Introduction

1. Ozone is a 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 it's 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 benign lung tumours in a strain sensitive to such tumour induction) but not the rat.

2. 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. (1,2) 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 (3); the advice of the COM was thus requested on this issue.


COC Conclusions


3. The COC reached the following conclusions on the potential carcinogenic hazard to humans in the light of advice from COM and the available evidence from the animal carcinogenicity bioassays.

(i) Ozone has been tested for potential carcinogenicity in mice and rats in long term inhalation bioassays as part of the ongoing National Toxicology Programme (NTP) in the USA. (4)

(ii) There was no evidence of treatment related carcinogenicity in male or female F344 rats exposed to 0.12, 0.5.1.0 ppm 6 hours/day, for 5 days/week, for up to 105 weeks or in a similar study where rats were exposed to 0.5 or 1.0 ppm for 6 hours/day, 5 days/week, for up to 125 wks. Ozone induced inflammation and non-neoplastic pathology (hyperplasia and metaplasia) throughout the respiratory tract in both sexes, particularly at the highest concentration.

(iii) Long term inhalation bioassays were also undertaken in B6C3F1 mice using exposures of 0.12, 0.5 or 1.0 ppm 6 hours/day, 5 days/week for 105 weeks. A separate life-time bioassay was performed using exposures of 0.5 or 1.0, for 6hours/day, 5 days/week, for 125 wks. The NTP reported the statistical analyses of the carcinogenicity data based on evaluation of the combined incidence of lung adenomas and carcinomas. The NTP consider that pulmonary tumours in mice form a spectrum of lesions and adenomas appear to progress into carcinomas with time. The results reported in this statement refer to the outcome of the NTP evaluation based on combinining the incidence of adenoma and carcinomas consistent with this approach to the assessment of data.

iv) A statistically significant increase in the incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was found in female B6C3F1 mice in the long-term bioassay at 1.0 ppm. This occurred in the presence of non-neoplastic pathology (inflammation, hyperplasia and/or metaplasia) throughout the respiratory tract. Evidence of chronic inflammation was documented in some female animals at 0.5 ppm but no increased incidence of lung tumours (combined adenoma and carcinomas) was reported at this dose level. No evidence of a carcinogenic or inflammatory response was documented in female mice at 0.12 ppm. A slight but statistically non-significant increase in the combined incidence of lung tumours (combined adenoma and carcinoma) occurred in male mice at 0.5 ppm and 1.0 ppm.

v) A slight but statistically non-significant increase in lung tumours (combined adenoma and carcinoma) was documented in the life-time bioassay in male mice at 0.5 ppm and 1.0 ppm and in female mice at 1.0 ppm. In separate analyses the increase in incidence of lung adenoma in female mice reached statistical significance at 1.0 ppm.

(vi) Thus ozone was carcinogenic by inhalation in female B6C3F1 mice producing lung tumours; this effect was associated with chronic irritation of the lung. There was equivocal evidence for a carcinogenic effect in male mice. Ozone was not carcinogenic in male or female F344 rats.

(vii) The COM has advised that there is some evidence for in-vivo mutagenic activity at the target site for carcinogenicity in the mouse. Additional work to reproduce ozone induced A-T transversions would provide additional information regarding this conclusion. The COM concluded that it would be prudent to assume that ozone may have in-vivo genotoxic potential.

(viii) The COC concluded that the mechanism of ozone carcinogenicity in the mouse is currently uncertain, leaving a question about whether the carcinogenic action is due to a genotoxic event(s) or chronic irritation. The carcinogenic activity of ozone appears to be specific to the mouse in the presence of chronic irritation and has not been observed in the rat. The animal data are thus inadequate to draw any conclusions regarding the potential carcinogenicity of ozone in humans.

(ix) The Committee agreed to review the situation in the future should more evidence of an in-vivo mutational effect by ozone become available.


COC Secretariat
July 1999



References

1. Department of Health (1998). 1997 Annual report of the Committees on Toxicity, Mutagenicity, Carcinogenicity of Chemicals in Food, Consumers Products and the Environment.

2. Battershill JM and Fielder RJ (1998). Mouse-specific carcinogens: an assessment of hazard and significance for validation of short-term carcinogenicity bioassays in transgenic mice. Human and Experimental Toxicology, 17, 193-205.

3. Sills RC, Hong HL, Greenwell A, Herbet RA, Boorman GA, Devereux TR (1995). Increased frequency of K-ras mutations in lung neoplasms from female B6C3F1 mice exposed to ozone for 24 or 30 months. Carcinogenesis, 16, (7), 1623-1628.

4. National Toxicology Program (1994). NTP Technical report on the toxicology and carcinogenesis studies of ozone and ozone/NNK in F344/N rats and B^C3F1 mice (inhalation studies). NTP, Research Triangle Park, NC 27709, October 1994, NIH Publication No-95-3371.

Top

copyright: © | updated: 30 July, 2002