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1 Biologic Significance of DNA Abducts and Protein AdJucts Current evidence suggests associations between the occurrence of adducts formed by specific compounds and various types of toxicity, such as mu- tation, cancer, and developmental effects. Clinical expression of the toxic effect is usually tissue-specific and can be delayed. DNA adducts form in many tissues, but some of them might be early markers of disease that could be reversed (NRC, 19871. This chapter 'describes what is known about mech- anisms and rates of DNA-adduct formation and removal, the significance of the adduct's position on the DNA, And the correlation of of adducts of certain specific compounds with toxic effects. In addition, protein adducts are dis- cussed as possible markers of exposure. Studies of laboratory animals and human chemotherapy patients have sug- gested that DNA adducts can serve as biologic dosimeters in providing es- timates of exposure, dose to the target tissue, and sometimes mutagenicity and carcinogenicity (Anderson, 1987; Wogan, 19881. For example, corre- lations between DNA-adduct formation and exposure, hepatocyte initiation, and hepatocellular carcinoma have been observed in experiments with di- ethylnitrosamine (Figures 1 1-1-3) (Dyroff et al., 1986), 2-acetylaminoflu- orene (Beland et al., 1988), aflatoxin Be (Croy and Wogan, 1981; Kensler et al., 1986), and N-methyl-4-aminoazobenzene (Tullis et al., 1987~. De- tection of unique DNA abducts in a population at risk would yield qualitative evidence of exposure. And the use of DNA adducts could perhaps reduce the uncertainty in quantitative risk assessment by providing better dose in- formation for dose-response evaluation. The use of DNA adducts to measure biologically effective dose is scientifically appealing. DNA adducts can in- dicate a measurable dose at a target site and thus make it possible to bypass 6

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Biologic Significance of DNA Adducts and Protein Adducts 7 ~ 10-5 ~ . ~ z _ ~ ~ _{ ~_ o 1 o-6 _ , , , , , , , , 0 10 20 30 40 50 60 70 DURATION OF DEN EXPOSURE (days) FIGURE 1-1 Relationship of diethylnitrosamine (DEN) exposure to DEN alkylation in 4-week- old Fischer-344 rats. Data points represent mean concentrations of moles of 04-ethyldeoxythymidine (04-EtdT) to moles of deoxythymidine (dT) + the standard error of the mean (SEM) for 2-4 animals. Adapted from Dyroff et al., 1986, with permission. or to confirm considerations of absorption, distribution, metabolic acti- vation, and detoxification (Hoer et al., 19831. The estimation of carcinogenic risk usually involves two basic pieces of information (NRC, 1983~. A chronic animal bioassay measures the admin- istered doses of a chemical and correlates dose with tumor incidence to provide a quantitative evaluation of carcinogenic hazard at the doses and in 500 cod ~ 400 a) - o 300 200 100 o t -; ~ I I I I I I I 0 10 20 30 40 50 60 70 DURATION OF DEN EXPOSURE (days) FIGURE 1-2 Relationship of DEN exposure to hepatocyte initiation in 4-week-old Fischer-344 rats. Data points represent mean ~y-glutamyl transferase-positive (GOT + ) foci per cubic centimeter + SEM for 10-12 animals. The plateau in initiation represents a steady state, where the number of newly initiated hepatocytes equals the number of previously initiated hepatocytes that die. Adapted from Dyroff et al., 1986, with permission.

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DRINKING WATER AND HEALTH 100 - o o- - 80 LL A 111 A a: o :D 40 20 60 o f 0 10 20 30 40 50 ED 70 DURATION OF DEN EXPOSURE (days) FIGURE 1-3 Relationship of DEN exposure to hepatocellular carcinoma in 4-week-old Fischer- 344 rats. Adapted from Dyroff et al., 1986, with permission. the species tested. Carcinogenic hazard is then combined with information about human exposure to estimate the human risk associated with the chem- ical. Unfortunately, animal bioassays are limited both practically and eco- nomically to measuring tumor incidences at exposures that are much higher than would be acceptable in human populations. Because these models are based on high experimental doses, the resulting data must be extrapolated to permit estimation of the dose-response relationship at doses far below those used in the bioassay. The selection of models that best represent true dose-response relationships in humans at low exposures is controversial. 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. Measuring DNA adducts provides one way to understand and even measure those differences. The following are examples: Male mice produce different types of DNA adducts from, and more hepatocarcinomas than, female mice after exposure to the same doses of the hepatocarcinogen N-hydroxy-2-acetylaminofluorene (B Bland et al., 19821. At equimolar doses, rat tissues have higher aflatoxin B~-adduct con- centrations than mouse tissues, possibly because mice have a higher rate of detoxification (Degan and Neumann, 1981; Monroe and Eaton, 1987~. Rat hepatocytes have a much greater metabolic ability than hepatic sinusoidal cells to activate diethylnitrosamine and thus form DNA adducts (Lewis and Swenberg, 19831. Dose-dependent changes in rates of metabolic activation and detoxification themselves can affect the relation between administered dose and formation

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Biologic Significance of DNA Adducts and Protein Adducts 9 of DNA abducts. For example, the tobacco carcinogen 4-(N-methyI-N-ni- ~osamino)-1-~3-pyr~dyl)-1-butanone (NNK) is more efficient per unit dose in producing 06-methylguanine at low doses than it is at high doses, perhaps because enzymes reach their capacity for activation of a xenobiotic com- pound. Thus, higher concentrations of the compound do not necessarily result in greater numbers of adducts (Belinsky et al., 19871. In contrast, the effi- ciency of benzo~aipyrene (BaP) (Adriaenssens et al., 1983) and formalde- hyde (Casanova-Schmitz et al., 1984) in forming DNA adducts and in binding covalently to DNA is greater per unit dose at high exposures, but in a nonlinear fashion. The effect of DNA repair on DNA-adduct accumulation might also be different at high and low doses. The 06-alkylguanine DNA alkyltransferases efficiently remove small amounts of the promutagenic adduct 06-alkyldeoxy- guanosine from DNi\, but become saturated as the concentration of o6- alkyIdeoxyguanosine in DNA increases (Peg", 1983~..As noted above, spe- cies, tissues, and cell types can differ in their concentrations of and abilities to induce these enzymes. For example, human livers have intrinsic concen- trations of 06-alky~guanine DNA alkyltransferase nearly lo times greater than Hose in rat livers (Peg", 19831. New unsensitive methods of detection make it possible to monitor DNA adducts in animals at exposures below those feasible in chronic bioassays and closer to those expected in the human population. Mathematical models that use such biologic dosimeters might yield more accurate extrapolations aIld thus improve quantitative risk assessment. Some problems in using DNA adducts to estimate human risks are related to differences between rodents and humans. We can calculate the risk as- sociated with DNA adducts in experimental animals, but interspecies ex- trapolations remain difficult to validate. Many experiments cannot ethically be performed in humans, and DNA adducts in human target cells or tissues would be expected to vary widely because of individual variations in DNA metabolism and repair. 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. Figure 1-4 shows how metabolic ac- tivation and detoxification affect the relationship between external concen- tration and DNA-adJuct concentration in three hypothetical cases of chronic exposure. The overall estimation of DNA adducts might not be useful, unless one can determine the ratio of biologically important to unimportant adducts.

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|0 DRINKING WATER AND H"LTH 1. - 4, . C' ~ :~$ Z o ~ F C, Z ~ In as Use Z O Z ~ - INCREASING EXTERNAL EXPOSURE CONCENTRATION ~ A . c 1 if: C,9 X al oo O ~ ~0 lo: F Z ~ _ ~ ~ Z =8 B c - INCREASING EXTERNAL EXPOSURE CONCENTRATION ~ FIGURE 1-4 Relations between chronic external exposures and DNA-adduct concentration for steady state of adduct formation and repair in thme hypothetical cases: (a) neither fonnation nor repair reaches capacity at high concentration; (b) metabolic activation (adduct formation) reaches capacity at high external concentration; (c) DNA repair or detoxification reaches capacity at high concentration. Both scales are linear scales. The best example of such a classification is demonstrated by the adducts produced by methylating agents; the major DNA abduct formed is N7-meth- y~guanine (N7-MG), but this abduct is not involved in base-pairing and thus is relatively innocuous biologically. A minor adJuct, 06-methylguanine (o6- MG), which is involved in base-pairing, more closely reflects the mutagen- icity and carcinogenicity of methylating agents. The ratio of the two adducts depends critically on the chemical nature of the methylating agent. Hence, the concentration of N7-MG is not particularly useful as a measure of ex- posure without information on the proportion of N7-MG to 06-MG and on the nature of the methylating agent itself. DNA-AdJuct Formation Rates In chronic exposures, the rate of formation of DNA abducts depends on the concentration of compound in the tissue and the rate constant of formation (kf3. The rate of formation varies over time, because of changes in the tissue concentration of reactants that reflect their absorption, transport, and elim- ination. Low chronic exposures generally do not produce concentrations of xenobiotic compounds at which metabolic activation or detoxification sys- tems 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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Biologic Significance of DNA Adducts and Protein Adducts 11 concentration of the parent compound. If C is the time-weighted average concentration of the toxicant that ultimately reacts with DNA, the average rate of formation of adducts at low chronic exposures is given by: dAldt= kfC, (1) where A is the average DNA adduct concentration (e.g., adducts per 10~ nucleotides). At high doses, when capacity limitation might be reached, a more elaborate analysis is needed (Travis et al., 19891. The concentration C in the target cell might vary with time and tissue. In addition, it will probably vary with the person whose DNA is investigated, because concen- trations of activating and detoxifying enzymes vary widely among people. DNA Repair DNA adducts are not necessarily stable; some decompose spontaneously at body temperature. For example, alkylation of the nitrogen in purines tends to labilize the glycosidic bond and gives rise to apurinic sites. In addition, enzymatic DNA repair systems can directly remove the adduct itself, remove the DNA base that contains the adduct (base excision repair), or remove nucleotides that contain the adducted base (nucleotide excision repair) (Fried- berg, 1985~. The DNA repair systems probably arose as evolutionary consequences of damage to DNA that resulted from ultraviolet radiation (repaired by nucleo- tide excision), other naturally occurring alkylating agents and mutagens in food (NRC, 1973), and endogenous chemical or enzymatic reactions. The latter reactions are so numerous that, if DNA repair did not occur, 10% of all human DNA bases would be altered in an average lifetime (Tice and Setlow, l9SS). 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. At chronic low doses, rates of DNA repair (he) are generally limited not by the capacities of repair systems, but by the time for repair enzymes or repair complexes to "find" an adduct. The rate of removal of adducts by repair may be expressed as -dAl~t = krA . (2) For chronic exposures, a steady state is reached when the rate of removal of adducts (Equation 2) equals the rate of production (Equation 1~: krA = kfC and A = (kflFr)C. (3) Under conditions of chronic low exposure, the maximal rate of repair is much

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12 DRINKING WATER AND HEALTH TABLE 1-1 Approximate Rates of DNA Damage and Repair in Human Cells at Body Temperature. Estimated Estimated Maximal Occurrences Repair Rate, of Damage Base Pairs per Hour per Hour Type of Damage per Celia . per Cella References Endogenous Depur~nation 1,000 b Setlow, 1987; Tice and Setlow, 1985 Depyr~midination 55 b Tice and Setlow, 198S Cytosine deamination 15 b Setlow, 1987; Tice and Setlow, 1985 Single-strand breaks 5,000 2x 105 Setlow, 1987; Tice and Setlow, 1985 N7-methylguanine 3,500 Not reported Saul and Ames, 1986 O6-methylguanine 130 104 Setlow, 1987; Tice and Setlow, 1985 Oxidation products 120 105 Saul and Ames, 1986; Setlow, 1987 Exogenous Background ionizing radiation Single-strand breaks Oxidation damage Ultraviolet irradiation of skin (noon Texas sunlight) Primidine dimers 10-4 2 x 105 10-4-10-3 105 5x104 5X104 Setlow, 1987 Saul and Ames, 1986 Setlow, 1987; Tiee and Setlow, 1985 aMight be higher or lower by a factor of 2 (Setlow, 1983). bNot reported, but the rates are at least 104, to judge from the concentration of repair activities in cell extracts. greater than the rate of introduction of damage (Table 1-1), so the steady- state value of A is low. Sensitive techniques are needed to detect these low values. At low exposure rates, DNA-adduct concentrations are proportional to C and hence to exposure concentrations or dose rates. The ratio of A to exposure concentration is constant (a curves in Figure 1-41. For exposures at high dose rates, the capacities for adduct formation, detoxification, and repair might be reached. 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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Biologic Significance of DNA Adducts and Protein Adducts 13 A is independent of exposure concentration, and the ratio of A to exposure concentration approaches zero as the latter continues to increase (b curves in Figure 1-4~. However, if detoxification or the repair rate reaches capacity at lower concentrations than the activation rate, adducts continue to increase with time, adduct concentration rises without limit, and the biologic system deteriorates (c curves in Figure 1-4~. DNA that contains adducts has altered template properties, so the rate of introduction of mutations depends on the rate of DNA synthesis. The rate of introduction of altered RNA (possibly leading to changes in gene expres- sion) depends on the rate of transcription. The rates of introduction of errors in replication or transcription depend on both A and the rates of replication and transcription. Increased rates of cell replication are frequently associated with high-dose toxicity. Furthermore, DNA synthesis, transcription, and repair vary from one tissue to another and from one subject to another. The magnitudes of the variations depend on the particular repair system involved, genetic and environmental factors, and the pharmacokinetic and toxic prop- erties of the chemical agent producing the adducts (Wogan, 19881. In bacterial systems, exposure to mutagens at low concentrations often induces synthesis of new repair enzymes and an increase in repair rate. Such an adaptation is well documented for ultraviolet irradiation, whose effects are repaired by nucleotide excision (Friedberg, 1985, pp. 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 high- molecular-weight (bulky) DNA adducts. Adaptation increases the value of k2 in Equation (2) and results in a decrease in the steady-state value of A. Adaptation reactions in human cells have not been well documented. Insofar as some DNA adducts have been shown to be important in mu- tagenesis and carcinogenesis, estimates of long-term risk would be expected to be proportional to the steady-state concentration of such adducts. The constant of proportionality depends not only on rates of transcription of RNA and replication of DNA, but on biologic factors, such as the location of abducts in the genome and the presence of endogenous promoters or inhib- itors. SITE RELEVANCE Many carcinogens and mutagens react at more than one site on DNA, producing several types of DNA adducts (Figure 1-54. As stated above, adducts at different sites can differ greatly in the rates at which they are formed and repaired and in their efficiency in causing mutations. Thus, data on overall covalent binding or a covalent binding index (Lutz, 1979) could be misleading. It is important to consider all available relevant biologic data,

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14 DRINKING WATER AND HEALTH DNA Components Binding Sites _ NH2 INS ~| Simple AJkyla20rs Aromatic Amines PAHe Epoxides Drugs Adenine: ~ ,1_ ~ N / N ~ 0H Guanine: J, 3 N NH2 N \ Cytosine: ~ ~ O ~ POOH I` N/~ CH3 Thymine: ~13 ll ~ OH'\ N / o 11 11 Phosphate: -0-P-O- ~ OH Cytostatic N1/N3/N6/N7 N1/N6/C8 N1/N6 N1/N3/N6 N3 N1_N6 N1 / N2 / N3 / o6 N1 / N2 / o6 N2 / N7 N7 / N1-N7 / N7 / N7-N7 N7 C8 o2 / N3 _ o2 / o4 / N3 _ + - + + N1-N2 N3 / N4 N3 / N3 N4 N3 FIGURE 1-5 Potential sites of binding in DNA. Specific nitrogen (N), oxygen (O), and carbon (C) atoms on the DNA components have different susceptibilities to binding. Adapted from Singer (1985) with additional information from Beland and Kadlubar (1985), Delclos et al. (1987), and Hemminki (1983). including mutagenic efficiency, when choosing DNA adducts to be used as molecular dosimeters or for risk assessment. Alkylation In DNA, the N7 position of guanine is the most nucleophilic site, and it is by far the site most often alkylated by electrophiles. All: the ring nitrogens

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Biologic Significance of DNA Adducts and Protein Adducts 15 of the DNA bases, except the nitrogen attached to the deoxyribose sugar, have been shown to be alkylated to some extent by a variety of agents (Singer, 1975~. Figure 1-5 shows all the potential sites for alkylation in the four bases found in DNA, as well as on its phosphate backbone. These sites include the N1, N3, N7, and CS of guanine; the N1, N3, N7, and CS of adenine; the N3 of thymine; and the N3 of cytosine. In addition, all the exocyclic nitrogens and oxygens can be alkylated; these sites include the N2 and o6 of guanine, the N6 of adenine, the o2 and 04 of thymine, and the o2 and N4 of cytosine. Some chemicals, such as ethyl nitrosourea (ENU), have also been shown to alkylate the phosphate oxygens on the DNA backbone, forming phosphotriesters. With ENU, about 60% of total DNA ethylation occurs on the phosphate group (Singer, 19821. All the nucleophilic sites in DNA mentioned above are potential sites of aLkylation, as determined by in vitro experiments, but not all are significantly affected in vivo. Configuration and secondary structure of DNA can play a major role in chemical reactivity (Brown, 1974; Singer and Fraenkel-Conrat, 19691. Other factors, such as the size of the binding electrophile and the association of proteins with chromosomal DNA, also appear to affect the sites or magnitude of DNA alkylation in vivo (Singer, 1982; Swenson and Lawley, 19781. Although many chemicals can alkylate DNA directly, others, such as aromatic amines and polycyclic aromatic hydrocarbons, often undergo com- plex 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 enzymat- ically modified chemicals and the adducts formed by simple alkylating agents (Hemminki, 1983~. Not only are many of the adducts formed by enzymat- ically modified chemicals large and aromatic, but for polycyclic aromatic hydrocarbons, the preferred site of reaction in DNA is different. They gen- erally alkylate exocyclic amino groups, particularly the N2 of guanine, whereas the preferred site of aromatic amines is the C8 of guanine. Base Mispairing During DNA replication and in newly synthesized DNA, hydrogen bonds become less stable, and mispairing can occur; thus, alkylation of the DNA bases at sites involved in hydrogen binding is potentially mutagenic (Kroger and Singer, 1979; Singer et al., 1978a, 1979, 1983a,b). Those sites include the N1, N2, and o6 of guanine; the o2, N3, and N4 of cytosine; the N1 and N6 of adenine; and the N3 and O4 of thymine. For example, alkylation of the o6 of guanine can cause miscoding by DNA and RNA polymerases (Abbott and Saffhill, 1979; Gerchman and Ludlum, 19739. O6-Alkylguanine has been shown to direct the misincorporation of substantial amounts of

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|6 DRINKING WATER AND HEALTH thymine, instead of the expected cytosine, into newly synthesized DNA (Abbott and Saffhill, 1979; Green et al., 1984; Lawley, 1974; Loechler et al., 1984~. There is also evidence that 06-alkylguanine can direct some misincorporation of adenine (Snow et al., 1983~. Bulky adducts distort the DNA, again increasing the likelihood of misincorporation. Hydrolysis The N3 and N7 alkylpurines can be hydrolyzed from DNA as a conse- quence of the instability of their glycosyl bonds, even at neutral pH. The half-lives of those adducts in DNA can range from a few hours to several days (Singer and Grunberger, 1983~. Their rates of spontaneous hydrolysis are about 106 times greater than the rates for the unmodified purines. The glycosyl bonds of pyrimidines are 100 times more stable than those of the purines. As a consequence, depyrimidination of even the most labile alkyl- pyrimidine, 02-alkylcytosine, has a half-life about 35 times that of N7- alkylguanine (Singer et al., 197Sb). Nevertheless, depyrimidination of o2- alkylcytosine can contribute significantly to the formation of apyrimidinic sites. 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) and later by Sun and Singer (1975), on the phosphate backbone of DNA does not make the chain unstable. Alkyl phosphotriesters have been reported to repair with a half-life of several days in rat liver (O'Connor et al., 1973, 1975) and rat brain (Gosh and Rajewsky, 1974), perhaps as a result of enzymic excision of these products. Miller et al. (1971, 1974) and Kan et al. (1973) reported that triesters exhibit changes in a number of properties that are likely to affect normal replication. However, Rajewsky et al. ~ 1977) found no correlation between the persistence of phosphotriesters in DNA of brain and liver and the sensitivity of these organs to carcinogenesis by ENU. Cross-Links DNA-DNA cross-links can be created by bifunctional or polyfunctional alkylating agents. Brookes and Lawley (1961) demonstrated that di~guanin- 7-yl) derivatives could be formed in DNA exposed to bifunctional alkylating agents. The cross-linking is normally expected to occur between guanines on opposite strands of DNA. Formation of such an adduct is generally be

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Biologic Significance of DNA Adducts and Protein Adducts 27 Sega noted that the proportion of DNA adducts formed in the sensitive stages of sperrniogenesis is small (e.g., MMS, EMS, and EtO) or not measurable (e.g., acrylamide). However, late spermatogenic cells are known to be repair- deficient, and it is possible that dominant lethal mutations occur because a small number of DNA lesions remain unrepaired. Further research is needed to investigate the mechanism by which these low-molecular-weight muta- genic 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. Experimental data correlating tumorigenesis with profiles of DNA- adduct dosimetry in the same animal tissues are sparse (they include studies on diethylnitrosamine and the liver carcinogens 4-(N-methyl-N-nitrosamino)- 1-~3-pyndyl)-1-butanone, 2-acetylaminofluorene, and aflatoxin). Some cor- relations have been observed between persistence of DNA adducts in target tissues and the induction of tumors, but with some compounds no correlations have been noted. This probably reflects the need to incorporate more biologic processes than DNA-adduct formation into risk assessment. No proof exists that developmental effects occur in humans; however, they are presumed to represent a percentage of the genetic damage known to occur. One immediate problem is the lack of appropriate data~sets from which models can be constructed and validated. Both acute and chronic testing should be performed over a wide dose range to acquire knowledge of the points at which detoxification and DNA repair reach their capacities and thus cause nonlinearities in dose-response relationship curves. Dose-response re- lationships for single exposures over a dose range of 103 have been established for tumor induction on only three carcinogens: dimethylnitrosamine, dieth- ylnitrosamine, and benzoLa~pyrene. Several compounds have been studied in bioassays in which the dose ranged over a factor of 100, but bioassays on most carcinogens use doses that range over a factor of 10 or less- including the largest study ever performed, the effective-dose (EDo~) bioassay of 2-acetylaminofluorene (Staffa and Mehlman, 19791. Few DNA-adduct studies have covered dose ranges and used exposure protocols that could be compared. Although a broader dose range is not always possible because of the occurrence of toxic effects, present adduct-detection methods are probably now capable of measuring the results of testing with very low doses. Correlations between DNA-adduct dose-response relationships and biol- ogic effects seem to be compound-specific and independent of chemical cIass or biologic end point. Even for a single compound, quantitative comparisons of chemical-DNA binding and hazard assessment are complicated. One re

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28 DRINKING WATER AND HEALTH lationship will not accurately describe all situations; it will vary with the compound, the specific target tissue, the organism's exposure history, the duration and time of exposure, etc. Individual rates of metabolic activation of carcinogens (particularly PAHs) and repair capacities are variable and moderated by personal exposure histones. Thus, because the same chemical exposure can produce widely varying numbers of adducts, prediction of the extent of exposure or the resultant cancer risk is much more difficult in humans on the basis of DNA adducts than in homogeneous laboratory ani- mals. In addition, for many toxic chemicals, the mutagenic or tumongenic adduct has not been identified and can occur among many others that may not produce deleterious effects; thus, measuring overall DNA binding at- tributable to a specific chemical could lead to errors in the estimation of hazard. Despite current gaps in knowledge, DNA-adduct research represents a very promising means to improve risk assessment. When more extensive data become available, they might be used in individual risk assessment to confirm suspected exposures, improve estimates of target tissue dose, and reveal metabolic activation and detoxification parameters that moderate the formation of DNA adducts by a specific carcinogen. In general risk assess- ment, they could be valuable in estimating dosimetry and systemic distri- bution and in establishing possible target tissues or organs and the potential for irreversible toxicity, such as cancer, mutation, or developmental effects. They might improve estimates of the rates of tumor and adduct formation in animals in response to low doses on the basis of high-dose effects and provide better models for predicting mechanisms in humans. Large-scale DNA-adduct dosimetry studies in humans are now becoming possible, but they must be validated and their limitations defined. In addition, protein adducts, such as those found in sperm protamine and hemoglobin, are ap- parently 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. REFERENCES Aaron, C. S., and W. R. Lee. 1978. Molecular dosimetry of the mutagen ethyl methanesul- fonate in Drosophila melanogaster spermatozoa: Linear relation of DNA alkylation per sperm cell (dose) to sex-linked recessive lethals. Mutat. Res. 49:27-44. Abbott, P. J., and R. Saffhill. 1979. DNA synthesis with methylated poly (dC-dG) templates: Evidence for a competitive nature to miscoding by 06-methylguanine. Biochim. Biophys. Acta. 562:51-61.

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