Grantee Research Project Results
Final Report: Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
EPA Grant Number: R828112C113Subproject: this is subproject number 113 , established and managed by the Center Director under grant R828112
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Health Effects Institute (2000 — 2005)
Center Director: Greenbaum, Daniel S.
Title: Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
Investigators: Turteltaub, Kenneth W
Institution: Lawrence Livermore National Laboratory
EPA Project Officer: Chung, Serena
Project Period: April 1, 2000 through March 31, 2005
RFA: Health Effects Institute (1996) RFA Text | Recipients Lists
Research Category: Human Health , Air Quality and Air Toxics , Air
Objective:
Human exposure to benzene is widespread because it is a component of gasoline and also is used extensively as an industrial solvent. Exposure to high levels of benzene is associated with development of leukemia and other blood disorders, but the risks of exposure to low levels of benzene are not well understood. In the 1990s, the Health Effects Institute (HEI) initiated a research program designed to study the effects of exposure to toxic air pollutants at ambient levels. As one part of this research program, HEI’s Request for Applications (RFA) 93-1 supported studies to develop reliable and sensitive assays for biomarkers of benzene exposure—both recent and longer-term—and of benzene effect. The biomarkers of recent exposure were urinary metabolites (measuring responses up to hours after exposure) and adducts of blood proteins (days to weeks after exposure). The biomarkers of longer-term exposure were chromosomal changes, integrating exposure over months to years. Because chromosomal changes may be determinants of subsequent health effects, they also may be considered early biomarkers of benzene effect. Chromosomal changes also may be due to causes other than exposure to benzene.
Summary/Accomplishments (Outputs/Outcomes):
Investigators, led by Dr. Kenneth Turteltaub, researched benzene metabolism in rodents over a hundred million–fold dose range. This range encompassed concentrations close to those of human ambient exposure, generally 1 to 10 parts per billion. Turteltaub and his colleague, Chitra Mani, administered radioactive benzene to mice and rats and subsequently analyzed bone marrow, liver, urine, and plasma from these animals. In most experiments, the investigators injected animals intraperitoneally with 14 C-labeled benzene, but in some experiments they exposed animals to radioactive benzene via inhalation. After exposure, the investigators coupled high-performance liquid chromatography (HPLC; to separate benzene metabolites) with the novel and sensitive technique accelerator mass spectrometry (to measure 14 C) in order to measure low levels of metabolites. Accelerator mass spectrometry was developed by nuclear physicists to measure low levels (10-15 to 10-18 molar) of long-lived isotopes such as 14C.
Conclusions:
In this innovative study of benzene metabolism, Turteltaub and Mani detected dose-dependent formation of benzene metabolites in plasma, bone marrow, and liver of mice over a wide range of doses (5 ng/kg to 500 mg/kg). Benzene metabolites, including DNA and protein adducts, were detected at levels 100 times lower than had been found in previous studies.
Even at low benzene exposure concentrations, the investigators detected higher levels of benzene metabolites in mouse and rat bone marrow and liver than in plasma. This finding indicates that benzene reaches tissues and is metabolized there, even at levels close to those to which humans are exposed in ambient air. In addition, Turteltaub and Mani found that the levels of DNA and protein adducts detected in bone marrow and liver in different rodents generally correlated well with the ability of benzene to induce tumors in that species or strain. This result suggests that the formation of adducts may be an early marker of benzene carcinogenicity.
All doses of benzene produced a similar pattern of metabolites in mouse urine, suggesting that the pattern of benzene metabolism is similar at widely disparate concentrations. This finding is of interest because other studies have suggested that the pattern of benzene metabolites differs depending on the benzene concentration to which animals are exposed. Such differences in metabolism of benzene could affect the shape of the exposure-response curve. However, Turteltaub and Mani’s results are difficult to compare with previous studies. Although the current study has greater intrinsic analytic sensitivity than previous studies, it did not detect a metabolite previously found in the urine of rodents exposed to benzene.
Although results of the current study show the potential of accelerator mass spectrometry coupled with HPLC, they also illustrate the drawbacks. First, in the current study, urine from mice exposed to radioactive benzene contained a large peak of radioactivity that could not be identified by HPLC. The investigators did not look for this material in plasma or bone marrow; thus, the peak also might have been present in samples from these tissues, with an uncertain impact on the results. This unidentified radioactive material may be a contaminant of the radioactive material used in the assays, a previously unidentified metabolite, or the decomposition product of a known benzene metabolite.
Second, the technique requires administering radiolabeled benzene to the study animals. Although the method uses extremely low levels of radioactive benzene, such an approach is not broadly applicable for controlled exposure studies with humans because benzene is classified as a known human carcinogen. Third, this study indicates the potential influence on results of varying methods of biomarker collection, storage, and processing. In the current study, glucuronidase inhibitors were not added to urine samples, which possibly resulted in the degradation of a major metabolite, hydroquinone glucuronide, that was detected in other studies of benzene metabolism.
Even given these challenges, Turteltaub and Mani provided important information about benzene metabolism at the lowest end (5–500 ng/kg body weight) of the range of benzene doses tested: the dose-response curve for metabolite formation was flatter than that of higher benzene doses but was above zero. This result indicates that metabolism of benzene to activated metabolites occurs even at very low doses. It further suggests, but does not show conclusively, that the dose-response curve for benzene in mice lacks an obvious threshold at the lowest exposure levels evaluated. This finding may have important ramifications for understanding the human response to low-level benzene exposures. Further studies are required to resolve the shape of the dose-response curve for humans at these low benzene levels.
References:
Aksoy M, Erdem S. 1978. Follow up study on the development of leukemia in 44 pancytopenic patients with chronic exposure to benzene. Blood 52:285–292.
American Conference of Government and Industrial Hygienists. 1999. Guide to Occupational Exposure Values. ACGIH, Cincinnati OH.
Arfellini G, Grilli S, Colacci A, Mazzullo M, Prodi G. 1985. In vivo and in vitro binding of benzene to nucleic acids and proteins of various rat and mouse organs. Cancer Lett 28:159–168.
Bailer AJ. 1988. Testing for the equality of area under the curves when using destructive sampling techniques. J Pharmacokinet Biopharm 16:303–309.
Bailer AJ, Piegorsch WW. 1990. Estimating integrals using quadrature methods with an application in pharmacokinetics. Biometrics 46:1201–1211.
Bauer H, Demitriadis EA, Snyder R. 1989. An in vivo study of benzene metabolite DNA adduct formation in liver of male New Zealand rabbits. Arch Toxicol 63:209–213.
Bechtold WE, Sabourin PJ, Henderson RF. 1988. A reverse isotope method for determining benzene and metabolites in tissues. J Anal Toxicol 12:176–179.
Bodell WJ, Levay G, Pongracz K, Pathak DN. 1994. DNA adducts formed by peroxidase activation of benzene metabolites. Polycyclic Aromatic Compounds 6:1–8.
Bodell WJ, Pathak DN, Levay G, Ye Q, Pongracz K. 1996. Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: Implications for molecular dosimetry. Environ Health Perspect 104:1189–1193.
Carere A, Antoccia A, Crebelli R, Di Chiara D, Fuselli S, Iavarone I, Isacchi G, Lagorio S, Leopardi P, Marcon F. 1995. Exposure to benzene and genotoxic effects among filling station attendants. Epidemiol Prev 19:105–119.
Cocheo V, Sacco P, Boaretto C, De Saegert E, Ballesta PP, Skov H, Goelen S, Gonzalezll N, Caracena AB. 2000. Urban benzene and population exposure. Nature 404:141–142.
Creek MR, Mani C, Vogel JS, Turteltaub KW. 1997. Tissue distribution and macromolecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice. Carcinogenesis18:2421–2427.
Cronkite EP. 1987. Chemical leukemogenesis: benzene as a model. Semin Hematol 1:2–11.
Cronkite EP, Bullis JE, Inoue T, Drew RT. 1984. Benzene inhalation produces leukemia in mice. Toxicol Appl Pharmacol 75:358–361.
Cronkite EP, Drew RT, Inoue T, Hirabayashi Y, Bullis JE.1989. Hematotoxicity and carcinogenicity of inhaled benzene. Environ Health Perspect 82:97–108.
Department of Health and Human Services (US). 1986. Toxicology and Carcinogenesis Studies of Benzene inF344/N Rats and Mice. National Institutes of Health/National Toxicology Prog Tech Rep Ser 289, CAS71-43-2. National Toxicology Program, Washington DC.
Eastmond DA, Smith MT, Irons RD. 1987. An interaction of benzene metabolites reproduces the myeolotoxicity observed with benzene exposure. Toxicol Appl Pharmacol 1:85–95.
Epe B, Harttig U, Stopper H, Metzler M. 1990. Covalent binding of estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation. Environ Health Perspect 88:123–127.
Frantz CE, Bangerter C, Fultz E, Mayer KM, Vogel JS, Turteltaub KW. 1995. Dose-response studies of MeIQx in rat liver and liver DNA at low doses. Carcinogenesis 16:367–374.
Golding BT, Watson WP. 1999. Possible mechanisms of carcinogenesis after exposure to benzene. IARC Sci Publ 150:75–88.
Goldstein BD. 1977. Hematotoxicity in humans. J Toxicol Environ Health 2(Suppl):69–105.
Goldstein BD, Witz G, Javid J, Amoruso M, Rossman T, Wolder B. 1982. Muconaldehyde: A potential toxic intermediate of benzene metabolism. In: Snyder R, Parke DV, Kocsis J, Jallow D, Gibson GG, Witmer CM, eds. Biological Intermediates II. Part A. New York, NY: Plenum Press, pp. 331–339.
Greenlee WF, Sun JD, Bus JS. 1981. A proposed mechanism of benzene toxicity: formation of reactive intermediates from polyphenol metabolites. Toxicol Appl Pharmacol 59:187–195.
Henderson RF. 1996. Species differences in the metabolism of benzene. Environ Health Perspect 104:1173–1175.
Huff JE, Eastin W, Roycroft J, Eustis SL, Haseman JK. 1988. Carcinogenesis studies of benzene, methyl benzene, and dimethyl benzenes. Ann N Y Acad Sci 534:427–440
Huff JE, Haseman JK, DeMarini DM, Eustis S, Maronpot RR, Peters AC, Persing RL, Chrisp CE, Jacobs AC. 1989. ultiple site carcinogenicity of benzene in Fischer 344rats and B6C3F1 mice. Environ Health Perspect 82:125–163.
Irons RD. 1985. Quinones as toxic metabolites of benzene. J Toxicol Environ Health 16:673–678.
Irons RD, Stillman WS, Colagiovanni DB, Henry VA. 1992. Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro. Proc Natl Acad Sci U S A 89:3691–3695.
Kautiainen A, Vogel JS, Turteltaub KW. 1997. Trichloroethylene covalently binds macromolecules dose dependently in mice. Chem Biol Interact 106:109–121.
Kivistö H, Pekari K, Peltonen K, Svinhufvud J, Veidebaum T, Sorsa M, Aitio A. 1997. Biological monitoring of exposure to benzene in the production of benzene and in a cokery. Sci Total Environ 199:49–63.
Kolachana P, Subrahmanyam VV, Meyer KB, Zhang LP, Smith MT. 1993. Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro andin the bone marrow in vivo. Cancer Res 53:1023–1026.
Laskin DE, Heck DE, Punjabi CJ, Laskin JD. 1987. Role of nitric oxide in hamatosuppression and benzene-induced toxicity. Environ Health Perspect 104:1283–1287.
Levay G, Bodell WJ. 1992. Potentiation of DNA adduct formation in HL-60 cells by combination of benzene metabolites. Proc Natl Acad Sci U S A 89:7105–7109.
Levay G, Pathak DN, Bodell WJ. 1996. Detection of DNA adducts in the white blood cells of B6C3F1 mice treated with benzene. Carcinogenesis 17:151–153.
Levay G, Ross D, Bodell WJ. 1993. Peroxidase activation of hydroquinone results in the formation of DNA adducts in HL-60 cells, mouse bone marrow macrophages and humanbone marrow. Carcinogenesis 14:2329–2334.
Longacre SL, Kocsis JJ, Snyder R. 1981. Influence of strain differences in mice on the metabolism and toxicity of benzene. Toxicol Appl Pharmacol 60:398–409.
Lutz WK, Schlatter CH. 1977. Mechanism of carcinogenicaction of benzene: Irreversible binding to rat liver DNA. Chem Biol Interact 49:241–245.
Maltoni C, Ciliberti A, Cotti G, Conti B, Belpoggi F. 1989. Benzene, an experimental multipotential carcinogen: Results of the long-term bioassays performed at the Bologna Institute of Oncology. Environ Health Perspect 82:109–124.
Maltoni C, Conti B, Cotti G. 1983. Benzene: A multipotential carcinogen. Results of long term bioassays performed at the Bologna Institute of Oncology. Am J Ind Med 4:589–630.
Mani C, Vogel J, Turteltaub KW. 1998. Strain differences in the covalent binding of benzene to macromolecules: B6C3F1 vs C57BL/6 mice. 89th Annual Meeting of American Association for Cancer Research. March 28–April 1, 1998. American Association for Cancer Research, New Orleans LA.
Mathews JM, Etheridge AS, Mathews HB. 1998. Dose dependent metabolism of benzene in hamsters, rats and mice. Toxicol Sci 44:14–21.
Mathsoft. 1999. S-PLUS 2000 User’s Guide. Mathsoft Data Analysis Products Division, Seattle WA.
Mauthe RJ, Dingley KH, Leveson SH, Freeman SP, Turesky RJ, Garner CR, Turteltaub KW. 1999. Comparison of DNA-adduct and tissue-available dose levels of MeIQx in human and rodent colon following administration of a very low dose. Int J Cancer 80:539–545.
Mazzullo M, Bartoli S, Bonora B, Colacci A, Grilli S, Lattanzi G, Niero A, Turina MP, Parodi S. 1989. Benzene adducts with rat and nucleic acids and proteins: Dose-response relationship after treatment in vivo. Environ Health Perspect 82:259–266.
Medinsky MA, Sabourin PJ, Lucier G, Birnbaum LS, Henderson RF 1989. A physiological model for simulation of benzene metabolism by rats and mice. Toxicol Appl Pharmacol 99:193–206.
Nillson RI, Nordliner RG, Tagesson C, Walles S, Jarvholm BG. 1996. Genotoxic effects in workers exposed to low levels of benzene from gasoline. Am J Ind Med 30:317–324.
Occupational Safety and Health Administration (US). 1987. Final rule on occupational exposure to benzene. Fed Regist 54:34660–34762.
Parke DV, Williams RT. 1953. Studies in detoxification 49. The metabolism of benzene containing [14C1]-benzene. Biochem J 54:231–238.
Pathak DN, Levay G, Bodell WJ. 1995. DNA adduct formation in the bone marrow of B6C3F1 mice treated with benzene. Carcinogenesis 16:1803–1808.
Pinheiro JC, Bates DM. 2000. Mixed Effects Models in S and S-PLUS. New York NY: Springer-Verlag.
Pongracz K, Bodell WJ. 1996. Synthesis of N2-(4-hydroxyphenyl)-2′-deoxyguanosine-3′-phosphate: Comparison by 32P-postlabeling with the DNA adducts formed in HL-60 cells treated with hydroquinone. Chem Res Toxicol 9:593–598.
Rappaport SM, Yeowell-O’Connell K. 1999. Protein adducts as dosimeters of human exposure to styrene, styrene-7,8-oxide and benzene. Toxicol Lett 108:117–126.
Reddy MV, Blackburn GR, Schreiner CA, Mehlman MA, Mackerer CR. 1989. 32P-analysis of DNA adducts in tissues of benzene-treated rats. Environ Health Perspect 82:253–257.
Reddy MV, Schultz SC, Blackburn GR, Mackerer CR. 1994. Lack of DNA-adduct formation in mice treated with benzene. Mutat Res 325:149–155.
Rinsky RA, Hornung RW, Landrigan PJ. 1989. Re: “Benzene and leukemia: A review of the literature and a risk assessment.” Am J Epidemiol 129:1084–1086.
Rothman N, Bechtold WE, Yin SN, Dosemeci M, Li GL, Wang YZ, Griffith WC, Smith MT, Hayes RB. 1998. Urinary excretion of phenol, catechol, hydroquinone and muconicacid by workers occupationally exposed to benzene. Occup Environ Med 55:705–711.
Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, Li GL, Dosemeci M, Linet M, Zhang L, Xi L, Wacholder S, Lu W, Meyer KB, Titenko-Holland N, Stewart JT, Yin S, Ross D. 1997. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1609C-->T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res 57:2839–2842.
Rushmore T, Kalf G, Snyder R. 1984. Covalent binding of benzene and its metabolites to DNA in rabbit bone marrow mitochondria in vitro. Chem Biol Interact 49:133–154.
Sabourin PJ, Bechtold WE, Birnbaum LS, Lucier G, Henderson RF. 1988a. Differences in the metabolism and disposition of inhaled [3H]benzene by F344/N rats and B6C3F1 mice. Toxicol Appl Pharmacol 94:128–140.
Sabourin PJ, Bechtold WE, Griffith WC, Birnbaum LS, Lucier G, Henderson RF. 1989. Effect of exposure concentration, exposure rate and route of administration on metabolism of benzene by F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol 99:421–444.
Sabourin PJ, Bechtold WE, Henderson RF. 1988b. A high pressure liquid chromatographic method for the separation and quantitation of water-soluble radiolabeled benzene metabolites. Anal Biochem 170:316–327.
Sabourin PJ, Chen BT, Lucier G, Birnbaum LS, Fisher E,Henderson RF. 1987. Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice. Toxicol Appl Pharmacol 87:325–336.
Sabourin PJ, Muggenburg BA, Couch RC, Lefler D, Lucier G, Birnbaum, LS, Henderson RF. 1992. Metabolism of 14C]benzene by cynomolgus monkeys and chimpanzees. Toxicol Appl Pharmacol 114:277–284.
Seaton MJ, Schlosser PM, Bond JA, Medinsky MA. 1994. Benzene metabolism by human liver microsomes in relation to cytochrome P450 2E1 activity. Carcinogenesis 15:1799–1806.
Seaton MJ, Schlosser P, Medinsky MA. 1995. In vitro conjugation of benzene metabolites by human liver: Potential influence of interindividual variability on benzene toxicity. Carcinogenesis 16:1519–1527.
Smith ET, Yager JW, Steinmetz KL, Eastmond DA. 1989. Peroxidase dependence metabolism of benzene’s phenolic metabolites and its potential role in benzene’s toxicity and carcinogenecity. Environ Health Perspect 82:23–29.
Smith MT. 1996. Overview of benzene-induced aplastic anaemia. Eur J Haematol 57:107–110.
Smith MT, Robertson ML, Yager JW, Eastmond DA. 1990. Role of metabolism in benzene-induced myelotoxicity and leukemogenesis. Prog Clin Biol Res 340B:125–136.
Snyder R, Hedli CC. 1996. An overview of benzene metabolism. Environ Health Perspect 104:1165–1171.
Snyder R, Kalf A. 1994. A perspective on benzene leukemogenesis. Crit Rev Toxicol 24:177–209.
Snyder R, Kocsis JJ. 1975. Current concepts of chronic benzene toxicity. CRC Crit Rev Toxicol 3:265–288.
Snyder R, Lee EW, Kocsis JJ. 1978. Binding of labeled benzene metabolites to mouse liver and bone marrow. Res Commun Chem Pathol Pharmacol 20:191–194.
Snyder R, Witz G, Goldstein BD. 1993. The toxicology of benzene. Environ Health Perspect 100:293–306.
Sun JD, Medinsky MA, Birnbaum LS, Lucier G, Henderson RF. 1990. Benzene hemoglobin adducts in mice and rats: characterization of formation and physiological modeling. Fundam Appl Toxicol 15:468–475.
Tompa A, Major J, Jakab MG. 1994. Monitoring of benzene-exposed workers for genotoxic effects of benzene: Improved-working-condition-related decrease in the frequencies of chromosomal aberrations in peripheral blood lymphocytes. Mutat Res 304:159–165.
Tuo JS, Deng XS, Loft S, Poulsen HE.1999. Dexamethasone ameliorates oxidative DNA damage induced by benzene and LPS in mouse bone marrow. Free Radic Res 30:29–36.
Turteltaub KW, Vogel JS. 1995. Application of accelerator mass spectrometry in toxicology: A highly sensitive tool for low-level isotope measurements. In: Burlingame AL, Carr SA, eds. Mass Spectrometry in the Biological Sciences. Totawa NJ: Humana Press, pp. 477–495.
Turteltaub KW, Vogel JS, Frantz C, Felton JS, McManus M. 1995. Assessment of the DNA adduction and pharmacokinetics of PhIP and MeIOx in rodents at doses approximating human exposure using the technique of accelerator mass spectrometry (AMS) and 32P-postlabeling. Princess Takamatsu Symp 23:93–102.
Turteltaub KW, Vogel JS, Frantz CE, Fultz E. 1993. Studies on DNA adduction with heterocyclic amines by accelerator mass spectrometry: A new technique for tracing isotope-labeled DNA adduction. In: Phillips DH, Castegnaro M, Bartsch H, eds. Postlabeling Methods for Detection of DNA Adducts. Lyon, France: International Agency for Research on Cancer, pp. 293–300.
Vogel JS. 1992. Rapid production of graphite without contamination for biological AMS. Radiocarbon 34:344–350.
Vogel JS, Turteltaub KW, Finkel R, Nelson DE. 1995. Accelerator mass spectrometry: Isotope identification at attomole sensitivity. Anal Chem 67:353A–359A.
Wallace LA. 1989. The exposure of the general population to benzene. In: Mehlman MA, ed. Benzene: Occupational and Environmental Hazards. Scientific Update. Princeton NJ: Princeton Scientific Publishers, pp. 113–130.
Wallace L. 1996. Environmental exposure to benzene: an update. Environ Health Perspect 12:1129–1136
Wallace L, Pellizzari E, Hartwell T, Rosenzweig M, Erickson M, Sparacino C, Zelon H. 1984. Personal exposure to volatile organic compounds. Direct measurement in breath zone air, drinking water, food and exhaled breath. Environ Res 35:293–319.
Witz G, Kirley TA, Maniara WM, Mylavarapu VJ, Goldstein BD. 1991. The metabolism of benzene to muconic acid, a potential biologic marker of benzene exposure. Adv Exp Med Biol 283:613–618.
Witz G, Maniara W, Mylavarapu V, Goldstein BD 1990. Comparative metabolism of benzene and trans,transmuconaldehyde to trans,trans-muconic acid in DBA/2N and C57BL/6 mice. Biochem Pharmacol 40:1275–1280.
Yeowell-O'Connell K, Rothman N, Smith MT, Hayes RB, Li G, Waidyanatha S, Dosemeci M, Zhang L, Yin S, TitenkoHolland N, Rappaport SM. 1998. Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene. Carcinogenesis 9:1565–1571.
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Poulson A, Sorensen M, Hvidtfeldt U, Ketzel M, Christensen J, Brandt J, Frohn L, Khan J, Jensen S, Lund T, Raaschou-Nielsen O. Air pollution and stroke; effect modification by sociodemographic and environmental factors. A cohort study from Denmark. INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH 2023;251(114165). |
R828112C113 (Final) |
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Supplemental Keywords:
particulate matter, air toxics, epidemiology, health effects, ambient air quality, ozone, particulate matter, exposure and effects, ambient air quality, immune response, inhalation toxicology, aerosol particles, human health risk, air pollutants, particulates, respiratory, neurotoxic, exposure, human health, neurotoxicityRelevant Websites:
http://pubs.healtheffects.org/getfile.php?u=36 Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R828112 Health Effects Institute (2000 — 2005) Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R828112C042 Does Inhalation of Methanol Vapor Affect Human Neurobehavior?
R828112C043 Human Responses to Nitrogen Dioxide
R828112C044 The Role of Inflammation in Ozone-Induced Lung Injury
R828112C045 How Does Exercise Affect the Dose of Inhaled Air Pollutants?
R828112C046 How Do Chemicals in Diesel Engine Exhaust Damage DNA?
R828112C047 Effect of Nitrogen Dioxide on Bacterial Respiratory infectionin Mice
R828112C048 Effects of Ozone Exposure on Airway Epithelium
R828112C049 Inhalation of Aldehydes and Effects on Breathing
R828112C050 Does Ozone Cause Precancerous Changes in Cells?
R828112C051 Effects of Formaldehyde on Human Airway Epithelial Cells Exposed in a Novel Culture System
R828112C052 Carbon Monoxide and Cardiac Arrhythmias
R828112C053 Effects of Formaldehyde and Particle-Bound Formaldehyde on Lung Macrophage Functions
R828112C054 Mechanisms for Protecting Lung Epithelial Cells Against Oxidant Injury
R828112C055 Relationship of Nitropyrene-Derived DNA Adducts to Carcinogenesis
R828112C056 Particle Trap Effects on Heavy-Duty Diesel Engine Emissions
R828112C057 Carbon Monoxide and Atherosclerosis
R828112C058 Nitrogen Dioxide and Respiratory Illness in Children
R828112C059 Noninvasive Methods for Measuring Ventilation in Mobile Subjects
R828112C060 Oxidant Air Pollutants and Lung Cancer: An Animal Model
R828112C061 Detection of Carcinogen-DNA Adducts: Development of New Methods
R828112C062 Effects of Carbon Monoxide on Heart Muscle Cells
R828112C063 Development of Personal Ozone Samplers: Three Approaches
R828112C064 Development of Biomarkers to Monitor Carcinogen Exposure
R828112C065 Effects of Prolonged Ozone Inhalation on Collagen Structure and Content in Rat Lungs
R828112C065II Prolonged Ozone Exposure and the Contractile Properties of Isolated Rat Airways
R828112C065III Changes in Complex Carbohydrate Content and Structure in Rat Lungs Caused by Prolonged Ozone Inhalation
R828112C065IV Genetic Control of Connective Tissue Protein Synthesis After Prolonged Ozone Inhalation
R828112C065V Pulmonary Function Alterations in Rats After Chronic Ozone Inhalation
R828112C065VII Prolonged Ozone Exposure Leads to Functional and Structural Changes in the Rat Nose
R828112C065VIII - IX Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone
R828112C065X An Innovative Approach to Analyzing Multiple Experimental Outcomes: A Case Study of Rats Exposed to Ozone
R828112C065XI The Consequences of Prolonged Inhalation of Ozone on Rats:
An Integrative Summary of the Results of Eight Collaborative Studies
R828112C066 Interactive Effects of Nitropyrenes in Diesel Exhaust
R828112C067 Detection of FormaldehydeDNA Adducts: Development of New Methods
R828112C068I Comparison of the Carcinogenicity of Diesel Exhaust and Carbon Black in Rat Lungs
R828112C068II An Investigation of DNA Damage in the Lungs of Rats Exposed to Diesel Exhaust
R828112C068III No Evidence For Genetic Mutations Found In Lung Tumors From Rats Exposed To Diesel Exhaust or Carbon Black
R828112C069 Noninvasive Determination of Respiratory Ozone Absorption: The Bolus-Response Method
R828112C070 The Effects of Inhaled Oxidants and Acid Aerosols on Pulmonary Function
R828112C071 Biochemical Consequences of Ozone Reacting with Membrane Fatty Acids
R828112C072 DNA Mutations in Rats Treated with a Carcinogen Present in Diesel Exhaust
R828112C073 Developmental Neurotoxicity of Inhaled Methanol in Rats
R828112C074 Methanol Distribution in Non Pregnant and Pregnant Rodents
R828112C075 Is Increased Mortality Associated with Ozone Exposure in Mexico City?
R828112C076 Effects of Fuel Modification and Emission Control Devices on Heavy-Duty Diesel Engine Emissions
R828112C077 Metabolic Studies in Monkeys Exposed to Methanol Vapors
R828112C078 Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects
R828112C079 Improvement of a Respiratory Ozone Analyzer
R828112C080 Mechanism of Oxidative Stress from Low Levels of Carbon Monoxide
R828112C081 Long-Term Exposure to Ozone: Development of Methods to Estimate Past Exposures and Health Outcomes
R828112C082 Effects of Ambient Ozone on Healthy, Wheezy, and Asthmatic Children
R828112C083 Daily Changes in Oxygen Saturation and Pulse Rate Associated with Particulate Air Pollution and Barometric Pressure
R828112C084 Evaluation of The Potential Health Effects of the Atmospheric Reaction Products of Polycyclic Aromatic Hydrocarbons
R828112C085 Mechanisms of Response to Ozone Exposure: The Role of Mast Cells in Mice
R828112C086 Statistical Methods for Epidemiologic Studies of the Health Effects of Air Pollution
R828112C087 Development of New Methods to Measure Benzene Biomarkers
R828112C088 Alveolar Changes in Rat Lungs After Long-Term Exposure to Nitric Oxide
R828112C089 Effects of Prenatal Exposure to Inhaled Methanol on Nonhuman Primates and Their Infant Offspring
R828112C090 A Pilot Study of Potential Biomarkers of Ozone Exposure
R828112C091 Effects of Concentrated Ambient Particles on the Cardiac and Pulmonary Systems of Dogs
R828112C092 Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites
R828112C093 Effects of Concentrated Ambient Particles in Rats and Hamsters: An Exploratory Study
R828112C094I The National Morbidity, Mortality, and Air Pollution Study: Methods and Methodologic Issues
R828112C094II The National Morbidity, Mortality, and Air Pollution Study: Morbidity and Mortality from Air Pollution in the United States
R828112C095 Association of Particulate Matter Components with Daily Mortality and Morbidity in Urban Populations
R828112C096 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice
R828112C097 Identifying Subgroups of the General Population That May Be Susceptible to Short-Term Increases in Particulate Air Pollution
R828112C098 Daily Mortality and Fine and Ultrafine Particles in Erfurt, Germany
R828112C099 A Case-Crossover Analysis of Fine Particulate Matter Air Pollution and Out-of-Hospital Sudden Cardiac Arrest
R828112C100 Effects of Mexico City Air on Rat Nose
R828112C101 Penetration of Lung Lining and Clearance of Particles Containing Benzo[a]pyrene
R828112C102 Metabolism of Ether Oxygenates Added to Gasoline
R828112C103 Characterization and Mechanisms of Chromosomal Alterations Induced by Benzene in Mice and Humans
R828112C104 Acute Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles
R828112C105 Genetic Differences in Induction of Acute Lung Injury and Inflammation in Mice
R828112C106 Effects on Mice of Exposure to Ozone and Ambient Particle Pollution
R828112C107 Emissions from Diesel and Gasoline Engines Measured in Highway Tunnels
R828112C108 Case-Cohort Study of Styrene Exposure and Ischemic Heart Disease Investigators
R828112C110 Effects of Metals Bound to Particulate Matter on Human Lung Epithelial Cells
R828112C111 Effect of Concentrated Ambient Particulate Matter on Blood Coagulation Parameters in Rats
R828112C112 Health Effects of Acute Exposure to Air Pollution
R828112C113 Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
R828112C114 A Personal Particle Speciation Sampler
R828112C115 Validation and Evaluation of Biomarkers in Workers Exposed to Benzene in China
R828112C116 Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study
R828112C117 Peroxides and Macrophages in the Toxicity of Fine Particulate Matter in Rats
R828112C118 Controlled Exposures of Healthy and Asthmatic Volunteers to Concentrated Ambient Particles in Metropolitan Los Angeles
R828112C119 Manganese Toxicokinetics at the Blood-Brain Barrier
R828112C120 Effects of Exposure to Concentrated Ambient Particles from Detroit Air on Healthy Rats and Rats with Features of Asthma or Mild Bronchitis
R828112C121 Field Evaluation of Nanofilm Detectors for Measuring Acidic Particles in Indoor and Outdoor Air
R828112C123 Time-Series Analysis of Air Pollution and Mortality: A Statistical Review
R828112C126 Effects of Exposure to Ultrafine Carbon Particles in Healthy Subjects and Subjects with Asthma
R828112C128 Neurogenic Responses of Rat Lung to Diesel Exhaust
R828112C130-I Relationships of Indoor, Outdoor, and Personal Air (RIOPA). Part I. Collection Methods and Descriptive Analyses
R828112C132 An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
1 journal articles for this subproject
Main Center: R828112
9 publications for this center
6 journal articles for this center