m.
\ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
a
•--•' WASHINGTON, D.C, 20460
March 9, 1988 SAB-EHC-88-013
Hbn, tee M. Ihcmas TH
Administrator
U.S. Environmental Protection
Agency
401 M Street SW
Washington, D.C, 20460
Dear Mr. Thomas;
On August 13-14 1987 the Halogenated Grganies Subcommittee of the
Science Advisory Board's Environmental Health Oonwdttee met in Washington,
D.C. to review two documents prepared by EPA's Office of Research and
Development that assess health effects associated with dichlorcroethane
(methylene chloride). These documents included;
o a June 1987 Craft Technical Analysis of New Methods and Data
Regarding Dichlorcmethane Hazard Assessments, and
o a July 1987 Draft Addendum to the Health Assessment Document for
DLChlorcme thane: Pharmaeokinetics, Mechanism of Action and Epi-
demiology.
The Subectanittee's evaluation of these documents is presented in
two parts: 1) a discussion of scientific issues related to phannaco-
kinetics and metabolism, and 2) review of specific issues pertinent
to the addendum. Ihe Subcommittee focused less attention on the former
document because much of its scientific content overlapped with the Addendum.
The Subcownittee concludes that the Addendum was one of the best docu-
ments it has reviewed in terms of its clarity, coverage of the data and
analysis of scientific issues. This document clearly demonstrates the
potential utility of phamacokinetic data in risk assessment. EPA should
continue to use this approach in future risk assessments, whenever scien-
tifically possible.
For reasons discussed in the attached report, the Subcommittee concludes
that the level of uncertainty is greater and the hazard posed by dichloro-
methane may be less than that expressed ty the categories of EPA's cancer
risk assessment guidelines.
-------
—2—
The Subcommittee appreciates the opportunity to conduct this scientific
review. In igbalf of the Subcommittee we request that the Agency formally
respond to the scientific advice provided in its attached report,
Sincerely,
Por'tbn Nelson, Chair
Executive Ccnwiittee
Richard A. Griesemer,
Environment*
u.
air
,ee
y
Qrganics Subcoratrattee
-------
Halogenated Grganics Subcommittee
Review of the June 198? draft Technical Analysis of New Methods and
EBta Regarding Dichloranethane Hazard Assessments: and July 1987 Draft
Addendum to the Health Assessment Document for ttchloromethane: pharntaco-
kinetics, Mechanism of Action and Epidemiology
Pharntacojci'netics and Metabolism
The application of a physiologically based pharmacokineties (PBPK) model
presented in the document is generally well conceptualised and organized.
This application represents a novel approach that can sharpen EPA's ability
to refine human risk estimates in the future. Ihe Subcommittee commends
SPA for incorporating such information into the weight of evidence deter-
mination of the carcinogenic potential of dichlorcroethane. .Adoption of the
Reits-Anderson model, with certain modifications, is a positive step for-
ward for the Agency's risk assessment process. Ihe critical analysis of
the constraints Of the model are thoroughly discussed and scientifically
balanced. EPA, for example, is justified in adjusting the estimates of
Reitz-Andejrson for breathing rates traditionally used in EPA models. Ihe
rationale for using surface area factor adjustment, and contrary arguments,
are clearly described,
The PBPK model has appeared in the published peer reviewed literature.
The novel applications of the latest data concerning the model that were
presented at the meeting are new and received enthusiastic support from the.
Subcommittee, which also recommends publication of this approach. Ihe Sub-
committee recognizes that validation will be required for this and other
compounds before using this approach generally for human risk calculations.
One possible problem is that the metabolic conversion of dichloromethane
by different animal species by either the cytochrorae P-450 oxidase system (mixed
function oxidase or MFO) or the glutathione-S-transferase system (GST) was
not supported by data indicating that measurements in each species were
conducted at conditions optimal for pH» ionic strength or temperature for
that substrate in that tissue for each specific species, unless such
conditions are utilized, interspecies quantitative data may be meaningless,
and the basis for the use of this approach in human risk estimation could
be flawed.
Comparative _in vitro studies with rat, mouse, hamster and human cytosol
showed that the dichlororoethane-GST conjugation rates in humans were at least
50 times lower than in mice. The Subcommittee points out that: 1) mice
have the highest activity and liver tumor induction that correlates with
GSH-r&etabolite production above saturation of the MFO system; 2) hamsters
have much lower activity and no liver tumors? and 3) humans have even lower
activity indicating very low, if any, liver tumor inducing potential for
dichloromethane. Ihere was a good correlation between the relative rates
of dichloromethane-GSH conjugation and susceptibility of liver tumors. The
conclusion that, at low exposure levels, the carcinogenic hazard to humans
-------
frcm dichlorcitiethane appears very low needs to be clearly stated in the
document.
Ihe document could be simplified by eliminating the Chapter 7 discussion
of a "rationale" for surface area scaling and replacing it with the statement
on page 107 that, "Ihe fact that there is no clear basis for choosing the use
of surface area correction or not..*is a weakness of the current state-of-the-
art of quantitative risk assessment."
jDLscusslon of Specific Scientific Issues Related to the Addendum
1. In considering an overall weight of evidence approach to risk
assessment, other factors, such as the nature of the animal tumor response,
mechanistic data (such as binding of the chemical to ENA), genotoxic activ-
ity and epidemiological data should also be discussed.
2. In evaluating the tumor data* the Subcommittee urges caution in ex-
trapolating the existing animal bioassay to humans. Although diehlorcraethane
induced both lung and liver tumors in the mouse models, these observations
occurred only at high doses which likely influenced the compound's overall
metabolism. Other bioassays in other species, or at lower doses in mice,
induced negative results. Ihe fact that the Reitz-Anderson model is able
to predict these responses suggests that an interspecies correction factor
based on surface area may not be necessary for extrapolating the tumor
data to humans* This is particularly true when hamster and rat data (GSH
transferase) are considered using the PBPK analysis. Ihe observation of
benign mammary tumors and salivary gland tumors in rats should not be used
as strong evidence for human carcinogenic potential given the uncertain
significance of these lesions. The benign mammary tumors have very low
potential for predicting malignancy even in the rat, and salivary gland
tumors were reported in only one of the studies.
3. EPA should discuss the findings of several investigators (Shumann
et. al., Dow Chemical; Green et. al., ICI, U.K.) that indicate that dichlOTO-
methane or its metabolites do not exhibit any potential to alkylate liver or
lung ENA following j.n vivo exposure. Such findings raise the clear possibil-
ity that dichloronethane may have produced its carcinogenic responses in
mice by non-genotoxic mechanisms, and may include an important contribution
of cytotoxieity in the overall tumorigenic process. Such data become par-
ticularly relevant as carcinogenicity was observed only at extremely high
exposures and was absent at lower, potentially noncytotoxic doses.
4. Critical uncertainties remain regarding the relationship between
dose to target tissues and tumor incidence, since little information on the
mechanism of action is available for dichloronethane. The Subcommittee
accepts EPA's use of a surface area scaling factor for delivered dose as
appropriate for calculating an upper bound estimate, but it views this
usage as more conservative than the usual "default" assumption frcm the
Agency cancer guidelines, scaling administered dose by surface area frcm
animals to humans. Further research may indicate that, at least for some
substances, scaling delivered dose on the basis of body weight is more
appropriate than scaling by surface area.
-------
-3-
5. the degree of nonlinearity in the dose reponse relationship for deliver-
ed dose is an important source of uncertainty. As noted on page 110 of the
Addendum, EPA uses the linearized multi-stage model to calculate an upper
bound estimate. The true dose response curve may fall off more rapidly than
a linear relationship at low doses. Biological information supporting a non-
linear or threshold type of dose response relationship is potentially ijmpor-
tant for risk management decision making because it becomes less likely that
the default plausible upper bound linear estimate will be an accurate estimate
of human risk, especially at low exposure levels in the ambient environment,
6. The Subcommittee was presented with a brief report on the current
status of the Kodak epideraiologieal study of dichlorcmethane. A slight
excess of pancreatic cancer deaths has been separately reported. However, the
study is based only on death certificate data and has not included a histopatho-
logic review of biopsies or surgical specimens from such patients. Ihe incidence
of pancreatic cancers tended to cluster, and only with further surveillance
of the population can a more definitive statement be made on human health risk.
The clinical diagnosis of pancreatic cancer is difficult and may be easily
confused with other abdominal malignancies. Thus, without pathologic confirm-
ation, the Subcommittee cannot necessarily conclude that an excess of pancreat-
ic cancer deaths has occurred. Kwever, neither can it be concluded that
dichloromethane is safe for humans at the occupational exposure levels seen
in the study. The Agency should determine the criteria of the Kodak epidendo-
logical study necessary to substituting the animal derived risk estimate with a
human derived risk estimate. Finally, the Subcommittee recommends the continua-
tion of this important study.
7. Although there is an impressive weight of evidence implicating metab-
olites of dichlorcmethane in tumors, the possibility should not be discounted
that the actual tumor inducing agent is the parent ccmpound(s). In order to
present a more balanced document, this possibility should be discussed at
greater length, perhaps in Chapter 8.
8. Both the scaling factor and the shape of the dose response relationship
are important areas for further work in order to aid development of risk assess-
ment methods that incorporate available scientific data and judgement on bio-
logical mechanisms. As better information is developed on pharmacokinetlcs,
phamaccdynamies and mechanisms for chemical carcinogenesis, it should be
possible to further reduce uncertainties in human risk estimates.
9. For all of the above reasons, therefore, the Subcommittee concludes
that the level of uncertainty is greater and that the hazard for dichlorc-
methane may be less than that expressed by the Agency's classification system
in its cancer risk assessment guidelines.
More detailed discussion of these and other issues by individual Subcom-
mittee members has been forwarded to the office of Research and Development.
-------
U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Ccnmittee
Halogenated Qrganics Subooranittee
Roster for August 13-14, 1987 Review of the Draft
Assessment Documents for DLchloreraethane
Dr. John Doull, Chairrnan, Professor of Pharmacology and Toxicology, Univer-
sity of Kansas Medical Center, Kansas City, Kansas 66103
Dr, Seymour Abrahamson, Vice-chairman, Professor of Zoology and Genetics,
Department of Zoology, University of Wisconsin* Madison, Wisconsin 53706
Suboonroittee Membersand Consultants
Dr, Linda Birnbatjm, National Institute of Environmental Health Sciences, P.O.
Box 12233, Research Triangle Park, North Carolina 27709
Dr. George T. Bryan, Department of Human Oncology, University of Wisconsin,
K-4, Roan 528, 608 Clinical Science Center, 600 Highland Ave., Madison,
Wisconsin 53792
Dr. Janes Bus, Pathology and Toxicology Research, Upjohn Company, Kalarnazoo,
Michigan 49001
Dr, Robert Dedrick, Chief, Chemical Engineering Section, National Institutes
Health, Building 13, Rocra 3W13, Bethesda, Maryland 20892
Dr. David Gaylor, National Center for Toxicological Research, Jefferson,
Arkansas 72079
Or* Ronald D* Hood, Professor and Coordinator, Cell and Developmental Biology
Section, Department of Biology, University of Alabama, and Principal
Associate, R»D. Bood and Associates, Consulting lexicologists, P.O. 1927,
University, Alabama, 35486
Dr. K. Roger Hornbrook, Department of Pharmacology, P.O. Box 26901, University
of Oklahoma, Oklahoma City, Oklahoma 73190
Dr. Curtis Klaassen, Professor of Pharmacology and lexicology, University of
Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, Kansas 66103
Dr. Karl K. Rozman, Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas, Kansas City, Kansas 66103
Dr. Stephen Safe, Department of veterinary Medicine, Physiology and Pharmacology,
College of Veterinary Medicine, lexas ASM University, College Station, Texas
77843-4
DC. Robert Squire, 1515 Labelle Ave., Ruxton, Maryland 21204
Dr. Thomas Starr, CUT, P.O. Box 12137, Research Triangle Park, North Carolina
27709
-------
' Participating Members of the Environmental Health Ccnniittee
DC. Richard A, Griesaner, Biology Division, Oak Ridge National Laboratory,
Martin Marietta Energy Systems, Inc., P.O* Box Y, Oak Ridge, Tennessee
37831
Cr. D. Warner North, Principal, Decision Focus Inc., IDS Altos Office
Center, Suite 200, 4984 El Canuno Real, IDS Altos, California 94022
Executive Secretary
Cr. C* Richard Cothern, Executive Secretary, Environmental Health Committee,
Science Advisory Board {A-10IP), U.S. Environmental Protection
401 M Street, SW, Washington, D.C, 20460
------- |