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Biomarkers of exposure

The US National Academy of Sciences’ Institute of Medicine has defined a biomarker of exposure (BoE) as: "a constituent or metabolite that is measured in a biological fluid or tissue that has the potential to interact with a biological macromolecule; sometimes considered a measure of internal dose" and ideally is:-

  • Specific to the source compound
  • Correlated with exposure dose
  • Easy to obtain
  • Able to be measured accurately[1]

There is wide recognition by external scientists that BoEs are an effective way of measuring exposure to environmental chemicals.

The published literature currently describes four basic biomarker groups in use today: biomarkers of exposure (which include markers of external exposure and of internal dose); biomarkers of biologically effective dose; biomarkers of effect (which include markers of health impairment and early disease precursors); and susceptibility biomarkers (which include intrinsic genetic or other characteristics or pre-existing diseases that result in an increase in internal dose, biologically effective dose, or target tissue response)[2,3].

Use of Biomarkers of Exposure

Biomarkers of exposure are being developed as tools to assess exposure to tobacco and tobacco smoke constituents in humans. They offer the potential to measure smoke constituent and toxicant exposure independent of subjects’ smoking behaviour (see Smoking Behaviour page) i.e. number of cigarettes smoked, puffing pattern, mouth spill and inhalation pattern. The data generated by this form of exposure assessment could then be used to support a weight of evidence approach, which we believe to be necessary for the evaluation of reduced toxicant prototypes[4].

It is probable that no single biomarker will satisfy such assessment needs, and so a panel of biomarkers must be used.  The biomarkers will be assessed for their specificity, sensitivity, reproducibility, and ability to discriminate between different doses[5,6]. In addition, the utility of new biomarkers must be established for different consumer populations (i.e. those varying in behaviour, gender, age, genetics, and prior tobacco use).

BoEs are currently available for 8 groups of tobacco smoke toxicant chemicals and proof of concept studies are being used to test whether these BoEs can differentiate between smokers and non-smokers, and between differing doses of tobacco smoke constituents. A selection of these biomarkers may also be applicable in the assessment of smokeless products such as SNUS, while new ones are continually being explored for future use.

Inter-laboratory ring trials are being used to assess the robustness of biomarker analysis methods while metabolism studies are being used to identify new BoEs for specific tobacco smoke toxicants, and to better understand the behaviour of BoEs.

Future BoE development will be based on (though not exclusively driven by) externally prepared Priority Toxicant lists[7], which could be used to advise new technology development as part of our Harm Reduction programme.

A variety of biomarkers have been assessed for their suitability in discriminating toxicant exposure between different ISO tar yield cigarette smokers, and their applicability in evaluating future potential reduced exposure tobacco products[8,9]. Data from clinical correlation studies, conducted with external contract laboratories, have demonstrated dose-response relationships between levels of specific urinary, plasma and salivary biomarkers and indicators for daily smoke exposure[10,11]. Some of our recent research has involved evaluating the extent to which these biomarkers of exposure for crotonaldehyde, acrolein, NNK, pyrene and 1,3-butadiene correlate with nicotine exposure. We are also working on the stability of the biomarkers under different storage conditions, and comparisons of spot urine samples with 24 hour collections.

We continue to expand the number of biomarkers of exposure available for our use, investigating both combustible and smokeless products. We are currently working on new techniques for measuring exposure to:

  1. Acrylonitrile,
  2. Acetaldehyde,
  3. and Formaldehyde.

Using literature reviews and metabolism pathways we are developing new techniques and capabilities e.g. metabolomics to investigate the metabolism of smoke toxicants, in order to generate new biomarkers of exposure.

Future use

We have confirmed that analysis of spent filters - which estimates the potential maximum mouth level exposure to cigarette smoke constituents - correlates well with certain biomarkers of exposure[11,12]. Furthermore, the data support the use of these biomarkers in estimating exposure from cigarette smoke.  The filter analysis approach has not yet been taken up widely by scientists outside the tobacco industry and we will continue to use BoEs from smokers in clinical and ambulatory studies to investigate exposure to smoke toxicants. 

  1. Institute of Medicine. (2001). Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. National Academy Press, Washington, DC.
  2. Schmidt, C.W. (2006). Signs of the times: biomarkers in perspective. Environmental Health Perspectives. 114: A700-A705.
  3. Puntmann, V.O. (2009). How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgraduate Medical Journal. 85(1008):538-45.
  4. Ryan, P.B., Burke, T.A., Cohen Hubal, E.A., Cura, J.J., McKone, T.E. (2007). Using biomarkers to inform cumulative risk assessment. Environmental Health Perspectives. 115:833-40.
  5. Watson, W.P., Mutti, A. (2004). Role of biomarkers in monitoring exposures to chemicals: present position, future prospects. Biomarkers. 9:211-42.
  6. Clearing the Smoke: The Science Base for Tobacco Harm Reduction. (2001). Edited by K. Stratton, P. Shetty, R. Wallace, and S. Bondurant. Board on Health Promotion and Disease Prevention. Washington, DC: National Academy Press.
  7. Burns, D.M., Dybing, E., Gray, N., Hecht, S., Anderson, C., Sanner, T., O’Connor, R., Djordjevic, M., Dresler, C., Hainaut, P., Jarvis, M., Opperhuizen, A., Straif, K. (2008). Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tobacco Control. 17:132–141.
  8. Hagedorn, H.W., Scherer, G., Engl, J., Riedel, K., Cheung, F., Errington, G., Shepperd, J., McEwan. M. (2009). Urinary excretion of phenolic polycyclic aromatic hydrocarbons (OH-PAH) in nonsmokers and in smokers of cigarettes with different ISO tar yields. Journal of Analytical Toxicology. 33:301-9. Full text link .
  9. Kavvadias, D., Scherer, G., Cheung, F., Errington, G., Shepperd, J., McEwan, M. (2009). Determination of tobacco-specific N-nitrosamines in urine of smokers and non-smokers. Biomarkers. 14:547-53. Full text link  
  10. Theresa J. Smith, Zuyu Guo, Frank J. Gonzalez, F. Peter Guengerich, Gary D. Stoner, and Chung S. Yang (1992) Metabolism of 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone in Human Lung and Liver Microsomes and Cytochromes P-450 Expressed in Hepatoma Cells. Cancer Research 52, 1757-1763.
  11. St. Charles, F. K., Krautter, G. R., Dixon, M., Mariner, D.C. (2006). A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites. Psychopharmacology. 189:345–354. Full text link. 
  12. Shepperd, C.J., Eldridge, A.C., Mariner, D.C., McEwan, M., Errington, G., Dixon, M. (2009). A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure. Regulatory Toxicology and Pharmacology. 55:97-109. Abstract link. 
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