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phyrins in urine; dermatological examination; and quantitation of serum and
adipose organohalide body burdens (PBB, PCB, DDT, DDE and etc.). The con-
tractor also quantitatively evaluation the compartmental ization of PBB in
specific subsets of leukocytes and serum components.

During the past year, the contractor has focused on an extensive indepth eva-
luation of individuals demonstrating altered lymphocyte function during the 1979
- 1982 reevaluation with emphasis on individuals demonstrating impaired immuno-
logical responsiveness to mitogens and al loanti gens , altered cell surface marker
distribution, and altered immunoglobulin levels. The purpose of this limited
indepth evaluation was to characterize the immune alterations in those most
seriously affected and to determine the underlying mechanism. To achieve this
objective, the principal investigator has evaluated the responsiveness of



534



lymphocytes from these individuals to biologic response modifiers; the ability
of their cells to express natural killer cell activity, an indepth characteriza-
tion of T lymphocyte subsets using monoclonal antibodies for cell surface marker
characterization; and an in vitro evaluation of antibody synthesis and regula-
tion.

MAJOR FINDINGS AND PROPOSED COURSE : During the past six months the contractor
has focused on correcting statistical analysis deficiencies observed during
the last review of this contract. The principal investigator and his staff
have made consi derable progress with the detailed statistical analysis of the
immune function abnormalities, in developing criteria for determining which
immune function parameters are abnormal using a 95% confidence interval based
on control values, and in cluster analysis to determine how immune abnormali-
ties clustered among individuals and families. Some progress was also made in
correlating immune dysfunction with clinical abnormalities.

Clinical Findings: Of the 336 adult farm residents and 29 chemical workers
evaluated, 134 (37%) gave a history of neurological symptoms which included
frequent headaches, dizziness, paresthesias, loss of balance, fatigue, nervous-
ness, and loss of memory. In addition, 149 (42%) expressed musculo-skeletal
symptoms including joint pain and swelling of joints. Neurological and musculo-
skeletal symptoms were persistent from the earlier observation in 1976 and are
the two most prevalent symptoms reported. A reevaluation of clinical and neuro-
logical symptoms was conducted on 40 of the original 45 individuals studied
during the 1976 study and 19 of these individuals (47.5%) continued to present a
history of neurological symptoms of the same nature as they had previously
reported. Fourteen (35%) of the 40 individuals restudied continued to complain
of joint pain often associated with swelling of joints.

Clinical chemistry evaluation of these 40 individuals indicated liver function
tests remained constant and normal from 1976 to 1980 with the exception of
SGOT. Most of the study subjects both past and present have normal liver
function tests and this also applies to both Michigan general population
groups.

A large proportion of the 336 Michigan farm residents continued to exhibit
cutaneous hyper reactivity to the recall antigens mumps (28-51%) and to vari-
dase (45-62%). It should be noted that some general hypereacti vity was noted in
the general Michigan population to these two antigens. An evaluation of Immu-
noglobulin levels revealed that 50% of the Michigan dairy farmer residents had
abnormal levels of IgG as compared to an "abnormality" rate of 20% in the Michigan
chemical workers and 23% in the general Michigan population. Some abnormal
expression of IgM and IgA were also seen in a few individuals although the
frequency does not approach that seen with IgG. Similar results were found when
one examined serum complement (C) components. For example, abnormal values of
C3C were found in 58% of the Michigan farm residents as compared to 26% of tOe
chemical workers and 24% of the Michigan general population using the 95 percen-
tile cut-off for Wisconsin farm residents.

Examination of cell-mediate immunity and the cell types involved revealed the
following data. Michigan farm residents and chemical workers expressed a signi-
ficantly decreased level of T lymphocytes and a statistically significant
increase in circulating level of null cells (i.e., cells without either T or B



535



cell surface markers). The mean null cell percentage in Wisconsin dairy farmers
was 11.8 as compared to 21.3 and 25.3 in Michigan farm residents and chemical
workers, respectively. This alteration in the peripheral expression of T
lymphocyte subpopulations may suggest some alteration in maturation or cell sur-
faces by PBB exposure. In addition, Michigan farm family members and chemical
workers also demonstrated significantly depressed proliferative responses of
lymphocytes to PHA, PWM, CON A and in mixed leukocyte culture. Using cluster
analysis, the immune dysfunctions seen in the Michigan dairy farm population
were divided into four subgroups as follows: 1) Individuals with low lympho-
cyte response to PHA, CON A, PWM with normal percentages of T, B and null cells
(n = 52/331); 2) Individuals with low lymphocyte response to PHA, CON A, PWM
with abnormal percentages of T and null cells (n = 30/331); 3) Individuals with
increased levels of immunoglobulins G, A and C3 with normal percentages of T, B
and null cells and normal lymphopro-li ferati ve responses (n = 26/331); 4)
Individuals with increased levels of immunoglobulins G, A and C3 with abnormal
percentages of T, B and null cells and impaired lymphoprol i feTati ve responses to
PHA and CON A (n = 25/133); and 5) Individuals with no or only 1 abnormal immune
parameter (n = 199/331). Attempts were then made to correlate clinical changes
within each of these subgroups. Individuals with immune abnormalities also more
frequently demon-strated the clinical symptoms previously described.

The clinical findings most frequently associated with Subgroup 1 were neurologi-
cal and musculoskeletal system involvement. Subgroup 2 had a high percentage of
neurological and musculo-skeletal symptoms and in addition 4 individuals (13%)
developed neoplasias since the 1976 field survey. This observation was
interesting since the individuals in this subgroup had both a numerical and
functional impairment of T and B lymphocytes. Individuals in Subgroup 3 showed
an elevated ASO titer both in frequency and level of response. These indivi-
duals also had increased serum levels of IgG and IgA. Subgroup 4 represents 25
dairy farmers with the most serious multiple immune dysfunctions. These are
polycolonal hypergammaglobulinemia, increased ASO titers, reduced T cell popula-
tions and functions, and increased null cell populations. These abnormal immu-
nological findings were accompanied by a significantly hypersen-siti vity in vivo
response to the recall antigens mumps and varidase. Multiple clinical symptoms
primarily characterized by abnormalities in neurological and musculo-skeletal
systems were predominant in this group. Six farmers (24%) developed cancer
since the 1976 survey. The PBB levels in this group ranged between 0.6 to 70
and remained unchanged or increased since the 1976 survey.

A cluster analysis of immunological abnormalities by husband and wife revealed
that there was a strong correlation of immunologic abnormalities in both part-
ners suggesting that exposure and not genetic predisposition was probably the
underlying factor in this abnormality. Finally, the principal investigator has
provided very nice scatter plots of the comparison of immuno-logical measure-
ments among 40 of the 45 individuals studied in 1976 and again in 1981. For all
immunological abnormalities examined at both time periods there was a high
degree of correlation and significant correlation coefficients were provided.
These data indicate that the abnormalities observed in 1976 have persisted
through 1981. The degree of correlation between these two datasets in the
retested individuals was extremely encouraging and speaks to the generally high
quality of the studies performed by the PI and his staff.

Preliminary data from the indepth characterization of 25 subjects from
subgroup 1 and 20 subjects from subgroup 4 are preliminary and as follows:



536



1) Individuals within subgroup 4 have a marked increase in the proportion of
lymphocytes positively stained for cytoplasmic IgG and IgM, concomitant with an
increase in IgM and IgG secretion i n vitro . 2) A strong correlation was found
between rheumatoid factor positive responses and joint pain and swelling in this
subgroup. Hypersensitivity to the recall antigens mumps and varidase was per-
sistent and accompanied by elevated ASO titers and immunoglobulin levels in
subgroups 3 and 4. 4) Natural killer cell activity was markedly lower than the
control population in individuals in both subgroup 1 and 4.

Progress in the chemistry area has been good and can be summarized as
follows: These investigators have confirmed the initial observation that the
-lipoproteins are the major carrier proteins for PBB and determined that
approximately 75% of protein-bound PBB is carried by these proteins. Serum
albumin and othe, serum protein constituents serve to carry little PBB. The in
vitro mixing of C-label hexachlorobiphenyl with human sera provides a good
model for investigation the distribution of these components in environmentally
contamined subjects. The techniques developed for negative ionization mass
spectroscopy has been validated and are currently being used in the final
phases of the study. In summary, the overall progress on immunological data
analysis, analysis of the serum protein distributions of PBB and preliminary
data on the indepth study appears to be excellent.

SIGNIFICANCE TO BIOMEDICAL RESEARCH IN THE PROGRAM OF THE INSTITUTE : The
complex relationship between PBB exposure, PBB body burden, PBB distribution
among lymphoid cells, clinical symptoms associated with PBB expoure and immune
alteration seen in Michigan farmers and chemical workers exposed to PBB still
remains complex. Individuals in subgroups 2 and 4 have the most clinical symp-
toms which may or may not be PBB related, but was of interest since they are
found in subgroups with the most serious forms of immune dysfunction. The long-
term health consequences, if any, in individuals exposed to PBB is still not
f ul ly understood.



537



FOOD AND DRUG ADMINISTRATION

National Center for Toxicol ogical Research (NCTR)

Bethesda, Maryland 20205

(222Y01-ES-00052)



TITLE: Teratogenicity Testing of Chemicals for the National Toxicology Program
CONTRACTOR'S PROJECT DIRECTOR: Carole A. Kimmel, Ph.D.
PROJECT OFFICER (NIEHS): John A. Moore, D.V.M.
DATE CONTRACT INITIATED: May 1, 1980



CURRENT LEVEL: $655,000



PROJECT DESCRIPTION



OBJECTIVES : The objective is to provide testing of chemical agents for their
potential to cause teratogenicity and developmental "toxicity . This effort is
attributed to reproductive testing of chemicals designated for study by the
National Toxicology Program,

METHODS EMPLOYED : Testing of environmental chemicals in at least two of four
species of pregnant laboratory animals (mice, rats, rabbits, hamsters) and deve-
loping data on the susceptibility of their embryos/fetuses to developmental
toxicity following the administration of test chemicals during development.

MAJOR FINDINGS AND PROPOSED COURSE : The testing of chemicals for teratogenicity
has continued on contract in FY 1983. Fifteen studies on 10 chemicals have been
completed, and an additional 9 studies on 5 chemicals are underway (Table 1).
Four abstracts on the teratologic evaluation of diphenhydramine, 5-hydroxytryp-
tophan and diethyl hexyl phthal ate were presented at the Teratology Society
meeting in June, 1983. NCTR's current contract ends September, 1983, and a new
contract is being negotiated to begin October 1, 1983. Selection of chemicals
for conventional teratology testing for FY 1984 is underway and is coordinated
with the selection of chemicals for and results of the short-term in vivo repro-
ductive toxicity assay and the sperm morphology/vaginal cytology assay.

SIGNIFICANCE TO BIOMEDICAL RESEARCH AND THE PROGRAM OF THE INSTITUTE : The goal
is to determine the relative safety of those chemicals to which a wide segment
of the population is exposed. In this case, the population consists primarily
of women of childbearing age, specifically pregnant women.



538



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INTRAAGENCY AGREEMENT
222Y01-ES-20081

TITLE: Toxicology Data Management System

PROJECT OFFICER (NCI/NTP): Michael P. Dieter (NIEHS)

Albert J. Konvicka (NCTR)

DATE CONTRACT INITIATED: January 15, 1982

CURRENT ANNUAL LEVEL: $1,386,000

PROJECT DESCRIPTION

OBJECTIVES : NCTR will implement and maintain automated support of the infor-
mation processing requirements (Toxicology Data Management System [TOMS]) for
the animal bioassay portion of the NIEHS Toxicology Research and Testing
Program, a major operating component of the National Toxicology Program. TOMS
will replace the Carcinogenesis Bioassay Data System and then will serve as
the principal data base for all animal bioassays. To accomplish TDMS imple-
mentation, it is necessary to purchase the appropriate hardware components and
prepare and validate the appropriate computer programs for data collection and
data retrieval. Data retrieval capability must be continually available for
transmittal, examination, and utilization by NIEHS, NCTR, and participating
contract laboratories.

METHODS EMPLOYED : Generally, for each contract laboratory, specific require-
ments for implementation of the TDMS will be done in three phases: 1) intro-
duction of manual data collection forms; 2) installation of available
microprocessor terminals and software; and 3) complete automated support of
all NIEHS bioassay studies.

MAJOR FINDINGS AND PROPOSED COURSE : One contract laboratory. Southern
Research Institute, has served as a model for TDMS implementation. All of the
bioassay studies there are on-line; the data is being captured on terminals
and transmitted to the mainframe computer at NCTR. With the assistance of
Southern Research Institute systems development for animal room data, toxi-
cology data, and pathology have been completed and can now be used by other
contract labs. Reports suitable for contract lab usage and others designed
for NIEHS usage (summaries of the data) have been developed and verified.
Suitable storage and retrieval, verification, and user authorization systems
for the computer-stored data have been developed.

Six other contract laboratories, Battelle-Columbus, Microbiological
Associates, EG&6 Mason, International Research and Development Corporation,
Bioassay Systems, and Hazleton Laboratories America, have begun automated data
entry this fiscal year.

TDMS support of pathology by NIEHS scientists, quality assurance of pathology,
and other selected NIEHS studies are commencing.

Additional hardware for contract labs and for NIEHS have been ordered.
Installation of this equipment will permit direct data access by NIEHS scien-
tists and communication between NIEHS and contract labs. A query language

540



processor system is proposed to enable NIEHS to examine the data arranged in
various desired formats.

Successful completion of the above phases will enable NIEHS to collect all
types of prechronic data at all of the laboratories.

SIGNIFICANCE TO BIOMEDICAL RESEARCH AND TO THE PROGRAM OF THE INSTITUTE :
Implementation of IDMS will permit rapid management decisions for contract
operations, improve the accuracy and uniformity of data collection, and enable
better comparisons with a historical data base of toxicology and carcino-
genicity. These improvements will enhance the quality of the data on each
chemical tested that will ultimately be utilized as guidelines for evaluating
potential human risk.



541



CARLTECH ASSOCIATES, INC.

Columbia, MD 21044

MOl-ES-2-5020

TITLE: Support for Preparation of Toxicology and Carcinogenesis Studies
Technical Reports

CONTRACTOR'S PROJECT DIRECTOR: Marcia Rodgers

PROJECT OFFICER (MIEHS): James E. Huff, Ph.D.

DATE CONTRACT INITIATED: September 30, 1982

CURRENT LEVEL: $527,000

PROJECT DESCRIPTION

OBJECTIVES : To provide technical reports preparation services for approximately
50 reports per jear.

METHODS EMPLOYED : Preparation of technical toxicology and carcinogenesis
reports on chemicals shall overlap in that 10-20 reports will be in varying sta-
ges of completion. Maintenance of a well-organized data file on each chemical
for which a technical report is being or will be prepared. Word processing
equipment is used for technical report preparation and for transmission of
information to and from NTP offices.

MAJOR FINDINGS AND PROPOSED COURSE : Technical Reports preparation support ser-
vices are provided to Chemical Managers, Discipline Leaders, and the Toxicology
Research and Testing Program Technical Reports Review Conmittee, in writing,
editing, and doing successive draft revisions in close collaboration with
National Toxicology Program staff. Designated groups of reports are prepared in
completed form with strict deadlines for review by the in-house Staff Review and
subsequently by the NTP Board of Scientific Counselors Peer Review Panel. Final
camera-ready material is provided for printing of Technical Reports by a
Government Printing Office contract printer.

SIGNIFICANCE TO THE PROGRAM OF THE INSTITUTE : A necessary resource to the
National Institute ot Environmental Health Sciences, National Toxicology Program
for the organization of laboratory collected data and materials, collection and
preparation of reports to be drafted and printed for chemicals being tested for
the NTP Toxicology and Carcinogenesis Program.



542



DEPARTMENT OF ENERGY - OAK RIDGE NATIONAL LABORATORY
(222 YOl-ES-1-0072)

TITLE: Environmental Mutagen Information Center

CONTRACTOR'S PROJECT DIRECTOR: John Wassom

PROJECT OFFICER (NIEHS): J.E. Huff, Ph.D.

DATE INTERAGENCY INITIATED: FY 1971

CURRENT ANNUAL LEVEL: $300,000

PROJECT DESCRIPTION

Chemical Mutagenesis Literature - Supported by the NTP, the Environmental
Mutagen Information Center (EMIC) collects, organizes, and disseminates pri-
marily published information on chemicals tested for mutagenicity. Located
since inception in 1969 at the Oak Ridge National Laboratory, the EMIC com-
puterized data file contains 46,321 (May 1983) records, most of v/hich are
available online from TOXLINE (at the National Library of Medicine) and from
RECON (at the ORNL). Each record contains bibliographic information, assay
systems, and keywords defining agents tested and organisms studied. All
articles are obtained prior to entry onto computer and are on file at the EMIC.
The number of unique chemicals identified from these 46,321 documents equals
13,813.



543



DEPARTMENT OF ENERGY - OAK RIDGE NATIONAL LABORATORY
(222 YOl-ES-1-0073)

TITLE: Environmental Teratology Information Center

CONTRACTOR'S PROJECT DIRECTOR: John Wassom

PROJECT OFFICER (NIEHS): J.E. Huff, Ph.D.

DATE INTERAGENCY INITIATED: FY 1975

CURRENT ANNUAL LEVEL: $300,000

PROJECT DESCRIPTION

Chemical Teratogenesis Literature - Developed and supported by the NTP since
1975, the Environmental Teratology Information Center collects, organizes, and
disseminates information on chemicals tested for teratogenicity, the ETIC data
file contains 29,399 (as of May 1983) records, the majority of which are
available online from TOXLINE AND RECON. The number of unique chemicals iden-
tified from these 29,399 documents equals 5,422,

ETIC, located at NIEHS, has established a microform document library containing
copies of 23,999/29,399 (82%) papers referenced in the computer file. Each
citation has been indexed with all bibliographic information, common and taxono-
mic name of test object, and Chemical Abstract Service (CAS) Registry Number.
Titles and abstracts may be searched using key words. Chemicals in the ETIC
Agent Registry may be searched by primary name, synonym, CAS number, fragment as
a part of a chemical name, and molecular formula.



544



INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

Lyon, France

N01-ES-1-5009

TITLE: Establishment and Maintenance of an International Register of Persons
Exposed to Phenoxy Acid Herbicides and Contaminants

CONTRACTOR'S PROJECT DIRECTOR: Rodol fo Saracci , M.D.

PROJECT OFFICER (NIEHS): J.E. Huff, Ph.D.

DATE CONTRACT INITIATED: July 20, 1981

CURRENT LEVEL: $122,705

PROJECT DESCRIPTION

OBJECTIVES : To identify, learn about, and assess the suitability for epide-
miologic study of cohorts (outside of the United States) with defined exposure
to phenoxy herbicides and contaminants, principally chlorinated dibenzo-p-
dioxins. To identify a scientist in each country having at least one potential
cohort who is interested in collaborating with lARC on this project and to learn
from these contacts about other potential cohorts.

METHODS EMPLOYED : Phenoxy herbicides and chlorophenol manufacturers outside the
United States are being identified from published literature and from scientists
and company officials. Potential epidemiologic collaborators are identified and
the lARC plan is described with intent of enlisting assistance in learning about
potential cohorts.

MAJOR FINDINGS AND PROPOSED COURSE : Major factories and many collaborators have
been identified. Key contacts have been made and plans discussed for the
collection of specific information on the cohorts. The proposed course is to
assemble more specific information about the company are available and suitable
for an lARC Registry, and perhaps ultimately for an epidemiologic study.

SIGNIFICANCE TO THE PROGRAM OF THE INSTITUTE : The initiation and maintenance of
an international registry of persons exposed to phenoxy acid herbicides and con-
taminants, principally chlorinated dibenzo-p-dioxins. These data will be made
compatible with those being collected in the United Stated by the National
Institute of Occupational Safety and Health.



545



TITLE: Information Resources

PROJECT OFFICER: Joan W. Chase

DATE CONTRACT INITIATED: October 1, 1982

CURRENT ANNUAL LEVEL FOR ALL CONTRACTS: 350,000

BIOSPHERIES, INC., ROCKVILLE, MD

CONTRACTOR'S PROJECT DIRECTOR: Frances P. Lederer

CAPITAL SYSTEMS GROUP, KENSINGTON, MD
CONTRACTOR'S PROJECT DIRECTOR: Williani Hassler

ENVIRONMENTAL CONTROL, INC., ROCKVILLE, MD
CONTRACTOR'S PROJECT DIRECTOR: John R. Strange

ENVIRONMENTAL RESOURCE CENTER, SILVER SPRINGS, MD
CONTRACTOR'S PROJECT DIRECTOR: Brian Karnovsky

GEOMET TECHNOLOGIES

CONTRACTOR'S PROJECT DIRECTOR: Harriet Stern



NOl-ES-28028
NOl-ES-28029
NOl-ES-28030
NOl-ES-28031

NOl-ES-28032



PROJECT DESCRIPTION

OBJECTIVES : To supply technical information services to the staff of TRTP/NIEHS
mainly and to the NIOSH and NCTR portions of the NTP on an ad hoc basis.

METHODS EMPLOYED : At present the contract is vested entirely in Environmental
Resources Center which does library searches for journal articles, and xeroxes
and delivers two copies to the Project Officer for distribution to the Chemical
Manager and to Carl tech for report writing. Special translating services are
also supplied on an ad hoc basis.

MAJOR FINDINGS AND PROPOSED COURSE : Information services are supplied as
needed. Other services (i.e. customized searches, reports) can be done as tasks
are required.



546



DEPARTMENT OF ENERGY - BROOKHAVEN NATIONAL LABORATORY
(NIEHS Interagency Agreement ES-9-0043)

TITLE: Evaluation of Repository Mechanics and Other Endpoints as Indices of
Chemical Toxicity

CONTRACTOR'S PROJECT DIRECTOR: R.T. Drew, Ph.D. and R.S. Kutzman, Ph.D.

PROJECT OFFICER (NIEHS): J. A. Moore, D.V.M., Deputy Director

National Toxicology Program

DATE INTERAGENCY INITIATED: July 16, 1979

CURRENT ANNUAL LEVEL: $350,000

PROJECT DESCRIPTION

OBJECTIVES : The interagency agreement is for the conduct of a research program
for eval uation of respiratory mechanics and other endpoints as indices of chemi-
cal toxicity. Brookhaven National Laboratory will conduct investigations on six
chemicals, one animal species, and three dose levels that: (a) compare changes
in functional indices to changes determined through microscopic morphology; (b)
assess the in vitro mutagenic potential of these chemicals using cytogenetic



Online LibraryNational Institute of Environmental Health ScienceAnnual report : National Institute of Environmental Health Sciences (Volume 1983) → online text (page 49 of 89)