Document N2ogGdRG1bO8bdbXrr8kGgVpR

AR226-1381 -4^ M SvG - /3>2/ 31t*4 S ^ * 4 i [*~=<iif ? Fs. ? STUDY OF PREGNANCY OUTCOME IN WASHINGTON WORKS EMPLOYEES! RESEARCH PROPOSAL Employee Relations Department Medical Division Epidemiology Section April 13, 1981 ^ 'S r .t Ifuf EID106191 000124 WEF000117 Objectives The study's objectives are to determine whether a. Pregnancy outcome among female Washington Works employees is causally related to their occu pational exposure to C-8. b. Pregnancy outcome among wives of Washington Works employees is causally related to their husbands' exposure to C-8. Background and Rationale There have been five toxicologic experiments in which C-8 was 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 of C-8 for a subsequent oral teratology study in rats. Suspensions of 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 15 Of 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 sacri ficed. Four fetuses were examined from each of four dams in the 150 and 25 mg/kg/day dose groups. All of the readable fetuses EID106192 000125 sectioned had eye lens abnormalities. The authors noted that two previous teratology studies with chemically related compounds resulted in fetuses with similar abnormal changes in the lens of the eye. At Washington Works significant occupational exposure to C-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. * Feiftale workers are studied because they may have been exposed to C-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 / Histories of pregnancy outcome and of potential exposure to C-8 will be ascertained for a. Washington Works active female employees, and 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-administered questionnaires * given to female employees and wives of male employees. EID106193 000126 WEF000118 If an association is observed between pregnancy outcome and having had potential exposure to C-8, the association will be assessed as to whether it is causal or whether it is dne to other confounding factors. 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 high or low potential for exposure. * 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 service and process operators have the highest potential for exposure based on blood organic fluoride levels. Some mechanics, non-semiworks laboratorians, and chemists/engineers occasionally come in contact with C-8. However, the natures of their jobs and of the personnel record keeping system make it very difficult to determine these workers' exposure, to ^ EID106194 000127 WEF000119 C-8 or to other chemicals. For this reason, mechanics, non-semiworks laboratorians, and * chemists/engineers 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 ex cluded 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) 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 as a control. Matching will be on payclass, birth date (+ 3 years), and adjusted service date (+ 3 years). The control for each exposed worker will E1D106195 000128 WEF000120 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. Sources of Data 1. 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. WEF000121 These histories will be assembled from personnel records, medical records, and employee interviews. The work histories should contain: name color (white/non-white) birth date payclass date hired all jobs having C-8 exposure potential month and year the worker moved 'in and out of C-8 jobs EID106196 * 000133  each job's exposure potential (high or low) blood organic fluoride level and date taHen 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 question naire 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 irir wives (e.g., because of divorce, separation, or death) will be asked to complete the pregnancy outcome question naire 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. Major Response Variables The major measures of pregnancy outcome, which are to be ascertained via a self-administered questionnaire, include: 1. # Pregnancies f2. Spontaneous abortions/miscarriages 3. i Stillbirths 4. # Induced abortions (for medical or personal reasons) 5. # ,,Live-born children 6. f Live-born children with birth defects or other problems at birth EID106197 000130 WEF000122 7. Types of birth defects or problems ob served at birth 8. Birth weights D. Potentially Confounding Variables # Information on a number of potentially confounding factors will be ascertained via the pregnancy outcome question naire. These include: 1. Maternal age 2. Paternal age 3. Infectious diseases (e.g., rubella) 4. Family history of malformations/miscarriages/ stillbirths 5. Medications/drugs 6. Ionizing radiation 7. Smoking ' 8. Chemical exposures outside the plant (e.g., ' other occupations) 9. Alcohol 10. Number of previous marriages 11. Birth control/desire for more children 12. Color/ethnicity (to be determined by plant personnel). 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 100% of the female workers * question naires 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 v EID106198 000131 WEF000123 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 10% 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 ir* *. * After work histories for exposed and nonexposed sub jects have been sent to Medical Division, data from a 10% 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 no potential C-8 exposure. It will allow us to pre-test the pregnancy outcome questionnaire and other study procedures. WEF000124 Sample Size A. Female Employees Currently there are 32 exempt, 130 non-exempt, and 159 wage roll females actively employed at the plant. As of April 1, about 50 of these women worked in the Teflon EID106199 000132 area. Only about one dozen of these women were in jobs having a high potential for C-8 exposure. i t From 1965 through 1980 there were 103 leaves of absence, due to pregnancy (fable II). Thirteen of these leaves were among wage roll employees. 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 in cluded in the study will be over 600. The number of active ^workers who no longer work in the Teflon area is unknown. The number of births to wives of male employees is also unknown. Statistically Significant Excesses 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. Given these background rates, table III shows the minimum number 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 5 0 .nonexposed births. EID106200 000133 WEF000125 WEF000126 Analyses 1. Data on C-8 exposed female workers will be analyzed separately 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 W.W. workers never exposed to C-8 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^ 'The analyses will be adjusted for the effects of the potent ially 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. Confidentiality and Informed Consent Any female employees, male employees, or wives of male employees who are asked to participate in this stujdy will be EID106201 000134 asked to first read, understand, and then sign an informed con sent statement. This informed consent statement will clearly describe: t The study's purpose and design. Potential risks and benefits to individuals who decide to participate in the study. How the data will be used. The individual's right to refuse to participate at any time in the study without prejudice to him/her. How the study's results will be reported back to the individual. 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. WEF000127 EID106202 000135 TABLE I: EXPOSURE CATEGORIZATION SCHEME USED IN LIVER FUNCTION STUDY OF C-8 WORKERS AT WASHINGTON WORKS WO. 4-1 6-j 4-5 6-7 6-9 S-ll 8-13 6-15 VS-17 HIGH EXPOSURE POTENTIAL * NO. LOW EXPOSURE POTENTIAL . TIE Service Operator TFE Process'Operator PEP Service Operator PEP Process Operator /* Semiworks Laboratorian Mechanic (good possible) Mechanic (possible) Laboratorian (Tech Assistant) Engineer or Chemist 4-2 . ' * 6-4 4-6 : 6-8 ' 6-10 6-12 7-14 8-16 WS-18 6-20 VS-20 - TPE Service Operator TFE Process Operator FEP Service Operator FEP Process Operator Semiworks Laboratorian TEFZEL-TELOMZR A Operator MONOMER Operator Mechanic (unlikely) TFE Production Foreman Laboratorian Chemist or engineer WEF000128 EID 106203 00036 WAGE SALARY TOTAL TABLE II NUMBER OF PREGNANCIES BY YEAR (OF LEAVE OF ABSENCE) ANO BY PAYCLASSt WASHINGTON WORKS FEMALE EMPLOYEES 1965 - 1980 WEF000129 Year of leave of absence 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 0000010001121232 65 - 80 13 6 7 7 4 7 10 12 8 7 4 4 3 2 3 3 3 90 6 7 7 4 7 11 12 8 7 5 5 5 3 5 6 5 103 EID106204 C3 9 * .* I TABLE III: MINIMUM NUMBER OF MALFORMATION? NEEDED TO SHOW STATISTICAL SIGNIFICANCE Type of malformation Malformation incidence nation-wide Minimum number of births with malformations that must be observed in the study group to be significantly higher than the national incidence# given a study group with N live births : N=5 N=10 N-50 WEF000130 craniofacial 2 per 1000 1 2 2 all malformations 20 per 1000 2 2 4 <N Q W 00 C? ri o Number of live births in the plant control group 50 50 50 # births with malformations in the control group 0 1 2 Minimum number of births with malformations that must be observed in the study group to be significantly higher than the control group's incidence# given a study group with N live births: N=5 N10 N-50 22 6 23 8 3 4 10 STUDY OF PREGNANCY OUTCOME IN WIVES OF C-8 EXPOSED WORKERS EID106180 000139 WEF000105 STUDY OF PREGNANCY OUTCOME IN FEJiALE WORKERS EXPOSED TO C-8 EID106215 000140 WEF000167