Drinking Water and Health, Volume 9 Selected Issues in Risk Assessment (1989) / Chapter Skim
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2 DNA-Adduct Technology
2 DNA-Adduct Technology
Pages 38-56
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From page 38... ...
New DNA-adduct technology embodies striking technologic improvements in sensitivity and specificity and permits measurement of mammalian response to small, intermittent environmental exposures. For example, molecular dosimetric assays and mutation analysis in mammalian cells in tissue culture suggest that low exposures to genetic toxicants produce DNA lesions at approximately 2,000 per cell in the lung after exposure to aromatic amines and 100,000 per cell in the upper layer of skin after exposure to the ultraviolet component of sunlight (Lohman et al., 1985~.
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From page 39... ...
The polarity and size of DNA adducts, or fragments of DNA adducts, can markedly influence the separation power and thus the sensitivity of these techniques. Each analytic method possesses potentially good to high resolving power, but the suitability and sensitivity of any method or combination of methods commonly depends on the physicochemical properties of the adduct or the class of adducts to be tested.
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From page 40... ...
FLUORESCENCE LINE-NARROWING SPECTROMETRY (FLNS) Particularly useful for fluorescent adducts of polycyclic aromatic hydrocarbons, FENS uses low temperature and laser excitation to improve sensitivity in the quantitative fluorometric analysis of DNA adducts (Jankowiak et al., 1988)
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From page 41... ...
Counting requires that samples be manually removed from each well (Farmer et al., 1987; Santella, 1988~. m mu noh istochem ice ~ Tech n iq ues Enzyme-staining with a fluorescence or peroxidase end point can identify the specific cell types in which DNA adducts occur (and thus the cells that are targets for carcinogens)
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From page 42... ...
TECHNIQUES FOR DETECTING PROTEIN ADDUCTS Some of the same methods for detecting DNA adducts are applied to the determination of protein adducts (GC, GC-MS, immunoassay, and fluorescence detection with HPLC)
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From page 43... ...
Although technologic improvements make feasible the sensitive measurement of exposure to genetic toxicants in animal models and humans, no generally applicable methods have been developed for estimating genetic risk (Wogan, 19881. Attempts are under way to relate target dose in humans to biologically adverse effects of small exposures to genetically toxic agents (Ehrenberg, 1988~.
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From page 44... ...
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From page 45... ...
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From page 46... ...
46 .O o Cal Cal ¢ .Q Do EM Ct as I:: I_ 3 m o .~ an o o 4of Cot Cal Cal Cal Cal ¢ Cal m ¢ Em cat a' 04 Cal Cal Cal ._ Cal CJ ~4 en I: Cal ~0 cat ID O _t ~0 ~ lo.= O i ~ ~ .= ~ O ~ ~ 0 ~I: ~ ~ - ~ ° Cal ~ ~ ~ ~ 3 ~ ~ o LU ~ o cat C: ° ~ ~ o .= I a, ~ a, C)
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From page 47... ...
It appears that adduct technology could be extremely valuable in estimating dosimetry and systemic distribution, in establishing possible target tissues or organs, and in determining the potential for irreversible toxicity such as cancer, mutation, or developmental effects. Table 2-3 lists some potential applications of DNA-adduct analysis to the toxicologic evaluation of drinking water contaminants for risk assessment.
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From page 49... ...
With the exception of benzoLalpyrene, for which considerable data exists concerning adduct analysis, the chemicals have not been the subject of extensive DNA-binding studies. Epidemiology and Human Monitoring Proper investigation of relationships between disease in humans and exposure to drinking water contaminants has been hampered by the difficulty of assessing exposure to contaminants appropriately and by the limitations inherent in the use of traditional end points, such as the development of cancer, which are both rare and characterized by long latency.
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From page 50... ...
( + ) + Sensitivity For some environmental exposures For occupational exposures For acute exposures Chemical specificity Absence of confounding factors Absence of background adducts Simplicity Ease of sample storage Current applicability In research In routine use ?
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From page 51... ...
Although the measurement of DNA-adduct formation in humans holds substantial promise for epidemiologic and monitoring studies, interpretation of data derived from DNA-adduct measurements is extremely complex, particularly in humans. In general, further experimental work is required before measurements of DNA adducts can be successfully incorporated into studies that assess toxicity from drinking water contaminants in humans.
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From page 52... ...
and DNA-adduct formation and repair, DNA-adduct concentrations are likely to involve complex dynamics. When technically feasible, the use of protein adducts might prove more appropriate for exposure assessment; such adducts in the hemoglobin of red blood cells have demonstrated chemical stability and linear dose-response relationships for a variety of compounds and thus can provide integrated exposure information.
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From page 53... ...
1988. Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention.
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From page 54... ...
Pp. 157-165 in Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention, H
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From page 55... ...
Pp. 249-257 in Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention, H
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From page 56... ...
Pp. 9-12 in Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention, H
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