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. 1998 Dec;106(Suppl 6):1337–1346. doi: 10.1289/ehp.98106s61337

Lung tumorigenic interactions in strain A/J mice of five environmental polycyclic aromatic hydrocarbons.

S Nesnow 1, M J Mass 1, J A Ross 1, A J Galati 1, G R Lambert 1, C Gennings 1, W H Carter Jr 1, G D Stoner 1
PMCID: PMC1533448  PMID: 9860890

Abstract

The binary, ternary, quaternary, and quintary interactions of a five-component mixture of carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) using response surface analyses are described. Initially, lung tumor dose-response curves in strain A/J mice for each of the individual PAHs benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), dibenz[a,h]anthracene (DBA), 5-methylchrysene (5MC), and cyclopenta[cd]pyrene (CPP) were obtained. From these data, doses were selected for the quintary mixture study based on toxicity, survival, range of response, and predicted tumor yields. The ratios of doses among PAHs were designed to simulate PAH ratios found in environmental air and combustion samples. Quintary mixtures of B[a]P, B[b]F, DBA, 5MC, and CPP were administered to male strain A/J mice in a 2(5) factorial 32-dose group dosing scheme (combinations of five PAHs each at either high or low doses) and lung adenomas were scored. Comparison of observed lung adenoma formation with that expected from additivity identified both greater than additive and less than additive interactions that were dose related i.e., greater than additive at lower doses and less than additive at higher doses. To identify specific interactions, a response surface analysis using response addition was applied to the tumor data. This response surface model contained five dose, ten binary, ten ternary, five quaternary, and one quintary parameter. This analysis produced statistically significant values of 16 parameters. The model and model parameters were evaluated by estimating the dose-response relationships for each of the five PAHs. The predicted dose-response curves for all five PAHs indicated a good estimation. The binary interaction functions were dominated for the most part by DBA and were inhibitory. The response surface model predicted, to a significant degree, the observed lung tumorigenic responses of the quintary mixtures. These data suggest that although interactions between PAHs do occur, they are limited in extent.

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Selected References

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  1. Back S. O., Goldstone M. E., Kirk P. W., Lester J. N., Perry R. Concentrations of particulate and gaseous polycyclic aromatic hydrocarbons in London air following a reduction in the lead content of petrol in the United Kingdom. Sci Total Environ. 1992 Jan 15;111(2-3):169–199. doi: 10.1016/0048-9697(92)90354-u. [DOI] [PubMed] [Google Scholar]
  2. Beach A. C., Agarwal S. C., Lambert G. R., Nesnow S., Gupta R. C. Reaction of cyclopenta[c,d]pyrene-3,4-epoxide with DNA and deoxynucleotides. Carcinogenesis. 1993 Apr;14(4):767–771. doi: 10.1093/carcin/14.4.767. [DOI] [PubMed] [Google Scholar]
  3. Berenbaum M. C. The expected effect of a combination of agents: the general solution. J Theor Biol. 1985 Jun 7;114(3):413–431. doi: 10.1016/s0022-5193(85)80176-4. [DOI] [PubMed] [Google Scholar]
  4. Calabrese E. J. Toxicological consequences of multiple chemical interactions: a primer. Toxicology. 1995 Dec 28;105(2-3):121–135. doi: 10.1016/0300-483x(95)03206-u. [DOI] [PubMed] [Google Scholar]
  5. Carmichael P. L., Platt K. L., Shé M. N., Lecoq S., Oesch F., Phillips D. H., Grover P. L. Evidence for the involvement of a bis-diol-epoxide in the metabolic activation of dibenz[a,h]anthracene to DNA-binding species in mouse skin. Cancer Res. 1993 Mar 1;53(5):944–948. [PubMed] [Google Scholar]
  6. Deutsch-Wenzel R. P., Brune H., Grimmer G., Dettbarn G., Misfeld J. Experimental studies in rat lungs on the carcinogenicity and dose-response relationships of eight frequently occurring environmental polycyclic aromatic hydrocarbons. J Natl Cancer Inst. 1983 Sep;71(3):539–544. [PubMed] [Google Scholar]
  7. Fuchs J., Mlcoch J., Platt K. L., Oesch F. Characterization of highly polar bis-dihydrodiol epoxide--DNA adducts formed after metabolic activation of dibenz[a,h]anthracene. Carcinogenesis. 1993 May;14(5):863–867. doi: 10.1093/carcin/14.5.863. [DOI] [PubMed] [Google Scholar]
  8. Gennings C. An efficient experimental design for detecting departure from additivity in mixtures of many chemicals. Toxicology. 1995 Dec 28;105(2-3):189–197. doi: 10.1016/0300-483x(95)03212-x. [DOI] [PubMed] [Google Scholar]
  9. Gennings C., Carter W. H., Jr, Harris L. W., Carchman R. A., Campbell E. D., Boyle R. M., Talbot B. G., Solana R. P. Assessing the efficacy of azaprophen and physostigmine as a pretreatment for soman-induced incapacitation in guinea pigs by response-surface modeling. Fundam Appl Toxicol. 1990 Feb;14(2):235–242. doi: 10.1016/0272-0590(90)90204-w. [DOI] [PubMed] [Google Scholar]
  10. Gennings C., Sofia R. D., Carchman R. A., Carter W. H., Jr, Swinyard E. A. Analysis of anticonvulsant and neurotoxic responses to combination therapy with carbamazepine, felbamate and phenytoin by response-surface modeling. Arzneimittelforschung. 1995 Jul;45(7):739–748. [PubMed] [Google Scholar]
  11. Gessner P. K. Isobolographic analysis of interactions: an update on applications and utility. Toxicology. 1995 Dec 28;105(2-3):161–179. doi: 10.1016/0300-483x(95)03210-7. [DOI] [PubMed] [Google Scholar]
  12. Gibb H. J., Chen C. W. Multistage model interpretation of additive and multiplicative carcinogenic effects. Risk Anal. 1986 Jun;6(2):167–170. doi: 10.1111/j.1539-6924.1986.tb00204.x. [DOI] [PubMed] [Google Scholar]
  13. Habs M., Schmähl D., Misfeld J. Local carcinogenicity os some environmentally relevant polycyclic aromatic hydrocarbons after lifelong topical application to mouse skin. Arch Geschwulstforsch. 1980;50(3):266–274. [PubMed] [Google Scholar]
  14. Hecht S. S., Bondinell W. E., Hoffmann D. Chrysene and methylchrysenes: presence in tobacco smoke and carcinogenicity. J Natl Cancer Inst. 1974 Oct;53(4):1121–1133. doi: 10.1093/jnci/53.4.1121. [DOI] [PubMed] [Google Scholar]
  15. Hughes N. C., Phillips D. H. Covalent binding of dibenzpyrenes and benzo[a]pyrene to DNA: evidence for synergistic and inhibitory interactions when applied in combination to mouse skin. Carcinogenesis. 1990 Sep;11(9):1611–1619. doi: 10.1093/carcin/11.9.1611. [DOI] [PubMed] [Google Scholar]
  16. Lavoie E. J., Braley J., Rice J. E., Rivenson A. Tumorigenic activity of non-alternant polynuclear aromatic hydrocarbons in newborn mice. Cancer Lett. 1987 Jan;34(1):15–20. doi: 10.1016/0304-3835(87)90068-1. [DOI] [PubMed] [Google Scholar]
  17. Mass M. J., Abu-Shakra A., Roop B. C., Nelson G., Galati A. J., Stoner G. D., Nesnow S., Ross J. A. Benzo[b]fluoranthene: tumorigenicity in strain A/J mouse lungs, DNA adducts and mutations in the Ki-ras oncogene. Carcinogenesis. 1996 Aug;17(8):1701–1704. doi: 10.1093/carcin/17.8.1701. [DOI] [PubMed] [Google Scholar]
  18. Mass M. J., Jeffers A. J., Ross J. A., Nelson G., Galati A. J., Stoner G. D., Nesnow S. Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. Mol Carcinog. 1993;8(3):186–192. doi: 10.1002/mc.2940080309. [DOI] [PubMed] [Google Scholar]
  19. Melikian A. A., Amin S., Hecht S. S., Hoffmann D., Pataki J., Harvey R. G. Identification of the major adducts formed by reaction of 5-methylchrysene anti-dihydrodiol-epoxides with DNA in vitro. Cancer Res. 1984 Jun;44(6):2524–2529. [PubMed] [Google Scholar]
  20. Nemeroff C. B., DeVane C. L., Pollock B. G. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry. 1996 Mar;153(3):311–320. doi: 10.1176/ajp.153.3.311. [DOI] [PubMed] [Google Scholar]
  21. Nesnow S., Ross J. A., Nelson G., Wilson K., Roop B. C., Jeffers A. J., Galati A. J., Stoner G. D., Sangaiah R., Gold A. Cyclopenta[cd]pyrene-induced tumorigenicity, Ki-ras codon 12 mutations and DNA adducts in strain A/J mouse lung. Carcinogenesis. 1994 Apr;15(4):601–606. doi: 10.1093/carcin/15.4.601. [DOI] [PubMed] [Google Scholar]
  22. Nesnow S., Ross J. A., Stoner G. D., Mass M. J. Mechanistic linkage between DNA adducts, mutations in oncogenes and tumorigenesis of carcinogenic environmental polycyclic aromatic hydrocarbons in strain A/J mice. Toxicology. 1995 Dec 28;105(2-3):403–413. doi: 10.1016/0300-483x(95)03238-b. [DOI] [PubMed] [Google Scholar]
  23. Nesnow S., Triplett L. L., Slaga T. J. Studies on the tumor initiating, tumor promoting, and tumor co-initiating properties of respiratory carcinogens. Carcinog Compr Surv. 1985;8:257–277. [PubMed] [Google Scholar]
  24. Okuda H., Nojima H., Miwa K., Watanabe N., Watabe T. Selective covalent binding of the active sulfate ester of the carcinogen 5-(hydroxymethyl)chrysene to the adenine residue of calf thymus DNA. Chem Res Toxicol. 1989 Jan-Feb;2(1):15–22. doi: 10.1021/tx00007a003. [DOI] [PubMed] [Google Scholar]
  25. Pfeiffer E. H. Oncogenic interaction of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons in mice. IARC Sci Publ. 1977;(16):69–77. [PubMed] [Google Scholar]
  26. Rao V. R. Binary effects of carcinogens and tumor promoters--a preliminary chemical structural analysis of BCIDB and PCIDB. J Toxicol Environ Health. 1991 Jun;33(2):237–248. doi: 10.1080/15287399109531521. [DOI] [PubMed] [Google Scholar]
  27. Reif A. E. Synergism in carcinogenesis. J Natl Cancer Inst. 1984 Jul;73(1):25–39. [PubMed] [Google Scholar]
  28. Rogan E. G., Devanesan P. D., RamaKrishna N. V., Higginbotham S., Padmavathi N. S., Chapman K., Cavalieri E. L., Jeong H., Jankowiak R., Small G. J. Identification and quantitation of benzo[a]pyrene-DNA adducts formed in mouse skin. Chem Res Toxicol. 1993 May-Jun;6(3):356–363. doi: 10.1021/tx00033a017. [DOI] [PubMed] [Google Scholar]
  29. Ross J. A., Nelson G. B., Wilson K. H., Rabinowitz J. R., Galati A., Stoner G. D., Nesnow S., Mass M. J. Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res. 1995 Mar 1;55(5):1039–1044. [PubMed] [Google Scholar]
  30. Schmähl D., Schmidt K. G., Habs M. Syncarcinogenic action of polycyclic hydrocarbons in automobile exhaust gas condensates. IARC Sci Publ. 1977;(16):53–59. [PubMed] [Google Scholar]
  31. Solana R. P., Chinchilli V. M., Carter W. H., Jr, Wilson J. D., Carchman R. A. The evaluation of biological interactions using response surface methodology. Cell Biol Toxicol. 1987 Sep;3(3):263–277. doi: 10.1007/BF00117864. [DOI] [PubMed] [Google Scholar]
  32. Surh Y. J., Kwon H., Tannenbaum S. R. Sulfotransferase-mediated activation of 4-hydroxy- and 3,4-dihydroxy-3,4-dihydrocyclopenta[c,d]pyrene, major metabolites of cyclopenta[c,d]pyrene. Cancer Res. 1993 Mar 1;53(5):1017–1022. [PubMed] [Google Scholar]
  33. Weyand E. H., Cai Z. W., Wu Y., Rice J. E., He Z. M., LaVoie E. J. Detection of the major DNA adducts of benzo[b]fluoranthene in mouse skin: role of phenolic dihydrodiols. Chem Res Toxicol. 1993 Jul-Aug;6(4):568–577. doi: 10.1021/tx00034a028. [DOI] [PubMed] [Google Scholar]
  34. Wilson J. D., Carter W. H., Jr, Campbell E. D., Kessler F. K., Carchman R. A. Application of response-surface methodology to detect interactions of genotoxic agents in cultured mammalian cells. J Toxicol Environ Health. 1986;19(2):173–183. doi: 10.1080/15287398609530918. [DOI] [PubMed] [Google Scholar]
  35. You L., Wang D., Galati A. J., Ross J. A., Mass M. J., Nelson G. B., Wilson K. H., Amin S., Stoner J. C., Nesnow S. Tumor multiplicity, DNA adducts and K-ras mutation pattern of 5-methylchrysene in strain A/J mouse lung. Carcinogenesis. 1994 Nov;15(11):2613–2618. doi: 10.1093/carcin/15.11.2613. [DOI] [PubMed] [Google Scholar]

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