National Toxicology Program

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

Names (NTP)

• Benzo(e)pyrene
• 1,2-BENZOPYRENE

Human Toxicity Excerpts

• Mortality studies have demonstrated that exposure to coke oven emissions, which contain a variety of PAHs, caused increased incidences of lung and genitourinary cancer mortality in coke oven workers ... . /Polycyclic aromatic hydrocarbons/ [DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 330 (1994)]**PEER REVIEWED**
  
• Workers exposed to creosote containing numerous PAHs developed skin tumors ... . /Polycyclic aromatic hydrocarbons/ [DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 330 (1994)]**PEER REVIEWED**
  
• Exposures to other chemical mixtures that contain PAHs, such as cigarette smoke, coal tar, coal tar pitch, and bitumens, have been associated with increased incidences of lung cancer in humans. /Polycyclic aromatic hydrocarbons/ [DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 330 (1994)]**PEER REVIEWED**
  
• Dermal exposure to coal tar and shale oils containing PAHs have been associated with increased incidences of skin tumors in humans ... . /Polycyclic aromatic hydrocarbons/ [DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 330 (1994)]**PEER REVIEWED**
  
• Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons (PAHs) alter Ca(2+) homeostasis and inhibit activation of both B and T lymphocytes obtained from rodents and humans. In the present studies, we demonstrate that a-naphthoflavone (ANF), an inhibitor of cytochrome p4501A activity, reduced the Ca(2+) elevation produced by benzo(a)pyrene in human peripheral blood mononuclear cell (HPBMC) lymphocytes. These results suggested that benzo(a)pyrene metabolites may play a role in intracellular Ca(2+) homeostasis in human lymphocytes. Reactive oxidative intermediates of benzo(a)pyrene produced in human peripheral blood mononuclear cell are known to be highly carcinogenic and have also been shown to be immunosuppressive. We examined the effects of benzo(a)pyrene (BaP), 7,12-dimethylbenz(a)anthracene (DMBA), benzo(e)pyrene (BeP), and anthracene, as well as certain benzo(a)pyrene metabolites, on the levels of intracellular Ca(2+) and glutathione in human peripheral blood mononuclear cell. While benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, benzo(e)pyrene, and anthracene did not cause a statistically significant decrease in GSH in human peripheral blood mononuclear cell at concentrations of 1 or 10 uM following a 6-, 48-, or 72-hr exposure, reactive benzo(a)pyrene metabolites including 4,5-epoxide benzo(a)pyrene and 7,8-diol-9,10-epoxide benzo(a)pyrene consistently produced a 20-30% depletion of glutathione in human peripheral blood mononuclear cell following a 6-hr treatment period. These benzo(a)pyrene metabolites also elevated intracellular Ca(2+) in human peripheral blood mononuclear cell during a 6-hr incubation. Results of these experiments suggest that metabolism of benzo(a)pyrene to certain epoxide metabolites lay be responsible for sulfhydryl damage leading to transient GSH depletion and Ca(2+) elevation. These results are consistent with the hypothesis that sulfhydryl damage by certain PAH metabolites may lead to altered Ca(2+) homeostasis, leading to inhibition of cell activation and proliferation in human peripheral blood mononuclear cell. [Romero DL et al; Toxicol and Applied Pharmacol 144 (1): 62-9 (1997)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• A single application of 1.0 mg benzo(e)pyrene in 0.1 ml acetone to the skin of 20 female ICR/Ha Swiss mice, eight weeks old, induced no tumor in an experiment lasting 64 weeks. In a similar group of mice, the same treatment was followed by repeated paintings with 25 ug croton resin in 0.1 ml acetone, 2/20 animals developed a papilloma. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 227 (1983)]**PEER REVIEWED**
  
• A group of 20 female Swiss mice [age unspecified] received applications of a 0.1% solution of benzo(e)pyrene (purity unspecified) in acetone thrice weekly by skin painting for life. Of five animals that survived 13 months after the start of treatment, two had skin papillomas and three had carcinomas. There was no survivor after 14 months. In the same study, similar or lower concentrations of benzo(a)pyrene and dibenz(a,h)anthracene given under the same experimental conditions produced more tumors: 80% papillomas and 20% carcinomas at six months with 0.1% dibenz(a,h)anthracene and 95% papillomas and 95% carcinomas at 11 months with 0.01% benzo(a)pyrene.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 227 (1983)]**PEER REVIEWED**
  
• INFLAMMATORY REACTION WAS MORE INTENSE THAN PRODUCED BY SOLVENT, OLIVE OIL, BUT NO ATYPICAL MITOSIS OR MALIGNANT CHANGES WERE FOUND IN EYES OF RATS AFTER 5-6 MO. [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 182]**PEER REVIEWED**
  
• CO-CARCINOGENESIS ON MOUSE SKIN: CARCINOGEN B(A)P, CO-CARCINOGEN & DOSE (MG) BENZO(E)PYRENE 0.005, DAYS TO 1ST PAPILLOMA 249, TOTAL NUMBER OF PAPILLOMAS 24/33, MICE WITH SQUAMOUS CARCINOMAS 9; DOSE 0.015, DAYS TO 1ST PAPILLOMA 246, TOTAL NUMBER OF PAPILLOMAS 33/79, MICE WITH SQUAMOUS CARCINOMAS 27. /FROM TABLE/ [Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976., p. 35]**PEER REVIEWED**
  
• COMPARISON OF TUMOR-PROMOTING & CO-CARCINOGENIC ACTIVITIES: BENZO(E)PYRENE, TUMOR-PROMOTING ACTIVITY QUESTIONABLE, COCARCINOGENIC ACTIVITY POSITIVE. /FROM TABLE/ [Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976., p. 37]**PEER REVIEWED**
  
• B(E)P IN MICE HAD VERY WEAK TUMORIGENIC ACTIVITY @ 252 UG/40 WK & NONE @ 100 UG. @ 100 UG TWICE/WK, INDUCED 2.1 PAPILLOMAS/MOUSE @ 30 WK, & 25% HAD CARCINOMA @ 40 WK. B(E)P WAS MODERATE TUMOR PROMOTER IN CONJUNCTION WITH DIMETHYLBENZANTHRACENE. [SLAGA ET AL; CANCER LETT 7 (1): 51-9 (1979)]**PEER REVIEWED**
  
• IN PRESENCE OF HEPATIC MICROSOMES FROM AROCLOR 1254-PRETREATED RATS OR CYTOCHROME P450-DEPENDENT MONOOXYGENASE SYSTEM PURIFIED TO NEAR HOMOGENEITY FROM THESE MICROSOMES, B[E]P WAS METAB TO PRODUCTS HAVING LITTLE OR NO MUTAGENIC ACTIVITY TOWARD S TYPHIMURIUM TA 98 & TA 100.[WOOD ET AL; J BIOL CHEM 254 (11): 4408-15 (1979)]**PEER REVIEWED**
  
• It has been observed to cause violent uveitis when injected intraocularly in oil soln in animal eyes. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 142]**PEER REVIEWED**
  
• A group of 30 female Sencar mice, seven to nine weeks old, received a single topical application of 2 umol benzo(e)pyrene (purity, >95%) in acetone, followed one week later by twice-weekly applications of 2 ug 12-O-tetradecanoyl- phorbol-13-acetate for 14 weeks. A control group of 30 animals received 12-O-tetradecanoylphorbol-13-acetate alone. At 15 weeks, the percentages of mice with skin tumors (and the numbers of papillomas/mouse) were 17 (0.2) in the treated group and 10 (0.1) in the control group. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 228 (1983)]**PEER REVIEWED**
  
• A group of 20 female CD-1-mice, eight weeks of age, received a single topical application of 10 umol benzo(e)pyrene in acetone, followed one week later by twice-weekly applications of 5 umol 12-O-tetradecanoylphorbol-13-acetate for 34 weeks. A control group of 30 mice received 12-O-tetradecanoylphorbol-13-acetate only (10 umol). Tumor incidence was 85% in the treated group, with 5.77 papillomas/mouse, whereas a 3% tumor incidence was found in control mice; this difference was statistically siginficant. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 227 (1983)]**PEER REVIEWED**
  
• Groups of 30 female CD-1 mice, seven to eight weeks old, received single applications of 1.0, 2.5 or 6.0 umol benzo(e)pyrene (purity, 99%) in 200 ul acetone containing 10% dimethyl sulphoxide, followed seven days later by twice-weekly applications of 16 nmol 12-O-tetradecanoylphorbol-13-acetate in 200 ul acetone for 25 weeks. The percentages of mice with papillomas (and the numbers of papillomas/mouse) were 15 (0.15), 11 (0.11) and 14 (0.14) in the three benzo(e)pyrene-treated groups, respectively. In the control group, which received only 12-O-tetradecanoylphorbol-13-acetate, 7% of mice had tumors with 0.07 papillomas/mouse. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 228 (1983)]**PEER REVIEWED**
  
• Groups of 30 female Charles River CD-1 mice, seven to nine weeks of age, received 100 ug benzo(e)pyrene (purity, >99%) in 0.2 ml acetone by skin application twice weekly for 30 weeks. At 30 weeks, 68% of the mice had papillomas (2.1 papillomas/mouse); and at 40 weeks, 24% of mice had carcinomas. In a group of 30 female mice of the same strain twice-weekly administration for 30 weeks of 10 ug 12-O-tetradecanoylphorbol-13-acetate by skin application resulted in papillomas in 14% of mice (0.2 papillomas/mouse); at 40 weeks no carcinoma was observed. In two other groups, 30 female mice of the same strain received a single topical application of 100 or 252 ug benzo(e)pyrene followed one week later by twice-weekly skin application of 10 ug 12-O-tetradecanoylphorbol-13-acetate for 30 weeks. With the high dose of benzo(e)pyrene 19% of mice had papillomas (0.4 papillomas/mouse) at 30 weeks and no carcinoma at 40 weeks; no activity was detected with the low dose of benzo(e)pyrene. In another group of 30 mice of the same strain, benzo(e)pyrene (100 ug twice weekly for 30 weeks) was administered one week after a single topical application of 51 ug 7,12-dimethylbenz(a)anthracene; at 30 weeks, 92% of mice had papillomas (4.5 papillomas/mouse) and at 40 weeks 45% of mice had carcinomas. No skin tumor was observed in 30 corresponding control mice treated with a single dose of 51 ug 7,12-dimethylbenz(a)anthracene. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 228 (1983)]**PEER REVIEWED**
  
• Groups of 20 female Fischer 344 rats (aged unspecified) received implants of beeswax pellets containing either 1 mg benzo(a)pyrene, 0.5 mg benzo(a)pyrene, 1 mg benzo(e)pyrene (purity unspecified), 0.5 mg benzo(a)pyrene + 1 mg benzo(e)pyrene, or 1 mg benzo(a)pyrene + 1 mg benzo(e)pyrene in tracheas from isogenic donors transplanted subcutaneously in the retroscapular region (two tracheas/animal). All surviving animals were killed 28 months after the start of exposure. Benzo(e)pyrene did not induce tumors in tracheal explants, while 1 mg benzo(a)pyrene induced carcinomas in 65% of the grafts. Benzo(e)pyrene appeared to reduce the incidence of carcinomas from 65% (benzo(a)pyrene alone) to 40% (benzo(a)pyrene plus benzo(e)pyrene). However, the incidence of sarcoma in tracheal and peritracheal explants was enhanced two- to three-fold by benzo(e)pyrene given with benzo(a)pyrene compared with benzo(a)pyrene alone. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 229 (1983)]**PEER REVIEWED**
  
• Newborn Swiss-Webster BLU:Ha (ICR) mice of both sexes were given ip injections on day 1, 8 and 15 of life, of 0.4, 0.8 and 1.6 umol benzo(e)pyrene (purity, 99%) (total dose, 2.8 umol) in dimethyl sulphoxide, respectively. Other newborn mice of both sexes were given ip injections of 0.8, 1.6 and 3.2 umol benzo(e)pyrene on the same days (total dose 5.6 umol). At the end of the experiment (62-66 weeks), 30 male and 30 female mice from the low-dose group and 25 male and 23 female mice from the high-dose group were still alive. No tumor related to the treatment was seen in any organ, including the lung and liver, in any animals from either dose group. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 229 (1983)]**PEER REVIEWED**
  
• Three groups of 30-35 female Osborne-Mendel rats, three months old, body weight 245 g, were injected directly into the lung after thoracotomy (with 0.05 ml) of a mixture of beeswax + tricaprylin (1:1) containing 0.2, 1.0 or 5.0 mg benzo(e)pyrene (purity, 99.7%) (0.8, 4.2 or 20 mg/kg bw). Three similar groups of 35 rats received 0.1, ... /0.3/ or 1.0 mg benzo(a)pyrene (positive controls); and an untreated group of 35 rats and a group of 35 rats receiving only the vehicle were also available. The rats were observed until spontaneous death; mean survival times were 117, 111, 104, 111, 77, 54, 118 and 104 weeks for the 0.2, 1.0, 5.0 mg benzo(e)pyrene-treated, the 0.1, 0.3, 1.0 mg benzo(a)pyrene- treated, the untreated and the vehicle-control groups, respectively. Pulmonary squamous-cell carcinomas were found in one of the high-dose animals treated with benzo(e)pyrene, and a pulmonary sarcoma was seen in the mid-dose group. The incidences of pulmonary carcinomas in the positive-control groups were 4/35, 21/35 and 33/35 in the low-, mid- and high-dose groups, respectively; six low-dose rats and two mid-dose rats of the positive-control groups also developed a pulmonary fibrosarcoma. No lung tumor was observed in the vehicle or untreated controls. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 228 (1983)]**PEER REVIEWED**
  
• Benzo(e)pyrene was mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. It did not induce mitotic recombination in yeast. It did not induce mutations or sister chromatid exchange in cultured mammalian cells and was negative in assays for morphological transformation. It induced unscheduled DNA synthesis in HeLa cells in the presence of an exogenous metabolic system, but not in primary rat hepatocytes. In the one available report, it did not induce chromosomal aberrations in vitro. In the one available in-vivo study, it induced sister chromatid exchange, but not chromosomal aberrations in hamster bone marrow. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 232 (1983)]**PEER REVIEWED**
  
• High levels of anti-phosphatidylinositol autoantibodies have been previously described in sera of cancer patients and in plasma of dimethylbenzanthracene treated female Sprague-Dawley rats. The presence of anti-phosphatidylinositol autoantibodies was tested in model of highly malignant sarcomas induced by a single dose of benzo(a)pyrene diluted in sesame oil and injected in female Sprague-Dawley rats. Significantly elevated levels of anti-phosphatidylinositol autoantibodies were found in sera of benzo(a)pyrene treated rats 40 days after benzo(a)pyrene administration, whereas no significant levels of anti-phosphatidylinositol autoantibodies were noted in oil or benzo(e)pyrene treated rats. After day 60, autoantibody levels plateaued in benzo(a)pyrene treated rats, and highly malignant sarcomas appeared with 100% efficiency around day 100. Anti-phosphatidylinositol autoantibodies avidity and specificity were found to be high. [Faiderbe S et al; Cancer Res 52 (10): 2862-5 (1992)]**PEER REVIEWED**
  
• The mutagenicities of cyclopenta-benzo(e)pyrene and cyclopenta(ij)benzo(a)pyrene were examined in the standard Ames tester strains, and the effects of varying the amount of S9 protein used for metabolic activation in this assay was examined. The activity of cyclopenta-benzo(e)pyrene and cyclopenta(ij)benzo(a)pyrene was compared to that of parent polycyclic aromatic hydrocarbon benzo(e)pyrene and benzo(a)pyrene in Salmonella typhimurium strains (TA-98), (TA-100), and (TA-104). Both cmpd required S9 metabolic activation, and showed optimal activity at low S9 concn. Both induced frameshift and base pair substitution mutations, being active in strains (TA-98), (TA-100), (TA-1537), (TA-1538), and (TA-104), but not in strain (TA-1535). More activity was demonstrated by cyclopenta(ij)benzo(a)pyrene than by cyclopenta-benzo(e)pyrene, and both were more potent than their parent ring systems, benzo(a)pyrene, and benzo(e)pyrene, respectively. More activity was demonstrated by cyclopenta(ij)benzo(a)pyrene in strain (TA-104) than in (TA-100) or (TA-98) as was benzo(a)pyrene. More activity was demonstrated by cyclopenta-benzo(e)pyrene in (TA-100) than (TA-104) or (TA-98) as was the case for benzo(e)pyrene. The relative potencies of the four cmpd are in accord with predictions based on perturbational molecular orbital calculations. Both derivatives exhibited higher bacterial genotoxicity than the parent, and their activity was highly dependent on the amount of S9 protein added for metabolic activation. The peak of activity at low S9 concn is consistent with epoxidation at the cyclopentafused ring being the major route of metabolic activation for both these cyclopentafused cmpd. [Ball LM et al; Mutation Research 260 (3): 271-279 (1991)]**PEER REVIEWED**
  
• Immunosuppressive effects of benzo(a)pyrene and benzo(e)pyrene were compared to those of anthracene in female B6C3F1 mice in vivo and in vitro. Mouse spleen cell cultures were treated with sheep red blood cells to produce T-dependent antibodies or with lipopolysaccharide to produce polyclonal antibodies. Cultures were then exposed to 0.0002 to 200 ug/ml of the test chemicals. In vivo, mice were sc injected daily for 14 days with 5, 20, or 40 mg/kg of the test chemicals. One day post exposure mice were sacrificed and spleen cells cultures prepared for antibody response testing. Benzo(a)pyrene and benzo(e)pyrene reduction of anti sheep red blood cells plaque forming cell responses was dose dependent. Addition of 2, 20, and 200 ug/ml benzo(e)pyrene resulted in 26, 79 and 100% inhibition. Addition of 10, 50, or 100 ug/ml anthracene reduced antibody responses to 55, 45, and 8% of vehicle treated controls. Culture viabilities were reduced only at the highest concn of benzo(a)pyrene or benzo(e)pyrene. Similar inhibition was found in polyclonal antibody responses. Benzo(e)pyrene produced 83% reduction of plaque forming cells at 20 ug/ml. Benzo(e)pyrene in vitro was more inhibitory early in the culture period; the presence of the chemicals was required during the first three days of culture for inhibition. In vivo exposure to benzo(e)pyrene for 7 or 14 days caused 48 and 51% reduction, respectively, in antibody response. It was concluded that benzo(e)pyrene significantly suppresses T-dependent and polyclonal antibody responses in vitro and affect these in vitro responses following in vivo chemical exposures. [Blanton RH et al; Cancer Research 46 (6): 2735-9 (1986)]**PEER REVIEWED**
  
• Hepa lclc7 (WT), TAOclBPrcl (CI), and BPrcl (CI) mouse hepatoma cells were exposed to benzo[e]pyrene (B[e]P) or benzo[a]pyrene (B[a]P). B[e]P induced activity of a rat CYPlAl reporter gene construct (-3015 to +2545 bp) by 1.8- to 2-fold and 5-fold in WT and CI cells, respectively. B[e]P caused a 2-fold induction of a truncated CYPlAl reporter gene construct (-658 to +2545 bp) in WT cells and induced ethoxyresorufin O-deethylase (EROD) activity by 24- and 13-fold in WT and CI cells. B[a]P also induced CYPlAl reporter gene and ethoxyresorufin O-deethylase activity in these cells. WT and CII cells had both 8S (Ah) receptor and 4S polycyclic hydrocarbon (PAH)-binding activity, while CI cells exhibited a lower 4S binding activity; 8S binding activity was not detected in CI cells under two separate binding conditions. 8S binding activity in the presence of sodium molybdate was 60-fold greater in WT cells than in CII cells. The absence of sodium molybdate resulted in a dramatic decrease of 8S binding activity in WT cells. The ability of B[e]P to induce CYPlAl promoter-reporter gene activity and ethoxyresorufin O-deethylase activity in WT and CI cells suggested a role for the 4S PAH-binding protein in the induction of CYPlAl. The lack of detectable 8S binding activity in CI cells was in concert with this role.[Sterling K et al; Toxicol Appl Pharmacol 128 (1): 18-24 (1994)]**PEER REVIEWED**
  
• UDP-glucuronosyltransferases (UGTs) are cytoprotective and may also be genoprotective. Since over 10% of the population have hereditary deficiencies in UDP-glucuronosyltransferases, this family of enzymes could constitute an important determinant of susceptibility to chemical carcinogenesis, teratogenesis, and neurodegeneration. Fibroblasts contain Phase I and II drug-metabolizing enzymes, including UDP-glucuronosyltransferases, and undergo mitosis, rendering them susceptible to xenobiotic genotoxicity associated with micronucleus formation, which is thought to reflect carcinogenic initiation. Accordingly, skin fibroblasts may provide an accessible model for elucidating genoprotective mechanisms in both animals and humans and for characterizing the potential role of UDP-glucuronosyltransferases as determinants of individual toxicological susceptibility. To test this hypothesis, the carcinogen/teratogen benzo(a)pyrene [B(a)P], or its noncarcinogenic B(e)P isomer, was incubated with cultured skin fibroblasts obtained from male RHA-J/J rats. These rats have a hereditary homozygous deficiency in bilirubin UDP-glucuronosyltransferases and demonstrate reduced xenobiotic glucuronidation, enhanced cytochrome p450-catalyzed bioactivation, covalent binding, and toxicity of acetaminophen and benzo(a)pyrene. Control fibroblasts were cultured from UGT-normal congenic homozygous male RHA-(+/+) rats and male Wistar rats. The cells were incubated with 10 uM benzo(a)pyrene or B(e)P either for assessment of micronucleus formation or for quantifying the bioactivation and covalent binding of benzo(a)pyrene and the glucuronidation of its hydroxylated metabolites. Compared to control fibroblasts incubated only with buffer, micronucleus formation was not enhanced by either DMS0 vehicle or B(e)P. In contrast, benzo(a)pyrene significantly enhanced micronucleus formation in all cells, and UDP-glucuronosyltransferase-deficient cells (RHA-J/J) had a > 2-fold higher benzo(a)pyrene-initiated micronucleus formation compared to UGT-normal cells (RHA-(+/+)) (P < 0.05). Glucuronidation of total benzo(a)pyrene metabolites was 10% lower in RHA-J/J UDP-glucuronosyltransferase-deficient fibroblasts, and the covalent binding of benzo(a)pyrene to protein, reflective of an electrophilic reactive intermediate and DNA-alkylating agent, was up to 3-fold higher in RHA-J/J UGT-deficient fibroblasts or fibroblast homogenates compared to UDP-glucuronosyltransferase-normal controls (P < 0.05). In fibroblast homogenates, addition of the UDP-glucuronosyltransferase cosubstrate UDP-glucuronic acid reduced benzo(a)pyrene covalent binding, corroborating the cytoprotective importance of UDP-glucuronosyltransferases. There was a highly significant correlation between decreasing glucuronidation of benzo(a)pyrene metabolites and increasing bioactivation and covalent binding of benzo(a)pyrene (r = -0.889; P = 0.018) in fibroblasts from RHA-J/J and RHA-(+/+) rat strains, indicating an important genoprotective role for UDP-glucuronosyltransferase. These results provide the first evidence that hereditary UDP-glucuronosyltransferase deficiencies may enhance susceptibility to chemical carcinogenesis and suggest that skin fibroblasts may provide a useful and highly sensitive model for human risk assessnent.[Vienneau DS et al; Cancer Res 55 (5): 1045-51 (1995)]**PEER REVIEWED**
  
• The mechanism of the co-carcinogenic activity of benzo[e]pyrene (BeP) was investigated by determining the effects of benzo[e]pyrene on the binding of the carcinogen benzo[a]pyrene (BaP) to DNA in Sencar mouse epidermis. The dose of benzo[a]pyrene used was 20 nmol/mouse a dose which is not carcinogenic in a single application but is carcinogenic after multiple treatments such as those in the benzo[a]pyrene-benzo[e]pyrene co-carcinogenesis experiments described by Van Duuren and Goldschmidt. After 3 hr of exposure to [3H]benzo[a]pyrene and benzo[e]pyrene at benzo[a]pyrene:benzo[e]pyrene dose ratios of 1:3 and 1:10, [3H]benzo[a]pyrene-DNA adducts in both benzo[e]pyrene-treated groups were lower than in an acetone-benzo[a]pyrene control group. After 12 and 24 hr of exposure the benzo[a]pyrene-benzo[e]pyrene (1:10 ) group contained 19% and 33% higher [3H]benzo[a]pyrene-DNA adduct levels than the control. In the benzo[a]pyrene-benzo[e]pyrene 11:3) group the amount of [3H]benzo[a]pyrene-DNA adduct levels was higher than the control after 12 hr. Benzo[e]pyrene cotreatment with either [3H]benzo[a]pyrene-7 8-dihydrodiol or anti-[3H]benzo[a]pyrene had no effect on the amount of benzo[a]pyrene DE-DNA adducts present. These results demonstrate that the cocarcinogen benzo[e]pyrene increases the amount of a low dose of benzo[a]pyrene that binds to mouse epidermal DNA and indicate that the increase in benzo[a]pyrene-DNA adducts results from increased metabolism of benzo[a]pyrene to the proximate carcinogen benzo[a]pyrene-7 8-dihydrodiol.[Lau HH, Baird WM; Cancer Lett 63 (3): 171-266]**PEER REVIEWED**
  
• Hepatic microsomes were prepared from immatture C57BL/6J mice 24 hr after receiving intraperitoneal injections of either corn oil, benzo[e]pyrene (BeP, 50 mg/kg) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 4 x 10(-3) mg/kg). The capacity of these hepatic microsomes to bioactivate aflatoxin Bl (AFBl), 2-aminoanthracene (AA), benzo[a]pyrene (BaP), 3-methylcholanthrene (MC), 7,12-dimethylbenzanthracene (DMBA), benzo[e]pyrene and pyrene (PY) was measured using strain TA100 in the Salmonella typhimurium/microsome reversion assay. Benzo[e]pyrene pretreatment of mice resulted in a 33% increase in mutagenic potency (MP) of aflatoxin Bl over the corn oil controls and a 70% increase in mutagenic potency relative to tetrachlorodibenzo-p-dioxin-pretreated microsomes. With 2-aminoanthracene, benzo[a]pyrene and 7,12-dimethylbenzanthracene as promutagens, benzo[e]pyrene pretreatment reduced mutagenic potency an average of 24%, while tetrachlorodibenzo-p-dioxin pretreatment increased mutagenic potency of these 3 promutagens 263% compared to controls. Since the general effects of BeP and tetrachlorodibenzo-p-dioxin on murine hepatic cytochrome p450 (p450)-medicated activities in this study were discordant, it appears that changes in p450 activity by benzo[e]pyrene pretreatment are not mediated through the Ah receptor.[Ma XF et al; Toxicol Lett 59 (1-3): 51-8 (1991)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• None found

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Absorption, Distribution and Excretion

• None found

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Metabolism/Metabolites

• The 4,5-dihydrodiol is the major metabolite of benzo(e)pyrene, but the 9,10-dihydrodiol has also been detected as a minor product following incubation of benzo(e)pyrene with a rat liver preparations. Glucuronic acid conjugates of 3-hydroxy-benzo(e)pyrene and of the 4,5-dihydrodiol have been reported in hamster embryo cells. The formation of the 4,5,9,10-tetraol and the 9,10,11,12-tetraol as well as unidentified phenols from the precursor 9,10-dihydrodiol have also been reported using hepatic microsomal preparations from various species including humans. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 229 (1983)]**PEER REVIEWED**
  
• THE MAJOR ORGANIC SOLVENT SOL METABOLITE FORMED IN EXTRACELLULAR MEDIUM AFTER 24 HR OF CULTURE (HAMSTER EMBRYO CELLS) WITH B[E]P WAS K-REGION DIHYDRODIOL 4,5-DIHYDRO-4,5-DIHYDROXYBENZO[E]PYRENE & SMALL AMT MONOHYDROXYBENZO[E]PYRENES.[MACLEOD ET AL; CANCER RES 39(9) 3463-70 (1979)]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.