Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment




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Mutagenicity of ozone
COM statement COM/99/S3 - May 1999

Introduction

Ozone is an ubiquitous air pollutant due to its formation in the atmosphere by photochemical reaction between volatile hydrocarbons and nitrogen oxides. The Expert Panel on Air Quality Standards have recommended a very low standard (50 ppb as a running 8 hour average) based on its irritant effects on the respiratory tract at 100 ppb and above. Ozone is also one of a limited number of chemicals that have been shown to be carcinogenic in the mouse (producing lung adenomas/carcinomas in a strain sensitive to such tumour induction) but not the rat. The COC have reviewed the need for carcinogenicity bioassay data in the mouse, and as part of this work are considering the public health significance of such apparent mouse specific carcinogens. A key aspect of these is consideration of the genotoxic potential of such compounds. The COC felt it important to draw conclusions on the possibility of a genotoxic mechanism, particularly in the light of recent data on K ras mutations in lung neoplasms from ozone exposed mice (1); the advice of the COM was thus requested on this issue.

Conclusions

i. Ozone is a powerful oxidising agent and reacts readily with most biological macromolecules including DNA. (2-11) It has been shown to produce gene mutation in Salmonella typhimurium TA102 in the presence or absence of rat S-9.(12-14) There are no data from in vitro studies to adequately investigate its clastogenic potential (15) but it has been shown to induce SCEs in mammalian cells.(16-18) The available in vitro data indicate that ozone has mutagenic potential.

ii. The in vivo clastogenicity of ozone in bone marrow or peripheral blood has been investigated in the Chinese hamsters (19-21), mouse (19,20) and rat (22). Although all these studies have limitations, the results do suggest that ozone is not clastogenic in bone marrow. Only one very limited study has been carried out in germ cells (21); this was negative, which is consistent with the bone marrow data. However, clastogenic effects have been demonstrated in lung cells (macrophages) of rats exposed to ozone gas.(23)

iii. In addition, examination of the K-ras mutational spectra of ozone induced lung neoplasms in mice indicated a high frequency of mutations, including A-T transversions in codon 61. (1) These appeared to be specific to ozone and did not occur in spontaneous lung neoplasms in mice. Thus, there is some evidence for in-vivo mutagenic activity at the target site for carcinogenicity in the mouse.

iv. Members recommended that additional work to reproduce ozone induced A-T transversions that would provide additional reassurance regarding conclusion iii). This would comprise an assessment of whether ozone induced mutational signatures in-vitro and analysis of lung tumours in mice exposed to an inert particle such as titanium dioxide.

v. The COM concluded that it would be prudent to assume that ozone may have in-vivo genotoxic potential. Members agreed that it would be acceptable for the Committee to adopt the approach normally used for in-vivo mutagens, ie to assume a linear dose-response.

References

1. Sills RC, Hong HL, Greenwell A et al. Increased frequency of K-ras mutations in lung neoplasms from female B6C3F1 mice exposed to ozone for 24 or 30 months. Carcinogenesis, 16, 1623-8 (1995).

2. Christensen E, Giese AC. Changes in absorption spectra of nucleic acids and their derivatives following exposure to ozone and ultraviolet radiation. Arch Biochem Biophys, 51, 208-16 (1954).

3. Prat R, Nofre C, Cier A. Effects de l'hyperchlorite de sodium, de l'ozone et des radiations ionisantes sur les constituants pyrimidiques d'esherichia coli. Ann Inst Pasteur, 114, 595-607 (1968).

4. Omura H, Tsutsumi M, Ariyhsi K, Ishikita R. Variation of nucleic acids by ozonation [in Japanese with English summary]. Sci Bull Fac Agr Kyushu Univ, 26, 517-23 (1972).

5. Ishizaki K, Shinriki N, Ikehata A, Ueda T. Degradation of nucleic acids with ozone, I. Degradation of nucleobases, ribonucleosides and ribonucleoside-5'-monophosphates. Chem Pharm Bull, 29, 868-72 (1981).

6. Shinriki N, Isizaki K, Ikehata A et al. Degradation of nucleic acids with ozone. II: Degradation of yeast RNA, yeast phenylalanine tRNA and tobacco mosaic virus RNA. Biochem Biophys Act, 655, 323-8 (1981).

7. Shinriki N, Ishizaki K, Sato S et al Degradation of nucleic acids with ozone, VI: Labilization of the double-helical structure of calf thymus deoxyribonucleic acid. Chem Pharm Bull, 32, 3636-3640 (1984).

8. Sawadaishi K, Miura K, Ohthuka E et al. Mode of degradation of plasmid DNA with ozone. Nucleic Acids Symp Ser, 15, 151-4 (1984).

9. Sawadaishi K, Miura K, Ohtsuka E et al. Sequence specificity of ozone-degradation of bases in supercoiled plasmid DNA. Nucleic Acids Symp Ser, 16, 205-8 (1985).

10. Sawadaishi K, Miura K, Ohthuka E et al. Structure- and sequence-specificity of ozone degradation of supercoiled plasmid DNA. Nucleic Acids Res, 14, 1159-69 (1986).

11. Hamelin C. Production of single- and double-strand breaks in plasmid DNA by ozone. Int J Radiat Oncol Biol Phys, 11, 253-7 (1985).

12. Shepson PB, Kleindienst TE, Edney GR et al. The mutagenic activity of irradiated toluene, NO2, H2O, air mixtures. Env. Sci. Technol, 19, 249-55 (1985).

13. Victoria K, Stahlberg M. A method for studying the mutagenicity of some gaseous compounds in Salmonella typhimurium. Env. Mol. Mut, 11, 65-77 (1988).

14. Dillon D, Combes R, McConville M, Zeiger E. Ozone is mutagenic in Salmonella. Env. Mol. Mut, 19, 331-7 (1992).

15. Fetner RH. Chromosome breakage in vicia faba by ozone. Nature, 181, 504-5 (1958).

16. Guerrero RR, Rounds DE, Olson RS, Hackney JD. Mutagenic effects of ozone on human cells exposed in vivo and in vitro based on SCE analysis. Env. Res,. 18, 336-46 (1979).
17. Shiraishi F, Bandow H. The genetic effects of the photochemical reaction products of propylene plus NO2 on cultured Chinese hamster cells exposed in vitro. J. Toxicol. Environ. Health, 15, 531-8 (1985).

18. Hsueh JL, Xiang W. Environmental mutagenesis research at Fudan University. Env. Sci. Res, 31, 755-69 (1984).

19. Zalac RE, Comroy HL, Bolch WE et al. Inhaled ozone as a mutagen I chromosome aberrations induced in Chinese hamster lymphocytes. Environ. Res, 4, 262-82 (1971).

20. Tice RR, Bender MA, Ivett JL, Drew RT. Cytogenetic effects of inhaled ozone. Mut. Res, 58, 293-304 (1978).

21. Gooch PC, Creasia DA, Breven JG. The cytogenetic effects of ozone: inhalation and in vitro exposure. Env. Res, 12, 188-95 (1976).

22. Zhurkov VS, Pechennikova EV, Feldt EG et al. Analysis of chromosome aberrations in bone marrow cells of rats after inhalation exposure to ozone. Gig Sanit, 9, 12-4 (1979).

23. Rithidech K, Hotchkiss JA, Griffith WC et al. Chromosome damage in rat pulmonary alveolar macrophages following ozone inhalation. Mut Res, 241, 67-73 (1990).

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