Biologic Markers in Pulmonary Toxicology (1989) / Chapter Skim
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2 Markers of Exposure
2 Markers of Exposure
Pages 17-42
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From page 17... ...
In the absence of toxicokinetic data, however, atmospheric concentrations used in toxicologic studies can be misleading, if the internal dose is not linearly related to the atmospheric concentration, especially at the high concentrations often used in such studies. If the mechanism of a toxic effect is 17
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From page 18... ...
. All those assessments of dose-i.e., biologically effective dose, dose to critical tissues, internal dose, and atmospheric concentration-are required for various aspects of health-effects studies, and biologic markers of each would be useful.
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From page 19... ...
The effect of breathing mode on particle deposition in humans is evident from Figure 2-1. Nasal inhalation results in greater total deposition of particles with diameters over 0.5 Am than does oral inhalation, because collection in the upper respiratory tract is greater.
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From page 20... ...
100 90 80 70 ~ 60 o 50 O 40 ILL 30 20 10 PARTICLE DIAMETER (um) FIGURE 2-2 Particle deposition efficiency in human upper respiratory tract.
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From page 21... ...
The removal of particles in more proximal airways determines the shape of the pulmonary deposition curves. For example, increased upper respiratory and tracheobronchial deposition would be associated with a reduction of pulmonary deposition; thus, nasal breathing results in less pulmonary penetration of larger particles, and a smaller fraction of deposition of entering particles, than does oral inhalation.
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From page 22... ...
Adsorption or condensation of gases from the atmosphere can produce a high surface concentration on particles that are already airborne. If those processes are diffusion-limited, the condensation and coagulation will be quantitatively proportional to particle diameter MARKERS IN PULMONARY TOXICOLOGY FIGURE 2-4 Particle deposition efficiency in human alveolated anways.
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From page 23... ...
will increase the dose proportion of a reactive gas that reaches the lung. CLEARANCE OF INHALED MATERIAL FROM THE RESPIRATORY TRACT Insoluble Particles The toxic response to inhaled particles depends on both the amount of material deposited at target sites and the duration of retention of deposited material.
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From page 24... ...
The mucociliary system of the lung provides a major line of defense in eliminating bacteria, inhaled particles, toxicants, and cellular debris. Bates ( 1989)
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From page 25... ...
The following sections discuss the types of human samples that can be analyzed to obtain information on exposure history, internal dose, and dose to target tissue and how animal toxicokinetic data can be extrapolated with modeling techniques to predictions for humans. In animal inhalation exposure studies, one can determine the fraction of an inhaled substance that is absorbed, the time it takes to reach a steady-state concentration of the substance and its metabolites in the blood, equilibrium concentrations in tissues, major routes and rates of excretion of the substance and its metabolites, and times required for their elimination from each tissue and from the whole body.
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From page 26... ...
The difference was explained biologically by analysis of effective dose, as opposed to administered dose, the external exposure concentration (Starr and Gibson, 1984~. The mice were more sensitive to the sensory irritation properties of formaldehyde than the rats and thus had a smaller minute volume during exposure and received a lower internal dose (Barrow et al., 1983~.
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From page 27... ...
The lung would have to be fixed for electron microscopy within several hours after exposure; otherwise, substantial numbers of inhaled particles would have been transported from the alveolar surfaces by epithelial cells, macrophages, and the alveolar lining layer (Brody et al., 1981~. Particle deposition is a good marker of exposure in animals, because it can predict whether the subject is likely to develop lung disease, where the disease will originate, and the nature of the pathogenic process.
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From page 28... ...
· Minimally invasive techniques foranalysis of particle burden. Use of labels, such as technetium-99, permits determination ot particle size and total lung burden of inhaled particles with whole-lung scanning.
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From page 29... ...
In addi 29 lion, the remanent field from dust in the lungs is much weaker than the earths steady magnetic field or field variations due to environmental sources; thus, measurements must be performed in a magnetically shielded chamber or with a gradiometer field sensor that reduces sensitivity to both uniform background fields and local fluctuating fields. Table 2-1 shows some representative field strengths due to contaminants in the lungs, compared with background fields of the earth and the chest.
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From page 30... ...
After the region of interest is measured, the particles in MARKERS IN PULMONARY TOXICOLOGY it are demagnetized, so that they do not interfere with later measurements in an adjacent region. LPG can be extended to provide information on the depth distribution of dust in the thorax by serial measurements of remanent field after successive degrees of demagnetization from the chest surface inward.
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From page 31... ...
A major one is that the relationship between remanent field and thoracic dust burden is highly variable, even in one person. The accuracy with which measurements of remanent field can be used to measure thoracic burden depends on the validity of the assumptions made about the distribution of magnetic particles in the thorax.
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From page 32... ...
Exhaled Air Exhaled air contains an array of volatile organic constituents that are likely to be in equilibrium with a number of compartments in the lung or can arise from endogenous or absorbed volatile substances circulating in the blood. In addition, some substances in lung air might be in equilibrium with alveolar lining material.
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From page 33... ...
That caused the investigators to conclude that"breath measurements may be capable of providing rough estimates of preceding exposures." The same group used analysis of exhaled air to determine exposure to benzene during the filling of a gasoline tank, exposure to tetrachloroethylene in dry-cleaning shops, exposure to chloroform from hot water in the home, and exposure to aromatic compounds in tobacco smoke. A potential approach that has been little studied is the analysis of exhaled air for volatile metabolites that might 33 be involved in lung disease.
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From page 34... ...
has centered around the use of hemoglobin adducts for monitoring. Hemoglobin adducts formed from reactive metabolites are being investigated for their potential as biologic markers of exposure.
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From page 35... ...
For example, phenol in urine has long been used to monitor worker exposure to benzene (Teisinger et al., 1955~. More recently, DNA adducts have been monitored in urine (Groopman et al., 1985)
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From page 36... ...
Monoclonal antibodies have been developed for such specific DNA adducts as those formed from benzofa~pyrene dial epoxide, 1-aminopyrine,
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From page 37... ...
Such work to determine quantitative relationships between exposure and adduct formation is needed for other carcinogens in the environment. Recent advances in analytic techniques allow the detection of DNA adducts in lymphocytes.
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From page 38... ...
. They then extrapolated the values to humans and found that the model accurately predicted the amount of styrene that had previously been published to be in blood and exhaled air of humans exposed in clinical studies (Ramsey et al., 1980~.
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From page 39... ...
Some precautions should be mentioned. In the animal studies, it is important to determine how and at what rate a chemical and its metabolites are cleared from the body in different doses or exposure regimens, to find the range of doses over which the disposition and metabolism of the chemical are linearly related to dose.
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From page 40... ...
The yellow-stained fingers of a chronic cigarette-smoker might be just as useful "biologic markers" as are questions about smoking habits. Lung Sounds One item in a physical examination that is potentially useful as a biologic marker is the recording of lung sounds (Woolen et al., 1978~.
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From page 41... ...
Other studies of respiratory responses to ozone exposure in healthy, active children have also used standard respiratory function measures and found highly significant changes in PEER in response to changes in ambient ozone concentrations (Spektor et al., 1988~. Imaging Other noninvasive techniques that could be regarded as yielding biologic markers of exposure or disease include radiography and other imaging techniques.
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From page 42... ...
Techniques for analyzing markers are well advanced; e.g., new techniques allow analysis of exhaled air, sputum, nasal ravage fluid, and bronchoalveolar ravage fluid for chemical evidence of exposure to specific pollu tants. Mathematical modeling has advanced to the point where models now include physiologic measurements, such as blood flow rates, ventilation rates, metabolic rates, and both blood-air and blood-tissue partition coefficients.
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