Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data

Abstract

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10(-5) Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10(-7) Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker.

Figure 1.

Risk assessment paradigm for inhalation exposure to ambient particles (adapted from NRC, 1998).

Figure 2.

Disposition of smoke constituents from smoking article through the human body.

Figure 3.

Respiratory retention versus log (vapor pressure). Individual data points shown as open diamonds. Solid squared are averages grouped by log(VP) rounded to an integer. The circled data are for solanesol.

Figure 4.

Histogram of estimated mouth-spill from subjects in Canadian and German clinical studies.

Figure 5.

Carbonyl mouth level exposure (a) and dose (b) for the German clinical study.

Figure 6.

Tobacco-specific nitrosamine and pyrene mouth level exposure (a) and dose (b) for the German clinical study.

Figure 7.

Carbonyl and pyrene mouth level exposure (a) and dose (b) for the Canadian clinical study.

Figure 8.

Correlation of urinary HPMA (expressed as acrolein equivalents) with acrolein MLE (a) and Dose (b).

Figure 9.

Correlation of urinary 1-hydroxypyrene (expressed as pyrene equivalents) with pyrene MLE (a) and Dose (b).

Figure 10.

Correlation of urinary total NNAL (NNAL + glucuronide expressed as pyrene equivalents) with pyrene MLE (a) and Dose (b).