United StatM	Science Admsnry	IPA-SAB-OWC-S2-011
Environment*!	Board tA-101|	January 1992
Protection Aaancy
oEPA AN SAB REPORT: REVIEW
OF DRINKING WATER
HEALTH CRITERIA
DOCUMENT
REVIEW OF THE OFFICE OF
DRINKING WATER'S HEALTH
CRITERIA DOCUMENT ON
TRIHALOMETHANES BY THE
DRINKING WATER COMMITTEE

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S5
S3E2J
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C, 20460
January 22, 1992
FPA-^AR-nWC-Q?-011	office of
Cr/\ 3rt.r>-J-JYYV_ M UH	THE ADMINISTRATOR
Honorable William K, Really
Administrator
U.S. Environmental Protection Agency
401 M Street, S,W,
Washington, D.C. 20460
Subject; Review of Health Criteria Document for Trihalomethanes by the Drinking
Water Committee of the Science Advisory Board
Dear Mr, Reilly:
The Science Advisory Board's Drinking Water Committee met in Washington, DC on
October 25-26,1990 to review the Office of Drinking Water's background document Revised
External Draft for the Drinking Water Criteria Document for Trihalomeilianes.
Trihalomethanes (THMs) are by-products of disinfection with chlorine and to some
extent with chloramine and ozone (bromoform). The THMs include chloroform, bromo-
form, bromodichloromethane and dibromochloromethane. In 1979 these substances were
regulated in drinking water at a level of 0.10 mg/L. The regulation was based primarily on
tumor formation in mouse liver and rat kidney following chronic exposure to chloroform, but
health data were not available on brominated THMs at that time. Some new information has
been generated and the revised document addresses the issues related to the Maximum
Contaminant Level Goal (MCLG) for THMs. The Committee reviewed this document and
addressed specific and general issues concerning the toxicity of THMs,
At the meeting, EPA Staff presented to the Committee questions regarding the
carcinogenic and non-carcinogenic risk assessments for THMs. The attached report
addresses the Committee's responses. Additional issues raised by the Committee during its
deliberations are the lack of data on human exposure to THMs, and the concentrations of
chloroform in humans.. The Health Criteria Document for Trihalomethanes should include a
discussion of the pharmacokinetic properties of chloroform and other THMs because it is
important to know the dosed target tissues and organs and the rate of elimination from the
body. This information when combined with environmental exposure levels encountered by
people are critical for assessing risks.
Printed on Re--

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The Committee addressed the following issues:
1.	Does the SAB agree with the selection of the key studies serving as the basis
for carcinogenic and nwi-carciirogenic risk assessments? The Committee concluded
that the studies utilized for estimating carcinogenic risks are the best currently
available for deciding whether these chemicals are human carcinogens and for
estimating the potency of these chemicals as carcinogens but pointed out that it was
far from proven that these studies provide a basis for declaring that they are carcino-
gens at the concentrations encountered in drinMng water. The Committee found that
the studies selected for the non-carcinogenic endpoints of THM toxicity were appro-
priate in general. However, it is suggested that the Condie study be used for the 10-
day Health Advisory for bromoform and strong consideration should be given to the
chronic National Toxicology Program (NTP) study on bro-moform for determination
of the drinking water equivalent level (DWEL).
2.	Studies with chloroform indicate thai the vehicle of administration may
influence the toxicity exhibited by chloroform. Based on the available data, can the
same inference be made with the brominated THMs? Because hepatic tumors were
observed when com oil was used as the vehicle for chloroform but not when water
was the vehicle the Committee recommended that the hepatic carcinogenicity pro-
duced by THMs administered in an oil vehicle be disregarded from making quantita-
tive estimates of risk.
3.	The mutagenicity data for the THMs are largely negative or equivocal. Could
the THMs collectively or individually be considered epigenetic carcinogens? A
review of the data does not support a contention that these compounds can be
considered collectively as epigenetic carcinogens. Tribromomethane and bromo-
dichloromethane have demonstrated sufficient activity in several assays to be consid-
ered genotoxie whereas the evidence for chlorodibromomethane and trichloromethane
is inconclusive for genotoxicity.
4.	The THM standard applies to the sum of the four predominant THMs. Based
on the health effects of the individual THMs, is it reasonable to continue to consider
this group as a mixture or would separate assessments be more appropriate for
regulations? The Committee recommends that separate MCL values be calculated for
each of the THMs. One reason is because their carcinogenic properties differ
significantly in both quantitative and qualitative terms.
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5.	Ai«s there any restrictions to using mouse liver tumor data as the basis of -
quantitative risk assessments? The Committee recommended that mouse liver tumor
induction should be utilized in making the weight-of-evidence judgment that chloro-
form is a carcinogen. However, these data should not be used for making quantita-
tive assessments of risk. A number of comments are made to support this recommen-
dation,
6.	Is there reason to suspect chloroform acts on the rat kidney through the alpha-
2u-globulin mechanism? Based on published reports alpha-2u-globulin appears to play
no role in the etiology of chloroform-induced renal tumors in rats.
7.	Are hepatocellular adenomas and carcinomas the appropriate baas for quantifi-
cation of carcinogenicity for bromodichloromethane? Would the occurrence of these
tumor types be expected if the compound were administered in drinking water? Is the
current quantitation applicable to drinking water exposure? Should further research
be initiated testing this compound in drinking water? The Committee concludes that it
is inappropriate to consider hepatic tumors as the basis for quantification of carcinoge-
nicity for bromodichloromethane and recommends that EPA utilize renal of intestinal
tumors. The data suggest that the intestinal tumors would be more appropriate since
they are not commonly seen in rats and the resulting incidence is quite high m males
and observed in both sexes, Bromodichloromethane also produces tumors in the rat
kidney, a site which is probably independent of vehicle effects whereas hepatic tumors
are likely to be seen primarily, if not exclusively, with THMs administered in the
presence of a vehicle such as corn oil. Thus, quantitation of carcinogenic risks using
hepatic tumors appears not to be applicable to drinking water exposure. Appropriate
research has been proposed for studying the pharmacokinetics and metabolism of
bromodichloromethane. However, research on defining the mechanism by which the
compound induces tumors in non-hepatic target organs appears to be critical.
8.	EPA has classified dibromochloromethane in group C: possible human
carcinogen based on liver tumors in mice. Does the SAB agree with the conclusions
in light of the flaws of the studies conducted? The Committee recommends that based
on its definitions and criteria for classification of chemicals as carcinogen or non-
carcinogens, the EPA classify dibromochloromethane in group C. The gavage error
alluded to in the EPA briefing document occurred in a low-dose group only. There
was no indication of the intestinal or other tumor types in the high-dose group and no
evidence of carcinogenicity in rats.
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9. Is the weight-of-evidence classification for bromoform of B2 correct?
The Committee noted that the EPA classified bromoform in group B2 based
on the incidence of neoplastic lesions of the large intestine in female rats.
Classification of a compound as a probable human carcinogen based on the
induction of a tumor at a single tumor site at low incidence in a single
species is not scientifically defensible. However, the Committee noted that
the intestinal tract is not a common tumor site and that bromoform is the
one THM that is the most clearly mutagenic. Thus, in using all the avail-
able information (both carcinogenic and mutagenic) the Committee supports
the classification of bromoform in the B2 category.
In addition the Committee recommends that a section on human exposure and
body burden to chloroform be incorporated into the criteria document because it
provides direct evidence as to the magnitude and widespread occurrence of
chloroform in people.
We appreciate having been given the opportunity to conduct this particular
review. We request that the agency respond formally to the scientific advice
provided herein, particularly in regard to the Committee's concern about the
inclusion of exposure data.
Sincerely,
Cr
Raymond C. LoehrpCImir
Executive Committee
Science Advisory Board
Verne Ray, Chair —
Drinking Water (Mnmittee
Science Advisory Board
Enclosure
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NOTICE
This report has been written as part of the activities of the Science Adviso
ry Board, a public advisory group providing extramural scientific information and
advice to the Administrator and other officials of the U.S. Environmental Protec-
tion Agency, The Board is structured to provide a balanced expert assessment of
scientific matters related to problems facing the Agency, This report has not been
reviewed for approval by Agency*, and, hence, the contents of this report do not
necessarily represent the views and policies of the Environmental Protection
Agency or other agencies in the Federal Government Mention of trade names or
commercial products does not constitute an endorsement or recommendation for
use.
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ABSTRACT
The Science Advisory Board's Drinking Water Committee met in Washington, DC on
October 25-26, 1990 to review the Office of Drinking Water's document Revised External
Draft for the Drinking Water Criteria Document for Trihalomethanes (THM), addressing
issues concerning the toxicity of THMs. The 1979 THM regulations were based primarily
on tumor formation in mouse liver and rat kidney following chronic exposure to chloroform.
Health data were not available on brominated THMs at that time. Some new information has
been generated and the revised document addresses the issues related to the Maximum
Contaminant Level Goal (MCLG) for THMs,
The Committee addressed the selection of the key studies serving as the basis for
carcinogenic and non-carcinogenic risk assessments (The Committee concluded that the
studies utilized for estimating carcinogenic risks are the best currently available); the effects
of the vehicle of administration on the toxicity exhibited by chloroform (The Committee
recommended that the hepatic carcinogenicity produced by THMs administered in an oil
vehicle be disregarded from making quantitative estimates of risk); the designation of the
THMs collectively or individually as epigenetic carcinogens (The Committee found that the
data does not support a contention that these compounds can be considered collectively as
epigenetic carcinogens. Tribromomethane and bromodichloromethane have demonstrated
sufficient activity in several assays to be considered genoloxic whereas the evidence for
chlorodibromomethane and trichloromethane is inconclusive for genotoxicity); The consider-
ation of the four predominant THMs as a group or mixture, opposed to using separate assess-
ments for regulations (The Committee recommends that separate MCL values be calculated
for each of the THMs, since their carcinogenic properties differ significantly in both
quantitative and qualitative terms); Restrictions to using mouse liver tumor data as the basis
of quantitative risk assessments (The Committee recommended that mouse liver tumor
induction should be utilized in making the weight-of-evidence judgment that chloroform is a
carcinogen); the role of the alpha-2u-globulin mechanism in renal tumor induction (Based on
published reports it does not appear to play a role in the etiology of chloroform-induced renal
tumors in rats); The use of hepatocellular adenomas and carcinomas as a basis for quantifi-
cation of carcinogenicity for bromodichloromethane (The Committee found it inappropriate to
consider hepatic tumors as the basis for quantification of carcinogenicity for bromodichlor-
omethane and recommends that EPA utilize renal of intestinal tumors); The classification of
dibromochloromethane in group C: possible human carcinogen, based on liver tumors in
mice (The Committee recommends that the EPA classify dibromochloromethane in group C);
The weight-of-evidence classification for bromoform as B2 (The Committee supports the
classification of bromoform in the B2 category).
The Committee also recommended that a section on human exposure and body burden to
chloroform be incorporated into the criteria document.
KEYWORDS; Trihalomethanes; chlorodibromomethane; dibromochloromethane; trichloro-
methane; Maximum Contaminant Level Goal (MCLG); renal tumors.
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ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
DRINKING WATER COMMITTEE
IMlwlomefchane Panel, February 1991
CHAIRMAN
Dr. William H. Glaze, University of North Carolina
VICE CHAIR
Dr. Verne Ray, Pfizer Inc.
MEMBERS
Dr. Richard Bull, College of Pharmacy, Washington State University
Dr. Gary Carlson, School of Pharmacy, Purdue University
Mr. Keith E. Cams, East Bay Municipal Utility District, Oakland, CA 94607
Dr. David Kaufman, University of North Carolina
Dr. Nancy Kim, Director, New York State Department of Health
Mr. Ramon G. Lee, American Water Works Service Company, Inc.
Dr. Edo D. Pellizzari, Research Triangle Institute
Dr. Vern Snoeyink, University of Illinois
Dr. Mark D, Sobsey, University of North Carolina
Dr. James Symons, University of Houston
Dr. Thomas Tephly, University of Iowa
Dr. R. Rhodes Trussell, James M. Montgomery Consulting Engineers, Inc.
SCIENCE ADVISORY BOARD STAFF
Dr. C. Richard Cothern, Designated Federal Official Environmental Protection
Agency, Science Advisory Board, Washington, D.C. 20460
Mr. Robert Flaak, Assistant Staff Director and Acting Designated Federal Official,
Environmental Protection Agency, Science Advisory Board, A-10 IF, Washing
ton, D.C. 20460
1 Serving w Chair fiace October, 1991
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Ms, Darlene A, Sewell, Staff Secretary, Environmental Protection Agency, Science
Advisory Board, A-10IF, Washington, D.C. 20460
Dr, Donald G. Barnes, Environmental Protection Agency, A-101, Washington, DC
20460
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TABLE OF CONTENTS
1.	EXECUTIVE SUMMARY				 							1
2.	INTRODUCTION . .	. , ,		 .	5
3.	SPECIFIC ISSUES 								7
3.1	Selection of the key studies for carcinogenic and non-carcinogenic
risk assessments?		7
3.1.1	Carcinogenic Risk Studies 			7
3.1.2	Non-Carcinogenic Risk Studies 				8
3.2	Vehicle of administration and the toxicity of brominated THMs ...	9
3.3	Could the THMs collectively or individually be considered epige-
netie carcinogens? 					10
3.4	Should EPA consider THMs as a mixture for regulatory purpos-
es? . . 								11
3.5	Restrictions to using mouse .-liver tumor data as the basis of
quantitative risk assessments 		11
3.6	The alpha-2u-globulin mechanism ,			12
3.7	A basis for quantification of carcinogenicity for bromodichloro-
methane? 				...»		 .	12
3.8	Classification issues; flaws of the supporting studies ..........	13
3.9	Is the B2 weight of evidence classification for bromoform correct? .	13
3.10	Information other than that presented in the Criteria Document
concerning exposure? 			 				14
4.0 REFERENCES										16
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1. EXECUTIVE SUMMARY
The Science Advisory Board's Drinking Water Committee met in Washing-
ton, 1X3 on October 25-26, 1990 to review the Office of Drinking Water's back-
ground document Revised External Draft for the Drinking Water Criteria Docu-
ment for Trihalomethanes (THM). Trihalomethanes are by-products of disinfection
with chlorine and to some extent with chloramine. The THMs include chloroform,
bromofortn, bromodichloromethane and dibromo-chloromethane, In 1979, these
substances were regulated in drinking water at a level of 0.10 mgfL. The regula-
tion was based primarily on evidence of tumor formation in mouse liver and rat
kidney following chronic exposure to chloroform, but health data were not avail-
able on brominated THMs at that time. Some new information has been generat-
ed since that time and the revised Drinking Water Criteria Document represents a
revised draft which would address the issues related to the Maximum Contaminant
Level Goal (MCLG) for THMs in drinking water. The Drinking Water Committee
reviewed this document and has addressed specific and general issues concerning
the toxicity of THMs.
A number of general and specific issues were presented to the Committee
for response. In addition, one issue which the Committee raised and which is
deficient in the Agency's draft report is discussed at length. It deals with the
need to obtain information other than that presented in the Criteria Document
concerning human exposure and body burden to THMs which should be incorpo-
rated into the document in order to gain information as to the magnitude (i.e.,
concentrations) and occurrence of chloroform in humans. Further, a consideration
of the pharmacokinetic properties of chloroform and other THMs should be
discussed because of importance in knowing the dosed target tissues and organs,
the rate of elimination form the body and environmental exposure levels encoun
tered by people and other issues which need to be addressed in humans.
General Issues
a. Does the SAB agree with the selection of the key study serving as the
bask for carcinogenic and non-carcinogenic risk assessments?
The Committee concluded that the studies utilized for estimating carcino-
genic risks with THMs are the best that are currently available for deciding
whether these chemicals are human carcinogens and for estimating the
potency of these chemicals as carcinogens but pointed out that it was far
from proven that these studies provide a basis for declaring that these
chemicals are carcinogens at the concentrations they are encountered In
drinking water. The Committee found that the studies selected for the non-
carcinogenic endpoints of THM toxicity were appropriate in general. One
exception was noted. Namely, the Condie study should be used for the 10-
day Health Advisory (HA) for bromoform just as it was for bromodichloro-
methane and dibromochloromethane and strong consideration should be
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given to the chronic NTP study on bromoform for determination of the
drinking water equivalent level (DWEL) for this compound.
b.	Studies with chloroform indicate that the vehicle of administration may
influence the toxicity exhibited by chloroform. Based on the available data,
can the same inference be made with the bruminated THMs?
Because hepatic tumors were observed when corn oil was used as the
vehicle for chloroform but not when water, the more relevant vehicle, was
used, the Committee recommended that the hepatic carcinogenicity producet
by THMs administered in an oil vehicle be disregarded from making quanti-
tative estimates of risk.
c.	The mutagenicity data for the THMs are largely negative or equivocal.
Could the THMs collectively or individually be considered as epigenetic
carcinogens?
A review of the data does not support a contention that these compounds
can be considered collectively as epigenetic carcinogens, Tribromomethane
and bromodichloromethane have demonstrated sufficient activity in several
assays to be considered genotoxic whereas the evidence for chlorodibromo-
methane and trichloromethane is inconclusive for genotoxicity. A discussior
is presented dealing with differences in- methodology which influence
interpretation of results. Further, reference is made to studies which
suggest that THM concentrations that may have provoked mutagenic
responses were orders of magnitude higher than those found in drinking
water.
d.	The THM standard applies to the sum of the four predominant THMs.
Based on the health effects of the individual THMs, is it reasonable to
continue to consider this group as a mixture or would separate assessments
be more appropriate for regulation?
The Drinking Water Committee recommends that separate MCL values be
calculated for each of the THMs. One reason for this recommendation is
because their carcinogenic properties differ significantly in both quantitative
and qualitative terms,
e.	Are there any restrictions to using mouse liver tumor data as the basis
of quantitative risk assessments?
The Committee recommended that mouse liver tumor induction should be
utilized in making the weight-of-evidence judgment that chloroform is a
carcinogen. However, these data should not be used for making quantitativ
assessments of risk. A number of individual comments are made in order t<
support this recommendation.
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£ Is there reason to suspect chloroform acta 011 the rat kidney through the
alpha-2u-giobulin mechanism?
The alpha-2u-globulin appears to play no role in the etiology of chloroform-
induced renal tumors in rats.
g.	Are hepatocellular adenomas and carcinomas the appropriate basis for
quantification of carcinogemciiy for bromodichloromethane? Would the
occurrence of these tumor types be expected if the compound were adminis-
tered in drinking water? Is the current quantitation applicable to drinking
water exposure? Should further research be initiated testing this compound
in drinking water?
The Committee concludes that it is inappropriate to consider the induction
of hepatic tumors as the basis for quantification of carcinogenicity for
bromodichloromethane. The Committee recommends that EPA utilize renal
or intestinal tumors to estimate the carcinogenic risks for humans. The
data reviewed suggests that the induction of intestinal tumors would be
more appropriate since a site is involved where tumors are not commonly
seen in rata and the resulting incidence is quite high in males and observed
in both sexes. It was noted that bromodichloromethane also produces
tumors in the rat kidney, a site which is probably independent of vehicle
effects with chloroform whereas hepatic tumors are likely to be seen primar-
ily, if not exclusively, with THMs administered in the presence of a vehicle
such as corn oil. Thus, quantitation of carcinogenic risks using hepatic
tumors appear not to be applicable to drinking water exposure. Appropriate
research has been proposed for studying the pharmacokinetics and metabo-
lism of bromodichloromethane. However, research on defining the mecha-
nism by which the compound induces tumors in non-hepatic target organs
appears to be critical.
h.	Based on its definitions and criteria for the classifications of chemicals
as carcinogens or non-carcinogens EPA has classified dibromochloromethane
in group C: possible human carcinogen based on liver tumors in mice.
Does the SAB agree with the conclusions in light of the flaws of the studies
conducted?
The Committee recommends that the EPA classify dibromochloromethane in
group C. The gavage error alluded to in the EPA briefing document
occurred in a low-dose group only. There was no indication of the intestinal
or other tumor types in the high-dose group and no evidence or carcinoge-
nicity in rats.
i.	Is the weight-of-evidence classification for bromoform of B2 correct?
The Committee noted that the EPA classified bromoform in group B2 based
on the incidence of neoplastic lesions of the large intestine in female rats.
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Classification of a compound as a probable human carcinogen based on the
induction of a tumor at a single site at low incidence in a single species is
not scientifically defensible. However, the Committee noted that the
Intestinal tract is not a common tumor site and that bromofonn is the one
THM that is the most clearly mutagenic. Thus, the Drinking Water Com-
mittee supports the classification of bromofonn in the B2 category.
j. Is there information other than that presented In the Criteria Document
concerning exposure?
The Committee recommends that a section on human exposure and body
burden to chloroform be incorporated into the Criteria Document because it
would provide direct evidence as to the magnitude (i.e., concentrations) and
occurrence of chloroform in people. In addition, the pharmacokinetic
properties of THMs should be discussed because it is important to know the
dose to target organs and tissues, and its rate of elimination from the body
at the environmental exposure levels encountered by people. Pharmacokin-
etic data in animals and humans, have been reported for chloroform; these
data should be discussed in this section of the Criteria Document. Expo-
sure, body burden and pharmacokinetic information on chloroform would
significantly better place into perspective the potential toxieologieal implica-
tions. Much of the information on exposure could be obtained from the
records from utilities routinely applied to state agencies.
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2. INTRODUCTION
The Science Advisory Board's Drinking Water Committee met on October
25-26, 1990 to review the Office of Drinking Water's document Revised External
Draft for the Drinking Water Criteria document on Trihalomethanes (THMs).
During the meeting the Committee received oral presentations from EPA staff.
The Committee appreciates the opportunity to review the document prior to the
final preparation of the criteria document.
The Committee addressed the following issues;
a.	Does the SAB agree with the selection of the key study serving as the
basis for carcinogenic and non-carcinogenic risk assessments?
b.	Studies with chloroform indicate that the vehicle of administration
may influence the toxicity exhibited by chloroform. Based on the
available data, can the same inference be made with the brominated
THMs?
c.	The mutagenicity data for the THMs are largely negative or equivo-
cal. Could the THMs collectively or individually be considered as
epigenetic carcinogens?
d.	The THM standard applies to the sum of the four predominant
THMs. Based on the health effects of the individual THMs, is it
reasonable to continue to consider this group as a mixture or would
separate assessments be more appropriate for regulation?
e» Are there any restrictions to using mouse liver tumor data as the
basis of quantitative risk assessments?
f,	Is there reason to suspect chloroform acts on the rat kidney through
the alpha-2u-globulin mechanism?
g,	Are hepatocellular adenomas and carcinomas the appropriate basis for
quantification of carcinogenicity for bromodichloromethane? Would
the occurrence of these tumor types be expected if the compound were
administered in drinking water? Is the current quantitation applica-
ble to drinking water exposure? Should further research be initiated
testing this compound in drinking water?
h,	Based on its definitions and criteria for the classifications of chemi-
cals as carcinogens or non-carcinogens EPA has classified dibromo-
chloromethane in group C: possible human carcinogen based on liver
tumors in mice. Does the SAB agree with the conclusions in light of
the flaws of the studies conducted?
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Is the weight-of-evidence classification for bromoform of B2 correct?
Is there information other than that presented in the Criteria Docu-
ment concerning exposure? (Question raised by the Committee.)

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3. SPECIFIC ISSUES
3,1 Does the SAB agree with the selection of the bey studies serving m the basis
for carcinogenic and non-carcinogenic risk assessments?
3.1.1 Carcinogenic Risk Studies
The Committee has evaluated the studies selected by the agency and
concludes that the studies utilized for estimating carcinogenic risks with THMs are
the best currently available for deciding whether these chemicals are human
carcinogens and for estimating the potency of these chemicals as carcinogens. The
Drinking Water Committee has to point out, however, that because of the very
high levels of exposure employed is the studies on animals, it is far from proven
that these studies provide a basis for declaring that these chemicals are carcino-
gens at the concentrations they are encountered in drinking water. While more
specific comments are made below about studies involving individual THMs, a
number of points apply to all these chemicals.
a.	The induction of renal and hepatic tumors occurs at doses which also
produce cytotoxic effects and subsequent reparative hyperplasia.
While the Agency makes the argument that these effects do not
uniformly result in tumor induction (a true statement), there are
strong indications that these phenomena play a role along with
speciea and/or strain dependent reactions. There is every indication
that liver damage is responsible for liver tumor induction in B6C3F1
mice and cannot be excluded as playing a role in renal induction in
rats,
b.	Although the mechanism is not clear, there is strong evidence that a
corn oil vehicle/chloroform interaction is responsible for the induction
of liver tumors in mice since they were observed when corn oil was
used as the vehicle but not when water served as a vehicle . Al-
though the Agency recognized this when assessing risks from chloro-
form, the possibility of such interactions in the induction of liver
tumors by bromodichloromethane (BDCM) and dibromochloromethane
CDBCM) has apparently not been considered. In the case of bromodi-
chloromethane, tumors were induced at organ sites that are apparent-
ly not sensitive to vehicle effects. Thus, it would seem prudent to
concentrate on these other organ sites in assessing risk for this
compound. In case of dibromochloromethane, induction of liver
tumors in mice is the only evidence of carcinogenicity. Therefore, the
C classification for dibromochloromethane taken by the Agency would
appear to be appropriate.
c.	It is notable that the order of potency of the THMs for induction of
hepatic tumors in mice parallels their potency as hepatotoxins (BDCM
> CHClg - DBCM > Hrr3). Therefore, the Committee recommends
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that the Agency consider a non-hepatic target organ for bromodi-
chloromethane. The proposed selection of target organs with regard
to the carcinogenicity of the other THMs appears justified.
3.1,2 Non-Carcinogfinic Risk Studies
Concerning the question as to whether or not the selection of the studies
for the non-carcinogenic endpoints of the trihalomethanes is correct, the Commit-
tee generally finds these studies to be appropriate. In many cases, the results of
other studies reinforce the one selected.
For chloroform, the study by Jones et al.4 for the one-day Health Advisory
(HA) is appropriate for use in classifying the non-carcinogenic effects, although the
time between the dosing and histological observation (72 hours) may have been too
long to observe any transient effects of the lower doses.
The 10-day HA is based on the study of Thompson et al.5 which used
pregnant rabbits. General toxicity was not the intended purpose of this study so
that its use may be questionable. However, since it addresses a sensitive popula-
tion and also gives a Lowest Observed Adverse Effect Level (LOAEL) similar to
that of the study of Chu et al. which examined the more conventional endpoints
in a better designed 28-day study, it would not be unreasonable to use the
Thompson study.
The use of the Drinking Water Equivalent Level (DWEL) value in calculat-
ing the long-term HA to avoid having the long-term HA higher than the short-
term HA is appropriate. The use of the studies of Heywood et al, for both the
DWEL and long-term HA is warranted. These were chronic studies (7.5 years) in
dogs and appear to have been adequately conducted. The resulting HA values are
more conservative than those jvhich would have been calculated from the results
of the studies of Palmer et al. or Jorgenson et al.
For bromodichloromethane, setting the one-day HA on the same study as
the ten-day HA is warranted in view of the lack of any other good information.
The 14-day study of Condie et al. is quite appropriate since it was intended for
this purpose. Furthermore, the value is very close to that which would be derived
from the National Toxicology Program (NTP) 14-day study where mortality,
clinical signs and gross pathology were examined. For the long-term HA, the NTP
data from a 90-day study in mice are applicable even though corn oil g&vage was
used. It should be noted that the study by Chu et al. using water as the vehicle
would yield similar numbers. Similarly a DWEL based on the NTP chronic study
is reasonable even though it requires the use of an additional uncertainly factor.
For dibromochloromethane, the use of the same study (Condie) for the one-
day HA and the ten-day HA in lieu of an appropriate single dose study is merited.
The 90 day NTP study11 is appropriate for the longer term Has especially since
there are supporting studies which would give similar values. The use of the 90-
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day NTP study to establish the DWEL from a No Observed. Adverse Effect Level
(NOAEL) with an added uncertainly factor is not unreasonable.
For bromoform, a problem with the study of Burton-Fanning12 can be cited;
the endpoinc is limited to central nervous system effects and the possible involve-
ment of other systems is unknown. There is a reluctance by EPA to use the data
of Condie et al for the ten-day HA because the calculated value of 14,5 mgAiter
would be higher th|n the one-day HA. EFA therefore proposes to use the NTP
90-day study data. The Committee recommends that since the Condie study was
intended for short-term exposures, was adequately conducted using the correct
endpoints, and used mice which are an appropriate model, the data in the investi-
gation should be used. Because of the reasonable concern in establishing a 10-day
HA which would be higher than a one-day HA, it would seem appropriate to use 5
mg/liter for the 10-day HA also. It should be noted that the concern over the high
one-day HA may be tempered by the findings of Condie et al. The NTP data are
suitable for the long term HA. The Committee concurs with the suggestion that
the EPA examine the use of the chronic NTP study data for determining the
DWEL. This could change the DWEL in either direction. If similar exposure
levels are used in both studies, it could increase the DWEL by eliminating the
additional uncertainty factor of 10 used because a 90 day study was the basis.
However, the DWEL would be decreased if a significantly lower NOAEL or
LOAEL had to be used in the calculations.
The Committee recommends that EPA use references given in draft criteria
document for the non-carcinogenic risk assessments with the exceptions noted.
Namely, the Condie study should be used for the 10-day HA for bromoform just as
it was for bromodlchloromethane and dibromochloromethane, and strong consider-
ation should be given to the chronic NTP study on bromoform for determination
of the DWEL for this compound.
3,2 Studies with chloroform indicate that the vehicle of administration may
influence the toxicity exhibited by chloroform. Based on the available data,
can the same influence be made with the brominated THMs?
There is strong evidence that the interaction between corn oil and chloro-
form is responsible for the induction of liver tumors in mice, The possibility of
such interactions in liver tumor induction by bromodichloromethane and dibromo-
chloromethane must be seriously considered. The quantity and quality of corn oil
administered are of concern. The possible effect of com oil contamination and the
effect of corn oil dosage might be factors which could perturb the normal physiolo-
gy of the organism.
Thus the Committee recommends that the hepatic carcinogenicity produced
by THMs administered in an oil vehicle be disregarded for making quantitative
estimates of risk. There is no evidence to suggest that this vehicle affected
tumorigenicity at other target sites.
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3,3 The mutagenicity data for the THMs are target negative or equivocal. Could
the THM* collectively or individually be considered epigenetic aireiiiogeiis?
The Committer addressed the question of whether the mutagenicity data on
the THMs collectively or individually support a label of epigenetic carcinogens. A
review of the data, aa indicated below, does not support a contention that these
compounds can he considered collectively as epigenetic carcinogens. Even if there
existed a broad consensus on the meaning of the term epigenetic carcinogen, the
four compounds - tribromomethane, chlorodibromomethane bromodichloromethane
and trichloromethane would not qualify because tribromomethane and bromodi-
chloromethane have demonstrated sufficient activity in several assays to be
considered genotaxic and the evidence for chlorodibromomethane and trichloro-
methane is inconclusive for genotoxicity.
Literature from the draft THM criteria document provided to the Committee
as well as additional references are also included in this review. Also telephone
communications with Dr. Errol Zeiger of the NTP program and Dr. Angela Auletta
of the Gene-Tox program of EFA's Office of Toxic Substances were conducted to
acquire perspective and other test data. The majority of the data from the NTP
program have been published recently.
The major difficulty encountered with the Ames Salmonella results on the
THMs is the method of testing. Some investigators have used a closed container
(desiccator) to incubate the agar plates and others have not. When a closed
environment was used, these types of compounds have tended to produce positive
results. Another example of this is the closely related compound dichloromethane.
There are a number of conflicting results in the literature on the genotox-
icity of the THMs. Part of this condition is due to differences in methodology,
part due to interpretation of results and part due to the physical nature of the
compounds. This condition makes analysis difficult and places additional emphasis
on distinguishing between levels of human exposure and levels used in the in vitro
assays. This distinction is identified in the paper of Morimoto and Koizumi,
who comment that the THM concentrations that caused significant increases in
SCE frequencies in their experiments were 10 -10 times higher than those found
in drinking water.
The Committee recommends, therefore, that these THMs not be considered
by the Agency as epigenetic carcinogens.
3.4 The THM standard applies to the sum of the four predominant: THMs. Based
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on the health effects of the individual THMs, is it reasonable to continue to
consider this group as a mixture op would separate assessments be more
appropriate for regulation?
The Committee recommends that separate MCL values be calculated for
each of the THMs because their carcinogenic properties differ significantly in both
quantitative terms.
3.5 Are there any restriction! to using mouse liver tumor data as the basis of
quantitative risk assessments?
Based on the implied differential toxicity of chloroform in corn oil vs. water,
EPA quantified the cancer risk for chloroform basal on kidney tumors in rats
given chloroform in drinking water, The evidence of mouse liver tumors was
considered qualitatively in the total weight of evidence for carcinogenicity. It is
doubtful that the Agency should consider the mouse liver in quantitative assess-
ments.
The use of the mouse liver tumors induced by chloroform with com oil in
the qualitative classification of chloroform as a carcinogen is prudent, Its use for
quantitative risk assessment is suspect for the following reasons^
a.	Liver tumors could not be produced in mice in the absence of corn
oil.
b.	Liver tumors are not induced in other species by administering
chloroform alone.
c.
Initiation of the rat liver by dimethylnitrosamine allowed promotion
of liver tumors by chloroform in corn oil.
d.	Chloroform given without vehicle or in aqueous media to mice initiat-
ed with dimethylnitrosamine inhibited development or liver tumors.
e.	Recent data has clearly demonstrated that the liver of C3H mice, the
parental strain of the B6C3F1 hybrid from which the high spontane-
ous rate is inherited, has a high population of immortal cells that are
promotable, relative to the C57BL, the parenteral strain with a low
spontaneous incidence of liver tumors.
f.	Chloroform administered in corn oil is clearly hepatotoxic at doses
used in the bioassays, Chloroform in an aqueous vehicle was without
observable effect, adding to the argument that these tumors are
secondary to cell necrosis and reparative hyperplasia.
g.	Recent research indicates that the capacity for metabolizing THMs by
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reductive dehalogenation is a prominent pathway in mice, but not in
rats. TWs substantial difference in the hepatic metabolism of the
THMs could be responsible for species differences in tumorigenic *
responses.
The Committee recommends that mouse liver tumor induction should be
utilized in making the weight-of-evidence judgment that chloroform is a carcino-
gen. However, these data should not be used for making quantitative assessments
of risk because these tumors have been observed only when corn oil and not water
is used as the vehicle and because of the uncertainty nature of these mouse
r- tumors.
3.6	Is there reason to suspect chloroform acts on the rat kidney through the
alpha-2u-globulm mechanism?
It would appear that alpha«2u-globulin has no apparent role in the etiology
of chloroform - induced renal tumors in rats as proposed for other chemicals
(unleaded gasoline, d-limonene, perchloroethylene.
3.7	Are hepatocellular adenomas and carcinomas the appropriate basis for
quantification of carcinogenicity for bromodichloromethane? Would the
occurrence of these tumor types be expected if the compound was adminis-
tered In drinking water? Is the current quantitation applicable to drinking
water exposure? Should further research be initiated testing this compound in
drinking water?
Based on the experiments with chloroform and corn oil, it seems inappropri-
ate to consider the induction of hepatic tumors in B6C3F1 mice for quantitating
risks. Bromodichloromethane induces tumors at other sites, at least one of which
(the rat kidney) appears to be independent of the vehicle effects observed with
chloroform. A cursory examination of the data suggests that the induction of
intestinal tumors might actually be more appropriate for estimating risk because it
involves a site where tumors are not commonly seen in the rat and the resulting
incidence is quite high in males and observed in both sexes. The only drawback is
that there have been no studies of the mechanism by which bromodichloromethane
produces tumors at this site.
If these other sites are considered the actual impact on the risk assessment
is minimal, but it is important to adhere to the principle that the most appropri-
ate data should be utilized rather than falling back to the most sensitive site
default.
It is clear from bioassay results bromodichloromethane is the critical THM
produced in drinking water disinfection. It fits both EPA and International
Agency for Research on Cancer (IARC) criteria for weight of evidence in that it
produces tumors in multiple species at multiple sites, including sites at which
tumors are relatively rare in the test species. Therefore, this compound is critical
12

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to the assessment of whether THMa produced in the disinfection of drinking
water present a carcinogenic risk to humans, Appropriate research has been
proposed for Btudying the pharmacokinetics and metabolism of this THM in some
detail However, research on defining the mechanism by which the compound
induces tumors in non-hepatic target organs is at least as critical The Committee
recommend, therefore that EPA undertake such studies.
Therefore, the Committee recommends that EPA utilize renal or intestinal
tumors to estimate the carcinogenic risks to man. There can be little confidence
that the hepatic tumors induced in mice by bromodiehloromethane are not
dependent upon the com oil vehicle utilized in the NTP bioassay.
3.8	EPA has classified dibromoehloromethane 111 group C: possible human
carcinogen baaed oil liver tumors in mice. Does the SAB agree with the
conclusions in light of the flaws of the studies conducted?
The classification of dibromoehloromethane in group C appears appropriate.
The gavage error alluded to in the EPA briefing document occurred in the low
dose group. There was no indication of the intestinal or other tumor types in the
high dose group and no evidence of carcinogenicity in rats.
Although this reduced the statistical power of the study somewhat, it is
hard to imagine that additional studies would uncover any other significant tumors
sites. Therefore, the Committee recommends that EPA classify dibromoehloro-
methane in group C. This is consistent with the action taken by the IARC.
3.9	Is the B2 weight of evidence classification for bromoform correct?
EPA has classified bromoform in group B2 based on the incidence of
neoplastic lesions of the large intestine in female rats. The IARC concluded that
the incidence of this tumor type was not sufficient to consider bromoform as a
probable human carcinogen.
Classification of a compound as a probable human carcinogen based' on the
induction of a tumor at a single tumor site at low incidence in a single species is
not scientifically defensible. Since the positive results were observed in the same
study that failed to indicate a carcinogenic response in a second species, the only
strict interpretation possible is that the response is species specific for the rat and
not extrapolatable to other species. On the other hand, the Committee notes that
the intestinal tract is not a common tumor site and that bromoform is the one
THM that is more clearly mutagenic, (These points were also debated by the
IARC working group and the issue of classification was a close call for the
working group.) Although the Committee feels that it is far from established that
chlorinated drinking water represents a carcinogenic hazard, it is notable that
intestinal tumors are one site that has been associated with chlorination in
epidemiological studies. The Committee recognized that the data supporting
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classification of bromoform in the B2 vs. C category is not clear cut.
Therefore, the Committee concurs with EPA's classification of bromoform as
a B2 carcinogen.
3,10 Is there information other than that presented in the Criteria Document
concerning exposure?
It in recommended that a section on human exposure and body burden to
chloroform be incorporated into the criteria document because it provides direct
evidence aa to the magnitude (i.e., concentrations) and widespread occurrence of
chloroform in people. In addition, the pharmacokinetic properties of chloroform
should be discussed because it is important to know the dose to target organs and
tissues, and its rate of elimination from the body at the environmental exposure
levels encountered by people.
Pharmacokinetic data in animals and humans have been reported for
chloroform; these data should be discussed in this section of the Criteria Docu-
ment, Exposure, body burden and pharmacokinetic information on chloroform
would significantly better place into perspective the potential toxicological implica-
. tions.
Even though national surveys on prevalence/occurrence of chloroform and
other volatile organic chemicals in drinking water have been performed they do
not provide insight to human exposure and body burden. This information is vital
to the understanding of the prevalence and extent to which people have been
exposed to chloroform from drinking water and its relative importance to other
routes and sources of exposure (e.g., ingestion from food, inhalation, dermal).
Temporal variations in human exposure may also occur as new control technolo-
gies or alternate disinfection processes are employed in the future, and the trends
in long-term temporal variations (by seasons and over several years) will be
important information regarding the effectiveness of changing technologies.
A national survey of human exposure to chloroform, other THMs and
volatile organics in drinking water has not been performed. There are, however, a
number of pertinent geographical probability-based studies which have been
conducted over the past 10 years to assess human exposure and body burden.
Populations in locations such as Sayonne and Elizabeth, NJ; Devils Lake, ND;
Greensboro, NC; Antioeh, Carson, El Legundo, Lomita, Hermosa Beach, Manhat-
tan Beach, Pittsburgh, Redondo Beach, Torrance, and West Carson, CA; Niagara
Falls and Buffalo, NY; Baton Rouge, LA; Beaumont and Houston, TX; and Chapel
Hill, NC have been surveyed.20"24
In most of these populations a 3-stage probability sample was selected so
that inferences could be drawn to the target population of interest. Briefly, first-
stage sampling units (FSU) defined by Census blocks were selected. Then clusters
of housing units were selected at the second stage within the FSU's and these
14

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homes were screened to identify individuals with characteristics believed to be
positively correlated with exposure to the chemicals (including chloroform) of
interest. The third stage was a stratified sample of screened eligible individuals,"
These studies also provide for a comparison of the routes of exposure (e.g.,
drinking water vs. air) and short-term temporal variations.
The literature contains other small-scale non-probability based investigations
on human blood levels of chloroform for the Gulf Coast and other areas.
These data should be critically evaluated, however, since subsequent methodologi-
cal investigations in the early 1980s have demonstrated shortcomings in the
heated purge and trap procedure used for measuring chloroform. Pfaffenburger et
al. reported information of chloroform from trichloroacetic acid (TCA) at
elevated pH, TCA is a metabolite from 1,1, l-trichloroethane» which is ubiquitous
in human blood originating from inhalation exposure.
Recently, the Centers for Disease Control has completed the development
and validation of an isotopic dilution method for about two dozen VOCs in
blood. Blood chloroform measurements are planned for the future and it is
recommended that the Office of Drinking Water utilize this information for
developing future criteria documents.
Preliminary reports also indicate that chloroform in drinking water may
lead to significant inhalation (from showers, washing clothes) and dermal (bathing
swimming) exposure. Such information is relevant in developing strategies for
Health Advisory documents.
Finally, it is recommended that ODW coordinate with Agency for Toxic
Substances Diseases Research (ATSDR) when compiling information on human
exposure to VOCs. including chloroform and other THMs, since ATSDR also
develops criteria documents for hazardous waste sites containing much of the same
information (metabolism, pharmacokinetics, exposure).
In summary, the drinking water criteria document on chloroform is severely
deficient on human exposure and pharmacokinetic issues. It is recommended that
the Office of Drinking Water compile relevant information on human exposure,
body burden, and pharmacokinetics and toxicological implications. In many cases
routine monitoring data are being obtained by water utilities and reported to state
agencies but are not being systematically collected by EPA. The Committee
recommends that the Agency avail itself of this information on THMs, and induced
other water contaminants, for use in assessing exposures.
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Antonie, I.R. DeLeon, and R.M. O'Dell-Smith. Bull. Environ. Contam.
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using Purge/Trap Gas Chromatography Mass Spectrometry, Centers for
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chlorinated tap water. Wan K. Jo, C.P. Weisel, and P.J. Lioy. International
Symposium on Measurement of Toxic and Related Air Pollutants, 1990
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