National Toxicology Program

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

Names (NTP)

• Benzo(a)pyrene
• 3,4-BENZOPYRENE

Human Toxicity Excerpts

• PERSISTENT NODULE ... DIAGNOSED AS SQUAMOUS EPITHELIOMA DEVELOPED IN A MAN WHO HAD BEEN EXPOSED TO B(A)P FOR 3 WK WHILE HE WAS CARRYING OUT AN EXPERIMENT IN 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)., p. V3 115 (1973)]**PEER REVIEWED**
  
• CULTURES OF HUMAN EPIDERMAL CELLS EXHIBIT TOXIC RESPONSE IN PRESENCE OF B(A)P, SUGGESTING THAT CELLS POSSESS MICROSOMAL ARYL HYDROLASE SYSTEM WHICH IS CAPABLE OF CONVERTING THE HYDROCARBON INTO A TOXIC METABOLITE. [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. V3 114 (1973)]**PEER REVIEWED**
  
• IN CELL TRANSFORMATION STUDIES, 3,4-BENZOPYRENE WAS SLIGHTLY POSITIVE IN THE ACTIVATED HUMAN WI-38 TEST & PRACTICALLY NEGATIVE IN THE NON-ACTIVATED /TEST/ ... [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3364]**PEER REVIEWED**
  
• A 1% soln of benzo(a)pyrene in benzene was applied daily to protected & unprotected surfaces of skin of 26 patients suffering from pemphigus vulgaris, mycosis fungoides, prokeratosis, xeroderma pigmentosum, basal cell cancer, squamous cell cancer, lupus erythematosis, psoriasis, syphilis in various stages or ringworm. The period of application did not exceed 4 mo, & diameter of treated area was 2 cm. A progressive series of alterations developed in normal skin (chronically): erythema, pigmentation, desquamation, formation of verrucae, /clinically not true verrucae/ & infiltration. The manifestations regressed completely within 2 to 3 mo of cessation of treatment. Clinically, perceptible erythema occurred in only 2 patients with basal cell cancer. Pigmentation, which occurred in all patients, consisted of an increase in melanin in basal cell layer of epidermis & was more evident in exposed skin (eg, hand, face). It developed more readily in skin of senile individuals than in younger patients. Rarely, small masses of pigment granules were found in the more superficial layers. Desquamation was proportional in extent to erythema of the 1st stage. The formation of verrucae was the most constant manifestation caused by treatment. The skin of patient with xeroderma pigmentosum did not react differently ... from that of other patients. [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 216 (1983)]**PEER REVIEWED**
  
• Human bronchial mucosa treated with benzo(a)pyrene in organ culture showed destruction of all cell types & distortion of columnar cell morphology but not of regenerative epithelium. [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 216 (1983)]**PEER REVIEWED**
  
• The effects of B(a)P on ... human fetal lung ... /cultures have been observed to produce/ epithelial hyperplasia & inhibition of connective tissue growth. [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 214 (1983)]**PEER REVIEWED**
  
• A previously reported case-referent study of 85 cases of bladder cancer among aluminum smelter workers and 255 matched referents revealed an excess risk among workers exposed to coal tar pitch volatiles. For the study reported in the present investigation these data have been augmented by estimates of past workplace exposure to total tar (benzene soluble matter) and to benzo(a)pyrene (BaP). From these new data, exposure-response relationships have been estimated by maximum likelihood. A linear relationship between cumulative exposure and relative risk and a minimum latency period of ten years were assumed ... and found compatible with the data. Under these assumptions, relative risk increased for each year of exposure to benzene-soluble matter at a concentration of 1 mg/cu m by 13%, the 95% confidence interval being 5-31. The corresponding figure for BaP (as micrograms/cu m X year) was 2.3%. On the basis of these estimates, 40 years of exposure to benzene-soluble matter at the current exposure limit of 0.2 mg/cu m would lead to a relative risk of 2.4. [Armstrong BG et al; Scand J Work Environ Health 12 (5): 486-93 (1986)]**PEER REVIEWED**
  
• Workers in coke oven plants have a higher incidence of lung cancer than the general population. They are exposed to a variety of chemicals, in particular the polycyclic aromatic hydrocarbons (PAH), including benzo(a)pyrene. To evaluate the genotoxic effects of PAH exposure, air samples and urine samples were analyzed for PAH by capillary gas chromatography and high-performance liquid chromatography, respectively. Since benzo(a)pyrene is activated to 7-beta,8-alpha-dihydroxy-(9- alpha,10-alpha)-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) and binds to DNA, we have used ultrasensitive enzymatic radioimmunoassay and synchronous fluorescence spectrophotometry to measure BPDE-DNA adducts in lymphocyte DNA. The mean PAH exposure levels are reduced 60% when the workers wore masks during work. When compared to exposure levels, the urinary excretion of PAH was relatively low. Approximately one-third of the workers had detectable putative BPDE-DNA adducts in lymphocytes by ultrasensitive enzymatic radioimmunoassay, and 10% of the samples had emission peaks at 379 nm by synchronous fluorescence spectrophotometry. The four most positive samples were the same in both of the assays. Antibodies to an epitope(s) on BPDE-DNA were found in the sera of approximately one-third of the workers. Detection of DNA adducts and antibodies to these adducts are internal indicators of exposure to benzo(a)pyrene. [Haugen A et al; Cancer Res 46 (8): 4178-83 (1986)]**PEER REVIEWED**
  
• Serum was taken from male human subjects (age 20-40 years) and the uptake /during in vitro incubation/ of (14)C-benzo(a)pyrene (B(a)P) and subsequent extraction of bound B(a)P was determined by radio-scintillation techniques. The initial uptake velocity for B(a)P by human (60 ug/ml x hr) was similar to that of rat serum for all concentrations of B(a)P used. Maximum uptake of B(a)P was estimated at 230 ug/ml for human serum. Gel filtration of human serum containing (14)C-B(a)P revealed that 80% was associated with low-density lipoproteins (LDL), 15% with high-density lipoproteins (HDL), and 5% with albumin. B(a)P binding at concentrations up to and including 50 ug B(a)P/ml was not saturable. In human serum the highest amount of bound B(a)P was associated with LDL (44-47%) and HDL (32-35%) components. [Aarstad K et al; Toxicology 47 (3): 235-45 (1987)]**PEER REVIEWED**
  
• Benzo(a)pyrene constitutes ... between 1 and 20% of the total carcinogenic polycyclic aromatic hydrocarbons found in water. [Health & Welfare Canada; Polycyclic Aromatic Hydrocarbons p.1 (1979) Report No. 80-EHD-50]**PEER REVIEWED**
  
• Epidemiologic evidence suggests that workers intimately exposed to the products of combustion or distillation of bituminous coal are at an increased risk for cancers of the skin, respiratory tract, bladder, and kidney. /Coal tar pitch volatiles/ [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 2]**PEER REVIEWED**
  
• ... Human tissues are most active in metabolizing B(a)P, exhibiting at least a threefold higher covalent binding to DNA than hamsters, dogs, monkeys, or rats. [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. 128]**PEER REVIEWED**
  
• ...NUMEROUS CARCINOGENS OF ELECTROPHILIC REACTANT TYPE...BIND TO DNA. ... WITH...B(A)P, THROUGH ITS ACTIVATED FORM, 7,8-DIHYDRODIOL-9,10-EPOXIDE, /ALKYLATION/ REACTION IS THRU 10 CARBON...TO THE 2-AMINO POSITION IN GUANYLIC ACID. IN ADDN, THERE ARE MINOR INTERACTIONS WITH OTHER PURINES & PYRIMIDINES... /BENZO(A)PYRENE/ [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 114]**PEER REVIEWED**
  
• 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 have shown that polycyclic aromatic hydrocarbons (PAHs) mobilize intracellular Ca2+ in human T cells by inositol trisphosphate-dependent mechanisms resulting from activation of phospholipase C-gamma by SRC-related protein tyrosine kinases, thereby mimicking antigen-receptor activation. Ca2+ appears to play an important second messenger role in growth factor control of cell proliferation in human mammary epithelial cells (HMEC) such as the epidermal growth factor receptor pathway. The purpose of the present studies was to determine if polycyclic aromatic hydrocarbons are able to increase intracellular Ca2+ in primary cultures of human mammary epithelial cells and increase cell proliferation. Two carcinogenic and two non-carcinogenic polycyclic aromatic hydrocarbons were tested for their ability to increase intracellular Ca2+ in human mammary epithelial cells. The carcinogenic polycyclic aromatic hydrocarbons dimethylbenz(a)anthracene (DMBA) and benzo[a] pyrene (BaP) were able to cause Ca2+ elevation in human mammary epithelial cells at early time points (2 hr) and caused sustained alterations in Ca2+ homeostasis (18 hr). Dimethylbenz(a)anthracene showed maximal effects at early time points (2 hr), while benzo(a)pyrene showed maximal effects on sustained Ca2- (18 hr). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent dioxin and tumor promoter, produced maximal Ca2+ elevation at 2 hr, with a return to near baseline levels by 6 hr. The non-carcinogenic polycyclic aromatic hydrocarbons benzo[e]pyrene and anthracene did not significantly alter intracellular Ca2+ at any time point. alpha-Naphthoflavone significantly reduced the Ca2+ response induced by benzo(a)pyrene treatment, but not by dimethylbenz(a)anthracene or 2,3,7,8-Tetrachlorodibenzo-p-dioxin, suggesting that p450 lA or lB metabolism of benzo(a)pyrene may be important in the sustained Ca2+ elevating response. In evaluating the effects of benzo(a)pyrene on human mammary epithelial cells proliferation, benzo(a)pyrene was found to increase the number of cells recovered after 4 days in culture in the absence or presence of various concentrations of epidermal growth factor. These studies provide initial evidence that Ca2+ signaling may be associated with mitogenesis in human mammary epithelial cells, which may play a role in tumor promotion and progression produced by polycyclic aromatic hydrocarbons.[Tannheimer SL et al; Carcinogenesis 18 (6): 1177-82 (1997)]**PEER REVIEWED**
  
• The relative contributions of biologic and environmental factors on embryo-fetal development were elucidated in a population of pregnant women who were exposed to varying amounts of active cigarette smoke and women who were not exposed to cigarette smoke. The neonatal weight at birth, placental weight at delivery, duration of pregnancy, and placental xenobiotic (polynuclear aromatic hydrocarbon, PAH) metabolism potential were assessed in this population. The overall metabolic capability in exposed and unexposed placental tissue was measured by in vitro assays using microsomes and a polynuclear aromatic hydrocarbon substrate, benzo[a]pyrene (B[a]P). Toxicity potential was determined by benzo[a]pyrene-metabolite-DNA adduct generation under the same incubation condition. Cigarette smoke exposure increased the overall polynuclear aromatic hydrocarbon metabolism potential in placental tissues by approximately 200% (nonsmoker 176.2 + or - 33.6, n = 25; smoker 524.5 + or - 75.5, n = 32 pmol/mg protein) whereas polynuclear aromatic hydrocarbon-DNA adduct formation potential did not increase significantly over the basal level (nonsmoker 5002 + or - 830, n = 15; smoker 6172 + or - 1443, n = 22 fmol benzo[a]pyrene equivalent/umol DNA/mg protein). Exposure to cigarette smoke during pregnancy is deleterious to fetal development as reflected by reduced neonatal weight at birth. In contrast, placental weight reduction is indistinct, but placentae expressed markedly augmented overall xenobiotic (PAH) metabolism capability in response to cigarette smoke exposure during pregnancy, indicating placental metabolism may be an important mediator of adverse effects induced by such xenobiotic exposure.[Sanyal MK et al; Reprod Toxicol 8 (5): 411-8 (1994)]**PEER REVIEWED**
  
• Polycyclic aromatic compounds (PAC) are ubiquitous pollutants in urban air that may pose risks to human health. In order to better assess the health risks associated with this class of compounds, a total of 67 polycyclic aromatic compounds that either have been identified (55) or are suspected to be present (12) in urban aerosol samples were tested for mutagenicity in a forward mutation assay based on human B-lymphoblastoid cells. The cell line used (designated hlAlv2) constitutively expresses the cytochrome p4501Al, which is known to be necessary for the metabolism of many promutagens. The polycyclic aromatic compounds tested included 39 polycyclic aromatic hydrocarbons (PAH), 19 oxygen-containing polycyclic aromatic hydrocarbons (oxy-PAH) and nine NO2-substituted polycyclic aromatic hydrocarbons (nitro-PAH). A total of 26 polycyclic aromatic hydrocarbons were mutagenic. In comparing the minimum mutagenic concentrations of the mutagenic polycyclic aromatic hydrocarbons with that of benzo(a)pyrene (B[a]P) it was found that dibenzo(a,l)pyrene (DB(al)P), cyclopenta(c,d))pyrene (CPP), naphtho(2,1-a)pyrene, dibenzo(a,e)pyrene (DB(ae)P) and l-methylbenzo(a)pyrene were 24 + or - 21, 6.9 + or - 4.2, 3.2 + or - 3.0, 2.9 + or - 2.9 and 1.6 + or - 1.4 times, respectively, more mutagenic than benzo(a)pyrene, and that dibenzo(a,k)fluoranthene and benzo(a)pyrene were approximately equally mutagenic. The 19 other mutagenic polycyclic aromatic hydrocarbons were between tested only phenalenone, 7H-benz(d,e)anthracen-7-one, 3-nitro-6H-dibenzo(b,d)pyran-6-one, cyclopenta(c,d)pyren-3(4H)-one, 6H-benzo(c,d)pyren-6-one (BPK) and anthanthrenequinone were mutagenic; however, with the exception of 6H-benzo(c,d)pyren-6-one, these were over 50 times less active than benzo(a)pyrene. 6H-benzo(c,d)pyren-6-one was benzo(a)pyrene. Seven of the nitro-polycyclic aromatic hydrocarbons were mutagenic including 9-nitroanthracene, l-nitrofluoranthene, 3-nitrofluoranthene, 1,3-dinitropyrene, 1,6-dinitropyrene (1,6-DNP) and 1,8-dinitropyrene. 1,6-dinitropyrene wasnic nitro-polycyclic aromatic hydrocarbons were between 20 and 380 times less active than benzo(a)pyrene. These results are discussed in terms of their relevance for determining the most important mutagens in ambient air. Based on reported concentrations of polycyclic aromatic compounds in ambient aerosols, it is possible that cyclopenta(c,d))pyrene, dibenzo(a,e)pyrene, dibenzo(a,l)pyrene and 6H-benzo(c,d)pyren-6-one could account for a greater proportion of the mutagenicity than benzo(a)pyrene in some aerosols.[Durant JL et al; Mutation Research 371 (3-4): 123-57 (1996)]**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 great amount of literature exists which conclusively demonstrates the carcinogenicity of BaP. In all animal species tested to date (mouse, rat, hamster, rabbit, guinea pig, duck, newt, dog, monkey) and in fish, BaP has proven carcinogenic. BaP acts locally, as evidenced by tumor development at the site of administration. BaP also acts systemically, however, an action best evidenced by pulmonary adenomas in mice resulting from any route of administration. Because BaP is a procarcinogen, potency is directly dependent upon the levels of activation enzymes (ie P450s, sulfotransferases); therefore, carcinogenic potency is exceptionally species- and condition-specific. [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. 125]**PEER REVIEWED**
  
• Marked differences in toxic effects of B(a)P have been reported in different strains of mice depending on ... genetic constitution. The Ah locus, which determines inducibility of aryl hydrocarbon hydroxylase, appears to be of particular importance. ... Oral admin of about 120 mg/kg body wt B(a)P per day with diet induced aplastic anemia in nonresponsive (poorly inducible) AKR/N mice (Ah(d)/Ah(d) type) & death within 4 weeks, whereas responsive (markedly inducible) mice (Ah(b)/Ah(b) type) remained healthy for at least 6 months. In former, bone marrow was hypocellular with myeloid precursors & promegakaryocytes. When B(a)P was injected ip (500 mg/kg body wt) instead of being given orally (120 mg/kg body wt), survival time of responsive mice (Ah(b)/Ah(b) type) was ... significantly shorter than that of nonresponsive mice (Ah(d)/Ah(d) type). These differences may be explained in part by the greater capacity of bowel & liver of responsive mice to detoxify an orally admin dose of B(a)P metabolically. However, if the hydrocarbon reaches bone marrow & other distal tissues in responsive mice, it is metabolized to toxic metabolites to a greater extent. [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 214 (1983)]**PEER REVIEWED**
  
• Ip admin of single doses of 10 mg B(a)P produced immediate & sustained reduction in growth rate of young rats. [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 214 (1983)]**PEER REVIEWED**
  
• The effects of B(a)P on organ cultures of rat trachea, ... have been reported. Consistent findings in rat trachea were suppression of mesenchyme, stimulation of basal-cell replication & induction of metaplasia. ... When B(a)P (in beeswax pellet) was implanted into isogenically transplanted rat trachea, persistent hyperplasia & metaplasia were observed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V32 214 (1983)]**PEER REVIEWED**
  
• A single topical application of 0.05 ml of 1% soln of B(a)P in acetone to the interscapular area of hairless mice (hr/hr) induced an increase in the mitotic rate of epidermal cells. [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 214 (1983)]**PEER REVIEWED**
  
• NO STOMACH TUMORS WERE FOUND AT END OF 110-DAY TREATMENT WITH DIETS CONTAINING UP TO 30 PPM B(A)P. TUMOR INCIDENCES LOWER THAN 10% WERE OBSERVED IN MICE RECEIVING 40-45 PPM FOR 110 DAYS, WHEREAS MICE BEARING STOMACH TUMORS EXCEEDED 70% AMONG THOSE GIVEN 50-250 PPM B(A)P FOR 122-197 DAYS. [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. V3 103 (1973)]**PEER REVIEWED**
  
• SINGLE INTRAGASTRIC ADMIN OF 0.2 MG/MOUSE IN POLYETHYLENE GLYCOL PRODUCED TOTAL OF 14 TUMORS /IN FORESTOMACH/ IN 5 /OF 11/ ANIMALS ... TUMORS APPEARED FOLLOWING SINGLE DOSES OF 0.05 & 0.012 MG/MOUSE IN 0/9 & 2/10 MICE. DIET CONTAINING 250 PPM B(A)P FED FOR DIFFERENT PERIODS OF TIME PRODUCED THE FOLLOWING INCIDENCES OF TUMORS OF FORESTOMACH: 1 DAY OF FEEDING, 0%; 2-4 DAYS OF FEEDING, 10%; 5-7 DAYS OF FEEDING, 30-40%; 30 DAYS OF FEEDING, 100%. IN SUBSEQUENT EXPERIMENT, DIET CONTAINING 250 PPM ... FED 140 DAYS TO MICE OF SAME STRAIN STARTING AT 18-30 DAYS OF AGE ... PRODUCED LEUKEMIAS & LUNG ADENOMAS IN ADDN TO STOMACH TUMORS. THE ABILITY OF B(A)P TO PRODUCE LUNG ADENOMAS WHEN ADMIN IN DIET WAS CONFIRMED IN ANOTHER STUDY. [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. V3 102 (1973)]**PEER REVIEWED**
  
• SINGLE ORAL ADMIN OF 100 MG B(A)P TO 50-DAY-OLD FEMALE SPRAGUE-DAWLEY RATS PRODUCED MAMMARY TUMORS IN 8 OF 9 ANIMALS. IN ANOTHER STUDY WITH SPRAGUE-DAWLEY RATS OF BOTH SEXES AGED 3.5 MO AT BEGINNING OF EXPT, DAILY DOSES OF 2.5 MG B(A)P PER RAT INDUCED PAPILLOMAS IN ESOPHAGUS & FORESTOMACH IN THREE OUT OF 40 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)., p. V3 103 (1973)]**PEER REVIEWED**
  
• BI-WEEKLY ADMIN OF 2-5 MG B(A)P IN OIL BY STOMACH TUBE PRODUCED 5 PAPILLOMAS OF STOMACH IN 67 HAMSTERS TREATED FOR 1-5 MONTHS, 7 PAPILLOMAS & 2 CARCINOMAS IN 18 TREATED FOR 6-9 MONTHS & 5 PAPILLOMAS IN 8 TREATED FOR 10-11 MONTHS. IN SUBSEQUENT EXPT WITH 13 HAMSTERS, A DIET CONTAINING 500 PPM B(A)P GIVEN FOR 4 DAYS/WK FOR UP TO 14 MONTHS CAUSED TOTAL OF 12 TUMORS (2 IN ESOPHAGUS, 8 IN FORESTOMACH & 2 IN INTESTINE) IN 8 HAMSTERS. [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. V3 104 (1973)]**PEER REVIEWED**
  
• ... DOSE-RESPONSE STUDIES, INCL A NO-EFFECT DOSE LEVEL ... INDICATE THAT THE THRESHOLD DOSE IS AFFECTED BY THE STRAIN OF MOUSE & THE SOLVENT CHOSEN. THREE WEEKLY APPLICATIONS OF B(A)P IN ACETONE TO CAF1 MICE INDUCED NO SKIN TUMORS AT CONCN OF 0.0005%, TOTAL OF 6 PAPILLOMAS & 2 CARCINOMAS AMONG 19 MICE AT CONCN OF 0.001% & INCREASING INCIDENCE OF BENIGN & MALIGNANT TUMORS WITH PROGRESSIVELY SHORTER LATENT PERIODS AT HIGHER DOSES. IN SWISS & C57BL MICE, TUMORS WERE NOT INDUCED AT CONCN OF 0.001% OR LESS, WHEREAS INCIDENCES APPROACHING 100% WERE FOUND AT 0.005% OR HIGHER CONCN. [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. V3 104 (1973)]**PEER REVIEWED**
  
• ... /In dose-response study/ toluene was used as solvent & SWR, C3HeB & A/He mice were painted 3 times weekly with different amounts of B(a)P. In SWR & C3HeB mice the lowest effective dose was 0.38 ug B(a)P per application, with an obvious dose-response relationship above this dose for both percentage of tumor-bearing animals & the shortening of latent period; doses of 0.15 ug were ineffective. On the other hand, in A/He mice, paintings with 0.15 to 3.8 ug B(a)P were ineffective, whereas tumors were induced following doses of 19 ug or more. With acetone as solvent & using Swiss mice, borderline activity was detected following 3 times weekly painting with 0.1 to 1.0 ug B(a)P, while tumors appeared with 3 ug & above. [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. V3 104 (1973)]**PEER REVIEWED**
  
• ... SEVEN /SKIN/ PAPILLOMAS & FOUR CARCINOMAS /WERE PRODUCED/ AMONG 15 RATS PAINTED WEEKLY WITH 0.5 TO 1% SOLN OF B(A)P IN BENZENE /IN EXPT LASTING 150 DAYS. [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. V3 106 (1973)]**PEER REVIEWED**
  
• BI-WEEKLY PAINTINGS WITH A 0.01% SOLN OF B(A)P IN ACETONE FOR 40 DAYS DID NOT PRODUCE SKIN TUMORS AMONG 10 SYRIAN GOLDEN HAMSTERS. A TOTAL OF 8 APPLICATIONS OF 4 DROPS OF 0.8% SOLN IN MINERAL OIL PRODUCED 1 MELANOMA AMONG 25 SURVIVORS AT 33 WEEKS. [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. V3 106 (1973)]**PEER REVIEWED**
  
• TWICE-WEEKLY PAINTING WITH 0.3% SOLN OF B(A)P IN BENZENE FOR 400 DAYS PRODUCED 1 CARCINOMA & 10 PAPILLOMAS AMONG 10 RABBITS. THIS RESULT HAS BEEN CONFIRMED REPEATEDLY ... SOME EVIDENCE OF DOSE-RESPONSE RELATIONSHIP ... /COMES/ FROM STUDY ON SMALL GROUPS OF RABBITS PAINTED 5 TIMES WEEKLY WITH CONCN OF B(A)P IN ACETONE RANGING BETWEEN 0.0001% & 0.5%: TUMORS APPEARED FOLLOWING APPLICATION OF ... 0.005% OR MORE. [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. V3 107 (1973)]**PEER REVIEWED**
  
• ... ONE OR 5 INTRATRACHEAL ADMIN OF 100 MG B(A)P TO 8 RATS PRODUCED AT LEAST 3 LUNG TUMORS. ... 10 MONTHLY INTRATRACHEAL INJECTIONS OF EITHER 0.0005, 0.002, 0.01, 0.05, 0.25, OR 2.5 MG B(A)P MIXED WITH BLOOD SUBSTITUTE, BK-8, & INDIA INK WERE ... /OBSERVED/ FOR 2 YR. NO LUNG TUMORS WERE FOUND AT 2 LOWEST CONCN ... AT HIGHER DOSAGES PERCENTAGES OF ANIMALS DEVELOPING LUNG TUMORS WERE, RESPECTIVELY, 14%, 28%, 43%, & 80% . [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. V3 107 (1973)]**PEER REVIEWED**
  
• SEVERAL DOSE-RESPONSE STUDIES ARE AVAIL, SOME ... PERMIT COMPARISON WITH OTHER CARCINOGENS TESTED UNDER SAME CONDITIONS IN SAME LAB. ... ON INDUCTION OF LOCAL SARCOMAS FOLLOWING SINGLE INJECTIONS OF B(A)P IN TRICAPRYLIN, NO TUMORS WERE FOUND FOLLOWING DOSES OF 0.031 MG OR LESS, WHEREAS 4 OF 20 C3H MICE DEVELOPED TUMORS WITH 0.062 MG, HIGHER TUMOR INCIDENCES ... FOLLOWING GREATER DOSES. THE THRESHOLDS OF CARCINOGENICITY FOR 3-METHYLCHOLANTHRENE (MC) & DIBENZ(A,H)ANTHRACENE (DB(A,H)A) IN THE SAME EXPT WERE, RESPECTIVELY, 0.0078 & 0.0019 MG. ... AVG MINIMAL LATENT PERIODS WERE 3 MONTHS FOR B(A)P, 2.5 MONTHS FOR MC & 3.7 MO FOR DB(A,H)A. [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. V3 109 (1973)]**PEER REVIEWED**
  
• INDUCTION OF HEPATOMAS &/OR LUNG ADENOMAS & OCCASIONAL TUMORS AT OTHER SITES IN MICE OF DIFFERENT STRAINS WAS RECORDED FOLLOWING ADMIN OF B(A)P DURING FIRST DAYS OF LIFE AT DOSES OF 20-40 UG/MOUSE IN DIFFERENT SOLVENTS. [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. V3 110 (1973)]**PEER REVIEWED**
  
• WEEKLY IP INJECTIONS OF 2 MG B(A)P AS COLLOIDAL SUSPENSION IN WATER TO 80 ST/A MICE INDUCED ABDOMINAL FIBROSARCOMAS IN 81% OF 40 FEMALES & 73% OF 40 MALES WITH AVERAGE LATENT PERIOD OF 33 WK. [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. V3 112 (1973)]**PEER REVIEWED**
  
• SINGLE IP ADMIN OF 10 MG B(A)P PRODUCED 2 MAMMARY & 2 UTERINE CARCINOMAS AMONG 10 WISTAR RATS WITHIN 1 YR, WHEREAS NO MAMMARY TUMORS WERE FOUND IN 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. V3 112 (1973)]**PEER REVIEWED**
  
• A DOSE OF 39 MG/KG IN LIPID EMULSION GIVEN IV TO 50-DAY-OLD FEMALE SPRAGUE-DAWLEY RATS INDUCED MAMMARY CARCINOMAS IN NINE OF 30 ANIMALS WITHIN 98 DAYS. [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. V3 112 (1973)]**PEER REVIEWED**
  
• AT ORAL DOSES EST TO BE BETWEEN 6-12 MG/KG BODY WT/DAY, LEUKEMIA DEVELOPED 100 OR MORE DAYS LATER IN NONRESPONSIVE AHD/AHD HOMOZYGOUS MOUSE BUT NOT IN RESPONSIVE AHB/AHD HETEROZYGOTE. AN EXCESS OF DIETARY ALPHA-NAPHTHOFLAVONE (ANF) 20 TIMES GREATER THAN THE AMT OF B(A)P PREVENTED THESE HEMATOPOIETIC NEOPLASMS. ANF-SENSITIVE METABOLISM OF B(A)P PRESUMABLY CYTOCHROME P1-450 IN THE BONE MARROW OF AHD/AHD INDIVIDUALS MAY BE RESPONSIBLE FOR CAUSING THE LEUKEMIA. [NEBERT DW, JENSEN NM; BIOCHEM PHARMACOL 28 (1): 149-52 (1979)]**PEER REVIEWED**
  
• TO IMPROVE AMES CHEM CARCINOGEN SCREENING TEST, SEVERAL SPECIES OF ANIMALS, INCL RATS, MICE, GUINEA PIGS, HAMSTERS, & RABBITS, WERE PRETREATED WITH POLYCHLORINATED BIPHENYL (PCB), 3-METHYLCHOLANTHRENE (3-MC) & PHENOBARBITAL (PB) & TESTED FOR THE EFFECTS OF THE INCREASE OF REVERTANTS COLONIES OF SALMONELLA TYPHIMURIUM TA98 & TA100. AMONG 12 STRAINS OF 5 MAMMALIAN SPECIES, S-9 FRACTION FROM PCB-TREATED HARTLEY GUINEA PIGS PROVED MORE EFFECTIVE THAN THAT FROM PCB-TREATED SD RATS IN DETECTING 3 DIFFERENT TYPES OF MUTAGENS WHICH INCLUDED B(A)P. [SUZUKI H ET AL; J PESTIC SCI (NIHON NOYAKUGAKU KAISHI) 2 (4): 421-6 (1977)]**PEER REVIEWED**
  
• ... STERILITY /WAS OBSERVED/ IN FEMALE /OFFSTRING OF/ MICE EXPOSED TO 40-160 MG/KG ON GESTATION DAYS 7-16. [Shepard, T.H. Catalog of Teratogenic Agents. 4th ed. Baltimore, MD: Johns Hopkins University Press, 1983., p. 52]**PEER REVIEWED**
  
• ... A dose of 5 mg/day SC to pregnant rats, can cause death of all fetuses. ... Oral admin of 10 mg/kg body wt B(a)P to CD-1 mice during pregnancy resulted in marked & specific reduction of gonadal wt but had no effect on body wt of ... male or female offspring. Reduction in fertility & reproductive capacity occurred. With 40 mg/kg body wt/day ... almost complete sterility was observed in offspring of both sexes. [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 214 (1983)]**PEER REVIEWED**
  
• IP admin of 100-150 mg/kg body wt B(a)P to C3H/Anf mice in mid- or late pregnancy results in marked & persistent suppression of the immune system in the offspring. Application of B(a)P to skin of pregnant mice (strain unspecified) over 4 generations resulted in sensitization of the offspring to the effects of B(a)P, so that an increase in rate of appearance of papillomas & carcinomas was observed following skin application to offspring over that in control mice that had not been treated in utero. [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 215 (1983)]**PEER REVIEWED**
  
• THREE SC OR IP INJECTIONS TO ICR/HA MICE OF 2-4 MG B(A)P AT 11TH, 13TH & 15TH DAY OF PREGNANCY RESULTED IN INCR INCIDENCE OF LUNG ADENOMAS & INITIATION OF SKIN CARCINOGENESIS IN OFFSPRING. FOSTER NURSING DID NOT ALTER THESE EFFECTS. [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. V3 113 (1973)]**PEER REVIEWED**
  
• Transplacental carcinogenesis has ... been shown in rabbits. [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 215 (1983)]**PEER REVIEWED**
  
• ... /AMONG RATS FED/ 1 MG /B(A)P/ PER G OF DIET DURING PREGNANCY ... MANY RESORPTIONS & DEAD FETUSES /WERE OBSERVED,/ BUT ONLY ONE MALFORMED FETUS /WAS NOTED/ FROM 7 LITTERS. [Shepard, T.H. Catalog of Teratogenic Agents. 4th ed. Baltimore, MD: Johns Hopkins University Press, 1983., p. 52]**PEER REVIEWED**
  
• OOCYTE DESTRUCTION BY POLYCYCLIC HYDROCARBONS REQUIRES DISTRIBUTION OF THE PARENT HYDROCARBON TO THE OVARY WHERE OVARIAN ENZYMES METABOLIZE THE COMPOUND TO REACTIVE INTERMEDIATES RESPONSIBLE FOR OVOTOXICITY. DESCRIPTIVE ASSAYS OF POLYCYCLIC HYDROCARBON METABOLIC ACTIVATION SUCH AS THE ARYL HYDROCARBON (BENZO(A)PYRENE) HYDROXYLASE ASSAY ARE NOT GOOD PREDICTORS OF STRAIN OR SPECIES DIFFERENCES IN SENSITIVITY TO POLYCYCLIC HYDROCARBON OVOTOXICITY. USING BENZO(A)PYRENE AS A PROBE OF OVARIAN METABOLIC PROCESSING SUGGESTS THAT THE RATE OF FORMATION OF METABOLITES ALONG THE METABOLIC PATHWAY TO THE 7,8-DIHYDRODIOL-9,10-EPOXIDE MAY BE THE APPROPRIATE MEASURE OF THE ROLE OF METABOLIC ACTIVATION IN STRAIN OR SPECIES DIFFERENCES IN SENSITIVITY TO OOCYTE DESTRUCTION IN RATS & MICE. [MATTISON DR ET AL; PROG CLIN BIOL RES 117: 191-202 (1983)]**PEER REVIEWED**
  
• ... The in-utero toxicity in relation to the allelic differences at the Ah locus in mice /was studied/. A dose of 50-300 mg/kg was given ip on days 7 or 10. ... the Ah genotype of individual fetuses /was identified/ by measurement of AHH inducibility & ... /showed/ that when the mothers were Ah nonresponsive, the fetuses with Ah responsive genotype showed decreased body wt & higher resorption & malformation rates while Ah nonresponsive fetuses in the same uterus did not. The type of defect included mainly club foot, hemangioma, cleft lip, & cleft palate. All of these defects tend to be assoc with late organogenesis. ... using the same general protocol & 150 or 300 mg/kg on day 8 /another study/ confirmed the findings of ... toxicity (reduced fetal wt & incr resorptions) but ... not ... the same increase in malformations. ... only an increase in cervical ribs ... /which/ occurred among fetuses from Ah responsive mothers /was found/. [Shepard, T.H. Catalog of Teratogenic Agents. 4th ed. Baltimore, MD: Johns Hopkins University Press, 1983., p. 52]**PEER REVIEWED**
  
• THE CARCINOGENIC POTENTIAL IN NONHUMAN PRIMATES (MONKEYS) OF A VARIETY OF CHEMICALS, DIFFERING WIDELY IN CHEMICAL STRUCTURES, ENVIRONMENTAL POLLUTANTS, MODEL RODENT CARCINOGENS, & NITROSO CMPD WAS EXAMINED. WITH THE EXCEPTION OF URETHANE, NONE OF THE MODEL RODENT CARCINOGENS WAS CARCINOGENIC IN THE OLD & NEW WORLD SPECIES OF MONKEY, ALTHOUGH BENZO(A)PYRENE PRODUCED TUMORS IN MORE PRIMITIVE PRIMATES (BUSH BABIES & TREE SHREWS), THAN IN RODENTS. [ADAMSON RH, SIEBER SM; BASIC LIFE SCI 24 (ORGAN SPECIES SPECIF CHEM CARCINOG): 129-56 (1983)]**PEER REVIEWED**
  
• THE TUMORIGENICITY OF BENZO(A)PYRENE (B(A)P) APPLIED TOPICALLY AS A SKIN TUMOR INITIATOR IN SENCAR MICE & THE FORMATION OF EPIDERMAL B(A)P/DEOXYRIBONUCLEOSIDE ADDUCTS WERE COMPARED OVER A SIMILAR RANGE OF DOSES (50-1600 NMOL). THE TUMOR-INITIATING ACTIVITY OF B(A)P, ITS COVALENT BINDING TO MOUSE EPIDERMAL DNA, & THE FORMATION OF THE MAJOR HYDROCARBON/DEOXYRIBONUCLEOSIDE ADDUCT SHOWED APPROX PARALLEL DOSE-RESPONSE CURVES. THE HALF-LIFE OF THE B(A)P/DEOXYRIBONUCLEOSIDE ADDUCTS & THE TOTAL RADIOACTIVITY BOUND TO THE DNA WERE 4.5 & 5.5 DAYS, RESPECTIVELY. HOWEVER, IN SPITE OF THE LOSS OF MEASURABLE DNA-BOUND MATERIAL, THE TUMOR YIELD WAS UNCHANGED REGARDLESS OF WHETHER PROMOTION WAS BEGUN 7 OR 21 DAYS AFTER INITIATION. THUS, THERE WAS A POSSIBLE CAUSAL RELATION BETWEEN B(A)P/DEOXYRIBONUCLEOSIDE ADDUCT FORMATION & PAPILLOMA FORMATION IN MOUSE SKIN. [ASHURST SW ET AL; CANCER RES 43 (3): 1024-9 (1983)]**PEER REVIEWED**
  
• In a series of soil and hydrocultures of the higher plants, tobacco, rye, and radish, as well as algae cultures of lower plants (Chlorella vulgaris, Scenedesmus obligurus, and Ankistrodesmus) /results indicate/ that certain polycyclic aromatic hydrocarbons have growth-promoting effects on plants. Further, the degree of the promoting effect corresponded to the oncogenic activity of the hydrocarbon. The six polycyclic aromatic hydrocarbons found in plants were tested one at a time or in combination. Considerable growth-promotion was noted (near to 100% in some cases) with the effectiveness of hydrocarbons ranked as follows: (1) Benzo(a)pyrene (2) Benzo(a)anthracene (3) Indeno (1,2,3-cd)pyrene, Benzo(b)fluoranthene (4) Fluoranthene (5) Benzo(ghi)perylene. [Health & Welfare Canada; Polycyclic Aromatic Hydrocarbons p.67 (1979) Report No. 80-EHD-50]**PEER REVIEWED**
  
• Histological and skeletal examinations were performed on rainbow trout alevins reared in 0.00, 0.08, 0.21, 0.39, 1.48, 2.40, or 2.99 ng/ml aqueous benzo(a)pyrene (BaP). Nuclear pycnosis and karyorrhexis were most common in neuroectodermal and mesodermal derivatives and in liver of BaP-treated alevins. Microphthalmia was noted in 17% of the test fish and was frequently associated with a patent optic fissure. Depressed mitotic rates in the retina and brain, but not liver, were seen in alevins reared in 0.21 to 1.48 ng/ml aqueous BaP. Test alevins had a significantly higher incidence of skeletal malformations in the skull and vertebral column and abnormalities of vertebral arcualia often corresponded to areas of kyphoscoliotic flexures. The ecological significance of such morphological abnormalities would be decreased feeding and growth and inability to escape predation, leading to reduced survival. Persistent mixed function oxygenase induction in less affected larvae would lead to continuing production of cytotoxic, mutagenic, and carcinogenic BaP metabolites resulting in anemia, impaired ability to respond to environmental stress and disease, and possibly latent tumorigenesis. [Hose JE et al; Arch Environ Contam Toxicol 13 (6): 675-84 (1984)]**PEER REVIEWED**
  
• The teratogenic effects of environmental levels of ... benzo(a)pyrene, were investigated using the purple sea urchin (Strongylocentrotus purpuratus) and were related to embryonic cytotoxicity and genotoxicity as evidenced by the presence of aberrant chromosome arrangements during mitosis. Developmental abnormalities were observed in gastrulae treated with initial benzo(a)pyrene concentrations of 1-50 ng/ml relative to solvent (ethanol)-treated control embryos. However, genotoxic effects were significant at the lowest benzo(a)pyrene dose tested, 0.5 ng/ml. Micronucleus formation, a widely used test of genotoxicity in mammals was observed in embryos exposed to 1 to 50 ng/ml of benzo(a)pyrene. the results from this cytogenetic analysis demonstrated that mitotic inhibition and aberrations are more sensitive indicators of benzo(a)pyrene induced damage than are developmental effects. [Hose JE et al; Arch Environ Contam Toxicol 12 (3): 319-32 (1983)]**PEER REVIEWED**
  
• Thirty-four ducks were given single intratracheal dose of 50-200 mg B(a)P in Tween 80. Survival rate was poor. One ... /duck/ developed a lung carcinoma & two had bronchial squamous metaplasia. [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. V3 109 (1973)]**PEER REVIEWED**
  
• B(a)P has been shown to be carcinogenic in exptl animals. ... /It/ is embryotoxic & teratogenic in mice; the inducibility of aryl hydrocarbon hydroxylase activity in dams & fetuses is an important factor in determining these effects. A reduction in fertility in ... male & female offspring was observed in mice following exposure ... in utero. B(a)P undergoes metabolism to reactive electrophiles capable of binding covalently to DNA. It was active in assays for bacterial DNA repair, bacteriophage induction & bacterial mutation; mutation in Drosophila melanogaster; DNA binding, DNA repair, sister chromatid exchange, chromosomal aberrations, point mutation & transformation in mammalian cells in culture; & in tests in mammals in vivo, including DNA binding, sister chromatid exchange, chromosomal aberration, sperm abnormality & the somatic specific locus (spot) test. There is sufficient evidence that benzo(a)pyrene is active in short-term tests. [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 216 (1983)]**PEER REVIEWED**
  
• Buffalo river sediment extracts contained polynuclear aromatic hydrocarbons (PAH) which caused skin darkening, hyperplasia, skin papillomas, mild coarsening and local pigmentations in the brown bullhead (Ictalurus nebulosus). Sixteen PAH were identified in the sediment extract: fluorene, phenanthrene, anthracene, fluoranthene, 2-methylphenanthrene, pyrene, 2-methylanthracene, benzanthracene, chrysene, perylene, benzo(f)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, dibenz(a,h)anthracene, benzo(g,h,i)perylene, and indeno(1,2,3-c,d)pyrene. [Black JJ; Polynucl Aromat Hydrocarbons Int Symp 7th 99-11 (1983)]**PEER REVIEWED**
  
• The teratogenicity of benzo(a)pyrene (BP), after direct injection into embryonal Swiss mice /was studied/. The compounds were dissolved in acetone and trioctanoin (1:1) and injected at doses ranging from 0.4 to 16.0 nmol/embryo on days 10, 12, and 14 of development. The transplacental effects of BP given at the same gestational days and at comparable dose levels were also evaluated. The control groups received 0.5, 1.0, or 2.0 ul/embryo of vehicle on days 10, 12, or 14 of pregnancy, respectively. The fetuses were examined when they were 18 days old. On the basis of gross external and internal malformations, the administration of BP (both transplacental and intraembryonal injection) caused no significant increase of malformed fetuses in any of the developmental stages considered. [Barbieri O et al; Cancer Res 46 (1): 94-8 (1986)]**PEER REVIEWED**
  
• Rats and mice were exposed to combustion gases of coal-burning furnace enriched with benzo(a)pyrene (50-90 ug/cu m) and other polycyclic aromatic hydrocarbons (PAH) 16 hr/day, 5 days/wk. After approx 22-mo exposure, the incidence of lung neoplasm was approx 10-fold above controls. [Heinrich U et al; Exp Pathol 29 (1): 29-34 (1986)]**PEER REVIEWED**
  
• In animal studies, exposure to high levels of diesel exhaust particulates overwhelms the normal clearance mechanisms and results in lung burdens of diesel exhaust particulates that exceed those predicted from observations at lower exposure concentrations. A variable amount of the mass of diesel exhaust particulates is extractable with strong organic solvents. The extracted material contains more than a thousand individual compounds and is mutagenic in a number of bacterial and mammalian cell assays. Bioassay-directed chemical analysis of diesel exhaust particulates had identified several hundred compounds. Many are PAHs, some of which are considered to have human carcinogenic potential. The association of benzo(a)pyrene and nitropyrene with diesel exhaust particulates prolongs their retention in the lungs. [McClellan RD; Annu Rev Pharmacol Toxicol 27: 279-300 (1987)]**PEER REVIEWED**
  
• Poeciliopsis lucida and Poeciliopsis monacha are freshwater viviparous fishes susceptible to tumorigenesis by exposure to waterborne procarcinogens. The hepatic monooxygenase system and the uptake, toxicity, and distribution of benzo(a)pyrene (BP) were characterized as a first step in exploring relationships between xenobiotic metabolism and cancer in these fishes. Waterborne BP was lethal at a dose of 3.75 mg/l with a 24 hr exposure. During a 24 hr exposure to 1.0 mg/l (3.97 umol/l) BP, an average of 8.27 nmol of BP was taken up per fish. Of this total, 64-70% was in the gallbladder or gut, indicating rapid metabolism and excretion. Basal levels of aryl hydrocarbon hydroxylase (AHH) activity were fairly high, about 0.6 nmol/min/mg. Maximal induction by BP occurred at a dose of 1.0 mg/l, but with aryl hydrocarbon hydroxylase activities only about twice the levels in untreated fish. Sensitivity to inhibition by alpha-naphthoflavone increased slightly in treated fish. Induced aryl hydrocarbon hydroxylase and also 7-ethoxyresorufin O-deethylase activities declined slowly after a single treatment, approaching pre-exposure levels after 7 days. ... [Kathryn A et al; Am Soc Pharm Exp Ther 15 (4): 449 (1987)]**PEER REVIEWED**
  
• Benzo(a)pyrene is metabolized to approximately 20 primary and secondary oxidized metabolites and to a variety of conjugates. Several metabolites can induce mutations, transform cells and/or bind to cellular macromolecules; however only a 7,8-diol-9,10-epoxide is presently considered to be an ultimate carcinogenic metabolite. [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 215 (1983)]**PEER REVIEWED**
  
• The results of both the Salmonella/microsome mutagenicity assay and HPLC analysis were used to evaluate the interactions of binary mixtures of benzo(a)pyrene and several different polychlorinated aromatic hydrocarbons. Binary mixtures of either 2-nitro-3,7,8-trichlorodibenzo-p-dioxin or pentachlorophenol with benzo(a)pyrene produced synergism, whereas strictly additive effects were observed with mixtures of octa- or heptachlorodibenzo-p-dioxin and benzo(a)pyrene. At a dose of 50 ug/plate, benzo(a)pyrene induced 120 total revertants, whereas the binary mixture of benzo(a)pyrene and pentachlorophenol induced 303 total revertants. The binary mixture of benzo(a)pyrene at 1 ug/plate and 2-nitro-3,7,8-trichlorodibenzo-p-dioxin at 0.5 ug/plate induced 261 net revertants, whereas benzo(a)pyrene alone induced 42 net revertants. HPLC analysis of the mixtures indicated that preincubation of benzo(a)pyrene with 2-nitro-3,7,8-trichlorodibenzo-p-dioxin increased the quantity of benzo(a)pyrene-7,8-dihydrodiol, and 9,10-dihydrodiol metabolites detected. The data suggest that nonmutagenic components of a complex mixture may alter the metabolism of promixate mutagens. Thus, in the present study, 2-nitro-3,7,8-trichlorodibenzo-p-dioxin appears to have inhibited the detoxication of benzo(a)pyrene metabolites. [Donnelly KC et al; Environ Mol Mutagen 16 (4): 238-45 (1990)]**PEER REVIEWED**
  
• Administration of benzo(a)pyrene (BP, 50 mg/kg/d) to pregnant rats significantly increased Glutathione S-transferase (GST) activity in placental tissue-extract (Vmax = 40 mnol/min/mg protein and 69 nmol/min/mg protein in controls versus treated animals respectively; p < 0.01) and total fetal tissue-extract (Vmax = 5) nmol/min/mg protein and 82 nmol/min/mg protein in controls versus treated animals respectively; p < 0.011 indicating an induction effect of benzo(a)pyrene on the Glutathione S-transferase system. An increase in the Km values was also observed: 1.61 x 10(-3) M and 2.84 x lO(-3) M in control versus treated placentae; 1.38 x 10(-3) M and 2.05 x 10(-3) M in control versus treated fetuses. A competitive effect on the enzyme by the benzo(a)pyrene present in the sample may also be involved. The glutathione content in both tissues did not show any changes after the treatment with benzo(a)pyrene. This increase in the Glutathione S-transferase system was not sufficient to protect the fetus. Benzo(a)pyrene affected the reproductive performance of pregnant rats by significantly increasing the number of resorptions and fetal wastage, and, also, by decreasing the fetal weight. [Cervello I et al; Placenta 13 (3): 273-80 (1992)]**PEER REVIEWED**
  
• In utero exposure to the environmental contaminant benzo[a]pyrene (BaP) was found to alter expression of murine thymocyte and liver fetal cell-surface markers. Pregnant mice were treated (via gavage) with 0, 50, 100, or 150 mg benzo[a]pyrene/kg/d on gestational days (gd) 13-17, and offspring were examined on gestational days 18. Severe thymic atrophy and cellular depletion were found in benzo[a]pyrene-exposed fetal mice. Flow cytometric analysis indicated that the benzo[a]pyrene treatment resulted in a significant decrease in the percentage of CD4-8+ fetal thymocytes, as well as significantly increased CD4-8- and CD4-8+ thymocytes. Staining of thymocytes with anti-mouse heat-stable antigen (HSA) and CD8 monoclonal antibodies produced similar results. These data suggest that benzo[a]pyrene, in addition to producing thymic hypocellularity, inhibits normal thymocyte naturation processes. The benzo[a]pyrene treatment was also found to decrease total fetal liver cellularity including numbers of cells within resident hematopoietic subpopulations. In particular, prolymphocytic cells, identified by CD44 and CD45R antigen expression and by presence of nuclear terminal deoxynucleotidyl transferase (TdT), were significantly decreased in animals gestationally exposed to benzo[a]pyrene. These data, taken together, indicate that postnatal suppression of cell and humoral-mediated immune function following in utero exposure to benzo[a]pyrene may result from multiple targeting of immune cells at different hematopoietic levels. Furthermore, results of the present study identify both qualitative and quantitative changes in fetal immune cell antigen expression that correlate well with the postnatal immunosuppression that occurs in experimental animals exposed to this carcinogenic polycyclic aromatic hydrocarbon.[Holladay SD, Smith BJ; J Toxicol Environ Health 42 (3): 259-73 (1994)]**PEER REVIEWED**
  
• The association of small quantities of ferric oxide with benzo[a]pyrene (BaP) appears to increase in vivo the toxic effect of benzo[a]pyrene. The effect of Fe203 may be mediated by the recruitment of alveolar macrophages. These cells would contribute to the production of toxic and carcinogenic benzo[a]pyrene metabolites and would stimulate development of tumors by producing cellular mediators of inflammation. In order to understand the mechanism of the synergic effect, we have instillated male Sprague Dawley rats 3 weeks of age with a single dose: Fe203 (3 mg) or benzo[a]pyrene (3 mg)/combination Fe203-benzo[a]pyrene (3 mg-3 mg) in 200 ul of physiological saline solution. Control group of identical size (treated with physiological saline solutions and untreated were used for this study. Animals were sacrificed 48 hours after instillation and a bronchoalveolar lavage (BAL) was performed. With each bronchoalveolar lavage we have obtained protein measurement, cells were stained with May-Grunwald-Giemsa method and slides were studied with polarized light. The malonaldehyde (MDA) was measured by High Performance Liquid Chromatography. The PMN elastase determination was performed by IMAC (immuno-activation) technology. An automated kinetic method for measuring cathepsins B and L was carried out using a fluorogenic substrate: Z-Phe-Arg-AMC, a specific inhibitor E64 and AMC as an internal standard. After a quantitative Dot-Blot of the samples of bronchoalveolar lavage, an immunodetection of alpha(l)-antitrypsin (alpha(l)AT) was performed. The inhibitory capacity of alpha(l)antitrypsin was determined by an enzymatic reaction with porcine pancreatic elastase. We have observed an increased malonaldehyde level for rats intoxicated with Fe203 (123%), benzo[a]pyrene (31%) and Fe203 + benzo[a]pyrene (56%). The levels of PMN elastase and cathepsin B and L were increased: Fe203 (51-58%), benzo[a]pyrene (52-27%). This effect was not seen for rats intoxicated by Fe203 + benzo[a]pyrene. The free alpha(l)antitrypsin was decreased with the three toxics (Fe203: 44%--benzo[a]pyrene: 42%--Fe203: 41%). The inhibitory capacity of alpha(l)antitrypsin was lower in groups of rats instilled with toxics.[Gosset P et al; Cent Eur J Public Health (4): 56-7 (1996)]**PEER REVIEWED**
  
• Sustained cell-mediated immunosuppression after exposure to benzo(a)pyrene (BP) implicates adverse effects on T cell ontogeny. We hypothesize that quantitative and qualitative deficiency is a function of changes that occur in development of T cell subsets leading to persistent defective T cell behavior. By serology, fetal thymus (FT), fetal liver (FL), and fetal spleen cells expressing T antigens are disoriented. In perinatal thymus, Thy1+, Lyt1+, Lyt2+ are reduced; in FL Thy1 are reduced, Lyt1 unchanged and Lyt2 enhanced. For perinatal spleen Thy1 are reduced, but enhanced post-birth (also for Lyt2). Gestation thymic mixed lymphocyte response (MLR) is enhanced, but depressed post-birth. Isolated (magnetic activated cell sorting) T subsets (including L3T41) are deficient in the presence of concanavalin A, while in FL and postnatal cells (thymus and spleen) MLR deficiency occurs for Thy1 and L3T4 cells. An increase in double negatives and decrease in double positives occurs in the thymus as seen by flow cytometry. In 18 day gestation FL there is a decrease in L3T4 cells, and in FT rearranged V(gamma3)J(gamm1) is re-expressed. Finally, benzo[a]pyrene-7,8-diol-9,10-epoxide (BP) metabolic intermediate) is detected in FL and in thymus after birth. Taken together, the data indicate benzo[a]pyrene disruption of T cell embryogenesis which persists post-birth. Thus, subsequent anomalus T cell behavior likely plays a significant role in enhanced growth of nascent neoplasms possibly by defective recognition of antigens.[Urso P et al; FASEB J 8 (4): A482 (1994)]**PEER REVIEWED**
  
• Dolphin kidney cells (CDK) were exposed in vitro to benzo(a)pyrene (BaP) in the presence or absence of 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD), a cytochrome p450-inducing agent, and/or alpha-naphthoflavone (alpha NF), an inhibitor of cytochrome p450 induction. Benzo(a)pyrene inhibited mitosis in Dolphin kidney cells cells in a dose-dependent manner. 2,3,7,8-Tetrachlorodibenzo(p)dioxin, while inhibiting cell proliferation, did not show a strict dose-dependent mode of action. Benzo(a)pyrene inhibition of mitosis was decreased by alpha alpha-naphthoflavone, which also decreased the inhibitory effects of 2,3,7,8-tetrachlorodibenzo(p)dioxin on Dolphin kidney cells proliferation. Benzo(a)pyrene treatment initiated both 3H-thymidine incorporation and the increased alkali liability of DNA functions of the initiation of excision repair. Cells pre-treated with 2,3,7,8-tetrachlorodibenzo(p)dioxin and then exposed to benzo(a)pyrene exhibited increased Benzo(a)pyrene-DNA adduct levels and increased DNA excision repair. These data indicate that dolphin cells metabolized benzo(a)pyrene in vitro as a function of cytochrome p450-associated activities, that benzo(a)pyrene metabolites covalently bound to cellular DNA and initiated excision repair. Inhibition of the cytochrome p450-mediated metabolism of benzo(a)pyrene decreased the benzo(a)pyrene-associated inhibition of mitosis in dolphin cells. [Carvan MJ 3rd et al; Chemosphere 30 (1): 187-98 (1995)]**PEER REVIEWED**
  
• Few studies have investigated the chronic cytokinetic effects of carcinogen exposure in the mouse skin. We report two experiments involving the repeated application of benzo[a]pyrene (BaP) to the dorsal skin of female Ha/ICR mice. In the first experiment, the cytokinetic, inflammatory, and DNA adduct responses were studied daily over a 9-day period encompassing the fourth and fifth weekly applications of benzo[a]pyrene at doses of 16, 32, and 64 micrograms. The second experiment involved the same cytokinetic measurements at 1, 3, 5, and 8 months, and the weekly benzo[a]pyrene doses were 4, 8, and 16 micrograms. The first study showed that after each application of 32 or 64 micrograms benzo[a]pyrene, there was a wave of slow DNA synthesis in the epidermis which peaked at 24 hr, in coincidence with a wave of benzo[a]pyrene-DNA adducts, followed by the appearance of dead and damaged keratinocytes. For the first few days after benzo[a]pyrene application there was a depression in the mitotic rate which recovered several days before the next benzo[a]pyrene application. There was a predominantly monocytic dermal inflammation throughout the observation period. In the second experiment, at the lower benzo[a]pyrene doses, there was proliferative depression at 1 month, without dermal inflammation. With continued exposure, the proliferative depression changed to a dose-dependent increase in the rate of proliferation and dermal inflammation. The level of benzo[a]pyrene-DNA adducts was followed in the 4 ug/week dose group, which showed a threefold increase after 4 months with the appearance of inflammation and heightened cell proliferation. These results suggest that the delayed inflammatory reaction, possibly based on a cell-mediated immune reaction to benzo[a]pyrene, might have been responsible for the late cytokinetic responses and the associated increase in the level of benzo[a]pyrene-DNA adducts.[Albert RE et al; Toxicol Appl Pharmacol 136 (1): 67-74 (1996)]**PEER REVIEWED**
  
• The mutagenicity of benzo[a]pyrene (B[a]P), dibenzo[ae]pyrene (DB[ae]P), dibenzo[ah]pyrene (DB[ah]P), dibenzo[ai]pyrene (DB[ai]P), and dibenzo[al]pyrene (DB[al]P) was measured in quantitative forward mutation assays with bacteria (Salmonella typhimurium TM677) and a metabolically competent cell line derived from human B-lymphoblastoid cells (MCL-5) that contained activity for five cytochrome p450s and microsomal epoxide hydrolase found in human liver. Dibenzo[al]pyrene and benzo[a]pyrene, both potent animal carcinogens, were the most mutagenic substances in both assays. Dibenzo[al]pyrene was nearly 50-fold more potent than benzo[a]pyrene in human cells, but only 60% more mutagenic in Salmonella. The carcinogenic isomer dibenzo[ah]pyrene, though nonmutagenic in bacteria, was active in human cells. The following mutagenic potency series, expressed as the minimum detectable mutagen concentration (MDMC) in nmol/mL, was obtained with Salmonella in the presence of rat liver postmitochondrial supernatant (PMS): dibenzo[al]pyrene (3.7), benzo[a]pyrene (5.8), dibenzo[ae]pyrene (6.9), DB[ai]P (14.9), dibenzo[ah]pyrene (> lO0). None of the compounds were mutagenic in the absence of postmitochondrial supernatant. In human MCL-5 cells the potency series was: dibenzo[al]pyrene (3.l x lO(-4)), benzo[a]pyrene (1.5 x 10(-2)), dibenzo[ae]pyrene (2.5 x 10(-2)), dibenzo[ah]pyrene(0.5), dibenzo[ai]pyrene (3.2). The human cell assay thus exhibited over a lO,000-fold range between the most mutagenic and least mutagenic compound, whereas in the bacterial assay there was only a corresponding four-fold difference if the nonmutagenic dibenzo[ah]pyrene was excluded. The results were discussed in terms of their concordance with animal carcinogenicity studies.[Busby WF Jr et al; Mutat Res 342 (1-2): 9-16 (1995)]**PEER REVIEWED**
  
• Experimental evidence suggests that inorganic lead and benzo[a]pyrene (BaP) suppress the development of primordial oocytes during fetal life. We examined the single and combined effects of prenatal exposure to benzo[a]pyrene and moderate doses of lead. The fertility and ovarian morphology of Fl female NMRI mice in four treatment groups (nine mice per group) were investigated: control; lead (F0 given 1 g PbC12/L in drinking water until mating); benzo[a]pyrene (10 mg/kg body weight daily by oral intubation on days 7-16 of F0 pregnancy); and combined lead and benzo[a]pyrene. Fl groups exposed prenatally to benzo[a]pyrene either alone or in combination with inorganic lead showed markedly reduced fertility with few ovarian follicles compared to controls, whereas the group exposed to lead only had measures comparable to the controls. Mice exposed to both lead and benzo[a]pyrene had a significantly longer gestation period (days to litter) compared to mice exposed only to benzo[a]pyrene, lead, or controls. There is a nonsignificant indication that the compounds together further reduce number of offspring, number of litters, and litter size. These results suggest that lead and benzo[a]pyrene have synergistic effects on impairment of fertility. The possibility of synergism may be of human relevance as inorganic lead and benzo[a]pyrene are ubiquitous environmental pollutants.[Kristensen P et al; Environ Health Perspect 103 (6): 588-90 (1995)]**PEER REVIEWED**
  
• Exposure of humans to polycyclic aromatic hydrocarbons is an ongoing concern because of the carcinogenicity of these substances. DNA adducts are being increasingly used as indicators of carcinogen exposure. While considerable experimental evidence exists to support their use there are aspects that require further attention, especially after repeated exposure, which has led to this series of experiments. Male Sprague-Dawley rats were dosed with 10 mg/kg benzo[a]pyrene (B[a]P) ip, 3 times/week for 2 weeks. At 1, 3, 7, 14, 28 and 56 days after the last treatment liver, lung, spleen and peripheral blood mononuclear cells (PBMNs) were sampled. The DNA adduct levels, as measured by the 32P-postlabelling technique, were significantly increased in all tissues, with lung having the highest levels. At day 14 total DNA adducts in lung, spleen and peripheral blood mononuclear cells were still > 50% of the level at day 1. The removal of total DNA adducts was found to be fastest in liver > spleen > peripheral blood mononuclear cells > lung. A consistent correlation of total adducts between the lung and peripheral blood mononuclear cells was observed. A major adduct, designated adduct 1, was detected in all tissues, while adduct 4 was only found in liver and lung. Adduct 5 was detected only in lung, where it constituted approximately 38-49% of total adducts and persisted at a higher level than either adduct 1 or adduct 4 for the entire post-exposure period. These results indicate that benzo[a]pyrene induced a significant increase in DNA adduct levels in all tissues tested and that total adducts in peripheral blood mononuclear cells reflect total lung adduct levels. DNA adducts were still readily detectable 56 days after exposure ceased. Thus the results support the use of peripheral blood mononuclear cells as surrogates for estimation of benzo[a]pyrene exposure in lung, the primary target organ, and indicate that samples taken days or weeks after repeated exposure will still yield DNA adducts at detectable levels. The role and significance of adduct 5 deserves further investigation, as it was detected only in the primary target organ for benzo[a]pyrene-induced cancer.[Qu SX, Stacey NH; Carcinogenesis 17 (1): 53-9 (1996)]**PEER REVIEWED**
  
• Detection of micronuclei (MN) in skin cells from mice treated with chemical or physical agents may provide a useful technique for investigating possible cancer-initiating substances and for distinguishing between these and noncarcinogens. In the present study, micronuclei induction and cell survival were estimated in cytokinesis-blocked keratinocytes, cultured for 4d in vitro, after a single topical dose of various organic compounds. Dose-dependent increases in micronuclei were observed with 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, catechol, chrysene and urethane. These chemicals resulted in increased numbers of micronucleated keratinocytes, down to the lowest doses administered in the present study (0.128, 0.5, 2, 50 and 50 ug, respectively). Although reduced keratinocyte recovery occurred following exposure of mice to acetone, pyrene and other chemicals, there was no evidence that these cytotoxic effects contributed to micronuclei scored in keratinocytes. Moreover, pyrene failed to induce micronuclei at doses from 2.5 ug to 2.5 mg/mouse. The available data suggest that micronuclei induction may prove a sensitive parallel indicator of cancer initiation in the skin. [Baker RS, He S; Teratology 42 (3): 329-30 (1990)]**PEER REVIEWED**
  
• Several well-documented examples of human exposure to carcinogens involve complex mixtures of polycyclic aromatic hydrocarbons (PAHs). Although the biological properties of many pure polycyclic aromatic hydrocarbons have been investigated, less is known about their effects when present as components of mixtures. As the ability to form DNA adducts in vivo is generally indicative of carcinogenic activity of polycyclic aromatic hydrocarbons, we have compared the DNA binding potencies of dibenzo(a,e)pyrene (DB(a,e)P), dibenzo(a,h)pyrene (DB(a,h)P), dibenzo(a,i)pyrene (DB(a,i)P), dibenzo(a,l)pyrene (DB(a,l)P) and benzo(a)pyrene (B(a)P), when applied topically, either singly or in combination, to the skin of male Parkes mice. DNA isolated from the skin and lungs was analyzed by 32P-postlabelling. The adducts formed by each polycyclic aromatic hydrocarbon exhibited markedly different chromatographic mobilities on polyethyleneimine-cellulose TLC plates. The relative binding potencies of the compounds in both skin and lungs were: dibenzo(a,l)pyrene > dibenzo(a,i)pyrene > dibenzo(a,e)pyrene, in good agreement with their reported carcinogenicities in mouse skin. The majority of adducts were removed from DNA within 21 days of treatment, but low levels of adducts were found to persist for at least 3 months in both tissues. When dibenzo(a,l)pyrene, dibenzo(a,e)pyrene and benzo(a)pyrene were applied together to mouse skin, a total binding 31% lower than expected was detected, while with a mixture of dibenzo(a,e)pyrene and benzo(a)pyrene the binding to DNA in skin was 65% higher than expected from the binding levels of the carcinogenes when applied singly. Other binary combinations of these three polycyclic aromatic hydrocarbons gave adduct levels similar to the sum of the binding levels of the individual components when applied singly. The results demonstrate the usefulness of 32P-post-labelling for the assessment of the DNA binding potencies of polycyclic aromatic hydrocarbons in mouse tissues, and for the detection of interactions between components of mixtures of carcinogens. [Hughes NC, Phillips DH; Carcinogenesis (EYNSHAM); 11 (9): 1611-20 (1990)]**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-glucuronosyltransferase 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 UDP-glucuronosyltransferase-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 UDP-glucuronosyltransferase-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 UDP-glucuronosyltransferase-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 = 0.0181 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 assessment.[Viemneau DS et al; Cancer Res 55 (5): 1045-51 (199)]**PEER REVIEWED**
  
• AT ORAL DOSES EST TO BE BETWEEN 6-12 MG/KG BODY WT/DAY, LEUKEMIA DEVELOPED 100 OR MORE DAYS LATER IN NONRESPONSIVE AHD/AHD HOMOZYGOUS MOUSE BUT NOT IN RESPONSIVE AHB/AHD HETEROZYGOTE. AN EXCESS OF DIETARY ALPHA-NAPHTHOFLAVONE (ANF) 20 TIMES GREATER THAN THE AMT OF B(A)P PREVENTED THESE HEMATOPOIETIC NEOPLASMS. ANF-SENSITIVE METABOLISM OF B(A)P PRESUMABLY CYTOCHROME P1-450 IN THE BONE MARROW OF AHD/AHD INDIVIDUALS MAY BE RESPONSIBLE FOR CAUSING THE LEUKEMIA. [NEBERT DW, JENSEN NM; BIOCHEM PHARMACOL 28 (1): 149-52 (1979)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Mouse intraperitoneal about 250 mg/kg [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 213 (1983)]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• ... Readily absorbed from the intestinal tract & tend to localize primarily in body fat & fatty tissues such as breast. Disappearance of B(a)P from blood & liver of rats following single IV injection is very rapid, having a half-life in blood of less than 5 min & a half-life in liver of 10 min. In ... blood & liver ... initial rapid elimination phase is followed by slower disappearance phase, lasting 6 hr or more. ... A rapid equilibrium is established between B(a)P in blood & that in liver & ... the cmpd fast disappearance from blood is due to ... metabolism & distribution in tissues. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 257]**PEER REVIEWED**
  
• B(a)P crosses the placenta in mice & rats ... . [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 214 (1983)]**PEER REVIEWED**
  
• (14)C METABOLITES WERE SECRETED INTO BILE OF RATS WITHIN 7 MIN OF IV DOSE OF (14)C-BENZO(A)PYRENE. PRETREATMENT OF ANIMALS WITH THIS CARCINOGEN ... ENHANCED BILIARY SECRETION OF (14)C. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 153]**PEER REVIEWED**
  
• MALE RATS CANNULATED IN THE BILE DUCT RECEIVED IV INJECTIONS OF RADIOLABELED BENZO(A)PYRENE NONCOVALENTLY BOUND TO THE VERY-LOW-DENSITY, LOW-DENSITY, OR HIGH-DENSITY LIPOPROTEINS IN EQUIMOLAR AMOUNTS. CUMULATIVE BILIARY EXCRETIONS OF BENZO(A)PYRENE COMPLEXED WITH RAT LIPOPROTEINS WERE 39.6, 24.6, & 21.2% FOR VERY-LOW DENSITY, LOW-DENSITY, & HIGH-DENSITY LIPOPROTEIN, RESPECTIVELY. VALUES FOR EXCRETION OF BENZO(A)PYRENE COMPLEXED WITH RAT OR HUMAN LIPOPROTEINS WERE COMPARABLE. EXCRETION INCREASED AS THE DEGREE OF B(A)P HYDROXYLATION INCREASED. THE EXCRETION OF B(A)P BOUND TO VERY-LOW-DENSITY, LOW-DENSITY, OR HIGH-DENSITY LIPOPROTEINS IN AROCLOR-INDUCED RATS WAS NOT GREATER THAN THE CONTROL. HENCE, 60-80% OF INJECTED B(A)P & 50-60% OF INJECTED B(A)P METABOLITES WERE NOT EXCRETED IMMEDIATELY IN CONTROL OR INDUCED ANIMALS. THIS B(A)P MAY REPRESENT A CARCINOGEN POOL THAT IS SLOWLY EXCRETED. [SHU HP, BYMUN EN; CANCER RES 43 (2): 485-90 (1983)]**PEER REVIEWED**
  
• BENZO(A)PYRENE METABOLISM & MACROMOLECULAR BINDING WERE STUDIED IN EXPLANTS FROM 4 TISSUES (BLADDER, SKIN, BRONCHUS, & ESOPHAGUS) FROM 8 HUMAN DONORS SAMPLED WITHIN 4 HR AFTER DEATH. EXPLANTS WERE INCUBATED WITH B(A)P FOR 24 HR, THEN METABOLITES EXTRACTED & ANALYZED. FIBROBLASTS WERE GROWN FROM EXPLANTS FROM 2 PATIENTS & ALSO INCUBATED WITH B(A)P. METABOLITE PROFILES WERE QUALITATIVELY THE SAME FOR EXPLANTS & FIBROBLASTS WITH SIMILAR PRODUCT RATIOS, ALTHOUGH FIBROBLASTS WERE LESS ACTIVE IN B(A)P METABOLISM. DNA BINDING STUDIES SHOWED A BROAD VARIANCE AMONG PATIENTS & TISSUES WITH THE RELATIVE DISTRIBUTION BEING THE WIDEST IN BLADDER, FOLLOWED BY SKIN, BRONCHUS, & ESOPHAGUS, RESPECTIVELY. [SELKIRK JK ET AL; CANCER LETT (SHANNON, IREL) 18 (1): 11-9 (1983)]**PEER REVIEWED**
  
• Benzo(a)pyrene, a lipophilic promutagen, reached maximal concentrations in the thoracic duct lymphatic circulation within 2 hr after gastric instillation. Benzo(a)pyrene in lymph obtained by thoracic duct cannulation decreased to approximately control levels within 4 hr after treatment. When lymph was not allowed to enter the blood vascular circulation, serum levels of benzo(a)pyrene increased very slowly, suggesting minimal mesenteric blood vascular absorption of the lipophilic hydrocarbon. Benzo(a)pyrene partitions into lymph lipoproteins as a function of the lipoprotein concentration. Data suggest that low-density lipoproteins may take up benzo(a)pyrene more efficiently than do very low-density or high-density lipoproteins, and that lymph components other than lipoproteins do not take up and transport benzo(a)pyrene. The authors propose that lipophilic xenobiotic compounds interact with cells of the immune system via lymphatic lipoprotein transport of potentially mutagenic, carcinogenic, or immunosuppressive agents. [Busbee DL et al; J Toxicol Environ Health 13 (1): 43-51 (1984)]**PEER REVIEWED**
  
• The uptake and distribution of ... benzo(a)pyrene in northern pike (Esox lucius) were investigated by whole body autoradiography and scintillation counting. (3)H-Benzo(a)pyrene was administered in the diet or in the water. The levels of this cmpd employed corresponded to levels found in moderately polluted water. The uptake and distribution of this cmpd and its metabolites were followed from 10 hr to 21 days after the initial exposure. The autoradiography patterns observed with both routes of administration suggested that benzo(a)pyrene was taken up through the gastrointestinal system and the gills, metabolized in the liver and excreted in the urine and bile. The gills may not have been a major route of excretion for benzo(a)pyrene and its metabolites in the northern pike. Benzo(a)pyrene may have been taken up from the water directly into the skin of this fish. Benzo(a)pyrene and its metabolites were heterogeneously distributed in the kidney of the northern pike. Little radioactivity accumulated in the adipose tissue. With scintillation counting, uptake of radioactivity from the water occurred rapidly in all organs, reaching a plateau in most cases after about 0.8 days. The concentrations of radioactivity in different organs ranged between 50 (many organs) and 80,000 (gallbladder + bile)-fold that found in the surrounding water. Since most of the radioactivity recovered in different organs of the pike after 8.5 days of exposure was in the form of metabolites, metabolism may have played an important role in the bioconcentration of xenobiotics in fish. [Balk L et al; Toxicol Appl Pharmacol 74 (3): 430-49 (1984)]**PEER REVIEWED**
  
• Polynuclear aromatic hydrocarbons (PAH), some of which are potent carcinogens, are common environmental pollutants. The transport processes for these hydrophobic compounds into cells and between intracellular membranes are diverse and are not well understood. A common mechanism of transport is by spontaneous desorption and transfer through the aqueous phase. From the partitioning parameters, we have inferred that the rate limiting step involves solvation of the transfer species in the interfacial water at the phospholipid surface. Transfer of 10 PAH ... out of phosphatidylcholine vesicles has been examined. ... Results show that the molecular volume of the PAH is a rate-determining factor. Morever, high performance liquid chromatography (HPLC) data confirms the hypothesis that the rate of transfer is correlated with the size of the molecule and with the partitioning of the molecule between a polar and hydrocarbon phase. The kinetics and characteristics of the spontaneous transfer of carcinogens are likely to have a major impact on the competitive processes of PAH metabolism within cells. /Polynuclear aromatic hyrocarbons/ [Plant AL et al; Chem-Biol Interact 44 (3): 237-46 (1983)]**PEER REVIEWED**
  
• Poeciliopsis lucida and Poeciliopsis monacha are freshwater viviparous fishes susceptible to tumorigenesis by exposure to waterborne procarcinogens. The hepatic monooxygenase system and the uptake, toxicity, and distribution of benzo(a)pyrene (BP) were characterized as a first step in exploring relationships between xenobiotic metabolism and cancer in these fishes. Waterborne BP was lethal at a dose of 3.75 mg/l with a 24 hr exposure. During a 24 hr exposure to 1.0 mg/l (3.97 umol/l) BP, an average of 8.27 nmol of BP was taken up per fish. Of this total, 64-70% was in the gallbladder or gut, indicating rapid metabolism and excretion. Basal levels of aryl hydrocarbon hydroxylase (AHH) activity were fairly high, about 0.6 nmol/min/mg. Maximal induction by BP occurred at a dose of 1.0 mg/l, but with aryl hydrocarbon hydroxylase activities only about twice the levels in untreated fish. Sensitivity to inhibition by alpha-naphthoflavone increased slightly in treated fish. Induced aryl hydrocarbon hydroxylase and also 7-ethoxyresorufin O-deethylase activities declined slowly after a single treatment, approaching pre-exposure levels after 7 days. ... [Kathryn A et al; Am Soc Pharm Exp Ther 15 (4): 449 (1987)]**PEER REVIEWED**
  
• Comparison of disposition of benzo(a)pyrene (BaP) among Sprague-Dawley rats, Gunn rats, hamsters, and guinea pigs was performed. BaP was administered intratracheally to animals, and the rate of excretion of radioactivity into bile, types of metabolites of BaP in bile, and distribution of radioactivity were qualitatively similar among these species although quantitative differences were observed. In hamsters, the rate of excretion was essentially independent of dose at the concentrations examined (0.16 and 350 ug). The major difference between hamsters and the other species was that increased amounts of radioactivity were retained in lung of hamsters at the lower dose with a proportional decrease in the amount of radioactivity excreted into bile. [Weyland EH, Bevan DR; Am Soc Pharm Exp Ther 15 (4): 442 (1987)]**PEER REVIEWED**
  
• In an attempt to understand route of administration dependency, 3H-benzo(a)pyrene, (14)C-urethane and (14)C-acrylamide were administered as single doses orally or topically to male SENCAR mice. Distribution in skin, stomach, liver, and lung was determined for time periods up to 48 hr. The binding of these compounds to DNA, RNA, and protein in these tissues was determined 6 and 48 hr after administration. For all three compounds, high concentrations were found in the skin following topical application, but very little material reached this target organ following oral administration. The internal organs generally contained more material after oral administration compared to topical application, whereas the opposite was true for the skin. Differences in distribution to the skin and binding to macromolecules following oral or topical administration cannot explain the greater tumorigenicity of urethane and acrylamide after oral administration in the SENCAR mouse. [Carlson GP et al; Environ Health Perspect 68: 53-60 (1986)]**PEER REVIEWED**
  
• Serum was taken from fasting, male Sprague-Dawley rats and the uptake of (14)C-benzo(a)pyrene (B(a)P) and subsequent extraction of bound B(a)P was determined by radio-scintillation techniques. The initial uptake velocity for B(a)P was similar to human serum for all concentrations of B(a)P used. Maximum uptake of B(a)P was estimated at 120 ug/ml for rat serum. In rat serum, low-density lipoproteins contained 50% of the bound B(a)P, high- density lipoproteins contained 40%, and albumin contained 10% of the total B(a)P added. In rat serum, the HDL component contained 40-50% of B(a)P, and the LDL component contained 19-22% of the added B(a)P. After removal of the lipoproteins from the serum, bound B(a)P was associated entirely with albumin. [Aaarstad K et al; Toxicology 47 (3): 235-45 (1987)]**PEER REVIEWED**
  
• The influence of maternal binding of benzo(a)pyrene (BaP) on its disposition into fetal tissue was investigated in pregnant Swiss-Webster mice. Low doses (10 ng/mouse) of radiolabeled benzo(a)pyrene were administered by intravenous injection on day 15 of gestation. Benzo(a)pyrene was administered along with normal rabbit serum (NRS) (low binding paradigm) or anti-benzo(a)pyrene antiserum (high binding paradigm) and animals killed at various time points. Total radioactivity in the fetus increased with time to peak concentrations in whole fetal homogenates at 12 hours. In contrast, maternal serum, liver, and lung showed a decrease in total radioactivity over the same time period. Total radioactivity/gram of fetal tissue was significantly higher in NRS-treated animal 5 compared to anti-benzo(a)pyrene-antiserum-treated animals. Since the levels of the parent compound, benzo(a)pyrene, in fetal tissue fell over time similar to maternal liver and lung, the increase in total radioactivity in the fetus was due to an increased concentration of a benzo(a)pyrene metabolite fraction in both the low binding and high binding groups. Significantly, a lower level of this metabolite fraction was found in fetal tissue from the anti-benzo(a)pyrene-antiserum-treated animals. The present study shows that maternal exposure to this environmental pollutant, even at low doses, results in an accumulation of a metabolite-rich fraction in the fetal compartment, which may contribute to the teratogenic potential of benzo(a)pyrene. The data also demonstrate that the amount of this accumulation can be diminished by increasing maternal binding proteins, such as by treatment with anti-benzo(a)pyrene antiserum. [McCabe DP, Flynn EJ; Teratology 41 (1): 85-95 (1990)]**PEER REVIEWED**
  
• The maternal-fetal exchange of the tobacco related carcinogen, benzo(a)pyrene, was studied in women smokers during pregnancy. The number of cigarettes smoked per day by each of the women in the study was assessed via questionnaire and by measurement by immunoassay of serum and urine cotinine in maternal and fetal blood samples. Maternal and fetal blood samples were classified as coming from nonsmokers (n = 74), individuals smoking less than 1 pack of cigarettes per day (n = 16), individuals smoking 1 pack of cigarettes per day (n = 19), individuals smoking 1-2 packs of cigarettes per day (n = 19), and individuals smoking greater than 2 packs of cigarettes per day (n = 20). Both maternal and fetal blood samples were obtained at the time of delivery. After lysing the red cells with chilled deionized water, the globin was precipitated using acidified acetone. Paired globin samples were hydrolyzed under acidic conditions to remove the bound benzo(a)pyrene from the protein. Benzo(a)pyrene tetrols were isolated using a C18 Sep-Pak cartridge eluted with water and methanol. Tetrols were evaporated to dryness under nitrogen and stored at -20 degrees C until analysis by HPLC and GC/MS. Background levels of benzo(a)pyrene - Hb adducts were detected in maternal nonsmokers (6.83 + or - 3.46 pmol BP tetrol/g Hb, mean + or - SD) and in fetal samples (3.46 + or - 1.81 pmol/g Hb). Increasing levels of benzo(a)pyrene - Hb adducts were found as the smoking status of the women increased ranging from (8.93 + or - 5.21 (less than 1 pack per day) to 96.75 + or - 18.66 (greater than 2 packs per day). A corresponding increase in the presence of fetal benzo(a)pyrene Hb adducts was also detected (10.31 + or - 3.11; less than 1 pack/day to 52.55 + or - 14.26; greater than 2 packs/day). This study confirms that the tobacco related carcinogen, benzo(a)pyrene, crosses the human placenta and binds to fetal Hb in significantly higher concentrations in smokers when compared to nonsmokers. [Spinnato JA et al; Toxicologist 30(1 Pt 2): 238 (1996)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• THE FACIAL SELECTIVITY OF PURIFIED RAT LIVER CYTOCHROME P-450C TOWARD EPOXIDATION OF BENZO(A)PYRENE (BP) AT ITS 4,5-POSITION (K-REGION) WAS DETERMINED BY FORMATION, SEPARATION, & QUANTITATION OF DIASTEREOMERIC TRANS-ADDITION PRODUCTS OF GLUTATHIONE WITH ENZYMATICALLY PRODUCED BENZO(A)PYRENE 4,5-OXIDE. CORRELATION OF THE GLUTATHIONE CONJUGATES OBTAINED FROM BP 4,5-OXIDE DERIVED FROM CYTOCHROME P-450C CATALYZED OXIDATION OF BP WITH THOSE OBTAINED FROM THE SYNTHETIC ENANTIOMERS INDICATED THAT 97% OF THE ENZYMATICALLY FORMED ARENE OXIDE WAS THE + OR - (4S,5R) ENANTIOMER. [ARMSTRONG RN ET AL; BIOCHEM BIOPHYS RES COMMUN 100 (3): 1077-84 (1981)]**PEER REVIEWED**
  
• HUMAN LIVER MICROSOMAL FRACTIONS FROM 13 DIFFERENT INDIVIDUALS WERE CHARACTERIZED WITH RESPECT TO SDS (SODIUM DODECYLSULFATE)- POLYACRYLAMIDE GEL ELECTROPHORETIC PROFILES & REGIONAL SPECIFICITY IN THE METABOLISM OF THE POLYAROMATIC HYDROCARBON BENZO(A)PYRENE. PRONOUNCED INTERINDIVIDUAL DIFFERENCES IN THE COMPOSITION OF MICROSOMAL PROTEINS IN THE MOLECULAR WT RANGE OF 49,000-60,000 WERE FOUND. MOST OF THE VARIATIONS AMONG PROFILES OF MICROSOMAL PROTEINS ARE INTERINDIVIDUAL DIFFERENCES IN THE COMPOSITION OF ISOENZYMES OF CYTOCHROME P450. LARGE VARIATIONS AMONG THE HUMAN LIVER MICROSOMAL SAMPLES WERE ALSO SEEN IN BENZO(A)PYRENE METABOLISM. THE RESULTS INDICATE THE PRESENCE OF 7-8 DIFFERENT FORMS OF CYTOCHROME P450 IN HUMAN LIVER MICROSOMES & INTERINDIVIDUAL VARIATIONS SEEN IN DRUG METABOLISM MAY AT LEAST IN PART BE EXPLAINED BY VARIATIONS IN THE DISTRIBUTION OF THESE ISOENZYMES. [EKSTROEM G ET AL; ACTA PHARMACOL TOXICOL 50 (4): 251-60 (1982)]**PEER REVIEWED**
  
• THE ABILITY OF THREE PURIFIED FORMS OF RAT LIVER CYTOCHROME P450 TO METABOLICALLY ACTIVATE BENZO(A)PYRENE TO MUTAGENIC PRODUCTS WAS EXAMINED USING SALMONELLA TYPHIMURIUM STRAINS TA98 & G46 IN A RECONSTITUTED MONOOXYGENASE SYSTEM. THE ISOZYMES EXAMINED WERE CYTOCHROME P450-PB (THE MAJOR PHENOBARBITAL INDUCIBLE FORM), & THE TWO MAJOR 3-MC INDUCIBLE FORMS (CYTOCHROMES P448(52,000 MOL WT) & P448(55,000 MOL WT)). ONLY CYTOCHROME P448(55) METABOLIZES BENZO(A)PYRENE & ITS 7,8-DIHYDRODIOL DERIVATIVE TO MUTAGENIC PRODUCTS. [ROBERSTSON IG ET AL; CARCINOGENESIS 4 (1): 93-6 (1983)]**PEER REVIEWED**
  
• COLONIC BIOPSY SPECIMENS FROM PATIENTS WITH ULCERATIVE COLITIS & NORMAL SUBJECTS WERE STUDIED FOR THE ABILITY TO METABOLIZE BENZO(A)PYRENE. APPROX 73% OF 30 COLONIC BIOPSY SPECIMENS FROM 7 ULCERATIVE COLITIS PATIENTS COULD METABOLIZE BENZO(A)PYRENE TO OXIDIZED PRODUCTS, WITH AN AVERAGE PRODUCTION OF 11.6 NMOL/MG BIOPSY PROTEIN. IN CONTRAST, 39% OF 23 BIOPSY SPECIMENS FROM 5 NORMAL PERSONS SHOWED AN AVERAGE METABOLIC ACTIVITY, 2.79 NMOL. BENZO(A)PYRENE OXIDATION ACTIVITY IN COLONIC TISSUE FROM COLITIS PATIENTS WAS, ON THE AVERAGE, FOURFOLD GREATER THAN THAT IN NORMAL SUBJECTS. THIS STUDY SUGGEST THAT THE COLONIC MUCOSA OF PATIENTS WITH ULCERATIVE COLITIS HAS A GREATER ABILITY THAN THAT OF NORMAL SUBJECTS TO OXIDIZE SUCH CHEMICALS POSSIBLY TO ELECTROPHILES WITH HIGHER MUTAGENIC POTENTIAL. [MAYHEW JW ET AL; GASTROENTEROLOGY 85 (2): 328-34 (1983)]**PEER REVIEWED**
  
• Lobster (Homarus americanus) in Maine and the spiny lobster (Panulirus argus) in Florida were selected as exptl invertebrate models for studies of the disposition and metabolism of xenobiotics. Hepatopancreas microsomes from both species contained relatively high amounts of cytochrome p450 (> = 1 nmol/mg protein), but NADPH-dependent monooxygenase activity was very low or undetectable with several substrates, including benzo(a)pyrene. NADPH-dependent cytochrome c reductase activity was also very low in these microsomes. (14)C-Benzo(a)pyrene (1 mg/kg) was metabolized and excreted very slowly after intracardial administration to lobsters. The half-life for disappearance of radiolabel was approximately 2 mo, and most of the radioactivity was stored in the hepatopancreas. Similar studies in the spiny lobster demonstrated that metab and excretion were considerably faster in this species (half-life approximately 1 wk in the summer and approximately 2 wk in the winter). In reconstituted monooxygenase systems containing spiny lobster hepatopancreas cytochrome p450, benzo(a)pyrene was metabolized primarily to phenolic products (approximately 50% of the total metabolites). Benzo(a)pyrene metabolites, benzo(a)pyrene 4,5-, 7,8-, and 9,10-benzo(a)pyrene-dihydrodiol were formed in approximately equal amounts and accounted for approximately 20% of the total metabolites. Collectively, these results are consistent with the production of carcinogenic metabolites of benzo(a)pyrene in vivo by the marine crustacean species examined. [Bend JR et al; Proc Int Symp Princess Takamatsu Cancer Res Fund 11: 179-94 (1981)]**PEER REVIEWED**
  
• FISH EXPOSED TO BENZO-A-PYRENE (B(A)P) & NAPHTHALENE IN SEDIMENT CONTAINING PRUDHOE BAY CRUDE OIL. B(A)P METAB TO GREATER EXTENT. NAPHTHALENE WAS METAB TO 1,2-DIHYDRO-1,2-DIHYDROXYNAPHTHALENE GLUCURONIDE. [VARANASI ET AL; AQUAT TOXICOL 1 (1): 49 (1981)]**PEER REVIEWED**
  
• Among the foreign compounds metabolized by adrenal monooxygenases are the carcinogens, benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene (DMBA). [Thomas, J.A., K.S. Korach, J.A. McLachlan. Endocrine Toxicology. New York, NY: Raven Press, Ltd., 1985., p. 38]**PEER REVIEWED**
  
• Benzo(a)pyrene is metabolized to approximately 20 primary and secondary oxidized metabolites and to a variety of conjugates. Several metabolites can induce mutations, transform cells and/or bind to cellular macromolecules; however only a 7,8-diol-9,10-epoxide is presently considered to be an ultimate carcinogenic metabolite. [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 215 (1983)]**PEER REVIEWED**
  
• The types and relative amounts of conjugated and nonconjugated metabolites of BaP were similar in bile of Sprague-Dawley rats and hamsters. Smaller amounts of glucuronides and larger amounts of sulfate conjugates were detected in bile of Gunn rats than in bile of Sprague-Dawley rats or hamsters. Metabolites in bile of guinea pigs were markedly different from those in the other species in that approximately 90% of the metabolites were thioether conjugates. ... [Weyland EH, Bevan DR; Am Soc Pharm Exp Ther 15 (4): 442 (1987)]**PEER REVIEWED**
  

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TSCA Test Submissions

• The effects of subchronic benzo(a)pyrene (BaP) exposure on the resistance of B6C3F1 female mice to exposure to infectious pathogens or tumor cells were evaluated. Groups of female mice (8/group except vehicle controls, 12/group) were dosed with BaP at 0, 5, 20 or 40 mg/kg in corn oil vehicle by subcutaneous injection daily for 14 days and one control group received no BaP treatment. On day 15 the animals were challenged with a pathogen or tumor cells and observed for mortality and other toxicity signs. The effect of BaP exposure on host resistance to pathogens was as follows (pathogen/effect on resistance): Listeria monocytogenes/increased resistance, B16F10 Melanoma cells/decreased resistance, Herpes Simplex Type 2/decreased resistance, Influenza A2/no change in resistance, and Streptococcus pneumonia/decreased resistance.[Medical College of Virginia; Effects of Subchronic Fourteen Day Exposure to Benzopyrene in B6C3F1 Female Mice on Host Resistance. (1984), EPA Document No. FYI-AX-1084-0309]**UNREVIEWED**
  
• A subcutaneous study was conducted with female B6C3F1 mice injected subcutaneously with 0, 5, 20 or 40 mg/kg benzo(a)pyrene (BaP) in corn oil vehicle daily for 14 days and then challenged with organisms or tumor cells at 4 challenge levels/BaP dose level. Subchronic exposure to BaP resulted in a BaP dose-dependent increase in protection to Listeria monocytogenes infection. Exposure to BaP caused a dose-dependent increase in the pulmonary tumor burden of mice administered B16F10 melanoma cells intravenously 1 day after the last BaP exposure. Exposure to BaP caused a decrease in resistance to Herpes Simplex Type 2 virus (not dose-dependent) and Streptococcus pneumonia (dose-dependent). There was no effect observed due to exposure to BaP on the level of protection to Influenza A2.[Medical College of Virginia; Effects of Subchronic Fourteen Day Exposure to Benzopyrene in B6C3F1 Female Mice on Host Resistance. (1985), EPA Document No. FYI-AX-0485-0220, Fiche No. OTS0000220-2]**UNREVIEWED**
  
• A subcutaneous study was conducted with male and female B6C3F1 mice (72-139/group) injected subcutaneously with 0.01 ml/g body weight of solutions in corn oil vehicle at concentrations of 0, 0.5, 2.0 or 4.0 mg/ml benzo(a)pyrene (BaP) daily for 14 days. There were significant differences between treated and control animals in the following: increased body and absolute liver weights (males at all doses), decreased absolute spleen weight (males at high-dose), decreased relative and absolute thymus weight (females at high-dose), decreased relative brain and spleen weights (both sexes, all dose levels), decreased blood levels of hemoglobin, hematocrit, leukocytes, erythrocytes, (both sexes at high-dose), and total protein and globulin levels (decreased in both sexes at high-dose and increased in low-dose males), and decreased in various serum immunoglobulin levels (high- and mid-dose females, males at all doses). There were no significant differences between treated and control animals in the following: absolute brain, kidney, and lung weights, relative liver, kidney and lung weights, blood levels of lymphocytes, neutrophils, monocytes, eosinophils, globulin, and serum complement levels.[Medical College of Virginia; Effects of Subchronic Fourteen Day Exposure to Benzopyrene in B6C3F1 Male and Female Mice on Specific Immunological Parameters, Final Report. (1985), EPA Document No. FYI-AX-1283-0220, Fiche No. OTS0000220-1]**UNREVIEWED**
  
• A subcutaneous study was conducted with male and female B6C3F1 mice (72-139/group) injected subcutaneously with 0.01 ml/g body weight of solutions in corn oil vehicle at concentrations of 0, 0.5, 2.0 or 4.0 mg/ml benzo(a)pyrene (BaP) daily for 14 days. Groups of 8-12 rats each were immunized with sheep red blood cells (SRBC) on day 10 or 11 of exposure and the humoral immune response was evaluated by measuring the spleen IgM antibody forming cells (AFC) response 1 day after the last exposure to BaP. Significant decreases were observed in the number of AFC in animals treated with BaP and SRBC when compared to solvent controls. Delayed hypersensitivity response to SRBC was suppressed in high-dose female and male animals to a level of 59% and 45% of controls, respectively. The ability of male and female mice to produce antibodies to the T-dependent antigen sheep erythrocytes was inhibited although the parameters used to measure the functional aspects of cell mediated immunity were unaltered. BaP treatment also resulted in a suppression in the bacterial lipopolysaccharide response which was more intense for females. No differences were observed between BaP treated and control animals in the following: basal serum immunoglobulin levels, serum complement levels, delayed hypersensitivity response to Keyhole Limpet Hemocyanin, acute inflammatory response to carrageenin, and vascular clearance of rate of sheep erythrocytes. There were no dose-dependent changes in hepatic phagocytosis.[Medical College of Virginia; Effects of Subchronic Fourteen Day Exposure to Benzopyrene in B6C3F1 Male and Female Mice on Specific Immunological Parameters, Final Report. (1985), EPA Document No. FYI-AX-1283-0220, Fiche No. OTS0000220-1]**UNREVIEWED**
  
• The effects of subchronic exposure to benzo(a)pyrene (BaP) were evaluated in male Fischer 344 rats (32/exposed groups, 40 in negative control group) injected subcutaneously with BaP at dosages of 0, 2.5, 10 or 20 mg/kg (2 ml/kg of corn oil solutions of BaP) daily for 14 days. There were significant differences between treated and control animals in the following: increased absolute weights of liver (mid-dose level), spleen and lungs (all levels), increased relative weights of liver (mid- and high- doses), spleen and lungs (all levels), decreased relative thymus and kidney weights (mid-dose level), and differential and absolute count of monocytes (low-dose level). There were no significant differences between treated and control animals in the following: body weight, body weight change, relative and absolute brain weight, absolute thymus and kidney weight, and differentials and absolute counts of total leukocytes, lymphocytes, neutrophils, and eosinophils.[Medical College of Virginia; Immunotoxicity of Benzopyrenes in Fischer 344 Rats (Final Report). (1986), EPA Document No. FYI-AX-0686-0309, Fiche No. OTS0000309-2]**UNREVIEWED**
  
• The effects of subchronic exposure to benzo(a)pyrene (BaP) were evaluated in male Fischer 344 rats (32/exposed groups, 40 in negative control group) injected subcutaneously with BaP at dosages of 0, 2.5, 10 or 20 mg/kg (2 ml/kg of corn oil solutions of BaP) daily for 14 days. Groups of 10 rats each were immunized with sheep red blood cells (SRBC) on day 10 of the exposure period and the humoral immune response was evaluated by measuring the spleen IgM antibody forming cells (AFC) response 1 day after the last exposure. There were differences between treated and control animals in the following: increased spleen weight (high- and low-BaP-dose), increased IgM AFC/spleen cell and /spleen (low-dose), and decreased IgM AFC/spleen cell and /spleen (high-dose). Rats immunized with SRBC on day 12 of exposure exhibited increased spleen weight (mid-dose level), increased IgM AFC/spleen cell and /spleen (low-dose level), and increased IgM AFC/spleen cell (high-dose level). There were no changes in delayed hypersensitivity response to keyhole limpet hemocyanin or SBRC in treated animals relative to solvent controls.[Medical College of Virginia; Immunotoxicity of Benzopyrenes in Fischer 344 Rats (Final Report). (1986), EPA Document No. FYI-AX-0686-0309, Fiche No. OTS0000309-2]**UNREVIEWED**
  

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Footnotes

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