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"7 1. objectives
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.
The study's objectives are to determine whether
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a. Pregnancy'sutcone among female Washington Works
employees is causally related to their occu-
pational exposure to C-8.
be Pregnancy outcome among wives of Washington Works
employees is causally related to their husbands' H
exposure to C-8.
S
II. Background and Rationale There have been five toxicologic experiments in which C-8
vas administered repeatedly to experimental animals and in which the male reproductive system was examined. In none of the studies were treatment-related testicular changes observed.
Recently 3M conducted an oral rangefinder study of C-8. The purpose of this study was to determine the upper dose level f C-8 for a subsequent oral teratology study in rats. Suspensions f C-8 and corn oil were given by oral intubation to 5 groups of time-mated female rats (Charles River Sprague-Dawley derived). The doses received were 150, 100, 75, 50, or 25 mg/kg/day of C-8. These doses were given on days 6 through 150f gestation (i.e., the period of organogenesis). There was one control group that received only corn oil by intubation on these same days. Each dosed and control group consisted of 6 time-mated female rats.
At day 20 of gestation the rats from the 3M study were sacrificed. Four fetuses were examined from each of four dams in the 150 and 25 mg/kg/day dose groups. All of the readable fetuses
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sectioned had eye lens abnormalities. The authors noted that
.
two previous teratology studies with chemically related compounds
"I resulted in fetuses with sinilar abnormal changes in the lens
- of the eye. -
.
At Washington Works significant occupational exposure to
-8 is limited to the Teflon area. C-8 is a dispersing agent
that is used in nearly all Teflon polymer and copolymer processes.
The monomers do not contain C-8. Based on previous analyses of
blood organic fluoride levels of workers, the greatest potential
for C-8 exposure occurs in four jobs: TFE process operator, FEP proce
+ operator, TFE service operator, and FEP service operator.
In the proposed study of pregnancy outcome, exposed female employees and wives of exposed male employees will be studied.
Feffale workers are studied because they may have been exposed to
-8 during or immediately prior to their pregnancies. Wives of male workers are studied because the husbands may somehow bring C-8 home with them and expose their wives at home. There is no evidence at present to suggest that C-8 exposure affects the husband's reproductive system.
III. Specific Aims
.
Ristories of pregnancy outcome and of potential exposure
0 C-8 will be ascertained for
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a. Washington Works active female employees, and
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b. Wives of Washington Works active male employees.
Potential exposure to C-8 will be determined from personal records, medical records, and employee interviews. Pregnancy
outcome will be determined via self-adninistered questionnaires
given to female employees and wives of male employees.
:
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If an association is observed between pregnancy outcome end having had potential exposure to C-8, the association will
be assessed as to whither it is causal or whether it is dne to
other confounding factors.
Iv. Methods
A. study Groups
1. Workers with potential C-8 exposure
a. Definition of exposure: Teflon area
All Teflon area jobs will be defined as
having potential exposure to C-8. These jobs
will be further categorized as having either
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high or low potential for exposure.
ct
Table I shows the exposure categorization
scheme used in the previous liver function study
of C-8 workers. Notice that several job titles
appear in both the high and low exposure potential
columns. This happens because exposure potentials
for most Teflon area jobs depend on the particular
time period and task considered. Within the
high potential category, current TFE/FEP
5
service and process operators have the highest g
potential for exposure based on blood organic
s
fluoride levels.
Some mechanics, non-semiworks laboratorians, and chemists/engineers occasionally come in contact with C-8. However, thenaturesof their jobs and
of the personnel record keeping system make it very
difficult to determine these workers' exposure. to
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C-8 or to other chemicals. For this reason, mechanics, non-semivorks laboratorians, and
chenistsengineers will be defined as having unknown exposure potential.
b. Selection of exposed workers All active male and female workers who have
ever worked in a C-8 exposure job (as defined above) will be identified. Brief questionnaires will be given to these workers to determine who has ever been married. All ever married workers will be included and all never married will be excluded from the study.
"2. Workers with no potential C-8 exposure
a. Definition of non-exposure
ALL non-Teflon area jobs, with the exception of the jobs with unknown exposure potential (e.g., mechanic), will be defined as having no potential for C-8 exposure.
b. Selection of non-exposed workers (controls)
3
ALL of the plant's non-exposed active female
workers will be selected as controls for the ex-
posed female workers.
For each C-8 exposed active male employee, one matched non-exposed male employee will be chosen 2s a control. Matching will be on payclass, birth date (+ 3 years), and adjusted service date (+ 3 years). The control for each exposed worker will
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be the first eligible employee appearing
in the yearly employee roster after the
exposed worker's name.
+ Each male and female control will be given
a questionnaire to determine whether he/she
has ever been married. All never married con-
trols will be dropped from the study. For the
male subjects, new controls will be chosen to
replace those controls who either were never
married or who refused to participate in the
study.
B. Sources of Data _ il. Exposure histories
Plant personnel will be responsible for: determining which active employees have ever had potential exposure to C-8.
collecting detailed exposure histories on the study subjects.
These histories will be assembled from personnel records,
medical records, and employee interviews. The work
histories should contain:
name
o color (white/non-white)
birth date
payclass
8
aate hired
all jobs having C-8 exposure potential
mCo-n8thjobasnd year the worker moved `in and out of
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each job's exposure potential (high or low) tbalkoeond organic fluoride level and date
Exposure histories will be recorded on code sheets
that will be designed and supplied by Medical Division.
2. Pregnancy outcome data All female study subjects will be asked to com-
plete a self-administered questionnaire on pregnancy outcome.
All male subjects will be given an initial questionnaire to determine whether they have ever been married and whether they are now living with their wives. Males ; who have been married but who no longer live with their "7 vives (e.g., because of divorce, separation, ordeath) will be asked to complete the pregnancy outcome questionnaire themselves. Males who are now living with their wives will be asked to give the questionnaire to their wives to complete. Never married workers will be dropped from the study.
C. Major Response Variables
The major measures of pregnancy outcome, which are to be
ascertained via a self-administered questionnaire, include:
1. 4 Pregnancies
2. # Spontaneous abortions/miscarriages
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3. 4 Stillbirths 4. 1 Induced abortions (for medical or personal
reasons)
5. # Live-born children 6. 4 Live-born children with birth defects or
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other problems at birth
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7. Tsyeprevsedofatbbiritrhthdefects or problems ob-
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8. Birth weights
D. Potentially Confounding Variables
Information on a number of potentially confounding
factors will be ascertained via the pregnancy outcome questionnaire. These include:
. "3% &
1. Maternal age 2. Paternal age 3. Infectious diseases (e.g., rubella) 4. Fsatmiilllybirhtihsstory of malformations/miscarriages/ 5. Medications/drugs 6. Ionizing radiation 7. smoking 8. oCthheemricaolccuepxaptoisounrse)s outside the plant (e.g., 9. Alcohol 10. Number of previous marriages 11. Birth control/desire for more children 12. pCeorlsoorn/neetlh)ni.city (to be determined by plant 3
E. Quality Control
If the final product of this study is to fair well
against peer review from outside of the Company, steps must
be taken to assure, measure, and document the quality of the
data collected.
1. Validation of pregnancy outcome supplied by female workers
The responses on 1008 of the female workers' questionnaires should be validated. A worker's responses could be validated by checking existing Du Pont medical records
and by contacting the worker's personal physician. This
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last step would only be done after having obtained the
worker's informed consent to do so.
2. validation of pregnancy outcome supplied by husbands
The responses on 108 of the questionnaires given
to workers' wives should also be compared with the
responses given independently by their working husbands.
This comparison will help document the quality of the responses given by husbands.
3. Validation of work histories supplied by the plant
After work histories for exposed and nonexposed sub-
. jects have been sent to Medical Division, data from a 7208 sample of these subjects will be auditted. For this
audit the plant will be asked to supply the records from
which these work histories have been assembled.
F. Pilot Study
:
Prior to giving questionnaires to all study subjects,
a pilot study should be done. This pilot study should include
about 5 male and 5 female workers who have had nopotential
-8 exposure. It will allow us to pre-test the pregnancy
outcome questionnaire and other study procedures.
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V. Sample Size
A. Female Employees
Currently there are 32 exempt, 130 non-exempt, and
159 wage roll females actively employed at the plant. Aas
f April 1, about 50 of these women worked in theTeflon
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area. Only about one dozen of these women were in jobs. having a high potential for C-8 exposure.
From 1965 though 1980 there were 103 leaves of absence. due to pregnancy (table IT). Thirteen of these leaves
were among vage roll employees.
B. Male Employees Over 300 men, or about ten percent of the plant's work-
force currently work in the Teflon area. Within the Teflon area, 60 to 70 workers are in jobs that have high potential
for C-8 exposure. Since each exposed male will be matched
with one non-exposed male, the total number of males inluded in the study will be over 600. The number of active . fuorkers who no longer work in the Teflon area is unknown. The number of births to wives of male employees is also unknown.
C. statistically Significant Excesss
The national incidence rate for craniofacial malformations is about 2 per 1000 live births, and the rate for malformations of all types is about 20 per 1000. 2 Given these background rates, table III shows the minimum S nunber of births with malformations that must be observed in the study group to say that there is a statistically significant excess ( p<0.05). For instance, 2 malformations in 10 exposed live births is a significantly higher rate than a national rate of 2 per 1000. Two malformations per 10 exposed live births is also significantly higher than a - Plant rate of 0 per 50.nonexposed births. .
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VI. analyses
. 1. Data on C-8 exposed female workers will be analyzed separately
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from data on wives of exposed male workers.
2. C-8 exposed female workers and wives of exposed male workers
will be compared with four control groups:
+ Female WW. vorkers never exposed to C-8
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Wives of male workers at W.W. never exposed to C-8 Non-W.W. female employees at another Du Pont plant
Wives of non-W.W. employees at another Du Pont plant.
3. All of the measures of pregnancy outcome mentioned in the
:
earlier section on major response variables will be analyzed.
4% "he analyses will be adjusted for the effects of the potent-
1ally confounding variables mentioned earlier. Binary regression and Mantel-Haenszel methods will be used for
these adjustments.
5. Analyses will take into account that only exposures occurring
:
immediately prior to conception or during the first tri-
mester of the pregnancy are likely to produce malformations.
6. Hypothesis testing will be two-tailed, and significance will be judged at the 0.05 probability level.
VII. Confidentiality and Informed Consent Any female employees, male employees, or wives of male
employees who are asked to participate in this study will be
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asked to first read, understand, and then sign an informed con-
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sent statement. This informed consent statement will clearly
TI describe:
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. The study's purpose and design. o dPeoctiednetiatlo prairstkisciapnadtebenineftihtes sttoudiyn.dividuals who How the data will be used.
Tatheaniynditivmieduainl'stherigshttudytowirtehfouuste hin/her.
ptroejpuadritcieciptaote
tHoowtthheeisndtiuvdiyd'usalr.esults will be reported back
All completed questionnaires, data forms, and raw data will be stored under lock and key or in limited-acess computer files. only the principal investigators will have unlimited
acdess to these data.
When the study is finished, the collected data will be stored in Du Pont's Hall of Records.
All results will be published in aggregate or group forms only. Individual workers will not be identified.
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TABLE I: SETXPUODSYUROEF CC-A8TEWGOORRKIEZRASTIAOTN WSACSHHEIMNEGTUOSNEDWOIRNKSLIVER FUNCTION :
wo.
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6-3:
4-5. 7
9
s-11
B13
15
S-17
:
HIGHEXPOSUREPOTENTIAL -
TPE Service Operator
TFE Process Operator
FEP Service Operator FEP Process Operator
Semivorks Laboratorian
Mechanic
Midhanic
(good possible)
(possible)
LZsnbgdirnaeetrorosranCh(eTneicshcAssistant)
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2.
C64
Lo 46 Fes |
6-10
6-12
7-3
8-16
us-18"
6-20 vs-20
Lo EXPOSUREPOTENTIAL
TFE Service Operator
TFE Process Operator
FEP Service Operator FEP Process Operator
Semivorks Leboratorian
TEFZEL-TELOMZR A
MONOMER Operator
. Operator
Mechanic (unlikely)
TPE Production Foresan
Laboratorssn
Chnist `or engineer
3
8
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