National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/hsdb-71-43-2

CAS Registry Number: 71-43-2 Toxicity Effects

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Benzene
  • BENZENE (TRANSGENIC MODEL EVALUATION II)
  • BENZOL
  • Transgenic model evaluation II (Benzene)

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). Available at: http://monographs.iarc.fr/index.php, 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/370577?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/604698?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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 href="http://www.ncbi.nlm.nih.gov/pubmed/767102?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/1069497?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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 href="http://www.ncbi.nlm.nih.gov/pubmed/495445?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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 href="http://www.ncbi.nlm.nih.gov/pubmed/629594?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/690739?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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). Available at: http://monographs.iarc.fr/index.php, 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6825102?dopt=Abstract" target=new>PubMed Abstract</a>
  • ... 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). Available at: http://monographs.iarc.fr/index.php, 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). Available at: http://monographs.iarc.fr/index.php, 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6832104?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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). Available at: http://monographs.iarc.fr/index.php, 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3277397?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3326982?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3347216?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3814544?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3302033?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3670339?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3828244?dopt=Abstract" target=new>PubMed Abstract</a>
  • ... 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6126935?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3903369?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3452294?dopt=Abstract" target=new>PubMed Abstract</a>
  • 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). Available at: http://monographs.iarc.fr/index.php, 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**

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Non-Human Toxicity Excerpts

  • Inhalation of air saturated with benzene vapor resulted in ventricular extrasystole in the cat & primate, with periods of ventricular tachycardia that occasionally terminated in ventricular fibrillation. ... In rabbit, sudden death from ventricular fibrillation has also been observed. ... In acute inhalation by male rats, benzene-induced resp paralysis occurred, followed by ventricular fibrillation.[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. 1318] **PEER REVIEWED**
  • ... DOGS INHALING BENZENE ... DEVELOPED HYPERTENSION. THIS WAS SOON FOLLOWED BY PARALYSIS OF VASOMOTOR SYSTEM DUE TO EFFECT OF BENZENE ON SMOOTH MUSCLE OF BLOOD VESSELS.[Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1221] **PEER REVIEWED**
  • Benzene in rabbit eye is a moderate irritant, causes conjunctival irritation, & ... transient slight corneal injury.[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. 1318] **PEER REVIEWED**
  • IN SERIES OF CHRONIC STUDIES, BILATERAL CATARACTS WERE FOUND IN 50% OF RATS EXPOSED /TO/ ... 50 PPM FOR 600 HR ...[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 689] **PEER REVIEWED**
  • Rats, guinea-pigs, & rabbits exposed to 80-88 ppm (256-281 mg/cu m) for 7 hr/day for 30-40 wk had incr testicular wt & degeneration of seminiferous tubules. ... Alteration of estrous cycles has been reported in rats exposed to 1.6 or 9.4 ppm (5 or 30 mg/cu m) for 4 mo ... but there was no effect on their subsequent fertility or litter size. ... In C3H(JAX) mice whose ovaries were painted directly ... & which were later mated, a high incidence of sc hemorrhages & tail defects was observed in offspring, which persisted through 4 generations.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 111 (1982)] **PEER REVIEWED**
  • ... STUDIES HAVE DEMONSTRATED THE INDUCTION OF CHROMOSOMAL ABERRATIONS IN BONE-MARROW CELLS FROM MICE, RATS, AND RABBITS TREATED WITH SINGLE OR MULTIPLE DAILY DOSES OF BENZENE RANGING FROM ABOUT 0.2 TO 2.0 ML/KG PER DAY & GIVEN EITHER SC OR IP. MOST OF THE INDUCED ABERRATIONS WERE BREAKS OR DELETIONS; BUT CHROMOSOME-TYPE ABERRATIONS ALSO OCCURRED, PARTICULARLY AFTER PROLONGED EXPOSURE, WHEN TOXICITY, MANIFESTED BY A DROP IN PERIPHERAL BLOOD LEUCOCYTE COUNT, APPEARED. ... A SIGNIFICANT ELEVATED LEVEL OF ABERRATIONS ARE SEEN UP TO 8 DAYS AFTER A SINGLE IP INJECTION OF 0.5 ML/KG BODY WT IN RATS, WHEREAS ABERRATIONS WERE SIGNIFICANTLY INCR IN MICE 24 HR BUT NOT 7 DAYS AFTER RECEIVING A SIMILAR DOSE, 0.5 ML/KG BODY WT.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 115 (1982)] **PEER REVIEWED**
  • ... 30 MALE AKR, DBA2, C3H OR C57BL6 MICE WERE GIVEN WEEKLY SC INJECTIONS OF 0.001 ML BENZENE IN 0.1 ML OLIVE OIL FOR LIFE. NO TUMORS WERE FOUND IN MICE OF DBA2, C3H OR C57BL6 STRAINS, THE MAX LIFESPAN BEING 730 DAYS. BETWEEN 7TH & 16TH MO OF TREATMENT 16/30 TREATED AKR MICE DIED WITH LEUKEMIA, IN ADDITION, 8 DIED BEFORE AGE OF 9 MO WITHOUT LEUKEMIA. HOWEVER, LEUKEMIA WAS ALSO OBSERVED IN 30/35 AKR UNTREATED MICE WHICH LIVED, ON AVG, LONGER THAN TEST ANIMALS.[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). Available at: http://monographs.iarc.fr/index.php, p. V7 209 (1974)] **PEER REVIEWED**
  • ... AFTER 5 TO 8 WK OF 5 HR/DAY, 5 DAYS/WK EXPOSURE AT 44 & 47 PPM, RATS DEVELOPED A MODERATE DEGREE OF LEUKOPENIA, BUT ... NONE RESULTED FROM 15 TO 31 PPM. ... DECR IN THE WHITE CELL COUNTS OF RATS /WAS OBSERVED/ FOLLOWING 756 HR OF EXPOSURE AT 50 PPM OF BENZENE ON A SCHEDULE OF 8 HR/DAY, 5 DAY/WK. REDUCED AMT OF DNA IN THE WHITE CELLS, A DEPRESSION IN MYELOCYTIC ACTIVITY, & AN INCR IN THE RELATIVE NUMBER OF RED CELL PRECURSORS IN THE BONE MARROW WERE ALSO OBSERVED.[American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986., p. 50] **PEER REVIEWED**
  • SPRAGUE-DAWLEY RATS WERE EXPOSED TO 100, 300, & 2200 PPM OF BENZENE VAPOR IN AIR FOR 6 HR DAILY ON DAYS 6-15 OF GESTATION. THE MEAN BODY WT & CROWN-RUMP LENGTH WERE LOWER THAN CONTROL GROUPS ONLY AT THE HIGHEST EXPOSURE LEVEL. SKELETAL EXAM SHOWED AN INCR IN THE NUMBER OF FETUSES WITH DELAYED OSSIFICATION OF STERNEBRAE IN THE 300- & 2200-PPM GROUPS. THE FEMALE OFFSPRING APPEARED TO BE AFFECTED TO A GREATER EXTENT THAN MALE FETUSES WITH RESPECT TO THE INCIDENCE OF DELAYED OSSIFICATION OF STERNEBRAE. LIFETIME EXPOSURE OF C57BL/6J MICE TO 100 OR 300 PPM (320 OR 958 MG/CU M) BENZENE PRODUCES ANEMIA, LYMPHOCYTOPENIA & NEUTROPHILIA ASSOC WITH A RELATIVE INCR IN THE NUMBER OF IMMATURE LEUCOCYTES & DECR IN MATURE LEUCOCYTES IN CIRCULATION. SC ADMIN BENZENE LED TO A SELECTIVE DEPRESSION IN B-LYMPHOCYTES IN RABBITS, WHEREAS T LYMPHOCYTES WERE MORE RESISTANT.[GREEN JD ET AL; TOXICOL APPL PHARMACOL 46 (1): 9-18 (1978)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/725954?dopt=Abstract" target=new>PubMed Abstract</a>
  • Male Charles River CD-1 mice (number unspecified) were exposed for 6 hr/day, 5 days/wk, for life to atmospheres containing ... levels of 0 (control), 100 ppm (320 mg/cu m) or 300 ppm (958 mg/cu m). Two mice in high-exposure group develop myelogenous (myeloid) leukemia. ... There was no evidence of leukemic response in 45 male 6 wk old Sprague-Dawley rats exposed to ... 900 mg/cu m (300 ppm) ... for 6 hr/day, 5 days/wk, for life. Exposure was terminated at wk 99 when the last test animal died. Controls were 27 males of same strain & age. ... Sprague-Dawley rats & AKR mice exposed to benzene (300 ppm, 958 mg/cu m) for 6 hr/day, 5 days/wk for life had lymphocytopenia, with little evidence of anemia. AKR mice were more sensitive to benzene-induced leucopenia than ... rats. /Mice also displayed agranulocytosis & reticulocytosis. No evidence of leukemia was reported/.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 108 (1982)] **PEER REVIEWED**
  • Single sc injection of 3 ml/kg body wt ... on 1 of days 11-15 of gestation to CFI mice caused cleft palate, agnathia & micrognathia in offspring ... . (No controls were used, & it is very likely that these effects were produced by stress of the injection). Several other studies in pregnant mice exposed to benzene, (2 & 4 ml/kg body wt sc, 0.3 to 1.0 ml/kg body wt orally or 500 ppm (1597 mg/cu m) by inhalation for 7 hr/day all failed to show any teratogenic effect, although reduced fetal wt & occasional embryolethality were observed. Similarly, several inhalation studies in rats have shown embryolethality & reduced fetal wt but only occasional teratogenic effects: Sprague-Dawley rats exposed to 10, 50, or 500 ppm (32, 160 & 1600 mg/cu m) for 7 hr/day had low incidence of brain & skeletal defects but no embryolethality at 50 or 500 ppm, & no abnormality or embryolethality at lower levels ... . No teratogenic effect was seen in pregnant rats exposed to 10 or 40 ppm (32 or 128 mg/cu m) for 6 hr/day ..., to 313 ppm (1000 mg/cu m) for 24 hr/day or for 6 hr/day ... or to 400 mg/cu m (125 ppm) for 24 hr/day (Tatrai et al 1980). No teratogenic effect has been reported in rabbits injected sc with 0.25 ml/kg of a 40% benzene soln daily during pregnancy ... or in rabbits exposed by inhalation to 500 ppm (1600 mg/cu m) for 7 hr/day on days 6-18 of pregnancy.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 111 (1982)] **PEER REVIEWED**
  • Rabbits and rats injected subcutaneously with 0.2 mg/kg/day showed an incr frequency of bone marrow mitoses.[Dobrokhotov VB; Gig Sanit 37: 36 (1972)] **PEER REVIEWED**
  • Bone marrow cells from mice orally dosed with 56-2050 mg/kg on two successive days showed dose-related incr in incidences of chromosomal gaps and single breaks, multiple breaks at or above 139 mg/kg, pulverization at or above 348 mg/kg, and cytotoxicity at 2050 mg/kg.[Siou G et al; Mutat Res 90: 273-8 (1981)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7329437?dopt=Abstract" target=new>PubMed Abstract</a>
  • Mice orally dosed with 0.22-1.65 g/kg showed a positive dose-related increase in polychromatic erythrocytes in the micronucleus test.[Schmidt W; Mutat Res 31: 9-15 (1975)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/48190?dopt=Abstract" target=new>PubMed Abstract</a>
  • Rats exposed continuously to 209.7 ppm for 10 days prior to breeding showed a complete absence of pregnancy. 1/10 rats exposed to 19.8 ppm had resorbed embryos. Females showed an inverse relationship between dose (0.3-209.7 ppm) and number of offspring.[Gofmekler VA; Hyg Sanit 33: 327 (1968)] **PEER REVIEWED**
  • Chromosomal abnormalities in bone marrow cells have been reported as a consequence of experimental benzene exposure in a number of species including rats, rabbits, mice, and amphibians.[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • Chromatid deletions in metaphase chromosomes of bone marrow cells have been found in rats given single doses of subcutaneous benzene at 2 ml/kg and in rats given 1 g/kg/day for 12 days.[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • After rats were dosed with 0.5 ml/kg intraperitoneally, no dominant lethality was found; however, incr chromatid and chromosomal aberrations were reported.[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • Benzene is a mitotic poison, producing a decr in DNA synthesis in animal bone marrow cells in vitro.[USEPA; Ambient Water Quality Criteria: Benzene p.C-45 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • Weanling male C57BL/6N mice were subcutaneously injected twice weekly for 44 weeks and once weekly for the last 10 weeks, gradually incr the dose from 450 mg/kg to 1.8 g/kg. The mice were killed 104 weeks after the first injection, and no evidence of carcinogenic activity was found in either the benzene-treated mice or the negative controls. Butylnitrosourea induced leukemia, lymphomas, and/or intestinal neoplasms/were observed/ in almost all the positive controls.[USEPA; Ambient Water Quality Criteria: Benzene p.C-48 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • TWO GROUPS OF 40 MALE C57BL/6J MICE, 6 WK OLD, WERE EXPOSED TO ATMOSPHERES CONTAINING 0 OR 900 MG/CU M (300 PPM) BENZENE FOR 6 HR/DAY, 5 DAYS/WK, FOR LIFE. THE EXPOSURE ENDED AFTER 488 DAYS WITH THE DEATH OF THE LAST TEST MOUSE. IN ADDN TO ANEMIA, LYMPHOCYTOPENIA, NEUTROPHILIA & BONE-MARROW HYPERPLASIA, 6 OF 40 MICE EXPOSED ... DEVELOPED LYMPHOCYTIC LYMPHOMA WITH THYMIC INVOLVEMENT (P< 0.01 FOR LYMPHOMAS, ACCORDING TO PETO'S LOG-RANK METHOD), 1 PLASMACYTOMA & 1 HEMATOCYTOBLASTIC LEUKEMIA. AVG SURVIVAL TIME OF THE 8 TUMOR-BEARING MICE WAS 262 DAYS. TWO OF THE 40 CONTROL ANIMALS DIED FROM LYMPHOCYTIC LYMPHOMA WITH NO THYMIC INVOLVEMENT AFTER 282 & 608 DAYS, RESPECTIVELY. DIFFERENCES IN INCIDENCE & INDUCTION TIME OF TUMORS BETWEEN THE GROUPS WERE STATISTICALLY SIGNIFICANT (SNYDER ET AL 1980). (THE WORKING GROUP NOTED THAT THYMUS WAS NOT EXAM ROUTINELY).[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). Available at: http://monographs.iarc.fr/index.php, p. V29 108 (1982)] **PEER REVIEWED**
  • THREE GROUPS OF 30 OR 35 MALE & ... FEMALE SPRAGUE-DAWLEY RATS, 13 WK OLD, RECEIVED 50 OR 250 MG/KG BODY WT BENZENE (PURITY UNSPECIFIED) DISSOLVED IN PURE OLIVE OIL BY STOMACH TUBE ONCE DAILY ON 4 OR 5 DAYS EACH WK DURING 52 WEEKS. GROUPS OF 30 MALE & 30 FEMALE CONTROLS RECEIVED OLIVE OIL ONLY. THE RATS WERE ALLOWED TO LIVE UNTIL SPONTANEOUS DEATH OR WERE KILLED AT 144 WEEKS, THE END OF EXPT; AVG SURVIVAL TIMES WERE UNSPECIFIED. OF FEMALES OF THE CONTROL, LOW- & HIGH-DOSE GROUPS, 0/30, 2/30 & 8/32, RESPECTIVELY, DEVELOPED ZYMBAL GLAND CARCINOMAS (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.001; FISHER EXACT TEST FOR CONTROL VERSUS HIGH-DOSE GROUP: P= 0.003); 3/30, 4/30 & 7/32 DEVELOPED MAMMARY GLAND CARCINOMAS; & 1/30, 2/30 & 1/32 DEVELOPED LEUKEMIAS. NO SUCH TUMORS WERE FOUND IN MALES, EXCEPT THAT LEUKEMIAS OCCURRED IN 4/32 HIGH-DOSE MALES (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.008; FISHER EXACT TEST: P< 0.069). BACKGROUND INCIDENCE OF ZYMBAL GLAND CARCINOMAS IN SEVERAL THOUSAND MALE & FEMALE RATS OF SAME STRAIN ... /WAS/ ABOUT 0.7%. AVG LATENT PERIOD OF MAMMARY GLAND CARCINOMAS WAS 88 WK IN EACH TEST GROUPS VERSUS 110 WK IN CONTROL ... .[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). Available at: http://monographs.iarc.fr/index.php, p. V29 106 (1982)] **PEER REVIEWED**
  • BLUE CRAB JUVENILES WHEN EXPOSED TO SUBLETHAL CONCN OF BENZENE (0.1 OR 5.0 PPM) IN A STATIC SYSTEM SHOWED AN INCR IN THE TIME NEEDED TO COMPLETE A MOLT CYCLE (50 DAYS IN CASE OF BENZENE-EXPOSED CRAB, AS COMPARED TO 33 DAYS FOR CONTROLS), A SLOWER RATE OF GROWTH OF REGENERATING LIMB BUDS, & A DEPRESSED ACTIVITY OF ATPASE IN MITOCHRONDRIA. OXYGEN CONSUMPTION BY THE CRAB DECR FROM EXPOSURE TO 1.0 PPM BENZENE.[CANTELMO A ET AL; PHYSIOL MECH MAR POLLUT TOXIC (PROC SYMP POLLUT MAR ORG): 349-89 (1982)] **PEER REVIEWED**
  • Toxicity threshold (cell multiplication inhibition test): bacteria (Pseudomonas putida) 92 mg/l; algae (Microcystis aeruginosa) >1400 mg/l; green algae (Scenedesmus quadricauda) >1400 mg/l; protozoa (Entosiphon sulcatum) >700 mg/l, & (Uronema parduczi Chatton-Lwoff) 486 mg/l. Algae (Chlorella vulgaris) /showed/ 50% reduction of cell numbers versus controls after 1 day incubation at 20 deg C at 525 ppm. Inhibition of photosynthesis (of a freshwater, nonaxenic unialgal culture of Selenastrum capricornutum) at 10 mg/l, 95% carbon-14 fixation (versus controls); at 100 mg/l, 84% carbon-14 fixation (versus controls); at 1000 mg/l, 5% carbon-14 fixation (versus controls). ... Young Coho salmon /showed/ no significant mortalities up to 10 ppm after 96 hr in artificial seawater at 8 deg C ... Mortality /was/ 12/20 at 50 ppm after 24 hr up to 96 hr & 30/30 at 100 ppm after 24 hr in artificial seawater at 8 deg C. Herring & anchovy larvae (Clupea pallasi & Engraulis mordex) /studies showed that/ 35-45 ppm caused delay in development of eggs & /produced/ abnormal larvae; 10-35 ppm caused delay in development of larvae, decrease in feeding & growth, & increase in respiration.[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 257] **PEER REVIEWED**
  • Groups of 5 to 10 pregnant Swiss-Webster mice were exposed to concentrations of 0, 5, 10, or 20 ppm benzene from days 6 through 15 of gestation and offspring of exposed dams were examined for untoward effects. Litter sizes, fetal weights, numbers of dead, resorbed, or malformed fetuses were within control limits. In the fetuses (day 16 of gestation), the number of mature erythroid precursor cells (CFU-E) was decreased at 20 ppm benzene. In the neonates, the number of CFU-E cells was increased at 20 ppm benzene. Granulocytic colony forming cells (GM-CFU-C) were affected by the 2 higher exposure concentrations. Adult mice treated in utero when re-exposed to benzene showed a more severe decrease in splenic GM-CFU-C than controls.[Keller KA, Snyder CA; Toxicology 42: 171-81 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3798466?dopt=Abstract" target=new>PubMed Abstract</a>
  • The best evidence that benzene must be metabolized to produce bone marrow depression is based on: 1) the observation that benzene toxicity is prevented by coadministration of toluene, which inhibits benzene metabolism; and 2) that partial hepatectomy (which decreases benzene metabolism) also decreases benzene toxicity.[USEPA; ECAO Atlas Document: Benzene IV-11 (1980)] **PEER REVIEWED**
  • Reports indicate that protection against benzene toxicity in phenobarbital treated animals reflects the fact that phenobarbital increased the detoxification rate of benzene in the liver. Inhibition of metabolism by toluene and by aminotriazole has been found to protect animals by decreasing the rate of formation of toxic metabolites.[USEPA; ECAO Atlas Document: Benzene IV-11 (1980)] **PEER REVIEWED**
  • The principal hydroxy metabolites of benzene, hydroquinone, catechol and phenol were assayed in tests for mitotic segregation induction in Aspergillus nidulans diploid strain 19. Hydroquinone was the most effective chemical, increasing the frequency of mitotic segregants up to 10 fold at 1-3 mM. Catechol was similarly active at 10-20 mM and phenol was weakly positive at 15 mM. Genetic characterization of induced abnormal segregating colonies by replating and complementary assays with haploid strain 35 suggest that gross chromosomal aberrations, instead of numerical abnormalities, are the primary genetic damages induced by hydroxybenzenes in Aspergillus. The protecting activity exerted by L-cysteine against equimolar concentrations of hydroquinone supports a free radical mechanism for hydroxy metabolite genotoxicity in Aspergillus nidulans.[Crebelli R et al; Mutagenesis 2 (3): 235-8 (1987)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3325750?dopt=Abstract" target=new>PubMed Abstract</a>
  • Benzene hematotoxicity and leukemogenesis were investigated to verify epidemiological estimates to the effect that leukemia had developed in human beings exposed to benzene for about 15% of their lifetime, and that the levels of exposure reached at times as high as 250 to 300 ppm for at least a portion of working day. Based on a review of the literature and ongoing studies, mice were exposed to benzene vapor for 6 hr/day, 5 days/week for 16 weeks. Exposure of male CBA/Ca mice to 300 ppm benzene proved to be highly carcinogenic and leukemogenic compared to unexposed controls. Male and female CBA/Ca mice exposed to 100 ppm benzene, according to the same schedule, showed 30% mortality as compared to 12% in controls, while for neoplasms the respective figures were 10% and 1%. In this case, exposure to benzene reduced the cellularity of the bone marrow and the number of stem cells, while DNA synthesis increased. /Data indicates/ that benzene is carcinogenic in both animals and man and although it is unlikely that the slope for animals and man would be the same, the investigation of the linearity of the response would be helpful.[Cronkite BP; Blood Cells 12 (1): 129-37 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3790732?dopt=Abstract" target=new>PubMed Abstract</a>
  • A review of recent advances in the metabolism and toxicity of benzene was presented. Metabolism of benzene was discussed including the microsomal metabolism of benzene, mitochondrial metabolism of benzene, effect and its metabolites on replication and transcription, and covalent binding of reactive metabolites of benzene with macromolecules. The toxicity of benzene, including genotoxicity, carcinogenicity, hematopoietic toxicity, and immunotoxicity, was reviewed. Mutagenicity and cytogenic toxicity were also covered. Effects on stem cells, progenitor cells, and on the stromal microenvironment were discussed. Cytogenetic effects observed in animals and humans following exposure to benzene were reviewed. Myeloclastogenic effects and clastogenic effects were covered. Leukemias and related diseases in humans, associated with repeated exposure to benzene at relatively high concentrations, were discussed. Aplastic anemia from benzene poisoning was also discussed. Progress made in understanding the bioactivation of benzene and in the elucidation of metabolites produced in the liver and bone marrow was discussed.[Kalf GF; CRC Crit Rev Toxicol 18 (2): 141-59 (1987)] **PEER REVIEWED**
  • Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part to altered differentiation of marrow lymphoid cells. The effect of acute exposure to the benzene metabolite, hydroquinone, on murine bone marrow B-lymphopoiesis was investigated. Bone marrow cell suspensions from B6C3F1 (C57BL/6J x C3H/HeJ) mice were depleted of mature surface IgM+ B cells and cultured for 0, 24, 48, or 72 hr and production of newly formed B cells was assayed both by mature surface expression and colony formation in soft agar cultures. One hr exposure of bone marrow cells to hydroquinone before culture reduced the number of mature surface cells generated in liquid cultures. Small pre-B cells (cytoplasmic mu heavy chain+, sIgM-) were numerically elevated as compared with control cultures. Hydroquinone exposure also decreased the number of adherent cells found in cultures of bone marrow cells. These results suggest that short-term exposure to hydroquinone, an oxidative metabolite of benzene, may in some way block the final maturation stages of B cell differentiation. This apparent differentiation block resulted in reduced numbers of B cells generated in culture and a corresponding accumulation of pre-B cells. Reduction of adherent cells in treated cultures may also suggest that toxicity to regulatory cells for the B lineage may be in part responsible for this aspect of hydroquinone myelotoxicity.[King AG et al; Mol Pharmacol 32 (6): 807-12 (1987)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3501069?dopt=Abstract" target=new>PubMed Abstract</a>
  • Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol, hydroquinone, benzquinone, and 1,2,4-benzenetriol had potent and varied effects on macrophage function and activation. Benzoquinone inhibited the broadest range of functions including release of hydrogen peroxide, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide triggering of cytolysis. Benzoquinone was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. Hydroquinone inhibited hydrogen peroxide release and priming for cytolysis and 1,2,4-benzenetriol inhibited phagocytosis and priming for cytolysis. Catechol only inhibited the release of hydrogen peroxide. None of the compounds tested inhibited the induction of class II histocompatibililty antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems.[Lewis JG et al; Toxicol Appl Pharmacol 92 (2): 246-54 (1988)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3422522?dopt=Abstract" target=new>PubMed Abstract</a>
  • Female Wistar rats were exposed to various solvent vapors 8 hr/day for 7 days. The leukocyte suspension and serum were prepared from peripheral blood and utilized for the determination of alkaline phosphatase activity with disodium phenyl phosphate as a substrate (leukocyte alkaline phosphatase and serum assay). While the exposure to benzene at 20 or 50 ppm did not cause significant changes in leukocyte alkaline phosphatase assay activity, the exposure at 100 to 300 ppm resulted in a dose-dependent increase of leukocyte alkaline phosphatase assay activity up to more than 100% over the control. No further increase was observed at 1000 or 3000 ppm. Similar exposure at 300 ppm to either toluene, m-xylene, n-hexane, trichloroethylene, methyl ethyl ketone, ethyl acetate, or methyl alcohol did not induce any changes in leukocyte alkaline phosphatase assay activity. Thus, the increase in leukocyte alkaline phosphatase assay activity was considered to be specific to benzene exposure. When the animals were exposed to toluene (300 ppm) in combination with benzene (300 ppm), not only was the benzene induced leukopenia alleviated as previously reported, but the benzene induced increase in leukocyte alkaline phosphatase assay activity was no longer observed. The parallel inhibitory effects of toluene on benzene induced increase in leukocyte alkaline phosphatase assay and leukopenia suggest that a relation may exist between increase in leukocyte alkaline phosphatase assay activity and leukopenia. No changes in serum alkaline phosphatase assay activities were observed in the rats under the exposure conditions examined.[Li GL et al; J Toxicol Environ Health 19 (4): 581-9 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3783773?dopt=Abstract" target=new>PubMed Abstract</a>
  • A review was presented of data for ... chemicals for which either ovarian toxicity or carcinogenicity, or both, have been documented in recent studies /conducted by/ the National Toxicology Program. In most cases, ovarian atrophy was commonly found after 90 days of exposure, and ovarian hyperplasia and neoplasia after longer periods. Benzene administered by gavage produced ovarian atrophy, cysts, hyperplasia and neoplasia in mice.[Maronpot RR; Environ Health Perspect 73: 125-30 (1987)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3665857?dopt=Abstract" target=new>PubMed Abstract</a>
  • Based on literature, the mechanism of multitoxic effects of benzene and lesions in the peripheral blood of affected animals were postulated. The effects of chronic benzene poisoning upon erythrocytes and erythropoiesis, granulocytes and granulopoiesis, lymphocytes and lymphopoiesis, thrombocytes and thrombopoiesis were presented. Differences were pointed out in toxic effects of benzene varying with the kind, concentration and administration route of benzene and quantitative and qualitative differences in the fodder given to animals during the experiment.[Moszczynski P, Lisiewicz J; Med Pr 36 (5): 316-24 (1985)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3913839?dopt=Abstract" target=new>PubMed Abstract</a>
  • The effect of a single dose of benzene (0.5 ml/kg body wt ip) on the heme saturation of tryptophan pyrrolase activity in liver was examined /in female albino rats/. There was a significant decrease in the heme saturation of hepatic tryptophan pyrrolase, suggesting depletion of regulatory heme. After benzene administration there was significant increase in delta-aminolevulinate synthetase activity while delta-aminolevulinate dehydratase activity was significantly decreased, however, ferrochelatase and heme oxygenase activities were unaltered. Administration of tryptophan to benzene pretreated rats showed a reversal of benzene effects on heme synthesizing enzymes: there is an increase in the heme saturation of tryptophan pyrrolase and decrease in delta-aminolevulinate synthetase. However, there was no significant alteration in the activity of delta-aminolevulinate dehydratase.[Siddiqui SM et al; Toxicol 48 (3): 245-51 (1988)] **PEER REVIEWED**
  • The effects of five straight alkane petroleum hydrocarbons (nC6 to nC10), as well as benzene and toluene upon lysosomal enzymes of the lung were investigated. Pulmonary alveolar macrophages were obtained from adult male Sprague Dawley rats and from 3 month old New-Zealand white rabbits by bronchial lavage. These cells were cultured and subsequently exposed to hydrocarbons in Leighton tubes. All hydrocarbons examined were cytotoxic to cultured pulmonary alveolar macrophages in a dose dependent manner, with benzene and toluene being least toxic. The concentration of hydrocarbon producing death in 50% of treated rat cells was 1.0 millimolar (mM) for nC8, 2.0 mM for nC7, 5 mM for nC9, and about 10 mM for nC6, nC10, benzene and toluene. Concentrations of hydrocarbons that killed 50% of rabbit macrophages were about half those observed in the rat. Cathepsin-D and, to a lesser extent, cathepsin-B release were stimulated upon addition of hydrocarbons to the cell media. A similar but more pronounced release of cathepsins was observed in isolated lysosomes as well. A significant decrease in cell respiration rate and a time and dose dependent increase in lipid peroxidation were also observed following exposure of macrophages to the tested hydrocarbons, particularly nC7 and nC8 alkanes. These results support the concept of an association between chain length and cytotoxicity of hydrocarbons in pulmonary alveolar macrophages.[Suleiman SA; Arch Toxicol 59 (6): 402-7 (1987)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3606384?dopt=Abstract" target=new>PubMed Abstract</a>
  • ... Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas, and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benigh mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. ...[Toxicology & Carcinogenesis Studies of Benzene in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 289 (1986) NIH Publication No. 86-2545 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] **PEER REVIEWED**
  • In animal models, benzene induces anemia, lymphocytopenia, and hypoplastic bone marrow. In addition, it has been suggested recently that this myelotoxicity may be a result of altered differentiative capacity in bone marrow-derived lymphoid cells.[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. 380] **PEER REVIEWED**
  • ... Solid tumors have been reported in animals exposed to benzene by inhalation or orally, suggesting that in mice and rats benzene may produce tumors in nonhematopoietic organs.[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**
  • When Sprague-Dawley rats and CD-1 mice of either sex were exposed to benzene by inhalation 6 hr/day, 5 d/wk for 13 wk at 1, 10, 30, or 300 ppm, treatment-related pathology was observed in the high-dose (300 ppm) groups of both species. In mice, hematologic changes included decreased hematocrit, total hemoglobin, erythrocyte/leukocyte count, platelet count, and myeloid: erythroid ratio. In rats, decreased lymphocyte count and a relative increase in neutrophil count were the only exposure-related clinical changes. Histopathological changes were observed in the testes and ovaries at concentrations below 300 ppm, and lesions were observed in the thymus, bone marrow, lymph nodes, spleen, ovaries, and testes in mice inhaling 300 ppm. The alterations were more severe in the males than in the females. In rats, the only exposure-related pathology was a slight reduction in femoral marrow cellularity at 300 ppm.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2] **PEER REVIEWED**
  • Hematopoietic depression in rodents was observed at benzene concentrations as low as 103 ppm after a 5 day exposure.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2] **PEER REVIEWED**
  • In a lifetime carcinogenicity bioassay in which oral doses of benzene were administered at 50 and 250 mg/kg body weight/day, 4-5 days per week for 52 weeks, there was a dose-dependent increase in total cancers. The most prominent rat tumors observed were Zymbal gland carcinomas, mammary carcinomas, and leukemia. When Wistar rats and Swiss mice were given benzene at 500 mg/kg/day, 4 days/wk for 104 wk or 5 days/wk for 78 wk, the numbers of Zymbal gland carcinomas, hemolymphoreticular neoplasias, and total malignant tumors were increased in the rats; increases in mouse Zymbal gland dysplasia and carcinomas, mammary carcinomas, pulmonary tumors, and total malignant tumors were observed.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2] **PEER REVIEWED**
  • Researchers: conducted an inhalation study in which pregnant Sprague-Dawley rats were exposed 7 hr/d to benzene at 10, 50, or 500 ppm on days 6 to 15 of gestation. Significant reductions in mean maternal body weight gain occurred. Mean fetal body weight was reduced. Fetal crown-to-rump distance was decreased significantly at 500 ppm, and developmental delay was evidence upon examination of the fetal skeletons. Benzene was judged ... to be fetotoxic in rats at 50 and 500 ppm and to manifest teratogenicity at 500 ppm.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-3] **PEER REVIEWED**
  • Researchers: exposed CFLP mice and NZ rabbits 24 hr/day to benzene at 154 or 308 ppm throughout days 6 to 15 of gestation. Benzene was detected in fetal blood and in amniotic fluid. At 308 ppm, retarded skeletal development and reduced fetal body weight were observed in mouse fetuses, and spontaneous abortions were reported in rabbits.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-3] **PEER REVIEWED**
  • Researchers: found a concentration-dependent increase in DBA/2 mouse bone marrow lymphocytes after a single 4-hr inhalation study of benzene at 28-3000 ppm; an increase in SCE was detected at 28 ppm. This response was strain-dependent because DBA/2 mice were more sensitive than C57BL/6 mice, young DBA/2 mice (3 mos old) were more sensitive than older mice (10 mos old), and male mice were more sensitive than female mice. Following intraperitoneal injection, a linear dose-dependent increase in SCE was observed in DBA/2 mice.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-4] **PEER REVIEWED**
  • When male DBA/2 mice inhaled benzene at 0, 10, 100, or 1000 ppm or male Sprague-Dawley rats inhaled benzene at 0, 0.1, 0.3, 1, 3, 10, or 30 ppm for 6 hr, significant (concentration-dependent) increases in SCE and micronuclei were observed in mice at greater than or equal to 10 ppm, and increased SCE and micronuclei were observed in rats inhaling greater than or equal to 3 ppm and at 1 ppm, respectively. These data are the lowest concentrations of inhaled benzene that have been reported to induce genotoxicity.[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-4] **PEER REVIEWED**
  • Benzene: has been shown to be fetotoxic following inhalation exposure in mice (1600 ug/cu m, 7 hr/day, gestation days 6-15) and in rabbits.[WHO; Environmental Health Criteria 150: Benzene p.16 (1993)] **PEER REVIEWED**
  • Toluene and benzene administered concurrently were reported to have an additive effect on induction of chromosomal aberrations. Toluene reduced the number of sister chromatid exchanges induced by benzene when both compounds were administered intraperitoneally to DBA/2 mice and reduced the clastogenic activity of benzene when the two compounds were simultaneously administered orally to CD-1 mice, intraperitoneally to Sprague-Dawley rats, or subcutaneously to NMRI mice.[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). Available at: http://monographs.iarc.fr/index.php, p. V47 99 (1989)] **PEER REVIEWED**
  • Rats exposed to 3,526-8,224 ppm of benzene in a closed chamber for 15 min exhibited an increased number of ectopic ventricular beats.[Magos GA et al; Neurotoxicol Teratol 12 (2): 119-24 (1990) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.43 (1997)] **PEER REVIEWED**
  • Sprague-Dawley SD/Tex rats were exposed to benzene vapor at 0 or 500 ppm for 5 days per week, 6 hr/day for 3 wk. Blood from the animals was evaluated for hematologic changes and the bone marrow for the presence of multinucleated erythroblasts. Animals exposed to 500 ppm showed decreased lymphocyte and leukocyte counts. Erythrocytes and hemoglobin values increased. In the bone marrow differential counts, rats showed a relative decrease in lymphoid and myeloid cells at the 500 ppm dose level and an increase in erythroid cells. In a companion study, purebred Duroc-Jersey pigs were exposed to 0, 20, 100, and 500 ppm benzene vapors 6 hr/day, 5 days/wk for 3 wk.[Dow; EPA/OTS Doc # 88-920003196 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.49 (1997)] **PEER REVIEWED**
  • Granulocytic hyperplasia has been detected in the bone marrow of mice exposed to 300 ppm benzene in air for 6 hr/day, 5 days/wk for 16 wk, and held 18 mos after the last exposure.[Farris GM et al; Fundam Appl Toxicol 20 (4): 503-7 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.50 (1997)] **PEER REVIEWED**
  • Researchers: observed a 26% decrease in spleen weight in male Kunming mice exposed to 12.52 ppm benzene 2 hr/day, 6 days/wk for 30 days. Examination of the bone marrow showed decreases in myelocytes, premyelocytes, myeloblasts, and metamyeloblasts at the same dose level.[Li L et al; Biomed Environ Sci 5 (4): 349-54 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.61 (1997)] **PEER REVIEWED**
  • Experimental DBA/2 mice were exposed to 300 ppm benzene for 6 hr/day for 5 days/wk (Regimen 1) or 3 day/wk (Regimen 2) for a duration of 1-13 wk. Polychromatic erythrocytes were affected by benzene inhalation independent of exposure duration and regimen, while normochromatic erythrocytes were affected only following Regimen 1 exposure. Males were more sensitive to benzene inhalation than females.[Luke CA et al; Mutat Res 203: 251-71 (1988) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.75 (1997)] **PEER REVIEWED**
  • Sprague-Dawley rats received a single dose of 950 mg/kg benzene by gavage and were sacrificed 2 hr after treatment. The control group received nothing. Brains were dissected ... Results showed that benzene decreased acetylcholine content of rat hippocampus. 3,4-Dihydroxyphenylalanine and norepinephrine content decreased in the rat midbrain. Dopamine, serotonin and 5-hydroxyindoleacetic acid content increased in the rat midbrain. Dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine, and 5-hydroxyindoleacetic acid content increased and serotonin content decreased in the rat hypothalamus after oral administration of benzene. Increased dopamine, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and serotonin content of rat medulla oblongata was observed. Decreased norepinephrine and 5-hydroxyindoleacetic acid content of rat medulla oblongata by benzene treatment was observed.[Kanada M et al; Ind Health 32: 145-64 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.117 (1997)] **PEER REVIEWED**
  • In /a/ study of cultured rat embryos, /researchers/ evaluated the embryotoxic effects of benzene and several of its metabolites. Benzene at 1.6 mM produced little embryotoxicity, with or without hepatic activating enzymes, but phenol showed significant embryotoxicity in the presence of hepatic activation at concentrations as low as 0.01 mM. Trans,trans-muconaldehyde was embryotoxic at 0.01 mM and embryolethal at 0.05 mM; hydroquinone, catechol, and benzoquinone were all 100% embryolethal at 0.1 mM.[Chapman DE et al; Toxicol Appl Pharmacol 128 (1): 129-37 91994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.208 (1997)] **PEER REVIEWED**
  • MICE WERE GIVEN SINGLE DOSES OF BENZENE SC & ITS EFFECT ON (59)FE UPTAKE WAS EVALUATED. NO SUPPRESSION WAS FOUND AFTER 1 & 12 HR & ALSO 72 HR, WHEREAS DOSE-DEPENDENT INHIBITION OF (59)FE UPTAKE WAS OBSERVED 24 HR & 48 HR AFTER TREATMENT WITH 440 OR 2200 MG/KG DOSE. THUS, THE DATA CAN BE INTERPRETED TO SUGGEST THAT (1) BENZENE DID NOT INTERFERE WITH AN INCORPORATION OF IRON INTO HEME, (2) BENZENE INTERFERED WITH PROLIFERATION OF NORMOBLASTS & PRONORMOBLASTS, & (3) BENZENE DID NOT DAMAGE HEMOPOIETIC STEM CELLS WHICH WERE IN THE G0 STATE AT THE TIME OF BENZENE INJECTION.[LEE EW ET AL; ENVIRON HEALTH PERSPECTIVE 39: 29-37 (1981)] **PEER REVIEWED**
  • When mitochondria are incubated in vitro with 2200 mg/kg of benzene there is an inhibition of RNA synthesis. Benzene also caused a dose-dependent inhibition of RNA synthesis in vitro in mitoplasts derived from cat and rabbit bone marrow mitochondria. Exogenous NADPH is required for inhibition of mitochondrial RNA synthesis in all these systems which suggests that benzene must be bioactivated within the organelle. Toluene does not inhibit RNA synthesis and the simultaneous addition of equimolar toluene and benzene results in protection against benzene inhibition. Both liver and bone marrow mitochondria incubated (3H) with benzene appear to activate benzene to a metabolite which can covalently bind to guanine residues of DNA. Benzene also inhibits mitochondrial translation.[Kalf GF et al; Chem-Biol Interact 42 (3): 353-70 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6185244?dopt=Abstract" target=new>PubMed Abstract</a>
  • ... Benzene hydroxylation was stimulated when rats were pretreated with phenobarbital and then exposed to 1,000 ppm of benzene vapor for 8 hr/day for 2 wk.[Ikeda M, Ohtsuji H; Toxicol Appl Pharmacol 20: 30-43 (1971) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.232 (1997)] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 MOUSE INTRAPERITONEAL 0.34 ML/KG 95% CONFIDENCE LIMITS 0.28 TO 0.42[KOCSIS JJ ET AL; SCIENCE 160: 427 (1968)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/5644044?dopt=Abstract" target=new>PubMed Abstract</a>
  • LD50 Rat oral 3306 mg/kg[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**
  • LC50 Rat ihl 10,000 ppm/7 hr[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**
  • LD50 Rat ip 2890 ug/kg[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**
  • LD50 Mouse oral 4700 mg/kg[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**
  • LC50 Mouse ihl 9980 ppm[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**
  • LD50 Mouse ip 340 mg/kg[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**
  • LD50 Mouse ip 340 mg/kg[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**

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Absorption, Distribution and Excretion

  • BENZENE IS READILY ABSORBED VIA LUNG, & ABOUT 40-50% IS RETAINED. ... IT IS TAKEN UP PREFERENTIALLY BY FATTY & NERVOUS TISSUES, & ABOUT 30-50% ... IS EXCRETED UNCHANGED VIA LUNG; A 3-PHASE EXCRETION PATTERN IS SEEN AT ... /APPROX/ 0.7-1.7 HR, 3-4 HR, & 20-30 HR.[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). Available at: http://monographs.iarc.fr/index.php, p. V7 211 (1974)] **PEER REVIEWED**
  • When benzene was placed on skin under closed cup it was absorbed at rate of 0.4 mg/sq cm/hr (Hanke et al 1961) ...[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). Available at: http://monographs.iarc.fr/index.php, p. V29 117 (1982)] **PEER REVIEWED**
  • MICE TREATED SC WITH 2 ML (3)H-LABELED BENZENE/KG CONTAINED IRREVERSIBLY BOUND RADIOACTIVITY WITH DECREASING BINDING MAGNITUDE IN THE FOLLOWING ORGANS: LIVER, BRAIN, KIDNEY, SPLEEN, FAT. MICE TREATED WITH 2 DAILY SC DOSES OF 0.5 ML (3)H-BENZENE/KG FOR 1-10 DAYS SHOWED A RADIOACTIVITY BINDING WITH LIVER & BONE MARROW RESIDUES WHICH INCREASED WITH TREATMENT DURATION, EXCEPT IN THE CASE OF BINDING TO BONE MARROW WHICH DECREASED AFTER DAY 6.[SNYDER R ET AL; RES COMMUN CHEM PATHOL PHARMACOL 20 (1): 191-4 (1978)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/663402?dopt=Abstract" target=new>PubMed Abstract</a>
  • When administered to mice subcutaneously, 72% of dose is recovered in expired air.[Andrews LS et al; Biochem Pharmacol 26: 293 (1977)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/849319?dopt=Abstract" target=new>PubMed Abstract</a>
  • Rats were exposed to 500 ppm benzene for 30 min to eight hr. Benzene concentrations reached steady state within four hr in blood (steady-state concn= 11.5 ug/g), six hr in fat (concn= 164.4 ug/g), and two hr in bone marrow (concn= 37.0 ug/g). Lesser concn were detected in the kidney, lung, liver, brain, and spleen.[Rickert DE et al; Toxicol Appl Pharmacol 49: 417-23 (1979)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/473208?dopt=Abstract" target=new>PubMed Abstract</a>
  • Benzene is absorbed from the gastrointestinal tract when ingested.[Goodman LS, Gilmann A; The Pharm Basis of Therapeutics p.936 (1970)] **PEER REVIEWED**
  • BENZENE CROSSES THE HUMAN PLACENTA, & LEVELS IN CORD BLOOD ARE SIMILAR TO THOSE IN MATERNAL BLOOD. ... THE MOST FREQUENT ROUTE BY WHICH HUMANS ARE EXPOSED TO BENZENE IS VIA INHALATION. TOXIC EFFECTS IN HUMANS HAVE BEEN ATTRIBUTED TO COMBINED EXPOSURE BY BOTH RESPIRATION & THROUGH THE SKIN ... IT IS ELIMINATED UNCHANGED IN EXPIRED AIR ... IN MEN & WOMEN EXPOSED TO 52-62 PPM (166-198 MG/CU M) BENZENE FOR 4 HR, A MEAN OF 46.9% WAS TAKEN UP, 30.2% WAS RETAINED & THE REMAINING 16.8% EXCRETED AS UNCHANGED BENZENE IN EXPIRED AIR. ... WHEN HUMANS WERE EXPOSED TO 100 PPM (300 MG/CU M) BENZENE, IT WAS DETECTED IN EXPIRED AIR 24 HR LATER, SUGGESTING THAT IT IS POSSIBLE TO BACK-EXTRAPOLATE TO THE BENZENE CONCENTRATION IN THE INSPIRED AIR.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 117 (1982)] **PEER REVIEWED**
  • ... In female & male rats with large body fat content, benzene was eliminated more slowly & stored longer than in lean animals. ... Distribution in rabbit was highest in adipose tissue, high for bone marrow, & lower for brain, heart, kidney, lung, & muscle, although direct binding was higher in liver than in bone marrow.[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. 1323] **PEER REVIEWED**
  • The solubility characteristics of benzene are such that it is easily taken up by the stratum corneum. Once in the stratum corneum, it does not meet many restraining forces to impede its movement and diffuses easily. The permeability constant for benzene, as determined in vitro, is higher than that of many other small molecules, particularly those having one or more polar groups. ... Even though these uncertainties exist, and more data are needed to support the ... conclusion that there is good overall agreement between in vitro and in vivo data. ... An adult working in ambient air containing 10 ppm of benzene, with 100 cm of glaborous skin in contact with gasoline containing 5% benzene, and his entire skin (2 sq m) in contact with ambient air, will absorb in an hr, 7.5 ul of benzene from inhalation, 7.0 ul from contact with gasoline, and 1.5 ul from body exposure to ambient air. Since ... in vitro techniques measure the penetration of benzene through strongly hydrated stratum corneum, the calculated flux may be higher than under some in vivo conditions. Nevertheless, it seems that unless good hygiene is maintained and care is taken to prevent lengthy exposure to solvents containing benzene, significant amounts of benzene may enter the body through the skin.[Blank IH, McAuliffe DJ; J Investigat Dermatol 85: 522-6 (1985)] **PEER REVIEWED**
  • Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates. Most of the phenol and catechol was excreted within 24 hr, and the hydroquinone within 48 hr.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 117 (1982)] **PEER REVIEWED**
  • In men and women exposed to 52-62 ppm (166-198 mg/cu m) benzene for 4 hr, a mean of 46.9% was taken up, 30.2% was retained and the remaining 16.8% excreted as unchanged benzene in expired air.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 117 (1982)] **PEER REVIEWED**
  • In animals, expired air is the main route of elimination of unmetabolized benzene, while urine is the major route of excretion of benzene metabolites (with very little fecal excretion).[WHO; Environmental Health Criteria 150: p.54 (1993)] **PEER REVIEWED**
  • In a series of experiments conducted in a single-family residence from June 11 to 13, 1991, exposure to benzene through contaminated residential water was monitored. The residential water was contaminated with benzene and other hydrocarbons in 1986. Exposure was monitored for a person taking a 20-min shower and for people in other parts of the house during and after the shower. An average dermal dose of 168 ug was calculated for a 20-min shower using this water. The total benzene dose resulting from the shower was estimated to be approximately 281 ug (40% via inhalation, 60% via dermal), suggesting a higher potential exposure to benzene via dermal contact from the water than through vaporization and inhalation. This exposure was 2-3.5 times higher than the mean 6-hr inhalation dose received by the sampling team members in other parts of the house.[Lindstrom AB et al; Journal of Exposure Analysis and Environmental Epidemiology 4 (2): 183-95 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.135 (1997)] **PEER REVIEWED**
  • In Sprague-Dawley rats administered a single dose of 0.15, 1.5, 15, 150, or 500 mg/kg of 14C-benzene by gavage, benzene was rapidly absorbed and distributed to various organs and tissues within 1 hr of administration. One hour after rats were dosed with 0.15 or 1.5 mg/kg of benzene, tissue distribution of benzene was highest in liver and kidney, intermediate in blood, and lowest in the Zymbal gland, nasal cavity tissue, and mammary gland. At higher doses, beginning with 15 mg/kg, benzene disproportionately increased in the mammary glands and bone marrow. Bone marrow and adipose tissue proved to be depots of benzene at the higher dose levels. The highest tissue concentrations of benzene's metabolite hydroquinone 1 hr after administration of 15 mg/kg of benzene were in the liver, kidney, and blood, while the highest concentrations of the metabolite phenol were in the oral cavity, nasal cavity, and kidney. The major tissue sites of benzene's conjugated metabolites were blood, bone marrow, oral cavity, kidney, and liver for phenyl sulfate and hydroquinone glucuronide; muconic acid was also found in these sites. Additionally, the Zymbal gland and nasal cavity were depots for phenyl glucuronide, another conjugated metabolite of benzene. The Zymbal gland is a specialized sebaceous gland and a site for benzene-induced tumors. Therefore, it is reasonable to expect that lipophilic chemicals like benzene would partition readily into this gland. However, benzene did not accumulate in the Zymbal gland; within 24 hr after administration, radiolabel derived from 14C-benzene in the Zymbal gland constituted less than 0.0001% of the administered dose.[Low LK et al; Environ Health Perspect 82: 215-22 (1989) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.139 (1997)] **PEER REVIEWED**
  • Monkeys were dosed intraperitoneally with 5-500 mg/kg radiolabeled benzene, and urinary metabolites were examined. The proportion of radioactivity excreted in the urine decreased with increasing dose, whereas the dose increased, more benzene was exhaled unchanged. This indicated saturation of benzene metabolism at higher doses. Phenyl sulfate was the major urinary metabolite. Hydroquinone conjugates and muconic acid in the urine decreased as the dose increased.[Sabourin PJ et al; Toxicol Appl Pharmacol 114 (2): 277-84 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.159 (1997)] **PEER REVIEWED**

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Metabolism/Metabolites

  • ... In human system /benzene/ is metabolized through a variety of major & minor pathways. The primary site of action is liver, where benzene is oxidized to phenol (hydroxybenzene), catechol (1,2-dihydroxybenzene), or quinol (1,4-dihydroxybenzene). Phenol is subsequently conjugated with inorganic sulfate to phenylsulfate, the other hydroxybenzenes are conjugated to a lesser extent, & all excreted in urine. Minor pathways incl further oxidation of catechol to hydroxyhydroquinol (1,2,4-trihydroxybenzene) or catabolism to cis, cis- or trans, trans-muconic acids, & phenol conjugation with glucuronic acid to form glucuronides, or with cysteine to produce 2-phenylmercapturic acid.[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. 1320] **PEER REVIEWED**
  • METABOLIC PRODUCTS IN RAT ... ARE PHENOL, HYDROQUINONE, CATECHOL, HYDROXYHYDROQUINONE, & PHENYLMERCAPTURIC ACID. CONJUGATED PHENOLS HAVE BEEN REPORTED ... EXCEPT FOR A SMALL AMT OF FREE PHENOL, ALL THE PHENOLIC METABOLITES WERE EXCRETED IN CONJUGATED FORM. WHEN (3)H-BENZENE WAS ADMIN TO MICE, (3)H2O WAS ALSO RECOVERED FROM URINE.[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 688] **PEER REVIEWED**
  • YIELDS N-ACETYL-S-PHENYL-CYSTEINE IN RAT. YIELDS BENZYL ALCOHOL IN GUINEA PIGS. ... YIELDS CIS-1,2-DIHYDRO-1,2-DIHYDROXYBENZENE IN PSEUDOMONAS. PHENOL IN PSEUDOMONAS & ACHROMOBACTER. YIELDS CIS,CIS-MUCONIC ACID IN RABBIT. /FROM TABLE/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. B-4] **PEER REVIEWED**
  • In the rabbit, the major hydroxylation product of benzene was phenol, which along with some catechol and hydroquinone, was found in the urine conjugated with ethereal sulfate or glucuronic acid.[USEPA; Ambient Water Quality Criteria: Benzene p.C-11 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • Unconjugated phenol has been found in mouse and rat urine after benzene administration.[USEPA; Ambient Water Quality Criteria: Benzene p.C-11 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • The formation of benzene oxide, an epoxide of benzene is involved in the metabolism of benzene. This highly unstable intermediate rearranges non-enzymatically to form phenol. This step accounts for the occurrence of phenol as the major metabolite of benzene in urine. Catechol formation is thought to result from the hydration of benzene oxide by the enzyme epoxide hydratase followed by oxidation to catechol. It appears that catechol and phenol are formed by two distinctly different metabolic pathways. Hydroquinone is thought to result from a second passage of phenol through the mixed function oxidases.[Jerina D, Daly JW; Science 185: 573 (1974) as cited in USEPA; Ambient Water Quality Criteria: Benzene p.C-12 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • The metabolism of benzene in vitro can be altered by the use of enzyme inducers administered to animals prior to sacrifice or by the addition of inhibitors to the mixtures. Benzene, phenobarbital, 3-methylcholanthrene and dimethyl sulfoxide are all microsomal stimulants for the metabolism of benzene. Benzene metabolism in vitro can be inhibited by carbon monoxide, aniline, metyrapone, SKF-525A /proadifen/, aminopyrine, cytochrome c, aminotriazole, or toluene.[USEPA; Ambient Water Quality Criteria: Benzene p.C-12 (1980) EPA 440/5-80-018] **PEER REVIEWED**
  • Benzene, when administered sc at 880 mg/kg twice daily for 3 days, decreased erythropoiesis much more markedly in DBA/2 mice than in C57BL/6 mice. Total urinary benzene metabolites and the % of the dose excreted in the urine were the same in both strains. Although the metabolic profile differed between the two strains, it was very similar when equitoxic doses of benzene were administered. The levels of both free and covalently bound benzene were higher in all organs of the DBA/2 mice. Phenol, hydroquinone, resorcinol, and catechol had no effect on erythopoiesis.[Snyder R et al; Adv Exp Biol 136A: 245-56 (1982)] **PEER REVIEWED**
  • The urinary metabolites isolated by DEAE Sephadex A-24 anion-exchange chromatography from mice treated with radiolabeled benzene included phenol as the major component, as well as catechol, hydroquinone, and phenylmercapturic acid. The phenolic metabolites were excreted primarily as glucronides with the exception of a small amount of free phenol.[Longacre SL et al; Adv Exp Med Biol 136A: 307-17 (1982)] **PEER REVIEWED**
  • Benzene reduced the incorporation of (59)Fe into red cells by 75% at the higher dose when administered at 440 or 880 mg/kg to mice pretreated with (59)Fe 48 hr earlier. However, when toluene was administered simultaneously with benzene in a ratio of 2:1, the depression of (59)Fe uptake was prevented. Toluene reduced the appearance of benzene metabolites to 45% of controls at the higher dose and 30% at the lower dose. Thus toluene appears to inhibit benzene metabolism and by so doing, alleviates its toxicity.[Snyder R et al; Adv Mod Environ Toxicol 4: 123-36 (1983)] **PEER REVIEWED**
  • A sensitive high performance liquid chromatography method is described which separates urinary metabolites from benzene-treated male CD-1 mice. Phenol, trans, trans-muconic acid and quino in the 48 hr urine, accounted, respectively for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440, and 220 mg/kg body wt). Catechol occurred in trace amounts. Trans, trans-muconic acid was identified and was unique to benzene as none was detected in urine of mice dosed orally with phenol, catechol, or quinol. The potential existence of a toxic metabolite in the form of an aldehyde precursor of muconic acid in vivo is discussed.[Gadel K et al; Xenobiotica 15: 211-20 (1985)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/4024657?dopt=Abstract" target=new>PubMed Abstract</a>
  • In humans, phenol sulfate is the major metabolite of benzene until 400 mg/l levels are reached in the urine. Beyond than level, glucuronide conjugates are also present in the urine.[USEPA; Health Advisories for 25 Organics: Benzene p.19 (1987) PB 87-235578] **PEER REVIEWED**
  • Male Wistar rats were tested to determine the effect of enzymes with different kinetic characteristics on the metabolism of benzene, in vitro. Kinetic analysis of the enzymes in the liver of rats fed a normal diet revealed the presence of two benzene hydroxylases with low Michaelis constant values of 0.01 millimolar and 0.07 millimolar, respectively. After 1 day of food deprivation, the isozyme with a constant equal to 0.01 millimolar disappeared while the activity of the second isozyme increased. Following the administration of phenobarbital there was evidence of a third benzene metabolizing enzyme in the liver of the animals exposed to benzene in concentrations ranging from 0.0055 to 6.25 millimolar, in vitro; the value of the Michaelis constant for this enzyme was equal to 4.5 millimolar and was not evident in control animals. Treatment with phenobarbital failed to affect the activity of the other low Michaelis constants of benzene hydroxylases identified in the liver of normal rats. Treatment with ethanol resulted in significant increase in the activity of both normally occurring benzene hydroxylases in the normal liver.[Nakajima T et al; Biochemical Pharmacol 36 (17): 2799-804 (1987)] **PEER REVIEWED**
  • Mitoplasts (mitochondria with the outer membrane removed) from the bone marrow of rabbits were incubated sequentially with (3)H-labeled deoxyguanosine triphosphate and (14)C-labeled benzene to study the DNA adducts formed from benzene metabolites in mitochondria. Following isolation and isopycnic density gradient centrifugation in CsCl, the doubly labeled DNA was hydrolyzed to deoxynucleosides and separated on a Sephadex LH 20 column. At least seven deoxyguanosine adducts and one deoxyadenine adduct were present.[Snyder R et al; Arch Toxicol 60 (1-3): 61-4 (1987)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3619644?dopt=Abstract" target=new>PubMed Abstract</a>
  • Primary metabolism of benzene occurs predominantly in the liver via cytochrome P-450, the principal product being phenol. Phenol, in turn, undergoes further oxidation via cytochrome P-450 to produce the polyphenolic metabolites of benzene (principally hydroquinone), or alternatively, oxidation via peroxidases in extrahepatic tissues to form biphenols, hydroquinone, and its terminal oxidation product, p-benzoquinone. Muconic acid /is/ ... a minor urinary metabolite of benzene ...[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**
  • ... Literature identifies the following metabolites after incubation of benzene with mouse liver microsomes: phenol, hydroquinone, trans,trans-muconaldehyde, 6-oxo-trans,trans-2,4-hexadienoic acid, 6-hydroxy-trans,trans,2-4,-hexadienal, and 6-hydroxy-trans,trans-2,4-hexadienoic acid. Beta-hydroxymuconaldehyde, a new metabolite, was also identified.[Zhang Z et al; Biochem Pharmacol 50 (1): 1607-17 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.142 (1997)] **PEER REVIEWED**
  • Data produced in vitro by mouse and rat liver microsomes ... indicate species differences in benzene metabolism. Quantitation of metabolites from the microsomal metabolism of benzene indicated that after 45 min, mouse liver microsomes from male B6C3F1 mice had converted 20% of the benzene to phenol, 31% to hydroquinone, and 2% to catechol. In contrast, rat liver microsomes from male Fischer 344 rats converted 23% to phenol, 8% to hydroquinone, and 0.5% to catechol. Mouse liver microsomes continued to produce hydroquinone and catechol for 90 min, whereas rat liver microsomes had ceased production of these metabolites by 90 min. Muconic acid production by mouse liver microsomes was <0.04 and <0.2% from phenol and benzene, respectively, after 90 min.[Schlosser PM et al; Carcinogenesis 14: 2477-86 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.148 (1997)] **PEER REVIEWED**
  • Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates.[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). Available at: http://monographs.iarc.fr/index.php, p. V29 117 (1982)] **PEER REVIEWED**

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TSCA Test Submissions

  • An evaluation of fertility was made in female Charles River CD rats (26/group) exposed by inhalation to benzene at 0, 1, 10, 30 and 300 ppm for 6 hrs/day, 5 days/week during a 10 week pre-mating treatment period and ensuing mating period, and continued exposure for mated females daily for 6 hrs/day during gestation to day 20. Daily exposure was resumed on day 5 of lactation until weaning (day 21 of lactation). There were significant differences between treated and control animals in the following: decrease in pup survival index (for lactation day 4-21 at 10 ppm, no dose-response), decreased mean pup weights (days 14 and 21 of lactation for high-dose level), and decreased mean absolute liver weights (high-dose female pups). There were no significant differences between treated and control animals in the following: maternal mortality, body weights, in-life observations, pregnancy rates, mean number dead pups, mean liver weights (male pups at all levels), mean relative liver weights (female pups at all levels), mean relative and absolute kidney weights (all female pups), or gross postmortem examinations of adult females or pups.[Bio Dynamics Inc.; An Inhalation Female Fertility Study With Benzene in Rats, Final Report. (1980), EPA Document No. FYI-AX-0481-0110, Fiche No. 0110-0] **UNREVIEWED**
  • Teratogenic effects were evaluated in pregnant female Sprague Dawley rats (40/group) exposed via inhalation to benzene at 0 (two groups), 1, 10, 40 and 100 ppm for 6 hrs/day from days 6-15 of gestation. On day 20 of gestation, the dams were sacrificed and the fetuses removed by cesarean section. There were significant differences between treated and control groups only in the decreased mean fetal body weights of fetuses from dams exposed at the high-dose level. There were no significant differences between treated and control dams in the following: mortality, clinical observations, body weight data, maternal gross pathology, pregnancy rates, mean number of corpora and implantations, or implantation efficiencies. There were no significant differences between fetuses from treated and control dams in the following: mean incidence of fetal resorptions, mortality, mean percentage of male fetuses/litter, mean fetal body lengths, or fetal development.[Hazelton Laboratories America, Inc.; Inhalation Teratology Study in Rats, Benzene, Final Report. (1982), EPA Document No. FYI-AX-0482-0127, Fiche No. 0127-0] **UNREVIEWED**
  • The mutagenicity of benzene was evaluated in dominant lethal assay using four groups of 20 male Sprague-Dawley rats receiving whole body exposures to nominal concentrations of test material at 1, 10, 30 and 300ppm in a dynamic air flow chamber for 6hours/day, 5days/week for ten consecutive weeks. Following exposure, each male was mated with two untreated females per week for two consecutive weeks. There was no effect of treatment for all dosed male rats as indicated by: mortality, body weight data and in-life physical observations. Pregnancy rates and implantation efficiency ratios of females mated to treated males was not significant different from control group females. Slight increases in the mean number of dead implantations and mean mutagenic ratios (i.e. no. dead implants/total implants) were noted for each week of the post treatment mating period for females mated to high dose males, but these differences were not statistically significant compared to controls. Males were sacrificed after a 10-week post mating period and microscopic examination of testis/epididymides revealed two-high dose males with testicular lesions.[Bio/dynamics Inc.; A Dominant-Lethal Inhalation Study with Benzene in Rats, Final Report, (1980), EPA Document No. FYI-AX-0481-0110, Fiche No. OTS0000110-0] **UNREVIEWED**
  • As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) CD-1 mice receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of mice at the highest concentration (300ppm) exhibited statistically significant increases chromosome aberrations relative to the control.[Hazleton Laboratories America Inc.; Subchronic Inhalation Study in Mice and Rats, Final Report, (1983), EPA Document No. FYI-AX-0783-0203, Fiche No. OTS0000203-1] **UNREVIEWED**
  • As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) Sprague Dawley rats receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of female rats at all exposure levels exhibited statistically significant increases in chromosome aberrations relative to the control. No-exposure related cytogenic effects were apparent in any of the male rats.[Hazleton Laboratories America Inc.; Subchronic Inhalation Study in Mice and Rats, Final Report, (1983), EPA Document No. FYI-AX-0783-0203, Fiche No. OTS0000203-1] **UNREVIEWED**
  • The ability of benzene to increase the incidence of micronucleated polychromatic erythrocytes was evaluated in male and female CD-1 mice receiving nominal concentrations of 1, 10, 30 and 300ppm for 6hours/day, 5days/week for 13 weeks (Micronucleus Test). Groups of 20 mice (10/sex/sample time) were sacrificed after 0, 15, 30, 60 and 90 days of exposure. Exposure to 300ppm benzene caused a significant increases in micronucleated polychromatic erythrocytes (PCEs) and monochromatic erythrocytes (NCEs) in male and female mice at all sample times. Male mice exhibited a greater response than female mice. The frequency of micronucleated PCEs and the frequency micronucleated NCEs achieved steady state by the 30 day sample time. The rate of erythropoiesis, as measured by per cent of polychromatic erythrocytes in the peripheral blood, was not significantly altered by treatment.[Brookhaven National Laboratory; Evaluation of Micronuclei Frequency in the Peripheral Blood of Male and Female CD-1 Mice Exposed Chemically to Benzene for 90 Days, Final Report, (1985), EPA Document No. FYI-AX-1085-0393, Fiche No. OTS0000393-1] **UNREVIEWED**
  • The levels of benzene and it's metabolites in the blood were evaluated in twenty male Sprague-Dawley rats and eighty male Swiss albino mice receiving nominal concentration of benzene at 300ppm in a dynamic air flow chamber. Sixteen mice and four rats were removed from the chamber after 1, 2, 4, 8 and 12 hours for eye bleeding. The mean levels of benzene in the rat blood were < 1.0, 4.7, 4.8, 5.7, 5.3, and 7.1ppm at intervals of 0, 1, 2, 4, 8 and 12 hours respectively. No free metabolites (phenol, catechol & hydroquinone) were detected at any of the time intervals in rats. The mean levels of benzene in mouse blood were < 1.0, 3.7, 3.0, 2.4, 3.0 and 1.3ppm at intervals of 0, 1, 2, 4, 8 and 12 hours, respectively. The mean levels of free phenol in mouse blood were 2.0, 2.4, 2.2, 2.3, 2.5 and 2.3ppm at respective intervals. No free catechol or hydroquinone were detected at any of the time intervals in mice. Also determined were levels of conjugates in rat and mouse blood. The mean levels of conjugated phenol in rat blood were < 1.0, 3.0, 5.3, 4.2, 7.1 and 4.7ppm and the mean levels in the mouse blood were 2.7, 7.2, 8.7, 8.4, 9.1, and 3.7 at intervals 0, 1, 2, 4, 8 and 12 hours, respectively. No conjugated catechol or hydroquinone were detected at any of the time intervals in rats or mice. It was concluded, that its takes approximately one hour to achieve a steady state level of benzene in rat and mouse blood.[Bio/dynamics Inc.; Determination of Time to Steady State Level in Blood During Inhalation Exposure of Benzene to Rats and Mice, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0] **UNREVIEWED**
  • The levels of benzene and its's metabolites in blood were evaluated in male Sprague Dawley rats (4/group) and male Swiss albino mice (16/group) receiving nominal concentrations of benzene at 0, 3, 30, 300 or 1000ppm in dynamic air flow chamber for 6 hours. The mean levels of benzene in rat blood were < 1.0, < 1.0, < 1.0, 8.3 and 33.6ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. No free metabolites (phenol, catechol & hydroquinone) were detected at any exposure level in rat blood. The mean levels of benzene in the mouse blood were < 1.0, < 1.0, < 1.0, 1.44 and 29.5ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. A mean level of 1.2ppm of free phenol was only detected at the high dose level in mice. No free catechol or hydroquinone were detected in mouse blood. Also determined were the levels of conjugates in rat and mouse blood. The mean level of conjugated phenol in rat blood were < 1.0, < 1.0, 1.7, 6.0 and 6.3ppm and the mean levels of conjugated phenol in mouse blood were < 1.0, 1.1, 2.9, 7.9 and 15.5ppm at exposure levels of 0, 30, 300 and 1000ppm, respectively. No conjugated catechol or hydroquinone were detected at any exposure level in rats or mice. It was concluded that there was a direct correlation between increased exposure to benzene and increased blood concentration levels of benzene and conjugated phenol. Mice exposed to 1000ppm benzene had double the concentration of conjugated phenol in the blood relative to the 300ppm mice. In contrast, this effect was not observed in rats.[Bio/dynamics Inc.; Determination of Benzene, Phenol, Catechol and Hydroquinone in the Blood of Rats and Mice After Inhalation Exposure to Benzene at Various Concentrations, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0] **UNREVIEWED**
  • The concentration of benzene and it's metabolites were determined after 12, 24, 48 and 72 hours in the urine of five exposed male Sprague Dawley rats and 25 male Swiss albino mice which received a nominal concentration of benzene at 300ppm in dynamic air flow chamber for 6 hours. No level of benzene at or above the detection limit (1.0ppm) were detected in rat and mice urine at any of the sampling intervals. The level of free phenol in the rat urine were 2.0, 2.2, 1.7 and 3.2ppm and in mouse urine were 15.6, 4.7, 5.8 and 4.3ppm at 12, 24, 48 and 72 hours, respectively. The mean levels of free catechol in rat urine were < 2.0, 0.46, 0.32 and < 2.0ppm and in mouse urine were 1.09, 1.29, 1.56 and 7.76ppm at 12, 24, 48 and 72 hours, respectively. No free hydroquinone at or above the detection limit were determined in rat urine at any sampling time. The mean levels of free hydroquinone in mouse urine were 12.87, 1.49, 1.46 and 0.31ppm at 12, 24, 48 and 72 hours, respectively. The expired air of rats was bubbled through dichloromethane and the mean total levels of benzene detected were 440.6, 101.4, not detected and 22.2ug/sampling interval ending at 6, 12, 24 and 48 hours, respectively. Benzene in expired air of mice was only detected at the 48 hour sampling interval.[Bio/dynamics Inc.; Part II: Determination of Material Balance in Rats, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0] **UNREVIEWED**
  • The in vitro percutaneous absorption of 14C-benzene was evaluated in mammalian skin samples maintain in a dynamic culture system. C3H Mice (primary test subject), HRS mice, rabbit and guinea pig (strain not specified) dorsal skin, and human skin from elective surgery were all placed in culture medium chamber for penetration analysis. 14C-Benzene (20ul) was topically applied to cultured C3H mouse skin samples and radioactivity was detected in the effluent medium 15 minutes following treatment with no apparent lag phase. Penetration was linear and the rates were 2.97 +/- 0.03 and 3.70 +/- 0.03%/hr for metabolically viable (fresh skin) and nonviable skin (frozen skin), respectively. Analysis of the effluent medium indicated negligible conversion of benzene to phenol. Different rates of in vitro skin permeation were observed between male and female C3H mice, however this difference was not observed between sexes in similar studies with hairless HRS mice. In vitro penetration of benzene in hairless mice skin (2.44 +/- 0.07%) was lower than C3H mice. Additional in vitro penetration studies with 14C-benzene (20ul) were preformed with metabolically viable guinea pig, rabbit and human skin with rates of penetration of 0.04 +/- 0.01, 0.55 +/- 0.02 and 0.23 +/- 0.04%/hr, respectively. The lag phase of these additional studies were between 45-60 minutes and two hours from application followed by linear radioactivity. Toluene and unleaded gasoline containing 14C-benzene (20ul) produced rates of permeation of 2.32 +/- 0.04 and 2.81 +/- 0.4%/hr, respectively in C3H mice which appeared linear.[Oak Ridge National Laboratory; Toxicokinetics of Percutaneo us Penetration of Petroleum Products, Draft Final Report, (no date), EPA Documen t No. FYI-AX-0685-0356, Fiche No. OTS0000356-1] **UNREVIEWED**
  • The benzene uptake rate was evaluated in five male Sprague Dawley rats and twenty five male Swiss albino mice receiving benzene at a nominal concentration of 300ppm in a dynamic air flow chamber for 6 hours. Five individual rats were determined to have an internal mean benzene uptake rate of 152ml/min prior to conducting the six hour test and an mean pretest respiratory minute volume of 145ml/min. The mean benzene uptake rates as compared to pretest values for rats decreased to 33, 22 and 9% of the mean test value 1, 3 and 6 hours after administration, respectively. The mean minute volume for rats decreased to 85, 78 and 66% of the pretest at 1, 3 and 6 hours after administration, respectively. Rats had an estimated retained dose of 56mg/kg. Mice (5/group) had a mean total pretest benzene uptake rate of 188ml/min and a mean pretest total respiratory minute volume of 189ml/min. The mean total benzene uptake for the mice decreased 65, 76 and 81% of the pretest value, after 1, 3 and 6 hours of exposure, respectively. The mean total minute volume for groups of mice decreased 96, 84 and 69% of the pretest after 1, 3 and 6 hours, respectively. The mean total retained dose per mice was estimated to be 377mg/kg.[Bio/dynamics Inc.; Part I: Determination of Benzene Uptake by the Lungs in Rats and Mice, Under Conditions of Prolonged Exposure, (no date), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0] **UNREVIEWED**
  • The dermal absorption of benzene vapor was examined in 2 Rhesus monkeys exposed to the test article at saturated concentrations for 30 minutes using a hydration controlled chamber which was held tightly against the skin of the back. The radioactivity measured in the urine was used to determined absorption rate. A correction factor was included to account for radioactivity excreted by other routes. Under the 2 skin conditions, of 40% hydration and 100% hydration, the absorption rates were determined to be 0.02 microliter/sq cm and .15 microliter/sq cm, respectively. Total absorption was found to be 7.5-fold higher from a 100% relative humidity environment than from a 40% relative humidity environment. In a benzene liquid exposure experiment, the concentration of benzene was given by its density of 0.8787 gm/cu cm and the dermal absorption was 5.4 microliter/sq cm. The authors suggested that benzene absorption from the liquid state was less than expected due to a dehydrating effect on the stratum corneum.[American Petroleum Institute; Absorption of Petroleum Products Across the Skin of Monkey and Man, Final Report, (1987), EPA Doc. No. FYI-AX-1087-0185, Fiche No. OTS0000185-1] **UNREVIEWED**

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 12/12/2012.

The NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.