Benzene Overview
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Benzene is a highly ubiquitous, volatile, flammable solvent produced from petroleum with extensive industrial uses. Apart from its use as a solvent, benzene is used to produce other materials including styrofoam plastics, cumene resins, glues, paints, and nylon fiber. Naturally, benzene can be found in crude oils and combustion products, such as volcanic gasses, forest fire smoke, and cigarette smoke. Benzene exposures occur in the general population daily, mainly through inhalation. Of particular interest is that half of all benzene exposures come directly from smoking or inhaling cigarette smoke. As benzene is can be released by automobiles, manufacturing, and various products containing it, exposures are generally greater in cities than in more rural areas. Oral consumption of benzene is a far smaller source of exposure than inhalation. If a water source is contaminated, significant dermal exposure to benzene can occur when bathing or showering (although this is not the main route of exposure). Overall, those at greatest risk of exposure to higher levels of benzene are those working in industries that manufacture or use benzene products. Benzene concentrations in the environment are as follows:
- Outdoor Air = 0.02 – 34 parts per billion (heavily dependent on location)
- Average = 1.9 parts per billion
- Indoor Air, Home (Non-smoker) = 2.2 parts per billion
- Indoor Air, Home (Smoker) = 3.3 parts per billion
- Indoor Air, Bar (Smoker) = 8.08 – 11.3 parts per billion
All values reported per the EPA (Source)
The table below is included in the U.S. Department of Health and Human Services Agency for Toxic Substances and Disease Registry (ATSDR) profile for benzene. Major U.S. cities and the average air concentrations of benzene are listed.
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In addition to benzene that is produced upon combustion, tobacco products contain many other detrimental chemicals. See this video by the FDA for more information:
https://www.youtube.com/watch?v=EXdxl0yH904
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Mechanisms of Toxicity
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While two most concerning effects associated with systemic benzene toxicity are hematotoxicity and leukemogenicity, benzene is also a known direct irritant, causing skin, eye, and lung tissue irritation and damage. Benzene exposures have also been linked to female reproductive abnormalities, acute GI distress following high oral exposure, and acute pulmonary exposure to high atmospheric levels of benzene. To date, only the hematotoxic and leukemogenic effects have been studied sufficiently to propose a mechanism of toxicity.
Hematotoxicity and Leukemogenicity
According to mechanistic studies in mice, benzene’s hepatic metabolites readily distribute into the bone marrow through passive diffusion due to their small size and lipophilicity. Of particular concern are the phenolic metabolites of benzene (discussed in more detail below), which possess the capability to induce oxidative stress, directly damaging proteins and DNA of stem/progenitor cells. This stem/progenitor cell damage can cause apoptosis and impedes the formation of new red and white blood cells. DNA damage induced by benzene’s metabolites is also extensively linked to leukemia (cancer of the blood-forming organs). Overall, benzene’s more potent metabolites create oxidative stress, inducing DNA damage and causing different manifestations of hematic, lymphatic, and leukemogenic dysfunction.
Carcinogenicity
As described above, benzene is a known human carcinogen and, as such, is classified as Group 1 by the IARC. Benzene exposures have been linked to hematopoietic cancers, lymphatic cancers, and various leukemias. Benzene is carcinogenic through all routes of exposure, though inhalation is still the most prevalent of these.
The following is a video with more information detailing causes of leukemia, with benzene exposure and smoking featured extensively.
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Toxicokinetics
Benzene is readily absorbed via all routes of exposure due to its low molecular weight (78.11 g/mol), small size, and relative lipophilicity (logP = 2.13). Due to these properties, benzene is postulated to cross membranes via passive diffusion and be readily bound to plasma proteins. Benzene is widely distributed into fatty tissues due to its lipophilicity. As discussed above in mechanisms of toxicity, benzene’s hepatic metabolites are heavily implicated in its toxic effects. Benzene is rapidly metabolized in the liver via cytochrome p450 enzymes, namely CYP2E1, to phenolic compounds such as phenol, catechol, hydroquinone, 1,2,4-benzenetriol, and 1,2- and 1,4-benzoquinone as well as benzene oxide. Of these, the phenolic compounds are most notable for pathogenesis of the diseases caused by benzene exposure and are found in the bone marrow after inhalation exposures. Below is a figure from Cancer Epidemiology Biomarkers and Prevention detailing many of these toxic metabolites of benzene.
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Excretion
Inhaled, unmetabolized benzene is predominantly excreted via exhalation in a triphasic manner. Percentage of benzene exhaled unchanged appears highly dependent on dose in both rat and human models. In a study with 23 volunteers exposed to 47-110 ppm benzene-containing air for multiple hours, the percent of the benzene dose exhaled ranged from 16.4 to 41.6 percent. Rat and mouse studies also indicate that the higher the dose inhaled, the greater percentage of the benzene dose is exhaled. Phenolic benzene derivatives are primarily conjugated to glucaronides and sulfates and subsequently excreted via the urine in a biphasic manner. A very small amount (<3.5% for rats and <9% for mice) of benzene and its derivatives is excreted fecally. Benzene’s tissue half life is variable due to its multi-phasic elimination, with a range of 0.4 – 1.6 hours. Conjugated phenols have a half life of around 1 hour. In high-lipid tissues in some studies, benzene’s half life has been proposed to be around 24 hours. Overall, more studies are necessary to determine accurate half-life values for benzene in humans.
Genetic Variations
As described above, CYP450 metabolism of benzene to phenolic and other derivatives is incredibly important for its toxic effects. Following this reasoning, mice were pre-treated with CYP450 inhibitors before inhalation exposure to benzene. This inhibition of the ‘activating’ enzymes led to decreased genotoxicity, a hallmark for benzene. Therefore, it stands to reason that those with CYP450 deficiencies, especially CYP2E1, may have decreased benzene toxicity due to chronic inhalation exposure. More tests are necessary to fully elucidate the effects of genetic variations on benzene toxicity.
Biomarkers
If inhaled, unmetabolized benzene can be detected in expired air as well as, to some extent, in the urine. As benzene is primarily eliminated via urinary excretion of toxic metabolite conjugates, urinary phenol,trans,trans-muconic acid, and S-phenylmercapturic acid have all seen use to assess occupational exposures. However, these biomarkers appear to be useful in cases of prolonged occupational exposure or acute exposure to high levels of benzene. The accuracy of these markers to assess environmental exposures is less clear.
Symptoms of Toxicity
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Symptoms of benzene toxicity are dependent on the route and severity of exposure. Below are symptoms of toxicity broken up by these methods.
Acute Inhalation Exposure
Acute exposure to levels far higher than are found in the environment (10,000 to 20,000 parts per million, normal exposure values around 0.0019 parts per million) results in neurologic symptoms. Symptoms include drowsiness, confusion, dizziness, lightheadedness, headaches, tachycardia, and tremors. Symptoms typically resolve upon exposure to fresh, uncontaminated air.
Acute Oral Ingestion
Symptoms of GI distress after exposure to high levels or oral benzene are most likely related to its direct irritant effects. GI distress may be accompanied by unexplained neurologic symptoms to include: nausea, vomiting, dizziness, drowsiness, convulsions, and tachycardia.
Acute Dermal/Optical Exposure
Direct skin contact with benzene may cause symptoms of redness, sores, and pain. Benzene exposure in the eyes causes direct irritation, pain, inflammation, and corneal damage.
Chronic Inhalation Exposure
As discussed extensively above, benzene is a known carcinogen that may cause hematopoietic cancers. Mutations in the proteins and DNA of stem/progenitor cells may result in reduced numbers of lymphatic cells, decreased red blood cells (anemia), fatigue, weakness, dizziness, lightheadedness, shortness of breath, or excessive bleeding. Symptoms of anemia are depicted in Image 6 below. Chronic inhalation exposure has also been associated with reproductive abnormalities in women. Symptoms may include menstrual irregularities and decreased ovary size.
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Management of Poisoned Patients
The treatment of acute exposures to benzene focuses on exposure control. If exposed dermally or optically, the affected area should be rinsed (with sterile water or sterile normal saline) and any contaminated clothing removed. For high-level inhalation exposure, emphasis should be made on moving the patient to an environment with fresh, uncontaminated air. Symptoms of these type of exposures generally improve with source control. Should respiratory distress occur after an inhalation exposure, 100% humidified oxygen and mechanical ventilation may also be used. Once distributed, there are currently no methods to reduce total body burden of benzene. Myelotoxic effects of benzene exposure has been mediated using the non-steroidal anti-inflammatory (NSAID) drug indomethacin in mice. Developing research indicates that TNF may be useful in interfering with hematotoxic effects of benzene. However, far more research is required to optimize treatment of benzene toxicity and prevent the hematotoxic and leukemogenic effects.
Historical Exposure
One historical exposure of note stands out in the literature. Studies were performed on workers exposed to benzene in three separate Pliofilm factories in Ohio. In the 1987 study report, 1,165 white male employees were studied for their occupational exposure to benzene. Analyses of the data from these studies showed an undeniable correlation between benzene exposure and mortality related to leukemia. This study continued for another 15 years, concluding that the risk of these adverse effects dropped as the time since last exposure increased. Similar studies in China have also solidified the leukemogenic potential of benzene.
References
- Agency for Toxic Substances and Disease Registry (ATSDR). 2008. Toxicological profile for Benzene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
- Yoon BI, Hirabayashi Y, Kawasaki Y, Kodama Y, Kaneko T, Kim DY, Inoue T. Mechanism of action of benzene toxicity: cell cycle suppression in hemopoietic progenitor cells (CFU-GM). Exp Hematol. 2001 Mar;29(3):278-85. doi: 10.1016/s0301-472x(00)00671-8. PMID: 11274754.
- McHale CM, Zhang L, Smith MT. Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment. Carcinogenesis. 2012;33(2):240-252. doi:10.1093/carcin/bgr297.
- National Center for Biotechnology Information. PubChem Compound Summary for CID 241, Benzene. https://pubchem.ncbi.nlm.nih.gov/compound/Benzene. Accessed July 5, 2021.
- Kim S, Vermeulen R, Waidyanatha S, et al. Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures. Cancer Epidemiology Biomarkers & Prevention. 2006;15(11):2246-2252. doi:10.1158/1055-9965.epi-06-0262.
- Iron-refractory iron deficiency anemia: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/iron-refractory-iron-deficiency-anemia/#causes. Published August 18, 2020. Accessed July 5, 2021.
- U.S. Food and Drug Administration. Chemicals in Every Puff of Cigarette Smoke – Combustion Stage [Video]. YouTube. https://www.youtube.com/watch?v=EXdxl0yH904. Published February 13, 2017. Accessed July 5, 2021.
- UC Berkeley Events speaker Martin T. Smith. Finding the causes of leukemia [Video]. YouTube. https://www.youtube.com/watch?v=07_Snolni-g. Published June 21, 2012. Accessed July 5, 2021.