Clinical evaluation of an RCC case consists of a physical examination to identify a flank mass, which occurs in 10% of patients. A kidney x ray with contrast may delineate a renal mass and the solid or cystic nature is usually clarified by ultrasound or CAT scan. The tumours are highly vascular and have a characteristic appearance when the artery is injected with radio-opaque contrast material. Arteriography is performed to embolize the tumour if it is very large or to define the arterial blood supply if a partial nephrectomy is anticipated. Fine-needle aspiration may be used to sample suspect RCC.
Localized RCC tumours are surgically removed with regional lymph nodes and, operatively, early ligation of the artery and vein is important. Symptomatically, the patient may be improved by removing large or bleeding tumours that have metastasized, but this does not improve survival. For metastatic tumours, localized pain control may be achieved with radiation therapy but the treatment of choice for metastatic disease is biological response modifiers (Interleukin-2 or α-interferon), although chemotherapy is occasionally used alone or in combination with other therapies.
Markers such as the cancer gene on chromosome 3 observed in cancer families and in von Hippel-Lindau disease may serve as biomarkers of susceptibility. Although tumour marker antigens have been reported for RCC, there is currently no way to detect these reliably in the urine or blood with adequate sensitivity and specificity. The low prevalence of this disease in the general population requires a high specificity and sensitivity test for early disease detection. Occupational cohorts at risk could potentially be screened with ultrasound. Evaluation of this tumour remains a challenge to the basic scientist, molecular epidemiologist and clinician alike.
More than 90% of bladder cancers in Europe and North America are transitional cell carcinomas (TCC). Squamous cell carcinoma and adenocarcinoma account for 5 and 1%, respectively, of bladder cancer in these regions. The distribution of histopathological types in bladder cancer is strikingly different in regions such as the Middle East and Africa where bladder cancer is associated with schistosomal infection. For instance, in Egypt, where schistosomiasis is endemic and bladder cancer is the major oncogenic problem, the most common type is squamous cell carcinoma, but the incidence of TCC is increasing with the rising prevalence of cigarette smoking. The discussion which follows focuses on TCC.
Bladder cancer continues to be a disease of significant importance. It accounted for about 3.5% of all malignancies in the world in 1980. In 1985, bladder cancer was estimated to be 11th in frequency on a global scale, being the eighth most frequent cancer among men, with an expected total of 243,000 new cases. There is a peak incidence in the seventh decade of life, and worldwide the male to female ratio is around three to one. Incidence has been increasing in almost all populations in Europe, particularly in men. In Denmark, where annual incidence rates are among the highest in the world, at 45 per 100,000 in men and 12 per 100,000 in women, the recent trend has been a further rise of 8 to 9% every 5 years. In Asia, the very high rates among the Chinese in Hong Kong have declined steadily, but in both sexes bladder cancer incidence is still much higher than elsewhere in Asia and more than twice as high as that among the Chinese in Shanghai or Singapore. Bladder cancer rates among the Chinese in Hawaii are also high.
Cigarette smoking is the single most important aetiological factor in bladder cancer, and occupational exposures rank second. It has been estimated that tobacco is responsible for one-third of all bladder cancer cases outside of regions where schistosomal infection is prevalent. The number of bladder cancer cases attributed in 1985 to tobacco smoking has been estimated at more than 75,000 worldwide, and may account for 50% of bladder cancer in western populations. The fact that all individuals who smoke similar amounts do not develop bladder cancer at the same rate suggests genetic factors are important in controlling the susceptibility. Two aromatic amines, 4-aminobiphenyl and 2-naphthylamine, are carcinogens associated with cigarette smoking; these are found in higher concentrations in “black tobacco” (air-cured) than in “blend tobacco” (flue-cured). Passive smoke increases the adducts in the blood and a dose-response of adduct formation has been correlated with increased risk of bladder cancer. Higher levels of adduct formation have been observed in cigarette smokers who are slow acetylators compared to fast acetylators, which suggests that genetically inherited acetylation status may be an important biomarker of susceptibility. The lower incidence of bladder cancer in Black compared to White races may be attributed to conjugation of carcinogenic metabolic intermediates by sulphotransferases that produce electrophiles. Detoxified phenolic sulphates may protect the urothelium. Liver sulphotransferase activity for N-hydroxyarylamines has been reported to be higher in Blacks than Whites. This may result in a decrease in the amount of free N-hydroxymetabolites to function as carcinogens.
Occupational bladder cancer is one of the earliest known and best documented occupational cancers. The first identified case of occupational bladder cancer appeared some 20 years after the inception of the synthetic dye industry in Germany. Numerous other occupations have been identified in the last 25 years as occupational bladder cancer risks. Occupational exposures may contribute to up to 20% of bladder cancers. Workers occupationally exposed include those working with coal-tar pitches, coal gasification and production of rubber, aluminium, auramine and magenta, as well as those working as hairdressers and barbers. Aromatic amines have been shown to cause bladder cancer in workers in many countries. Notable among this class of chemicals are 2-naphthylamine, benzidine, 4-nitrobiphenyl and 3,3r´-dichlorobenzidine. Two other aromatic amines, 4,4´-methylene dianiline (MDA) and 4,4´-methylene-bis-2-chloroaniline (MOCA) are among the most widely used of the suspected bladder carcinogens. Other carcinogens associated with industrial exposures are largely undetermined; however, aromatic amines are frequently present in the workplace.
Screening and diagnosis of bladder cancer
Screening for bladder cancer continues to receive attention in the quest to diagnose bladder cancer before it becomes symptomatic and, presumably, less amenable to curative treatment. Voided urine cytology and urinalysis for haematuria have been considered candidate screening tests. A pivotal question for screening is how to identify high-risk groups and then individuals within these groups. Epidemiological studies identify groups at risk while biomarkers potentially identify individuals within groups. In general, occupational screening for bladder cancer with haematuria testing and Papanicolaou cytology has been ineffective.
Improved detection of bladder cancer may be possible using the 14-day hemastick testing described by Messing and co-workers. A positive test was observed at least once in 84% of 31 patients with bladder cancer at least 2 months prior to the cystoscopic diagnosis of disease. This test suffers from a false-positive rate of 16 to 20% with half of these patients having no urological disease. The low cost may make this a useful test in a two-tier screen in combination with biomarkers and cytology (Waples and Messing 1992).
In a recent study, the DD23 monoclonal antibody using quantitative fluorescence image analysis detected bladder cancer in exfoliated uroepithelial cells. A sensitivity of 85% and specificity of 95% were achieved in a mixture of low- and high-grade transitional cell carcinomas including TaT1 tumours. The M344 tumour-associated antigen in conjunction with DNA ploidy had a sensitivity approaching 90%.
Recent studies indicate combining biomarkers with haematuria testing may be the best approach. A list of the applications of quantitative fluorescence urinary cytology in combination with biomarkers is summarized in Table 1. Genetic, biochemical and morphological early cell changes associated with premalignant conditions support the concept that individuals at risk can be identified years in advance of the development of overt malignancy. Biomarkers of susceptibility in combination with biomarkers of effect promise to detect individuals at risk with an even higher precision. These advances are made possible by new technologies capable of quantitating phenotypic and genotypic molecular changes at the single cell level thus identifying individuals at risk. Individual risk assessment facilitates stratified, cost-effective monitoring of selected groups for targeted chemoprevention.
Table 1. Applications of urinary cytology
Detection of CIS1 and bladder cancer
Monitoring surgical therapy:
Monitoring bladder following TURBT2
Monitoring upper urinary tract
Monitoring urethral remnant
Monitoring urinary diversion
Monitoring intravesical therapy
Selecting intravesical therapy
Monitoring effect of laser therapy
Evaluation of patients with haematuria
Establishing need for cystoscopy
Screening high-risk populations:
Occupational exposure groups
Drug abuse groups at risk for bladder cancer
Decision criteria for:
Segmental ureteral resection versus nephroureterectomy
Detecting vesicoenteric fistula
Extraurological tumours invading the urinary tract
Defining effective chemopreventive agents
Monitoring effective chemotherapy
1 CIS, carcinoma in situ.
2 TURBT, transurethral resection for bladder tumour.
Source: Hemstreet et al. 1996.
Signs and symptoms of bladder cancer are similar to those of urinary tract infection and may include pain on urination, frequent voiding and blood and pus cells in the urine. Because symptoms of a urinary tract infection may herald a bladder tumour particularly when associated with gross haematuria in older patients, confirmation of the presence of bacteria and a keen awareness by the examining physician is needed. Any patient treated for a urinary tract infection which does not resolve immediately should be referred to a urology specialist for further evaluation.
Diagnostic evaluation of bladder cancer first requires an intravenous pyelogram (IVP) to exclude upper tract disease in the renal pelvis or ureters. Confirmation of bladder cancer requires looking in the bladder with a light (cystoscope) with multiple biopsies performed with a lighted instrument through the urethra to determine if the tumour is non-invasive (i.e., papillary or CIS) or invasive. Random biopsies of the bladder and prostatic urethra help to define field cancerization and field effect changes. Patients with non-invasive disease require close monitoring, as they are at risk of subsequent recurrences, although stage and grade progression are uncommon. Patients who present with bladder cancer that is already high-grade or invasive into the lamina propria are at equally high risk of recurrence but stage progression is much more likely. Thus, they usually receive intravesical instillation of immuno- or chemotherapeutic agents following transurethral resection. Patients with tumours invading the muscularis propria or beyond are much more likely to have metastasis already and can rarely be managed by conservative means. However, even when treated by total cystectomy (the standard therapy for muscle-invading bladder cancer), 20 to 60% eventually succumb to their disease, almost always due to metastasis. When regional or distal metastasis is present at diagnosis, the 5-year survival rates drop to 35 and 9%, respectively, despite aggressive treatment. Systemic chemotherapy for metastatic bladder cancer is improving with complete response rates reported at 30%. Recent studies suggest chemotherapy prior to cystectomy may improve survival in selected patients.
Bladder cancer staging is predictive of the biological potential for progression, metastasis, or recurrence in 70% of the cases. Staging of bladder cancer usually requires CAT scan to rule out liver metastasis, radioisotope bone scan to exclude spread to the bone, and chest x ray or CAT scan to exclude lung metastasis. A search continues for biomarkers in the tumour and the bladder cancer field that will predict which tumours will metastasize or recur. The accessibility of exfoliated bladder cells in voided specimens shows promise for using biomarkers for monitoring recurrence and for cancer prevention.
The control of occupational carcinogens is based on the critical review of scientific investigations both in humans and in experimental systems. There are several review programmes being undertaken in different countries aimed at controlling occupational exposures which could be carcinogenic to humans. The criteria used in different programmes are not entirely consistent, leading occasionally to differences in the control of agents in different countries. For example, 4,4-methylene-bis-2-chloroaniline (MOCA) was classified as an occupational carcinogen in Denmark in 1976 and in the Netherlands in 1988, but only in 1992 has a notation “suspected human carcinogen” been introduced by the American Conference of Governmental Industrial Hygienists in the United States.
The International Agency for Research on Cancer (IARC) has established, within the framework of its Monographs programme, a set of criteria to evaluate the evidence of the carcinogenicity of specific agents. The IARC Monographs programme represents one of the most comprehensive efforts to review systematically and consistently cancer data, is highly regarded in the scientific community and serves as the basis for the information in this article. It also has an important impact on national and international occupational cancer control activities. The evaluation scheme is given in table 1.
Table 1. Evaluation of evidence of carcinogenicity in the IARC Monographs programme.
1. The evidence for the induction of cancer in humans, which obviously plays an important role in the identification of human carcinogens is considered. Three types of epidemiological studies contribute to an assessment of carcinogenicity in humans: cohort studies, case-control studies and correlation (or ecological) studies. Case reports of cancer in humans may also be reviewed. The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:
2. Studies in which experimental animals (mainly rodents) are exposed chronically to potential carcinogens and examined for evidence of cancer are reviewed and the degree of evidence of carcinogenicity is then classified into categories similar to those used for human data.
3. Data on biological effects in humans and experimental animals that are of particular relevance are reviewed. These may include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on structure-activity relationship are used when considered relevant to the possible mechanism of the carcinogenic action of the agent.
4. The body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure (see table 2).
Agents, mixtures and exposure circumstances are evaluated within the IARC Monographs if there is evidence of human exposure and data on carcinogenicity (either in humans or in experimental animals) (for IARC classification groups, see table 2).
Table 2. IARC Monograph programme classification groups.
The agent, mixture or exposure circumstance is described according to the wording of one of the following categories:
|Group 1—||The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.|
|Group 2A—||The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.|
|Group 2B—||The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.|
|Group 3—||The agent (mixture, exposure circumstance) is not classifiable as to its carcinogenicity to humans.|
|Group 4—||The agent (mixture, exposure circumstance) is probably not carcinogenic to humans.|
Known and Suspected Occupational Carcinogens
At present, there are 22 chemicals, groups of chemicals or mixtures for which exposures are mostly occupational, without considering pesticides and drugs, which are established human carcinogens (table 3). While some agents such as asbestos, benzene and heavy metals are currently widely used in many countries, other agents have mainly an historical interest (e.g., mustard gas and 2-naphthylamine).
Table 3. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 1-Chemicals carcinogenic to humans1
|Exposure2||Human target organ(s)||Main industry/use|
|4-Aminobiphenyl (92-67-1)||Bladder||Rubber manufacture|
|Arsenic (7440-38-2) and arsenic compounds3||Lung, skin||Glass, metals, pesticides|
|Asbestos (1332-21-4)||Lung, pleura, peritoneum||Insulation, filter material, textiles|
|Benzene (71-43-2)||Leukaemia||Solvent, fuel|
|Benzidine (92-87-5)||Bladder||Dye/pigment manufacture, laboratory agent|
|Beryllium (7440-41-7) and beryllium compounds||Lung||Aerospace industry/metals|
|Bis(chloromethyl)ether (542-88-11)||Lung||Chemical intermediate/by-product|
|Chloromethyl methylether (107-30-2) (technical grade)||Lung||Chemical intermediate/by-product|
|Cadmium (7440-43-9) and cadmium compounds||Lung||Dye/pigment manufacture|
|Chromium (VI) compounds||Nasal cavity, lung||Metal plating, dye/pigment manufacture|
|Coal-tar pitches (65996-93-2)||Skin, lung, bladder||Building material, electrodes|
|Coal-tars (8007-45-2)||Skin, lung||Fuel|
|Ethylene oxide (75-21-8)||Leukaemia||Chemical intermediate, sterilant|
|Mineral oils, untreated and mildly treated||Skin||Lubricants|
|Mustard gas (sulphur mustard)
|Pharynx, lung||War gas|
|2-Naphthylamine (91-59-8)||Bladder||Dye/pigment manufacture|
|Nickel compounds||Nasal cavity, lung||Metallurgy, alloys, catalyst|
|Shale-oils (68308-34-9)||Skin||Lubricants, fuels|
|Talc containing asbestiform fibers||Lung||Paper, paints|
|Vinyl chloride (75-01-4)||Liver, lung, blood vessels||Plastics, monomer|
|Wood dust||Nasal cavity||Wood industry|
1 Evaluated in the IARC Monographs, Volumes 1-63 (1972-1995) (excluding pesticides and drugs).
2 CAS Registry Nos. appear between parentheses.
3 This evaluation applies to the group of chemicals as a whole and not necessarily to all individual chemicals within the group.
An additional 20 agents are classified as probably carcinogenic to humans (Group 2A); they are listed in table 4, and include exposures that are currently prevalent in many countries, such as crystalline silica, formaldehyde and 1,3-butadiene. A large number of agents are classified as possible human carcinogens (Group 2B, table 5) - for example, acetaldehyde, dichloromethane and inorganic lead compounds. For the majority of these chemicals the evidence of carcinogenicity comes from studies in experimental animals.
Table 4. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 2A—Probably carcinogenic to humans1
|Exposure2||Suspected human target organ(s)||Main industry/use|
|Acrylonitrile (107-13-1)||Lung, prostate, lymphoma||Plastics, rubber, textiles, monomer|
|Benzidine-based dyes||–||Paper, leather, textile dyes|
|1,3-Butadiene (106-99-0)||Leukaemia, lymphoma||Plastics, rubber, monomer|
|p-Chloro-o-toluidine (95-69-2) and its strong acid salts||Bladder||Dye/pigment manufacture, textiles|
|Creosotes (8001-58-9)||Skin||Wood preservation|
|Diethyl sulphate (64-67-5)||–||Chemical intermediate|
|Dimethylcarbamoyl chloride (79-44-7)||–||Chemical intermediate|
|Dimethyl sulphate (77-78-1)||–||Chemical intermediate|
|Epichlorohydrin (106-89-8)||–||Plastics/resins monomer|
|Ethylene dibromide (106-93-4)||–||Chemical intermediate, fumigant, fuels|
|Formaldehyde (50-0-0)||Nasopharynx||Plastics, textiles, laboratory agent|
|4,4´-Methylene- bis-2-chloroaniline (MOCA)
|Polychlorinated biphenyls (1336-36-3)||Liver, bile ducts, leukaemia, lymphoma||Electrical components|
|Silica (14808-60-7), crystalline||Lung||Stone cutting, mining, glass, paper|
|Styrene oxide (96-09-3)||–||Plastics, chemical intermediate|
|Oesophagus, lymphoma||Solvent, dry cleaning|
|Trichloroethylene (79-01-6)||Liver, lymphoma||Solvent, dry cleaning, metal|
|–||Plastics, textiles, flame retardant|
|Vinyl bromide (593-60-2)||–||Plastics, textiles, monomer|
|Vinyl fluoride (75-02-5)||–||Chemical intermediate|
Table 5. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 2B—Possibly carcinogenic to humans1
|Acetaldehyde (75-07-0)||Plastics manufacture, flavors|
|Acetamide (60-35-5)||Solvent, chemical intermediate|
|Acrylamide (79-06-1)||Plastics, grouting agent|
|p-Aminoazotoluene (60-09-3)||Dye/pigment manufacture|
|o-Aminoazotoluene (97-56-3)||Dyes/pigments, textiles|
|o-Anisidine (90-04-0)||Dye/pigment manufacture|
|Antimony trioxide (1309-64-4)||Flame retardant, glass, pigments|
|Auramine (492-80-8) (technical-grade)||Dyes/pigments|
|Benzyl violet 4B (1694-09-3)||Dyes/pigments|
|Bitumens (8052-42-4), extracts of
steam-refined and air-refined
|Bromodichloromethane (75-27-4)||Chemical intermediate|
|b-Butyrolactone (3068-88-0)||Chemical intermediate|
|Carbon-black extracts||Printing inks|
|Carbon tetrachloride (56-23-5)||Solvent|
|Ceramic fibers||Plastics, textiles, aerospace|
|Chlorendic acid (115-28-6)||Flame retardant|
|Chlorinated paraffins of average carbon chain length C12 and average degree of chlorination approximately 60%||Flame retardant|
|a-Chlorinated toluenes||Dye/pigment manufacture, chemical intermediate|
|p-Chloroaniline (106-47-8)||Dye/pigment manufacture|
|4-Chloro-o-phenylenediamine (95-83-9)||Dyes/pigments, hair dyes|
|CI Acid Red 114 (6459-94-5)||Dyes/pigments, textiles, leather|
|CI Basic Red 9 (569-61-9)||Dyes/pigments, inks|
|CI Direct Blue 15 (2429-74-5)||Dyes/pigments, textiles, paper|
|Cobalt (7440-48-4)and cobalt compounds||Glass, paints, alloys|
|p-Cresidine (120-71-8)||Dye/pigment manufacture|
|N,N´-Diacetylbenzidine (613-35-4)||Dye/pigment manufacture|
|2,4-Diaminoanisole (615-05-4)||Dye/pigment manufacture, hair dyes|
|4,4´-Diaminodiphenyl ether (101-80-4)||Plastics manufacture|
|2,4-Diaminotoluene (95-80-7)||Dye/pigment manufacture, hair dyes|
|p-Dichlorobenzene (106-46-7)||Chemical intermediate|
|3,3´-Dichlorobenzidine (91-94-1)||Dye/pigment manufacture|
|3,3´-Dichloro-4,4´-diaminodiphenyl ether (28434-86-8)||Not used|
|1,2-Dichloroethane (107-06-2)||Solvent, fuels|
|Diesel fuel, marine||Fuel|
|Di(2-ethylhexyl)phthalate (117-81-7)||Plastics, textiles|
|1,2-Diethylhydrazine (1615-80-1)||Laboratory reagent|
|Diglycidyl resorcinol ether (101-90-6)||Plastics/resins|
|Diisopropyl sulphate (29973-10-6)||Contaminant|
|2,6-Dimethylaniline (2,6-Xylidine)(87-62-7)||Chemical intermediate|
|3,3´-Dimethylbenzidine (o-Tolidine)(119-93-7)||Dye/pigment manufacture|
|1,1-Dimethylhydrazine (57-14-7)||Rocket fuel|
|1,2-Dimethylhydrazine (540-73-8)||Research chemical|
|Disperse Blue 1 (2475-45-8)||Dyes/pigments, hair dyes|
|Ethyl acrylate (140-88-5)||Plastics, adhesives, monomer|
|Ethylene thiourea (96-45-7)||Rubber chemical|
|Fuel oils, residual (heavy)||Fuel|
|Furan (110-00-9)||Chemical intermediate|
|Glycidaldehyde (765-34-4)||Textile, leather manufacture|
|HC Blue No. 1 (2784-94-3)||Hair dyes|
|Hexamethylphosphoramide (680-31-9)||Solvent, plastics|
|Hydrazine (302-01-2)||Rocket fuel, chemical intermediate|
|Lead (7439-92-1) and lead compounds, inorganic||Paints, fuels|
|2-Methylaziridine(75-55-8)||Dyes, paper, plastics manufacture|
|4,4’-Methylene-bis-2-methylaniline (838-88-0)||Dye/pigment manufacture|
|4,4’-Methylenedianiline(101-77-9)||Plastics/resins, dye/pigment manufacture|
|Methylmercury compounds||Pesticide manufacture|
|2-Methyl-1-nitroanthraquinone (129-15-7) (uncertain purity)||Dye/pigment manufacture|
|Nickel, metallic (7440-02-0)||Catalyst|
|Nitrilotriacetic acid (139-13-9) and its salts||Chelating agent, detergent|
|5-Nitroacenaphthene (602-87-9)||Dye/pigment manufacture|
|N-Nitrosodiethanolamine (1116-54-7)||Cutting fluids, impurity|
|Oil Orange SS (2646-17-5)||Dyes/pigments|
|Phenyl glycidyl ether (122-60-1)||Plastics/adhesives/resins|
|Polybrominated biphenyls (Firemaster BP-6) (59536-65-1)||Flame retardant|
|Ponceau MX (3761-53-3)||Dyes/pigments, textiles|
|Ponceau 3R (3564-09-8)||Dyes/pigments, textiles|
|1,3-Propane sulphone (1120-71-4)||Dye/pigment manufacture|
|b-Propiolactone (57-57-8)||Chemical intermediate; plastics manufacture|
|Propylene oxide (75-56-9)||Chemical intermediate|
|2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (1746-01-6)||Contaminant|
|Thioacetamide (62-55-5)||Textile, paper, leather, rubber manufacture|
|4,4’-Thiodianiline (139-65-1)||Dye/pigment manufacture|
|Thiourea (62-56-6)||Textile, rubber ingredient|
|Toluene diisocyanates (26471-62-5)||Plastics|
|o-Toluidine (95-53-4)||Dye/pigment manufacture|
|Trypan blue (72-57-1)||Dyes/pigments|
|Vinyl acetate (108-05-4)||Chemical intermediate|
1 Evaluated in the IARC Monographs, Volumes 1-63 (1972-1995) (excluding pesticides and drugs).
2 CAS Registry Nos. appear between parentheses.
Occupational exposures may also occur during the production and use of some pesticides and drugs. Table 6 presents an evaluation of the carcinogenicity of pesticides; two of them, captafol and ethylene dibromide, are classified as probable human carcinogens, while a total of 20 others, including DDT, atrazine and chlorophenols, are classified as possible human carcinogens.
Table 6. Pesticides evaluated in IARC Monographs, Volumes 1-63(1972-1995)
|2A—Probably carcinogenic to humans||Captafol (2425-06-1) Ethylene dibromide (106-93-4)|
|2B—Possibly carcinogenic to humans||Amitrole (61-82-5) Atrazine (1912-24-9) Chlordane (57-74-9) Chlordecone (Kepone) (143-50-0) Chlorophenols Chlorophenoxy herbicides DDT (50-29-3) 1,2-Dibromo-3-chloropropane (96-12-8) 1,3-Dichloropropene (542-75-6) (technical-grade) Dichlorvos (62-73-7) Heptachlor (76-44-8) Hexachlorobenzene (118-74-1) Hexachlorocyclohexanes (HCH) Mirex (2385-85-5) Nitrofen (1836-75-5), technical-grade Pentachlorophenol (87-86-5) Sodium o-phenylphenate (132-27-4) Sulphallate (95-06-7) Toxaphene (Polychlorinated camphenes) (8001-35-2)|
1 CAS Registry Nos. appear between parentheses.
Several drugs are human carcinogens (table 9): they are mainly alkylating agents and hormones; 12 more drugs, including chloramphenicol, cisplatine and phenacetin, are classified as probable human carcinogens (Group 2A). Occupational exposure to these known or suspected carcinogens, used mainly in chemotherapy, can occur in pharmacies and during their administration by nursing staff.
Table 7. Drugs evaluated in IARC Monographs, Volumes 1-63 (1972-1995).
|IARC GROUP 1—Carcinogenic to humans|
|Analgesic mixtures containing phenacetin||Kidney, bladder|
|Azathioprine (446-86-6)||Lymphoma, hepatobiliary system, skin|
|N,N-Bis(2-chloroethyl)- b-naphthylamine (Chlornaphazine) (494-03-1)||Bladder|
|1,4-Butanediol dimethanesulphonate (Myleran)
|1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU) (13909-09-6)||Leukaemia|
|Cyclosporin (79217-60-0)||Lymphoma, skin|
|Cyclophosphamide (50-18-0) (6055-19-2)||Leukaemia, bladder|
|Diethylstilboestrol (56-53-1)||Cervix, vagina, breast|
|8-Methoxypsoralen (Methoxsalen) (298-81-7) plus ultraviolet A radiation||Skin|
|MOPP and other combined chemotherapy including alkylating agents||Leukaemia|
|Oestrogen replacement therapy||Uterus|
|Oestrogens, nonsteroidal||Cervix, vagina, breast|
|Oral contraceptives, combined||Liver|
|Oral contraceptives, sequential||Uterus|
|IARC GROUP 2A—Probably carcinogenic to humans|
|Androgenic (anabolic) steroids||(Liver)|
|Bischloroethyl nitrosourea (BCNU) (154-93-8)||(Leukaemia)|
|1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) (13010-47-4)||–|
|Nitrogen mustard (51-75-2)||(Skin)|
|Phenacetin (62-44-2)||(Kidney, bladder)|
|Procarbazine hydrochloride (366-70-1)||–|
1 CAS Registry Nos. appear between parentheses.
2 Suspected target organs are given in parentheses.
Several environmental agents are known or suspected causes of cancer in humans and are listed in table 8; although exposure to such agents is not primarily occupational, there are groups of individuals exposed to them because of their work: examples are uranium miners exposed to radon decay products, hospital workers exposed to hepatitis B virus, food processors exposed to aflatoxins from contaminated foods, outdoor workers exposed to ultraviolet radiation or diesel engine exhaust, and bar staff or waiters exposed to environmental tobacco smoke.
The IARC Monograph programme has covered most of the known or suspected causes of cancer; there are, however, some important groups of agents that have not been evaluated by IARC—namely, ionizing radiation and electrical and magnetic fields.
Table 8. Environmental agents/exposures known or suspected to cause cancer in humans.1
|Agent/exposure||Target organ2||Strength of evidence3|
|Polycyclic aromatic hydrocarbons4||(Lung, bladder)||S|
|Nitrate and nitrite||(Oesophagus, stomach)||S|
|Radon and its decay products||Lung||1|
|Other X-irradiation||Leukaemia, breast, thyroid, others||E|
|Ultraviolet radiation A||(Skin)||2A|
|Ultraviolet radiation B||(Skin)||2A|
|Ultraviolet radiation C||(Skin)||2A|
|Use of sunlamps and sunbeds||(Skin)||2A|
|Electric and magnetic fields||(Leukaemia)||S|
|Chronic infection with hepatitis B virus||Liver||1|
|Chronic infection with hepatitis C virus||Liver||1|
|Infection with Helicobacter pylori||Stomach||1|
|Infection with Opistorchis viverrini||Bile ducts||1|
|Infection with Chlonorchis sinensis||(Liver)||2A|
|Human Papilloma virus types 16 and18||Cervix||1|
|Human Papilloma virus types 31 and 33||(Cervix)||2A|
|Human Papilloma virus types other than 16, 18, 31 and 33||(Cervix)||2B|
|Infection with Schistosoma haematobium||Bladder||1|
|Infection with Schistosoma japonicum||(Liver, colon)||2B|
|Tobacco, alcohol and related substances|
|Alcoholic beverages||Mouth, pharynx, oesophagus, liver, larynx||1|
|Tobacco smoke||Lip, mouth, pharynx, oesophagus, pancreas, larynx, lung, kidney, bladder, (others)||1|
|Smokeless tobacco products||Mouth||1|
|Betel quid with tobacco||Mouth||1|
|Toxins derived from Fusarium moniliforme||(Oesophagus)||2B|
|Chinese style salted fish||Nasopharynx||1|
|Pickled vegetables (traditional in Asia)||(Oesophagus, stomach)||2B|
|Fresh fruits and vegetables (protective)||Mouth, oesophagus, stomach, colon, rectum, larynx, lung (others)||E|
|Fat||(Colon, breast, endometrium)||S|
|Fiber (protective)||(Colon, rectum)||S|
|Nitrate and nitrite||(Oesophagus, stomach)||S|
|Vitamin A, b-carotene (protective)||(Mouth, oesophagus, lung, others)||S|
|Vitamin C (protective)||(Oesophagus, stomach)||S|
|IQ||(Stomach, colon, rectum)||2A|
|Reproductive and sexual behavior|
|Late age at first pregnancy||Breast||E|
|Low parity||Breast, ovary, corpus uteri||E|
|Early age at first intercourse||Cervix||E|
|Number of sexual partners||Cervix||E|
1 Agents and exposures, as well as medicines, occurring mainly in the occupational setting are excluded.
2 Suspected target organs are given in parentheses.
3 IARC Monograph evaluation reported wherever available (1: human carcinogen; 2A: probable human carcinogen; 2B: possible human carcinogen); otherwise E: established carcinogen; S: suspected carcinogen.
4 Human exposure to polycyclic aromatic hydrocarbons occurs in mixtures, such as engine emissions, combustion fumes and soots. Several mixtures and individual hydrocarbons have been evaluated by IARC.
Industries and Occupations
Current understanding of the relationship between occupational exposures and cancer is far from complete; in fact, only 22 individual agents are established occupational carcinogens (table 9), and for many more experimental carcinogens no definitive evidence is available based on exposed workers. In many cases, there is considerable evidence of increased risks associated with particular industries and occupations, although no specific agents can be identified as aetiological factors. Table 10 present lists of industries and occupations associated with excess carcinogenic risks, together with the relevant cancer sites and the known (or suspected) causative agent(s).
Table 9. Industries, occupations and exposures recognized as presenting a carcinogenic risk.
|Industry (ISIC code)||Occupation/process||Cancer site/type||Known or suspected causative agent|
|Agriculture, forestry and fishing (1)||Vineyard workers using arsenic insecticides Fishermen||Lung, skin Skin, lip||Arsenic compounds Ultraviolet radiation|
|Mining and quarrying (2)||Arsenic mining Iron ore (haematite) mining Asbestos mining Uranium mining Talc mining and milling||Lung, skin Lung Lung, pleural and peritoneal mesothelioma Lung Lung||Arsenic compounds Radon decay products Asbestos Radon decay products Talc containing asbestiform fibers|
|Chemical (35)||Bis(chloromethyl) ether (BCME) and chloromethyl-methyl ether (CMME) production workers and users Vinyl chloride production Isopropyl alcohol manufacture (strong-acid process) Pigment chromate production Dye manufacturers and users Auramine manufacture p-chloro-o-toluidine production||Lung (oat-cell carcinoma) Liver angiosarcoma Sinonasal Lung, sinonasal Bladder Bladder Bladder||BCME, CMME Vinyl chloride monomer Not identified Chromium (VI) compounds Benzidine, 2-naphthylamine, 4-aminobiphenyl Auramine and other aromatic amines used in the process p-chloro-o-toluidine and its strong acid salts|
|Leather (324)||Boot and shoe manufacture||Sinonasal, leukaemia||Leather dust, benzene|
|Wood and wood products (33)||Furniture and cabinet makers||Sinonasal||Wood dust|
|Pesticides and herbicides production (3512)||Arsenical insecticides production and packaging||Lung||Arsenic compounds|
|Rubber industry (355)||Rubber manufacture Calendering, tyre curing, tyre building Millers, mixers Synthetic latex production, tyre curing, calender operatives, reclaim, cable makers Rubber film production||Leukaemia Bladder Leukaemia Bladder Bladder Leukaemia||Benzene Aromatic amines Benzene Aromatic amines Aromatic amines Benzene|
|Asbestos production (3699)||Insulated material production (pipes, sheeting, textile, clothes, masks, asbestos cement products)||Lung, pleural and peritoneal mesothelioma||Asbestos|
|Metals (37)||Aluminum production Copper smelting Chromate production, chromium plating Iron and steel founding Nickel refining Pickling operations Cadmium production and refining; nickel-cadmium battery manufacture; cadmium pigment manufacture; cadmium alloy production; electroplating; zinc smelters; brazing and polyvinyl chloride compounding Beryllium refining and machining; production of beryllium-containing products||Lung, bladder Lung Lung, sinonasal Lung Sinonasal, lung Larynx, lung Lung Lung||Polycyclic aromatic hydrocarbons, tar Arsenic compounds Chromium (VI) compounds Not identified Nickel compounds Inorganic acid mists containing sulphuric acid Cadmium and cadmium compounds Beryllium and beryllium compounds|
|Shipbuilding, motor vehicle and railroad equipment manufacture (385)||Shipyard and dockyard, motor vehicle and railroad manufacture workers||Lung, pleural and peritoneal mesothelioma||Asbestos|
|Gas (4)||Coke plant workers Gas workers Gas-retort house workers||Lung Lung, bladder, scrotum Bladder||Benzo(a)pyrene Coal carbonization products, 2-naphthylamine Aromatic amines|
|Construction (5)||Insulators and pipe coverers Roofers, asphalt workers||Lung, pleural and peritoneal mesothelioma Lung||Asbestos Polycyclic aromatic hydrocarbons|
|Other||Medical personnel (9331) Painters (construction, automotive industry and other users)||Skin, leukaemia Lung||Ionizing radiation Not identified|
Table 10. Industries, occupations and exposures reported to present a cancer excess but for which the assessment of the carcinogenic risk is not definitive.
|Industry (ISIC code)||Occupation/process||Cancer site/type||Known (or suspected) causative agent|
|Agriculture, forestry and fishing (1)||Farmers, farm workers Herbicide application Insecticide application||Lymphatic and haematopoietic system (leukaemia, lymphoma) Malignant lymphomas, soft-tissue sarcomas Lung, lymphoma||Not identified Chlorophenoxy herbicides, chlorophenols (presumably contaminated with polychlorinated dibenzodioxins) Non-arsenical insecticides|
|Mining and quarrying (2)||Zinc-lead mining Coal Metal mining Asbestos mining||Lung Stomach Lung Gastrointestinal tract||Radon decay products Coal dust Crystalline silica Asbestos|
|Food industry (3111)||Butchers and meat workers||Lung||Viruses, PAH1|
|Beverage industry (3131)||Beer brewers||Upper aero-digestive tract||Alcohol consumption|
|Textile manufacture (321)||Dyers Weavers||Bladder Bladder, sinonasal, mouth||Dyes Dusts from fibers and yarns|
|Leather (323)||Tanners and processors Boot and shoe manufacture and repair||Bladder, pancreas, lung Sinonasal, stomach, bladder||Leather dust, other chemicals, chromium Not identified|
|Wood and wood products (33), pulp and paper industry (341)||Lumbermen and sawmill workers Pulp and papermill workers Carpenters, joiners Woodworkers, unspecified Plywood production, particle-board production||Nasal cavity, Hodgkin lymphoma, skin Lymphopoietic tissue, lung Nasal cavity, Hodgkin lymphoma Lymphomas Nasopharynx, sinonasal||Wood dust, chlorophenols, creosotes Not identified Wood dust, solvents Not identified Formaldehyde|
|Printing (342)||Rotogravure workers, binders, printing pressmen, machine-room workers and other jobs||Lymphocytic and haemopoietic system, oral, lung, kidney||Oil mist, solvents|
|Chemical (35)||1,3-Butadiene production Acrylonitrile production Vinylidene chloride production Isopropyl alcohol manufacture (strong-acid process) Polychloroprene production Dimethylsulphate production Epichlorohydrin production Ethylene oxide production Ethylene dibromide production Formaldehyde production Flame retardant and plasticizer use Benzoyl chloride production||Lymphocytic and haemopoietic system Lung, colon Lung Larynx Lung Lung Lung, lymphatic and haemopoietic system (leukaemia) Lymphatic and haemopoietic system (leukaemia), stomach Digestive system Nasopharynx, sinonasal Skin (melanoma) Lung||1,3-Butadiene Acrylonitrile Vinylidene chloride (mixed exposure with acrylonitrile) Not identified Chloroprene Dimethylsulphate Epichlorohydrin Ethylene oxide Ethylene dibromide Formaldehyde Polychlorinated biphenyls Benzoyl chloride|
|Herbicides production (3512)||Chlorophenoxy herbicide production||Soft-tissue sarcoma||Chlorophenoxy herbicides, chlorophenols (contaminated with polychlorinated dibenzodioxins)|
|Petroleum (353)||Petroleum refining||Skin, leukaemia, brain||Benzene, PAH, untreated and mildly treated mineral oils|
|Rubber (355)||Various occupations in rubber manufacture Styrene-butadiene rubber production||Lymphoma, multiple myeloma, stomach, brain, lung Lymphatic and haematopoietic system||Benzene, MOCA,2 other not identified 1,3-Butadiene|
|Ceramic, glass and refractory brick (36)||Ceramic and pottery workers Glass workers (art glass, container and pressed ware)||Lung Lung||Crystalline silica Arsenic and other metal oxides, silica, PAH|
|Asbestos production (3699)||Insulation material production (pipes, sheeting, textiles, clothes, masks, asbestos cement products)||Larynx, gastrointestinal tract||Asbestos|
|Metals (37, 38)||Lead smelting Cadmium production and refining; nickel-cadmium battery manufacture; cadmium pigment manufacture; cadmium alloy production; electroplating; zinc smelting; brazing and polyvinyl chloride compounding Iron and steel founding||Respiratory and digestive systems Prostate Lung||Lead compounds Cadmium and cadmium compounds Crystalline silica|
|Shipbuilding (384)||Shipyard and dockyard workers||Larynx, digestive system||Asbestos|
|Motor vehicle manufacturing (3843, 9513)||Mechanics, welders, etc.||Lung||PAH, welding fumes, engine exhaust|
|Electricity (4101, 9512)||Generation, production, distribution, repair||Leukaemia, brain tumors Liver, bile ducts||Extremely low frequency magnetic fields PCBs3|
|Construction (5)||Insulators and pipe coverers Roofers, asphalt workers||Larynx, gastrointestinal tract Mouth, pharynx, larynx, oesophagus, stomach||Asbestos PAH, coal tar, pitch|
|Transport (7)||Railroad workers, filling station attendants, bus and truck drivers, operators of excavating machines||Lung, bladder Leukaemia||Diesel engine exhaust Extremely low frequency magnetic fields|
|Other||Service station attendants (6200) Chemists and other laboratory workers (9331) Embalmers, medical personnel (9331) Health workers (9331) Laundry and dry cleaners (9520) Hairdressers (9591) Radium dial workers||Leukaemia and lymphoma Leukaemia and lymphoma, pancreas Sinonasal, nasopharynx Liver Lung, oesophagus, bladder Bladder, leukaemia and lymphoma Breast||Benzene Not identified (viruses, chemicals) Formaldehyde Hepatitis B virus Tri- and tetrachloroethylene and carbon tetrachloride Hair dyes, aromatic amines Radon|
1 PAH, polycyclic aromatic hydrocarbon.
2 MOCA, 4,4’-methylene-bis-2-chloroaniline.
3 PCBs, polychlorinated biphenyls.
Table 9 presents industries, occupations and exposures in which the presence of a carcinogenic risk is considered to be established, whereas Table 10 shows industrial processes, occupations and exposures for which an excess cancer risk has been reported but evidence is not considered to be definitive. Also included in table 10 are some occupations and industries already listed in table 9, for which there is inconclusive evidence of association with cancers other than those mentioned in table 9. For example, the asbestos production industry is included in table 9 in relation to lung cancer and pleural and peritoneal mesothelioma, whereas the same industry is included in table 10 in relation to gastrointestinal neoplasms. A number of industries and occupations listed intables 9 and 10 have also been evaluated under the IARC Monographs programme. For example, “occupational exposure to strong inorganic acid mist containing sulphuric acid” was classified in Group 1 (carcinogenic to humans).
Constructing and interpreting such lists of chemical or physical carcinogenic agents and associating them with specific occupations and industries is complicated by a number of factors: (1) information on industrial processes and exposures is frequently poor, not allowing a complete evaluation of the importance of specific carcinogenic exposures in different occupations or industries; (2) exposures to well-known carcinogenic exposures, such as vinyl chloride and benzene, occur at different intensities in different occupational situations; (3) changes in exposure occur over time in a given occupational situation, either because identified carcinogenic agents are substituted by other agents or (more frequently) because new industrial processes or materials are introduced; (4) any list of occupational exposures can refer only to the relatively small number of chemical exposures which have been investigated with respect to the presence of a carcinogenic risk.
All of the above issues emphasize the most critical limitation of a classification of this type, and in particular its generalization to all areas of the world: the presence of a carcinogen in an occupational situation does not necessarily mean that workers are exposed to it and, in contrast, the absence of identified carcinogens does not exclude the presence of yet unidentified causes of cancer.
A particular problem in developing countries is that much of the industrial activity is fragmented and takes place in local settings. These small industries are often characterized by old machinery, unsafe buildings, employees with limited training and education, and employers with limited financial resources. Protective clothing, respirators, gloves and other safety equipment are seldom available or used. The small companies tend to be geographically scattered and inaccessible to inspections by health and safety enforcement agencies.
The identification of carcinogenic risks to humans has been the objective of the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans since 1971. To date, 69 volumes of monographs have been published or are in press, with evaluations of carcinogenicity of 836 agents or exposure circumstances (see Appendix).
These qualitative evaluations of carcinogenic risk to humans are equivalent to the hazard identification phase in the now generally accepted scheme of risk assessment, which involves identification of hazard, dose-response assessment (including extrapolation outside the limits of observations), exposure assessment and risk characterization.
The aim of the IARC Monographs programme has been to publish critical qualitative evaluations on the carcinogenicity to humans of agents (chemicals, groups of chemicals, complex mixtures, physical or biological factors) or exposure circumstances (occupational exposures, cultural habits) through international cooperation in the form of expert working groups. The working groups prepare monographs on a series of individual agents or exposures and each volume is published and widely distributed. Each monograph consists of a brief description of the physical and chemical properties of the agent; methods for its analysis; a description of how it is produced, how much is produced, and how it is used; data on occurrence and human exposure; summaries of case reports and epidemiological studies of cancer in humans; summaries of experimental carcinogenicity tests; a brief description of other relevant biological data, such as toxicity and genetic effects, that may indicate its possible mechanism of action; and an evaluation of its carcinogenicity. The first part of this general scheme is adjusted appropriately when dealing with agents other than chemicals or chemical mixtures.
The guiding principles for evaluating carcinogens have been drawn up by various ad-hoc groups of experts and are laid down in the Preamble to the Monographs (IARC 1994a).
Tools for Qualitative Carcinogenic Risk (Hazard) Identification
Associations are established by examining the available data from studies of exposed humans, the results of bioassays in experimental animals and studies of exposure, metabolism, toxicity and genetic effects in both humans and animals.
Studies of cancer in humans
Three types of epidemiological studies contribute to an assessment of carcinogenicity: cohort studies, case-control studies and correlation (or ecological) studies. Case reports of cancer may also be reviewed.
Cohort and case-control studies relate individual exposures under study to the occurrence of cancer in individuals and provide an estimate of relative risk (ratio of the incidence in those exposed to the incidence in those not exposed) as the main measure of association.
In correlation studies, the unit of investigation is usually whole populations (e.g., particular geographical areas) and cancer frequency is related to a summary measure of the exposure of the population to the agent. Because individual exposure is not documented, a causal relationship is less easy to infer from such studies than from cohort and case-control studies. Case reports generally arise from a suspicion, based on clinical experience, that the concurrence of two events—that is, a particular exposure and occurrence of a cancer—has happened rather more frequently than would be expected by chance. The uncertainties surrounding interpretation of case reports and correlation studies make them inadequate, except in rare cases, to form the sole basis for inferring a causal relationship.
In the interpretation of epidemiological studies, it is necessary to take into account the possible roles of bias and confounding. By bias is meant the operation of factors in study design or execution that lead erroneously to a stronger or weaker association than in fact exists between disease and an agent. By confounding is meant a situation in which the relationship with disease is made to appear stronger or weaker than it truly is as a result of an association between the apparent causal factor and another factor that is associated with either an increase or decrease in the incidence of the disease.
In the assessment of the epidemiological studies, a strong association (i.e., a large relative risk) is more likely to indicate causality than a weak association, although it is recognized that relative risks of small magnitude do not imply lack of causality and may be important if the disease is common. Associations that are replicated in several studies of the same design or using different epidemiological approaches or under different circumstances of exposure are more likely to represent a causal relationship than isolated observations from single studies. An increase in risk of cancer with increasing amounts of exposure is considered to be a strong indication of causality, although the absence of a graded response is not necessarily evidence against a causal relationship. Demonstration of a decline in risk after cessation of or reduction in exposure in individuals or in whole populations also supports a causal interpretation of the findings.
When several epidemiological studies show little or no indication of an association between an exposure and cancer, the judgement may be made that, in the aggregate, they show evidence suggesting lack of carcinogenicity. The possibility that bias, confounding or misclassification of exposure or outcome could explain the observed results must be considered and excluded with reasonable certainty. Evidence suggesting lack of carcinogenicity obtained from several epidemiological studies can apply only to those type(s) of cancer, dose levels and intervals between first exposure and observation of disease that were studied. For some human cancers, the period between first exposure and the development of clinical disease is seldom less than 20 years; latent periods substantially shorter than 30 years cannot provide evidence suggesting lack of carcinogenicity.
The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:
Sufficient evidence of carcinogenicity. A causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.
Limited evidence of carcinogenicity. A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding cannot be ruled out with reasonable confidence.
Inadequate evidence of carcinogenicity. The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association, or no data on cancer in humans are available.
Evidence suggesting lack of carcinogenicity. There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and the studied cancer at any observed level of exposure. A conclusion of “evidence suggesting lack of carcinogenicity” is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies.
The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on time and place. The specific exposure, process or activity considered most likely to be responsible for any excess risk should be sought and the evaluation focused as narrowly as possible. The long latent period of human cancer complicates the interpretation of epidemiological studies. A further complication is the fact that humans are exposed simultaneously to a variety of chemicals, which can interact either to increase or decrease the risk for neoplasia.
Studies on carcinogenicity in experimental animals
Studies in which experimental animals (usually mice and rats) are exposed to potential carcinogens and examined for evidence of cancer were introduced about 50 years ago with the aim of introducing a scientific approach to the study of chemical carcinogenesis and to avoid some of the disadvantages of using only epidemiological data in humans. In the IARC Monographs all available, published studies of carcinogenicity in animals are summarized, and the degree of evidence of carcinogenicity is then classified into one of the following categories:
Sufficient evidence of carcinogenicity. A causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in two or more species of animals or in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.
Limited evidence of carcinogenicity. The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, for example, (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are some unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.
Inadequate evidence of carcinogenicity. The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.
Evidence suggesting lack of carcinogenicity. Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.
Other data relevant to an evaluationof carcinogenicity
Data on biological effects in humans that are of particular relevance include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on kinetics and metabolism in experimental animals are summarized when considered relevant to the possible mechanism of the carcinogenic action of the agent. The results of tests for genetic and related effects are summarized for whole mammals including man, cultured mammalian cells and nonmammalian systems. Structure-activity relationships are mentioned when relevant.
For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions:
These dimensions are not mutually exclusive, and an agent may fall within more than one. Thus, for example, the action of an agent on the expression of relevant genes could be summarized under both the first and second dimension, even if it were known with reasonable certainty that those effects resulted from genotoxicity.
Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure. An evaluation may be made for a group of chemicals when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative.
The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.
The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.
Group 2A. The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
Group 2B. The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.
Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.
The agent (mixture) is probably not carcinogenic to humans. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group.
Classification systems made by humans are not sufficiently perfect to encompass all the complex entities of biology. They are, however, useful as guiding principles and may be modified as new knowledge of carcinogenesis becomes more firmly established. In the categorization of an agent, mixture or exposure circumstance, it is essential to rely on scientific judgements formulated by the group of experts.
Results to Date
To date, 69 volumes of IARC Monographs have been published or are in press, in which evaluations of carcinogenicity to humans have been made for 836 agents or exposure circumstances. Seventy-four agents or exposures have been evaluated as carcinogenic to humans (Group 1), 56 as probably carcinogenic to humans (Group 2A), 225 as possibly carcinogenic to humans (Group 2B) and one as probably not carcinogenic to humans (Group 4). For 480 agents or exposures, the available epidemiological and experimental data did not allow an evaluation of their carcinogenicity to humans (Group 3).
Importance of Mechanistic Data
The revised Preamble, which first appeared in volume 54 of the IARC Monographs, allows for the possibility that an agent for which epidemiological evidence of cancer is less than sufficient can be placed in Group 1 when there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity. Conversely, an agent for which there is inadequate evidence of carcinogenicity in humans together with sufficient evidence in experimental animals and strong evidence that the mechanism of carcinogenesis does not operate in humans may be placed in Group 3 instead of the normally assigned Group 2B—possibly carcinogenic to humans—category.
The use of such data on mechanisms has been discussed on three recent occasions:
While it is generally accepted that solar radiation is carcinogenic to humans (Group 1), epidemiological studies on cancer in humans for UVA and UVB radiation from sun lamps provide only limited evidence of carcinogenicity. Special tandem base substitutions (GCTTT) have been observed in p53 tumour suppression genes in squamous-cell tumours at sun-exposed sites in humans. Although UVR can induce similar transitions in some experimental systems and UVB, UVA and UVC are carcinogenic in experimental animals, the available mechanistic data were not considered strong enough to allow the working group to classify UVB, UVA and UVC higher than Group 2A (IARC 1992). In a study published after the meeting (Kress et al. 1992), CCTTT transitions in p53 have been demonstrated in UVB-induced skin tumours in mice, which might suggest that UVB should also be classified as carcinogenic to humans (Group 1).
The second case in which the possibility of placing an agent in Group 1 in the absence of sufficient epidemiological evidence was considered was 4,4´-methylene-bis(2-chloroaniline) (MOCA). MOCA is carcinogenic in dogs and rodents and is comprehensively genotoxic. It binds to DNA through reaction with N-hydroxy MOCA and the same adducts that are formed in target tissues for carcinogenicity in animals have been found in urothelial cells from a small number of exposed humans. After lengthy discussions on the possibility of an upgrading, the working group finally made an overall evaluation of Group 2A, probably carcinogenic to humans (IARC 1993).
During a recent evaluation of ethylene oxide (IARC 1994b), the available epidemiological studies provided limited evidence of carcinogenicity in humans, and studies in experimental animals provided sufficient evidence of carcinogenicity. Taking into account the other relevant data that (1) ethylene oxide induces a sensitive, persistent, dose-related increase in the frequency of chromosomal aberrations and sister chromatid exchanges in peripheral lymphocytes and micronuclei in bone-marrow cells from exposed workers; (2) it has been associated with malignancies of the lymphatic and haematopoietic system in both humans and experimental animals; (3) it induces a dose-related increase in the frequency of haemoglobin adducts in exposed humans and dose-related increases in the numbers of adducts in both DNA and haemoglobin in exposed rodents; (4) it induces gene mutations and heritable translocations in germ cells of exposed rodents; and (5) it is a powerful mutagen and clastogen at all phylogenetic levels; ethylene oxide was classified as carcinogenic to humans (Group 1).
In the case where the Preamble allows for the possibility that an agent for which there is sufficient evidence of carcinogenicity in animals can be placed in Group 3 (instead of Group 2B, in which it would normally be categorized) when there is strong evidence that the mechanism of carcinogenicity in animals does not operate in humans, this possibility has not yet been used by any working group. Such a possibility could have been envisaged in the case of d-limonene had there been sufficient evidence of its carcinogenicity in animals, since there are data suggesting that α2-microglobulin production in male rat kidney is linked to the renal tumours observed.
Among the many chemicals nominated as priorities by an ad-hoc working group in December 1993, some common postulated intrinsic mechanisms of action appeared or certain classes of agents based upon their biological properties were identified. The working group recommended that before evaluations are made on such agents as peroxisome proliferators, fibres, dusts and thyrostatic agents within the Monographs programme, special ad-hoc groups should be convened to discuss the latest state of the art on their particular mechanisms of action.