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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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Representative terms from entire chapter:
protein adducts
