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Conclusions and Recommendations The subcommittee has reached the following conclusions regarding the application of DNA-adduct and protein-adduct assays to EPA's assessment of drinking water contaminants: · Tests that detect and measure DNA adducts and protein adducts can be used as quantitative and qualitative dosimeters of exposure and may permit calibration of internal versus external dose across several orders of magnitude for specific genetic toxicants. · The presence of DNA adducts or protein adducts might not in itself establish a risk, and tests for DNA adducts or protein adducts should not be used in isolation for hazard or risk assessments. · Current evidence suggests an association between the onset of specific types of toxicity (mutation, cancer, or developmental effects) and the con- centration of DNA adducts. The toxic effect is usually tissue-specific, al- though adducts can form in many tissues. The subcommittee cannot define a general concentration of adducts that might be tolerated by animals, but an evaluation in Chapter 1 of the limited in vitro and in viva data indicates that concentrations of 1-10,000 adducts per 107 normal bases are associated with adverse effects. Most of the methods described in Tables 2-1 and 2-2 can span that range. · Most current models for risk assessment do not incorporate such data as DNA alterations over a broad range of exposures. Risk assessments might be improved if new kinds of mathematical models can incorporate biologic data from studies of DNA damage over a range of doses to show where detoxification and DNA repair occur and reach their limits. However, such 57
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58 DRINKING WATER AND HEALTH models will need to be carefully evaluated before they are put into general use. · DNA-adduct detection methods, especially the 32P-postlabeling method, have demonstrated the presence of considerable persistent (mostly unknown) DNA lesions in various target cells of untreated animals. The toxicologic importance of those "background" lesions is unknown; they might reflect endogenous exposures from normal body constituents or processes or from naturally occurring mutagens and carcinogens in the environment, such as ultraviolet radiation and mutagens and carcinogens in foods and water. · If the goal is to assess exposure to a drinking water contaminant identified as genetically toxic, it might sometimes be more appropriate to use protein adducts as dosimeters. Although their biologic significance could be quite different from that of DNA adducts, hemoglobin adducts have demonstrated chemical stability and linear dose-response relationships for a variety of compounds. Germ cell studies have suggested that protamine adducts are relevant to genetic risk assessment. · Monitoring of the formation of DNA adducts or protein adducts among exposed humans, and among appropriate controls, holds promise for use in assessing the human risk associated with consumption of drinking water contaminated by potentially genotoxic agents. However, available infor- mation on baseline DNA-adduct concentrations, adduct persistence, inter- individual and intraindividual variability, dose-response relationships, and biologic significance in humans is scanty. In addition, human tissues available for such studies may not be the tissues relevant for the~major toxic end point, such as carcinogenesis. Interpretation of epidemiologic or monitoring studies of humans would therefore be difficult. The subcommittee recognizes that full application of adduct technology to toxicologic assessments would require the filling of gaps in information and advances in technology. The subcommittee offers the following rec- ommendations to EPA: · Investigations into the origin and role of the natural background of DNA adducts are needed. The resulting information will be relevant to the inter- pretation of DNA alterations induced by occupation, lifestyle, or environ- mental exposure. · Because most of the data describing the induction of DNA alterations are derived from acute-exposure studies, investigations aimed at understand- ing the induction and persistence of DNA alterations over a broad range of doses in subchronic and chronic regimens should be conducted and correlated with other toxic end points. · Investigations are needed to improve understanding of the kinetics and relative significance of DNA alterations and protein alterations as measures of somatic and germ cell risk in animals. ,
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Conclusions and Recommendations 59 · Animal models should be used to study the use of peripheral white blood cells as target cells for in viva analyses of DNA adducts, because such cells would be most accessible in human studies. · Baseline data should be established on chemicals in drinking water that are presumed to be genetically toxic, with an eye to revealing qualitative and quantative associations between DNA or protein alterations and other components of hazard identification. · Methods for detection, measurement, and identification of DNA adducts and protein adducts should be developed and validated, particularly for low- molecular-weight monofunctional and bifunctional aromatic and hydrophobic alkylating agents. Many drinking water contaminants (acrylamide, EDB, DBCP, etc.) are of this size and type. · Differences between in vivo DNA-adduct formation and repair in so- matic and germ cells should be studied. Although risk assessment using DNA-adduct measurements usually focuses on tumor formation, heritable effects of genetic toxicants should be considered a major burden for the human population. A repository of tissue samples with known DNA-adduct or protein-adduct concentrations should be established, from which a calibration process might be developed.
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