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Thirdhand Tobacco Smoke: Chemical Characterization, Human Exposure and Urinary Carcinogen Biomarkers

Periodic Reporting for period 1 - THSExposure (Thirdhand Tobacco Smoke: Chemical Characterization, Human Exposure and Urinary Carcinogen Biomarkers)

Reporting period: 2015-09-15 to 2017-09-14

Tobacco smoking is the leading cause of preventable disease worldwide. Compared with the rest of the world, the World Health Organisation European region has one of the highest proportions of deaths attributable to tobacco. According to the 2012 Eurobarometer survey the 33% of the Spanish and the 28% of the EU population aged 15 or more smoke. Although most of EU countries have introduced smoking bans in public places, domestic environments are still an important source of passive smoking exposure. Environmental tobacco smoke contains more than 4,000 chemicals many of which are toxic and carcinogenic and is estimated to be the cause of about 1.0% of worldwide mortality. In addition to passive inhalation, non-smokers, especially children, are also at risk through contact with surfaces and dust contaminated with residual smoke gases and particles, the so-called Thirdhand tobacco smoke (THS). Recent research demonstrated the occurrence of nicotine and some tobacco-related carcinogens on THS, such as tobacco specific nitrosamines, a leading class of tobacco carcinogens that can cause damage in DNA in human cell lines. Despite the emerging evidence on THS harms, the specific role of THS in tobacco-related illnesses has been questioned so far by the public health community because of the poor level of characterisation of THS constituents and mechanisms of formation, as well as the lack of studies focused on human exposure. The use of metabolomics tools in non-invasive human fluids, such as urine, for determining possible passive smoking biomarkers would imply a big step forward in this field that would help to reduce the occurrence of tobacco-related illnesses in non-smokers. However, to our knowledge metabolomics has not been applied in this field yet.
Hence, this project is based on the assumption that THS is an important pathway of passive exposure to tobacco-related carcinogens that has been underestimated up to now, and that the use of metabolomics combining the most up-to-date analytical instrumentation and powerful statistical tools will allow the development of reliable biomarkers of THS exposure in human urine.

The main aim of THSExposure project is to fill some of the important gaps on our current understanding of the chemistry, toxicology and exposure of the tobacco smoke carcinogens that remain on dust and surfaces, also called thirdhand tobacco smoke (THS), by using, for the first time, metabolomics approaches. This project was divided in five specific objectives:
1. Accurate characterization of THS chemical composition, including the targeted analysis of tobacco smoke carcinogens not yet investigated in THS.
2. Comparison of the house dust composition from smokers’ and non-smokers homes to elaborate profiles indicative of different stages of tobacco smoke exposure.
3. Use of metabolomics to find phenotypic profiles of human urine at different stages of tobacco exposure and to develop new biomarkers of tobacco exposure.
4. Development and validation of high throughput analytical methods for simultaneously determining specific biomarkers of tobacco exposure in human urine.
5. Monitoring of matching samples of house dust from smokers’ and non-smokers’ homes and the urine of the households, to assess cancer risk of this exposure.

The final objective is the diffusion of the results obtained here as evidences of THS harms and to influence in health educational programs, especially addressed to smoking parents, and tobacco-related public health policies as a part of a worldwide tobacco control strategy.
To the date, the main scientific achievements of the project have been:
- Development on an analytical method for the simultaneous determination of dozens carcinogen organic compounds in thirdhand smoke samples at ng/g levels.
- Identification of carcinogen compounds reported for the first time in THS, such as several types of polycyclic aromatic compounds, amines and carbonyls.
- Detection for the first time of NNA in aged tobacco smoke samples, that is a carcinogen tobacco-specific nitrosamine not detected to the date in THS real samples.
- Successful use of non-targeted metabolomics tools for the characterization of environmental samples, specifically of house dust and THS samples.
- Identification of sixteen nicotine-related metabolites in urine of animal models exposed to THS in conditions that mimic human exposure of non-smokers that live in smokers’ homes
- Identification of seventy-nine endogenous metabolites altered in urine samples of THS-exposed mice. These results are the first metabolomics study on THS-exposed animal models. If confirmed in humans, they will imply a huge step-forward on THS health effects and therefore, these results would have a crucial role on tobacco policies.
- The development of robust, highly selective and sensitive analytical method for determining nine nicotine-related metabolites in human urine.

The results of THSExposure project have been disseminated in eleven international scientific conferences and workshops and also through ten invited talks to tobacco and medical symposiums and public engagement activities. As direct results of the project, four scientific papers have been submitted to peer-reviewed scientific journals or are in preparation. Furthermore, the researcher has also collaborated in the development of metabolomics data processing tools. These indirect results have been already published in five high-impact scientific peer-reviewed publications.
To our knowledge, the results obtained from this fellowship are the most complete characterization of THS samples. The target analysis of dozens of carcinogen organic compounds in THS samples, allows a more complete evaluation of the estimated lifetime cancer risks of non-smokers exposed to THS. Moreover, the non-targeted tools developed in collaboration with other researchers, favour the identification of new chemical species in THS thus broadening even more our knowledge on THS chemical composition and providing new evidences of THS hazards. On the other hand, the molecular mechanisms of the possible health effects associated to THS exposure have been elucidated using animal models in conditions that mimic the human exposure in smoking environments. The identification of nicotine related metabolites on mice exposed to THS confirms that thirdhand tobacco smoke exposure is a new pathway of tobacco exposure that has to be included in tobacco-related environmental and health policies. Furthermore, the multiple metabolic dysregulations in THS-exposed mice, characterized for the first time in this fellowship, indicates the several health effects that could be associated to THS-exposure and must change the current accepted definition of passive-smoker. These results, are especially relevant to children with smoking parents and our efforts on the following months will be focused on the confirmation of the metabolic alterations in human urine and the dissemination of the results to medical doctors and other health professionals, teachers and parents.
Graphical abstract of THSExposure project.