Health Effects of Benzene: Exposure Limits and Routes of Exposure

Health Effects of Benzene – Benzene is an organic compound with the chemical formula C 6 H 6 . The benzene molecule is composed of six carbon atoms bonded in a ring, with one hydrogen atom attached to each carbon atom. Because benzene contains only carbon and hydrogen atoms, it is classified as a hydrocarbon.

Benzene is a natural constituent of crude oil and one of the essential petrochemicals. Because the ring has continuous pi bonds between the carbon atoms, benzene is classified as an aromatic hydrocarbon, [n]-anulene ([6]-anulene). Benzene is sometimes abbreviated as PhH. Benzene is a colorless, highly flammable and sweet-smelling liquid. Its presence gives a distinctive aroma at gas stations.

Its main use is as a precursor to manufacture chemicals with more complex structures, such as ethylbenzene and cumene, which are produced annually by billions of kilograms. Because benzene has a high octane number, gasoline (bbm) contains its aromatic derivatives such as xylene and toluene up to 25%. Benzene itself has been limited to less than 1% in gasoline because it is known to be a human carcinogen. Its non-industrial applications have been limited for the same reasons.

Benzene is found in trace amounts in petroleum and coal. It is a by-product of incomplete combustion of most materials. For commercial use, until World War II, most of the benzene was obtained as a by-product of coke production for the steel industry.

However, in the 1950s, when there was increasing demand for benzene, especially from the growing polymer industry, it became necessary to produce benzene from petroleum. Today, most of the benzene comes from the petrochemical industry, with only a small part being produced from coal.

Use of Benzene

The main use of benzene is as an intermediate for making other chemicals, most notably ethylbenzene, cumene, cyclohexane, nitrobenzene and alkylbenzenes. More than half of benzene production is processed into ethylbenzene, the precursor to styrene, which is used to make polymers and plastics such as polystyrene and EPS.

Some 20% of benzene production is used to make cumene, which is required in the production of phenol and acetone for resins and glues. Cyclohexane accounts for about 10% of world benzene production; mainly used in the manufacture of nylon fibers, which are processed into textiles and engineering plastics.

Small amounts of benzene are used to make several types of rubber, lubricants, dyes, detergents, drugs, explosives, and pesticides. In 2013, the largest benzene consuming country was China, followed by the United States. Benzene production is currently expanding in the Middle East and Africa, while production capacity in Western Europe and North America is stagnant.

Toluene is currently often used as a substitute for benzene, for example as a fuel additive. The dissolving properties of the two are similar, but toluene is less toxic and has a wider range of liquid phases. Toluene is also processed into benzene.

Benzene Health Effects

Benzene is classified as a carcinogen, which increases the risk of cancer and other diseases, and is also a major cause of bone marrow failure. A large body of epidemiological, clinical, and laboratory data links benzene to aplastic anemia, acute leukaemia, bone marrow disorders, and cardiovascular disease. Specific haematological malignancies associated with benzene include acute myeloid leukemia (AML), aplastic anemia, myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML).

The American Petroleum Institute (API) stated in 1948 that “it is generally considered that the only absolutely safe concentration of benzene is zero”. There is no safe level of exposure; even a small amount can cause damage. The US Department of Health and Human Services (DHHS) classifies benzene as a human carcinogen.

Long-term exposure to excessive levels of benzene in the air causes leukemia, a potentially fatal cancer of the blood-forming organs. In particular, acute myeloid leukemia or acute nonlymphocytic leukemia (AML & ANLL) are undoubtedly the result of benzene exposure. The IARC ranks benzene as “known to be carcinogenic to humans” (Group 1).

Because benzene is ubiquitous in gasoline and ubiquitous used hydrocarbon fuels, human exposure to benzene is a global health problem. Benzene attacks the liver, kidneys, lungs, heart and brain and can cause damage to DNA strands, damage to chromosomes, etc. Benzene causes cancer in animals, including humans. Benzene has been shown to cause cancer in both sexes in several species of laboratory animals exposed by various routes.

Benzene exposure

According to the Agency for Toxic Substances and Disease Registry (ATSDR) (2007), benzene is a chemical that is produced anthropogenic and occurs naturally from processes including volcanic eruptions, wild fires, synthesis of chemicals such as phenol, production of synthetic fibers, and manufacture of rubber, lubricants, pesticides, drugs, and dyes.

The main sources of exposure to benzene are tobacco smoke, car service stations, motor vehicle exhaust and industrial emissions. However, benzene can also be ingested and absorbed through the skin due to contact with contaminated water. Benzene is metabolized by the liver and excreted in the urine.

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Measurement of benzene levels in air and water was carried out by collecting them through activated charcoal tubes, which were then analyzed by gas chromatography. Measurement of benzene in humans can be done through urine, blood and breath tests. However, all of these have limitations because benzene is metabolized rapidly in the human body. Exposure to benzene can progressively cause aplastic anemia, leukemia, and multiple myeloma.

OSHA regulates benzene levels in the workplace. The maximum permissible amount of benzene in the workspace air for an 8-hour workday, 40-hour week is 1 ppm. Because benzene can cause cancer, NIOSH recommends that all workers wear special breathing equipment when they are likely to be exposed to benzene at levels in excess of the recommended exposure limit (8 hours) of 0.1 ppm.

Benzene Exposure Limits

The United States Environmental Protection Agency (US EPA) has determined the maximum contamination level (MCL) for benzene in drinking water to be 0.005 mg/L (5 ppb), as promulgated through the US Primary Drinking Water Regulations.

This regulation is based on the prevention of benzene leukemogenesis. The maximum contaminant level goal (MCLG), a non-enforceable health goal that will allow an adequate margin of safety for the prevention of adverse effects, is a zero concentration of benzene in drinking water. The EPA requires reporting a minimum of 10 pounds (4.5 kg) of benzene spills or accidental releases into the environment.

The U.S. Occupational Safety and Health Administration (OSHA) has set a permissible exposure limit of 1 part benzene per million parts air (1 ppm) in the workplace for an 8-hour work day, 40 hours per week. The short-term exposure limit for benzene in air is 5 ppm for 15 minutes.

These legal limits are based on research showing strong evidence of health risks for workers exposed to benzene. The risk of exposure to 1 ppm for years of service has been estimated as 5 excess leukaemic deaths per 1,000 exposed employees (this estimate has no threshold for the carcinogenic effect of benzene). OSHA has also set an action level of 0.5 ppm to encourage lower workplace exposures.

The US National Institute for Occupational Safety and Health (NIOSH) revised the Immediately Dangerous to Life and Health (IDLH) concentration for benzene to 500 ppm. The current NIOSH definition of an IDLH condition, as given in the NIOSH Respirator Selection Logic, is one that poses a threat of exposure to an airborne contaminant when that exposure is likely to cause death or immediate or delayed permanent health effects or prevent escape from an environment [NIOSH 2004].

The purpose of assigning IDLH values ​​is (1) to ensure that workers can escape from a contaminated environment in the event of failure of respiratory protective equipment and (2) to be considered the maximum level above that permitted only for highly reliable respirators providing maximum worker protection. . [NIOSH 2004].

In September 1995, NIOSH issued a new policy to develop recommended exposure limits ( RELs ) for substances, including carcinogens. Because benzene can cause cancer, NIOSH recommends that all workers use special respirators when they are susceptible to exposure to benzene at levels exceeding the REL (10-hour) 0.1 ppm. The NIOSH short term exposure limit (STEL – 15 minutes) is 1 ppm.

The American Conference of Governmental Industrial Hygienists (ACGIH) adopted Threshold Values ​​(TLV) for benzene at 0.5 ppm TWA and 2.5 ppm STEL. Regulation of the Minister of Health of the Republic of Indonesia No. 70 of 2016 concerning Standards and Requirements for Industrial Work Environment Health requires a Threshold Value (NAV) for benzene of 0.5 ppm TWA and 2.5 ppm STEL.

Benzene Toxicology

1. Exposure Biomarkers

Several tests can determine exposure to benzene. Benzene can be measured by inhalation, blood or urine, but such tests are usually limited to the first 24 hours after exposure because of the rapid removal of benzene by exhalation or biotransformation. Most people in developed countries have a baseline level of benzene and other aromatic hydrocarbons in their blood.

In the body, benzene is enzymatically converted to a number of oxidation products including muconic acid, phenylmercapturic acid, phenol, catechol, hydroquinone, and 1,2,4-trihydroxybenzene. Most of these metabolites are of value as biomarkers of human exposure, as they accumulate in the urine in proportion to the duration and degree of exposure.

In addition, they also persist for several days after exposure has stopped. The ACGIH biological exposure limits for occupational exposure are 500 μg/g creatinine for muconic acid and 25 μg/g creatinine for phenylmercapturic acid in end-of-shift urine specimens.

2. Biotransformation

Although not a common substrate for metabolism, benzene can be oxidized by bacteria and eukaryotes. In bacteria, the enzyme dioxygenase can add oxygen to the ring, and the unstable product is immediately reduced (by NADH) to a cyclic diol with two double bonds, destroying its aromaticity. Furthermore, the diol is reduced by NADH to catechol. The catechol is then metabolized to acetyl CoA and succinyl CoA, which are used by organisms primarily in the Krebs cycle for energy production.

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The metabolic pathway for benzene is quite complex and begins in the liver. Several enzymes are involved in it. These include cytochrome P450 2E1 (CYP2E1), quinine oxidoreductase (NQ01 or DT-diaphorase or NAD(P)H dehydrogenase (quinone 1)), GSH, and myeloperoxidase (MPO). CYP2E1 is involved in many steps: the conversion of benzene to oxepine (benzene oxide), phenol to hydroquinone, and hydroquinone to benzenetriol and catechol.

Hydroquinone, benzenetriol and catechol are converted to polyphenols. In the bone marrow, MPO converts these polyphenols into benzoquinones. These intermediates and metabolites induce genotoxicity through various mechanisms including inhibiting topoisomerase II (which maintains cell structure and organization), generating oxygen free radicals (unstable species) that trigger mutations, increasing oxidative stress, inducing DNA strand breaking, and DNA methylation graying (Fig. that can affect gene expression). NQ01 and GSH alter metabolism from toxicity. NQ01 metabolizes benzoquinones to polyphenols (counteracts MPO effect). GSH is involved in the formation of phenylmercapturic acid.

Genetic polymorphisms in these enzymes can lead to loss of function or gain of function. For example, mutations in CYP2E1 increase activity and result in an increase in toxic metabolites. NQ01 mutations result in loss of function and can lead to decreased detoxification. Mutations of myeloperoxidase result in loss of function and can lead to decreased formation of toxic metabolites. GSH mutations or deletions result in loss of function and result in decreased detoxification. These genes may be targets of genetic screening for susceptibility to benzene toxicity.

3. Molecular Toxicology

The paradigm of toxicological assessment of benzene is shifting towards the domain of molecular toxicology as it enables a better understanding of fundamental biological mechanisms. Glutathione appears to play an important role by protecting against benzene-induced DNA damage and is being identified as a new biomarker for its exposure and effects.

Benzene causes chromosomal aberrations in peripheral blood leukocytes and bone marrow which explains the high incidence of leukemia and multiple myeloma caused by chronic exposure. These deviations can be monitored using fluorine in situ hybridization (FISH) with DNA quarts to assess the effect of benzene together with haematological tests as markers of hematotoxicity.

Benzene metabolism involves enzymes encoded by polymorphic genes. Studies have shown that genotype at this locus can influence susceptibility to the toxic effects of benzene exposure. Individuals carrying the NAD(P)H variant: quinone oxidoreductase 1 (NQ01), microsomal epoxide hydrolase (EPHX) and deletion of glutathione S-transferase T1 (GSTT1) showed a greater frequency of single-stranded DNA breaks.

4. Biological Oxidation and Carcinogenic Activity

One way to understand the carcinogenic effects of benzene is to examine the products of biological oxidation. Pure benzene, for example, oxidizes in the body to produce an epoxide, benzene oxide, which is not excreted easily and can interact with DNA to produce dangerous mutations.

Benzene Exposure Routes

1. Inhalation

Outdoor air may contain low levels of benzene from auto repair shops, wood smoke, tobacco smoke, gasoline transfers, motor vehicle exhaust, and industrial emissions. Approximately 50% of total exposure to benzene nationally (United States) comes from smoking tobacco or from exposure to tobacco smoke. After smoking 32 cigarettes per day, the smoker will consume about 1.8 milligrams (mg) of benzene. This amount is about 10 times the average daily intake of benzene by non-smokers.

Most of the inhaled benzene is exhaled in its original form through exhalation. Human studies show that 16.4% to 41.6% of retained benzene is excreted via the lungs within five to seven hours, after exposure to 47 to 110 ppm for two to three hours, and only 0.07% to 0 The remaining .2% of benzene is excreted in its natural form in the urine.

After exposure to 63 to 405 mg/m 3 of benzene for 1 to 5 hours, 51% to 87% is excreted in the urine as phenol within 23 to 50 hours. In another study, 30% of benzene absorbed through the skin, which is mainly metabolized in the liver, was excreted as phenol in the urine.

2. Exposure to Soft Drinks

Under certain conditions and in the presence of other chemicals, benzoic acid (a preservative) and ascorbic acid (Vitamin C) may interact to produce benzene. In March 2006, the Food Standards Agency in the United Kingdom conducted a survey of 150 soft drink brands. It found that four contained benzene at levels above the limits set by the World Health Organization (WHO). The affected group (English: batch ) was withdrawn from circulation. A similar problem was reported by the FDA in the United States.

3. Contamination of Water Supply

In 2005, the water supply to the Chinese city of Harbin, with a population of nearly nine million people, was stopped due to exposure to large amounts of benzene. Benzene leaked into the Songhua river, which supplies drinking water to the city, after an explosion at a China National Petroleum Corporation (CNPC) factory in Jilin city on November 13, 2005.

4. Injection

The Nazis used injected benzene as one of several methods of assassination.