I UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. O,C, 20460
March 9, 1988
OF
THE ADMINISTRATOR
Hon. tee M. Ihonas S&BHEBC-88-016
Administrator
U.S. Environmental Protection
Agency
401 M Street SW
Washington, IXC. 20460
Dear Mr. Thomas?
The Halcgenated Cnganies Subcommittee of the Science Advisory Board's
Envirotmental Health Ccnroittee had completed its review of the Office of
Drinking Water's Draft Final Criteria EDciment for Crtho-Meta-Para-Dichloro-
benzene and is pleased to transmit its final report to you.
The major scientific/science policy issue discussed by the Subcommittee
concerns the evidence for careinegenicity and the classification of this com-
pound using EPA's guidelines for cancer risk assessment. EPA staff has used
a weight of evidence approach in recommending a classification of 83 *or drink-
ing water based upon the staff's review of existing animal studies. Hie reason-
ing offered for this conclusion is scientifically defensible, but it is not the
only defensible conclusion. In assessing the issue of careinegenicity, a key
question is the weight that should be. assigned to the rat data for purposes of
extrapolating risk to humans. Hie assessment of this and other issues led most
Subcommittee members to conclude that this ecmpound should more appropriately
be classified as Category C of EPA's guidelines* Hie position adopted by the
Subcoimittee follows the reasoning stated in a companion letter of March 9,
1988 jointly developed with the Environmental Baalth Comittee following a
recent evaluation of the scientific evidence for perehloroethylene. The dis-
cussion of these and other issues is presented in the attached report.
The Subcommittee appreciates the opportunity to conduct this scientific
review, Wa request that the Agency formally respond to our scientific advice.
Sincerely,
n Nelson, Chairman
Executive Ccnwdttee
esejner» Chairman
_r.'J:.
vlialooenated Organics Subcoifeittee
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Review of the Office of Drinking Water's
Draft Final Criteria Document for
Ortho-Meta-Para-Dichlorobenzenes
by the
Halcgenated Qrganics Subcommittee
Environmental Health Committee
Science Advisory Board
The Halogenated Organics subccrranittee conducted its review of the
Office of Drinking Water's Craft Final Criteria Cocuroent for QrtheHMeta-
Para- Diehlorobenzenes on April 20, 1987 in Kansas City, Kansas. In addition
to the criteria document, the Subcommittee received the following documents:
o National Primary Drinking Water Regulations: Para-OLChlorobenzene
Proposed Rule (Draft, December 18, 1986),
o Office of Pesticides and Toxic Substances (OPTS) Draft Summary
Report of the OPTS Toxicology Peer Review Committee (£pril 8, 1987).
o National lexicology Program: Toxicology and Carcinogenesis Studies
of 1,4 Hchlorobenzene in F344/N Rats and B6C3F1 Mice — Gavage Studies
(Galley Draft, May 1986).
Two additional documents prepared by the Office of Drinking Water for -
this rulemaking were not reviewed by the Subcommittee. Ihese included:
Analytical Methods/Monitoring for VOCs in Drinking Water (June, 1985) , and
Technologies and Costs for the Removal of Volatile Organic Chemicals From
Drinking Water (May, 1985). The Subcommittee also received cements on
the criteria document from members of the public.
Since the Subcommittee's meeting EPA has finalized its rulenaking for
Para-Dichlorobenzene. The Subcommittee recognized that many of the scien-
tific issues that it addressed in its review of Para-Dichlorobenzene were
cannon to halogenated compounds. Further, it and the Environmental Health
Conmittee evaluated these issues in the context of responding to a set
of questions posed by the EPA Administrator following their report of
January 27, 1987 on EPA 'a assessment of Perchloroethylene. Rather than
view these evaluations as unrelated events, the Subcommittee and the
Committee have chosen to defer final submission of the Para-Dichloroben-
zene report until a Committee-wide statement was prepared and transmitted.
Major Conclusions and
The major scientific/science policy issue discussed by the Subcommittee
concerns the evidence for carcinogenicity and the classification of this com-
pound using EPA's guidelines for cancer risk assessment. The criteria docu-
ment states two options: to classify Para-flchlorobenzene in category 62
(sufficient evidence of carcinogenicity in animals with limited or inadequate
evidence in humans), or to place it in category C (limited evidence of car-
cinogenicity in animals in the absence of human data). The National Toxicology
Program's (NTP) study concludes that "clear evidence of carcinogenicity" exists,
the highest of the five categories in NTP's ranking system.
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The Subcommittee's major conclusions and reccfmendations include the
following:
1. The criteria document represents a well written, scientifically
balanced interpretation of existing information for these compounds. The
current document is scientifically and editorially better than many other
EPA assessment or criteria documents previously reviewed by the Subcomittee.
Individual Subccnmittee members have made specific technical and editorial
comments that have already been forwarded to the Office of Erinking ffeter.
2. The conclusions of the NIP study that the administration of the
test compound resulted in the production of adenocarcinccnas in the kidneys
of male F344/N rats and adenomas and carcinomas in the livers of B6C3P1
mice of both sexes is supported by the data. There are also no questions
regarding the adequacy of the identification of these tumors* The Subcom-
mittee agrees with the reasoning in the POT study that indicates that not
all reported mouse liver tumors are of equal significance.
3. EPA staff has used a weight of evidence approach in reccnmending
a classification of Bg for drinking water based upon the staff's review of
existing animal studies. The reasoning offered for this conclusion is
scientifically defensible but, as noted below it is not the only defensible-
conclusion.
4. In assessing the issue of carcinogenicity, a key question is the
weight that should be assigned to the animal studies, particularly the rat
data, for purposes of extrapolating risk to humans. Most members of the
Subccnmittee (eight of nine) believe that this compound could justifiably
be classified in category C. The reasons are as follows:
o The absence of positive results in genotoxicity studies* Since the
compound does not appear to be mutagenic and the tumors observed in
the kidney of P344/N rats were identified histologically, it appears
to act via an epigenetic mechanism in the male rat rather than through
the formation of ENjV-adducts* in the case of liver carcinomas in
B6C3F1 mice, Para-Dichlorobenzene and other halogenated compounds may
promote the expression of oneogenes.
o The male rat kidney tumors may be the result of a mechanism that would
not play a role in humans. The Subcommittee and the Envirormental Health
Ccnmittee recently transmitted to you our position on this issue in the
context of Perchloroethylene. That position, forwarded to you on March 9,
1988 also applies to the Subcormittee's evaluation of Para-Dichlorobenzene.
o There is no support for a higher classification from human epidemiology
studies.
5. The selection of studies for the quantification of noncarcinogenic toxic-
ological effects, as well as the derivation of health advisories and acceptable
daily intakes, has been performed correctly.
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6. Hie proposed drinking water standards, based upon the presented inhalation
data, should also be designed to protect against developmental effects,
7. The statement on page VII1-7, that deaths in humans occur as a result
of central nervous system toxicity, is unsubstantiated by the material present-
ed in the document.
8. The Subcommittee generally concurs with the criteria document's con-
clusions on Ortho- and Meta-Dlchlorobenzene.
.... -' WnM^KiL.-*..^ ... . .
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Conmittee
HAIDGENATED QRGMJICS SUBCOMMITTEE
P-Dichlorobenzene Review
20, 1987
Dr. John Doull, [Chair], Professor of Pharmacology and Toxicology,
University of Kansas Medical Center, Kansas City, Kansas 66103 (913)
588-7508 or (913)588-7140
Dr* George T. Bryan, Department of Human Oncology, University of Wisconsin
K-4 Rm 528 608 Clinical Science Center 600 Highland Ave., Dfedison, Wisconsin
53792 (608) 263-5385
Dr. Gary Carlson, Department of Pharmacology and Toxicology, School of Pharmacy,
Purdue University, West Lafayette, Indiana 47909 (317) 494-1412
Dr. K, Roger Horrifcrook, Department of Pharmacology, P.O. Box 26901,
University of Oklahoma, Oklahoma City, Oklahoma 73190 (405)271-2100
Dr, Ronald D. Hood, Professor and Coordinator, Cell and Developmental
Biology Section, Department of Biology, The University of Alabama, and
Principal Associate, R»D. Hood and Associates, Consulting lexicologists,
P.O. Box 1927, University, Alabama 35486 (205)348-5960
Dr. Larry Kantinsky, Director, Vfedswortft Center for Laboratories and Research,
New York State 'Department of Health, Albany, New York 12201 (515)473-7578
Dr. Martha Radike, University of Cincinnati Medical Center, Department
of Environmental Health, 3223 Eden Avenue - M.L. f 56, Cincinnati, Ohio 45268
(513)872-5730
Dr. Verne Ray, Medical Research Laboratory Pfitzer, Inc., Groton, .
Connecticut, 06340 (202) 441-3564
Dr* Karl K. Rozman, Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas, 39th and Bairibow Blvd., Kansas City, KS 66103
(913)588-7717
Dr. Stephen Safe, Department of Veterinary, Physiology £ Pharmacology
Texas A&M University, College of Veterinary Medicine, College Station,
Texas 77843-4466 (409) 845-7261
Dr. Terry F. Yosie, Director, Science Advisory Board, A-101, U.S.
Environmental Protection Agency, Washington DC 20460 (202) 382-4126
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