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x>EPA AN SAB REPORT: REVIEW
OF DRINKING WATER
HEALTH CRITERIA
DOCUMENT
REVIEW OF THE OFFICE OF
DRINKING WATER'S HEALTH
CRITERIA DOCUMENT ON
CHLORINATED ACIDS/
ALCOHOLS/ALDEHYDES/KETONES
BY THE DRINKING WATER
COMMITTEE
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'
I UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHtNGTON. D.C. 20460 •'
or
EPA-SAB-DWC-92-002 ™f """•""••AT
November 27, 1991
The Honorable William K. Reilly
Administrator
U. S. Environmental Protection' Agency
401 M Street, S.W.
Washington, D.C. 20460
Subject: Review of Issues Relating to the Drinking Water Health Criteria
Document for Chlorinated Acids/Alcohols/Aldehydes/Ketones
Dear Mr. Reilly:
The Toxicology/Clinical Subcommittee of the Science Advisory Board's Drinking Water
Committee met April 4-5, 1991 in Washington, D.C. to review issues relating to the Office
of Drinking Water's Health Criteria Document on Chlorinated Acids/Alcohols/Aldehydes/
Ketones. As potential disinfection by-products, these compounds must be considered in
regulatory efforts. The Office of Drinking Water stressed that this is a very preliminary
draft and that SAB advice was being sought to strengthen the draft as it progressed through .
further iterations.
The Science Advisory Board was asked to address a number of issues, including the
identification of deficiencies due to significant gaps in data. These issues and our responses
are summarized below:
1) Which studies should serve as the basis for non-carcinogenic risk assessment?
With a few exceptions the studies selected for non-carcinogenic risk assess*
ment were appropriate and justified.
2) Does the Committee agree with the line of investigation on addressing the
question of a possible threshold for dichloro acetic acid (DCA) induced
hepatoceUular cancer in B6C3F1 mice? The approach being taken on evaluat-
ing the possibility of a threshold for the cartinogenicity of dichloroacetic acid
in mice is correct but is limited and should be expanded to include both rat
and mechanistic studies.
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3) Does the Committee agree with EPA that chloral hydrate (trichloroacetalde-
hyde) has a tumor potency in mice similar to that of DCA? The tumor
potency of chloral hydrate in mice may be similar to that of dichloroacetic acid
but further studies are needed as well as an evaluation of any epidemiological
studies that may have been done on this formerly widely used medication.
4) Should the MCLG for DCA be set on the basis of carcinogenitity or neurotox-
irity? We cannnot make a recommendation at the present time on this issue,
but the Committee recognizes the importance of neurotoxicity and strongly
urges EPA to continue research in this area.
5) What relative source contribution should be applied to the risk assessment of
these chemicals? This question cannot be answered since insufficient informa-
tion was provided upon which to make a judgment.
The Committee recommends that the health criteria document be separated into two or
three individual documents. As currently structured, it is very difficult to follow. The
compounds with the most information, dichloroacetic acid, trichloroacetic acid, and trichloro-
acetaldehyde, tend to become lost in minimal discussions of the ketones and alcohols. In
addition, the Committee offers specific comments related to the document which are
contained in the attached report.
In our opinion, the material presented on the occurrence of these compounds in
drinking water can be presented in a more detailed and informative fashion. We also
question why trichloroethanol is of concern as a pollutant when it does not appear to have
been found in drinking water. Furthermore, on the basis of information supplied by EPA
scientists at the meeting, we recommend an expansion of the discussion and evaluation of the
developmental toxicity studies. We would also like to suggest that the studies on immuno-
toxicity be sharply focused since there are already existing data which indicate that there may
be effects on the immune system. In addition, we strongly recommend that the Agency
define the toxicity/carcinogenicity of the brominated analogs of these chlorinated compounds
since they are likely to be formed with either chlorination or ozonation. Finally, we
recommend that a more complete description be - — Ln the document on possible mecha-
nisms, particularly the possibility of peroxisomai proliferation and how this might affect the
extrapolation of the murine liver tumor data to humans.
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The preliminary draft criteria document was prepared for the Criteria and Standards
Division, Office of Drinking Water, by ICAIR Life Systems Inc. of Cleveland Ohio. We
recommend that the procedure by which the data were developed should be added to the Life
Systems report.
We appreciate having been given the opportunity to conduct a review at such an early
stage in the development of this document and look foreword to a continuing dialogue as the
document progresses. We request that the Agency respond formally to the scientific advice
provided herein, particularly in regard to the Committee's concerns about the document
which go beyond the original questions posed by the Agency.
^mond C.
Chairman
Executive Committee
• ^*.
Veme Ray
Chairman
Drinking Water Committee
and
Chairman
Toxicology/Clinical
Subcommittee
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U. S. ENVIRONMENTAL PROTECTION AGENCY
NOTICE
This report has been written as a part of the activities of the Science Advisory Board, a
public advisory group providing extramural scientific information and advice to the Administra-
tor and other officials of the Environmental Protection Agency. The Board is structured to
provide balanced, expert assessment of scientific matters related to problems facing the Agency,
This report has not been reviewed for approval by the Agency and, hence, the contents of this
report do not necessarily represent the views and policies of the Environmental Protection
Agency, nor of other agencies in the. Executive Branch of the Federal government, nor does
mention of trade names or commercial products constitute a recommendation for use.
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U.S. Environmental Protection Agency
ABSTRACT
The Toxicology/Clinical Subcommittee of the Science Advisory Board's Drinking
Water Committee met April 4-5,1991 in Washington, DC to review issues relating to the
Office of Drinking Water's preliminary draft Health Criteria Document on Chlorinated
Acids/Alcohols/AJdehydes/Ketones. The Subcommittee answered specific questions posed by
the Office of Drinking Water, and obtained informational briefings from the Office of
Research and Development (ORD), in particular the Health Effects Research Laboratory
(HERL), concerning specific ongoing or anticipated research efforts to provide answers for
some of the questions regarding the toxicity of these disinfection by-products and to fill in
data gaps.
In reviewing the preliminary draft document presented by the Agency, the Subcom-
mittee concluded the following: 1) with a few exceptions the studies selected for non-
carcinogenic risk assessment were appropriate and justified; 2) the approach being taken on
evaluating the possibility of a threshold for the carcinogenicity of dichloroacetic acid in mice
is correct but is limited and should be expanded to include both rat and mechanistic studies;
3) the tumor potency of chloral hydrate in mice may be similar to that of dichloroacetic acid
but further studies are needed as well as an evaluation of any epidemiological studies that
may have been done on this formerly widely used medication; 4) no recommendation can be
made at the present time regarding whether the- MCLG for DCA should be made on the basis
of its carcinogenicity or neurotoxicity, but we'recognize the importance of the latter and
strongly urge EPA to continue research in this area; and 5) that there was insufficient
information to make a judgment concerning what relative source contribution should be
applied to the risk assessment of these chemicals.
The Committee recommends that the document be separated into two or three
individual documents. As currently structured, it is very difficult to follow. The compounds
with the most information, dichloroacetic acid, trichloroacetic acid, and trichloroacetalde-
hyde, tend to become lost in minimal discussions of the ketones and alcohols.
Kev Words; chlorinated acids; trichloroacetate; dichloroacetic acid; chloral hydrate; MCLG
it
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SCIENCE ADVISORY BOARD
DRINKING WATER COMMITTEE
CHAIRMAN
•Dr. Verne Ray, Medical Research Laboratory, Pfizer Inc., Groton, CT
/
MEMBERS/CONSULTANTS
*Dr. Richard Bull, College of Pharmacy, Washington State University, Pullman, WA
•Dr. Gary Carlson, Department of Pharmacology and Toxicology, School of Pharmacy, Purdue
University, West Lafayette, IN
Dr. Keith E. Cams, East Bay Municipal Utility District, Oakland, CA
•Dr. David Kaufman, Department of Pathology, University of North Carolina, Chapel Hill, NC
•Dr. Nancy Kim, Division of Environmental Health Assessment, New York State Department of
Health, Albany, NY
•Dr. Ellen O'Flaherty, University of Cincinnati Medical Center, Cincinnati, OH
•Dr. Edo Pdlkzari, Research Triangle Institute, Research triangle Park, NC
'
•Dr. Thomas Tepbly, Department of Pharmacology, University of Iowa, Iowa City, IA
Dr. Vera Snoeyink, Department of Civil Engineering, University of Illinois, Urbana, IL
• '
Dr. Mark D. Sobsey, Department of Environmental Sciences and Engineering, University of North
Carolina, Chapel Hill, NC
Dr. Jama Symons, Department of Civil and Environmental Engineering, University of Houston,
Houston, TX
* Served on Toxocology/Clinical Subcommittee
SCIENCE ADVISORY BOARD STAFF
Dr. C. Richard Comera, Designated Federal Official, U.S. EPA, Science Advisory Board (A-101F),
Washington, DC
Mr. A. Robert Flaak, Assistant Staff Director and Acting Designated Federal Official, U.S. EPA,
Science Advisory Board (A-101F), Washington, DC
Mrs. Mary Winston, Staff Secretary, U.S. EPA, Science Advisory Board (A-101F), Washington, DC
111
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TABLE OF CONTENTS
1. EXECUTIVE SUMMARY 1
2. INTRODUCTION 2
2.1 Background 2
2.2. Charge To The Committee 2
3. DISCUSSION OF ISSUES , 4
3.1 Which studies should serve as the basis for non-carcinogenic risk assess-
ment? 4
3.2 Does the SAB agree with the line of investigation on addressing the
question of a possible threshold for DCA-induced hepatocellular cancer
in B6C3F1 Mice? 4
3.3 Does the SAB agree with the following assessment: Chloral hydrate has a
clear record of genotoxicity in microbial and mammalian systems with
a propensity to induce aneuploidy in eukaryotic systems . . . .' 5
3.4 Does the SAB agree with EPA that chloral hydrate has a tumor potency in
mice similar to that of DCA? . . .' 5
3.5 Should the MCLG for DCA be set on the basis of carcinogenicity or
neurotoxicity? 5
3.6 What relative source contribution should be applied to the risk assessment
of these chemicals? 6
3.7 Additional issues addressed by the Subcommittee 6
4. REFERENCES 8
iv
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1.0 EXECUTIVE SUMMARY
The Toxicology/Clinical Subcommittee of the Science Advisory Board's Drinking
Water Committee reviewed issues related to the Office of Drinking Water's Health Criteria
Document on Chlorinated Acids/Alcohols/Aldehydes/Ketones. These compounds are
potential disinfection by-products and thus, are important to regulatory efforts.
/
In reviewing the preliminary draft document presented by the Agency1, the Subcom-
mittee concluded the Mowing: I) with a few exceptions the studies selected for non-
carcinogenic risk assessment were appropriate and justified; 2) the approach used to evaluate
the possibility of a threshold for the carcinogenicity of dichloroacetic acid in mice is correct
but is limited and should be expanded to include both rat and mechanistic studies; 3) the
tumor potency of chloral hydrate in mice may be similar to that of dichloroacetic acid (DCA)
but further studies are needed as well as an evaluation of any epidemiological studies that
may have been done on this formerly widely used medication; 4) no recommendation can be
made at the present time regarding whether the MCLG for DCA should be made on the basis
of its carcinogenicity or neurotoxicity, but we recognize'the importance of the latter and
strongly urge EPA to continue research in this area; and 5) that there was insufficient
information to make a judgment concerning what relative source contribution should be
applied to the risk assessment of these chemicals.
In our opinion, the material presented on the occurrence of these compounds in
drinking water can be presented in a more detailed and informative fashion. We also
questioned why trichloroethanol is of concern as a pollutant when it does not appear to have
been found in drinking water. Furthermore, on the basis of information supplied by EPA
scientists, we recommend an expansion of the discussion and evaluation of the developmental
toxicity studies. We would also like to suggest that the studies on immunotoxicity be sharply
focused since there are already existing data which indicate that there may be effects on the
immune system. In addition, we strongly recommend that the Agency define the toxicity/
carcinogenicity of the brominated analogs of these chlorinated compounds since they are
likely to be formed with either chlorination or donation. Finally, we recommend that a
more complete description be given in the document on possible mechanisms, particularly the
possibility of peroxisomal proliferation and how this might affect the extrapolation of the
murine liver tumor data to humans.
We recommend that the document be separated into two or three individual docu-
ments. As currently structured, it is very difficult to follow. The compounds with the most
information, dichloroacetic acid, trichloroacetic acid, and trichloroacetaldehyde, tend to
become lost in minimal discussions of the ketones and alcohols.
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wu Dr. WiUUm Brulin.
1
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2.0 INTRODUCTION
2.1 Background
The possible adverse effects of disinfectants and their by-products have been of long-term
interest to the Drinking Water Committee. There have been numerous interactions between
the Committee and the Office of Drinking Water. The Toxicology/Clinical Subcommittee of
the Science Advisory Board's Drinking Water Committee met April 4-5, 1991 in Washing-
ton, DC to review issues relating to the Office of Drinking Water's Health Criteria Docu-
ment on Chlorinated Acids/Alcohols/Aldehydes/Ketones. The purpose of this meeting was
two-fold. First, to answer specific questions posed by the Office of Drinking Water as
discussed in the charge. And second, to obtain information from the Office of Research and
Development (ORD), in particular the Health Effects Research Laboratory (HERL),
concerning specific ongoing or anticipated research efforts to provide answers for some of
the questions regarding the toxicity of these disinfection by-products and to rill in data gaps.
, . . • • ' i
We recognize that the criteria document is in a very formative stage. This gave us the
unique and exciting opportunity to have input at the level where it might greatly influence the
final document. In addition, it provided the chance to discuss and comment upon research
strategies that the Agency could take to answer some of these important questions. We
recognized not only the preliminary nature of the document, but also the fact that in some
cases there were ample experimental data and in others there was simply a paucity of
available information.
2.2 Charge to the •Sn
The Subcommittee went beyond only replying to the questions specifically asked by the
Agency. We felt that it was appropriate to help identify at an early stage, those points with
which the scientific community would clearly agree based on the experimental evidence,
those which may be of some controversy because of differences of opinion or interpretation
of results, and those which are in need of additional information. In the latter, case it is
important to recognize that priorities need to be established based on either the importance of
the toxic endpoint or the relationship to possible widespread human exposure.
The Subcommittee was asked to respond to the following questions:
a. , Which studies should serve as basis for non-carcinogenic risk assessment?
• * * . ' r
b. Does the Science Advisory Board agree with the following line of investiga-
tion: Hepatocellular cancers were observed in B6C3F1 mice given high
concentrations (1-5 g/L) of dichloroacetic acid (DCA) in less than a lifetime
. (52-61 weeks) of exposure (Herren-Freund et al., 1987; Bull et al., 1990). A
more recent study (DeAngelo et al., 1991) employed lower concentrations
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(0.05 • 0.5 g/L) over an exposure period of 75 weeks. In this study, increased
prevalence of liver cancer was correlated with pathologic changes, tissue
necrosis with nodular hyperplasia and increased peroxisome proliferation.
DCA appeared to lack activity when tested in a series of genotoxicity assays.
A recently completed study using 0.5 g/L over a lifetime exposure to B6C3F1
mice (Daniel and DeAngelo, personal communication) also measured an
increased prevalence of hepatocellular cancer. Thus, the pathologic changes
seen at the high doses do occur also with less severity at low doses. The
complete analysis of these changes is ongoing. Additional studies are planned
to address the issue of a threshold for DCA carcinogenlcity.
c. Does the Science. Advisory Board agree with the following assessment:
Chloral hydrate (trichloroacetaldehyde monohydrate) has a clear record of
genotoxicity in microbial (Hayworth et al., 1983) and mammalian (Russo et
al.t 1984) systems with a propensity to induce aneuploidy in eukaryotic
systems.
d. Acute and long-term exposures to DCA By humans and animals indicate
neuropathy as a toxic endpoint. In these studies, although doses are high,
there is no NOAEL indicated. Should extra uncertainty be added to the risk
assessment calculation to account for uncertainty regarding this endpoint?
Should the basis for the MCLG be set on carcinogenicity or neurotoxicity?
e. Which relative source contribution should be applied to the risk assessment of
these chemicals? For its draft calculations, EPA used 80% for chloral hydrate
since it is very unlikely to be found in food. For all others, 20%, the normal
default value was used.
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3.0 DISCUSSION OF ISSUES
3.1 Which Studies Should Serve as the Basis for Non-Carcinogenic Risk Assessment?
The study chosen for the ICMay health advisory for dichloroacetate is that of
Stacpoole et al. (1987). The text and table are inconsistent in that the text refers to the 50
mg/kg dose as a NOAEL (No Observed Adverse Effect Level) and the table classifies it as a
LOAEL (Lowest Observed Adverse Effect Level). Moreover, the newly completed 90-day
dog study should be incorporated in the derivation of the 10-day longer term health adviso-
ries.
The drinking water equivalent level (DWEL) derivation for DCA uses two factors of
10 and justifies their use because of the class C carcinogeniciry determination. The docu-
ment needs to clarify the basis for these factors. However, the new carcinogeniciry studies
need to be included in the DWEL and longer term health advisory determinations.
' , > * • '
Selection of the NOAEL of 7 mg/kg for the 1-day health advisory was based on a
single large study of hospitalized patients. The Committee questions the clinical experience
with this drug, which has been widely used for many years. We cannot help but believe that
there must be a better and more extensive data base in humans for selection of this NOAEL.
Factors to be considered should include in the selection of any clinical study for setting
standards for environmental agents:
a. the general health of the group under study compared to the universal popula-
tion of the United States,
b. administration clinically as a single large daily dose rather than subdivided,
throughout the day. Obviously the latter would more appropriately mimic
water intake.
Interaction between trichloroacetaldehyde and alcohol is not adequately handled in the
report. This is an often cited interaction. At the same time, it is a reflection of high doses
of the aldehyde as well as the ethanol. This material must be reworked to present a clear
rationale as to why or why not, under the conditions associated with drinking water, an
interaction might or might not be or potential concern.
3.2 Does the SAB Agree with the Line of Investigation on Addressing die Question of a
Possible threshold for DCA-Ioduced Hepatocellular Cancer in B6C3F1 Mice?
Evidence for a threshold for DCA carcinogenicity using B6C3F1 mice was presented
to the Subcommittee. We support the continued efforts to determine the dose-response
relationship for carcinogeniciry as an end-point for TCA and chloral hydrate. Such studies
are important not only in regard to DCA (and TCA) but also in determining the Agency's
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approach to dealing with agents which cause mouse liver tumors. We would also recom-
mend similar studies be performed with rats in order to support the classification of DCA as
either C or B2. Whether it is a B or C should be based on knowing whether it causes
tumors in rats, that is, on knowledge and not considering it only in one species, if others
have not been examined. If there is a difference in susceptibility of mice and rats to DCA,
we recommend that metabolic disposition and mechanistic studies should be carried out to
account for any species differences and, therefore, extrapolation of the murine findings to
humans.
3.3 Does the Science Advisory Board Agree with the Following Assessment: Chloral
Hydrate (Trichloroacetaldehyde Monohydrate) has a Clear Record of Gcnotoxicity in
Mioobial (Hayworth et al., 1983) and Mammalian (Russo et al., 1984) Systems with
a Propensity to Induce Aneuploidy in Eukaryotic Systems.
From the references cited, chloral hydrate would appear to be a weak mutagen in
Salmonella TA-100. However, studies of genetic activity in mouse germ cells indicate that
this chemical can produce effects on premeiodc and stamina! gonial cells. Significant
numbers of hyper-haploid cells were observed at both 82.7 and 165.4 mg/kg following i.p.
treatment of chloral hydrate. Due to both the level administered and the route of administra-
tion, the relevance of these studies for risk assessment in drinking water can be questioned.
•
3.4 Does the SAB Agree with EPA that Chloral Hydrate has a Tumor Potency in Mice
Similar to that of DCA?
It is appropriate to tentatively consider chloral hydrate as a hepatocarcinogen in mice
with similar potency as that observed with TCA (it makes more sense to compare to TCA
than to DCA for metabolic and weight of evidence reasons). However, final judgment about
the potential carcinogenic risk to humans, and hence classification by EPA, should await a
more thorough bioassay in both mice and rats. As noted above for DCA (Section 3.2), an
understanding of the advisability of species extrapolation based on mechanism (either dose or
species) is critical. In addition, we recommend searching for any epidemiological data on
this drug, which in the past, had been widely used for prolonged periods.
3.5 Sl»ddtbeMCXafbrDCAbcSetontheBasisofCan±»og^
At the present time we cannot recommend whether the Agency should establish the
MCLG for DCA based on its carcinogenicity or neurotoxicity. In the case of the former, it
is important that Dr. DeAngelo's results from his current studies on lower doses than
previously used be taken into consideration. In the case of the latter, there is a paucity of
data presented, but preliminary studies in rats suggest that neurotoxicity is a concern in
support of previous observations in both experimental animals and man. Additional
information is necessary before the NOAEL can be firmly established. This is an important
area for consideration by Dr. McPhail's neurotoxicity section.
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3.6 What Relative Source Contribution Should be Applied to the Risk Assessment of these
Chemicals? >
This question relates to what relative source contribution should be applied to the risk
assessment of these chemicals. We were unable to recommend any percentage for these.
The exposure section was not present in the document. This absence is a continued concern
of the Committee as these documents come to it for review. There appears to be no reason
for not considering drinking water as the sole source of these compounds (with the obvious
exception of trichloroacetaldehyde used in medicine), but in the absence of information no
definitive recommendation can be given. !
3.7 Additional Tyffre Addressed by the Subcommittee
i • , >' *- • '
We had additional comments, recommendations, and concerns beyond the original
questions posed by the agency. These include the following:
a. , We were very concerned about the manner, in which the levels of these chemi-
cals identified in the Drinking Water surveys were presented. Averages give
little information. We recommend a' more thorough analysis of the data,
possibly following the model of the American Water Works Association. This
occurrence data should include ranges and some measures of the frequency
distribution of concentrations (e.g. the 95% confidence interval). We further
. recommend that those chemicals which are disinfectant by-products have their
occurrence data segregated according to type of disinfectant and, if possible be
related to total organic carbon in the systems surveyed.
., ' , - • • ' ' .' V' •. '
b. From the data presented on occurrence, it was not clear why trichloroethanol
: •,. was included since it has not been identified in these sources. While a meta-
bolic intermediate in the metabolism of a number of chlorinated chemicals, it
, is doubtful that exposure to the compound itself will occur. We recommend
that the Agency consider not including this chemical in the document.
c. We recommend that the Agency greatly expand the discussion and evaluation
. of the developmental toxitity studies. The presentation by Dr. Robert Kovloch
of Dr. Kate Smith's work was most informative. The data from his studies
suggest that for some of these chemicals the endpoints need to be considered
as possible basis for establishment of reference doses or at least as support for
the data presented from other studies used to establish these RfD's.
d. We were interested in seeing the approach taken by Dr. Leubke in the area of
immunotoxicity, but would recommend that a more carefully focused approach
be taken to follow up studies that have already reported positive findings. We
recommend that studies specifically address the effects of these chemicals on
the immune system.
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e. We strongly recommend that the Agency define the toxicology/carcinogenicity
of brominated and mixed bromochloro analogs of the chlorinated acetic acids,
aldehydes and ketones. These compounds will be produced by both chlorina-
tion and ozonation of waters containing bromide. It is very likely that they
will possess many of the lexicological/carcinogenic properties of the chlorinat-
ed analogs. Since the relative proportions of brominated and chlorinated by-
products varies with the disinfectant used (chlorinated analogs higher with
chlorine, brominated compounds higher with ozone) their relative potency can
have a substantive impact on the choice between disinfectants in a given water
supply.
f. In a number of cases, the descriptions of key studies were inadequate for full
evaluation by the Subcommittee. For example, in the consideration of the
effects of DCA in humans, there is a concern over hypoglycemia. However,
without a knowledge of the magnitude of the effect and whether it occurs in
normal glycemic individuals, we cannot judge the relative importance of the
findings. We strongly recommend that for these key studies selected to be
used in establishing health advisory's andlhe DWEL, a more thorough,
quantitative description of the studies be presented.
«
g. In the consideration of possible mechanisms for the carcinogeniciry of DCA
and TCA, we recommend a more thorough discussion of hepatic peroxisomal
proliferation. This is critical not only for these compounds in and of them-
selves, but also in relationship to the Agency's other criteria documents such
as that on perchloroethylene.
h. We recommend that the Agency include in its Criteria Document a discussion
of the Human Exposure Studies performed to date on chlorinated acids/al-
cohols/aldehydes/ketones. An assessment is needed on what currently is
known about (1) the prevalence and geographical distribution of these chemi-
cals throughout the U.S., (2) the studies performed, if any, regarding human
body burden, and (3) the metabolism and pharmacokinetics for these chemi-
cals. Identifying the gaps in our knowledge in these areas will be most
beneficial in determining future research needs.
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4.0 REFERENCES CITED
Bull, R.J., Sanchez, I.M., Nelson, M.A., Larson, J.L., and Lansing, AJ. (1990). Liver
tumor induction in B6C3F, mice by dichloroacetate and trichloroacetate. Toxicology
63,341-359. .
DeAngelo, A.B., Daniel, F.B., Stober, J.A., and Olsen, G.R. (1991). The carcinogenicity
of dichloroacetic acid in the male B6C3F, mouse. Fund. Appl. Toxicol. 16, 337-347.
Hayworth, S., Lawlor, T., Mortelmans, K., Speck, W., and Zeiger, E. (1983). Salmonella
mutagenicity test results for 250 chemicals. Environ. Mutagen. Supplement 1, 3-142.
Herren-Freund, S.L., Pereira, M.A., and Olsen, G. (1987). The carcinogenicity of tri-
chloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid in
mouse liver. Tox. Appl. Pharmacol. 90, 183-189.
Russo, A., Pacchierotti, F., and Metalli, P. (1984). Nondisjunction induced in mouse
spermatogenesis by chloral hydrate, a metabolite of trichloroethylene. Environ.
Mutagen. 6, 695-703.
Stacpoole, P.W., Gonzalez, M.G., Vlasak, J. et al. (1987). Dichloroacetate derivatives.
Metabolic effects of pharmacodynamics in normal rats. Life Sciences, 41, 2167-
2176.
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