STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C 20460
SftB-EBC-88-005
Octeter 23, 1987
Honorable Lee M. Thomas THE *%".'«.1™.
Administrator
0, S. Environmental Protection Ageicy
401 M Street, 3. W.
Washington, D. C, 20460
Dear Mr. Thomas;
The Drinking Water Subcommittee of the Science Advisory Board's
Environmental Health Committee has completed its review of the Office of
Research and Development's Health Effects Research Laboratory's Drinking
Water Disinfection and Disinfection By-Products Research Program, and is
pleased to transmit its report, to you. The Subcotiwiittee reviewed this
program at a public meeting at the laboratory in Cincinnati, Ohio on June
4-5.
This review is a^pecially timely in view of the growing recognitions
among scientists, engineers, governmental officials and water simply
providers of the public health risks associated with :V continuing
incidence of waterborne disease, and the increasing need to investigate
the public health implications of the use oi! -al.hernativa disinfection
techniques and th«U' by-pn^ductri.
In general, the Subcommittee concludes that current research efforts
are well focused in that they appropriately address a number of scientific
issues that currently confront the Office of Drinking Mater, The caliber
of the research personnel and the quality of the individual research
projects is generally high. Each researcher appeared to be quite enthu-
siastic about his/her own research efforts and support:^/e of each other's
projects. The current research efforts presence! by 7^\ ^J.aff ho the
subcommittee focused almost exclusively in the area of dilorination and
the by-products resulting from this treatment process. This is understand-
able in view of the complexity of the problem, as well as the widespread
currant usage:of chlorine for disinfection.
The Subcommittee's major recommendation is that more attention should
be devoted to the potential coxicity problems that could arise from alter-
natives and/or adjuncts to ehlorination such as chloramination, and the
use of ozone, chloric dioxide and other disinfectant ococesses. In view
of the number of tc =•-*;.. *mt 3/stems that are turning to the use of alter-
native treatment approaches, it is necessary co expand the research focus
to determine which treatinent .nethods protect public health most effectively,
and to compare the relative effectiveness and risks associated with each
treatment technology.
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ptsi&B effort is spent in gathering data to fill in specific
gaps '..ilfet^lHBi^^base . While this, in itself, is not unproductive, the
Of f rce-:ci^^^^ttg Water and the Office of Exploratory Research should
more fpreef^i^,; encourage long-range planning and management as, for
example, the 'initiation of studies on ozone and other disinfectants. At
the same time, the investigators need to have the time and resources to
develop projects and programs in fundamental research on agents within
the framework of the disinfectants program. Specific benefits of this
latter approach are: 1) an increase in EPA's capability to identify
emerging problems, and 2) providing the scientific staff with opportunities
to further develop their skills and gain support for their work in the
scientific community. Both of these activities can directly benefit and
support EPA's ongoing regulatory activities.
There are definite deficiencies in the development and use in some
areas that the Subcommittee believes are important in determining the total
toxicological profiles of drinking water disinfectants and their by-products.
Notable among these would be neurotoxicology (including the need and feasi-
bility for behavioral studies), cardiovascular toxicology and imnunotoxicol-
ogy. The program is not sufficiently integrated with a readily available
battery of tests for neurotoxicity or inrounotoxicity. While the Sub- »
committee recognizes that the personnel and resources that can be assigned^
to the disinfectants program (and indeed the entire drinking water research!
program) are finite, such areas need to be addressed. It was somewhat
surprising to the Subcommittee that some of this work was not, or could
not, be conducted at the Health Effects Research Laboratory (HERL) in
Research Triangle Park.
The Science Advisory Board appreciates the opportunity to review
this research program. We request that the Agency formally respond to
the scientific evaluation and advice presented in the attached report.
Sincerely,
Richard Griesemer, Ph.D.
Chairman
Environmental Health Committee
Science Advisory Board
Norton Nelson, Ph.D.
Chairman
Executive Committs*
Science Advisory Board
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«ED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. DC, 20460
0 1987
•3FFICE or
T«E ADMINISTRATOR
Dr. Richard Grieseraer
Biology Division
Oak Ridge National Laboratory
P.O. Box Y
Oak Ridge, IN 37831
Dear Dr. Griesemer:
Enclosed is the report of the Drinking Water SubecRmittee
following its review of the Office of Research and Development's
Health Effects Research Laboratory's Disinfection and Disinfection
By-Products Research Program. I reported briefly on this review
at the meeting of the Environmental Health Cotanittee on August
11, 1987.
I am submitting this report for fihal approval by the Environ-
mental Health Coroittee and the Executive Consult tee,
Sincerely,
Gary arlson
Chairman
Drinking Water Subcenudttee
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SAB^MC-88-005
Review of the Office of Research and Development's
Health Effects Research Laboratoryfs
Drinking Water Disinfection and Disinfection By-products
Research Program
Report of the Drinking Water Subcommittee
Environmental Health Committee
Science Advisory Board
U.S. Environmental Protection Agency
October 1987
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-11-
U.S. Environmental Protection Agency
rtotioe
This report has been written as part of the activities of the Science
Advisory Board, a public advisory group providing extranural scientific
information and advice to the Administrator and other officials of the
Environroental Protection Agency. The Board is structured to provide a
balanced expert assessment of scientific matters related to problans
facing the Agency. This report has not been reviewed for approval Jsy
EPA and, hence, its contents do not necessarily represent the views'and
policies of the EPA, nor of other agencies in the Executive Branefir of
the Federal government, nor does mention of trade names or cannerciaj.
products constitute endorsement or recommendation for use.
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Ill
U.S. Environmental Protection Agency
Science Advisory Board
Drinking Water Subcommittee
Chair), Department of Pharmacology- and Toxicology, School
University, West Lafayette, Indiana 4790?
Or. J&racPl^lKtelnan, Graduate School of Public Health, 130 Desoto Street,
Parran Hall - Room A-711, University of Pittsburgh, Pittsburgh, PA 15261
Dr. Hose Dagisnanjian, Professor, Department of Pharmacology and Ibxicology t
University of Louisville, Louisville, Kentucky 40292
Mr. Jettme B. Gilbert, Manager, East Bay Municipal Utility District, 2130
Adeline Street, Oakland, California 94623
* Dr. Charles Gerba, Department of Microbiology and Immunology, Building 190
University of Arisaona, Tucson, hi 85721
Dr. William Glaze, Director, School of Public Health, University of California,
Los Angeles, 650 Circle Drive South, Los Angeles, CA 90024
Dr. J. Donald Johnson, Professor, School of Public Health, University of:
North Carolina, Chapel Hill, NC 27514
Dr. 6« Marshall Johnson, Professor and Chairman, Department of Anaton^,
Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107
' ^
Dr. David Kaufman, Department of Pathology, University of North Carolina,
Bm. 515 Brinkhous-Bullitt, Chapel Hill, North Carolina 27514
Mr. Richard Moser, Vice President for Water Quality, American Water Marks
Service Co., 4001 Greentree Executive Campus, Suite B, Marlton, N.J. 08053
Dr. Betty Olson, Program in Social Ecology, University of California,
Irvine, CA 92717
Dr. Verne Ray, Medical Research Laboratory, Pfitzer, Inc. Groton, Connecticut,
06340
Dr. Harold.Shechter, Professor, Chenistry Department, Ohio State University,
140 West 18th Avenue, Columbus, Ohio 43201
Dr. Robert Tardiff, (Vice-Chair) Principal, Environ Corporation, 1000 Potomac
St., N.W.,..Terrace Level, Washington, DC 20007
* Dr. Thomas Tephly, Professor, Department of Pharmacology, The Bowen Science
Building, University of Iowa, Iowa City, Iowa 52242
EXECUTIVE SECRETARY
Dr. C. Richard Cothern, Executive Secretary, Science Advisory Board
[A-1Q1F] U.S. Environmental Protection Agency, Washington, D.C. 20460
* Did not participate in the June 4-5 meeting to review the Health Effects
Research Laboratory's Disinfection and Disinfection By-Products Research
Program.
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Table of Contents
Page
I. EStBCuEfve^aroroary 1
ii. introduction 3
A. Drinking Water Disinfection and Disinfection 3
By-ProdUCts—An issue of Public Health Concern
B. Drinking Water Subcommittee Charge and Review 4
Process
III. Major Elanents in HERL's Research Progron for 6
Disinfectants and Disinfectant By-Products
A. Identification of Disinfection By-Products 6
B. Concentration for Toxicity Testing 7
C. Mutagenicity 7
D. Subacute and Subchronic Toxicity Testing 8
E. Developmental and Reproductive Toxicology . 9
E'. Biochemical Mechanisms of Toxicity 10
G. Evaluation of the Effects of Chlorine on 11
Atherogenic Potential of Chlorinated
Drinking Water
H. Short-Term ^n Vivo Tests for Screening 14
of Toxicants
I. Carcinogenicity 15
J, Exposure Assessment 16
K. Epidemiology 18
IV. Major Progran Recommendations 20
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I, Executive Summary
, Vfater Subcorruttee of the Environmental Health Cccmittee
of ESftSC; Advisory Board has completed its evaluation of the
sinfcction and Disinfection By-Products health research
pcogiaii.;"'~rai*eview is especially timely in view of the growing
recognition among scientists, engineers, governmental officials and water
supply providers of the public health risks associated with the continuing
incidence of waterbome disease, and the increasing need to investigate
the public health implications of the use of alternative disinfection
techniques and their by-products. Efforts currently taken to reduce
waterbome disease should not, in the Subccmmittee's view, ignore the
potential or actual risks that occur following the application of disin-
fection techniques.
The current research efforts presented by EPA staff to the Subcommittee
focused almost exclusively in the area of chlorination and the by-products
resulting froro this treatment process. Hi is is understandable in view of
the ccnplexity of the problem, as well as the widespread current usage of
chlorine for disinfection. The SuJbccnreittee strongly believes, however,
that more attention should be devoted to the potential toxicity problems
that could arise from alternatives and/or adjuncts to chlorination such
as chloranination, and the use of ozone, chlorine dioxide and other
disinfectant processes. In view of the number of treatment systens that
are turning to the use of alternative treatment approaches, it is neoessacfr
to expand the research focus to determine which treatment methods protect
public health most effectively, and to compare the relative effectiveness
and risks associated with each treatment technology.
Specific issues highlighted by the Subccranittee, in view of these
general conclusions, includes
0 The potential sccpe of the research program, in terms of the number
of eonpounds that may be present in drinking water as a result of disinfection,
and the large number of potential target organs and systems, is appreciated
by the investigators as well as the management of the program. The program
appears to have made good progress in view of the enormity of the disin-
fection problem and the limited personnel and funding resources. Current
research efforts are also well focused in that they appropriately address
a number of scientific issues that currently confront the Office of Drinking
Water,
o Identification of disinfectant by-product compounds. It should
not be assumed that separation and identification methods can be transferred
directly from the study of chlorine by-products to the more polar and
labile by-products expected fron ozone and chlorine oxide and the more
basic, higher molecular weight compounds expected from chloramines. Some
fundamental work in these analytical methods will few required, but it is
not clear to the Subcommittee that the program has sufficient personnel
or advanced instrumentation for these tasks. There is a need to field
test analytical methods. Interferences and other analytical difficulties
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of disinfectant residuals and' ty-products much
the ••f ieId than under controlled laboratory conditions.
,;'- '•
o Subacute and subchronic toxicity testing of disinfectant by-
products. To date, roost of the program's efforts have addressed chlorine
and its by-products, with lesser attention devoted to chlorine dioxide
and chloramine and none, as yet, to ozone and its byproducts, it should
re-examine the scientific rationale for using the 10-day test because
the more frequent practice is to use 14-day testa for subacute studies.
Consideration should also be given to initiating further studies on potential
adverse effects identified in these routine studies.
o Developmental and reproductive toxicology. Itie program currently
addresses a roost relevant scientific question, that is, the identification
of agents that have selective toxicity for the embryo while lacking toxicity
for the mother. Researchers in the program have identified at least two
agents capable of producing adverse effects in the conceptus at treatment
levels lower than those needed to produce acute signs of toxicity in the
mothers. Compounds such as these represent a significant developmental
hazard, and they merit further study as priority issues.
o There are definite deficiencies in the development and use In some ~
areas that the Subcommittee believes are important in determining the total"
toxioological profiles of drinking water disinfectants and their by-pifcxjucts.
rtotable among these would be neurotoxicology (including the need and feasi-
bility for behavioral studies}, cardiovascular toxicology and imnunatoxicol-
ogy. The program is not sufficiently integrated with a readily available
battery of tests for neurotoxicity or immunotoxicity. Wiile the Sub-
ccranittee recognizes that the personnel and resources that can be assigned
to the disinfectants program (and indeed the entire drinking water research
program) are finite", such areas need to be addressed. It was somewhat
surprising to the Subconmittee that sane of this work was not, or could
not, be conducted at the Health Effects Research Laboratory (HERD in
Research Triangle Kirk.
o More resources should be provided for epidemiological studies of
disinfection systems using both chlorination and other treatment techniques.
In this area interactions and joint funding with other organizations,
such as the national Cancer Institute, should be continued. Mso, further
review is needed of the "crash" effort to develop epidemiological and
other studies on the possible role of chlorination in relation to cardio-
vascular disease.
o There is a need to incorporate within research objectives a
continuing program for studying mixtures of compounas both in methodology
development and testing of water concentrates.
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.effort is spent in gathering data to fill in specific
* 'While this, in itself, is not unproductive, the
and the Office of Exploratory -Research should
more frSifuSly "encourage long-range planning and management as, for
example, the initiation of studies on ozone and other disinfectants. At
the sane time, the investigators need to have the time and resources to
develop projects and programs in fundamental research on agents within
the framework of the disinfectants program. Specific benefits of this
latter approach are: 1} an increase in ffiA's capability to identify
emerging problems, and 2) providing the scientific staff with opportunities
to further develop their skills and gain support for their work in the
scientific community. Both of these activities can directly benefit and
support EPA's ongoing regulatory activities.
o Related to the foregoing is the difficulty the Subcommittee had in
gaining a clear insight into how projects, other than those directly ...
related to data gathering, are initiated and continued. The criteria
used in judging the worthiness of individual projects and the mechanisms
for their initiation were also not clarified. Equally important is the
problem the Subcommittee had in ascertaining how projects are terminated
so that new ones may begin. Such endpoints are critical in the distri-
bution of the programs's limited resources.
.<••
II. Introduction
A. Drinking Water Disinfection and Disinfection By-Products:
An Issue of Public Health Concern
The primary method of disinfection currently used in public drinking
water supplies in the United states is chlorination. Through complex
chemical interactions the chlorination process can introduce carcinogenic
compounds into the drinking water such as the general class of trihalo-
methane compounds, including chloroform. The health effects resulting
from chlorination are only partially known to scientists and public
health officials. As part of its regulatory program, EPA's Office of
Drinking Water (QDW) is considering alternatives to chlorination such as
chloramination', and the use of ozone, chlorine dioxide and other disin-
fectant processes. To determine which treatment method(s) work most
effectively to-protect public health, a comparison of their relative
effectiveness and the risks associated with each treatment technology
needs to be performed.
The detection of synthetic organic chemicals in public water supplies
helped motivate the Congress to enact the Safe Drinking Water Act of 1974.
Amendments to this Act in 1977 reflected a growing Congressional awareness
and concern over the issue of disinfection by-products by mandating EPA to
conduct a study of the reaction of chlorine with humic acids to understand
the effects of the contaminants that result from such reaction on the
public health and on drinking water safety, including carcinogenesis.
Subsequent amendments in 1986 specified a time table for SPA to regulate
83 contaminants. By June, 1989, an additional 25 contaminants listed by
EPA must be regulated. Some of these latter compounds may also be
disinfection by-products. -
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{infection deficiencies viewed by EPA as responsible
for catbue^BCp»«tert»rnc disease fron 1971-1985, are presented in
Table ';Iv^^j(||MF^;&ver health effects associated with disinfection
agents 'anQ'"'aSnzt''by-products has centered on chlorofonn because of the
detection of high concentrations in drinking water and the known toxicity
of this compound fron other routes of exposure. During the past decade,
other studies, seme funded by the EPA, reported associations betweeen a
range of health endpoints (including cancer) and chlorinated water supplies.
Over tine, this work stimulated interest in examining alternatives to
chlorination techniques.
B. Subcommittee Charge and Review Process
At the request of the Deputy Administrator and the Assistant Administrator
for the Office of Research and Development (ORD), the Science Advisory Board
(SAB) Executive Committee agreed to carry cut a scientific review of the
component of EPA's research program on Drinking Water Disinfectants and
their By-Products conducted by the Health Effects Research laboratory*
The Committee authorized the Drinking Water Subcoramittee of the Board's
Environmental Health Committee to conduct the review. This action by the
Executive Comnittee is part of a continuing series of SAB research progran
reviews that is intended to provide independent scientific advice on the
objectives, relevance and quality of ongoing research, and to identify any
needed modifications to the content and direction of individual research?
programs. This specific program review was requested by senior EPA managers
because of their desire to obtain an expert evaluation of the capability of
this program to support the Agency's regulatory information needs.
The Drinking Water Subcommittee addressed four overriding issues in its
review. These included:
o Assessment of the scientific adequacy of the conceptual design of the
research program, the goals it sets and the needs it fulfills.
o Evaluation of specific objectives of the resea-Ch program as they support
the assessment of risks posed by drinking water disinfectants and their
by-products.
o Discussion of cross-cutting scientific issues and integration with other
research programs within EPA.
o Formulation of reconmendations regarding the program's ability to meet
future EPA needs, and flexibility for addressing future issues.
The Subccnmittee met in public session on June 4-5, 1987 in the auditorial
of EPA's Andrew N. Breidenbach Environmental Research Center, Cincinnati, Ohio.
Notice of the meeting was published in the Federal Register on May 15, 1987,
Volume 52, No. 94, Page 18447.
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Defficiency
Table 1
Water Supply Def ieiencies Radonsible
for
Haterborne Outbreaks, 1971-1985
Outbreaks
Reported
Illnesses
Surface Water Source:
Untreated
Disinfection Only, or
Inadequate Disinfection
Disinfection With Other
Treatment
Filtration
Ground Water Source:
Untreated
Inadequate Disinfection
Disinfection With Other
Treatment
Totals
Totals
Distribution Systems
Cross-connection
Contamination of Mains/Slunbing
Contamination of Storage
Corrosive Water
31
67
20
123
245
44
14
11
10
Totals 79
GRAND TOTAL (REPORTED)
(ESTIMATED)
Source? G.P, Craun, J. Am, Water Works Assoc., March 1987
1,647
23,028
969
9,852
35,496
154
90
1
11,266
40,893
22
52,181
8,124
3,413
6,244
147
17,928
105,605
300-500,000
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specific focus of the Subcommittee's meeting was the review of
Program on Drinking Water Disinfectants and Their
Prepared £or a SAB Program Review" (May 1, 1987),
.-the. Toxicology and Microbiology Division of the
Laboratory in Cincinnati. EPA staff provided
supplenental ooronents to the Subccranittee at its meeting, in addition to
oral presentations. Review and discussion of these materials furnished the
oasis of the Subcommittee's report. Subcommittee members had the opportunity
to question O1D scientific staff and research managers, and staff of the
Office of Drinking Water, as well as offer their own individual and collective
views on the research program.
The Subcoawittee enjoyed the full cooperation and support of EPA
staff during the course of its review and wishes to express particular
appreciation to Dr. Elmer Akin, Director (until July 19§7) of the research
progran on Drinking Water Disinfectants and Their By-Products, and Mr.
David Kleffman, ORD Office of Health Research, for their assistance in
coordinating the Agency's preparation for this SAB review.
III. Major Elements in HERL's Research Program for Disinfectants and
Disinfectant By-Products
A. identification of Disinfection By-Products
Until recently, research in this area conducted by EPA's Health Effects
Research Laboratory has focused almost exclusively on the .separation
and identification of chlorination by-products. This is an extremely relevant
area from a regulatory perspective, but the need to obtain information on
by-products of other chsnical oxidants/disinf ectants is becoming a much higher
priority. Current analytical chemistry research has abruptly shifted to the
study of ozone by-products, an area where major infonnation gaps exist.
The Subcommittee concurs that work in this area is needed and vital to
the Agency's mission, but it cautions that research on chlorine dioxide
and chloramines should not be neglected. Moreover, it cannot be assumed
that separation and identification methods can be transferred directly frem
the study of chlorine by-products to the more polar and labile by-products
expected from ozone and chlorine dioxide and the more basic, higher molecular
weight compounds expected from chloramines. Some fundamental work in these
methods will be required, but it is not clear to the Subcommittee that the
program has sufficient personnel or advanced instrumentation for these tasks.
Even closer working relationships with other EPA and extramural units that are
active in this area are essential if EPA is to gain maximum use from its limited
research resources. Staff experience in HPLC and HPUC/MS or MS/MS methods could
considerably aid this program's efforts as its changes its emphasis from non-
polar to polar by-products. An added benefit following the development of
an analytical methodology for polar ccmpounds such as ketones, aldehydes,
alcohols and acids would be the generation of contaminant data for these
chemicals in water supplies. Very little infonnation is available on
their occurrence in drinking water because a routine screening methodology
with a reasonably sensitive detection limit is not available, and yet
these compounds are widely used in industry and have a high potential for
contaminating drinking water from past or present use.
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the MX L Ml n m'llHKyiCtlve -in an _in vitro cytogenetics model but inactive
in the i ^WfCTBBBBiftrTfnn assay. It is also significant that use of a
(S-9) practically removes the activity
observed with TA-10Q, The prograa should emphasize the _in vitro - iri
vivo ccnparisoos in order to acquire an early indication of potential
hazard even if the Salmonella assay indicates a compound is a potent
nutagen.
There is an absence of knowledge on the biological activity of
disinfection by-products produced by alternate means of disinfection, A
strain of Salmonella typimurium, TA-102, has been derived that is sensitive
to oxidative nutagens. If the Salmonella model continues to be used as a
primary screen* this strain should be helpful to examine water concentrates
for potential nutagens derived frcro the ozonation process. Also, careful
applications of the Ames assay coupled to chronatographic techniques could
be useful in following the concentration of water samples to indicate
whether activity is associated with a chanical pre-existing in the water
sample itself or an artifact of the concentration process.
D. Subacute and Subchronie Toxicity Testing
The assessment of toxicological data for a variety of chemical substances
is a critical component of the research program, Subacute and subchronic
testing is used primarily to provide scientific support to develop Maximal
Contaminant Level Goals (MCUGs) and Maximum Contaninant Levels (MCLs) for
noncarcinogenie chemicals, in addition to preparing health advisories for
compounds with mutagenic or carcinogenic potential.
These uses necessitate continuous toxicological testing (and associated
continuity in resources) to initiate and cooplete tests to evalute those
chemicals whose potential public health impacts require further study, and
to establish testing priorities of chemicals on an annual basis. To date,
most of the progran's efforts have addressed chlorine and its by-products,
with lesser attention devoted to chlorine dioxide and chloramine and none,
as yet, to ozone and its by-products.
the basic protocols adopted for the subacute and subchronic studies
involve 4 and 3 dose levels, respectively, using 10 male and 10 female rats
with conrespondiiij controls. Routine body weights, hematology, serum
chemistries and urinalysis, along with selective histopathology are
monitored. These 14 day subacute studies are necessary to provide evidance
of organ toxicity, the nature and development of toxicological effects
and dose-response relationships between exposure and effects tested. In
addition, these provide the basis for selecting doses tor the 90-day
studies and ultimately the lifetime studies usually for carcinogenicity
or other long-term effects. The Subccntnittee recognizes that such studies
are time-consuming and place increased demands on the limited resources
that must be provided and guaranteed for short and long-term Agency connit-
ments,
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The ati^^^lisinfection by-products of ozone, chlorine dioxide and
chloraniiiii^ I] lu use of analytical methods that are applicable to
polar, ht^^^Sj^^mi^tit and labile by-products, such as HPLC, HPIC/J6
or ffi/MS -fflwJ^^^IPiftanced instrumentation and possibly new personnel to
support this effort will be needed.
One area that needs to receive more attention is that of analytical
methods development. A need that exists regarding the measurement of
disinfectant residuals and by-products is that analytical methods be
provided that have been field tested. Interferences and other analytical
difficulties often make measurement of disinfectant residuals and by-products
much more difficult in the field than under controlled laboratory conditions.
B. Concentration for Toxicity Testing
One important activity in this area consisted of an extramural evaluation
of several prcconcentration procedures, especially adsorption methods* the
study concluded that all of the methods tested have limitations, particularly
in the recovery of very polar ccmpounds. The researchers have also compared
low pH XAD-8 extraction with total lyophilization in order to determine if
the observed mutagenicity of low pH XAD extracts observed in an earlier '
study was an artifact. These represent important and complex efforts that
are relevant to regulatory decision making and should be continued. Th«y
will beecrae increasingly important as the program . begins to focus on polar
by-products fron ozonation and other oxidation/disinfection processes. ~ *'
Additional in-house expertise is needed on concentration methods for toxicity
testing of polar, higher molecular weight and mope labile by-products such
as those expected from the use of ozone, chlorine dioxide and chloramines.
C. Mutagenicity
Mutagenicity models have been a major feature of HERL's approach to
identify potentially hazardous substances resulting fron water disinfection,
primarily with chlorine. The Ames Salmonella assay has been useful in
measuring the nutagenic activity of water concentrates, isolation of active
components in a mixture and directing attention to specific chemical
structures for additional study. However, it is quite clear that the
Salmonella assay does not respond well to several classes of chemicals,
among which are certain chlorinated aliphatic and chlorinated aromatic
compounds. The Subcommittee advises the program to utilize a mammalian
cell gene mutation assay to augment the Salmonella model and thereby achieve
a greater sensitivity for compounds derived from the chlorination disin-
fection process.
The results presented at the review on ccnpounds derived from a
chlorinated humic acid sample, especially the MX furanone, can serve to
illustrate a principle of mutagenicity testing. That is the need to
examine multiple endpoints both m vitro and jii vivo to acquire perspective
on potential hazard and/or risk determinations. It is significant that
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mm Q _
several specific concerns with this part of the
ons the usefulness of the 10-day test. While
it tecoigsM% protocol was established to coincide with the
10-day heallS^^tsories, the more traditional subacute study involves
14-day testing. EPA should re-examine its scientific rationale for the
10-day test.
Second, the program is not adequately integrated with a readily
available battery of testing for neurotoxicity or innutnotoxicity, contrary
to what was indicated. For example, the 10-day testing of chloropicrin
suggested limnunotoxicity based on histopathology of the thyniis, and testing
of dichloroacetic acid indicated neurotoxicity, but these have not been fully
studied, Wtile HBRL conducts or contracts out seme of these studies, it
appears as if both of these functions are part of the activities in Research
Triangle Park. The Subcommittee could not identify efforts to readily
incorporate the necessary integration of inmunotoxicity or neurotoxictty
testing. Such integration is necessary not only from a scientific stand*
point but also in wisely utilizing resources. It should not be difficult
to achieve such integration. For example, the EPA neurotoxicology
group at HE1L in Research Triangle Park had been active in the design
and validation of relatively single neurological/behavioral tests which
have been adopted under the Toxic Substances Control Act.
As more rapid and efficient batteries of tests develop, (either in '
vitro or in vivo) the program should begin to incorporate them into
research protocols. Sane flexibility and opportunity to phase in studies
should be provided. This includes, for example, the possibility of
using biocheroical mechanisms of action, or SAR, and the study of cheraicals
other than chlorine, such as chlorandne and chlorine dioxide, ozone and
their by-products. However, until it can be demonstrated that _in vivo
testing using animals can be replaced by equal or better indicators of
toxicity, this phase of the program's activities should be maintained.
The Subconroittee is also concerned that there may not be adequate
opportunity to pursue additional studies on potential adverse effects
identified in those primarily extramural studies.
E. Developmental and Reproductive Toxicology
Substances to which large and diverse groups of individuals are exposed
by a variety of routes and intensities are priority areas for research.
Coupled with this is the fact that the _in utero eonceptas is uniquely
vulnerable to some test conpounds and, since part of the population
will be women of childbearing potential in which embrycxjenesis is
completed before the woman is aware of the fact that she is pregnant, it
is essential to have and continue major research efforts aimed at
detecting agents that are selectively toxic to embryos but essentially
nontoxic to the mother*
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The existing research in developmental and reproductive toxicology
addresseai a«*i^^Of the most relevant issues regarding developmental
toxicity^^BtfHBjwiff'test identifies agents that have selective toxicity
for the^'tiin^Sj^S^SaeB not discriminate the pattern of effects produced
by specif'i$r::4^p£^'but this is acceptable because the pattern of effects
is not highly meaningful information for early tests. In its expanded
version, which is now an abbreviated Segment II, the study also provides
an approximation of the No-Observed-Effeet-Level (NOEL), at least for the
rat, by the route of treatment used. Again, though not essential for a
screening-type test, this is useful information. Finally, the protocol
yields an approximation, or an impression, of the dose-response curve in
a definitive study. In short, the program is currently addressing the
most relevant scientific question, that is, the identification of agents
that may be present in drinking water and have selective toxicity for the
embryo. Pursuing this kind of inquiry, researchers can hope to avoid
repetition of a thalidonide type problem.
Researchers in the program have identified at least two agents
capable of producing adverse effects in the conceptus at treatment levels
lower than these needed to produce acute signs of toxicity in mothers.
Compounds such as these represent a significant developmental hazard. If
results of this magnitude were seen for other types of toxicity, e.g." an Ames
test, they would precipitate a series of concerns regarding both mutagenesis
and carcinogenesis, and would elevate the compound for more detailed testing.
Senior managers in the laboratory and within EPA need to more aggressively
investigate the implications of these findings that detect chemicals that^are
a significant potential hazard for the conceptus.
While the program has a reasonable focus in the area of developmental
toxicology, the Subcommittee believes that an additional emphasis should be
placed on reproductive effects. This is true for both males and females.
F. Determination of Biochemical Mechanisms of Toxicity
A major responsibility of EPA is to evaluate the health effects of
the chlorinated disinfection by-products in finished drinking water. A
much more difficult scientific problem is determining the biochemical
mechanisms by which these many chlorinated products exert their various
toxic reactions. As yet, little is known ot the target organ toxicity,
reproductive and developmental effects, or the carcinogenicity of the
varied halogenated compounds found in chlorinated drinking water.
As a portion of a long range study of possible biochemical mechanisms
of toxic action, EPA researchers have investigated the nucleophilic
capture of glutathione (GSH) _in vitro (pH range of 6-8) by chloroprcpanone
(MCP)', 1,1-dichloropropanone (1,1-DCP) and 1,3 dichloropropanone (1,3-ECP).
As expected, the reactions are base-catalyzed and presumably involve
bimolecular displacement of chloride from the haloketones by the glutathionyl
anion. The order of reactivity over the narrow pH range is: 1,1-DCP >
MCP > 1,3-DCP. The physical-organic chemistry of these displacements
appears to have been studied carefully and with insight,
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- 11 -
y reactions of the halopropanones may involve
ijsapture of glutathione rather than direct displace-
Wiat is not yet clear, however, is the biochemical relevance of
the above experiments, the propriety of the glutathione model and the
direction of future research in the above area. Can the SAR results
obtained be predictive or are they merely descriptive? It would presently
appear useful to establish the rates of disappearance, displacement,
hydrolysis and capture of certain halogenated organics that are suspected
to be highly toxic and are difficult to ranove from water. There are,
however, far too many chlorination products in drinking water whose
rate constants for disappearance should be determined. If there is
sufficient financial support, conjugate addition of glutathione to
alpha, beta- unsaturated compounds, nucleophilic displacement by, and
addition of, annonia and amine systems, and detoxification of certain
products of ozonolysis of drinking water should be modelled in vitro.
The Subccnroittee recognizes the difficulties of designing meaningful
in vitro experiments for determining the biochemical mechanisms of
toxicity of different levels of drinking water quality. As with other
projects, the Subccnmittee believes that research for determining the
in vitro mechanisms of toxicity of chlorinated water need independent
peer review.
G. Evaluation of the Effects of Chlorine on Atherogenic Potential of
Chlorinated Drinking Hater
Research on the atherogenic potential of chlorinated water incorporates
both animal and human trials as well as some epidemiological studies.
Studies with pigeons demonstrated that serum cholesterol levels became
elevated when birds were exposed to chlorinated drinking water. This
initiated further investigations with monkeys and human volunteers.
Currently, there are epideraiological evaluations of chlorinated and
nonchlorinated water supplies, but these investigations are linked to
hard and soft waters.
The Subconuittee has concerns regarding the design of studies and
the future direction of this component of the program. The Subcommittee
endorses the research review that is to take place in the fall. This
review is urgently needed. Its objectives should induce: 1) impartially
examine the entire program, 2) critically review progress to date, and
3) help focus on crucial design issues as well as help the progran
detenhine the critical research necessary to strengthen or verify the
evidence of an effect of chlorine in water on atherosclerosis. The
necessity to develop this research in the manner that roost quickly
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12 -
of chlorine in drinking water is of great
high percentage (approximately 33%) of the
that is devoted to this research effort.
is the strong potential for the investigators to become lost in the
rather ccnplex and voluminous biochemical issues that can be followed up
in this type of investigation, as opposed to identifying those critical
experiments that will prove or disprove the issue before the Agency.
This is especially true since there is really no basic hypothesis advanced
for such an effort. The investigators also nust guard against overstating
results, especially in light of the experimental designs used (i.e.,
internal controls).
Another concern to the Subccnmittee was the lack of reference in the
presentations to the current status of heart disease in this country in
relationship to the work being undertaken and some of the newly recognised,
though still highly controversial, issues that could influence both the
approach and the interpretation of the data currently generated. For
exanple, mortality for cardiovascular disease has decreased in the United
States by 34% and ischaaic heart disease by 42% since 19681. How this
information is factored into the relevance of the current or expected
findings frcro either epidemiological or human trials is unclear. For
example, how much variability of risk factors or how much of the disease
might be explained by chlorination of drinking water? ,
Also not addressed in any of the discussions was the Agency's view
of those individuals at high risk to cholesterol {familial hyper-
cholesterolania). It may be that this sensitive part of the population
is at higher risk from consumption of chlorinated drinking water than
the majority of the population, if the evidence thus far presented is
substantiated.
Several specific conraents related to research projects are described
below:
1. Epidemiological Studies
While understanding the rationale of selecting hard and soft water commun-
ities, the current design falls somewhat below the optimum because intermediate
hardness was not included and most likely represents the drinking water of a
large segment of the population.
Although the very preliminary data look especially interesting for women
in the cohort, a possible confounding factor may be due to dietary changes
that are effective at reducing total cholesterol by only 6.9%. Its value
will be decreased, if a number of factors have not been controlled (i.e.,
diet, smoking history, exercise, and familial hypercholesteroliemia.) This
National Center for Health Statistics, Vital Statistics Report,
Final Mortality Statistics, 1982.
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- 13 -
last fa»|§iiBHHfff^ *nr**'"* and EPA should consider the next type of
study uh|(^^B||^^pw«is effort. Appropriately designed retrospective
studies.--ialpwBBqifiskly' address sane of these issues and may be sensitive
enough to detect reasonably large effects.
2. Human Trials
While it is understandable to use individuals as internal controls
in order to convince the skeptics of the effect of diet and chlorine on
cholesterol and HDL, the effect of diet alone over long periods must be
ascertained. Without a nonchlorine-exposed control, this question cannot be
adequately answered. The population selected for study is not typical of
the U.S. population.
In the figure presented on "total cholesterol by the study period,"
the Subcommittee is concerned that the baseline value decreased so
dramatically although, from the information provided, it appears that
individuals had been placed on the high cholesterol diet upon entering
the hospital. This is important because, if this value had been higher,
the subsequent study values would most likely have not been significant*
An approach to resolve this issue would be to evaluate to baseline twice
before initiation of chlorine exposure.
3. Private Trials
In this component of the program it would-also be useful to have a
set of animals that receive only the high cholesterol diet. The Subcommittee
has a concern over the highly complex schedule of the protocol. The verifica-
tion of the study by an independent laboratory is useful, and perhaps this work
could include a control group that did not receive chlorine in the drinking
water. The future direction ot research in this phase should be carefully
considered as to the detail required in plaque formation to serve the
Agency's need. There was a tendency to overstate results and some lack
of awareness of the effect of diabetes on cholesterol and HDL.
All the studies should state the concentrations of chlorine related
to potential NOEL or Lowest-Observed-Effect-Levels (LOELs). Obviously,
the concentrations eliciting effects in animals are far in excess of the
concentrations likely to be experienced by the public. Thus, the need to
perform controlled studies in humans at still higher exposure levels is
questionable in view of the negative findings to date. A further general
question that should be directed to the Office of Drinking water is to document
the number of supplies that are likely to continue using chlorine as a primary
disinfectant as regulated TW1 levels decrease.
A general concern regarding both human and primate trials is the
toxicity of the disinfectant itself compared to the by-products produced
by these strong oxidants. The disinfectant itself reacts rapidly,
especially at the high concentrations used in these studies.
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- 14 -
Irt Vivo Tests for Screening of Toxicants
g-utilizing short-teem tests for identifying chemicals
that have nut^g«uc7or carcinogenic potential is an attractive one both
frcm scientific and economic considerations. However, the major problems
in implementing this approach are as follows:
o Not all carcinogens can be detected as genotoxic substances.
o The ability to identify and quantitate the probability of
effects are issues that arise due to the intrinsic nature of the
assays employed and criteria used to judge a particular response
as positive or negative.
o In vivo evaluations of KI vitro positive results depend in
sane cases on models whose sensitivities are low or require
extensive testing with large numbers of animals. There are
additional questions of whether the endpoint observed early
in a treatment regimen adequately represents a slowly developing
disease state produced by chronic administration of a chemical.
o The standard against which short-term tests are finally judged, the
rodent bioassay, has serious flaws due to methods of testing
and toxicity issues generated by dosage regimens that may not >
adequately reflect human exposure or potential hazard*
However, the tests suggested as a Tier I approach, the Ames assay and
30 iD. vitfQ cytogenetics model, are aroong those reccnmeaded for screening
consideration. As knowledge and experience accumulates, it would be prudent
to utilize short-term test models that have a sensitivity and specificity
spectrum appropriate for the chemical class being examined. This raises
important issues when testing mixtures. The Tier II assays that give
additional perspective on j£ vitro genotoxic positives include the micronucleus
test and in vivo metaphase analysis utilizing mouse or rat bone marrow cells.
The DMA damage assay using unscheduled DMA synthesis (UDS) in rat hepatocytes
has given a poor performance even with hepatooellular .carcinogens. It may
be more productive to quantify the number of cells in S phase in adult
rodent livers as a function of time and dose than to attenpt a UDS assay.
The sister-chronatid exchange assay is a more sensitive indicator of potential
i£ y.fop. genetic effects, but interpretation of its results represents a large
challenge. Cell transformation assays are becoming more useful, especially
when joined to the newer methods of DNA analysis, e.g. DNA fingerprinting
and hybridization techniques. These techniques should be part of an
exploratory toxicology program at the laboratory.
Other in vivo assays in a Tier II configuration, such as mouse skin
painting, are useful in determining carcinogenic potential of compounds
especially those where exposure patterns are best modeled by skin painting.
Both the rat liver altered enzyme and trouse lung adenoma models have
mechanistic and relevance problems that can be confounding for hazard
evaluation purposes.
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- 15 -
The utility of the matrix process could be quite substantive in
assisting de&ijnigttf on compound selection for further testing and hazard
evaluati<||tk|^^ȤCr the entry portal for compounds, the two mutagenicity
itodeIs,-:''ii*y::^KpE>-:.narrow to adequately identify subtances of concern.
Short-term and ^n vitro arrays for other types of toxicity should also
be examined for how they may aid evaluation of the large number and mixtures
generated by these processes.
I. Carcinogenicity
The carcinogenesis studies in progress focus on dichloroacetic acid
(DCA) and trichloroacetic acid (TCA). Previous studies have shown that
chronic administrations of either DCA or TCA are associated with an
increased incidence of hepatic tumors in male mice. Thus, by definition,
these two chemicals are formally designated as hepatocarcinogens. Ongoing
studies extend this work by testing whether these two chemicals demonstrate
a dose-response relationship for their carcinogenic activity in the male
mouse liver. The studies are also broadened by studying their activity
in female mice, including another species, the rat, and testing a related
chemical, monochloroaoetic acid. Other studies will be performed to
determine the genotoxicity of these chemicals. These studies will test
the induction of unscheduled DMA synthesis in hepatocytes, mutagenesis
in mammalian cells, and nuclear abnormalities in cells that ame into
contact with chlorinated drinking water. Additional studies will test
for other evidence of carcinogenic activity using assays of cell trans- *
formation in vitro, and will assay for initiation and promotion activity
using the rat liver focus bioassay and the neonatal mouse liver systen.
The topic considered most extensively irvthe presentation for this
part of the program was the issue of peroxisomal proliteration. Studies
were reported that described the extent of peroxisomal proliferation
induced by DCA and TCA in mouse and rat liver. Other studies reported
that prior initiation of hepatocarcincgenesis with ethylnitrosourea (2.5
ug/g b.w.) at 15 days of age did not increase tumor incidence. Studies
of enzyme induction by TCA and DCA showed only small incremental increases
of tumor incidence with further increases in peroxisone proliferation.
Other studies reported that induction of palroitoyl CoA oxidase activity was
notably lower -in rats than mice and that there was particular sensitivity
for the C57B1 strain of mice. In contrast to the mouse, TCA and DCA did
not induce palroitoyl CoA oxidase activity in green monkey or rat cells.
This component of the HERL-Cincinnati program is responsible for
evaluating of the Carcinogenicity of substances present in drinking water.
The choice of TCA and DCA for Carcinogenicity tests is well founded. Both
chemicals have been detected in drinking water, and initial studies have
successfully demonstrated Carcinogenicity in the livers of male mice.
Would these studies have been pursued with the same priority if this
categorical program did not exist? In general, however, this is a very
favorable component of the program.
The presentations and written documents did not discuss the process
used by this progran to select chemicals for evaluation or to establish
the order of priority for their testing. This question is important
because the choice of one chemical for testing may preclude the testing
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- 16 -
relevant and note hazardous chemical. Also the
-thia progran, the Office of Drinking Water, and
other iederareseurces such as the National lexicology Program, should
be considered in describing how the choices and priorities for
careinogenicity testing are determined.
The choice to focus rouch of the attention and financial resources of
thia group narrowly on the peroxiscmal proliferating potential of TCA and
DCA as a possible mechanism for their carcinogenic activity certainly
seine pranature. Before this line of investigation is vigorously pursued,
it would be valuable to establish that TCA and DCA have carcinogenic
activity in rats. The isolated observation of apparent carcinogenicity
exclusively in the mouse liver will allow the significance of this
observation to remain in doubt. Both TCA and DCA are strong organic
acids, and both have great potential to exert toxic effects in the incuse
liver following oral administration. Such toxicity could cause an
accelerated growth rate in surviving hepatocytes, and this proliferation,
coupled with the genetic instability of the mouse, could cause an increased
rate of "spontaneous" transfoonation. It could also be argued that
mechanises of carcinogenicity of peroxiscme proliferators will continue
to be studied by other laboratories that originated these observations.
These laboratories are likely to be far better eguipped to pursue this
topic. Conversely, it is less likely tMt independent investigators will'
pursue the questions of the role of toxicity in producing hepatocarcinomas
in mice. This might be a better choice for investigations by EPA.
Aside from the issue of the choice of areas of study, the design of
the experiment deserves coranent. The work presented was an interesting
collection of what seeraed to be original observations. The studies,
however, did not seem to have a clear focus and the individual investigations
did not appear to have a strong line of continuity. What has been proven
by these experiments? Are further unfocused investigations of this type
appropriate at this tiine?
In sunmary, this program component performs some studies that are
appropriate and probably of high priority (long-term cazrcinogenesis
studies), The short-teem studies on peroxiscme proliferation are probably
of lesser value. More long-term studies or the proposed assays of genotoxicity
are preferable? The larger issues about selection of chemicals for study,
the interactions between HEKL and ODW, and connections LO other Federal
units performing carcinogenicity testing, were not considered in sufficient
detail.
J. Exposure Assessment
The component of the program that addresses exposure assessment focuses to
varying degrees on a number of generic regulatory problems but also have
specific applicability to drinking water disinfectants and their by-products.
The staff presented five issues: 1) maercmolecular alkylation of physiologic
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- 17 -
>in (as an index of combined human exposures to
of selected chlorinated organic ccn^jounds
in fish fat and muscle (as an indicator of daily dose from one part of
the food supply); 3) examination of one class of chlorination byproducts,
the haloacetonitriles, for the ability to cause DMA strand breaks (as an
indication of chronic injuries relatable to short-term exposures); 4) a
search for improvements in low-dose extrapolation techniques by elucidating
pursuit of the underlying bases of cancer causation by trichlorcethylene
and isomers of dichloroethane in laboratory animals (to examine the weight
of evidence that cancers observed in laboratory mice may be more likely
due to promotional events related to secondary mechanisms invoked only
via high concentrations of hepatic raetabolities, hence possibly altering
the approach to estimating possible risks to human health); and 5) the
biological reactions postulated in the newly proposed MoolgavkarHotudson
multi-stage model.
The individual experimentation described is thoughtfully conceptualized
and carried out with appropriate technical rigor. In each case, there
is a clear understanding of the background information from which an
hypothesis is proposed, the hypothesis is clearly articulated, and the
results interpreted in a balanced fashion.
The selection by investigators of either research areas or individual
studies within areas was not discussed; hence, no comment can be made
about the relative technical merits of research undertaken or proposed.
The Subcommittee notes that no reference was made to the consideration of
the role of research activities in reducing uncertainties in the Agency's
evaluation of the consequences on human health of any or all of the
chlorination by-products (or other group of substances to which the generic
research could be of relative value). For example, what are the relative
advantages of using adducts to hemoglobin compared to other forms of
delimiters of systemic exposure? Were the documented gains substantial
in relation to other options? With limited resources, such a structured
analysis is not only desirable but essential.
Selecting 'research priorities requires an understanding of priorities
of the regulatory program that is the client for the research. Wien initiating
a new area of regulatory activity, it may be sufficient to ask researchers
to focus on naieraus frents simultaneously; however, as a regulatory area
matures, topics, of high relevance should surface and represent opportunities
to guide future research endeavors. It is clear that communication between
the research and regulatory staffs is open and continuous; but the level
at which priorities are assigned appears to be less than systematic to achieve
achieve a full harmonization between the two entities. For example, while
both agree that disinfection by-products are of paramount inpsrtance, agreement
is unclear that the indirect mechanisms of cancer (such as those suggested
for trichloroethylene and dichloroethylenes via trichloroaoetic acid and
dichloroacetic acid, respectively) are of value to articulated policy
objectives. Similarly, while scientific interest is ccmraendably high for a
more advanced low-dose extrapolation model than the presently used linearized
multi-stage model, it is unclear whether such activity is of major interest
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- 18 -
to the-.(^ar>*L?n9 Water which will be faced inexorably with the
selectWrPttlHK^'Vmodel incapable of being validated at low doses.
M a. f^^lpplf'fflJiOR of the issue of priorities, the method of measuring
tissue dose to classes of agents (e.g., genotoxicants) is of experimental
value particularly for epidemiologic studies? however, there is little
indication of how such a method would be used effectively to regulate
substances.
Although the presentation was necessarily brief, two inportant
emissions include: the absence of experimentation to reduce uncertainties
on extrapolating toxicity data from laboratory animals to humans: and
the absence of a significant effort to elucidate the collective toxicity
of mixtures at substances in tap water. The first is infxartant because
it addresses the question of the appropriateness of assuming that
rodent responses are in fact indicative of those in humans, in vitro
technology with human oell lines provides the tools by which to
enhance the certainty either of possible human injury from substances in
the environment or of the lack of relevance for htraans of a laboratory
observation. The second recognizes the complexity of chsnical exposures
in tap water, and can be addressed experimentally in ways that lead to
supportable conclusions regarding safe exposures and health risks.
Several research directions include: the examination of the toxicity xof
mixturesj the application of _in yjtro methods to bridge' the gap in extra-
polating test results from experimental animals to humans; the elucidation
of the relative contributions of exposures and injuries, by alternative routes
of exposure; the role of organ repair processes and reserve capacity for
estimating the potential for chronic toxicity; and evaluating the pathways
of pathology that are particularly critical to the manifestation of clinical
disease.
K. Epidemiology
The epidemiology program at the EPA-HERL in Cincinnati is modest in
size, meaning number of staff and budget. It was quite active before
1981 when it was essentially discontinued, and then resumed in 1983 with
fewer resources than in the pre-1981 period.
The prognw was last reviewed by an external advisory panel in
December 1983. At that time, additional epidemiologiesI research was
reconroended to?<3eteanine the associations between water quality and
cancer and cardiovascular diseases.
The program does not perfora in-house epidemiological investigations;
however, it does fund such external studies and the small staff interacts
substantially in the design and interpretation of the results of these
investigations* It cooperates with other goverrsnental organizations in
the development of these and related studies and in their joint funding.
These have included the National Center for Health Statistics and the
National Cancer Institute (NCI).
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19 -
1970's, small-budget "ecological" studies
presided preliminary evidence of relationships of
sane carMa^:'-wF
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- 20 -
IV. Maior: KsaaSOn Beconnendations
in geniElIptti* Subconmittee concludes that current research efforts
are well fuCMJ^T in that they appropriately address a number of scientific
issues that currently confront the Office of Drinking water. The caliber
of the research personnel and the quality of the individual research projects
is generally high. This group, including a number of relatively young
researchers, is professional. Each researcher appeared to be quite
enthusiastic about his/her own research efforts and supportive of each
other's projects.
Parts of this program to study drinking water disinfectants and their
by-products are relatively new. The number of compounds that may be present
in drinking water as a result of chlorine disinfection, and the large number
of potential target organs and systems, is appreciated by the investigators
as well as the management of the program. The program appears to have ™***
progress in view of the enormity of the problem and the limited degree of
staffing and funding, and lack of long-range (greater than two to three
years) planning and implementation.
The research efforts described to the Subcommittee have focused almost
exclusively in the area of chlorination and the by-products resulting from
this treatment process. This is understandable in view of the complexity
of the problem as mentioned above, as well as the widespread current usage
of chlorine for disinfection. The SubCcramittee strongly believes, however-,
that more attention should be paid to ozonation, and other disinfectants
because of the number of water supply systons that are turning to this
alternative process and the distinct likelihood that more treatment systems
will utilize ozonation in the future. Wiile the analytical group is presently
studying the results of ozonation using a humic acid prototype, it is not
clear what will trigger a more aggressive investigation of the toxicological
problems that may be associated with this disinfection method. It is
imperative that this group be on the forefront of this research. It may
well require critical thinking to establish new methods to assess toxicity
and less dependence on siroply assessing mutagenicity. Such an effort may
require additional support in terms of personnel and money.
Considerable effort is spent in gathering data to frill in specific
gaps in the data base. While this activity is not unproductive, more
effort must be spent in long-range planning as, for example, the initiation
of studies on ozone and other disinfectants. At the same time, the investi-
gators need to have the time and resources to develop their own projects
and programs in fundamental research on these agents within the framework
of the disinfectants progran. This is essential if the program is to avoid
becoming simply service oriented and not progressive in exploiting oppor-
tunities in the fundamental science of toxicology.
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21 -
The- Subaffi^:t«e is also concerned over possible conflicts between
direct jji i IU JJ^pifo**. **»»«*• iq»*-•*«•"«= and data gathering exercises versus
investigat£Qrt^pC« exploratory and longer term in nature, e.g. methods
development or'fundamental mechanisms. Greater emphasis for the latter
type of research is iisportant for two reasons: 1) it will increase EPA's
capability to identify emerging problems, and 2) it will provide the
scientific staff with opportunities to further develop their skills and
gain seaport for their work in the scientific ecranunity. Sane of these
concepts that have been discussed but not studied to any great extent,
such as studying the toxicological interaction of compounds as mixtures,
portend great difficulty but should not be impeded. In addition, these
activities can directly benefit and support EPA's regulatory mission.
Related to the above is the difficulty the Subcommittee had in
gaining a clear insight into how projects, other than those directly
related to data gathering, are initiated. The criteria used in judging
the worthiness of individual projects and the mechanises for their initiation
were also not clarified. Equally important is the problem the Subcommittee
had in ascertaining how projects are terminated so that new ones way begin.
Such endpoints are critical in the distribution of the program's limited
resources.
There are definite deficiencies in sane of the areas that the Sub-
committee believes are important in determining the total tosticological -
profiles of the drinking water disinfectants and their by-products. This
includes, for example, the compounds that may have effects on the nervous
system that would go undetected unless carefully examined. This would
include possible effects on behavior. Although studies are ongoing for
evaluating the relationship between chlorination and atherosclerosis,
other cardiovascular effects are not being considered. Itiese chemicals
might also have effects on the immune system, the presence and possible
inp^rtanee of which would go largely undetected. -
While it is fairly obvious that the personnel and resources that can be
assigned to the disinfectants program (and indeed the entire drinking
water program) is finite, such areas need to be addressed. The Subcommittee
believes that sane of this work could be conducted at the EPA Health
Effects Research Laboratory in Research Triangle Park, even though the
Subaatnmittee appreciates that the distribution of effort among EPA
laboratories is primarily along media lines, frhile it is encouraging to
note that a few of the research groups, e.g. reproductive and developmental
effects and careinogenesig, appear to have contact with similar research
groups in RTPr there is room for jnuch more interaction within EPA and
also'with various units of the National Institutes of Health.
In considering working relationships within EPA, tne Subcowtittee
concludes that stronger ties involving coordinated planning should be
established for issues involving water treatment technology and monitoring.
This should especially be encouraged within HEKL, The former certainly
impacts on the program with regard to what may be removed prior to chlorination,
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- 22 -
and the SitfeefWtb verification of what is in the drinking water from
many ccnnunities in comparison to what is found with the model chlorination
systero employing humic acid. The program also needs to be better attuned
to the engineering aspects as to how chemicals are used in the entire
water treatment process. For example, chlorine is being rapidly replaced
by other oxidizing agents such as ozone, chlorine dioxide and potassium
permanganate for chemical oxidation (as opposed to disinfection). This
will definitely influence the types of ccnqDOunds that are appearing and
will appear in the finished water.
It was quite clear from the extended discussions that the Office of
Drinking Water and Office of Research and Development spend considerable
effort planning the types of short-tern projects undertaken and the
direction of the research through the Water Research Conmittee's Disinfectant
By-products Workgroup, and informal discussions. The Subcommittee reoonmends
that, in addition, the drinking water disinfectants program should undergo
a through and continuous review of ongoing research as well as future
projects to insure that the long-term as well as the short-term needs of
the Agency are met. This could be conducted by competent external scientist^
Its purpose would not be to iiipede the activities of the program, prescribe f
what should be done or usurp the duties of the Agency, but to serve as -a *
gaide to the overall operation and direction of the prograa. This could
be done in a colleageal and non-adversary manner and provide expert
guidance and opinions on the worth of individual projects. Hiis mechanism
may be more satisfactory than simply relying on ad hoc advisory panels
that exist and have proven to be periodically useful.
Finally, and related to some of the other points outlined above, the
Subconmittee is apprehensive that the program and the individual scientists,
in particular, may beccme entrapped in a data gathering mode. "This is
reflected in the great dependence on outside contractors for much of the
work. The individuals within the unit need to be acutely aware of the keys
which trigger additional research in the various areas of the program*
Their input into when and how to follow \sp interesting and important
findings from "routine" subchronic and mutagenicity studies, and frcm
short-term reproductive toxicity tests, is essential. Moreover, they
need to share in the knowledge of how their data are used in the Agency's
decision making processes.
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UNI TED STATES ENVIRONMENTAL PROTECTION AGENCY
I WASHINGTON, D.C Z04SO
SAB-EHC-88-005
October 23, 1987
Honorable Lee M, Thomas TME *o»tN^l»
Administrator
U. S. Environmental Protect ion Agency
401 M Street/ 3. W»
Washington, D. C. 20460
Dear Mr. Thomas:
The Drinking Water "ubonmittee of the Science Advisory Board's
"nvironmental Health Committee has completed its review of the Office of
Research and Development's Health Effects Research Laboratory's Drinking
Water Disinfection and Disinfection By-Products Research Program, and is
pleased to transmit its report. to you. T:H vj'xonroittee reviewed this
program at a public meeting at the laboratory in Cincinnati, Ohio on June
4-5,
This cevUw U especially timely in view of the growing recognition
among scientists/ engineers, governmental officials and water supply
providers of the public health risks associated with '••'•> continuing
incidence of waterborne disease, and the increasing n-s--i to invest I j^t^
the public health implications oC the us** of: alternative disinfection
techniques and th^u- by—pc; •'ducts*.
In general, the Subcommittee concludes that current research efforts
are well focused in that they appropriately address a number of scientific
issues that currently confront the Office of Drinking Water. The caliber
of the research personnel and the quality of the individual research
projects is generally high. Each researcher appeared tn be quite enthu-
siastic about his/her own research efforts and support '.-/e of each other's
projects, Tnt? current research efforts pre<3*jiit«#J by """•„ ^i aTf to the
Subcommittee focused almost exclusively in the area oF ^hlorination and
the by-products resulting from this treatment process. This is understand-
able in view of the complexity of the problem, as well as the widespread
currant usage of chlorine for disinfection.
The Subcommittee's major recommendation is that more attention should
be devoted to the potential co/cicity problems that could arise fro-n aU.^c^
natives and/or adjuncts to chlorination such as chloratni nation, and the
use of ozone, chlorine dioxide and other disinfectant processes. In view
of the nuinbec; of :-.?'--<:. wit -systems that are turning to the use of alter-
native Lteabnenh approaches, it is necessary fco expand Uie research focus
to determine which treatment methods protect public health most effectively,
and to compare the relative effectiveness and risks associated with each
treatment technolocw.
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