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Everything You Need To Know About Benzene

Benzene can cause Aplastic anemia, Encephalopathy, chronic solvent Erythroleukemia, Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, and acute toxic solvent effects





BENZENE

Benceno is a killer, Acute Myeloid Leukemia or (AML) is a common disease associate with exposure to Benzene



HIGHLIGHTS: Benzene is a widely used chemical formed from both natural processes and human activities. Breathing benzene can cause drowsiness, dizziness, and unconsciousness; long-term benzene exposure causes effects on the bone marrow and can cause anemia and acute myeloid leukemia. Benzene has been found in at least 1,001 of the 1,662 National Priority List sites identified by the Environmental Protection Agency (EPA).

What is benzene? Benzene is a colorless liquid with a sweet odor. It evaporates into the air very quickly and dissolves slightly in water. It is highly flammable and is formed from both natural processes and human activities.

Bensene is also a toxic, volatile liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide.

Benzene is widely used in the United States; it ranks in the top 20 chemicals for production volume. Some industries use benzene to make other chemicals which are used to make plastics, resins, and nylon and synthetic fibers. Benzene is also used to make some types of rubbers, lubricants, dyes, detergents, drugs, and pesticides. Natural sources of benzene include volcanoes and forest fires. Benzene is also a natural part of crude oil, gasoline, and cigarette smoke. Benzene is also known as: (6)Annulene, AI3-00808, Benceno [Spanish], Benzeen [Dutch], Benzen [Polish], Benzene, Benzin, Benzin (Obs.), Benzine, Benzine (Obs.), Benzol, Benzol 90, Benzole, Benzolene, Benzolo [Italian], Bicarburet of hydrogen, CCRIS 70, Carbon oil, Caswell No. 077, Coal naphtha, Cyclohexatriene, EINECS 200-753-7, EPA Pesticide Chemical Code 008801, Fenzen [Czech], HSDB 35, Mineral naphtha, Motor benzol, NCI-C55276, NSC 67315, Nitration benzene, Phene, Phenyl hydride, Polystream, Pyrobenzol, Pyrobenzole, RCRA waste number U019, UN 1114, Systematic Names: Benzene, Benzene, pure, Superlist Names: Benzene, Benzene (including benzene from gasoline), Benzene [UN1114] [Flammable liquid], Benzol diluent, RCRA waste no. U109, UN1114

What happens to benzene when it enters the environment? Industrial processes are the main source of benzene in the environment. Benzene can pass into the air from water and soil. It reacts with other chemicals in the air and breaks down within a few days. Benzene in the air can attach to rain or snow and be carried back down to the ground. It breaks down more slowly in water and soil, and can pass through the soil into underground water. Benzene does not build up in plants or animals.

How might I be exposed to benzene? Outdoor air contains low levels of benzene from tobacco smoke, automobile service stations, exhaust from motor vehicles, and industrial emissions. Vapors (or gases) from products that contain benzene, such as glues, paints, furniture wax, and detergents, can also be a source of exposure. Air around hazardous waste sites or gas stations will contain higher levels of benzene. Working in industries that make or use benzene.

Percent Benzene Contained in Specific Brands with category, and form of Products: Champion Sprayon Flush Off Degreaser -Auto products -aerosol <1%, Parks Adhesive Remover-09/04/1998 Hobby/Craft liquid, Glidden Ultra Hide Alkyd Semi Gloss Interior Deep Tint Base- Home maintenance- liquid- 0.1-1.0%, Glidden Ultra Hide Alkyd Semi Gloss Interior Intermediate Tint Base -Home maintenance -liquid -0.1-1.0%

Benzene was used in the past as a solvent in inks, rubber, lacquers, and paint removers. Today, it is used mainly in closed processes to synthesize organic chemicals. Gasoline in some countries contains a high concentration of benzene (as high as 30%); the U.S. average is 1-3%. Workers who remove or clean underground storage tanks may be exposed to significant levels. Gasoline in North America now contains about 1% benzene.

Industrial Processes with risk of exposure to Benzene: Burning Synthetic Polymers, Firefighting, Metal Preparation and Pouring, Petroleum Refining, Working with Glues and Adhesives

Activities with risk of exposure of Benzene: Preparing, stuffing, and mounting the skins of animals (taxidermy), Smoking cigarettes

How can benzene affect my health? Breathing very high levels of benzene can result in death, while high levels can cause drowsiness, dizziness, rapid heart rate, headaches, tremors, confusion, and unconsciousness. Eating or drinking foods containing high levels of benzene can cause vomiting, irritation of the stomach, dizziness, sleepiness, convulsions, rapid heart rate, and death.

The major effect of benzene from long-term exposure is on the blood. Benzene causes harmful effects on the bone marrow and can cause a decrease in red blood cells leading to anemia. It can also cause excessive bleeding and can affect the immune system, increasing the chance for infection.

Diseases associated with exposure to Benzene: Aplastic anemia, Encephalopathy, chronic solvent Erythroleukemia, Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, acute toxic solvent effects

Some women who breathed high levels of benzene for many months had irregular menstrual periods and a decrease in the size of their ovaries. It is not known whether benzene will affect fertility in men.

How likely is benzene to cause cancer? Long-term exposure to high levels of benzene in the air can cause leukemia, particularly acute myelogenous leukemia, often referred to as AML. This is a cancer of the blood-forming organs. The Department of Health and Human Services (DHHS) has determined that benzene is a known carcinogen. The International Agency for Research on Cancer (IARC) and the EPA have determined that benzene is carcinogenic to humans.

How can benzene affect children? Children can be affected by benzene exposure in the same ways as adults. It is not known if children are more susceptible to benzene poisoning than adults.

Benzene can pass from the mother's blood to a fetus. Animal studies have shown low birth weights, delayed bone formation, and bone marrow damage when pregnant animals breathed benzene.

How can families reduce the risks of exposure to benzene? Benzene exposure can be reduced by limiting contact with gasoline and cigarette smoke. Families are encouraged not to smoke in their house, in enclosed environments, or near their children.

Is there a medical test to show whether I've been exposed to benzene? Several tests can show if you have been exposed to benzene. There is a test for measuring benzene in the breath; this test must be done shortly after exposure. Benzene can also be measured in the blood; however, since benzene disappears rapidly from the blood, this test is only useful for recent exposures.

In the body, benzene is converted to products called metabolites. Certain metabolites can be measured in the urine. The metabolite S-phenylmercapturic acid in urine is a sensitive indicator of benzene exposure. However, this test must be done shortly after exposure and is not a reliable indicator of how much benzene you have been exposed to, since the metabolites may be present in urine from other sources.

Has the federal government made recommendations to protect human health? The EPA has set the maximum permissible level of benzene in drinking water at 5 parts benzene per billion parts of water (5 ppb).

The Occupational Safety and Health Administration (OSHA) has set limits of 1 part benzene per million parts of workplace air (1 ppm) for 8 hour shifts and 40 hour work weeks.

References Agency for Toxic Substances and Disease Registry (ATSDR). 1997. Managing Hazardous Materials Incidents. Volume III – Medical Management Guidelines for Acute Chemical Exposures: Benzene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Agency for Toxic Substances and Disease Registry (ATSDR). 2005. Toxicological Profile for benzene. (Draft for Public Comment). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Where can I get more information? ATSDR can tell you where to find occupational and environmental health clinics. Their specialists can recognize, evaluate, and treat illnesses resulting from exposure to hazardous substances. You can also contact your community or state health or environmental quality department if you have any more questions or concerns.

For more information, contact:

Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, Mailstop F-32 Atlanta, GA 30333 Phone: 1-888-42-ATSDR (1-888-422-8737) FAX: (770)-488-4178 Email: ATSDRIC@cdc.gov

Benzene MSDS Information:

Contents:

Human Health Effects
Emergency Medical Treatment
Animal Toxicity Studies
Metabolism/Pharmacokinetics
Pharmacology
Environmental Fate & Exposure
Environmental Standards & Regulations
Chemical/Physical Properties
Chemical Safety & Handling
Occupational Exposure Standards
Manufacturing/Use Information
Laboratory Methods
Special References
Synonyms and Identifiers

BENZENE


CASRN: 71-43-2
Human Health Effects:

Toxicity Summary:

IDENTIFICATION: Benzene is an aromatic hydrocarbon used as a solvent. It is a clear liquid with a sweet odor. Origin of the substance: Benzene occurs naturally but is primarily produced from petroleum products. Uses: Description: Benzene is used as an intermediate in the manufacture of a number of chemicals, including ethylbenzene (used in the synthesis of styrene), cumene (used in the synthesis of phenol and for the manufacture of phenolic resins and nylon intermediates), cyclohexane (used to make nylon resins), and nitrobenzene (used in the synthesis of aniline). Benzene is also a precursor in the manufacture of urethanes, chlorobenzene, and maleic anhydride. Benzene was previously used widely as a solvent, but this use has decreased in many countries due to the concern over carcinogenic effects. HUMAN EXPOSURE: Main risks and target organs: Acute exposure to high concentrations of benzene in air results in neurological toxicity and may sensitize the myocardium to endogenous catecholamines. Acute ingestion of benzene causes gastrointestinal and neurological toxicity. Chronic exposure to benzene results primarily in hematotoxicity, including aplastic anemia, pancytopenia, or any combination of anemia, leukopenia, and thrombocytopenia Chronic benzene exposure is associated with an increased risk of leukemia. Summary of clinical effects: Acute neurological toxicity from benzene exposure may cause headache, dizziness, drowsiness, confusion, tremors, and loss of consciousness. Exposure to high concentrations may have effects on multiple organ systems. Sudden deaths occurring below anesthetic concentrations of benzene are apparently due to cardiac dysrhythmias. With ingestion, toxic signs and symptoms may include nausea, vomiting, and abdominal pain as well neurological toxicity. Chronic hematological effects include anemia, thrombocytopenia, leukopenia, pancytopenia, chromosomal abberations, and leukemia. Dermal exposure may cause skin irritation. High risk circumstances of poisoning: The most common form of exposure to benzene is occupational, and both occupational and environmental exposures to benzene are overwhelmingly through inhalation. Dermal contact is most often only a minor source of exposure. Environmental exposure is greatest in areas of heavy automobile use due to the presence of benzene in tailpipe emissions, near service stations and from tobacco smoke. In the United States, smoking accounts for approximately half of the total population exposure to benzene. In countries where benzene is used as a household cleaner, accidental or suicidal ingestion may occur. Occupationally exposed populations: Individuals working in industries involved with benzene production (petrochemical industry, coke manufacturing), rubber tire or cast rubber film manufacturing, transport or storage of benzene or benzene-containing products, and gas station employees all are at risk for excess benzene exposure. Although in the United States benzene has been removed from commercial solvents, the use of industrial solvents may still be a source of exposure. Historically, benzene used as a solvent in printing inks in the rotogravure industry and adhesives by shoemakers led to a high degree of exposure in these industries. Routes of entry Oral: Acute oral exposure is uncommon and usually results from accidental ingestion or attempted suicide. Benzene is a contaminant in drinking water. Inhalation: Inhalation is the primary route of exposure for benzene, both in the occupational and environmental setting. The relatively high vapor pressure of benzene creates a significant hazard when adequate workplace safeguards are not in place. Dermal: Dermal exposure may occur in the occupational setting, although it is quantitatively less important than inhalation exposure. Eye: Ocular exposure may occur through splashing or high vapor concentrations. Absorption by route of exposure: In humans absorption by inhalation ranges from 70 to 80% in the first 5 minutes and then decreases to approximately 50% thereafter. In rodents the percentage of retained benzene decreased as the inhaled vapor concentration increased from 10 to 1000 ppm. In vitro dermal absorption in humans is 0.2% over a period of 13.5 hours. Distribution by route of exposure: In human autopsies on individuals dying shortly after exposure, high levels of benzene were found in the brain, with lower levels in the fat, blood, kidneys, and liver. Exposure to 25 ppm of benzene for two hours produced an average maximum blood benzene concentration of 0.2 mg/L. Biological half-life by route of exposure: After inhalation exposure, benzene elimination in humans appears to follow a two compartment model, with half-lives of around 1 hour and 24 hours. The half life of exhaled benzene in humans varies depending on the benzene exposure concentration and duration. Exposure to 99 ppm for 1 hour resulted in an initial phase half-life of 42 minutes, and exposure to 6.4 ppm for 8 hours resulted in an initial phase half-life of 72 minutes, with a terminal phase half-life (from 10 to 100 hours after exposure) of 23 to 31 hours. In analysis of exhaled benzene in rats, exposure to 500 ppm for 6 hours results in an initial phase half-life of 42 minutes and a secondary phase half-life of 13.1 hours. Metabolism: Benzene is both exhaled unchanged in the lungs and excreted as metabolites in the urine. Metabolism occurs primarily in the liver. The first step in benzene metabolism is the formation of benzene oxide, an epoxide, by cytochrome P-450 dependent mixed function oxidases. There are at least two metabolic pathways proceeding from this intermediate. The first involves hydroxylation of the epoxide to phenol, which is then excreted as a glucuronide or sulfate conjugate, or converted to hydroquinone and benzoquinone. Phenol, hydroquinone glucuronide and hydroquinone sulfate serve as markers for this enzymatic pathway. The second pathway involves conversion of benzene oxide to muconic dialdehyde through an NADPH mediated process, and further conversion to muconic acid. Catechol is produced via this pathway through the intermediate benzene glycol, and is excreted as a glucuronide or sulfate conjugate. Elimination by route of exposure: In a human study 16.4 to 41.6% of retained benzene was eliminated through the lungs within five to seven hours after a two- to three-hour exposure to 47 to 110 ppm and only 0.07 to 0.2% of the remaining benzene was excreted unchanged in the urine. After exposure to 63 to 405 mg/m3 of benzene for 1 to 5 hours, 51 to 87% was excreted in the urine as phenol over a period of 23 to 50 hours. In another human study, 30% of absorbed dermally applied benzene was excreted as phenol in the urine. Mode of action: Acute benzene exposure produces central nervous system excitation and depression. In chronic exposures, benzene metabolites are considered the toxic agents, not the parent compound. The relative contribution of different benzene metabolic pathways may be dose related, with more toxic agents produced by high affinity low capacity pathways. Chronic benzene exposure can cause bone marrow stem cell depression, apparently through a cytotoxic effect on all lineages of hematopoietic progenitor cells, although there is some evidence for a mechanism involving injury to marrow stromal cells. Bone marrow macrophages have been shown to metabolize phenol to reactive compounds that bind irreversibly to protein and DNA. Hydroquinone and phenol are known hematotoxins. Toxicity: Human data: Adults: Inhalation exposure at 20,000 ppm for five to ten minutes may be fatal. Exposure to 150 to 650 ppm for 4 months to 15 years caused pancytopenia. Chronic exposure of up to eight years at a mean benzene concentration of 75 ppm was associated with the development of anemia and leukopenia, but no such association was found at mean exposure concentrations of 15 to 20 ppm for up to 27 years. Carcinogenicity: In epidemiologic studies, chronic exposure to benzene is associated with the development of acute myelogenous leukemia and its variants including erythroleukemia. Other forms of leukemia including acute lymphoblastic anemia, acute monocytic leukemia, and preleukemia have also been reported following benzene exposure. Other hematopoietic malignancies have been described in association with benzene exposure including malignant lymphoma, myeloid metaplasia, and multiple myeloma. The relative risk for leukemia was 6.97 times the risk in the unexposed group. A group of 748 workers producing rubber hydrochloride exposed to benzene concentrations of 10 to 100 ppm for up to 9 years had a relative risk of 10 for acute myelogenous and acute monocytic leukemia. 680 workers exposed to benzene at concentrations exceeding 2 ppm for 30 years had a relative risk of 3.93 for leukemia and other lymphopoietic cancers. In a study of 1165 workers in a rubber hydrochloride factory there were 9 deaths from leukemia. In a case report, one individual developed acute myelogenous leukemia after an occupational exposure to 2 ppm of benzene over an 18 month period, although he had previously worked in a saw mill which manufactured veneer. Teratogenicity: Benzene crosses the placenta and is present in cord blood in concentrations equal to or greater than maternal blood. An increased frequency of chromatid and isochromatid breaks was found in 14 children of women exposed during pregnancy to a mix of benzene and other solvents in chemical laboratories and the printing industry. Mutagenicity: In studies of occupational exposure, benzene was found to cause chromosome changes at concentrations that induced blood dyscrasias. At concentrations below 31 ppm, workers exposed for 10 to 26 years had significantly more chromosome breaks and gaps in peripheral lymphocytes than found in controls, and 31 of the 33 workers had no other evidence of clinical or hematological effects. At exposure levels of less than 10 ppm over one month to 26 years, workers also had a significantly higher number of chromosomal aberrations in peripheral lymphocytes than did controls. Interactions: Ethanol can increase the extent of hematotoxicity from benzene exposure. Previous administration of phenobarbital may decrease benzene hematotoxicity. Toluene reduces the metabolizm of benzene and reverses the benzene induced decrease in incorporation of iron into red blood cells. Hepatitis B may also increase the incidence of hematopoietic effects from benzene exposure. Eye contact: Ocular burning and transient epithelial injury may result from exposure to liquid. Exposure to high concentrations of benzene vapor may cause ocular irritation. Course, prognosis, cause of death: Most cases of acute benzene exposure resolve spontaneously or with supportive care without long term sequela. At extremely high benzene concentrations, death from acute exposure may occur immediately or within several hours after exposure. Death may be due to CNS depression, asphyxiation, or respiratory or circulatory arrest. In fatal cases autopsy has revealed haemolysis, cyanosis, and multiple organ hemorrhage. In chronic benzene exposures, patients developing minor hematologic abnormalities usually recover completely when removed from the exposure. In cases of benzene-induced pancytopenia, the patients may recover completely, die from complications of the pancytopenia, or develop leukemia at a later time. Chronic ingestion of benzene for therapeutic purposes reportedly led to bladder irritability and impotence in some patients. Chronic benzene exposure has been shown to affect both cellular and humoral immunity. In a study of 35 painters exposed to 3 to 49 ppm of benzene and higher concentrations of toluene and xylene, increased serum IgM, and decreased serum IgG and IgA were found. Decreases in cellular immunity have been documented through leucopenia. ANIMAL STUDIES: In animal models, benzene is well absorbed by the oral route, ranging from over 90% in rabbits to over 97% in rats and mice. Distribution by route of exposure: Following inhalation, benzene is distributed throughout the body, and animal data suggests it may distribute preferentially to adipose tissue due to its lipophilicity. Metabolism: In rat bone marrow after a six hour exposure to 500 ppm inhaled benzene, phenol was initially the main metabolite followed by catechol and hydroquinine at later times. In rabbits within two to three days after oral dosing of 340 to 500 mg/kg of benzene, 43% of benzene was exhaled unchanged, 23.5% was excreted in the urine as phenol, 4.8% as quinol, and 2.2% as catechol with a number of other phenolic compounds excreted as well. Animal experiments exposing pregnant mice and rats to inhaled benzene in general demonstrated increased fetal skeletal variants and reduced fetal weight, but failed to demonstrate consistent convincing evidence of teratogenecity. Rats exposed to 313 ppm for 24 hours/day on days 9 to 14 of gestation demonstrated reduced fetal weight and increased skeletal variants. Mice exposed to 500 ppm of benzene for 7 hours/day from days 6 to 15 of gestation had decreased mean fetal body weight and an increase in several minor skeletal variants. The same exposure (500 ppm for 7 hours/day) in rabbits on gestational days 6 to 18 did not affect fetal body weight, rather a decrease in two minor skeletal variants. In rats exposed to 100, 300, and 2200 ppm of benzene vapor for 6 hours/day on days 6 to 15 of gestation, an increase in skeletal variants was seen at all exposure concentrations, and only the highest exposure concentration resulted in decreased fetal weight. Exposure in utero to 20 ppm of benzene for 6 hr/day on days 6 to 15 of gestation in mice resulted in hematopoietic abnormalities. Exposures in rats to less than 10 ppm of benzene during pregnancy did not cause adverse fetal changes. Cardiovascular: Electrocardiographic studies in monkeys and cats exposed to high concentrations of benzene revealed ectopic beats and ventricular tachycardia, which resolved upon excision of the adrenal glands and stellate ganglion, and recurred with the subcutaneous administration of adrenaline. One report of sudden death after running and acute benzene exposure was felt to be due to benzene induced myocardial sensitivity to endogenous catecholamines. Immunological: Benzene administered to mice by intraperitoneal injection resulted in a decreased cultured spleen cell IgM production as demonstrated by plaque-forming cells assays at a dose of 44 mg/kg for three days, and a decreased lymphoproliferative response in cultured spleen lymphocytes exposed to Eschericha coli lipopolysaccharide or concanavalin A in animals administered a dose of 264 mg/kg for three days. The number of circulating lymphocytes was decreased only at dose of 440 mg/kg or higher. Mice given benzene contaminated water had significant immunotoxic effects on both the humoral and cellular immune responses at doses of 166 mg/L and higher for a four week period. Animal experiments exposing pregnant mice, rats, and rabbits demonstrated fetotoxicity associated with maternal toxicity, specifically fetal skeletal variants and reduced fetal weight.
[International Programme on Chemical Safety; Poisons Information Monograph: Benzene (PIM 063) (1999) Available from http://www.inchem.org/pages/pims.html as of October 24, 2005. ]**PEER REVIEWED**

Evidence for Carcinogenicity:

Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient; Overall summary evaluation of carcinogenic risk to humans is group 1: The chemical is carcinogenic to humans. /From table/
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. S7 120 (1987)]**PEER REVIEWED**

A1; Confirmed human carcinogen.
[ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinatti, OH, 2005, p. 13]**QC REVIEWED**

WEIGHT-OF-EVIDENCE CHARACTERIZATION: Benzene is classified as a "known" human carcinogen (Category A) under the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen Risk Asessment Guidelines (USEPA, 1996), benzene is characterized as a known human carcinogen for all routes of exposure based upon convincing human evidence as well as supporting evidence from animal studies. Epidemiologic studies and case studies provide clear evidence of a causal association between exposure to benzene and acute nonlymphocytic leukemia and also suggest evidence for chronic nonlymphocytic leukemia and chronic lymphocytic leukemia. Other neoplastic conditions that are associated with an increased risk in humans are hematologic neoplasms, blood disorders such as preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome. These human data are supported by animal studies. The experimental animal data add to the argument that exposure to benzene increases the risk of cancer in multiple species at multiple organ sites (hematopoietic, oral and nasal, liver, forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that these responses are due to interactions of the metabolites of benzene with DNA ... Recent evidence supports the viewpoint that there are likely multiple mechanistic pathways leading ... to leukemogenesis from exposure to benzene. HUMAN CARCINOGENICITY DATA: Benzene is a known human carcinogen based upon evidence presented in numerous occupational epidemiological studies. Significantly increased risks of leukemia, chiefly acute myelogenous leukemia, have been reported in benzene-exposed workers in the chemical industry, shoemaking and oil refineries. ANIMAL CARCINOGENICITY DATA:... many experimental animal studies, both inhalation and oral, also support the evidence that exposure to benzene increases the risk of cancer in multiple organ systems, including the hematopoietic system, oral and nasal cavities, liver, forestomach, preputial gland, lung, ovary, and mammary gland ....
[U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Benzene (71-43-2). Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000]**PEER REVIEWED**

Human Toxicity Excerpts:

Benzene is irritant to skin, & by defatting the keratin layer may cause erythema, vesiculation, & dry & scaly dermatitis.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1308]**PEER REVIEWED**

AFTER A SHORT EXPOSURE TO A LARGE AMT OF BENZENE, BY INGESTION OR BY BREATHING CONCENTRATED VAPORS, THE MAJOR TOXIC EFFECT IS ON THE CNS. SYMPTOMS FROM MILD EXPOSURE INCL DIZZINESS, WEAKNESS, EUPHORIA, HEADACHE, NAUSEA, VOMITING, TIGHTNESS IN CHEST, & STAGGERING. IF EXPOSURE IS MORE SEVERE, SYMPTOMS PROGRESS TO BLURRED VISION, TREMORS, SHALLOW & RAPID RESP, VENTRICULAR IRREGULARITIES, PARALYSIS, & UNCONSCIOUSNESS.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

Long-term exposure to benzene usually is due to the inhalation of vapor or to contact with the skin. Signs and symptoms of long-term exposure to benzene incl effects on the CNS & the GI tract (headache, loss of appetite, drowsiness, nervousness, & pallor), but the major manifestation of toxicity is aplastic anemia. Bone marrow cells in early stages of development are most the sensitive ... & arrest of maturation leads to gradual depletion of circulating cells.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

BENZENE (BENZOL) ... HAS SPECIFIC TOXIC EFFECT ON BLOOD FORMATION, CAUSING APLASTIC ANEMIA & TENDENCY TO HEMORRHAGE. OCCASIONALLY HEMORRHAGES IN RETINA & IN CONJUNCTIVA ARE FOUND IN SYSTEMIC POISONING BY BENZENE. IN RARE INSTANCES NEURORETINAL EDEMA & PAPILLEDEMA HAVE BEEN DESCRIBED ACCOMPANYING RETINAL HEMORRHAGES. IT HAS NOT BEEN ESTABLISHED THAT BENZENE CAN INDUCE RETROBULBAR NEURITIS OR OPTIC NEURITIS ...
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 140]**PEER REVIEWED**

PATHOLOGICAL FINDINGS FROM ... INHALATION INCL ACUTE GRANULAR TRACHEITIS, LARYNGITIS & BRONCHITIS, MASSIVE HEMORRHAGE OF LUNG, CONGESTIVE GASTRITIS, INFARCT OF SPLEEN, ACUTE CONGESTION OF KIDNEYS, & MARKED CEREBRAL EDEMA.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 906]**PEER REVIEWED**

Many acute deaths /from benzene exposure at high concn have been/ ... due to ventricular fibrillation ... /caused by exertion/ & release of epinephrine. This was probably the mechanism involved in the death of workers in tank cars which had contained benzene. Frequently, the man who went into the tank car to carry out an unconscious worker died during the effort of lifting the unconscious man up the ladder.
[Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972., p. 124]**PEER REVIEWED**

... A large number of workers exposed to but not seriously intoxicated by benzene /were studied & results showed/ that serum complement levels, IgG, & IgA, were depressed but that IgM levels did not drop & were in fact slightly higher (Lange et al 1973; Smolik et al 1973). ... These /& other/ observations, taken together with well-known ability of benzene to depress leukocytes ... may explain why benzene-intoxicated individuals readily succumb to infection & why terminal event in severe ... toxicity is often an acute, overwhelming infection.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 116 (1982)]**PEER REVIEWED**

IN EXPT IN VITRO, BENZENE DID NOT CHANGE THE NUMBER OF SISTER-CHROMATID EXCHANGES OR THE NUMBER OF CHROMOSOMAL ABERRATIONS IN HUMAN LYMPHOCYTES.
[GERNER-SMIDT P, FRIEDRICH U; MUTAT RES 58 (2-3): 313-6 (1978)]**PEER REVIEWED**

THE MUTAGENIC ACTIVITY UPON HUMAN LYMPHOCYTES WAS STUDIED AFTER ITS ADDN TO CULTURE ON THE 28TH HR OF CULTIVATION (G1-S PERIODS). CONCN OF 1, 10, 25, 50, 100, & 250 UG/ML WERE STUDIED. BENZENE IS A WEAK MUTAGEN. IT CAUSED ELONGATION OF CENTROMERE PORTIONS OF CHROMOSOMES & CHROMOSOMAL ABERRATIONS WERE MAINLY OF SINGLE & PAIRED FRAGMENT TYPE. MUTAGENIC ACTIVITY WAS ABOUT THE SAME IN THE G0 & G1-S PERIODS.
[MNATSAKANOV ST, POGOSYAN AS; BIOL ZH ARM 26 (12): 38-43 (1973)]**PEER REVIEWED**

A major concern is the relationship between long-term exposure to benzene & leukemia. Epidemiological studies have been conducted on workers in the tire industry & in shoe factories, where benzene was used extensively. Among workers who died from exposure to benzene, death was caused by either leukemia or aplastic anemia, in approx equal proportions.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

CHRONIC BENZENE TOXICITY IS EXPRESSED AS BONE MARROW DEPRESSION RESULTING IN LEUCOPENIA, ANEMIA, OR THROMBOCYTOPENIA (LEUKEMOGENIC ACTION). WITH CONTINUED EXPOSURE THE DISEASE PROGRESSES TO PANCYTOPENIA RESULTING FROM BONE MARROW APLASIA. EVIDENCE HAS ACCUM IMPLICATING BENZENE IN THE ETIOLOGY OF LEUKEMIAS IN WORKERS IN INDUSTRIES WHERE BENZENE WAS HEAVILY USED. IT HAS BEEN SUGGESTED THAT LEUKEMIA IS AS FREQUENT A CAUSE OF DEATH FROM CHRONIC BENZENE EXPOSURE AS IS APLASTIC ANEMIA.
[SNYDER R ET AL; LIFE SCIENCES 21 (12): 1709-22 (1977)]**PEER REVIEWED**

MANY CASES OF ACUTE LEUKEMIA DEVELOPING AS TERMINAL STAGE OF APLASTIC ANEMIA RESULTING FROM EXPOSURE TO BENZENE MAY HAVE BEEN MISSED BECAUSE BONE MARROW PUNCTURE WAS NOT PERFORMED. BENZENE LEUKEMIA IS ACUTE STEM CELL OR MYELOBLASTIC LEUKEMIA, SOMETIMES ALEUKEMIA. THERE MAY BE A LATENT PERIOD EXTENDING OVER SEVERAL YEARS BETWEEN CESSATION OF EXPOSURE WITH MORE OR LESS PRONOUNCED ANEMIA, & THE ONSET OF LEUKEMIA.
[VIGLIANI EC, FORNI A; ENVIRON RES 11 (1): 122-7 (1976)]**PEER REVIEWED**

A dose-related increase in the number of cells with chromosomal aberrations occurred in human lymphocyte cultures treated with 4X10-5 M and 3.0X10-3 M benzene for 53 hr prior to metaphase analysis. Cells in late G2 stage were the most susceptible to the effect of benzene.
[Morimoto K; Japan J Ind Health 8: 23-5 (1976)]**PEER REVIEWED**

Epidemiological studies (exposure to high concn is associated with hematotoxicity and acute myelocytic leukemia in humans ...)
[European Chemical Industry, Ecology and Toxicology Center p.44 (1984)]**PEER REVIEWED**

Italian shoemakers exposed to 200-500 ppm benzene in inks and glues showed an incidence of leukemia of 1 per 1,000.
[Vigliani EC; Ann NY Acad Sci 271: 143 (1976)]**PEER REVIEWED**

Follow up study at Massachusetts rubber coating plants of 38 workers exposed over 1-24 yr at 5-50 ppm (140 ppm peak) showed no evidence of blood dyscrasias or leukemia.
[Pagnotto LD et al; Am Ind Hyg Assoc J 40: 137 (1979)]**PEER REVIEWED**

A significantly incr frequency of chromatid and isochromatid breaks in the cultured lymphocytes of workers in chemical laboratories and in the printing industry has been reported.
[USEPA; Ambient Water Quality Criteria for Benzene p.C-46 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A significant incr of peripheral blood lymphocyte chromosomal aberrations in workers exposed to benzene was reported, but not in those exposed to toluene and xylene.
[Vigliani EC, Forni A; J Occup Med 11 p.148 (1969) as cited in USEPA; Ambient Water Quality Criteria for Benzene p.C-46 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A report on 52 workers exposed to benzene found chromosomal aberrations (chromosome breaks, dicentric chromosomes, translocations, and exchange figures) in peripheral lymphocytes at 2-3 times the rates found in controls. The 8 hr TWA exposure was 2-3 ppm, the average concn determined by 15 min sampling was 25 ppm, and the peak concn was 50 ppm.
[USEPA; Ambient Water Quality Criteria for Benzene p.C-47 (1980) EPA 440/5-80-018]**PEER REVIEWED**

An epidemiological study implicating benzene as a leukemogen (acute myelocytic leukemia) followed 748 white males exposed to benzene in the manufacture of a rubber product from 1940-1949. A statistically significant (p < or = 0.002) excess of leukemia was found when compared against two control populations. There was a 5 fold excessive risk of all leukemias and a 10 fold excessive risk of myelocytic and monocytic leukemias combined.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-58 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A hematological investigation was carried out on 147 workers (employed for +10 years) exposed to high benzene levels (320-470 ppm). Abnormalities were noted in at least one parameter in 73%, the most common one being thrombocytopenia, which occurred in 62% followed by anemia (35%) and leucopenia (32%). Pancytopenia occurred in 21% of the workers. During the 3 months following removal from exposure, hematological parameters returned to normal in 120 workers, and one subject died. After one year, 20 of the remaining workers had only minor abnormalities, six were still off work, and one was still hospitalized.
[Savilahti M; Arch Gewerbpathol Gewerbhyg 15: 147-57 (1956)]**PEER REVIEWED**

A retrospective mortality study of a cohort of 594 men exposed to benzene at levels ranging between 2 and 25 ppm (TWA) was carried out at the Dow Chemical Co between 1940-1973. No incr in total mortality was noted with 102 observed/128 expected (Standard Mortality Ratio (SMR) 80). A slight increase was noted in total deaths due to malignancies (30 observed/22.8 expected, SMR 132) and suicide (5 observed/3.2 expected, SMR 147) as well as deaths from leukemia (3 observed/0.8 expected) and cancers of the digestive organs and peritoneum (9 observed/6.9 expected, SMR 125). If 53 workers exposed to other chemicals are excluded from malignancies, the results would then be 24 observed/20.3 expected, SMR 108.
[Ott MG et al; Arch Environ Health 33: 3-10 (1978)]**PEER REVIEWED**

/A subset of 292 men of the 594 in the benzene exposure of Dow cohort who were still employed in 1967/ had an examination of the health status /evaluation/ carried out between 1967-1974 and compared to a control population selected from employees not exposed to benzene, using a matched pair design (matched for age, cigarette smoking habits and length of employment). No clinically significant differences were reported although slight decr in total bilirubin levels and red blood cell counts were noted.
[Towsent et al; J Occup Med 20: 543-8 (1978)]**PEER REVIEWED**

Thirty two patients who had recovered from a blood disease (bone marrow impairment) caused by benzene poisoning had significantly increased rates of "unstable" and "stable" chromosomes. Aberrations of chromosomes were present for several years after cessation of the exposure and after recovery from poisoning. Persistence of an increase of the "stable" changes was particularly remarkable.
[Waldbott GL; Health Eff of Envir Poll p.214 (1973)]**PEER REVIEWED**

NUMEROUS STUDIES HAVE BEEN CARRIED OUT ON THE CHROMOSOMES OF BONE-MARROW CELLS & PERIPHERAL LYMPHOCYTES FROM PEOPLE KNOWN TO HAVE BEEN EXPOSED TO BENZENE. ... IN MANY OF THESE STUDIES, SIGNIFICANT INCR IN CHROMOSOMAL ABERRATIONS HAVE BEEN SEEN, WHICH IN SOME CASES HAVE PERSISTED FOR YEARS AFTER CESSATION OF EXPOSURE. ... BONE-MARROW CELLS & PERIPHERAL LYMPHOCYTES /HAVE BEEN EXAM/ FROM WORKERS WITH CURRENT SEVERE BLOOD DYSCRASIAS, & ... /FOLLOW-UP STUDIES HAVE BEEN DONE ON/ SEVERAL WORKERS BY REPEATED CYTOGENETIC STUDIES UP TO 12 YR AFTER RECOVERY FROM BENZENE-INDUCED PANCYTOPENIA. GROSS CHROMOSOMAL ABNORMALITIES WERE CHARACTERISTIC OF THESE CELLS; 70% OF THE BONE-MARROW CELLS & LYMPHOCYTES IN PT WITH ACUTE POISONING SHOWED KARYOTYPIC ABNORMALITIES. THE AUTHORS COULD NOT RELATE THE FREQUENCY OR TYPE OF CHROMOSOMAL ALTERATIONS TO THE SEVERITY OF BLOOD DYSCRASIA. FIVE YR AFTER POISONING, ALL ... 5 PATIENTS STUDIED STILL SHOWED STABLE (Cs) & UNSTABLE (Cu) CHROMOSOMAL ABERRATIONS IN ... LYMPHOCYTES, ALTHOUGH ONLY 40% OF CELLS WERE NOW ABNORMAL. BY 12 YR ... NO CYTOGENETIC ABNORMALITIES REMAINED IN THE 4 PATIENTS STUDIED.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 118 (1982)]**PEER REVIEWED**

METABOLIC ACTIVATION OF BENZENE BY RAT LIVER MICROSOMES & A REDUCED NADP-GENERATING SYSTEM (S-9 MIX) INDUCED SISTER CHROMATID EXCHANGES (SCE) & CELL DIVISION DELAYS IN CULTURED HUMAN LYMPHOCYTES. THERE WERE OPTIMAL CONCN OF S-9 MIX FOR THE CONVERSION OF BENZENE INTO THE ACTIVE METABOLITES THAT EXERTED THESE CYTOTOXIC EFFECTS.
[MORIMOTO K; CANCER RES 43 (3): 1330-4 (1983)]**PEER REVIEWED**

... INCIDENCE OF ACUTE LEUKEMIA OR 'PRELEUKEMIA' AMONG 28,500 SHOE-WORKERS IN TURKEY /WAS ESTIMATED/ ON BASIS OF CASE ASCERTAINMENT BY CONTACT WITH MEDICAL CARE. THIRTY FOUR CASES WERE IDENTIFIED. ... INCIDENCE OF ACUTE LEUKEMIA WAS SIGNIFICANTLY GREATER AMONG WORKERS CHRONICALLY EXPOSED TO BENZENE, WHICH WAS USED AS A SOLVENT BY THESE WORKERS, THAN IN THE GENERAL POPULATION. OCCUPATIONAL EXPOSURES WERE DETERMINED BY WORK HISTORIES & BY ENVIRONMENTAL MEASUREMENTS. THERE WAS SAID TO BE EXPOSURE ONLY TO BENZENE IN SMALL, POORLY VENTILATED WORK AREAS; PEAK EXPOSURES ... WERE REPORTED TO BE 210-650 PPM (670-2075 MG/CU M). DURATION ... WAS EST TO HAVE BEEN 1 TO 15 YR (MEAN 9.7 YR). ANNUAL INCIDENCE WAS EST TO BE 13/100000, GIVING APPROX RELATIVE RISK OF 2 WHEN COMPARED WITH ANNUAL EST FOR GENERAL POPULATION, 6/100000. (THESE EST ARE LIMITED BY STUDY DESIGN CHARACTERISTICS & BY UNCERTAINTY ABOUT THE WAY IN WHICH CASES WERE ASCERTAINED, & HOW MANY OF THE STUDY POPULATION WERE EXPOSED & HOW MANY UNEXPOSED).
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 121 (1982)]**PEER REVIEWED**

OCCUPATIONAL EXPOSURES WERE IDENTIFIED IN ROTOGRAVURE PLANTS & SHOE FACTORIES. BENZENE CONCN NEAR ROTOGRAVURE MACHINES WERE 200-400 PPM (640-1280 MG/CU M), WITH PEAKS UP TO 1500 PPM (4800 MG/CU M); BENZENE CONCN IN AIR NEAR WORKERS HANDLING GLUE IN SHOE FACTORIES WERE 25-600 PPM (80-1920 MG/CU M), BUT WERE MOSTLY AROUND 200-500 PPM (640-1600 MG/CU M). EST LATENCY (YEARS FROM START OF EXPOSURE TO CLINICAL DIAGNOSIS OF LEUKEMIA) RANGED FROM 3-24 YR (MEDIAN, 9 YR). ... THE RELATIVE RISK OF ACUTE LEUKEMIA WAS /EST TO BE/ AT LEAST 20:1 FOR WORKERS HEAVILY EXPOSED TO BENZENE IN ROTOGRAVURE & SHOE INDUSTRIES IN THE PROVINCES STUDIED, WHEN COMPARED WITH GENERAL POPULATION. (THE RELATIVE RISK IS BASED ON A NON-VALIDATED ESTIMATE).
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 122 (1982)]**PEER REVIEWED**

A HISTORICAL COHORT MORTALITY STUDY WAS CONDUCTED OF 259 MALE EMPLOYEES OF A CHEM PLANT WHERE BENZENE HAS BEEN USED IN LARGE QUANTITIES. THE STUDY GROUP INCL ALL PERSONS WHO WERE EMPLOYED BY THE COMPANY ANY TIME BETWEEN JAN 1, 1947 & DEC 31, 1960. THE COHORT WAS FOLLOWED THROUGH DEC 31, 1977 AT WHICH TIME 58 KNOWN DEATHS WERE IDENTIFIED. THE ONLY UNUSUAL FINDING WAS FOUR DEATHS FROM LYMPHORETICULAR CANCERS WHEN 1.1 WOULD HAVE BEEN EXPECTED ON THE BASIS OF NATIONAL MORTALITY RATES. THREE OF THE DEATHS WERE DUE TO LEUKEMIA & 1 WAS CAUSED BY MULTIPLE MYELOMA. IN ADDN, 1 OF THE LEUKEMIA DEATHS HAD MULTIPLE MYELOMA LISTED ON THE DEATH CERTIFICATE. THE FINDINGS ARE CONSISTENT WITH PREVIOUS REPORTS OF LEUKEMIA FOLLOWING OCCUPATIONAL EXPOSURE TO BENZENE & RAISE THE POSSIBILITY THAT MULTIPLE MYELOMA COULD BE LINKED TO BENZENE, ALSO.
[DECOUFLE P ET AL; ENVIRON RES 30 (1): 16-25 (1983)]**PEER REVIEWED**

HEMATOLOGIC & IMMUNOCHEMICAL INVESTIGATIONS CARRIED OUT IN 270 WORKERS WITH CHRONIC EXPOSURE TO BENZENE DEMONSTRATED CHANGES OF THE NUCLEOLOGRAM & OF THE AREA OF LYMPHOCYTE NUCLEOLI & DISORDERS OF THE HUMORAL IMMUNE RESPONSE REVEALED BY RADIAL IMMUNODIFFUSION. THE NUMERICAL RISE OF BI- & POLYNUCLEOLATED CELLS, OF CELLS WITH IRREGULAR MACRONUCLEOLI & AN ENLARGEMENT OF THE NUCLEOLAR AREA REFLECTED INCR ENDOLYMPHOCYTIC AMT OF RNA. AN INCR CAPACITY OF IG FORMATION, PARTICULARLY OF IGM, WAS ALSO OBSERVED.
[CHIRCU V ET AL; REV ROUM MED INTERNE 19 (4): 373-8 (1981)]**PEER REVIEWED**

SOME ASPECTS OF QUANTITATIVE CANCER RISK ESTIMATION: ... RISK IS GREATEST AMONG THOSE WITH LONGEST EXPOSURE, RELATIVE RISKS OF APPROX 2, 14 & 32 BEING OBSERVED FOR EXPOSURES OF LESS THAN 5 YR (2 CASES), 5-9 YR (2 CASES) & 10+ YR (3 CASES), RESPECTIVELY. THE RELATIVE RISK ASSOC WITH AT LEAST 5 YR OF EXPOSURE IS THUS LIKELY TO BE LOWER BOUND FOR RISK ASSOC WITH LIFETIME EXPOSURE AT SIMILAR LEVELS. FOR THOSE WITH AT LEAST 5 YR EXPOSURE, 5 CASES WERE OBSERVED COMPARED WITH AN EXPECTED NUMBER OF 0.237, GIVING A RELATIVE RISK OF 21.1. SINCE THE EXPECTED CUMULATIVE MALE ADULT LIFETIME (FROM 20 YR TO END OF LIFE, TAKEN AS AGE 75) PROBABILITY OF DYING FROM LEUKEMIA IS APPROX 7 PER 1000 IN THE GENERAL POPULATION OF THE USA, AN EXPECTED RELATIVE RISK OF 21.1 WOULD GIVE AN EXTRA (21.1-1.0)X7= 141 CASES OF LEUKEMIA PER 1000 EXPOSED POPULATION.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 395 (1982)]**PEER REVIEWED**

The hematotoxicity of benzene is expressed primarily as a bone marrow effect leading eventually to complete destruction of myeloid and erythroid marrow components. This is manifested as a marked decrease in circulating formed elements, ie red blood cells, and platelets. The resultant aplastic anemia is a potentially fatal disorder which in its severe form has better than a fifty percent mortality rate. In both man and laboratory animals the extent of bone marrow damage appears proportional to the dose of benzene. Lesser degrees of bone marrow toxicity than aplastic anemia are more common in occupational exposure situations. Classically, the discovery of one individual with significant bone marrow toxicity has led to evaluation of the exposed work force and the finding of a wide variation in the extent of hematotoxicity. This has ranged from clinically significant pancytopenia, in which are decreases in white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia) to a situation in which only one of these is slightly below normal range. In the latter case it is of course difficult to distinguish a benzene effect from that due to the extremes of normal variation or to mild intercurrent disease.
[Mehlman MA, ed; Adv Mod Environ Toxicol Vol IV: Carcinogenicity and Toxicity of Benzene p.52 (1983)]**PEER REVIEWED**

The type of leukemia most commonly associated with benzene is acute myelogenous leukemia and its variants, including erythroleukemia and acute myelomonocytic leukemia. Acute myelogenous leukemia is the adult form of acute leukemia and, until recent advances in chemotherapy, it was a rapidly fatal disease. The other major acute form of leukemia, acute lymphocytic leukemia, has been reported to be associated with benzene exposure but evidence of a causal association is weak. There is a somewhat stronger, although still inconclusive, association in the literature between benzene exposure and the two common forms of chronic leukemia: chronic myelogenous leukemia and chronic lymphocytic leukemia. Other hematological disorders possibly associated with benzene exposure include Hodgkin's disease, lymphocytic lymphoma, myelofibrosis and myeloid metaplasia, paroxysmal nocturnal hemoglobinuria, and multiple myeloma.
[Mehlman MA, ed; Adv Mod Environ Toxicol Vol IV: Carcinogenicity and Toxicity of Benzene p.52 (1983)]**PEER REVIEWED**

An acute hemorrhagic pneumonitis is highly likely if ... aspirated into lung.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-398]**PEER REVIEWED**

Three cases of chronic leukemia were presented which had a history of chronic benzene exposure. These three patients were part of a larger group of 58 leukemia patients with benzene exposure histories. Case 1 presented at age 43 due to cardiac complaints. The patient owned a printing shop at which he mixed pigmented dyes with solutions of toluene or methyl alcohol ketone. The individual had a practice of sniffing the solutions as control measure. The toluene solution on analysis was shown to contain 2.8% benzene 95.3% toluene. Blood and bone marrow examination revealed chronic lymphatic leukemia. Case 2 was a 51 year old man with pain in the right quadrant. This individual had owned a small plastics facility between 1955 and 1965 where he was intermittently exposed to thinners containing 27.3% benzene. Subsequent exposure included cleaning solutions without benzene. He was also diagnosed with chronic lymphatic leukemia. The third case was a 50 year old manager of a plastic facility who was diabetic for 15 years and was hospitalized due to recurrent gluteal and inguinal furunculosis during the last 3 years. He had been heavily exposed to benzene between 1957 and 1965. He admitted having removed the dirt from his hands using thinners containing benzene. Hairy cell leukemia was diagnosed. The data suggests that differences in distribution of acute or chronic leukemias in chronic benzene exposure may be related to exposure levels, mode of exposure, or exposure to benzene homologs or other chemicals.
[Askoy M; Brit J Haematol 66 (2): 209-11 (1987)]**PEER REVIEWED**

A study conducted to measure the concentration of benzene in the air and solvents at 40 small and large workplaces in Turkey where workers had contracted leukemia and lymphoma. In addition, hematological examinations were performed on the 231 workers employed at the facilities. The facilities manufactured and repaired shoes, tires, leather works, automobiles, and farm equipment. The age of the workers ranged from 14 to 57 years and the mean duration of exposure was 8.8 years (range 1 month to 40 years). Case reports were presented for five workers with 2 to 15 years of exposure who had developed acute myeloblastic leukemia, acute lymphoblastic leukemia, acute myelomonocytic leukemia, Hodgkin's disease and poorly differentiated lymphoma. Benzene concentrations in the solutions and thinners used ranged from 3 to 7.5%. The concn of benzene in air samples from the plants ranged from 0 to 110 ppm while 76.4% of solvents contained more than 1% of benzene. Hematological examinations of the workers showed that 32% of them had abnormal values. There has been a decline in the use of benzene in Turkey since an earlier study in 1972, but that the percentages of benzene in most of the materials are still above permissible limits.
[Askoy M et al; Brit J Indust Med 44 (11): 785-7 (1987)]**PEER REVIEWED**

Benzene is widely recognized as a leukemogen, and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictly. The proposed new regulation is a limit of an eight hr time-weighted average of 1 ppm in place of the current limit of 10 ppm. The fundamental rationale for the change is a perception that the current standard is associated with an inordinate excess of leukemia. The epidemiologic literature on benzene and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the available data are too sparse, or /have/ other limitations, to substantiate the idea that this causal association applies at low levels (ie, 1-10 ppm) of benzene. Nonetheless, under the assumption that causation does apply at such low levels, a number of researchers have performed risk assessments using similar data but different methodologies. The assessments that is considered acceptable suggest that, among 1,000 men exposed to benzene at 10 ppm for a working lifetime of 30 years, there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower occupational benzene standard remain a decision for policy makers.
[Austin H et al; Am J Epidemiol 127 (3): 419-39 (1988)]**PEER REVIEWED**

Results of epidemiologic studies indicating an association between solvent exposure and the development of malignancies affecting hematopoietic and lymphatic tissues are reviewed. Clinical and cytogenetic data supporting this association are discussed. A variety of malignant disorders have been associated with solvent exposure, ie acute leukemia, Hodgkin's disease (odds ratio 2.8-6.6), non-Hodgkin's lymphoma (odds ratio 3.3) and myeloma, and there are some indications that solvent exposure may be a risk factor for myelofibrosis. The carcinogenic effect of benzene is epidemiologically and experimentally well documented and there are some indications that other solvents may also be hazardous. Possible mechanisms bringing about malignant transformation are discussed. The need for further epidemiologic, cytogenetic and clinical studies on the association between solvent exposure and malignant diseases is emphasized.
[Brandt L; Med Oncol Tumor Pharmacother 4 (3/4): 199-205 (1987)]**PEER REVIEWED**

Currently the most applied technique for monitoring biological effects of exposure to genotoxic chemicals in industrial workers is the measurement of chromosome aberrations in peripheral blood lymphocytes. In the Shell petrochemical complex in the Netherlands cytogenetic monitoring studies have been carried out from 1976 till 1981 inclusive, in workers potentially exposed to a variety of genotoxic chemicals, ie vinyl chloride, ethylene oxide, benzene, epichlorohydrin, epoxy resins. Average exposure levels to these chemicals were well below the occupational exposure limits. Results of thesse studies indicate that no biologically significant increase in the frequencies of chromosome aberrations in the exposed populations occurred compared with control populations. ... Experience with this methodology has shown that the results of chromosome analyses are difficult to interpret, due to the variable and high background levels of chromosome aberrations in control populations and in individuals. It is concluded that the method is not sufficiently sensitive for routine monitoring of cytogenetic effect in workers exposed to the low levels of genotoxic compounds.
[deJong G et al; Mutat Res 204 (3): 451-64 (1988)]**PEER REVIEWED**

The possibility of there being a link between the apparent predominance of men with specific on the job exposures to toxic materials among patients with hairy cell leukemia was explored. Of a total of 105 hairy cell leukemia patients, eight were in the medical profession (two X-ray technicians, one radiologist, two pneumologists, two orthopedists, and one internist), 21 were garage mechanics or divers of trucks or other heavy vehicles, eight worked in construction as painters, decorators or masons, three were in the printing industry as photogravure and equipment maintenance workers, ten were farmers, six were engineers and 49 held various technical or office positions. Interviews were conducted with 69 of the patients. All those in medicine had used radioscopy for periods exceeding 10 years. Exposure to petroleum derived substances was high not only among the garage mechanics and drivers, but among those 49 individuals whose occupations did not have particular exposure, but whose hobbies and paraprofessional activities involved use of benzene or other solvents. Of the 69 interviewed, 52 were able to document exposure to benzene or other solvents.
[Flandrin G, Collado S; Brit J Haematol 67 (1): 119-20 (1987)]**PEER REVIEWED**

The case of a 55 year old male with hairy cell leukemia associated with chronic exposure to benzene in an occupational setting was described. The subject had been employed as a coach paint sprayer for over 25 years at the time of diagnosis. When that patient was questioned, it was admitted that at the job site he did not usually take the normal protective measures to prevent exposure to the chemicals in the paints. The /investigators noted/ that spray painting is the one of the occupations which can involve exposure to benzene, due to the use of benzene containing solvents. The /researchers/ concluded that since three other cases of chronic leukemia have been previously associated with exposure to benzene, more retrospective demographic studies which take occupational exposures into account confirm the possible link between chronic benzene toxicity and leukemia, particularly the very rare hairy cell leukemia.
[Ng JP et al; Brit J Haematol 67 (1): 116 (1987)]**PEER REVIEWED**

The mutual metabolic suppression between benzene and toluene was studied. The subjects, 190 male Chinese workers employed in shoe manufacturing, printing, audio equipment manufacture, and automobile industries, were divided into four groups based on occupational exposure: 65 were exposed to benzene, 35 to toluene, 55 to both compounds, and 35 served as comparisons. The arithmetic mean exposure level of benzene was 31.9 and of toluene 44.7 ppm. The mixture contained benzene at 17.9 + - 29.3 and toluene at 20.5 + - 25.8 ppm. The exposure levels were measured using individual diffusive samplers. The geometric mean levels of the metabolites, phenol, catechol, hydroquinone, hippuric acid, and o-cresol, in unexposed workers were 6.9, 9.4, 4.8, 72.5, and 0.066 mg/l, respectively. Values corrected for creatinine and specific gravity were different from the values cited above. Multiple correlation coefficients for benzene exposure versus its three metabolites were for phenol, 0.740; for catechol, 0.629; and for hydroquinone, 0.762. Multiple correlation coefficients for toluene and its two metabolites were 0.649 for hippuric acid and 0.583 for o-cresol. The slopes of regression lines for the exposure to benzene in the presence of toluene were less than half of those obtained when the workers were exposed to benzene alone; however, the regression lines for benzene in mixture versus catechol were out 80% of higher than the lines observed with benzene as the sole pollutant. The regression lines for toluene in the mixture and excretion level of hippuric acid and hydroquinone showed reduced metabolic conversion compared to when exposure was limited to toluene alone.
[Inove O et al; Internat Arch Occupat Environ Health 60 (1): 15-20 (1988)]**PEER REVIEWED**

A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukemia was 11.4 years. Most (76.6%) cases of benzene leukemia were of the acute type. The mortality due to benzene leukemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukemia were exposed ranged from 10 to 1000 mg/cu m (mostly from 50 to 500 mg/cu m). Of the 25 cases of leukemia, seven had a history of chronic benzene poisoning before the leukemia developed.
[Jin C et al; Br J Ind Med 44 (2): 124-8 (1987)]**PEER REVIEWED**

Cytogenetic and environmental factors in the etiology of acute leukemias in adults were discussed. Epidemiological aspects of leukemia were considered. The leukemias currently account for approximately 3% of the total cancer incidence and 4% of the cancer deaths in the USA. The average annual incidence is eight cases per 100,000 for females and 11 cases per 100,000 for males. Leukemia is more common in whites than nonwhites and more common in males. Acute nonlymphocytic accounts for about 30% of the total leukemia incidence and for over 85% of the acute leukemia seen in persons over 40 years of age. Recent mortality data show very little change in leukemia death rates except for acute nonlymphocytic leukemia which increased by 20% from 1969 to 1977. Genetic and environmental factors were considered. Chromosome disorders and a family history may be etiological factors in both acute nonlymphocytic leukemia and lymphocytic leukemia. Exposures to benzene, ionizing radiation, and antineoplastic agents are known to cause chromosomal aberrations and leukemia; however, no evidence of a causal sequence of events has been obtained. Environmental risk factors such as ionizing radiation, cigarette smoke, and chemicals were described. Benzene is considered the best known and most widely occurring human leukemogen. A number of case reports and cohort studies have linked benzene exposure and acute leukemias. Benzene associated relative risk for overall leukemia generally range from 1.5 to 2.0. Cytogenetic aspects of leukemia were considered. Some studies have shown that prior chemical exposures are associated with chromosome aberrations in acute nonlymphocytic leukemic patients. Suggestions for improving epidemiological studies of leukemia were discussed.
[Sandler DP, Collman GW; Amer J Epidemiol 126 (6): 1017-32 (1987)]**PEER REVIEWED**

A study of mortality in automobile mechanics and gasoline service station workers in New Hampshire was conducted. A proportionate mortality ratio analysis of all deaths occurring among male residents 20 years or older who lived in New Hampshire between 1975 and 1985 was performed. Occupation, industry, age, and date and cause of death were obtained from death certificates. A total of 37,426 deaths were recorded. Of these, 453 were automobile mechanics and 134 were persons who had been employed in the gasoline service station industry. Automobile mechanics had statistically significant proportionate mortality ratio elevations for suicide. Nonsignificant increases in proportionate mortality ratio for leukemia, cancers of the oral cavity, lung, bladder, rectum and lymphatic tissue, and nonmalignant blood dyscrasias and cirrhosis of the liver were observed. Workers in the gasoline service station industry had statistically significant increases in mortality from leukemia and mental and psychoneurotic and personality disorders, proportionate mortality ratio 328 and 394, respectively; however, the number of deaths was small. Proportionate mortality ratio increases were also observed for emphysema and suicide. One or more of the exposures experienced by automobile mechanics and service station workers presents a carcinogenic risk. The finding of excess mortality from leukemia in both groups is consistent with exposure to benzene, a component of gasoline. ... Workers who pump gasoline should be informed of the potential cancer hazard. Gasoline should not be used as a solvent for removing grease and cleaning hands, and gasoline should not be siphoned by mouth.
[Schwartz E; Amer J Indust Med 12 (1): 91-9 (1987)]**PEER REVIEWED**

This paper presents a critical review more than 100 references on the possible leukemogenic (blastomogenic) effects of benzene, based upon clinical, epidemiological and experimental /studies/. /Evidence supports the conclusion that/ there exists reliable clinical and epidemiological /studies/, concerning increased leukemogenic risk on working place with high benzene concentrations in past years (tens and even hundreds of ppm). Most epidemiological studies, indicate now that this risk is also elevated in more favorable working conditions, although practical valuable dose-effect relationship between benzene concentrations and rate of leukemogenic risks is still unknown. Results of experimental investigations on problem of leukemogenic effects of benzene are contradictory. It was stated recently that there is a lack of adequate experimental models of benzene blastomogenesis. Taking into consideration increasing economic significance of benzene and existence of large contingents of workers dealing with benzene, it is necessary to continue appropriate experimental and epidemiological investigations.
[Sokolov VV, Frasch VN; J Hyg Epidemiol Microbiol Immunol 31 (2): 135-43 (1987)]**PEER REVIEWED**

The possible association of thinner, a mixture of seven organic solvents used in the Mexican auto and paint industry, with the frequency of sister chromatid exchanges in the peripheral lymphocytes of 24 industrial workers was investigated. The subjects worked in a factory and three workshops in which no protective measures against inhalation of vapors were taken. A matched comparison group consisted of 24 administrative and outdoor workers. Use of cigarettes, alcohol, and medicines, and presence of viral infections within the 3 previous months were determined by questionnaire. Blood was cultured for 72 hr with phytohemagglutinin, with 5-bromodeoxyuridine added at 24 hr and colchicine at 70 hr. Sister chromatid exchanges were scored from 50 metaphases from each individual. Air samples to determine concentrations of thinner components in the working atmosphere were taken on the day of blood sampling and analyzed by gas chromatography. Solvent concentrations in the samples from the factory air were methyl isobutyl ketone 2.4 ppm, methanol 0.6 ppm, isopropanol 3.3 ppm, toluene 3.3 ppm, benzene 6.0 ppm, and hexane 3.3 ppm. The concentrations were below the limits recommended by NIOSH ... except for benzene which was six times the NIOSH limit. One way analysis of variance of the sister chromatid exchanges frequency for the exposed and comparison groups showed no differences for exposures of either 5 years or less of 6 to 35 years. However, a significant increase of sister chromatid exchanges was found for tobacco use in the exposed group but not for the comparison group. The implications of this result were discussed principally in relation to benzene. ... Working conditions should be improved by a ventilation system and that a benzene free thinner be substituted for the one being used.
[Souza V, Puig M; Mutat Res 189 (3): 357-62 (1987)]**PEER REVIEWED**

Dose response analyses for a cohort study of chemical workers exposed to benzene were reported. Exposure information included 8 hour time-weighted averages and peak exposures and was used to calculate the latency, duration of exposure, and peak exposure for several types of lymphatic and hematopoietic cancers. The cohort included 4,602 male chemical workers from seven companies who were occupationally exposed to benzene for at least 6 months between 1946 and 1975. A comparison group included 3,074 workers at the same plants who were employed for at least 6 months without exposure to benzene. Workers exposed to benzene 5 and 14 years showed an increased risk of lung cancer with a statistically significant enhancement of the standardized mortality ratio. Increased in reticulosarcoma and lymphosarcoma were related to the duration of continuous benzene exposure. Increased latency was related to a slight enhancement for all cancers among the exposed workers. Analysis by cumulative exposure demonstrated an increasing trend for death due to lymphatic and hematopoietic cancer, lymphosarcoma, reticulosarcoma, and leukemia. Workers with a cumulative exposure of 180 to 719 ppm month showed a significant increase in lung cancer. No dose response relation was detected for any other causes of death.
[Wong O; Brit J Indust Med 44 (6): 382-95 (1987)]**PEER REVIEWED**

A mortality study of 7,676 male chemical workers occupationally exposed to benzene was described. The subjects were employed at nine plants belonging to seven member companies of the Chemical Manufacturers Association. Workers were classified according to their benzene exposure into occupationally exposed or comparison groups. Occupationally exposed workers received at least 6 months of continuous or intermittent job exposure to benzene between 1946 and 1975. The comparison group comprised workers with at least 6 months of employment at the same plant with no benzene exposure. Approximately 40% of the cohort were not occupationally exposed to benzene, and about 46% of the cohort had received continuous exposure to benzene. The remaining 14% fell into the intermittent exposure group. The observed mortality of the cohort was compared with the expected based on the United States mortality rates appropriately standardized. Standardized mortality ratios were determined for lymphatic and hematopoietic cancer, leukemia, non Hodgkin's lymphoma, and non-Hodgkin's lymphopoietic cancer. The number of observed deaths in the continuous exposure group was slightly but not significantly greater than expected. Deaths from lymphatic and hematopoietic cancers and from leukemia were greater than expected in the continuous exposure group. The mortality of the intermittent exposure group was comparable to the expected mortality. The standardized mortality ratios of the total group were greater than the comparison group. Statistically significant associations were demonstrated between benzene exposure and both lymphopoietic cancer and leukemia.
[Wong O; Brit J Indust Med 44 (6): 365-81 (1987)]**PEER REVIEWED**

Comprehensive comparative studies were conducted on the three groups of 148 male and 167 female workers exposed to benzene, toluene, or a combination of the two to evaluate subjective symptoms and hematologic effects of the compounds. Exposed workers were compared to 127 unexposed referents. The exposure intensity of the workers was estimated by diffusion dosimetry, and their subjective symptoms were obtained from questionnaires. The workers in the benzene group were engaged in shoe making and printing; the toluene group was engaged in shoe making and audio equipment production, and the mixed exposure group was employed in spray painting in automobile body shops. The mean age of the workers ranged from 26.7 to 39.0 years. The average 7 hr time weighted exposure to benzene was 33 and 59 ppm for men and women, respectively; the exposure concentrations of toluene were 46 and 41 ppm for men and women, respectively. In the mixed exposure group, men were exposed to 14 ppm of benzene and 18 ppm of toluene; the female mixed exposure was 18 ppm of benzene and 21 ppm of toluene. Hematological examinations showed no significant differences between exposed and nonexposed workers, although leukocytes were marginally decreased. The prevalence of subjective symptoms was dose related and statistically significant for both men and women. The number of symptoms per person during work was at least ten fold higher in the exposed than in the nonexposed groups. The most frequent symptoms were dizziness, sore throat, and headache which occurred during work as well as during non work time. This study provides no indication of pancytopenia, and that both liver and kidney functions are unchanged under exposure conditions.
[Yin S et al; Indust Health 25 (3): 113-30 (1987)]**PEER REVIEWED**

Of a total of 528,729 workers exposed to benzene or benzene mixtures in China, 508,818 (96.23%) were examined. Altogether 2,676 cases of benzene poisoning were found, a prevalence of 0.15%. A higher prevalence of benzene poisoning was found in the cities of Hangjou, Hefei, Nanjing, Shenyang, and Xian. The geometric mean concentration of benzene in 50,255 workplaces was 18.1 mg/cu m but 64.6% of the workplaces had less than 40 mg/cu m. There was a positive correlation between the prevalence of benzene poisoning and the concentration in shoemaking factories. The prevalence of benzene induced aplastic anemia in shoemakers was about 5.8 times that occurring in the general population. The results of this investigation show the need for a practicable hygiene standard to prevent benzene poisoning.
[Yin SN et al; Br J Ind Med 44 (3): 192-5 (1987)]**PEER REVIEWED**

... CYTOGENETIC APPROACHES APPEAR TO BE NEAREST TO ROUTINE SURVEILLANCE IN DETECTING EARLY BIOLOGIC EFFECTS IN EXPOSED HUMANS. BENZENE SHOWED CONTRADICTORY RESULTS IN CHROMOSOME ABERRATION TESTS & WAS NEGATIVE FOR SISTER CHROMATID EXCHANGE.
[SORSA M ET AL; TERATOG CARCINOG MUTAGEN 2 (2): 137-50 (1982)]**PEER REVIEWED**

Investigations on the association between environmental hazards and the development of various /forms/ of leukemia are reviewed. Regarding acute non-lymphocytic leukemia exposure to ionizing radiation is a well documented risk factor. According to several recent studies exposure to strong electronmagnetic fields may be suspected to be of etiologic importance for acute non-lymphocytic leukemia. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may be leukemogenic. Occupational exposure to petroleum products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenic studies in acute non-lymphocytic leukemia suggest that exposure to certain environmental agents may be associated with relatively specific clonal chromosome aberrations. These results are of interest because it has been proposed that chromosomal rearrangements may play a role in the activation of cellular oncogens. Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocytic leukemia in children. Unlike acute non-lymphocytic leukemia there seems at present to be little evidence that acute lymphocytic leukemia is related to exposure to some chemicals. Chronic myleoid leukemia may follow exposure to high doses of ionizing radiation whereas such exposure seems to be of insignificant importance in the development of chronic lymphocytic leukemia. According to some studies an abnormally high incidence of chronic lymphocytic leukemia may be found among farmers in the USA. These results have not been confirmed in Scandinaavian studies. There seems to be little evidence that chronic myleoid leukemia or chronic lymphocytic leukemia are related to occupational handling of some chemicals.
[Brandt L; Med Oncol Tumor Pharmacother 2 (1): 7-10 (1985)]**PEER REVIEWED**

Personal air monitors and breath samples were used to measure benzene and other volatile compounds in the breath of 200 smokers and 322 nonsmokers in New Jersey and California during 12 hr sampling periods. The monitor measured only sidestream and exhaled mainstream smoke. Concentrations were also measured in a subsample of homes and outdoor air. Compared to nonsmokers, benzene was significantly higher in the breath of persons who had smoked tobacco the day they were monitored (p< 0.001); values for smokers were 12 to 16 ug/cu m, nearly 10 times the breath level of nonsmokers. Values for personal air samplers were not always significantly higher. Benzene in breath was related to number of cigarettes smoked. Based on direct measurements of mainstream smoke, it was calculated that the typical smoker inhales 2 mg/day compared to the nonsmokers' intake of <0.2 mg/day. Both smokers and nonsmokers exposed to passive smoking at home or work had increased levels of benzene compared to nonsmoking situations (p< 0.05). Indoor air levels in homes with smokers were significantly greater than in nonsmoking homes in fall and winter but not during spring and summer.
[Wallace L et al; Arch Environ Health 42 (5): 272-9 (1987)]**PEER REVIEWED**

In both human and animal studies, it appears that benzene-induced bone marrow depression is a dose-dependent phenomenon.
[Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 742]**PEER REVIEWED**

Toxicities from inhalation /of benzene include/: irritation of conjunctiva and visual blurring, mucous membranes, dizziness, headache, unconsciousness, convulsions, tremors, ataxia, delirium, tightness in chest, irreversible brain damage with cerebral atrophy, fatigue, vertigo, dyspnea, respiratory arrest, cardiac failure and ventricular arrhythmias, leukopenia, anemia, thrombocytopenia, petechiae, blood dyscrasia, leukemia, bone marrow aplasia, fatty degeneration and necrosis of heart, liver, adrenal glands, fatal overdose. /From table/
[Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1494]**PEER REVIEWED**

Single exposures to concentrations of 66,000 mg/cu m (20,000 ppm) commercial benzene have been reported to be fatal in man within 5-10 minutes. At lower levels, loss of consciousness, irregular heart-beat, dizziness, headache and nausea are observed.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 116 (1982)]**PEER REVIEWED**

In general, acute symptoms are dependent on both the concentration and duration of exposure. Exposure to 7500 ppm for 30 min is life-threatening; 1500 ppm for 60 min produces significant symptoms; 50-150 ppm for 5 hr results in headache and weakness; whereas exposure to 25 ppm or less for 8 hr results in no demonstrable acute effect.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 724]**PEER REVIEWED**

... Benzene metabolism is a requirement for bone marrow toxicity.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 726]**PEER REVIEWED**

/Researchers/ examined the blood counts of 161 workers for whom pre-employment counts were done prior to exposure in the rubber factory. The results indicated that during the first year of employment in the rubber factory, employees exposed to benzene levels higher than the median exposure (estimated at 40-54 ppm) had significantly lower white and red blood cell counts than employees exposed to benzene levels below the median exposure.
[Cody RP et al; J Occup Med 35 (8): 776-82 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.45 (1997)]**PEER REVIEWED**

Leukopenia was observed ... in Chinese workers exposed to 0.69-140 ppm (mean = 6 ppm) benzene for more than 1 year.
[Xia Z-L et al; Biomed Environ Sci 8: 30-4 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.47 (1997)]**PEER REVIEWED**

After a fatal occupational exposure to benzene vapors on a chemical cargo ship for only minutes, autopsy reports on three victims revealed hemorrhagic respiratory tissues, and second degree burns on the face, trunk, and limbs.
[Avis SP, Hutton CJ; J Forensic Sci 38 (3): 599-602 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks.
[Midzenski MA et al; Am J Ind Med 22: 553-65 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

A retrospective cohort study of incident cases of hematopoietic neoplasms and related disorders among 74,828 benzene-exposed workers employed between January 1, 1972 to December 31, 1987 in 672 factories in 12 Chinese cities was conducted. Workers (35,805) not occupationally exposed to benzene employed in 109 factories during the same period were used for comparison. Follow-up of both exposed and nonexposed workers was carried out using occupational and medical records, and histopathologic material were reviewed for all patients with hematopoietic malignancies to ensure correct classification. Among benzene-exposed workers, 82 patients with hematopoietic neoplasms and related disorders were diagnosed: 32 (39%) cases of acute leukemia, 9 (11%) aplastic anemia, 7 (9%) myelodysplastic syndrome, 9 (11%) chronic granulocytic leukemia, 20 (24%) malignant lymphoma and related disorders, and 5 (6%) others. Among the nonexposed group, 13 hematologic malignancies were diagnosed: 6 (46%) patients with acute leukemia, 2 (15%) chronic granulocytic leukemia, 3 (23%) malignant lymphoma, and 2 (15%) others. The hematopathologic features of acute nonlymphocytic leukemia associated with benzene exposure resembled the hematological features following chemotherapy or radiotherapy. In addition, this study documented myelodysplastic syndrome in association with benzene exposure.
[Travis LB et al; Leukemia and Lymphoma 14: 91-102 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.80 (1997)]**PEER REVIEWED**

... Benzene metabolites can adversely affect human topoisomerases, enzymes involved in DNA replication and repair. /Benzene metabolites/
[Chen H, Eastmond DA; Carcinogenesis 16 (10): 2301-7 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.218 (1997)]**PEER REVIEWED**

Skin, Eye and Respiratory Irritations:

Benzene is irritant to skin.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1308]**PEER REVIEWED**

A severe eye and moderate skin irritant.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks.
[Midzenski MA et al; Am J Ind Med 22: 553-65 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

Drug Warnings:

Protected intercourse may be prudent following high exposure to benzene. As well, nursing mothers may be advised to discontinue nursing for 5 days following high exposure.
[Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 712]**PEER REVIEWED**

Medical Surveillance:

IF INDIVIDUALS ARE KNOWN TO BE EXPOSED TO BENZENE VAPORS IN THEIR WORKING ENVIRONMENT PROPHYLACTIC MEASURES SHOULD BE TAKEN. ALL POSSIBLE METHODS SHOULD BE USED TO PROTECT SUCH PERSONS AGAINST BREATHING THE FUMES. THEY SHOULD HAVE PERIODIC PHYSICAL EXAM, INCL BLOOD STUDIES. IN ADDN THE URINE SHOULD BE EXAM AT INTERVALS TO DETERMINE EXTENT OF EXCRETION OF BENZENE CONJUGATION PRODUCTS. ONCE POISONING HAS DEVELOPED, IT IS ESSENTIAL TO PREVENT FURTHER EXPOSURE.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 906]**PEER REVIEWED**

Assessment of fitness should incl consideration of previous medical ... & occupational history. Occupational history should take into account any previous exposure to benzene, radiomimetic substances or ionizing radiations. Medical exam should incl thorough physical ... & hematological examination. The latter ... should cover hemoglobin determination, red cell, white cell & platelet counts, white cell differential count & red cell & leukocyte morphology. Protect young persons of either sex under 18 yr of age from exposure to benzene since ... adolescents have lower resistance to bone-marrow poisons. Pregnant women & nursing mothers should not be exposed ... & special precautions are necessary where women of childbearing age are exposed to benzene hazard. ... Subjects with liver diseases & ... microcytemia should /be protected from exposure/. ... Periodic exam should be carried out in same way as pre-employment examination. ... Particular attention should be paid to any hematological abnormalities found during 1st periodic examination. ... Whenever there is slightest suspicion of leukemia, a bone-marrow biopsy is warranted.
[International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 260]**PEER REVIEWED**

Biological monitoring: Medical surveillance should incl blood pressure check, lung functions, blood chemistry, hematology, urinalysis & skin exam.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1326]**PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": ... In relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may preclude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 23]**PEER REVIEWED**

Populations at Special Risk:

INDIVIDUALS WITH G6PD /GLUCOSE 6-PHOSPHATE DEHYDROGENASE/ DEFICIENCY HAVE ... BEEN FOUND TO BE MORE SUSCEPTIBLE TO HEMOLYTIC EFFECTS OF ... BENZENE ...
[Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975., p. 139]**PEER REVIEWED**

... /It has been observed/ that levels of leukocyte agglutins were elevated in selected individuals exposed to benzene. ... /This/ suggested that in some people benzene toxicity may be accounted for in part by an allergic blood dyscrasia.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

... Workers with higher activities of /cytochrome P-450(2E1)/ are at more risk /of benzene hematoxicity/.
[International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 1.2]**PEER REVIEWED**

... It has been suggested that Thalassemia minor, and presumably other disorders in which there is increased bone marrow turnover, may predispose a person to benzene-induced aplastic anemia.
[International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 1.2]**PEER REVIEWED**

People living near hazardous waste sites who are chronically exposed to contaminated air, water, or soil may be at a higher risk for respiratory effects from exposure to /benzene/ ...
[U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.192 (1997)]**PEER REVIEWED**

Probable Routes of Human Exposure:

Human populations are primarily exposed to benzene through inhalation of contaminated ambient air particularly in areas with heavy traffic and around filling stations. In addition, air close to manufacturing plants which produce or use benzene may contain high concentrations of benzene(1,2). Another source of exposure is from inhalation of tobacco smoke(1). Although most public drinking water supplies are free of benzene or contain <0.3 ppb, exposure can be very high from consumption of contaminated sources drawn from wells contaminated by leaking gasoline storage tanks, landfills, etc(SRC).
[(1) IARC; Monograph, Some Industrial Chem and Dyestuffs 29: 99-106 (1982) (2) Graedel TE; Chem Compounds in the Atmos, NY, NY Academic Press (1978)]**PEER REVIEWED**

Rough estimates of average ambient ground-level benzene concentrations over an 8 hour period were calculated based on an emission rate of 100 g/sec from a manufacturing plant. Benzene concentrations (in pg/cu m) are estimated to be 11,000 at 0.15 km, 6,100 at 0.3 km, 3,800 at 0.45 km, 2,800 at 0.6 km, 2,100 at 0.75 km, 740 at 1.6 km, 370 at 2.5 km, 220 at 4.0 km, 120 at 6.0 km, 62 at 9.0 km, 34 at 14.0 km, and 20 at 20.0 km distance from the manufacturing plant(1).
[(1) Mara SJ, Shonh SL; Assesment of Human Exposures to Atmospheric Benzene. Menlo Park, CA: SRI. USEPA-450/3-78-031. NTIS PB 284 203 (1978)]**PEER REVIEWED**

NIOSH (NOES Survey 1981-1983) has statistically estimated that 272,275 workers (143,066 of these are female) are potentially exposed to benzene in the US(1). Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used(SRC). The general population may be exposed to benzene via inhalation of ambient air(2-4), ingestion of drinking water(5), and dermal contact with gasoline products(6) containing benzene(SRC).
[(1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (3) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (4) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (5) Krill RM, Sonzogni WC; J Am Water Works Assoc 78: 70-5 (1986) (6) Fruscella W; Kirk-Othmer Encycl Chem Technol. 4th ed. NY, NY: John Wiley and Sons 4: 80 (1992)]**PEER REVIEWED**

Benzene was detected in 3 out of 70 samples taken from 46 spray painting workshops in Sydney, Australia at a concn of 1 mg/cu m in 1989(1). In a study of in-auto and in-bus exposures to volatile organic compounds for commutes on an urban-suburban route in Korea from November 21 to December 22, 1994, revealed that mean in-auto concns of benzene were 30.6 ug/cu m along urban routes and 18.3 ug/cu m along suburban routes while mean in-bus concns were 20.2 ug/cu m along urban routes and 11.7 ug/cu m along suburban routes(2). In a 200-trip study of in-vehicle air of Los Angeles commuters, an avg concn of benzene at 40 ug/cu m during rush hour was detected(3).
[(1) Winder C et al; Ann Occup Hyg 36: 385-94 (1992) (2) Jo WK et al; Air Waste Manage Assoc 46: 749-754 (1996) (3) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Body Burden:

Benzene was detected in all 8 samples of mothers' milk from women living in 4 USA urban areas(1). Breath samples from persons without specific exposure to benzene ranged from 8 to 20 ppb(2). Whole blood samples from 250 subjects (121 males, 129 females) ranged from not detected to 5.9 ppb, (mean 0.8 ppb)(3). In FY82, the National Human Adipose Tissue Survey specimens found that of 46 composite samples, 96% tested positive to benzene (concns were >4 ppb for wet tissue) with a max concn of 97 ppb max(4).
[(1) Pellizzari ED et al; Environ Sci Technol 16: 781-5 (1982) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs. 29: 99-106 (1982) (3) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) (4) Stanley JS; Broad Scan Analysis of the FY82 National Human Adipose Tissue Survey Specimens Vol. I Executive Summary p. 5 USEPA-560/5-86-035 (1986)]**PEER REVIEWED**

In a 1980's study of non-occupational benzene exposure, it was found that smokers had an avg benzene body burden about 6 to 10 times that of nonsmokers, and received about 90% of their benzene exposure from smoking(1). The mean benzene concn found in the breath and blood of 1,683 individuals was 13.1 and 131 ng/l, respectively(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Average Daily Intake:

Two recent studies of benzene levels in foods have confirmed the conclusion that ingesting food and beverages are an unimportant pathway for benzene exposure(1). In a study of more than 50 foods, most contained benzene below 2 ng/g ppbw(1). A Canadian review of benzene exposures concluded that food and drinking water each contributed only about 0.02 ug/kg benzene per day compared to a total intake of 2.4 ug/kg per day from airborne exposures (3.3 ug/kg/day if exposed to cigarette smoke). In a 1980's study of non-occupational benzene exposure, it was found that more than 99% of the total personal exposure was through air and that a global avg personal exposure for benzene was about 15 ug/cu m(1). Roughly half the total benzene exposure in the United States was borne by smokers(1). For non-smokers, most benzene exposure u