Demian, Cristina MD, MPH; Martin, Christopher J. MD, MSc
Answered by Cristina Demian, MD, MPH, Senior Instructor, Department of Environmental Medicine, Division of Occupational and Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, and Christopher J. Martin, MD, MSc, Associate Professor and Director, Institute of Occupational and Environmental Health, West Virginia University, Morgantown, West Virginia.
A 40-year-old man presents with fevers, progressive fatigue, dry cough, sinus congestion, intermittent lightheadedness and dizziness, and right upper abdominal quadrant discomfort of several months duration. A complete blood count shows anemia, leukocytosis, and numerous peripheral blasts. Through bone marrow biopsy, acute myelogenous leukemia (AML) with maturation (FAB-M2) is diagnosed, and myelodysplasia (MDS) is also noted. During the course of 3 months after his diagnosis, the patient underwent induction chemotherapy with remission and prolonged periods of count recovery. Nine months after his diagnosis, the patient was admitted to intensive care unit with a suspected diagnosis of myocarditis. Repeated attempts at cardioversion were unsuccessful, and the patient died.
The patient smoked one pack of cigarettes per day for 20 years and drank alcohol occasionally. His occupational history reveals that he worked for more than 15 years as an automotive mechanic in several workplaces, where he was exposed to benzene, while maintaining and repairing equipment, cleaning tools, and cleaning up spills. Modeling performed by an industrial hygienist estimates that his combined dermal and inhalation exposure to benzene during the course of his career was 55 parts per million years “ppm-years.”
Cancer is a common disease in economically developed countries. According to the most recent American Cancer Society report (2009),1 over the course of their lifetime, one in two men and one in three women living in the United States will develop one form of cancer. The presence of modifiable factors, such as alcohol, biological agents, radiation, etc., and nonmodifiable (aka, genetic predisposition) factors, acting individually or in diverse combinations, can determine a person's risk of developing one form of cancer of another. Smoking is believed to be a cause for an estimated 30% of all cancers in the developing world,2 where another 30% is due to the group of risk factors represented by diet, obesity, and physical inactivity. Environmental and occupational exposures have been estimated by some authorities to contribute to 5% of all cancers.3
Malignancy is the result of a complicated process with multiple causes and different cellular mechanisms.4 Carcinogenesis consists essentially of several molecular alterations triggered by exposure to an agent or human carcinogen. Each of these alterations is possible when a particular cellular anticancer mechanism suffers disruptions.
There are widespread occupational exposures to carcinogens. Some toxic substances are demonstrated carcinogens, whereas most are only suspected. Furthermore, these substances can act individually or in synergy with other exposures that can occur both in the workplace and outside of it, making the distinction between occupational and nonoccupational cancers very challenging.3
When Might a Cancer be Due to Occupational Exposures?
The International Agency for Research on Cancer of the World Health Organization (WHO) has conducted extensive reviews and evaluations of hundreds of agents (chemicals, biologic products, processes, etc.) and has developed a classification system for environmental/occupational exposures and their carcinogenic potential.5 Table 1 shows the main categories of carcinogens together with the basis for their classification.
In the United States, the Department of Health and Human Services/Public Health Service, through its National Toxicology Program, issues a periodic report on carcinogens.6 The two categories of agents in these reports are 1) known to be human carcinogens (based on sufficient evidence in humans and from more than one species of animal), and 2) reasonably anticipated to be human carcinogens (based on sufficient evidence from more than one species of animal). Sites of cancer for which a strong association with occupation exists are bladder, nose and sinus, lung, pleura, liver, skin, and leukocytes. The most frequent agents in these circumstances are aromatic amines, nickel, chrome, cadmium, arsenic, asbestos, radon, vinyl chloride monomer, UV light, polycyclic hydrocarbons, and benzene.
The Occupational Safety and Health Administration maintains a carcinogen listing for individual chemicals.7 This listing is based on either an evaluation from one of the International Agency for Research on Cancer monographs, National Toxicology Program reports, or Occupational Safety and Health Administration's own regulations (specifically 29 CFR 1910, Subpart Z, Toxic and Hazardous Substances).
Because of the multifactorial nature of cancer, the lengthy induction period for malignancy and the high prevalence of cancers in the general population, identifying a causative occupational exposure is challenging. Nevertheless, there are several elements that increase the likelihood that a cancer may be occupational in origin.
Diagnosing an Unusual Cancer
Mesothelioma, a malignancy of the pleura, peritoneum, tunica vaginalis of the testis or the serous membrane covering the ovary is still an unusual diagnosis, although the incidence in the United States has increased in the eighth and nineth decades of the 20th century.8 Its association with asbestos exposure (even trivial amounts) and lack of association with smoking are well documented. Similarly, angiosarcoma of the liver, an exceedingly rare malignancy with roughly 25 cases diagnosed annually in the entire U.S. population,9 is clearly associated with vinyl chloride monomer exposure that is acquired exclusively through occupation. In one of the classic outbreaks of occupational cancer, identification of this link was made on the basis of four cases diagnosed among a working population of 270 persons during a short period of time (Table 2). Nevertheless, the vast majority of cancers that are attributed to an occupational exposure are the same as those observed in the general population (lung cancer, leukemia, and bladder cancer).
Increasing Frequency of a Cancer
Recognition of the first occupational cancer, scrotal cancer, in 1775 by Sir Percival Pott was possible due to its increased frequency among chimney sweeps, greater than in the general population. Typically, chimney sweeps were young boys who could more easily move in the confined spaces specific to this work. Pott10 was impressively well versed in the occupational diseases of his day and observed that, “Other people have cancers of the same parts; and so have others, besides lead-workers, the Poictou colic, and the consequent paralysis; but it is nevertheless a disease to which they are peculiarly liable; and so are chimney-sweepers to the cancer of the scrotum and testicles.”
Cancer Diagnosed Earlier than Expected
Cancers that occur at earlier ages than those in general population should raise suspicion about potential occupational exposures. Returning to Table 2, it is important to further note that most cases of angiosarcoma of the liver in the general population are diagnosed in the fifth and sixth decade of life,9 whereas three of four of the vinyl chloride workers were in their late thirties or early forties at the time of diagnosis.
Cancer Diagnosed at the Right Time After a Compatible Exposure
Epidemiologic studies of occupational cancers have provided insight to the length of time that typically elapses between exposure to a known carcinogen and the development of malignancy, a period of time commonly referred to as the latency period. The latency period varies depending on the type of cancer from 5 to 10 years for leukemia after ionizing radiation11 to 40 to 50 years of latency for mesothelioma after asbestos exposure.8,12
Therefore, in assessing workplace exposure conditions, consideration should not only be given to a compatible level of exposure but also to a compatible period of elapsed time between that exposure and the development of cancer. As shown in Table 2, all cases of angiosarcoma were exposed to the offending chemical for 14 or more years before the development of disease.
Multiple End-Organ Malignancies
Occupational carcinogens may cause additional end-organ effects beyond a specific malignancy. One example is benzene, which, in addition to its role in the development of AML, is also known to cause MDS.13 Therefore, an observation of more than one manifestation of compatible toxicity from an agent should raise the suspicion for a causal role for that agent.
Returning to the case, factors suggesting a role for exposure to benzene include a relatively young age at diagnosis (40 years vs a mean of 63 years in the general population),14 credible evidence of overexposure to benzene in the workplace, a compatible latency period, and the presence of more than one end-organ toxicity, with both AML and MDS being diagnosed. The patient's cigarette smoking may also have contributed to his AML. Although AML is associated with smoking in the general population, there is less compelling evidence for smoking as a risk factor for MDS. In this patient's case, AML was secondary to MDS, both of which are clearly associated with exposure to benzene.
From a practical perspective, for most common cancers, understanding the role of occupation is extremely challenging and having a thorough occupational history is important in the assessment of each case. By definition, any occupational cancer is entirely preventable and therefore primary preventive strategies in the workplace are paramount.
Exposures to known carcinogens in the workplace are addressed through the “as low as reasonably achieved” principle, in which the goal for exposure is to reduce it to 0. Recent specific measures to reduce the burden of occupational cancer promulgated by the World Health Organization include stopping the use of asbestos, substituting benzene in organic solvents, banning smoking, engineering measures to convert chromium to noncarcinogenic forms, and the use of sun protection measures for outdoor workers.15
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