Exposure to toxins in one’s occupation or the environment has long been recognized as a risk for developing cancer. One famous example is testicular cancer in chimney sweeps described by Dr. Percivall Pott in 1775. Toxic exposure continues to be a concern today, with emphasis on prevention from exposure. Several organization studies describe and publish known carcinogens. Carcinogens are classified differently by each organization, but generally are recognized based on the availability of scientific evidence. This evidence relies on studies in the laboratory on cells, tissue or animals as well as human studies in the form of epidemiologic studies. Each form of evidence has its strengths and weaknesses. The study of human toxicology is limited by the ethical constraint of intentionally exposing patients to known carcinogens, therefore the evidence that may be used in other fields of human disease is not available in toxicology.
Myelodysplastic syndrome is a malignancy of the bone marrow. Its cause in relation to toxic exposure continues to be studied. The description of Myelodysplastic syndrome (MDS) has evolved over time. In 1982, MDS was classified as five subentities: refractory anemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation, refractory anemia with ringed sideroblasts, and also chronic myelomonocytic leukemia. Other terms used to describe MDS included hyperplastic bone marrow with bone marrow failure, smoldering leukemia or preleukemia 1.
In 2000, the World Health Organization changed the way MDS was coded from uncertain, benign or malignant, to malignant. This resulted in MDS becoming a reportable condition in cancer registries, such as those used by the US National Cancer Institute 2. Because the definition has changed and its reporting requirements have recently been instituted, older literature and statistics are not consistent. MDS can be further classified as primary or secondary MDS. In primary MDS, no apparent risk factors can be found. Secondary MDS occurs because of damaged genetic material, such as DNA, from treatment for prior malignancies such as Hodgkin’s disease, non-Hodgkin lymphomas or multiple myeloma with alkylating chemotherapy such as nitrogen mustards. Secondary MDS can also occur after exposure to toxic materials, such as benzene or organophosphate or organochlorine type pesticides 3.
Primary MDS is more common than secondary MDS, approximately 80% of MDS is considered primary, with the remaining secondary. Several risk factors have been implicated in the etiology of MDS, including age greater than 60 years old, male gender, alcohol ingestion, cigarette smoking, ionizing radiation exposure, immunosuppressive therapy, viral infection, and benzene exposures 4. Less than 10% of patients with MDS are younger than age 50 years at time of diagnosis 5.
A number of occupational and environmental exposures have been implicated in MDS including machine operators and agricultural workers exposed to unspecified oils, solvents, and/or pesticides 6. One study interviewed individual MDS patients and found occupations reported as a maintenance supervisor exposed to unspecified solvents, an exterminator exposed to unspecified pesticides, and a gardening/repair person exposed to malathion, an organophophate class of pesticide. Lindane is a broad spectrum insecticide that is an isomer of benzene hexachloride and has also been implicated in MDS 7. Repeat studies have shown an in increased risk of MDS after occupational exposure to unspecified pesticides or organic solvents, such as benzene. The risk in these studies has been reported to double for pesticide exposure and up to 6-fold increased risk in those exposed to organic solvents 8,9.
It is worth noting that on as recently as June 23rd, 2015, the International Agency for Research on Cancer (IARC) listed a number of pesticides including gamma-hexachlorocyclohexane (lindane), dichlorodiphenyltrichloroethane (DDT) and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) as human carcinogens. On March 20, 2015, IARC listed commonly used pesticides such as glyphosate, malathion and diazinon as probable human carcinogens.
The lack of environmental measurements for an individual’s exposure is common. In the occupational setting, this can make it difficult to determine if an employee should be enrolled in a medical surveillance program, as is required by the Occupational and Safety and Health Administration. A surveillance program for benzene may produce early warning signs of bone marrow suppression. In order for a worker to be in a medical surveillance program, their employer is required to survey his work environment for hazards. Therefore, in the case of benzene exposure their employer should measure the environment for benzene concentrations in the air to determine if they meet a threshold that would trigger medical surveillance.
Consumer products contain benzene at known concentrations such as gasoline at less than 4.9%. Many contain benzene at unknown concentrations. Product manufacturers are not required to list chemicals on the Safety Data Sheet if the chemical concentration is less than of 0.1% by weight, per the Hazard Communication Standard. Many products are a mixture of hydrocarbon chemicals such as naphtha, Stoddard solvent, xylene, toluene, ethylbenzene, petroleum distillates (naphtha), aromatic petroleum distillate, distillates (petroleum), solvent-refined light paraffinic and aromatic hydrocarbons. The amount of benzene in each mixture can vary from 300 to greater than 10,000 parts per million (ppm). Experiments have demonstrated products containing 552 ppm of benzene can result in airborne concentrations greater than 5 ppm as averaged over a sampling period of 15 minutes, above the threshold described by Cal/OSHA regulation 10.
In these cases of toxin-induced cancer, there is usually a question of causation. There is no set calculation that objectively determines the cause of cancer. However, criteria, known as the Bradford Hill criteria 11, have been described and used repeatedly to assist in determine causation. Although the Bradford Hill criteria were first described for use in population studies of cancer related to tobacco smoke, they have also been used in the analysis of an individual with disease. The Bradford Hill criteria have been used in to demonstrate a causal relationship of benzene to hematologic cancer, such as Acute Myelocytic Leukemia 8. The criteria are as follows:
- Strength of association
- Consistency
- Specificity
- Temporality
- Dose-response relationship
- Plausibility
- Coherence
- Experimental evidence
- Analogy
Strength of association means, the stronger the association the more likely that the association is causal. Numerous studies have shown an increased risk of hematologic cancers with benzene exposure. However, this risk appears to vary depending on exposure from slightly elevated to a 23 fold increased risk.
Consistency requires that the association has been repeatedly observed in different studies, in different places, circumstances and times, which it has for both benzene alone and benzene combined with unspecified pesticide exposures.
Specificity describes the association as limited to a specific population and to particular sites and types of disease, which benzene is particularly in occupations that work with it such as machine operators and agricultural workers who develop hematologic malignancy, such as myelodysplastic syndrome.
Temporality mandates that exposure precede the disease in time, by a duration which is reasonable given the nature of the disease. The latency from exposure to disease has been described from 2 to 10 years 12.
The dose-response relationship means that a threshold must be met or exceeded for a cancer to occur. This can be difficult in cancer causation, as there is also an understanding that there are some exposures that need to only occur once, such that there is no threshold. Two exposure limits have been identified to result in hematologic cancer, including MDS. The strongest evidence is in daily exposure to 10 ppm or greater of benzene results in hematologic cancer. However, newer evidence supports development of MDS at levels below 10 ppm.
The plausibility, also known as the mechanism of action in toxicologic terms, is well understood for benzene and hematologic cancer. Benzene’s proposed mechanism involves its metabolite binding to DNA and proteins, thus inducing myelotoxicity, including MDS 13.
Coherence and experimental evidence are addressed above, as each describes mechanistic evidence, such as in the target organ bone marrow, which has previously been described.
Analogy refers to similar events occurring in similar biologic situations. Benzene is the prime example of aromatic hydrocarbon bone marrow toxicity, although analogous situations, such as ionizing radiation are known to cause similar effects.
Determining causation in a potential toxic exposure case can be difficult. There are many complex factors to account for when determining causation. A strong understanding of medicine, toxicological mechanism, exposure dynamics and epidemiology are required when evaluating a single individual or a population.
References
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- Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012;125(7 Suppl):S2-5.
- Hofmann WK, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16.
- Catenacci DV, Schiller GJ. Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005;19(6):301-319.
- Kuendgen A, Strupp C, Aivado M, et al. Myelodysplastic syndromes in patients younger than age 50. J Clin Oncol. 2006;24(34):5358-5365.
- Nisse C, Haguenoer JM, Grandbastien B, et al. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br J Haematol. 2001;112(4):927-935.
- Goldberg H, Lusk E, Moore J, Nowell PC, Besa EC. Survey of exposure to genotoxic agents in primary myelodysplastic syndrome: correlation with chromosome patterns and data on patients without hematological disease. Cancer Res. 1990;50(21):6876-6881.
- Descatha A, Jenabian A, Conso F, Ameille J. Occupational exposures and haematological malignancies: overview on human recent data. Cancer Causes Control. 2005;16(8):939-953.
- Rigolin GM, Cuneo A, Roberti MG, et al. Exposure to myelotoxic agents and myelodysplasia: case-control study and correlation with clinicobiological findings. Br J Haematol. 1998;103(1):189-197.
- (ATSDR) AfTSaDR. Toxicological profile for Benzene. In: U.S. Department of Health and Human Services PHS, ed. Atlanta, GA2007.
- Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965;58:295-300.
- Natelson EA. Benzene-induced acute myeloid leukemia: a clinician’s perspective. Am J Hematol. 2007;82(9):826-830.
- Nishikawa T, Miyahara E, Horiuchi M, et al. Benzene metabolite 1,2,4-benzenetriol induces halogenated DNA and tyrosines representing halogenative stress in the HL-60 human myeloid cell line. Environmental health perspectives. 2012;120(1):62-67
