Clearing the Smoke Assessing the Science Base for Tobacco Harm Reduction (2001) / Chapter Skim
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11 Exposure and Biomarker Assessment in Humans
11 Exposure and Biomarker Assessment in Humans
Pages 309-366
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From page 309... ...
biomarkers estimating the biologically effective dose (Perera, 1987)
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From page 311... ...
Biomarkers are intuitively more informative and better disease risk markers when measured in the target tissue through biopsies (e.g., oral mucosa, lung, bladder)
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From page 312... ...
predictive value for the potential harm reduction is more difficult. It should be noted that the biomarkers discussed in this chapter refer to either target or surrogate tissue or fluid assays, but that the biologically effective dose refers to the assessment of a mechanistically relevant biomarker only in the target organ.
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From page 313... ...
. Surrogate biologically effective doses, once validated, estimate a biological effect in a target organ (e.g., hemoglobin adducts or white blood cell carcinogen-DNA adducts)
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From page 314... ...
314 TABLE 11-3 Methods for PREP Assessment CLEARING THE SMOKE Type of Target vs. Category Measurement Surrogate Examples Strengths External External Neither Questionnaire data, FTC yield Inexpens exposure exposure assessment Biomarker of Internal dose Target Polycyclic aromatic hydrocarbon in lung Provides exposure tissue tissue exposu Surrogate Urinary measurement of tobacco tissue constituent or metabolite, exhaled CO, carboxyhemoglobin, urinary mutagenicity Easily ac measure smokir host ca clearer Biologically Biologically Target Carcinogen-DNA adducts in human Reflects i effective effective dose tissue lung tissue, exfoliated bladder cells, expose dose or oral mucosa activat: cycle c Surrogate Carcinogen-DNA or hemoglobin Does not tissue adducts; DNA adducts; lipid greater peroxidation availat epidemic Biomarker of Early biological Target Changes in RNA or protein expression, Assessm~ potential and genetic tissue somatic mutations, and LOH in leading harm effects normally or abnormally appearing tissue; change in methylation or gene control; mitochondrial mutations, mRNA expression arrays, or proteomics Alterations in Target Osteoporosis, hypertension, cough, Greater a morphology, tissue hyperplasia, dysplasia, lipids, blood with m structure, or coagulant pathways, mRNA function expression arrays, or proteomics Surrogate assays Surrogate tissue Leukocytosis; HPRT mutations; Easily ac chromosomal aberrations; circulating measure lymphocytes; mRNA or protein smokir expression via microarrays in cultured host ca blood cells clearer Effect Measures of Neither Genetic polymorphisms for genes Reflects 1 modifiers interindividual involved in disease pathways high to variation Target Enzyme induction of metabolizing enzymes Integrate expose expose NOTE: HPRT=hypoxanthine phosphoribosyltransferase; LOH=loss of heterozygosity.
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From page 315... ...
EXPOSURE AND BIOMARKER ASSESSMENT IN HUMANS 315 Strengths Limitations Inexpensive In in lung to haled CO Oman er cells, m presslon, ~ . ~ in taring I or gene :ions, ugh, ,, blood nlcs Aculating ein ~ cultured yes ~mg Provides integrated measure of external exposure and smoking behavior Easily accessible; provides integrated measure of external exposure and smoking behavior; metabolites reflect host capacity for metabolism and clearance Reflects integrated measure of external exposure, smoking behavior, metabolic activation, DNA repair capacity, cellcycle control, and capacity for apoptosis Does not require invasive procedures, greater amount of tissue is generally available; more likely to be used in an epidemiological setting Assessment of mechanistic pathway leading to disease Greater ability to identify risk for disease with marker Easily accessible; provides integrated measure of external exposure and smoking behavior; metabolites reflect host capacity for metabolism and clearance Reflects lifetime response to exposure; high throughput possible Integrated assessment of how prior exposures or genetic traits affect exposures and harm Does not reflect actual internal doses Expensive; may not be specific for tobacco products; does not necessarily reflect biologically effective dose; tissue may be difficult to access; may be difficult to validate as a risk marker for disease May not be specific for tobacco products; does not necessarily reflect biologically effective dose; may be difficult to validate as a risk marker for disease Difficult to measure and validate as a disease risk marker, predictive value for disease risk is insufficiently studied, more commonly reflects internal dose to a target macromolecule rather than disease risk Relationship to disease risk is not fully established Tissue difficult to obtain; technically difficult; relationship to disease risk difficult to establish; harmful effects may already be present; bioinformatics with which to process information not yet available Tissue difficult to obtain; late effects where harm has already occurred; bioinformatics with which to process information not yet available Relationship to target organ effect is difficult to prove; specificity for tobacco product needs to be proved; bioinformatics not yet available Candidate gene approach will typically study many polymorphisms that are not related to disease risk Tissue technically difficult to obtain; laboratory validation difficult osity.
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From page 316... ...
Importantly, the effects of the biomarker should be measurably different over the range of human exposures, so that the assessment can predictably measure the effects of exposure reduction from a PREP. Currently, there are some biomarker assays that have been assessed in former smokers or smoking cessation trials.
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From page 317... ...
Sensitivity, specificity, and predictive value are all important to consider. EXTERNAL EXPOSURE ASSESSMENT: THE FTC METHOD AND QUESTIONNAIRE DATA External exposure markers attempt to measure the amount of a tobacco smoke or tobacco product constituent that may enter at a portal to the body.
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For example, using modified protocols to stimulate human smoking behavior, the medium-yield (0.9-1.2 mg nicotine per cigarette) and low-yield (0.8 mg nicotine per cigarette)
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Youth Risk Behavior Surveillance System (YRBSS) Sixth to twelfth grade students University of Michigan Survey Research Center CDC Eighth, tenth, and twelfth grade students Ninth to twelfth grade students Approxi~ 50,000 from p private schools effort to validate self-report measures and to reveal any ETS exposure can be found in the National Health and Nutrition Examination Survey (NHANES; see Table 11-5)
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From page 321... ...
These surveys do provide insight into trends of tobacco product use within and across a variety of sociodemographic groups, including age, sex, race or ethnicity, educational status, and economic status. The data can be compared to morbidity and mortality registries to understand new or changing consequences of use patterns or specific products.
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From page 322... ...
Thus, these measures approximate the level of actual exposure and, as described below, become less reliable in assessing exposure reduction. Smoking topography is an additional method of assessing external exposure (e.g., how much smoke enters the lung, estimated by measuring puff volume, number of puffs per cigarette, puff duration, total inhalation time, and interpuff interval)
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reflect smoking topography and exposures from an individual cigarette. Technologies exist for directly measuring internal exposure to tobacco smoke constituents in target organs through biopsies (e.g., PAHs in the lung)
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324 TABLE 11-6 Biomarkers of Exposurea b CLEARING THE SMOKE Associated Variables Used Dose-Response with Cessation Chemical Specific t. Category in literature Data Available or Half-life Specificity Tobacco Nicotine-related Nicotine Yes 2 hr Yes Yes (excc biomarkers using ~ replace therap' Nicotine boost (pre- Yes and post-cigarette nicotine levels)
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. ~ClflClty Specific to Tobacco Related to a Disease Risks Strengths Limitations Yes (except when .
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In some cases, the macromolecule may be a surrogate for a target molecule. The biologically effective dose represents the net effect of metabolic activation, decreased rate of detoxification, decreased repair capacity, loss of cell-cycle checkpoint control, and decreased rates of cell death.
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These reactive intermediates bind to macromolecules such as DNA and protein and disrupt their normal processes. For cancer, a common assessment of the biologically effective dose is the measurement of carcinogen-DNA adduct levels.
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328 CLEARING THE SMOKE TABLE 11-7 Biomarkers Estimating the Biologically Effective Dosea b Target Dose- Tissue Variables Used Response Associated with Assay Chemical Category in literature Data Cessation or Half-life Available Specificit' Carcinogen- Nonidentified Yes Yes Yes No DNA adducts adducts/ 32P-postlabeling PAM-DNA Yes 9-13 weeks Yes Yes adducts (blood) 4-Aminobiphenyl- Yes Yes Yes Yes DNA adducts NNK-DNA Yes NDA Yes Yes adducts 8-hydroxydeoxy- No Yes Yes Yes guanosine 5-(Hydroxy- No NDA No Yes methyl~uracil N-Nitrosamine- NDA 26 hr (blood; 06- Yes Yes related-DNA methyldeoxy adducts guanosine)
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Highly specific for smoking Yes Yes No NDA Can be measured in Assay has large any tissue interlaboratory variation; it is easy to introduce oxidative damage into laboratory assay; low sensitivity makes assay use limited in large-scale studies No Yes No Not Sufficient sensitivity Technically difficult avail- to use for ETS able Yes Yes No NDA Can be measured Low sensitivity makes assay in any tissue use limited in large-scale studies. Diet a common source continues
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From page 330... ...
Evidence exists that carcinogen-DNA adduct levels in target and nontarget organs are modulated by interindividual differences (Badawi et al., 1995; Grinberg-Funes et al., 1994; Kato et al., 1995;
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Interestingly, in former smokers, age of initiation may influence lung adduct levels (Wiencke et al., 1999~. In humans, only a few studies have investigated a link between carcinogen-DNA adducts and cancer
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However, since no published prospective studies of tobacco smoking show a relationship of adducts to cancer, the case-control studies must be interpreted cautiously because there may be an effect due to differential metabolism or DNA repair. The utility of carcinogen-DNA adduct measurements in assessing harm reduction is suggested by studies showing that lung adduct levels are lower in persons who smoked filter cigarettes (van Schooten et al., 1990~.
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From page 333... ...
Among the most promising biomarkers of effect for assessing harm reduction claims for cancer are those that measure DNA damage or alterations of genetic function (mutations, gross chromosomal changes, DNA methylation of promoter regions, etc.~. While these biomarkers are envi
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334 TABLE 11-8 Biomarkers of Potential Harmful Effectsa b CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Enzymatic Aryl hydrocarbon No >30 d Yes Yes No induction hydroxylase CYP1A2 No NDA Yes Yes No DNA repair NDA Yes Yes NA enzymes No Microarray assays NDA NDA Yes NA No for mRNA expression and proteomics Chromosomal Chromosomal Yes Yes Yes No No alterations aberrations Micronuclei Yes Yes Yes No No Sister chromatic Yes Yes No No No exchanges Loss of Yes Yes Yes No No heterozygosity Mutations in Yes Yes No No reporter genes (HPRT, GPA)
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established; significant lack of Can be measured in persons specificity and wide overlap without cancer between smokers and nonsmokers Jo No NDA Facile assay Lack of specificity Jo No No Easy to do in blood as surrogate Very nonspecific; relationship tissue. Can be measured in to target organ is not persons without cancer established; predictivity for disease risk not established.
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336 TABLE 11-8 Continued CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Mutational load NA NDA Yes No No in target genes (p53, K-ras) ~ r Mitochondrial Deletions, NDA NDA Yes No No mutations insertions Epigenetic Whole genome NDA NDA Yes No No cancer methylation effects Hypermethylation NDA NDA Yes No No of promoter regions Blood lipids: Yes NDA Yes Yes No HDL, LDL, oxidized LDL, triglycerides Cardiovascular Heart rate, blood No Yes Yes NA response pressure No Thrombosis Bleeding time No NDA Yes No No Fibrinogen NDA NDA Yes Yes No Prothrombin time, partial thromboplastin time, plasminogen activator inhibitor, Creactive protein Yes NDA Yes Yes Urinary Yes No No Yes thromboxane and prostacyclins No No
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From page 337... ...
Substantial confounders exist, and many persons are on medications Jo No No Minimally invasive Very nonspecific (es No NDA Pathogenically related to Does not distinguish levels of disease smoking. Nicotine might separately affect these parameters so limited use in persons using NRT (es No NDA Leave a fingerprint at the site of their formation (es No Yes Maybe markers of platelet- Technically difficult.
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From page 338... ...
338 TABLE 11-8 Continued CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Platelet activation Yes NDA Yes No No and survival Blood cell White blood cell Yes Yes Yes Yes No parameters counts (i.e., lymphocytes, neutrophils, total counts) Hematocrit, Yes Yes Yes No No hemoglobin, red blood cell mass Bronchio- Inflammatory Yes Yes Yes No No alveolar cells, protein, ravage cytokines response Neutrophil Yes Yes Yes No No elastase al antiprotease complex ocl-antitrypsin No No Yes Yes Yes Inflammatory Leukotrienes Yes NDA No Yes mediators of response No Pulmonary FEV1, FVC Yes Yes Yes No No function tests Periodontal Periodontal Yes Yes Yes No No disease height Gum bleeding Yes Yes Yes No No Osteoporosis Fractures Yes NDA NA No No Bone density NDA NDA Yes No No Skin Premature Yes NDA NA No No wrinkling
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From page 339... ...
Smoking increases platelet counts (es No Yes Can be a surrogate marker for Relationship to disease several processes including uncertain, although atherosclerosis and thrombosis alterations in levels are linked epidemiologically to disease. Wide interindividual and intraindividual variation and large number of confounders Jo No No Can reflect both cardiac and Insensitive; wide interindividual respiratory disease risk differences Jo No NDA Provides different types of data Bronchoscopy is too invasive for with single procedure large epidemiological studies Jo No NDA Provides different types of data Bronchoscopy is too invasive for with single procedure large epidemiological studies (es Yes NDA May be specific to tobacco Requires invasive test; short smoke half-life (es No NDA May be measured in urine, Substantial number of bronchioalveolar ravage, and confounders serum Jo No Yes Widely available Low sensitivity for mild disease.
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From page 340... ...
Nonetheless, a reduction in the level of genetic damage would logically be required if a tobaccorelated PREP were to be successful in reducing cancer risk, although how much reduction of genetic damage would be needed to derive a benefit in terms of disease risk is unknown. Several types of assays are available.
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From page 341... ...
Among all the assays that have potential application to assessing harm reduction claims, only two studies have assessed prospectively the cancer predictive value of chromosomal aberrations (Bonassi et al., 1995; Hagmar et al., 1994) , but they consisted of pooled heterogenous populations and were not focused on tobacco.
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From page 342... ...
An important area that has not been well studied is the effect of tobacco toxicants on the induction of enzymes that might affect cancer risk. For example, cytochrome P-450 enzymes are induced with tobacco smoking (e.g., arylhydrocarbon hydroxylases [AHHs]
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From page 343... ...
Several biomarkers can be studied in relation to cardiovascular disease risk, but none of these are specific to tobacco smoking, such as blood lipid level (sullen et al., 1997; Freeman et al., 1993; Hellerstein et al., 1994; Ludviksdottir et al., 1999; Stubbe et al., 1982; Wald et al., 1989) , which changes with cessation (Green and Harari, 1995)
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Some of these parameters are covariates (lames et al., 1999~. Thus, such markers would be less useful for assessing harm reduction claims but might be useful for assessing exposure reduction claims.
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From page 345... ...
in. specific genes; microarray RNA expression; proteomics Inexpensive, simple to perform, specific gene effect when exists, high throughput available Reflects integrated measure of multiple genotypes; provides complex data potentially usable for rapid identification of important risk factors Functional relationship of genotype to phenotype difficult to prove; disease risk for lowpenetrant genes difficult to prove Difficult to perform; relationship to disease risk technically difficult to prove; requires extensive laboratory validation; RNA and protein m~croarray assays are expensive; large-scale studies are needed; bioinformatics not available
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From page 346... ...
, so that the effects of both tobacco toxicants and heritable capacity on DNA repair can be considered in assessing harm reduction products. It should be noted that cigarette smoking induces levels of some repair enzymes (Drin et al., 1994; Hall et al., 1993; Slupphaug et al., 1992)
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From page 347... ...
There has been less study of genetic susceptibilities for coronary artery disease (Gealy et al, 1999~. It is likely that these genes also will play a role in modifying disease risk (see Chapter 13~.
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From page 348... ...
The most consistently used biomarkers are those that reflect exposures, namely cotinine (serum, plasma, or urine) , rather than biologically effective doses or biomarkers of effect.
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From page 349... ...
CONCLUSIONS The assessment of a PREP will have to consider external exposure and markers of internal exposure, estimates of the biologically effective dose, and biomarkers of potential harm. A risk reduction claim should be based on disease reduction, but time limitations mandate the use of biomarkers for both exposure and risk reduction assessments.
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From page 350... ...
However, no single biomarker has been sufficiently validated and related to disease risk to be recommended as an intermediate biomarker of cancer risk. Thus, different types of biomarkers along the pathway from internal exposure to biologically effective dose, and to potential harm are needed, and additional research is necessary to identify the best combination of markers to be used.
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From page 351... ...
It is typically easier to show a direct relationship of external exposure to biomarkers in the following order: internal exposure, biologically effective dose, and potential harm. Conversely, it is typically easier to show a direct relationship of disease outcome to biomarkers in the following order: potential harm, biologically effective dose, and internal exposure.
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From page 352... ...
The recommendation that harm reduction products should be assessed with the use of biomarkers reflects sufficient available data to show that the public is composed of individuals with different cultural and heritable traits that affect how people use tobacco products and respond to them. To achieve the best confidence that a PREP will reduce risks for persons who cannot stop smoking, both well-validated methods for predicting risk, including external exposure indicators, and the best available biomarker assays should be used.
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From page 353... ...
This is the best way to identify a relationship between exposure, a biomarker, and disease risk. Substantial research is needed to identify the relationships between biomarkers to exposure, biologically effective doses, and biomarkers of harm.
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From page 354... ...
To identify those biomarkers most useful for assessing harm reduction products, current efforts have to be focused on clinical trials that assess the effects of switching brands, using new products, and reducing daily consumption of tobacco through the concomitant use of nicotine replace therapy or other aids used for smoking cessation. There are unique opportunities in epidemiological studies to validate biomarkers for use in assessing harm reduction strategies.
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From page 355... ...
-1-butanone-hemoglobin adducts as biomarkers of exposure to tobacco smoke: validation of a method to be used in multicenter studies. Cancer Epidemiol Biomarkers Prev 7~9~:817-821.
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From page 356... ...
in smokers' urine. Cancer Epidemiol Biomarkers Prev 4~6~:635-642.
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From page 357... ...
Cancer Epidemiol Biomarkers Prev 8~4 Pt 1~:297-302.
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From page 358... ...
1994. Polycyclic aromatic hydrocarbonDNA adducts in smokers and their relationship to micronutrient levels and the glutathione-S-transferase M1 genotype.
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From page 359... ...
Cancer Epidemiol Biomarkers Prev 6~12~:1075-1080. Izzotti A, De Flora S
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From page 360... ...
1995. Epidemiological evaluation of the use of genetics to improve the predictive value of disease risk factors.
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From page 361... ...
Cancer Epidemiol Biomarkers Prev 4~6~:627-634. Morrow JD, Frei B
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From page 362... ...
Cancer Epidemiol Biomarkers Prev 7~8~:703-709. Patrick DL, Cheadle A, Thompson DC, Diehr P
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From page 363... ...
1990. Formation of polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells during consumption of charcoalbroiled beef.
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From page 364... ...
Cancer Epidemiol Biomarkers Prev 7(6)
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From page 365... ...
Cancer Epidemiol Biomarkers Prev 4~4~:341-346. Tang D, Warburton D, Tannenbaum SR, Skipper P
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From page 366... ...
H: quinone oxidoreductase polymorphism. Cancer Epidemiol Biomarkers Prev 6~2~:87-92.
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