Drinking Water and Health, Volume 9 Selected Issues in Risk Assessment (1989) / Chapter Skim
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1 Biologic Significance of DNA Adducts and Protein Adducts
1 Biologic Significance of DNA Adducts and Protein Adducts
Pages 6-37
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From page 6... ...
In addition, protein adducts are discussed as possible markers of exposure. Studies of laboratory animals and human chemotherapy patients have suggested that DNA adducts can serve as biologic dosimeters in providing estimates of exposure, dose to the target tissue, and sometimes mutagenicity and carcinogenicity (Anderson, 1987; Wogan, 19881.
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Adapted from Dyroff et al., 1986, with permission. or to confirm considerations of absorption, distribution, metabolic activation, and detoxification (Hoer et al., 19831.
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All the mathematical models now used yield similar estimates at high doses, but estimates for low doses deviate widely. The rates and routes of metabolic activation and detoxification of chemicals differ between sexes, species, and tissues and between high and low doses.
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DYNAMICS OF DNA-ADDUCT FORMATION AND REMOVAL The chain of causation from toxic chemicals in drinking water or air to alterations of DNA in mammalian cells involves many pharmacokinetic steps. The rate constants of those steps depend on the chemical, species, sex, tissue, and, within a given tissue, cell type.
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From page 10... ...
The rate of formation varies over time, because of changes in the tissue concentration of reactants that reflect their absorption, transport, and elimination. Low chronic exposures generally do not produce concentrations of xenobiotic compounds at which metabolic activation or detoxification systems reach capacity, so the rate of formation of DNA adducts, ciAIdt, can be considered roughly proportional to the concentration of a toxicant that ultimately reacts with DNA, which in turn is proportional to the extracellular
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. The enzymatic DNA repair mechanisms all seem to have capacities far in excess of what is needed to handle the low rate of damage from endogenous reactions and low chronic exposures to most exogenous agents (Table 1-11.
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If adduct formation reaches capacity, but repair does not, the rate of formation approaches a constant KfmaX; at the steady state, KfmaX = krA and A = KfmaxIkr
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431, 432~. An increase in the rate of repair of DNA damage can also be produced by aLkylating agents and such other agents as benzoLa~pyrene that yield highmolecular-weight (bulky)
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From page 14... ...
. including mutagenic efficiency, when choosing DNA adducts to be used as molecular dosimeters or for risk assessment.
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Although many chemicals can alkylate DNA directly, others, such as aromatic amines and polycyclic aromatic hydrocarbons, often undergo complex enzymatic modifications before they can alkylate DNA (Brookes, 1977; Kriek and Westra, 1979; Miller, 1978; Sims and Grover, 1974~. There are some striking differences between the DNA adducts produced by enzymatically modified chemicals and the adducts formed by simple alkylating agents (Hemminki, 1983~.
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From page 16... ...
If apurinic or apyrimidinic sites are present in DNA at the time of replication, any base can be misincorporated into the newly synthesized DNA opposite the gap in the parental strand (Langley and Brookes, 1963~. Phosphate AdJucts The formation of alkyl phosphotriesters, first measured by Bannon and Verly (1972)
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DNA ADDUCTS AND TOXIC EFFECTS Relating information concerning DNA-adduct site and molecular biologic consequences of adduct formation to multistep processes like mutagenesis and carcinogenesis is difficult at best. Specific toxic effects of specific DNA adducts must be correlated with the induction of gene mutation, germ cell mutation, or tumor formation in animal models before the impact of DNAadduct formation can be assessed in humans.
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In Vivo Germ Cell Mutation Little is known about the effect of DNA adducts on germ cell mutation. In two studies of male germ cells, the frequency of sex-linked recessive lethal mutations in Drosophila melanogaster (Aaron and Lee, 1978)
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From page 19... ...
Detecting all DNA adducts derived from a single carcinogen is complex, however, because they can form at many sites on all four DNA bases and on the phosphate backbone of DNA, and they are repaired at different rates (Wogan, 1988~. Few studies have shown a correlation between adduct formation early in carcinogen exposure and tumor formation in the same biologic system (Beland et al., 1988; Croy and Wogan, 1981; Dyroff et al., 1986; Kensler et al., 1986; Tullis et al., 1987)
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Tumors induced by chronic exposures to methylating hepatocarcinogens are predominantly hemangiosarcomas (involving nonparenchymal cells) , whereas exposures to ethylating agents cause hepatocellular carcinomas (involving hepatocytes)
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When metabolic activation reaches capacity, a less than linear dose response is evident (Appleton et al., 19829; and when detoxification or DNA repair reaches capacity, a greater than linear dose response occurs (Adriaenssens et al., 1983; Casanova-Schmitz et al., 19841. Chronic Exposures of Animals Dose-response curves for DNA adducts formed in animals during chronic carcinogen administration have characteristic profiles that reflect the combined processes of DNA-adduct formation and their removal by DNA repair systems.
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From page 22... ...
For example, when diethylnitrosamine was given continuously to male Fischer-344 rats in drinking water, an increase in concentration from 0.4 ppm to 40 ppm caused a 100-fold increase in the steady-state adduct concentration in the livers of male Fischer-344 rats; however, further exposures up to 100 ppm did not cause any additional increase in adduct formation (Boucheron et al., 1987~. This nonlinearity in doseresponse primarily reflects killing of cells that contain adducts.
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From page 23... ...
(1985) used the same antiserum in a USERIA to measure BaP-DNA antigenicity in the white blood cells of roofers and foundry workers, two groups known to have substantial occupational exposure to BaP.
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, and among unexposed, nonsmoking pregnant women (Ready et al, 1987~. DNA was isolated from specimens from 12 exposed women (8 white blood cells, 4 placentas)
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For example, heterogeneity of human polycyclic aromatic hydrocarbon activation is well established, and the extent of DNA-adduct formation varies over a 1,000-fold range (Harris et al., 19821. In addition, some compounds, such as antioxidants and other dietary ingredients, modulate metabolism and thereby alter adduct formation.
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and MMS produced significant increases in alkylation in late spermatids and early spermatozoa (the most genetically sensitive germ cell stages) that could not be attributed to increased DNA alkylation but were correlated with sperm protamine alkylation and dominant lethal mutations.
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Further research is needed to investigate the mechanism by which these low-molecular-weight mutagenic compounds cause dominant lethal mutations and elucidate the relative roles of protamine alkylation and DNA alkylation. SUMMARY To use DNA adducts in risk estimation, one must relate them to other biologic events, such as germ cell mutation, tumorigenesis, or developmental effects.
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From page 28... ...
In addition, protein adducts, such as those found in sperm protamine and hemoglobin, are apparently stable for the lifetime of the cell, accurately indicate recent exposure, and should be considered in the estimation of genetic or carcinogenic risk whenever they can be correlated with DNA binding. Monitoring protein adducts has generally been considered to be a good surrogate procedure for measuring DNA-adduct formation in the target organ, but this should be validated in laboratory animals for each compound of interest.
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From page 29... ...
pyrene-DNA adduct levels and genotoxic effects in mammalian cells. Cancer Res.
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1987. Ethylnitrosourea-induced transplacental Carcinogenesis in the mouse: Tumor response, DNA binding, and adduct formation.
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pyrene diol epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in sera from coke oven workers exposed to measured amounts of polycyclic aromatic hydrocarbons in the work atmosphere. Cancer Res.
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1979. Metabolic activation of aromatic amines and amides and interaction with nucleic acids.
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1986. Drinking Water and Health, Vol.
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1988. Monitoring occupational exposure to carcinogens: Detection by 32P-postlabeling of aromatic DNA adducts in white blood cells from iron foundry workers.
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1987. Binding of ethylene oxide in spermiogenie germ cell stages of the mouse after low-level inhalation exposure.
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1982. Cell speeif~e differences in 06-alkylguanine DNA repair activity during continuous exposure to carcinogen.
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1985. Quantitative comparison of genetic effects of ethylating agents on the basis of DNA adduct formation: Use of O6-ethylguanine as molecular dosimeter for extrapolation from cells in culture to the mouse.
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