Document B864Jwvp4GzDmeqkprRXwEzbJ

r. NORTHWESTERN MEDICAL FACULTY FOUNDATION. INC. 222 East Superior Street Chicago. Illinois 60611 (3121849*6940 January 30, 1985 S. 3 George Roush, M.D. ;' Medical Director ' Department of Medicine and Environmental Health MONSANTO COMPANY G2WG 800 North Lindberg Boulevard St. Louis, Missouri 63167 -- Dear Doctor Roush: We are forwarding to you the revised protocol for the "Epidemiologic Investigation of the Health Status of Monsanto Employees with Past Exposure to Chlorophenols, Chlorphenoxy Acids, and Their Dioxin Contaminants at the W.G. Krumnrich Plant in Sauget, Illinois".. ... This revision incorporates many of the excellent-suggestions. of the Peer Review CcnnrLttee. .' We believe that each worker will look upon the examination as a valuable benefit provided by Monsanto. We also believe that this study will be a major contribution to the scientific literature on dioxins. The study is designed to answer many of the. previously unresolved questions regarding the possibility of chronic health . effects in workers with past exposure to dioxins. - "" . The Peer Review Comnittee was unanimous in connending Monsanto: for, its sponsorship of this study. We appreciate your confidence in ' selecting us to design and carry out this important research. We wish to extend our personal thanks to you and your staff for your assistance and the courtesy you have shewn us during the, design of . this study. .. - .. . .. Warren Wallace, M.D. JEW/WW:pjw DSW 476038.0475 STLCOPCB4042638 EPIDEMIOLOGIC INVESTIGATION OF THE HEALTH STATUS OF MONSANTO EMPLOYEES WITH PAST EXPOSURE TO CHLOROPHENOLS, CHLORPHENOXY ACIDS, AND THEIR DIOXIN CONTAMINANTS AT THE W.C. KRUMMRICH PLANT IN SAUGET, ILLINOIS: STUDY PROTOCOL Principal Investigators Daniel O. Hryhorczuk, M.D., M.P.H. Warren H. Wallace, M.D. Co-Investigators . James R. Webster, Jr., M.D. Victoria Persky, M.D. Department of Medicine Department of Preventive Medicine and Community Health Northwestern University Medical School Chicago, Illinois January, 1985 DSW 476038.0476 STLCOPCB4042639 TABLE OF CONTENTS 1. 2. 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 3. 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 ' 4. 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 4.2.8 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.3.9 Executive Summary PURPOSE OF STUDY BACKGROUND Plant History Products Previous Studies of Plant Population Tillman, 1977 Suskind, 1980 Zack, 1980 LITERATURE REVIEW Overview Ortho Chlorophenol Parachlorophenol 2,4-Dichlorophenol Pentachlorophenol 2,4-Dichlorophenoxyacetic Acid 2,4,5-Trichlophenoxyacetic Acid Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzofurans (PCDFs) DESIGN Study Design Ascertainment of Exposure Processes Industrial Hygiene Chloracne Registry Maintenance Employees Definition of Exposed Cohort Demographic Characteristics of the Exposed Cohort Follow-Up, Accessibility and Participation of the Exposed Cohort Internal Control Group Ascertainment of Health Status Medical History Questionnaire Reproductive History Dietary History Physical Activity Assessment Occupational and Environmental History Medical Records Review Internist's Physical Examination Dermatologic Examination Neurologic Examination 1 1 1 1 2 2 2 3 4 8 8 10 10 11 14 16 17 36 36 36 51 61 61 63 65 65 69 72 72 73 74 74 74 74 75 76 76 DSW 476038.0476.3 STLCOPCB4042640 Table of Contents (page 2) 4.3.10 4.3.11 4.3.12 4.3.13 4.3.14 4.3.15 4.3.16 4.3.17 5. 5.1 5.2 5.3 5.3.1 5.3.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.4 6. 6.1 6.2 6.3 6.4 6.5 6.5.1 6.5.2 6.6 6.7 7. 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8 9. 10. Electrocardiogram Pulmonary Function Tests Chest X-Ray Quantitative Sensory Examination Nerve Conduction Velocities Neurobehavioral Testing Blood Tests Urine Tests DATA ANALYSIS Data Entry, Processing, and Storage Quality Control Analysis Classification of Exposure Classification of Disease Confounders and Effect Modifiers Demographic Characteristics Lifestyle Characteristics Chemical Exposures Effect Modifiers Statistical Tests IMPLEMENTATION Identification and Recruitment of the Study Population Development of Survey Instruments Medical Examinations Data Analysis Reports Reports to Individual Participants Final Report Timetable Human Subjects Review STUDY LIMITATIONS AND CORRECTIVE MEASURES Loss to Study Survival Incidence-Prevalence Bias Recall Bias Interviewer/Examiner Bias Misclassification of Exposure Confounding Chemical Exposures Repeated Measures Statistical Power Limitations REFERENCES PEER REVIEW COMMITTEE BUDGET 76 76 76 76 77 77 77 78 83 85 87 87 88 88 88 88 89 90 90 92 92 92 93 93 93 93 94 94 96 96 97 97 97 97 98 98 99 105 115 116 DSW 476038.0477 I STLCOPCB4042641 TABLE OF TABLES Title Page Observed and Expected Deaths (Non-White Males) 6 Observed and Expected Deaths (White Males) 7 Possible Number of Isomers of PCDDs and PCDFs 18 PCDDs and PCDFs Reported in Phenols 19,20 PCDDs in 2,4,5,-T and 2,4-D 21,22 Summary of Acute Toxicity of 2,3,7,8 - TCDD 26 Toxic Effects of 2,3,7,8 - TCDD in Man 28 Occupational Exposures Resulting in Illness (Chlorinated Phenols) 29,32 Epidemiologic Studies on Carcinogenicity of TCDD 33 Symptomology of Yusho Cases, 1969-72 35 Job Descriptions Monsanto/CWU 42,43 Levels of PCDD in PCP, PCP-Cuts and PCP Residue 53 PCP Air and Wipe Samples (Dept. 236) 54 PCDD in Wipe Samples (Dept. 236) 56 Air Levels of Chlorinated Phenols (Dept 237) 58 Levels of PCDD in 0-CP and D-CP 59 Demographic Characteristics of Maintenance Workers 62 Exposed Cohort by Length of Exposure and Employment Status 64 Age Distribution of Exposed Cohort as of 1984 66 Comparison Between Exposed and Internal Controls 70 Summary of Comprehensive Medical Exam 80,82 Forms for Collection, Recording and Coding of Data 84 Power Analysis for Dichotomous Variables 100,102 Power Analysis for Continuous Variables 103,104 DSW 476038.0478 STLCOPCB4042642 TABLE OF FIGURES J.N Tide Page 1 Chemical Structure 9 2 Plant Geography 37 3 Chlorination and Acid Scrubbing (Dept. 236) 39 4 Prilling and Packaging (Dept. 8-236) 40 5 Chlorination Step (Dept. 237) 44 6 Overhead Layout (Dept. 237) 45 7 Pre-Mix Slurry (Dept. 268) . 47 S Reaction (Dept. 268) 48 9 Neutralization and Filtration 49 10 Estimated Follow-up, Accessibility and Participation 67 11 Quality Control of Data Entry 86 12 Study Timetable 95 DSW 476038.0479 STLCOPCB4042643 EXECUTIVE SUMMARY OF THE STUDY PROTOCOL The purpose of this study is to determine if workers at Monsanto's Krummrich Plant in Sauget, Illinois suffered any long term health effects as a result of their past exposure to chlorinated phenols, esters of 2,4-D and 2,4,5-T, and their chlorinated dioxin contaminants. The health status of the exposed employees will be compared to the health status of Krummrich employees who were not exposed to these compounds. The exposed cohort will consist of all Krummrich employees who were engaged in the production of chlorinated phenols or chlorphenoxy herbicides for one or more days between January 1, 1938 and December 31, 1983. Maintenance employees who were assigned to these areas and who developed chloracne will also be Included in the exposed cohort. One thousand and fifty-five employees meet the definition of exposure of whom 221 are deceased. Four hundred and four exposed workers are expected to participate in the study. This exposed cohort will be comprised of 221 active, 106 retired, 60 terminated, and 17 other workers whose employment status is as yet unknown. One thousand seventy-seven Krummrich employees were considered to be non-exposed during this same time period. Four hundred and nine are expected to participate as internal,controls. This group will be comprised of 218 active, 50 retired, and 141 terminated workers. Study participants will undergo a comprehensive medical examination, including a medical history, occupational and environmental history, reproductive history, physical examination, dermatologic examination, neurologic examination, electrocardiogram, pulmonary function tests, chest DSW 476038.0480 STLCOPCB4042644 x-ray, quantitative sensory examination, nerve conduction velocity studies, neurobehavioral testing, blood tests, and urine tests. Questionnaire items will be confirmed by medical record review. The health status of the exposed cohort will be compared to the health status of the internal controls. The strategy for statistical analysis will consist of 1) examination of crude associations, 2) stratified analysis, 3) tests for dose response, and 4) multivariate analysis. DSW 476038.0481 STLCOPCB4042645 1 1. PURPOSE OF THE STUDY The purpose of this study is to determine if workers at Monsanto's Krummrich Plant in Sauget, Illinois suffered any long term health effects as a result of their past exposure to chlorinated phenols, esters of 2,4,-D and 2,4,5-T and their chlorinated dioxin and dibenzofuran contaminants. .2 BACKGROUND 2.1 Plant History The plant was established in 1907 as the Commercial Acid Company. At that time it occupied 30 acres and employed 70-100 people. Monsanto purchased the plant in 1917 to insure a supply of mineral acids. The plant was referred to as "Plant B" until 1951, when it was renamed the William G. Krummrich Plant in honor of a former plant manager. The Krummrich Plant currently occupies 329 acres and employs approximately 1100 people. The plant produces about 1 billion tons of material per year. The plant is administered by two of Monsanto's four operating companies: Monsanto Industrial Chemicals and its guest company, Monsanto Polymer Products. The Krummrich Plant is organized by the International Chemical Workers Union, Local 12. The plant is located in Sauget, Illinois, which is 3 miles southeast of downtown St. Louis. Fifteen percent of the plant's total resources in manpower, time, and money are devoted to its environmental monitoring and control program. The plant employs 2 part-time physicians and several nurses in addition to a large staff of industrial hygiene, safety, and environmental personnel. Monsanto's Corporate Medical Program provides oversight and support of the plant program, including computerization of employee exposure and medical surveillance data. DSW 476038.0482 STLCOPCB4042646 2 2.2 Products The Krummrich plant currently uses more than 75 different raw materials to produce approximately 20 different intermediate chemical products. The major raw materials include chlorine, phosphorus, benzene, sulfur, and salt. Major products include chlorinated benzenes, chlorophenols, orthonitrophenol, nitroanilines, PCl^, POCl^, ?2S5* chlorine, sulfuric acid, chlorosulfonic acid, muriatic acid, chlorine bleaches and stabilizers, detergent materials, feed grade antioxidants, and elastomers. The manufacture of chlorophenols began in 1938. Production of pentachlorophenol was discontinued in 1978; the production of mono- and di-chlorophenols was discontinued in 1983. Esters of 2,4-D and 2,4,5-T were produced between 1960 and 1970. This plant was a producer of PCBs until 1977 when production was discontinued. 2.3 Previous Studies of the Plant Population 2.3.1 Tillman, 1977 In 1977 Dr. Ernest Tillman reviewed the plant medical records of 60 employees in the Pentachlorophenol Unit at the W. G. Krummrich Plant. The study group included all persons who were working in Department 236 in 1977 and all persons who had worked in Department 236 for 1 year or more since 1951. The lengths of exposure ranged from 3 months to 13 years. Forty-eight percent of the cases studied developed chloracne at some time while assigned to Department 236. In the majority of cases of active employees, chloracne appeared within 1 year of being assigned to Department 236. No difference in the frequency of occurrence was found on the basis of race or age. Chloracne occurred at all times between 1959 and 1977 with SW 476038.0483 ! STLCOPCB4042647 3 no peak at any particular time. Seventy-seven percent of the study group made repeated comments about weight variations from one periodic examination to the next. The review of the periodic health questionnaires and physical examinations failed to identify any other abnormalities. 2.3.2 Suskind, 1980 In 1979 Dr. Raymond Suskind conducted a medical survey to determine the health status of employees of the W. G. Krummrich Plant who had been . exposed to chlorinated phenols. The study population included active employees who had worked in either Department 236 (pentachlorophenol) or Department 237 (chlorophenols). The total number of active employees who worked in these two areas was 157. One hundred fifteen persons volunteered for examination and 106 of these completed the physical examination. The medical survey included the completion of an administered questionnaire, a medical history, a dermatologic examination, and examination of other organ systems if indicated by the clinical history. Skin biopsies were done when indicated. Clinical laboratory tests included: blood Ca, P, BUN, creatinine, BUN-creatinine ratio, uric acid, fasting blood sugar, total protein, albumin, globulin, total bilirubin, direct bilirubin, SGOT, SGPT, alkaline phosphatase, LDH, cholesterol, iron, magnesium, sodium, potassium, chloride, GGT, triglycerides and lipoprotein profiles; CBC and differential; urinalysis and urinary copro porphyrin, uroporphyrins, and creatinine. Personal medical histories were comfirmed by reviewing plant medical and personnel records. Sixty-six of 115 workers had a history of chloracne. Forty-three were found to have residual chloracne and of these cases 67.6% were mild and 32.5% DSW 476038.0484 i STLCOPCB4042648 moderate. All of the residual cases were comedonal In type, and 32.5Z of those had cystic lesions as well. Five of 106 persons were found to have malar hirsutism and 12 were found to have actinic elastosis. In the analysis of laboratory data, test results were compared between employees with and without a history of chloracne or residual chloracne. While a small number of elevated total serum lipids were observed, there was no correlation between the serum lipids and the presence of chloracne. While persons with elevated triglycerides were found in both groups, there was no correlation between serum triglycerides and presence or absence of chloracne. No significant differences in levels of cholesterol, LDL, SGOT, SGPT, and GGT were found between the chloracne and non-acne groups. Urinary porphyrins could not be interpreted due to technical error. The frequency of abnormal levels of VLDL was significantly increased in those persons with a history of chloracne or with residual chloracne as compared to those who never had chloracne. There appeared to be less residual chloracne in the group with HDL levels of 45 or more than those in the group with levels less than 45. There was also significantly less chloracne found in workers who did not smoke at the time of examination than those who did smoke. 2.3.3 Zack, 1980 In 1977, The Chemical Manufacturers Association contracted with Tabershaw Occupational Medicine Associates to conduct an industry-wide epidemiologic study of workers exposed to benzene. The W.G. Krummrich Plant was one of the nine plants chosen to participate in this study. Judith Zack conducted a separate Standardized Mortality Ratio analysis of the data from ! DSW 476038.0485 i STLCOPCB4042649 5 che Krummrich population. Her study cohort consisted of all male, hourly employees active on or after January 1, 1946 with six months or more of employment prior to December 31, 1977. Vital status was ascertained as of December 31, 1977. The population of the United States was used as the standard. Three thousand twenty-two employees fit the cohort entrance criteria, 'but 114 were excluded because of incomplete data. Two thousand seventy-two of the 2908 member study cohort were verified as living, 736 were identified as deceased, 702 of these by death certificate. The SMR's for white and non-white employees for specific causes of death are shown in Tables 1 and 2. There were no statistically significant elevations in SMR's observed among male Krummrich employees for any of the cause-of-death categories examined. Re-analysis of this data by work area is currently being done by Monsanto epidemiologists. Past employees of Department 236 and Department 268 (agricultural esters) have been included in NIOSH's industry-wide mortality study of workers exposed to dioxin. DSW 476038.0486 STLCOPCB4042650 Table 1 Observed and Expected Deaths for Krummrich Plant Study Population Non-white Males Cause of Death 8th Rev. ICD Code All causes of death : 001-998 All malignant neoplasms 140-209 Buccal cavity and pharynx 140-149 Observed 225 42 1 Expected 256.87 44.54 1.54 SMR 88* 94 65 Digestive organs and peritoneum 150-159 9 15.34 59* Respiratory system 160-163 17 13.20 129 Genitourinary organs 185-189 6 6.88 87 Lymphatic and hematopoietic tissue 200-209 Leukemia and aleukemia 204-207 6 3.02 199 2 1.09 183 Other lymphopoietic cancer - 4 1.93 207 Other malignant neoplasms - 3 4.56 66 Circulatory diseases 390-458 117 123.01 95 Arteriosclerotic heart disease 410-413 62 58.34 106 Cerebrovascular disease 430-438 25 28.01 89 Other circulatory diseases - 30 36.66 82 Respiratory diseases 460-519 4 14.90 27* All other diseases - 19 47.79 40* All external causes of death 800-998 31 25.47 122 Total Residual 12 1.16 * p <.05 Number persons observed * 584 Number person-years observed = 12925.1 DSW 476038.0487 STLCOPCB4042651 Table 2 Observed and Expected Deaths for Krummrich Plant Study Population-White Males Cause of Death 8th Rev. ICD Code Observed Expected SM^ All causes of death 001-998 All malignant neoplasms 140-209 Buccal cavity and pharynx 140-149 Digestive organs and peritoneum 150-159 Respiratory system 160-163 Genitourinary organs 185-189 Lymphatic and hematopoietic tissue 200-209 Leukemia and aleukemia 204-207 Other lymphopoietic cancer _ Other malignant neoplasms - Circulatory diseases 390-458 Arteriosclerotic heart disease 410-413 Cerebrovascular disease 430-438 Other circulatory diseases - Respiratory diseases 460-519 All other diseases - 511 98 2 17 46 6 7 2 5 20 273 201 30 42 20 41 522.43 101.76 3.54 28.45 34.76 11.01 10.58 4.14 6.44 13.42 261.06 188.14 30.60 42.32 27.90 69.49 93 96 56 60* 132 54* 66 48* 78 149 105 107 98 99 72 59* All external causes of death Total Residual 800-998 57 59.62 96 22 2/60 p^.os Number persons observed = 2324 number person-years observed = 54509.1 DSW 476038.0488 /I I STLCOPCB4042652 8 3. LITERATURE REVIEW 3.1 Overview The health effects of 2,3,7,8-TCDD, 2,4,-D, and 2,4,5-T have been studied extensively in recent years and are the subjects of several excellent reviews (Kimbrough, 1980; Esposito et al, 1980; Huff et al, 1980; HALTS, 1980; JRB, 1981; Clement, 1984). The occupational morbidity studies done to date suffer from inadequate characterization of exposure and lack of adequate controls. The occupational mortality studies are limited by small numbers. Very few studies have followed affected workers over time. Little is known about the health effects of exposure to PCDDs other than 2,3,7,8-TCDD. The only human data on the health effects of exposure to PCDFs comes from the outbreaks of Yusho disease in Japan and Taiwan in the past two decades (Kuratsune et al, 1972). These observations are confounded, however, by the co-ingestion of PCBs and chlorinated quaterphenyls. Acute poisoning from pentachlorophenol has been well described. Studies of chronic effects, however, have been limited to small numbers of active workers. There is very little animal data and no human data on the toxicities of the mono- and dichlorophenols. The structures of the chemicals discussed in this review are shown in Figure 1. A description of the actual manufacturing- processes and re sulting exposures is provided in Sections 4.2.1 and 4.2.2. 3.2 Ortho Chlorophenol Ortho chlorophenol (0-CP) is a light amber liquid used as an intermediate in chemical synthesis. 0-CP is prepared by the direct chlorination of phenol. It is soluble in water (2.85/100 parts water), alcohol, and ether; its vapor DSW 476038.0489 STLCOPCB4042653 9 Fig.I CHEMICAL STRUCTURES OF CHLOROPHENOLS, CHLORPHENOXY ACIDS, AND THEIR DIOXIN AND DIBENZOFURAN CONTAMINANTS OH OH OH Cl o-CHLOROPHENOL p-CHLOROPHENOL OH Cl Cl PENTACHLOROPHENOL 2,4-D 2,4-DICHLOROPHENOL 2,4,5-T DSW 476038.0490 i i STLCOPCB4042654 10 pressure is 1 mm at 12.1 C. . The oral LD^q. of, O-CP is 670 mg/kg in rats (NIOSH, 1983) and 625-750 mg/kg in chickens (Bubnov et al, 1971). Toxic effects in rats include restlessness, increased respiratory rate, tremors, and clonic convulsions. Pathologic changes in chickens include inflammatory loci in the cerebral cortex and dystrophic changes in the liver and myocardium. O-CP decreased hemoglobin content; increased alkaline phosphatase, LDH, and glutamate-oxaloacetate; and produced pathologically evident liver tissue degeneration in rats (Chung, 1978). O-CP did not affect the immune system in rats at oral concentrations of 500 ppm (Exxon and Koller, 1983). 0-CP is fetotoxic in rats and high doses (Exxon and Koller, 1982). 3.3 Parachlorophenol Parachlorophenol (P-CP) is a white to straw-colored crystalline compound prepared by the direct chlorination of phenol. Solutions of P-CP are used as topical antiseptics. P-CP is soluble in water (2.71/100 parts water) and very soluble in alcohol and ether. The oral LD^q of P-CP is 261 mg/kg in the rat (NIOSH, 1983). Toxic effects include restlessness, increased respiratory rate, tremors, and convulsions. P-CP is irritating to rabbit eye and skin. 3.4 2,4-Dichlorophenol 2,4-Dichlorophenol (2,4-DCP) is a colorless crystalline compound prepared by the direct chlorination of phenol. 2,4-DCP is used as an intermediate in the synthesis of 2,4-Dichlorophenoxy acetic acid. It is sparingly soluble in water. (.45/100 parts water), and very soluble in alcohol and ether. DSW 476038.0491 I STLCOPCB4042655 11 Somani et al (1981) studied the kinetics of 2,4-DCP in rats. 2,4-DCP was conjugated to glucuronide and other conjugates. The kidney had the highest amounts- of free compound, followed by the liver and fat. The LD^q of 2,4-DCP is 580-4,500 mg/kg in rats and 1,630 mg/kg in mice (Kobayashi et al, 1972). Toxic effects in rodents include decreased spontaneous locomotor activity, loss of righting reflex, and sedation. The maximum chronic no-effect level in mice is 100 mg/kg/day (Kobayashi, 1972). 2,4-DCP in doses of .1 mg/kg is fetotoxic in rats (Konstantinova et al, 1976). 3.5 Pentachlorophenol Pentachlorophenol (PCP) is the second most heavily used pesticide in the U.S. Its major application is wood preservation. PCP is a dark-colored crystalline compound which is produced in the U.S. by the direct liquid phase chlorination of phenol (Boehringer process). PCP produced by the Boehringer process may contain 4-12% tetrachlorophenol, 1-5% hydroxychloro-diphenyl ether, 0.1% trichlorophenol, and trace amounts of PCDDs and PCDFs. Very little is known about the toxicity of hydroxychlorodiphenyl ethers. One of these pre-dioxins, 2-hydroxy-2,4,4-trichlorodiphenyl ether, has a low acute toxicity in rats, with an LD^q of about 5000 mg/kg (Williams, 1982). The sodium salt of PCP is produced by reacting pentachlorophenol with sodium hydroxide. While PCP and its sodium salt vary in their solubilities in different solvents, their toxicities are basically the same. PCP and its sodium salt are usually used as 1-5% solutions in organic solvents (PCP) or water (Na PCP). The main routes of occupational exposure to PCP are inhalation and skin contact. Skin absorption is facilitated by the presence of organic solvents or by cuts and abrasions of the skin. PCP is bound to plasma proteins. Repeated DSW 476038.0492 i STLCOPCB4042656 12 workday exposures to the TLV of 0.5 mg/m^ results in a maximum steady state plasma concentration of 0.5 ppm (Wood, 1983). PCP is eliminated from the plasma via distribution to the tissues, metabolism via glucuronidation and oxidation to tetrachloro-p-hydroquinone, and excretion of PCP and its metabolites in the urine and, to a lesser extent, the feces. PCP may undergo enterohepatic circulation. Elimination follows a first order, single compartment model with a half life of 30.2+4 hours in healthy human volunteers. (Braun, 1979). Elimination half lives in workers may be longer. Technical-grade PCP is irritating to the skin and mucous membranes of the eyes and upper respiratory tract. Skin irritation occurs with frequent contact to PCP solutions of 1% or stronger. Eye and respiratory tract irritation occur at PCP air levels greater than 1.0 mg/m^. Skin contact with technical-grade PCP can produce chloracne, though this is most likely due to the HCDD (and perhaps other PCDD/PCDF) contaminants. PCP produces its systemic toxicity by interfering with electron transport in mitochondria. The resulting uncoupling of oxidative phosphorylation results in an increase in metabolic heat production and hyperpyrexia. The acute oral LD^q of PCP is 40-130 mg/kg in rabbits and 27-78 mg/kg in rats. PC? contaminated with HCDD, HeCDD, and 0CDD has produced hepatic effects in rats, including hepatic porphyria and increases in aryl hydrocarbon hydroxylase (AHH) and glucuronyl transferase (GGT) activity (Goldstein, 1977). Pure PCP was not porphyrogenic and produced only a slight effect on GGT activity. Technical PCP has also produced hepatocellular degeneration and necrosis in rats (Kimbrough and Linder, 1978). PCP has not been shown to be carcinogenic in DSW 476038.0493 I I STLCOPCB4042657 13 animals. PCP with its HCDD contaminant, however, may be fetotoxic and teratogenic (Cirelli, 1978). There are numerous case reports of acute PCP poisoning resulting from occupational exposures (Truhaut et al, 1952; Menon, 1958; Wood et al, 1983). Symptoms include hyperpyrexia, diaphoresis, tachycardia, tachypnea, weakness, nausea, vomiting, abdominal pain, anorexia, thirst, pain in the extremities, progressive coma, and death. Acute PCP poisoning may present with hepatic and renal dysfunction and metabolic acidosis with an increased anion gap. Skin absorption appeared to be the primary route of exposure in many of these cases. Sporadic cases of aplastic anemia, leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma of the skin have been reported among PCP workers, but the association with PCP exposure is not conclusive (Roberts, 1983). Chronic occupational exposure to PCP has been associated with an increased prevalence of conjunctivitis, chronic sinusitis, bronchitis, polyneuritis, and dermatitis (Baader and Bauer, 1951; Klemmer et al, 1980). Chloracne has occurred in PCP workers, but is most likely due to the PCDD and PCDF contaminants. Treibig et al (1981) found a significant decrease in sensory nerve conduction velocities in PCP production workers, but they could not demonstrate a dose response relationship. Zober et al (1981) found elevated GLDH-activities in workers producing and applying PCP. Begley et al (1977) demonstrated a significant improvement in creatinine clearance and phosphorus reabsorption in PCP wood treatment workers following a 20-day vacation. Bauchinger et al (1982) analyzed the chromosomes from peripheral lymphocytes from PCP production workers. They found a small, but significant, increase in the frequency of dicentrics and acentrics, but no significant increase of sister-chromatid exchanges. DSW 476038.0494 i STLCOPCB4042658 14 3.6 2.4 Dichlorophenoxyacetic Acid 2.4- Dichlorophenoxyacetic acid (2,4-D) is a widely used post-emergent herbicide. 2,4-D is a white powder produced by reacting 2,4-dichlorophenol with chloroacetic acid in a solvent mixture of water and sodium hydroxide. The esters are produced by reacting 2,4-D with the appropriate alcohol. 2,4-D may be contaminated with Di-CDD, Tri-CDD, and 1,3,6,8-TCDD as well as with a variety of derivatives of phenoxyacetic acid and phenol, such as Bis (2,4-dichlorophenoxy) methane. Bis (2,5-Dichlorophenoxy) methane and 2,2,4,6- tetrachlorodiphenoxy methane. Most commercial 2,4-D preparations contain the ester or the salt rather than the free acid due to their better solubility characteristics. Alcohols are often used as solvents in 2,4-D formulations. The concentration of 2,4-D in commercial preparations is highly variable and may range from 1-80% (Halts, 1980). 2.4- D is rapidly absorbed from the gastrointestinal tract in healthy male volunteers with peak plasma levels occurring in 4-24 hours. The volume of distribution is .28-.29 1/kg. Elimination is first order with a plasma half life of 7-33 hours. 2,4-D is excreted in the urine as the free acid, though a small percent may appear in the urine as conjugates. (Kohli et al, 1974; Sauerhoff et al, 1977). Since 2,4 D is a weak organic acid, urinary excretion is pH dependent. Prescott (1979) increased renal clearance of 2,4-D in a case of accidental ingestion by alkalinizing the urine. Feldman and Maichbach (1974) found that 5% of 2,4-D applied to the forearm was absorbed and excreted. 2.4-D's mechanism of toxic action has not been well established. 2,4-D may produce its neuromuscular effects by interfering with organic acid anion transport in neuromuscular tissues. (Podolak, 1981 a,b; Kim, 1981). 2,4-D has also been shown to induce mixed function oxidases in animals (Rivieri and Bach, 1981). DSW 476038.0495 STLCOPCB4042659 15 The LD50 of 2,4-D in animals ranges from 100 mg/kg to a few thousand mg/kg depending on the form of 2,4-D and the species tested (IARC, 1977). Toxic effects are apparent after a latent period of 2-9 days and include loss of appetite, weight loss, myotonia, and muscle weakness progressing to paralysis, coma, and death. Pathological changes have been described in the gastrointestinal tract, liver, lungs, and kidneys. The free acid appears to be more toxic than the esters, and equal in toxicity to the sodium salt ( HALTS, 1980). 2,4-D increased the frequency of tumors in rats (Hansen et al, 1971; but most other studies have not shown a carcinogenic effect in animals. 2,4-D is fetotoxic in high doses and may be a weak teratogen. Duffard et al (1981) demonstrated reduced hatchability and an increased frequency of malformations in chick eggs painted with 2,4-D. In a second study, painting eggs with 2,4-D resulted in postnatal alterations in the chemical composition of chick brain (Duffard et al, 1982) The LD50 of 2,4-D in man is estimated at 80-800 mg/kg. Autopsy findings from two fatal human ingestions showed acute demyelination in the brain (patient with senile dementia), peripheral neuropathy, degenerative changes in the ganglion cells, hepatic necrosis, and congestion of most organs (Nielsen et al, 1965; Dudley and Thapar, 1972). Seven cases of peripheral neuropathy following dermal exposure to 2,4-D have been reported in the literature (Goldstein et al, 1959; Todd, 1962; Berkeley and Magee, 1963; Wallis et al, 1970; Halts, 1980). Signs and symptoms of a symmetric, "dying back," sensorimotor neuropathy began within 1-2 weeks after exposure. While nerve conduction times were at or slightly below the lower limit of normal, electromyography revealed denervation phenomena in the most severely affected patients. Recovery was slow w'ith some residual deficits. DSW 476038.0496 STLCOPCB4042660 16 Epidemiologic studies of occupational exposure to the phenoxy herbicides are discussed under the section on PCDDs and PCDFs. 3.7 2,4,5-Trichlophenoxyacetic Acid 2.4.5- Trichlorophenoxyacetic Acid (2,4,5-T) was widely used as a post- emergent herbicide for controlling woody plant growth until 1979, when many of its uses were curtailed by the US EPA. 2,4,5-T is a light tan solid produced by reacting 2,4,5-Trichlorophenol with chloroacetic acid under alkaline conditions. The esters are produced by reacting 2,4,5-T with the appropriate alcohol. 2,4,5-T may be contaminated with 2,3,7,8-TCDD, HCDD, and perhaps some PCDFs. Most commercial preparations contain the ester or.amine salt. The amine salts are soluble in water while the esters are emulsifiable in water and soluble in most oils. 2.4.5- T is rapidly absorbed from the gastrointestinal tract in healthy male volunteers (Matsumura, 1970; Gehring et al, 1973; Kohli et al, 1974). Rates of skin absorption vary from 0.22-1.13 mg/sq ft/hr for spray concentrations of 2-32 lb 2,4,5-T/100 gal (GRB, 1981). Elimination is first order with a plasma half life of 19-23 hours. Metabolites have been detected in animals but not in humans. 2,4,5-T propylene glycol butyl ether ester is rapidly hydrolyzed to the free acid in rats (Young et al, 1981). The LDjq of 2,4,5-T and its derivatives ranges from 100 to 940 mg/kg in various species (JRB, 1981). The free acid appears to be more toxic than the salts or esters. Acute toxic effects in animals include anorexia, vomiting, diarrhea, locomotive disturbances, and depression. Histopathologic changes are nonspecific. The mechanism of toxic action of 2,4,5-T is unknown. 2,4,5-T with less than 1 ppm TCDD produced cleft palate and growth DSW 476038.0497 i STLCOPCB4042661 17 retardation in mice (Roll, 1971; Hood et al, 1979). 2,4,5-T increased the incidence of tumors in C3Hf mice (Muranyi-Kovacs et al, 1976). Tumor incidence was not increased, however, in other strains of mice or in other animal species. The health effects observed in humans after chronic exposure to 2,4,5-T are usually ascribed to Che 2,3,7,8-TCDD contaminant. There are no reported cases of acute poisoning with pure 2,4,5-T in humans. 3.8 Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzofurans (PCDFs) -~ PCDDs and PCDFs are two series of tricyclic aromatic compounds which are inadvertantly formed during the synthesis of chlorinated phenols and their derivatives. The dibenzo-p-dioxin and dibenzofuran nuclei can hold from one to eight chlorine atoms. The numbers of possible positional PCDD and PCDF isomers are given in Table 3. Each 0f the 75 PCDD and 135 PCDF isomers may have different chemical, physical, and toxicological properties. As a general trend in both series, solubility in most solvents and volatility decrease with an increasing number of chlorine atoms. Levels of PCDDs and PCDFs reported in mono-, di-, and pentachlorophenols are shown in Table 4. PCDDs do not appear to be common contaminants of mono- and di-chlorophenols. The levels of PCDFs in these compounds are unknown. Hexa, hepta, and octa-dibenzo-p-dioxins and dibenzofurans have been repeatedly detected in PCP. The tetra- and penta-dibenzofuran congeners have been detected in numerous samples of 2,4,5-T. 2,4-D is frequently contaminated with DCDD, tri-CDD, and 1,3,6,8-TCDD.(Table 5). The various PCDD and PCDF isomers vary considerably in toxic potential. The LD5QS range from 0.6--2.0 mcg/kg for 2,3,7,8-TCDD in guinea pigs to over DSW 476038.0498 STLCOPCB4042662 18 TABLE 3. POSSIBLE NUMBER OF POSITIONAL ISOMERS OF PCDDs AND PCDFs. Chlorine Substitution ' Number of Isomers PCDDs PCDFs monoditri- 24 10 16 14 28 tetra- 22 38 penta- 14 28 hexa- 10 16 hepta- 24 oc'ta- 11 75 135 DSW 476038.0499 STLCOPCB4042663 TABLE 4. Chlorophenol Monochlorophenol o-chlorophenol o-chlorophenol PCDDs find PCDFs Reported in o--chlorophenol, 2,It-Dichlorophenol and Pentnchlorophenol monoCDD DCDD triCDD PCDDs, ppma TCDD pentaCDD hexaCDD heptaCDD OCDD ND ND _ _ __ ND ND ND __ 0.037 (2,3,7,8)b ,, ND ND ND __ Dichlorophenol 2,4-dichlorophenol ND Pentachlorophenol PCP (Dowcide 7) PCP -- Na-PCP (1967) ND Na-PCP (1969) PCP (1970) PCP (1970) PCP (1967) PCP (1969) PCP (1970) PCP (1970) PCP (1978) ND ND ND ND ND ND ND .-- Pentachlorphenate -- PCP formulation __ PCP (technical grade) -- PCP (reagent grade) PCP (many samples pcr's (17) -- -- -- ND -- ND ND ND ND ND ND ND ND -- -- __ -- -- -- -- ND ND ND ND ND ND 9 235 250 -- ND (0.5) -- 10-100 100-1000 100-1000 ND ND ND 14 14.5 3.8 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND -- ND(O.l) -- 20 39 35 0.17 13 0.19 15 19 11.3 49 23 ND 47 2.1 23 140 3.3 15 ND ND ND 5.3 15 432 __ --- . -- -- + 4- __ __ __ -- -- 870 50-3300 -- ND -- 33-42 19-24 7-11 -- ND -- 0.02-0.03 0.04-0.09 0.02-0.03 -- ND -- 9-27 90-135 575-2510 __ __ __ 0-23 __ 0-3600 Data Source , r"> Omo ocdo g ^ Firestone et al, 1972 W Esposito et ax, 1972 Firestone et al, 1972 Buser, 1975 Woolson et al, 1972 Firestone et al, 1972 fl If fl If If If USEPA, 1978 Jensen and Renberg,1972 II Villanueva et II If If (cont inue to to CM o OQ O Q. O O _l </> DSW 476038J Table 4 (cont.) PCP or PCP-Na (7) mono CDF -- PCP (Dowcide 7 1970) -- PCP (Dowcide 7 1970) -- (distilled) PCP -- Na-PCP(Dowcide G 1978) -- DCDF -- -- -- -- -- Pentachlorophenol z> PCP (USA) u PCP (USA) PCP (USA) PCP (Germany) PCP -- -- -- -- -- -- -- -- triCDF -- -- -- -- -- -- -- -- -- PCDDs, ppma TCDFs -- -- -- -- -- o 1o0 pentaCDFs -- -- -- -- -- IlexsCDFs 0.03-10 4 1.0 9-27 ND-2 HeptaCDFs 0.06-180 OctaCDFs 5.5-370 125 2500 6.5 15 -- 1-12 575-2510 4-173 >! Data Source Buser and Bosshardt,1976 USEPA, 1978 If \ Johnson, 1973 ft PPDFs, ppm 0.9 -- _<0.4 -- 0.20 4 -- 40 -- 0.20 32 30 90 0.03 13 120 130 80 80 400 260 0.8 1.3 70 55 Rappe, 1978 USEPA, 1978 Goldstein, 1977 Rappe, 1981 Buser and Bosshardt, 1976 g Key to abbreviations and symbols: ND = Not detected (minimum detection level, ppm). Other numbers in parentheses indicate year chlorophenol sample was obtained, or specific dioxin detected. -- = Not analyzed or not reported. ^Presence of 2,3,7,8-TCDD confirmed but not quantitatively reported. TABLE 5. PCDDs IN 2,4,5-T AND 2,4-D Pesticide Sample 2,4,5-T (1973) 2,4,5-T Acid (1952) 2,4,5-T Ester 2,4,5-T Ester 2,4,5-T Ester (1960) 2,4,5-T Ester (1962) 2,4,5-T Ester (1966) 2,4,5-T Ester (1967) 2,4,5-T Ester (1967) 2,4,5-T Ester (1967) 2,4,5-T Acid (1964) 2,4,5-T Acid (1969) Herbicide Orange Herbicide Orange Herbicide Orange 2,4-D Ester (1980) 2,4,-D Ester (198Q) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) MonoCDD a -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- DCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2.72 4.20 0.10 1.24 0.11 0.10 -- TriCDD -- -- -- -- -- -- -- -- -- -- -- -- '-- -- -- 0.35 2.08 1.63 0.64 1.82 0.93 0.68 -- TCDD 10.0 i.iob PCDDs ppm PentaCDD -- -- 0.50 0.05 0.40 0.95 0.10 0.05 0.22 0.18 4.8 6.0 0.12 1.1 5.1 0. 23c -- -- -- -- -- -- -- -- -- -- -- -- -- -- 0.72 1.75 0. 32 0.85 0.49 0.32 __ <-- -- -- -- -- -- __ HexaCDD 10.0 -- -- -- -- -- -- -- -- -- -- -- -------: -- -- -- -- -- -- -- -- -- __ HeptaCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- OCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- ' -- -- Data Source Fishbein, 197 Rappe and Buser, 1980 It t ft II It II II If II It II II It II Cochrane et al, 1982 II II II -- -- It __ II STLCOPCB4042667 TABLE 5 (cont.) PCDDs in 2,4,5-T and 2,4-D Pesticide Sample 2,4,-D Ester (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D (1972) MonoCDD -- -- -- -- -- -- -- -- DCDD 0.20 -- -- 0.005 -- 0.033 -- -- TriCDD 0.16 0.038 0.58 0.054 -- 0.53 -- -- TCDD PCDDs ppm PentaCDD 0.21 -- 0.054 0.28 0.02 -- 0.21 -- -- -- -- -- -- -- -- -- llexaCDD -- -- -- -- -- -- -- -- 0.5-10 HeptaCDD -- -- -- -- -- -- -- -- " OCDD -- -- -- -- -- -- -- -- Data ' Source Cochrane et al, 1982 n i it it it it if ii Woolson et al, 1972 Co1O0 00 Co<NO0- 5 </> o Not detected, not tested, or not reported. ^Levels of TCDD in this and subsequent 2,4,5-T formulations are of the 2,3,7,8 isomer. cLevels of TCDD in this and subsequent 2,4-D formulations are of the 1,3,6,8 isomer. 23 4.0 x 106 mcg/kg for OCDD in mice. (Esposito et al, 1980). The LD5q for 2,3,7,8-TCDF in guinea pigs is 2 to 4-fold higher than that reported for 2,3,7,8-TCDD (More et al, 1979). Chemical structural requirements for toxicity in both series appear to be chlorine substitutions at positions 2,3, and 7 with at least one hydrogen remaining on the nucleus. The mechanism of toxic action of PCOOs and PCDFs is still unknown. A cytosol receptor has been identified in mouse and rat liver which binds certain PCDDs and corresponds to their potency to induce aryl hydrocarbon hydroxylase activity (Huff et al, 1980). The ability of these compounds to induce aryl hydrocarbon hydroxylase correlates with their toxicity in animal studies. Iron deficiency protects mice from some of the toxic effects of 2,3,7,8-TCDD, but the mechanism of this interaction is unclear (Jones and Sweeney, 1982). The toxicokinetics of 2,3,7,8-TCDD have been studied in several species including rats, guinea pigs, and monkeys (Piper at al, 1973; Rose et al, 1976; Nolan et al, 1979; Gasiewicz and Neal, 1978; Van Miller, et al, 1976). 2,3,7,8-TCDD is moderately well absorbed from the gastrointestinal tract in most species. There are significant differences in the tissue distribution of this compound among various animal species. Following a single administration of 14 C-2,3,7,8-TCDD, the largest percentage of the dose appears in the liver in rats and in the adipose tissue in guinea pigs and monkeys. Materials other than 2,3,7,8-TCDD constitute a significant fraction of the 14 C activity in the feces, but no metabolites have yet been identified. After repeated oral dosing in the rat, a fraction of the 14 C acivity may also appear in the urine. The excretion of a single oral dose of 14 C-2,3,7,8-TCDD-in rats follows a onecompartment, open model with a half life of 31 days. DSW 476038.0504 I STLCOPCB4042668 24 The toxicokinetics of other PCDDs can differ considerably from those of 2,3.7,8-TCDD. Norback (1975) studied the toxicokinetics of OCDD in the rat following chronic oral dosing: OCDD concentrated in rat liver and was excreted mainly by the urinary system with a half-life of about 3 weeks. Tulp and Hutzinger (1978) studied the rat metabolism of a series of PCDDs. They demonstrated that some PCDDs can be metabolized by hydroxylation at the lateral (2,3,7 and/or 8) positions in the molecule. When these positions are blocked by chlorine atoms, metabolism via epoxide formation is much less likely to occur. Decad et al (1982) studied the toxicokinetics of 2,3,7,8-TCDF in guinea pigs, rats, and monkeys. Gastrointestinal absorption of 2,3,7,8-TCDF was nearly complete in rats and guinea pigs. The liver was the major initial depot for 2,3,7,8-TCDF in all three species with lesser amounts in adipose tissue, skin, and muscle. Rats, and to a lesser extent, monkeys were able to metabolize 2,3,7,8-TCDF whereas guinea pigs could not. The whole body half-life of TCDF in guinea pigs, monkeys, and rats was 20, 8, and 2 days respectively. The metabolism of PCDF isomers in man may depend on the positions of the chlorine atoms on the dibenzofuran nucleus. Rappe analyzed liver samples for PCDFs from two patients with Yusho disease and compared the distribution of the isomers to that found in the ingested rice oil (Rappe et al, 1981). He found that the PCDF isomers which had apparently been excreted had two vicinal hydrogenated carbon atoms in at least one of the two rings; these unblocked positions are presumably involved in the metabolism by forming epoxides. DSW 476038.0505 STLCOPCB4042669 The toxic effects produced by PCDDs and PCDFs vary quantitatively and qualitatively among different species. Within a given species, the effects produced by the toxic PCDD and PCDF isomers are similar to those of 2,3,7,8TCDD, differing mainly in the intensity of toxic effect. In all laboratory animals the lethal effect is slow and ensues days or weeks after a single dose. The spectrum of acute toxic effects of 2,3,7,8-TCDD in mice, guinea pigs, and monkeys is presented in Table 6. The most striking finding in most species is substantial loss of body fat. Involution of the thymus and testicular alterations have been observed in all species studied. Bio chemical effects of 2,3,7,8-TCDO include induction and/or suppression of various enzyme systems, changes in porphyrin metabolism, and alteration of lipid pro files. 2,3,7,8-TCDD and HCDD have produced chloracne in animals. Rats fed TCDD were found to have decreased thyroxine, free thyroxine index, glucose, and insulin levels in the serum (Potter et al, 1983). Doses of 2,3,7,8-TCDD which do not produce overt clinical or pathological changes may still be capable of causing immunosuppression. (Thigpen et al, 1975). Moore et al (1979) studied the toxicity of TCDF in mice, guinea pigs, and monkeys. The toxic effects in guinea pigs and monkeys were similar to those pro duced by 2,3,7,8-TCDD but required 2-20 fold higher doses of TCDF. Mice did not demonstrate clinical signs of toxicity at a dose of TCDF which was 23 fold higher than the TCDD LDjq^q. The interspecies variation in acute toxicity may be due to differences in detoxification metabolism (Decad et al, 1982). 2,3,7,8-TCDD increases the incidence of neoplasms in rats and mice. (Van Miller et al, 1977; Kociba et al, 1978; Toth et al, 1979). The data implicating 2,3,7,8-TCDD as a mutagen are conflicting, and it is unclear whether 2,3,7,8-TCDD acts as an initiator or a promotor. Carcinogenecity studies of other DSW 476038.0506 STLCOPCB4042670 Table 6. Summary of Acute Toxicity Effects of 2,3,7.8-TCDd Thymus involution Spleen reduction (white pulp) Bone-marrow hypoplasia Liver, megalocytosis/degeneration Bile-duct hyperplasia Testicular degeneration Renal-pelvis hyperplasia Urinary-bladder hyperplasia Adrenal-cortical atrophy (Zona Glomerulus) Hemmorhage: Intestinal Adrenal Acites Cutaneous lesions Mice__________ Guinea pigs +-H- +++ ++ + ++ -H-f - ++ ++ +++ - ++ - ' ++ - ++ ++ - ++ ++ - Monkeys (female) +++ + + - +++ N/A + - + +++ ^Source: Esposito, Tiernan, and Dryden, 1980 Key as follows: - no effect + mildly affected ++ moderately affected +++ severely affected DSW 476038.0507 STLCOPCB4042671 27 PCDDs are in progress. The carcinogenic potentials of PCDFs have not been studied. 2,3,7,8-TCDD is teratogenic in mice and hamsters. The threshold teratogenic dose in mice was estimated to be 0.1 meg per day (Smith et al, 1976). 2,3,7,8-TCDD has been shown to be fetotoxic in a wide variety of species, including primates. HCDD was teratogenic in rats at a dose of 100 meg/kg per day (IARC, 1977) There is as yet no data on the fetotoxic potentials of PCDFs in animals. The toxic effects of 2,3,7,8-TCDD in man are summarized in Table 7. The toxic effects most consistently observed in occupational studies are chloracne, liver dysfunction, neuropsychiatric disturbances, and abnormalities in porphyrin metabolism. Table 8 summarizes the findings of the morbidity studies of workers exposed to 2,3,7,8-TCDD to date. The few follow-up studies which have been done show resolution of gross liver dysfunction and porphyrin abnormalities following removal from exposure. (Pazderova-Vijlupkova et al, 1981; Suskind, 1984). Several of the occupational exposures occurred as the result of uncontrolled exothermic reactions during the production of trichlorophenol. A similar process accident at Seveso, Italy in 1976 resulted in widespread community exposure to 2,3,7,8-TCDD. Health effects included chloracne, primarily in children, and peripheral neuropathy in a small percent of those exposed (Pocchiari et al, 1979). ' The epidemiologic studies on the carcinogenecity of TCDD are summarized in Table 9. While individual occupational mortality studies reveal no excess of cancer, the pooled data suggest an excess of soft tissue sarcoma (Honchar and Halperin, 1981). _ DSW 476038.0508 STLCOPCB4042672 Table 7. Toxic Effects of 2.3,7,8-Tetrachlorodibenzo-p-dioxin in Man.a Effects_____________ __________________________________________ DERMATOLOGICAL Chloracne . Porphyria cutanea tarda Hyperpigmentation and hirsutism INTERNAL Liver damage^ Elevated serum hepatic enzyme levels Disorders of fat metabolism Disorders of carbohydrate . metabolism Cardiovascular disorders Urinary tract disorders Respiratory disorders Pancreatic disorders NEUROLOGICAL Polyneuropathies (perpheral neuritis) Lower extremity weakness Sensory Impairments (sight, hearing, smell, taste) PSYCHIATRIC Neurasthenic or depressive syndromes____________________ aSource: Huff, Moore, Saracci, and Tomatis, 1980 ^Mild fibrosis, fatty changes, hemofuscin deposition and parenchymal-cell degeneration were observed in a few cases. DSW 476038.0509 II l STLCOPCB4042673 TABLE 8. REPORTED OCCUPATIONAL EXPOSURES IN CHLORINATED PHENOLS RESULTING IN HUMAN ILLNESSa Year,Place,and chemical(s) Type of exposure and no. of cases 1936 Michigan Tetrachlorophenol 2-(2-chlorophenyl) phenol Production 21 Effects on the skin Chloracne, hyperkeratosis Neurological effects Effects on the liver and serum lipids Other effects Fatigue, weight loss 1936 Mississippi Tetrachlorophenol Wood treat ment 300-400 1949 West Virginia Trichlorophenol 2,4,5-T Explosion 117 Production 111 1949 Germany Trichlorophenol Tetrachlorophenol Pentachlorophenol Production, Ihdustrial Laboratory 17 Chloracne,facial erythema, vesiculation, ulceration, hyperkeratosis, hyperpigmentation Fatigue, colored urine, urinary problems, venous thrombosis Chloracne, facial erythema, hyper pigmentation, melanosis Nervousness, Hepatomegaly, ab irritability, normal liver Insomnia, function, toxic personality hepatitis, elevat- change,de- ed triglycerides pression, and cholesterol headache, vertigo, pain and weakness lower extrem- eties, paresis, peripheral neuro pathy, abnormal nerve biopsy (loss of myelin) Fatigue, weight loss, weakness, decreased libido, impotence, intol erance to cold, increased sus ceptibility to infection (es pecially respir atory) Chloracne, hyperpigment ation,. scarring Lower extremity Abnormal liver pain and weak function. ness, paresis cirrhosis without atrophy. paresthesia, polyneuritis Fatigue, severe bronchitis, de creased libido, impotence, bursi tis, myocardial damage References j Butler, 1937 Anonymous, 1936: Stingily 1940 Ashe and Suskind, 1949, 1950; Suskind, 1953; Suskind, 1977 Baader and Bauer, 1951 DSW 476038.0510 rI-D~- CM 1952 Germany Trichlorophenol Production 31 1953 Germany Tr Ichlorophenol Explosion 55 1956 France TrIchlorophenol L966 France TrIchlorophenol L956 New Jersey Trichlorophenol Production 17 Explosion 21 Production 29 1963 Holland TrIchlorophenol M,5-T Explosion 106 Chloracne, hyperpigmen tation Lower extremity Toxic hepatitis, pain and weak- abnormal liver ness,paresthesia, memory and con biopsy centration defi cits, sleep disturbances, hy persomnolence , abnormal psycho logical tests (apathy, dulled emotional response) Fatigue, chronic bronchitis, per sistent blepharoconj unctlvitis, myocardial dam age, intolerance to alcohol Suskind, 1977 'V i Chloracne Sensory impair- Toxic hepatitis ment of smell,taste, hearing; tendency to orthostatic collapse, limited paresis, peripheral neuropathy, reading difficulties Fatigue, drowsiness, bronchitis, laryn gitis, blepharo conjunctivitis, hemorrhagic pleuritis, myocardial damage, increased susceptibility to infect ion Goldman, 1973 Chloracne Peripheral neuropathy Toxic hepatitis, elevated tryglycerides and choles terol Dugois et al, 1956; Dugois et al, 1968 Chloracne, Clinical exam hyperpigmen ination normal tation, hy pertrichosis, acquired porphy ria cutanea tarda Chloracne, facial erythema No information Abnormal liver Right upper function, abnor- quadrant pain mal liver biopsies (parenchymal cell degeneration, fluorescence) Liver function normal Fatigue Bleiberg et al, 1964 Vos et al, 1977 STLCOPCB4042675 1966 USSR Tr ichlorophenol 2,6,5-T Production 128 1968 England TrIchlorophenol Explosion 79 1965-1968 Czechoslovakia Trichlorophenol Pentachlorophenol 2,-4,5,-T Production 80 1969 New Jersey Trichlorophenol 2,4,5-T 2,6-D 1978 England Trichlorophenol no longer in production Production 73 Followup of plant . studied by Bleiberg (above) Followup of 61 workers in 1968 explosion (above) 61 Chloracne Headache, loss of memory, somnolence, sleeplessness, increased sweating Fatigue, joint pain, stomach pain Telegina and Bikbulatovk, 1970 CT--M oin co eo ^ g (a/) Cloracne, facial erythema Abnormal liver function Transient glyco suria, mild con junctivitis May, 1973; Jensen and Walker, 1965; Jensen et al, 1972 _ Chloracne, hyperpigmenta tion, hyper trichosis , scarring, ac quired porphyria cutanea tarda Lower extremity Hepatomegaly, ab- Fatigue, weight weakness and normal liver func- loss, abnormal pain,somnolence, tion, abnormal blucose tolerance, headache, insom- liver biopsies no evidence of nia, emotional (mild steatosis, myocardial or and psychiatric periportal fibro- renal damage or disorders, peri- sis, fluorescence) . of increased eye pheral neuro- Elevated triglyc- inflammation or pathy (confirmed erides, phospho- respiratory in by abnormal EMG) lipids, and fection cholesterol Jiraskek et al, 1966; PazderovaVejlupkova et al, 1980; PazderovaVejlupkova et al, 1981 Chloracne in 68, hypertrichosis in 16, hyperpig mentation in 30, no overt por phyria cutanea tarda Lower extremity No significant weakness, corre- abnormalities lation between chloracne and hypomania scale on MMPI Eye irritation, mild uroporphyrinuria in one worker Poland et al, 1971 (see Bleiberg et al, 1966) Chloracne Elevated CCT, elevated tri glycerides, elevated urinary D-glucaric acid May, 1982 STLCOPCB4042676 1949 West Virginia Trichlorophenol 2,3,5-T 1949 West Virginia Trichlorophenol 2,4,5-T 228 Followup of plant studied by Ashe and Suskind (above) 204 Followup of plant studied by ABhe and Suskind and Moses et al (above) Chloracne 70-residual 47-by his tory Abnormal sensory findings in those with chloracne Chloracne in 107 Actinic Elastosis Elevated CGT In those with chloracne Decreased libido, sexual dysfunction Moses et al, 1984 History of GI ulcer Lower pulmonary function In exposed smokers Suskind and Hertzberg, 19&4 1978 Seveso Trichlorophenol No. not given 1CMESA workers follow-up five years after explosion Elevated Aik. Phos. Elevated urinary porphyrins Chezzi et al, 1984 a Source: Moses et a1, 1984 STLCOPCB4042678 Table 9 a Epidemiologic Studies on the Carcinogenicity of TCDD. Type and Place of Exposure Number of Cases Accidental, Monsanto, USA 228 Accidental, Boeliringer, RFG 24 Accidental, Basf, RFG 55 Accidental, Philips, Netherland 50 Accidental, Dow Chemical, USA 60 Accidental, Spolana, Czechoslovakiai 78 Accidental, Coalite, UK 79 Accidental, Chemie Werke, Linz, Austria 50 Herbicide Spraying, Sweden, Backsprayers 348 Herbicide Spraying, Finland, Backsprayers 1960 Herbicide Contamin ation, Sweden 72 Agent Orange Spraying USAF, VietNam 1242 TCDD Level of Exposure Unknown U nknown Unknown 10,000 ppb Unknown 24,200 ppb 400 ppb 140 ppb 0.00315 ppt 0.00315 ppt 0.0001 ppb 0.1 ppt 1.9 ppm Time Elapsed Since Exposure 30 years 28 years 27 years 17 years 16 years 15 years 12 years 7 years Over 10 years Over 10 years Over 10 years Over 13 years Frequency of Cancer Jleath No Excess No Excess Excess of Stomach Cancer No Excess No Excess No Excess No Excess Ref erence Zack, 1980 Krause, 1978 --------- TJ- oirr>toooooo (50 o Theiss, 1982 Vos, 1978 '' Cook, 1980 Jlrasek, 1978 May, 1980 Excess of Stomach Cancer No Excess No Lymphomas Excess of Lymphomas No Excess AxeIson, 1979 Rihmaiki, 1980 Hardell, 1979 Lathrop, 1983 a Source: Reggiani, 1980 34 A review of these cases revealed that several were not true soft tissue sarcomas; moreover, exposure in a few of the cases was minimal (Fingerhut et al, 1984). Swedish case-control studies of soft tissue sarcoma found an association with previous exposure to phenoxy acids or chlorophenols (Hardell et al, 1979; Eriksson et al, 1979) The Yusho cases provide our only data on the human toxicity of PCDFs. Yusho disease was caused by ingestion of rice oil accidentally contaminated with PCDFs, PCBs, and polychlorinated quarterphenyls; as such it is difficult to separate the effects of the various toxic principles. The clinical symptomatology of the Yusho cases is presented in Table 10. The Yusho oil was clearly fetotoxic. There is as yet no data on the carcinogenic potential of PCDFs in man. DSW 476038.0515 STLCOPCB4042679 35 Table 10. Clinical Symptomology of Yusho Cases, 1969-1972.a Effects . Percent Skin Acneform eruptions, distinctive hair follicles, red plaques on limbs, dark brown pigmentation of nail, skin and mucous membranes, itching, sweating of palms. Ocular manifestation Increased eye discharge, swelling of the upper eyelids, hyperemia of- con junctives, transient visual disturb ance. Jaunidce No abnormalities of liver functions in the majority of cases. Numbness of the limbs, feeling of weak ness, spasm of the muscles Reduced sensory and motor nerve conduc tion velocity in few cases Hearing difficulties Headaches, vomiting, diarrhea Chronic Bronchitis Lower serum Ig A and Ig M. sputum PCB in the Irregular menstrual cycles Dark brown skin pigmentation of newborn, which gradually faded away, retarded growth and abnormal teeth number and shape. ^Source: Reggiani, 1980 82-87% 83-88 10 32-39 9 18 17-39 40 60 DSW 476038.0516 STLCOPCB4042680 36 4. DESIGN 4.1 Study Design The design of this study combines elements of both cohort and cross sectional designs. Two historical cohorts, exposed and non-exposed, will be identified and followed to ascertain their current vital and employment status. The health status of surviving members of both cohorts will be assessed by an in-depth medical survey to determine prevalence of clinical and sub-clinical disease states. Previous incidence of disease will be ascertained by subjects' self-reporting and verified by medical record review. Differences in health outcomes between the two cohorts will be compared statistically, after adjusting for the effects of confounding variables. 4.2 Ascertainment of Exposure The departments where employees were most likely to be exposed to PCDDs include Departments 226 (Santobrite), 236 (Penta), 237 (chlorophenols) and Department 268 (agricultural esters). The locations of these departments within the plant are shown in Figure 2. 4.2.1 Processes Departments 236 (Penta) and 226 (Santobrite) The production of Pentachlorophenol (PCP) began at the Krummrich Plant in 1938. PCP was marketed in the flake form from 1939 to the late 1950's or early 1960's. At that time Penta (PCP)and Penta 60 (so called because it contained 60% PCP and 35% tetrachlorophenol) were offered in prilled form. From 1970, PCP was also offered in the 2000 lb. block form. The sodium salt of PCP (first called Santophen 20S and later Santobrite) was produced in powder, briquette, and 30% aqueous solution forms throughout its history. DSW 476038.0517 Il i STLCOPCB4042681 37 STLCOPCB4042682 T6oTf~ 38 Santophen 20 P.A. (a PCP/pine oil/alcohol mixture) was only offered for a few years. The production of Na PCP was discontinued in 1972. The production of PCP and Penta 6Q was discontinued in 1978. Over the years, the chemistry for the production of Penta and Santobrite remained essentially the same. The flow sheets for the process are shown in Figures 3 and 4. Department 236 was contained in a building which has since been dismantled. Phenol, or chlorophenol fractions from the production of o-, p-, or 2,4-dichlorophenol were progressively chlorinated with subsequent increases in reaction temperature until the appropriate crystallization point was reached (for Penta, 174-182 C; for Penta 60, 145 C). Iron powder was first used as the catalyst; later, it was replaced by aluminum. Santobrite was simply the neutralization of Penta with sodium hydroxide. Flaked Penta was produced by feeding molten Penta into a container from which it was picked up on the surface of a cold rotating drum. The material was flaked off the surface as the drum rotated against a stationary blade. The material was then mechanically conveyed to a packing area where it was bagged into cylindrical fiber backs or loaded into steel drums. Prilled Penta was produced by dispersing molten Penta into fine streams using a shower head type prill plate. The molten streams would solidify by cooling with ambient air. The cooling chamber was an 8' diameter x 40' high prill tower. The prilled material would be further cooled in a Roto-Louvre cooler and would then be conveyed in a bucket elevator to a storage hopper to await packaging. The prills were packed into fiber packs or drums using a pneumatic packer. The air used for cooling passed through a Venturi scrubber where it was scrubbed with a dilute caustic solution . DSW 476038.0519 STLCOPCB4042683 FIGURE 3 tMW ROT 'v' ztmxfWi. ore* <iA Mt30* r<vr* TAMC CAH. 1 refMtnlM>mf*rl LVV")J TO ft Ann fl n<r.|ioL *cnuo*i:M MCI AMO tnACC mr.tioUCJ PIV1 chtaaihcb LIQUID) CHLORINATION ANO ACID SCRUBBING DEPTHS FLOW SMELT ltd TO ttrAMtitNt III Code No. 810.80 * a/8/65 DSW 476038.0520 FIGURE 4. DSW 476038.0521 41 Penta blocks were produced by pouring molten Penta info large tapered molds and allowing it to set. The material was removed from the mold by heating it with a welding torch. Penta 60 was produced in the same way as molten Penta, except that the chlorination was terminated earlier (batch temperature 153-157 C; 145 crystalization point). It was prilled in the same manner as molten Penta. A list of the job titles in Department 236 is given in Table 11. Department 237 (Chlorophenols) The production of chlorophenols began at the Krummrich plant in 1938 and continued through 1983. The principal products of this Department were o-chlorophenol, p-chlorophenol, and 2,4-dichlorophenol. P-chlorophenol was transferred to Department 239 where it was reacted with benzyl chloride to produce Santophen 1 (orthobenzyl p-chlorophenol). 2,4-dichlorophenol was transferred to Department 262 where it was reacted with chloroacetic acid to produce 2,4-dichlorophenoxyacetic acid. Chlorophenol fractions from Department 237 were also used as feedstock for production of pentachlorophenol in Department 236. The flowsheets for the production of mono- and di-chlorophenols are shown in Figure 5. The overhead layout of the work area is shown in Figure 6. Department 237 was an open area located adjacent to Department 236. The chemistry for the production of the chlorophenols appears to have remained unchanged over the years. Crude monochlorophenol was prepared by the batchwise chlorination of phenol at a temperature of 70-90 under a pressure of 2-5 psig in a Monel chlorinator. Crude mono contained 45% DSW 476038.0522 ,i STLCOPCB4042686 DEPT 226 236 CM -vt TABLE 11 JOB DESCRIPTION Relief Foreman Chief Operator Operator Helper Day RepaLrman JOB DESCRIPTIONS LISTED IN THE MONSANTO COMPANY/ CHEMICAL WORKERS UNION WORKING AGREEMENTS 00 O' o H CM r> CO m <r <t <r -v*. rs oo O' O H CM m CO <r <r <r X XX X X XXX X X XX X x x 2; X YEARS 00 O' *--i rM cn vt m vO oo <r in in m m m in m m N v^ oo O' f--l CM m <t in vO oo <t <r m in m m m m m XXXXXX X XXXXXXX XXXXAXX XXXXXXX XXXXXXX m 00 v> vO CO vO mvO ovOo I CO CM in o 00 tN rv 00 CO ocho- 5 CoO Relief Foreman Chief Operator Repairman Operator Building BD Operator Building BO Intermediate Op. Bldg. BD B Operator - Oiler Pelletizer Operator Helpei* Porter A Operator Bldg. BD B Operator Bldg. BD Briquette Operator Bldg. BD Premium Operator Bldg. BD Helper Porter Santobrite Operator Packer Helper Operator Premium Operator XXXA X AXX XXXXXXXX X X X X X X X X X XX X X X XXXX X XX XXXX XXX X XXXXXXX X X X X X V A X X XX XXXXXXX X XX X XX X X X X XXX XXXXX XXXX X XXX XXX XX XXXXX XXXXXX X XXXX XXXX XXXX XXX XX XX X STLCOPCB4042687 STLCOPCB4042688 JOB DEPT___________________DESCRIPTION 236 (Cont'd) A Operator B Operator Briquette Operator 237 Operator JOB DESCRIPTIONS LISTED IN THE MONSANTO COMPANY/ CHEMICAL WORKERS UNION WORKING AGREEMENTS YEARS CnO <j\ o CM in vO <3 00 CTn vcr CmM ooin vO on min in in in rn in oo NO vO NO r^ o00 rm* o r> O CM n <3 in nO r-*. oo ovnt CmM in vO oo ON m m m m in cn NO in NO oo NO MCM N r^ XXXX XXXX XXX XXX CM loO oo <Ncooo5 w Q 737 ro Relief Foreman Operator Helper Shift Operator New Dept, Operator Old Dept. Repairman Helper Day Chief Operator X XX XXX X X X XXX XXXXXXX XXXXXX XXXXXX XXX X X X X X X. XXX XXX X X X X X X xxxxxxxxxx XXX X X X X X X X X X X X XXXXXXXXXXXXX 2o8 Premium Operator Intermediate Operator Utility Helper XXXX X XXX X <Z3 FIGURE 5 . .... # PROGRESS FLOWSHEET FOR CHLOROPHENOLS e \ s CHLORINATION STEP OEPT.237 ' 910,91 fl to.84 Ftft- 1974" , } in 0ion4 ocoo o ChD5wQ \ STLCOPCB4042689 STLCOPCB4042690 parachlorophenol (P-CP), 282 orthochlorophenol (O-CP), and 2% dichlorophenol (DCP) The crude material was blown with air to remove dissolved HC1 gas. The byproduct HC1 gas was piped to Department 236's clean-up system. The crude mono was neutralized with 50% caustic and distilled in a Linde tray fractionating column. Normal cuts from this batch distillation were water, wet fractions, O-CP, dry fractions, aid P-CP. The dry fractions were transferred to Department 236 for use as raw materials in the production of molten pentachlorophenol. Crude dichlorophenol was prepared by the batchwise chlorination of phenol at 80-90 C and at atmospheric pressure. The crude material contained 85.5% 2,4-DCP, 6.0% 2,6-DCP, 0.5% O-CP, 7.8% 2,4,6 trichlorophenol, 0.1% P-CP, and 0.1% phenol. The chlorinated crude material was blown with air to remove the bulk of dissolved HC1; the remaining HC1 was neutralized with caustic. The 2,4 isomer in the crude DCP was recovered by vacuum batch distillation in a Monel fractionating column. The remaining chlorophenol fractions stripped from the crude were transferred to Department 236 for use in pentachlorophenol production. The byproduct HC1 was sent to Department 236's clean-up system. A list of the job titles in Department 237 is given in Table 11. Department 268 (Agricultural Esters) The production of the butyl, isobutyl, and isooctyl esters of 2,4,5trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D) began at the Krummrich plant in 1960 and continued through about 1970. The 2,4,5-T was shipped in from Monsanto's plant in Nitro, West Virginia. The 2,4-D was transferred to Department 268 from Department 262. The flow sheets for the pre-mix, reaction, and neutralization/filtration stages of the process are shown in Figures 7, 8, and -9, respectively. DSW 476038.0527 STLCOPCB4042691 FIGURE 7. A. rnE-MIX (SLUnnY) DEPT.2G8 BUTYL 2,4,5-T 894.12 oo CM 0o0 CO STLCOPCB4042692 FIGURE 8 D. nE/VCTION DEPT. 2G8 BUTYL 2,4,5-T ; BD4.12 q co FIGURE 9 CTCL0tCKTtAMV4C 3imCAvLMB n* W cron -- t). BUTYL 2,4,5-T ISO BUTYL 2/4,5-T 894.12 094.20 \ rnoDucr MOLD* TANK 4f0t CAt, mil. : i' " rounimo nLrcn f TANK FARM \ DSW 476038.0530 50 The esters were produced by reacting the chlorphenoxy acids with the appropriate alcohol using a small amount of sulfuric acid as a catalyst. The materials were pre-mixed in a slurry tank, then dropped into the reactor where the sulfuric acid was added. The reactor was then set at the appropriate temperature and pressure (butyl and isobutyl esters of 2,4,5-T; 130-140 C, 580 mm Hg; isooctyl ester of 2,4,5-T; 135-140 C, 200 mm Hg.) The reaction was originally driven to completion by removing the binary alcohol/water azeotrope and, on cooling and separating, recycling the alcohol. The 1969 processes for the butyl and isobutyl esters used toluene as a solvent for increased efficiency in driving the reaction to completion and in the water/alcohol separation. When the reaction was complete, the alcohol and toluene were stripped off maintaining the reactor at 50 mm Hg and 140-150 C for two hours. The batch was then neutralized with cyclohexylamine. After filtration, the product was pumped to storage, tank cars, tank trucks, or 55 gallon drums. A list of the job titles in Department 268 is given in Table 1 1. DSW 476038.0531 Ii STLCOPCB4042695 51 4.2.2 Industrial Hygiene Departments 226 and 236 Chemical exposures in Departments 226 and 236 included pentachlorophenol, tetrachlorophenol, phenol, chlorophenol fractions, chlorine, hydrochloric acid, sodium hydroxide, iron, aluminum and PCDDs/PCDFs. Repeated over exposure to phenol may result in chronic phenol poisoning. Symptoms include vomiting, difficulty in swallowing, diarrhea, lack of appetite, headache, fainting, dizziness, dark urine, mental disturbances, and possibly skin rash. Liver and kidney damage and discoloration of the skin may also occur. Chlorine, hydrogen chloride, and sodium hydroxide are irritating to the skin, eyes, and mucous membranes. Overexposure to chlorine and hydrogen chloride gas may result in tracheobronchitis and pulmonary edema (NIOSH, 1977). Exposures to the iron and aluminum powder catalysts are not likely to result in serious health effects. The toxicities of the chlorophenols have been reviewed in Section 3. The earliest information regarding the industrial hygiene conditions in Department 236 comes from a report of an inspection conducted in 1947 by the State Department of Labor's Division of Factory Inspection. The report listed several conditions which needed improving: 1) the drum flakers on the first floor of Building BD (Dept. 236) emitted considerable fumes and dust under ordinary operating conditions; 2) maintenance personnel who handled the Draco Dust Collector System were exposed to the product when the Draco bags occasionally broke; 3) employees involved in the drumming and bagging operation which was connected to the Draco Dust Collection System bagged much of the material by hand; 4) the hopper which fed the Santobrite pelletizing system was frequently blocked and was dug out by hand; and 5) the ventilation system on the Penta briquette operation was poor. A 1954 company memo acknow- DSW 476038.0532 iI STLCOPCB4042696 52 ledges a chioracne problem in Department 236 which had existed for several years. In 1963 a Schneible Dust Collector System was installed in both the Penta and Santobrite operations. On October 24, 1965 a fire broke out in one of the chlorinators. The batch in the chlorinator was in the trichlor-tetra stage. The cause of the fire was unknown. No material was lost from the chlorinator. The operators who were on duty did not appear to suffer any acute health effects. In 1967 a central fume scrubber was installed for sample hoods, tank vents, and loading areas. Monsanto began reviewing the literature on dioxins in 1970. That same, year the Medical Department established a registry of employees at the Krummrich Plant who had developed chioracne or who worked in Departments where chioracne was prevalent. In 1972 Monsanto began monitoring the dioxin levels in PCP. The levels of PCDDs in PCP, PCP-cuts, and PCP residue from 1972 to 1-979 are given in Table 12. The production of Santobrite stopped in 1972. The same year special hygiene practices (showers, clothes changes, washing, cleansing housing with Seba-Nil Solution) were begun for employees who continued to produce PCP in Department 236. Environmental monitoring for PCP began in 1977. Levels of PCP in air and wipe samples are given in Table 13. All of the air samples collected between April and October of 1977 were below the TLV of .5 mg/m^. In May of 1977, MIC staff personnel conducted an environmental audit of Department 236. The audit concluded that: 1) overchlorination of PCP could potentially cause major process accidents; 2) since 1975, 40% of the DSW 476038.0533 I STLCOPCB4042697 TABLE 12. LEVELS OF PCDD IN PCP, PCP-CUTS, AND PCP RESIDUE (ppm) DATE SAMPLE C1 C2 C3 C4 C5 C6 1972 6/75 8/75 4/16/79 PCP PCP PCP Blown Crude Dry Fraction Phenol Cut Para-Rich Cut PCP-Cut - - (BDL) It tl II II "3000 ppm Total Dioxin1 II - - (<01) (<07) - (<01) ( < 07) 11 - (BDL) II II II II (BDL) II 11 II II (BDL) II 11 II II (BDL) II II 11 II (BDL) II It II It C7 220-538 II (BDL) II It If II C8 460 490 (BDL) HI t It If 11 1 2/28/79 3/1/79 3/2/79 3/11/79 5/11/79 4/6 t-o 6/9/79 4/25 to 6/9/79 PCP Residue with Caustic If 63 59 15 3.1 6.7 240 190 64 6.2 .1 250 200 35 5.9 1.9 240 1,400 1 ,600 410 4.7 1.3 .44 5.2 .62 2.2 .08 1.3 .81 .44 .14 .16 .17 PCP Residue without Caustic (<D PCP with Caustic 2 -22 PCP Without Caustic (<01) -.52 (<D (<D (<D 1 -5.4 .18 -1.4 (<01) (<01) -.47 (<-01) -.11 (<.01) -.016 (<D (<05) (<05) (<D (<D (<D (<05) (<02) (<.025) (<05) (<02) (<06) C1O0 o CO CoO Cr*O*. (Q50 STLCOPCB4042698 TABLE 13. PCP AIR (mR/m3) AND WIPE (meg/100 cm2) SAMPLES FROM DEPARTMENT 236 DATE SAMPLE PCP AIR oo V 4/26/77 Personal, 8-Hour Operator If .14 8/10/77 10/7/77 3/77 Area, 2nd Level Outside Control Room Personal, 8-Hour Operator If II (All Penta Control Room) Sink Area Table Ice Box Cabinet Desk Table Booksbe If .026 .066 .034 .026 .025 8/77 , Sink Area Table Ice Box Cablnet Desk Table Bookshelf PCP WIPE 15.5 30.7 24.5 24.2 13.0 216 39 6.14 11.10 1.39 15.1 8.89 1.89 4.64 IT) C1O0 o 00 oCO ChO- 5w Q STLCOPCB4042699 55 personnel in Department 236 had developed chloracne; 3) the TLV and STEL for PC? were at times; exceeded during the block pouring, sawing of the 1000 pound molds, and chlorinator sampling operations; and 4) serious sources of direct operator contact with the dusty product included prilling, prill bagging, bulk loading, and routine cleaning. In 1977 Monsanto instituted more stringent industrial hygiene practices (disposable dishes, midshift shower for dirty jobs). Wipe sampling (Table 13) showed a reduction in the levels of surface contamination in the Penta Control Room between March and August of 1977. Monsanto decided to shut down the Penta operation and to explore ways to further reduce the levels of product and workplace contamination. In 1978 the Penta operation was shut down. In 1979 Monsanto developed the capability to measure PCDDs with greater analytical precision. Wipe sampling of the Department (Table 14 ) revealed surface contamination with trace amounts of higher chlorinator PCDDs. That same year, Monsanto discovered that the levels of PCDDs in PCP could be greatly reduced by removing sodium hydroxide from the process (Table 12). Department 236 was not re-opened, however, and the building was subsequently dismantled. Department 237 Chemical exposures in Department 237 included phenol, o-chlorophenol, p-chlorophenol, 2,4-dichlorophenol, 2,6-dichlorophenol, 2,4,6-trichlorophenol, PCP (possibly from adjacent Dept. 236), chlorine, hydrochloric acid, and the lower-chlorinated PCDDs. The earliest record of any problem in Department 237 dates back to April 25, 1952 when an explosion destroyed a 2,4-DCP transfer pump. The DSW 476038.0536 i STLCOPCB4042700 TABLE l4. LEVELS OF PCDDs IN WIPE SAMPLES FROM DEPARTMENT 236 DATE 6/6/79 SAMPLE Blower (m cR/m2) Cl (BDL) (BDL) Office Wall (") Handral1 (") If II II II Beam Wall (") (") It II II II (BDL) ft If II I* c4 (BDL) 4.5 (BDL) 10 1 C5 (BDL) If II II It c6 400 (BDL) II 60 (BDL) C7 8,000 50 14 140 2 Cr 58,000 9,000 1,800 47,060 700 5/81 Penta Purification Column 3rd Level (ng/100 cm2) Top of Column (") Open Top Wall (") 1 44 112 34 7 61 46 16 9 74 46 10 36 38 36 oINCOOnoo (!oO. (50 Q STLCOPCB4042701 57 pimp overheated after it ran dry. The two operators who were in the vicinity did not appear to suffer any serious health effects. Chloracne does: not appear to have been prevalent in Department 237. Early company memos dealing with the chloracne problem do not identify Department 237 as a problem area. Only one of six employees who had worked exclusively in this Department was found to have questionable chloracne by Dr. Suskind in 1979. Environmental monitoring for phenol and chlorophenols began in 1977. Air levels of these chemicals in Department 237 between 1977 and 1982 are given in Table 15. None of the air levels for phenol exceeds the TLV of 3 19 mg/m . TLVs for o-chlorophenol, p-chlorophenol, and 2,4-dichlorophenol have not been established. Air levels of PCP exceeded the TLV on several occasions. Air samples for chlorine and hydrochloric acid were collected between September of 1979 and January of 1980. Air levels of HC1 ranged from .06 .32 mg/m 3 , well below the 7 mg/m 3 ceiling value. Air levels of chlorine 3 ranged from .02-.10 mg/m . One air sample collected near the chlorinator 3 showed an unusually high chlorine level of 5.4 rag/ra , which is above the 3 mg/m3 TLV. In 1979 Monsanto analyzed batches of o-chlorophenol and 2,4-dichloro phenol for PCDDs. (Table 16) O-chlorophenol was contaminated with ppb levels of mono-, di-, and tri-CDDs. 2,4-dichlorophenol was contaminated with mono-, di-, tri-, and tetra CCDs. Removal of the caustic addition resulted in a marked reduction in PCDD contamination. An OSHA inspection in 1979 found 300 ppb of PCDDs (>50% 2,3,7,8-TCDD) in an ortho-crude spill, but Monsanto questioned the validity of this analysis. ' DSW 476038.0538 i STLCOPCB4042702 LE 15 AIR LEVELS OF CHLORINATED PHENOLS AND PHENOL IN DEPARTMENT 237 (mfi/m3) DATE PHENOL O-CP P-CP 3/15/77 3/16/77 3/31/77 4/14/77 3/10/78 1980 7/80 8/80 7/28/81 5/82 8/21/82 Personal, 8-Hour If If tf II ff ft ff fl If tf If ft If tf " (Operator) ft ft " (Control Room) Personal, 8-Hour Samples Personal, 8-Hour , ft Area, Analytical Shed Personal, 8-Hour ft It It Area, Shift, Control Room GLC Room .15 .12 .075 .39 .13 .21 .53 .14 .06 .16 .38 .28 .37 .03 .53 1.70 .20 .21 -.66 .73 .75 .90 .62 .67 .18 -.31 .40 -.53 .59 .10 .30 .25 .19 .93 .10 .57 .44 .34 .27 .76 .20 .44 .40 .02 1.88 12.66 .18 .20 - .70 .1C -.14 .01 -1.5 .02 .05 - - - -- .18 .12 -.18 .07 -.14 .19 -1.2 .24 .06 D-CP - -' .09 .04 .06 4.13 .06 .06 .12 .05 .23 .06 .09 .10 -.11 .15 .79 .67 .37 .19 .02 -.03 .03 -.29 .24 .50 T-CP PCP - .05 - .55 - .05 - .50 - .05 - .32 \ .48 - .04 - .05 - .14 - .18 - . 14 - .05 - .15 -- .57 .93 -- -. -- 2.35 1.33 - 1.15 - 4.88a - 5.17a - '- (<.01) (c.Ol) (<.01) - O) CmO o oo N<oC0O. (0 Q STLCOPCB4042703 A o "d STLCOPCB4042704 TABLE 16. LEVELS OF PCDDs IN O-CP AND 1>-CP (ppm)_______________________ date sample c1 c2 2/28 to 4/16/79 0-CP With Caustic (< 05) -.89 (<02) -.18 C3 (<03) -.45 C4 (<.01) C5 (<05) C6 (<05) C7 (<02) 8 (<05) O in o 06 coCNoO- 5 wa o00 V o V 4/25/79 0-CP Without Caustic (<.01) (<01) (<01) (<05) (<.05) 3/3 to 4/18/79 D-CP With Caustic (<02) -9.5 (<01) -29 (<.02) -13 (<02) -.19 (<.02) (<05) (<.10) (<.10) 5/15 to 5/31/79 D-CP Without Caustic (<.oi) (<01) -.04 (<01) -.25 (<.01) -.04 (<05) (<.05) (<01) - 60 Trace amounts of OCDD were found in surface wipes of the chief operators desk and the desk in the Department 237 Control Room. It is not known whether these samples were analyzed for other PCDDs. PCDFs were not routinely measured in the samples collected for PCDD analysis. Department 268 Chemical exposures in Department 268 included 2,4,5-T, n-butyl alcohol, isobutyl alcohol, isooctyl alcohol, toluene, sulfuric acid, and cyclohexylamine. Exposures to high concentrations of the alcohol vapors may cause headache, dizziness, and drowziness. Keratitis characterized by corneal vacuoles has been reported following exposure to the vapors of n-butyl and isobutyl alcohols. Toluene is a central nervous system depressant. Prolonged, heavy over-exposure may result in permanent encephalopathy. Cyclohexylamine and sulfuric acid are skin and eye irritants. Repeated inhalation of sulfuric acid mist may lead to chronic bronchitis. The only information regarding industrial hygiene conditions in Department 268 comes from an internal industrial hygiene survey (undated) conducted in the 1960s. The report states that some dust was generated when 2,4-D was loaded into the fill hopper through the front end pay loader. 2,4,5-T was received from the Nitro plant in Lever packs; this was changed over to tote bins to reduce the amount of dust exposure during charging. The Drumming Station was not vented. The filter press was cleaned every three days. The operators - who were not manually handling the material operated the equipment from an air- conditioned control room. The 2,4-D and 2,4,5-T esters were apparently not analyzed for PCDDs. The levels of PCDDs in these products were probably not much different from those reported in the literature (Table 5). DSW 476038.0541 STLCOPCB4042705 61 4.2.3 Chloracne Registry In 1970 the Medical Department at the Krummrich Plant instituted a registry of current employees who had developed chloracne or who had worked in departments where chloracne was prevalent. Employees were examined for chloracne if they 1) worked in Department 236 or 237; 2) worked in Maintenance and had worked for more than 200 hours in the area containing Departments 236 and 237; or 3) were self-referred because of concern over chloracne. One hundred forty-five employees appear on the Chloracne Registry. Fifty-five of these were noted to have chloracne on at least one visit. Thirty-three of the employees were working in Maintenance at the time of .examination. Twenty of these were noted to have chloracne. 4.2.4. Maintenance Employees In addition to the production workers in Departments 226, 236, 237, and 268, an unknown number of maintenance workers were exposed to chlorophenols, chlorphenoxy acids and dioxins in these work areas. One thousand nine hundred and forty employees held maintenance jobs between 1940 and 1980 and are presently alive according to company records. The demographic characteristics of these workers are shown in Table 17. A review of personnel and payroll records and interviews with maintenance supervisors have revealed that there are no existing records of Department assignments for maintenance workers prior to 1976. Self reporting was considered as a means for ascertaining maintenance worker exposure. Moses et al (1984) attempted this approach and found it unfeasible in their study of the Nitro plant. Fingerhut and her co-workers at NIOSH are not including Krummrich maintenance workers in the Dioxin Registry due to the difficulties in assigning exposure. DSW 476038.0542 l STLCOPCB4042706 62 TABLE 17 DEMOGRAPHIC CHARACTERISTICS OF MAINTENANCE WORKERS EMPLOYED BETWEEN 1940 AND 1980. CHARACTERISTIC Employment Status Active/Temp. Inac. Terminated Retired Payroll Hourly Salaried Sex ' Male Female Unknown Race White Black Unknown Age <20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ . N (Total - 1940) 741 572 627 1,629 311 1,871 68 1 1,602 317 21 2 2 37 55 72 130 146 118 272 311 312 483 Percent 38 29 32 84 16 96 4 <1 83 16 1 <1 <1 2 3 4 7 8 6 14 16 16 25 DSW 476038.0543 STLCOPCB4042707 63 Ve have decided to adopt the approach of Moses et al (1984) and use chloracne as a marker of exposure for maintenance workers. These workers will be identified through a review of plant medical records. In addition we will consider any maintenance worker who appears on the Chloracne Registry as exposed. This approach is expected to identify approximately 48 maintenance workers with the highest dioxin exposures. 4.2.5 Definition of Exposed Cohort The exposed cohort in this study will consist of all past and present Krummrich employees who are alive and who meet one or more of the following criteria: 1) Hourly and salaried employees who had worked in Departments 226, 236, 237, or 268 for one or more days between January 1, 1938 and December 31, 1983. 2) Maintenance employees who appear on the Chloracne Registry. 3) Employees who were noted to have chloracne on plant medical records (with the exception of employees who were exclusively engaged in the production of PCBs or tetrachlorobenzene). The first entry criterion encompasses most of the members of the exposed cohort. One thousand seven employees worked in Departments 226, 236, 237, and 268 between 1/1/46 and 1/1/75. The identification of employees who were hired and left before 1946 or between 1976 and 1980 has not yet been completed. Two hundred twenty-one of the 1007 employees are deceased, leaving 786 survivors. The distribution of 720 of these employees by length of employment in one or more of these departments and_by employment status is given in Table 18. ' DSW 476038.0544 I I STLCOPCB4042708 64 TABLE IS. DISTRIBUTION OF EXPOSED COHORT BY LENGTH OF EXPOSURE AND EMPLOYMENT STATUS AS OF 1/1/843 Employment Status Length of Exposure (months) <1 l-<3 > 3--_<6 >6-<12 >12 Active Retired Transferred within Monsanto Leaves of Absence Military Leave Other Terminations 55 33 2 4 9 35 42 24 0 7 10 47 48 39 22 33 20 82 65 2 5 5. 8 11 14 9 34 43 30 Total 138 130 122 134 196 Total 266 177 6 29 53 189 720 b Cohort limited to employees who had worked in Departments 226, 236,237, and 268 between 1/1/46 and 1/1/75. bSixty six additional employees have as yet not been classified by length of exposure DSW 476038.0545 I STLCOPCB4042709 65 Thirty-three Maintenance personnel are included on the Chloracne Register indicating that they had either developed chloracne or had worked in Departments 226, 236, 237, or 268 for more than 200 hours after 1970. Company documents dated before 1970 contain lists of names of employees who had developed chloracne. An additional 15 names are expected to result from this entry criterion. The current estimate of the total number of individuals in the exposed cohort is approximately 834. 4.2.6. Demographic Characteristics of the Exposed Cohort At this time demographic information is available on the employees who had worked in Departments 226, 236, 237, and 268 between 1/1/46 and 1/1/76. These individuals comprise about 90Z of the total exposed cohort. Eighty-five percent of these workers are white, 14Z are black, and in 1Z the race is unknown. Ninety-seven percent of these workers are male. The age distribution of these workers is given in Table 19. Fifty percent are 60 years of age or older. Ninety-three percent of the workers were hourly employees and 7Z were salaried. 4.2.7. Follow-Up, Accessibility, and Participation of the Exposed Cohort The size of the exposed population which will undergo medical examination will depend on the rates of follow-up, accessibility for examination, and participation. These rates are expected to vary by employment status. The effects of these rates in determining the size of the examined cohort are shown in Figure 10. Follow-up is expected to be complete for active and temporarily inactive workers. An estimated 90Z of these workers will be accessible for DSW 476038.0546 ! STLCOPCB4042710 TABLE 19. AGE DISTRIBUTION OF THE EXPOSED COHORT AS OF 1984 AGE 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70 + TOTAL N 13 9 14 60 74 64 160 145 115 132 786 PERCENT 2% 1 2 8 9 8 20 18 15 17 100% DSW 476038.0547 STLCOPCB4042711 FIGURE 10. ESTIMATED FOLLOW-UP, ACCESSIBILITY, AND PARTICIPATION OF TI1E EXPOSED COHORT TOTAL EXPOSED ALIVE EMPLOYMENT STATUS FOLLOW UP ACCESSIBLE PARTICIPATE tal Number Participating = 404 oo to o 00 CoO ChO- 5 tn Q STLCOPCB4042712 68 medical examination. In Suskind's 1979 survey of this same population, 68Z of the active employees chose to participate. A similar participation rate in the present study would result in 221 active and temporarily inactive workers. The follow-up rate for retirees is estimated at 95Z, since these workers are traceable through pension records. Over ninety percent are known to be living within 300 miles of St. Louis and accessible for examination. A participation rate of 60Z would result in 106 retirees. The follow-up rate for terminated workers is projected at 90Z. The locating of terminated workers will be performed by Equifax. An estimated 75Z are still living within 300 miles of St. Louis. Approximately 30 employees who had worked in Department 268 terminated employment at the Krummrich Plant when their area of the plant was sold to the Edwin Cooper Company. This group of employees will be especially targeted for participation in the study. A participation rate of 40Z would result in 60 terminated workers. Retired and terminated workers will receive a reasonable reimbursement for their time and travel. The follow-up rate for employees whose employment status is as yet unknown is estimated at 90Z. The accessibility and participation rates for these employees are estimated at 75Z and 50Z respectively, resulting in an additional 17 workers. A total of 404 exposed employees are expected to participate in the medical examinations. Present and past employees who choose not to participate in the study will be surveyed as to their reasons for non-participation and general health status. This information will be useful in detecting and measuring non-responder bias. DSW 476038.0549 STLCOPCB4042713 69 4.2.8 Internal Control Group The internal control group will consist of all present and past employees at_the Knimmrich Plant who are alive and meet all of the following entry criteria: 1) Never worked in Departments 226, 236, 237, or 268. 2) Did not appear on the Chloracne Registry. 3) Were not listed on company documents as having chloracne. 4) Never worked in Maintenance. 5) Never worked in Department 239 (Sar.tophen). 6) Never worked in Department 224 (chlorinated benzenes). 7) Never worked in Department 262 (2,4-D). 8) Never worked in Department 218 (muriatic acid - chlorinated benzene). 9) Never worked in Department 246 (PCBs). 10) Never worked in Department 233 (chlorinated benzene). 11) Never worked in Department 861 (laboratory). One thousand seventy-seven employees meet the entry criteria for the internal control group. Thirty-three percent are active workers, 59% are terminated, and 9% are retired. Ninety-five percent are hourly employees and 5% are salaried. Ninety-six percent are male. Seventy-eight percent are white, 11% are black, and in 11% the race is unknown. The demographic characteristics of the exposed cohort and the internal controls, are compared in Table 20. The exposed and non-exposed groups are similar with respect to age, sex, race, and payroll. A larger percentage of the internal controls are terminated employees. A larger percentage of the exposed cohort are retired, regardless of whether the terminated employees . DSW 476038.0550 i STLCOPCB4042714 70 TABLE 20. COMPARISON OF THE PERCENT DISTRIBTUIONS OF DEMOGRAPHIC CHARACTERISTICS BETWEEN THE EXPOSED COHORT AND THE INTERNAL CONTROLS CHARACTERISTIC Employment Status Active/Temp. Inactive) Terminated Retired Payroll Hourly Salaried Sex Male Female Unknown Race White Black Unknown Age <20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ . Exposed (n786) 46 28 26 91 9 97 3 <1 85 14 1 0 0 2 1 2 8. 9 8 20 18 15 17 Control Cn-1077) 33 59 9 95 5 96 4 <1 78 11 11 1 0 1 2 6 7 6 9 20 20 11 17 DSW 476038.0551 Jl STLCOPCB4042715 71 are included or excluded. Overall, the two groups are acceptably comparable with respect to the major demographic variables. If we.assume similar rates of follow-up, accessibility, and participation,* an estimated 218 active, 50 retired, and 141 terminated workers are expected to comprise the internal controls. The 409 internal controls and 404 exposed result in a control:exposed allocation ratio of 1.01:1. *Thirty-three percent of non-exposed terminated workers are expected to participate in the study as opposed to 40Z of the exposed terminated workers. DSW 476038.0552 STLCOPCB4042716 4.3 Ascertainment of Health Status The comprehensive medical examination will ascertain the subjects' present and past health status. The incidence of past health events will be determined through the medical questionnaire and validated through medical record review. The examiners will be blinded as to the exposure status of the exposed cohort and the internal controls. The components of the medical examination are summarized in Table 21. 4.3.1. Medical History Questionnaire A trained medical interviewer will administer a standard medical history questionnaire which will be a modification of the questionnaire previously used by the U.S.A.F. School of Aerospace Medicine in their Ranch Handy Study (Lathrop et al, 1983). The questionnaire will contain the following elements: 1. Current health status including any chief complaints or medical problems. 2. Past medical history, including hospitalizations for medical illness, surgical procedures, or transfusions. Specific questions will be asked about the presence of hypertension, cardiovascular, cerebrovascular, pulmonary, hepatic, intestinal, urogenital, reproductive, neurologic, mental, and psychiatric diseases. 3. Family history including health status of all first degree relatives, causes of death, hospitalizations, etc. 4. Social history including marital status (current and previous spouses), habits of alcohol and tobacco use. DSW 476038.0553 STLCOPCB4042717 73 5. Review of systems Including: Constitutional symptoms of weight change, energy level, etc. b. Headaches c. Eye (vision, pain, discomfort) d. Ear (hearing, pain, discharge) e. Nasal (congestion, discharge, sense of smell) f. Mouth (lesions, dental, dysphagia) g. Respiratory (sputum, cough, dyspnea, etc.) h. Cardiac (chest pain, palpitations, PND) 1. Abdomen (pain, diarrhea, constipation, nausea, vomiting, etc.) j. Urogenital (dysuria, urgency, frequency, infection, nephrolithiasis, sexual dysfunction) k. Joints (pain, swelling, deformity) l. Neurologic (weakness, paresthesia, memory change, etc.) m. Psychologic (sleep disturbance, anxiety, depression) n. Dermatologic (rashes, blisters, sunburn, excess hair) o. Gynecologic (regularity of menses, character of flow, etc.) 6. Medication history which will include current as well as past use of prescription and over-the-counter preparations. 4.3.2 Reproductive History At the time of the medical history, permission will be sought to conduct a phone interview with current and previous spouses concerning reproductive outcomes. The Ranch Hand spouse's questionnaire will be administered by trained, medical telephone interviewers and will include questions on the number of pregnancies, their outcomes, and any congenital DSW 476038.0554 i i STLCOPCB4042718 74 malformations in offspring of the subjects. Permission will be sought to verify reported congenital malformations in offspring through medical record review. . 4.3.3 Dietary History Participants will be asked to complete a three-day dietary history. They will be instructed in the completion of this diary by a trained nutritionist. 4.3.4. Physical Activity Assessment Participants will be administered a seven-day activity recall questionnaire (Taylor et al, 1984) to determine their level of physical activity. 4.3.5. Occupational and Environmental History A trained interviewer (other than those administering the other components of the medical examination) will administer a questionnaire designed to determine each of the following items as best remembered by the subject: 1. Job classification, duration, and duties for each position held at the Krummrich plant. 2. Job classification, duration, and duties for all employment other than at the Krummrich plant. 3. Description of any hobbies or other pursuits involving exposure to chemicals which might be confounding. 4. Military history (if any) with particular attention to service in Vietnam, especially Operation Ranch Hand. 4.3.6. Medical Records Review Permission will be sought for review and release of medical records from treating physicians and hospitals for purposes of confirming the DSW 476038.0555 l STLCOPCB4042719 75 previously obtained medical histories. The medical records will be reviewed by registered medical record technicians. Diagnoses and procedures will be classified into ICD-9. 4.3.7 Internist's Physical Examination The general physical examination will be performed by an internist blinded to the exposure history of the worker. The examination will consist of the following: 1. General appearance and vital signs: supine and sitting blood pressure and pulse, respiratory rate, height and weight. 2. Head: shape, evidence of trauma. 3. Eyes: pupillary response, presence of conjunctivitis, icterus. 4. Ears: hearing, appearance of tympanic membranes. 5. Nose: appearance of mucosa, purulent secretions, polyps. 6. Mouth: appearance of teeth, tonsils, mucous. 7. Neck: adenopathy, size and consistency of thyroid, range of motion. 8. Lungs: percussion, auscultation. 9. Heart: size and description of PMI, abnormalities of heart sounds, extra sounds and murmurs. 10. Abdomen: tenderness, masses, bowel sounds, liver and spleen size. 11. Genital (males): testicular size and consistency, hernias. 12. Rectal: mucosal surfaces, prostate size and consistency (males), stool hemocult. DSW 476038.0556 tI i STLCOPCB4042720 76 13. Joints: range of motion, effusion, deformity. 14. Back: range of motion, tenderness. 13. Breasts, (females): masses, discharge. 16. Pelvic (females): cervix, adnexal tenderness or masses. 17. Peripheral pulses. 4.3.8 Dermacologic Examination The dermatologists will be trained in the diagnosis of chloracne by an internationally recognized expert in the field. The dermatologic examination will be performed and recorded in a standardized manner to permit quantitative assessment of the findings. Particular attention will be devoted to the detection and scoring of chloracne, porphyria cutanea tarda, and basal cell carcinoma. 4.3.9. Neurologic Examination A neurologist will perform a mental status examination and examine the cranial nerves, motor, and sensory systems. Reflexes and cerebellar function will be tested. 4.3.10. Electrocardiogram A trained technician will do a 12-lead, resting electrocardiogram. 4.3.11. Pulmonary Function Tests A trained technicial will measure the subject's forced vital capacity and forced expiratory volume at one second. 4.3.12. Chest X-ray A trained technician will take a standard PA and lateral film. 4.3.13. Quantitative Sensory Examination A trained technician will quantitate the subject's perception of temperature and vibration. _ DSW 476038.0557 STLCOPCB4042721 77 4.3.14. Nerve Conduction Velocities A trained technician, under the supervision of the neurologist, will measure the nerve conduction velocities of the median and sural nerves (one side only) using standardized methods. 4.3.15. Neurobehavioral Testing A trained technician will administer an automated neurobehavioral test battery (Baker et al, 1984) using computer terminals, which will include the following tests: 1. Paired associate learning 2. Mood scales 3. Continuous performance 4. Vocabulary 5. Symbol-digest substitution 6. Hand-eye coordination 7. Visual retention 8. Digit span 9. Paired associate recall 4.3.16. Blood Tests Venous blood will be drawn after a 12-hour fast and distributed in the following manner: 1. 5cc of EDTA anticoagulated blood for complete blood count, differential white cell count, and platelet count. 2. 5cc of EDTA anticoagulated plasma for total cholesterol, HDL and LDL cholesterol and triglycerides. DSW 476038.0558 STLCOPCB4042722 78 3. 5cc of serum for SMA 20 (albumin, alkaline phosphatase, bilirubin, calcium, chloride, bicarbonate, creatine, GGT, glucose, phosphorus, potassium, LDH, protein, GOT, GPT, sodium, BUN, acid.). 4. 5cc of serum for LH, FSH, testosterone. 5. 2cc of serum for T4, T3 resin uptake and free thyroid index, TSH. 6. 3cc of serum for IgA, IgC, IgM. 7. lcc of frozen serum for CPK. 8. 4.5cc of blood drawn into blue-top tube and delivered on ice for prothrombin time. 9. 5cc of EDTA plasma for apoproteins AI, All, B, and E (Dr. Schoenfeld's laboratory). 10* 20cc of heparinized blood for lymphocyte stimulation studies (concanavalin A, phytohemaglutin, and Poke week mitogen). 11. 20cc of heparinized whole blood, 3cc of EDTA anticoagulated blood and 2 slides will be drawn for T and B cell determinations, T helper and suppressor cell ratio. 12. lOcc of serum will be frozen and banked to permit future analyses. '\ 4.3.17. Urine Tests The subjects will be asked to provide a clean catch, mid-stream urine DSW 476038.0559 STLCOPCB4042723 79 specimen for urinalysis after which a 24-hour urine collection will be begun using a light-proof container. The 24-hour urine collection will be kept refrigerated and appropriate preservatives will be used. Aliquots will be sent for: 1. Creatine (creatinine clearance) 2. Protein (24-hour protein excretion) 3. Quantitative porphyrins DSW 476038.0560 STLCOPCB4042724 80 TABLE 21. SUMMARY OF COMPREHENSIVE MEDICAL EXAMINATION I. Medical History Questionnaire (trained interviewer) Current medical problems Past medical history Family history Social history Review of systems Medication 2. Reproductive History (telephone interview by trained interviewer) 3. Dietary History (nutritionist-instructed 3-day diary) 4. Physical Activity Assessment 5. Occupational and Environmental History (trained interviewer) 6. Medical Record Review (internist) 7. General Physical Examination (internist) 8. Dermatologic Examination (dermatologist) 9. Neurologic Examination (neurologist) 10. 12-lead EKG (EKG technician) II. Pulmonary Function Tests (PFT technician) 12. Chest x-ray, PA and lateral (technician) 13. Quantitative Sensory Examination (technician) 14. Nerve Conduction Velocities (NCV technician) 15. Neurobehavioral Testing Paired associate learning Mood scales Continuous performance - Vocabulary ! DSW 476038.0561 II ` ' STLCOPCB4042725 81 TABLE 21 (continued) Symbol-digest substitution Hand-eye coordination . Visual retention Digit span Paired associate recall 16. Blood Tests Complete blood count Platelet count Cholesterol HDL and LDL cholesterol ' Triglycerides Apoproteins AI, All, B, and E Glucose BUN Creatinine Electrolytes Uric Acid Protein Albumin Bilirubin Alkaline phosphatase LDH, GOT, GPT GGT LH, FSH, testosterone CPK I SW 476038.0562 i STLCOPCB4042726 82 TABLE 21. (continued) T4, T3 resin uptake, free thyroid index, TSH IgA, IgG, IgM Prothrombin time Lymphocyte stimulation studies T and B cell populations, T helper and suppressor ratio Banked serum. 17. Urine Tests Urinalysis Creatinine clearance 24-hour protein excretion Quantitative porphyrins . I DSW 476038.0563 lI ' STLCOPCB4042727 83 5. DATA ANALYSIS 5.1. Data Entry, Processing, and Storage Data management and analysis will be performed at the Northwestern University Medical School. The data management system will include quality control measures at each step of the process to ensure completeness and accuracy of data entry. Data entry and quality control will be facilitated through the use of standardized data entry forms. Whenever possible, original data will be recorded on the data entry forms to minimize transcription errors. A list of the original data, initial records, and data entry forms is given in Table 22. The data from each employee's health examination will be visually inspected on site for completeness,.legibility, and obvious inaccuracies. Errors in data collection or recording will be corrected on site. The data will be transported by courier to the Northwestern University Medical School for processing and storage. Results of laboratory analyses will be mailed to the School and inserted in each employee's data file. Recording of data will be performed by data entry clerks following specific procedures under the supervision of the Data Manager. Data contained in the data entry forms will be entered into intelligent terminals using an Intelligent Data Entry program. A screen image of the data entry form will appear on the CRT. Spaces will be included for entering values as they are reported on the data entry form. The Intelligent Data Entry program will have checks on range values and numeric types to trap transcription errors. Transactions from a forms entry session will be transmitted from the mini computer to the main frame over a phone line. The entry will be checked against DSW 476038.0564 I - STLCOPCB4042728 TABLE 22 . FORMS FOR COLLECTION, RECORDING, AND CODING OF DATA Components of Health Survey Original Data Information for Follow-up Personnel Record Employment Record Personnel Record Medical History Face to Face Interview Occupational History Face to Face Interview Reproductive History Phone Interview Internist's Exam Physical Exam Dermatologist's Exam oo Neurologist's Exam Physical Exam Physical Exam PFT's Flow-Volume Loop Volime-Time Graph CXR Film Quantitative Sensory Sensory Exam EKG EKG EMG/NCV Tracing Automated Neurobehavioral Test Neurobehavioral Exam Blood Tests Blood Specimen Urine Tests Non-Participant Survey Urine Specimen Phone Interview Initial Record Computer Printout Computer Printout Questionnaire Questionnaire Questionnaire Exam Form Exam Form Exam Form Computer Printout Data Entry Form Recoded Recoded Same Same Same Same Same Same Recoded 1 Radiologist's Report Exam Form Cardiologist's Report EMG/NCV Form Computer Printout Recoded Same Recoded Same Same Lab Report Lab Report Questionnaire Recoded Recoded Same icno ion ocood ChOTT 5 co o STLCOPCB4042729 85 i i the full data base on certain data items to prevent duplicate and other invalid entry. The original data will be stored and archived in the ; Northwestern University Medical School. Entered data will be stored on disks with archive copies to prevent inadvertant loss of the data base. 5.2. Quality Control Personnel data on employment history which is supplied by Monsanto ; will be checked for accuracy by comparing a 10% random sample of this data to the original personnel records. The employee's occupational history will serve as a further check on the accuracy of the personnel data. ' The most important step in the quality control of data management is the complete and accurate recording of data. Each employee's medical examination data will be visually inspected on site for completeness, legibility, and obvious inaccuracies. Transcription errors during data entry will be minimized through the use of the previously described intelligent data entry system. Duplicate and other invalid entry will be prevented by comparing each entry against the full data base. The final step in quality control will be an ongoing comparison of a 10% random sample of entries against the original data. Errors will be traced to their source and control measures taken to prevent their recurrence. Inaccurate or incomplete data will be corrected and re-entered. These quality control measures are summarized in Figure 11. Error tolerance will be set at .1%. DSW 476038.0566 I STLCOPCB4042730 86 FIGURE 11. QUALITY CONTROL OF OATA ENTRY Visual i nspection at site Intel1igent data entry system Point of entry interrogation Random sample check Identify source of error and take corrective measures DSW 476038.0567 STLCOPCB4042731 87 5.3 Analysis 5.3.1 Classification of Exposure Each individual's exposure will be classified 1) dichotomously, 2) by length of exposure, and 3) by exposure score. All three exposure variables will be treated as categorical variables. The exposed cohort will be analyzed as a whole and, where sample size permits, by individual department. In the dichotomous classification of exposure, individuals who meet one or more of the exposure criteria will be classified as exposed, and those who do not will be classified as non-exposed. As an employee's length of employment in a department Increases, his exposure to the chemicals in that department is expected to increase. The length of employment will be divided into the following four intervals: 1) 0 months, 2) >0-<3 months, 3) >3--<12 months, and 4) >12 months. Classification by length of exposure will permit analyses for dose-resonse. NIOSH is currently developing a dioxin exposure score for the Dioxin Registry. The exposure score will be a numerical scale based on the department, job titles, length of exposure, and industrial hygiene data. The exposure score will be directly applicable to Krummrich employees, since employees from this plant are included in the Dioxin Registry. The exposure score is expected to be ready by March, 1985, and will be assigned to each employee without knowledge of the results of the medical examination. While the exposure score may be a continuous variable, we will treat it more conservatively as an ordinal varible with four exposure categories. Our review of the industrial hygiene and process information leads us to conclude that analyses by individual departments are warranted. While DSW 476038.0568 !' STLCOPCB4042732 88 all four departments share the possibility of PCDD exposure, the mix of PCDDs was different for reach department. Employees in Department 237 were exposed to the lower chlorinated dioxins, while employees in Departments 226 and 236 were exposed to the higher chlorinated dioxins. While no PCDD analyses were performed on the products from Department 268, historical information indicates that these employees were exposed to 2,3,7,8-TCDD. The departments will be categorized as 226/236, 237, 268, and Maintenance/Other. 5.3.2. Classification of Disease The comprehensive health status evaluation, which Includes a medical history, reproductive history, medical record review, physical examination, and laboratory tests, will generate a large number of categorical and continuous health outcome variables. The details of the medical survey are given in Section 4. The problem of repeated measures is discussed in Section 7.8. 5.3.3. Confounders and Effect Modifiers 5.3.3.1. Demographic Characteristics The potential demographic confounders in this study include age, sex, race, socio-economic status, employment status, and urban/rural residence. The internal controls are similar to the exposed cohort with respect to age, sex, race, and payroll class. The effects of confounding will be controlled through stratified and multivariate analysis. 5.3.3.2. Lifestyle Characteristics The potential lifestyle confounders in the study include smoking, alcohol consumption, physical activity, and diet. These variables will be ascertained through the medical history and controlled for in the statistical analysis. DSW 476038.0569 I STLCOPCB4042733 89 5.3.3.3. Chemical Exposures Employees at the Krummrich Plant are potentially exposed to chemicals other than the chlorophenols, phenoxy acid esters, and their contaminants. The major chemical products and intermediates are discussed in Section 2.2. The average Krummrich employee rotates from between 10 to 20 departments prior to retirement. The Krummrich Plant contains approximately 110 active and discontinued departments. Each employee will be dichotomously classified as having worked or not worked in each department. An employee will be considered as having worked in a department if he had worked in that department for a total of more than 3 months during his term of employment. A list of the chemical exposures in each department is available through Monsanto's MEHI computer system. Each significant health finding in the comparison with the internal controls will be reviewed to determine if it could be associated with chemical exposures in a department where the employee had previously or subsequently worked (e.g. tremor on neurologic exam and exposure to mercury in the Denora Cell House). If the potential for confounding exists, the extent of confounding will be determined by cross-tabulating the confounding exposure with the abnormal health finding. If confounding is present, we will re-examine the original association after adjusting for confounding using Mantel-Haenszel methods. Major abnormal findings may warrant nested case-control study. The Krummrich employees may have had exposure to chlorophenols, chlorphenoxy herbicides, and dioxins outside of their employment. These outside exposures will be ascertained through the administered questionnaire (e.g. history of farm use of chlorphenoxy herbicides). Confounding by , DSW 476038.0570 STLCOPCB4042734 90 outside exposures will be controlled through the use of the aforementioned methods. 5.3.3.4. Effect Modifiers A factor which will influence the prevalence of residual health effects is the time since last exposure. The few longitudial morbidity studies of dioxin-exposed occupational cohorts have shown that several acute health effects improve with time. The time since last exposure will be considered in the multivariate analysis. Another factor which may influence our measurement of exposure is the calendar time of exposure. The industrial hygiene Information suggests that the chemical exposures in Departments 226 and 236 were higher before 1970 than after 1970. There is no information to suggest a similar variation in exposure in Departments 237 or 268. The temporal variation in exposure will probably be factored into the NIOSH Exposure Score. If not, we will include it as a variable for study in the analysis of the data from Departments 226 and 236. 5.3.4, Statistical Tests The strategy for statistical analysis of parametric data will consist of I) examination of crude associations; 2) stratified analysis; 3) tests for dose-response; and 4) multivariate analysis using SAS statistical packages. Crude associations between dichotomous variables will be examined by cross-tabulation, calculation of prevalence odds ratios, and testing for significance using Fisher's Exact or Chi Square Tests. Differences in means between continuous variables will be tested using the Student T Test. In the next step of the analysis, we will stratify on major confounding variables and calculate factor-adjusted odds ratios using DSW 476038.0571 STLCOPCB4042735 91 Mantel-Haenszel methods. Differences In means between continuous variables will be adjusted for confounding and tested for significance using analysis of covariance. Dose-response relationships between the ordinal exposure variables and dichotomous dependent variables will be examined using the test for trend. Confounding variables will be controlled using the Mantel extension. Multivariate analysis of dichotomous dependent variables will be performed using multiple logistic regression. Multivariate analysis of continuous dependent variables will be performed using multiple linear regression. Multivariate analysis of categorical dependent variables will be performed using log linear analysis. DSW 476038.0572 STLCOPCB4042736 6. IMPLEMENTATION 6.1 Identification and Recruitment of the Study Populations The exposed and non-exposed employees at the Kmmmrich Plant will be identified through 1) Monsanto's MEHI computer system; 2) the chloracne register; and 3) a review of company memoranda dealing with chloracne at the Krumorich Plant prior to 1970. The addresses of active employees are available through current personnel records. The present addresses of retirees are available through the company's pension plan. Terminated workers will be located through Equifax. Northwestern University will work together with Monsanto's Public Relations Department, and the international Chemical Worker's Union, and in recruiting Monsanto employees for the study. Active workers will be approached through the individual plants. Northwestern researchers will meet with the workers at the plants to discuss the purpose, scope, and implementation of the study. Retirees will be contacted by mail and also through existing retiree associations. Terminated workers will be contacted by mail. 6.2 Development of Survey Instruments The medical history, occupational and environmental history, and non-participant questionnaires will be developed in conjunction with the Survey Research Laboratory. The Survey Research Laboratory will also provide trained medical interviewers to administer these instruments. 6.3 Medical Examinations Northwestern University will place a team of health professionals at the plant sites to conduct the medical examinations. An examination is expected to take 8 hours of an employee's time, including breakfast and lunch. The examination will be completed during a single 8-hour shift with I DSW 476038.0573 f STLCOPCB4042737 93 the exception of the 24-hour urine collection, 3-day dietary history, and spouse's reproductive history. The team will be able to examine 18 employees per day by: using a rotating-statlon examination system. Blood and urine samples will be processed and sent to the appropriate laboratories in daily batches. Consent for medical record review will be sought at the time of examination. The medical records will be mailed to the Department of Medicine for review by medical record technicians after the examinations have been completed. The female spouses of the study participants will be asked to consent to a telephone interview to obtain pertinent reproductive history. The telephone interviews will be conducted by trained interviewers from the Survey Research Laboratory. 6.4 Data Analysis Data analysis is discussed in detail in Section 5. 6.5 Report 6.5.1. Reports to Individual Participants Each participant will be debriefed as to available medical findings on site upon completion of the medical examination. In addition, each participant will receive a report summarizing the results of his medical examination. The report will be prepared by the internist who examined the participant. The report will contain recommendations for further medical follow-up by the participant's personal physician when appropriate. If the participant so desires, the results of individual tests will be forwarded to the participant's physician. 6.5.2. Final Report Northwestern University will submit a final report to Monsanto upon completion of the study. A draft of the final report will be reviewed by the DSW 476038.0574 i iI 1 STLCOPCB4042738 94 Peer Review Committee prior to submittal to Monsanto. The report will contain an introduction, presentation of methods, results of analyses, discussion, and conclusions. 6.6 Timetable The study is expected to take 78 weeks to complete. The duration and timing of specific tasks are presented in Figure 13. 6.7 Human Subjects Review The study is contingent upon approval by Northwestern University's Human Subjects Review Board. The major risks to participants are the discomfort of the medical examination and breach of confidentiality. The medical examination is by design non-invasive, with the exception of venopuncture. Venopuncture will be performed by a certified technician under the supervision of the examining physician. Each participant's examination results will be confidential and will not be released to other parties without the participant's signed consent. Each participant will receive a study code number which will serve as his identifier. No personal identifiers will be entered into the computer or included in the group data file. A participant may elect to have his test results sent to his personal physician. A Monsanto employee may also elect to have his test results sent to the Monsanto Medical Department in lieu of his annual medical surveillance examination. - DSW 476038.0575 STLCOPCB4042739 FIGURE 12. Study Timetable O INDIVIDUAL REPORTS SENT DATA ENTRY AND ANALYSIS ^ ^TELEPHONE SURVEY ^ '>') KRUMMRICH EXAMS DEVELOPMENT OF SURVEY INSTRUMENTS IDENTIFICATION AND PECRUITOENT OF COHORTS ^ FINAL ^ REPORT QPEER REVIEW Q STUDY DRAFT vo Ln O' CONTRACT SIGNED O FINAL DRAFT OF PROTOCOL D C/> O peep. REVIEW OoO-*>4 DRAFT OF PROTOCOL CO CO cn a>->i -------------------------------------- --------------------------------------1------------------------------------- 1--........ ...............................1------------------------------------- 1i.......................................................... ............................:--------------------------------------:i_ 10 20 30 40 50 60 70 80 WEEKS 90 STLCOPCB4042740 96 7. Study Limitations and Corrective Measures 7.1 Loss to Study Losses to the study may occur through 1) incomplete follow-up, 2) inaccessibility for examination, and 3) non-participation. If the losses are not random, then the study sample may not be representative of the entire exposed cohort. Losses will be especially damaging to the validity of the study if they are due to exposure and disease. For example, if exposure leads to illness, and illness results in termination, then losses due to terminations will bias the study in the negative direction. Less than 10Z of the exposed cohort are expected to be lost due to incomplete follow-up. These losses should not result in serious bias. Losses due to inaccessibility for examination are expected to be low, since 90Z of the retirees and 75Z of the terminated employees are estimated to be living within 300 miles of St. Louis. Non-participation is expected to result in substantial losses despite intensive recruitment efforts. We will compare the study sample with the entire exposed cohort on the basis of age, sex, race, payroll, work area, length of employment, and hospitalization rates while employed (available through the health insurance carrier) to determine if the sample is representative of the target population. We will also survey non-participants as to their reasons for non-participation and general health status. 7.2 Survival If exposure results in the death of the most susceptible individuals, then a morbidity survey of survivors will underestimate the strength of the association between the exposure and disease. The mortality study conducted by Zack (1980) suggests that exposures at the Krummrich Plant are not resulting in excessive mortality. DSW 476038.0577 STLCOPCB4042741 7.3 Incidence-Prevalance Bias Medical surveys are designed Co measure the prevalence of disease at the time Of the survey; they are much less sensitive at detecting incident events that may have occurred many years before. The present study is aimed at measuring long-term health effects; as such, prevalence is an appropriate measure of disease frequency. The incidence of past events remains of interest, however, and will be measured by 1) asking incidence-type questions on the medical history (e.g. "Have you ever been hospitalized for an ulcer"), and by 2) medical record review. 7Recall Bias The exposed employees will know the purpose of Che study and may be more likely to recall information on the medical history than non-exposed employees. This source of bias will be controlled by 1) medical record confirmation of major health events and 2) correlating physical and laboratory findings with medical history findings. 7.5 Interviewer/Examiner Bias The medical interviewers and examiners may be biased in their measurement of health status if they know the subject's exposure history. This source of bias will be eliminated through 1) blinding the interviewers and examiners with respect to the subject's exposure status; 2) training of interviewers and examiners; and 3) use of standardized questionnaires and physical examination protocols. , 7.6 Misclassification of Exposure Employees at the Kruimrrich Plant may be misclassified with respect to their degree of exposure due to 1) temporal changes in exposure; 2) personal DSW 476038.0578 STLCOPCB4042742 98 differences in work practices; and 3) non-documented exposures. Misclassification of exposure will bias the study in the negative direction. Our chief concern is the frequent and undocumented assignment of employees to the Utility work force which may briefly place them in an exposed work area. These exposures will be ascertained through the occupational and environmental history questionnaire. 7.7 Confounding Chemical Exposures Differences in health status between the exposed cohort and the internal controls may be due to the confounding effect of chemical exposures incurred in other departments. We will code the employment histories of Krummrich employees to allow for statistical search for confounding. Exposures incurred outside the Krummrich Plant will be analyzed in a similar manner. If confounding appears to be present for major health outcomes, a nested case-control approach may be warranted. 7.8 Repeated Measures The comprehensive medical survey will provide data on a large number of health outcomes. If we set out alpha error at .05, one out of twenty will be significant by chance alone. A reduction of the alpha error would result in an unacceptably high beta error for low frequency events. The judgement of causality will not rely on statistical significance alone Associations will be judged for causality on the following criteria: 1. Statistical significance 2. Temporal Sequence: The exposure must have preceded the disease. 3. Consistency: The association should be consistent with findings from previous studies. , DSW 476038.0579 t ! STLCOPCB4042743 99 4. Strength of Association: The larger the value of the prevalence odds ratio or the greater the difference in means, the less likely the association is to be spurious. 5. Dose-Response: The frequency and severity of disease should increase as the exposure Increases. 6. Specificity: Alternative causes, such as confounding by demographic, lifestyle, or outside exposure variables, have been ruled out. 7. Biological Plausibility: The association is plausible in light of existing toxicological and epidemiological data. 7.9 Statistical Power Limitations The study is limited in its statistical power to detect some associations by the size of the exposed cohort. Power analyses for dichotomous variables by size of the prevalence odds ratio are given in Table 25. Power analyses for continuous variables by the difference in means is given in Table 26. As is clear from these Tables, the sample size is adequate to detect mean differences of 10Z for most of the continuous variables and prevalence odds ratios of 2 for many of the important dichotomous variables. These estimates are conservative in that they are based on a total sample size of only 600 participants. A sample size of 800 would provide an additional 10-30Z increase in power for many of the study variables. , DSW 476038.0580 1 STLCOPCB4042744 100 TABLE 23 POWER ANALYSIS FOR DICHOTOMOUS VARIABLES BY SIZE OF THE ODDS RATIOS (EXPOSED = 328; CONTROLS = 283; a =.05) iriable story Acne tf Chloracne Skin Cancer Control Prevalence CZ.) RH3 35.2 sb 29.5 s 0.0 S 2.5 1.1 .14 .13 1.25 .37 .35 Power by <|> 1.5 1.75 2 .78 .96 .99 . 76 .95 .99 .07 .11 .20 . 32 .54 Other Cancer Any Cancer s 1.2 RH 40 .06 .09 .14 .20 .27 .08 .14 .27 .44 .61 Hepatitis J aundice Clrrhosis UG1 Ulcer RH 4.1 RH 4.5 RH .4 S 5.5 .08 .14 .28 .45 .62 .08 .14 .29 .48 .66 .06 .07 .09 .11 .13 .08 .16 .33 .54 .72 Heart Disease RH " " Verified RH Myocardial Infarction RH " " Verified RH Coronary Artery bisease S Angina S Hypertension S Psychosis Anxiety Other Neuroses RH RH RH 17.6 14.1 .5 .4 6.1 6.1 24.5 .5 .5 .8 o 00 .12 .28 .64 .89 .98 .11 .25 .58 .84 .95 .06 .07 .10 .12 .15 .06 .07 .09 .11 .13 .09 . 16 .36 .58 .77 .09 .16 .36 .58 .77 .13 .33 .73 .94 .99 .06 .07 .10 .12 . 15 .06 .07 .10 .12 .15 .06 .12 .16 .20 34 .99 .99 .99 .99 5 .99 .99 .87 .99 ' .99 .59 .85 .97 .99 .97 .99 .97 .99 .98 .99 .25 .39 .99 .99 .99 .99 .55 .99 .99 .99 .99 .99 .30 .48 .25 .39 .99 .99 .99 .99 .99 .99 .30 .48 .30 .48 .44 .69 .99 .99 .66 .55 .99 .99 .99 . 66 .66 .87 omo o oCoOo CO Thj-- 5 aw STLCOPCB4042745 101 STLCOPCB4042746 TABLE 23 (continued) Variable Alcohol Dependence Nervousness/Anxiety/ Depression Decreased Libido Impotence Control RH S S S Prevalence(%) .3 11.7 15.3 11.7 Power by T 1.1 1.25 1.5 1.75 2 .06 .07 .08 . 10 .11 .10 .23 .53 .79 .93 .11 .26 .60 .86 .97 .10 .23 .53 .79 .93 Chronic Sinusitis and Upper Resp. Disease Kidney Disease RH RH 55.7 3.5 .14 . 38 .79 . 96 . 99 .08 .13 .25 .40 .57 Miscarriage 1 Stillbirth f Birth Defects ft Physical Exam Appears 111 RH 13.6 S 11.8 RH .8 S 1.3 RH 6.5 S 2.9 RH .1 .17 .49 .92 .99 .99 .16 .46 .89 .99 .99 .07 .11 .19 .30 .43 .08 .13 .26 .57 .60 .12 .32 -72 .94 .99 .09 .20 .45 .71 .88 .05 .06 .06 .07 .07 Chloracne 'Acne Vulgaris Hirsutism Comedones Acneiform Lesions Acneiform Scars Cysts Hyperpigmentation S S S RH RH RH RH RH 00 0.0 11.7 20.7 17.5 10.4 10.5 7.1 .10 .23 .53 .79 .93 .07 . 10 .17 .26 .36 .12 .31 .69 .92 .99 . .12 .28 . 64 .89 .98 .10 .22 .49 .76 .91 .10 .22 .50 .76 .91 .09 .18 .39 .63 .81 34 .19 . 30 .99 .99 ,99 .99 .99 .99 5 .42 .99 .99 .99 i\ .99 .99 .99 .95 .99 .99 .99 .99 .85 .97 .99 .99 .99 .99 .98 .99 .99 .99 . 99 .99 .99 .99 .99 .99 .09 .11 .14 .99 . 99 .76 .96 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 CM oifo) o oo CoO ChO- 5 CO Q TABLE 23 (continued) Variable Hepatomegaly Pinprick Light Touch Muscle Status Vibra tion Patellar Achilles Biceps Babinski Tremor Coordination Romberg Gait Lab Sed Rate <40 y.o. >40 y.o. , RBCs on U/A Protein on U/A ECG <40 y.o. >40 y.o. Control RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH 00 STLCOPCB4042747 Prevalence(%) .8 1.1 .06 9.6 7.5 3.6 8.8 .6 3.4 .5 .3 4.0 3.9 19.1 1.8 .10 .09 .08 .09 .06 .08 .06 .06 .08 .08 .12 .07 1.25 .08 Power by T 1.5 1.75 .12 .16 2 . 20 .21 .47 .73 .89 .41 .65 .83 .13 .25 .41 .57 . 20 .45 .70 .87 .07 .12 .16 .17 .13 .25 .40 .56 .07 .10 .12 .15 .07 .08 .10 . 11 .14 .27 .44 .61 .14 .27 .43 .60 .30 .67 .90 .98 .10 .17 .26 .36 34 .44 .69 5 .87 .99 .99 .99 .99 .99 .99 .95 .99 , .99 .99 .99 .99 .34 .56 .75 .95 .99 .99 .30 .48 .66 .19 .30 .42 .97 .99 .99 .97 .99 .99 .99 .99 .99 .76 .96 .99 4.2 5.4 1.3 2.6 23.1 28.4 .07 .10 .18 .28 .39 .07 .11 .21 .33 .46 .06 .09 .14 . 21 .28 .07 .11 .21 .33 .46 . 10 .21 .46 .71 .87 .10 .22 .50 .75 .90 .80 .97 .87 .99 .63 .88 .87 .99 .99 .99 .98 .99 .99 .99 .99 .99 .99 .99 ocoo oin oo` oCO NCO. 5 CO Q TABLE 24- VARIABLE Aik. Phosphatase GGT Males LDH Males SGOT (AST) SGPT (ALT) Males T riglycerides Glucose Urea Nitrogen Great inine Males Total Protein Total Bi1irubin LDL HDL LH Males FSH Males Testosterone Males T-*t by RIA T-3 Uptake Ratio Free Thyroxine Index POWER ANALYSIS FOR CONTINUOUS VARIABLES BY DELTA % (Exposed=300: Controls==300) 5 101 15 .59 .99 1 17 .53 .86 .99 1 1 .38 .91 1 .25 .73 .97 .44 .95 1 111 74 1 1 CO 11 111 .31 .84 .99 .92 1 .7 1 1 1 .43 .73 .94 .26 74 .98 .5** .98 1 .8*i 1 I I 1 Power by Delta 30 40 104 STLCOPCB4042749 Table 24 (continued) WBC Hemoglobin HCT Platelet Count Ferritin Creatinine Clearance Delta Ammino Levulinic Acid Porphobi1inogen CopropophyrIn IgG 1 gA IgM Total Protein-Urine T-Pan T-He1 per T-Suppres sor T-HeIper/T-Suppressor 5 12 .85 1 11 11 1& 1 1 1 . 66 1 1 .09 .22 M .98 1 1 .13 37 69 .4 .93 1 .2 .6 .91 .86 1 1 .28 .8 .99 .4 93 1 .86 1 1 .67 1 1 .38 91 1 36 .97 1 .56 99 1 Power by Delta % 20 30 II II II 40 I1 .67 .95 II .91 I II 99 1 11 11 11 11 II 1I 11 1I moo oin 50 75 100 od coo Cf-O </) Q 105 8. 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Kimbrough, R.D. (Ed.) (1980) Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. Elsevier/North Holland, New York. Kimbrough, R. and Linder, R. (1978) The Effect of Technical and Purified Pentachlorophenol in the Rat Liver. Toxicol. Appl. Pharmacol. 46:151. Klemmer, H.W., Wong, L., Sato, M.M., Reichert, E.L., Korsak, R.J., and Rashap, M.N. (1980). Clinical Findings in Workers Exposed to Pentachlorophenol. Arch. Environm. Contam. Toxicol. 9:715. Kobayashi, S., Toida, Kawamura, H. Chang, H. , Fukuda, T. , Kawaguchi, K. (1972) Chronic Toxicity of 2,4-Dichlorophenol in Mice. Toho Igakkai Zasshi (J. Med. Soc. Toho Uni) 19 (3--4):356. - DSW 476038.0590 ! STLCOPCB4042754 110 Kociba, R. J., Reyes. D.G., Beyer, J.E., Carreon, R.M., Wade, C.E., (1978) Results of a Two-Year Chronic Toxicity and Oncogenicity Study of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Rats. Toxicol. Appl. Pharmacol. 46:279. 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Lathrop, G.D., (1983) An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides: Baseline Mortality Study Results. USAF-UFSC. May, G. (1973) Chloracne from the Accidental Production of TCDD. Brit. J. Indus. Med. 30:276. May G. (1982) TCDD: A Survey of Subjects Ten Years After Exposure. Brit. J. Indust. Med. 39:128. Menon, J.A. (1958) Tropical Hazards Associated with the Use of Pentachlorophenol. Br. Med. J. 1:1156. Moore, J.A., McConnell, E.E., Dalgard, D.W., and Harris, M.W. (1979) Comparative Toxicity of Three Halogenated Dibenzofurans in Guinea Pigs, Mice, and Rhesus Monkeys. Ann. NYAS 320:151. Moses, M., Lilis, R., Crow, K.D., Thornton, J., Fischbein, A., Anderson, H.A., and Selikoff, I.J. (1984) Health Status of Workers with Past Exposure to 2,3,7,8-TCDD in the Manufacture of 2,4,5-T: Comparison of Findings With and Without Chloracne. Am. J. Ind. Med. 5:157. Muranyi-Kovacs, I., Rudali, G., and Imbert, J. (1976) Bioassay of 2,4,5-Trichlorophenoxyacetic Acid for Carcinogenicity in Mice. Br. J. Cancer 33:626 , DSW 476038.0591 I STLCOPCB4042755 Ill Muranyi-Kovacs, I., Rudali, G.-, and Imbert, J. (1976) Bioassay of 2,4,5-Trichlorophenoxyacetic Acid for Carcinogenicity in Mice. Br. J. Cancer 33:626. : Nielsen, K., Kaempe, B., and Jensen-Holm, J. (1965) Fatal Poisoning in Man by 2,4-Dichlordphenoxyacetic Acid. Acta Pharmacol. Toxicol. 22:224. NIOSH (1983) Registry of Toxic Effects of Chemical Substances. U.S. Dept. HHS/CDC/NIOSH, Cincinnati. Nolan, R.J., Smith, F.A., and Hefner, J.G. (1979) Elimination and Tissue Distribution of 2,3,7,8-TCDD in Female Guinea Pigs Following a Single Oral Dose. Toxicol. Appl. Pharmacol. 48:A162. Norback, D.H. (1975) Tissue Distribution and Excretion of Octachlorodibenzo-p-Dioxin in the Rat. Toxicol. Appl. Pharmacol. 32:330. Pazderova-Vejlupkova, J., Lukas, E., Nemcova, M., Pickova, J., and Jirasek, L. (1980). Chronic Poisoning by 2,3,7,8-TCDD. Prac. Lek. 32:204. Pazderova-Vejlupkova, J., Nemcova, M., Pickova, J., Jirasek, L., and Lukas, E. (1981) The Development and Prognosis of Chronic Intoxication by TCDD in Men. Arch. lEnv. Health 36:5. Piper, W.N., Rose, J.Q., and Gehring, P.J. (1973). Excretion and Tissue Distribution of 2,3,7,8-TCDD in the Rat. Environ. Health Persp. 5:241. Pocchiari, F., Silano, V. , and Zampieri, A. (1979) Human Health Effects From Accidental Release of TCDD at Seveso, Italy. Ann. N.Y. Acad. Sci. 320:311. Podalak, M. (1981a) Dose-Dependence of the Effects Caused by Acute Intoxication with 2,4-D.I. Biogenic Amines. Bromat. Chera. Toksykol. 14:17. Podolak, M. (1981b) Dose-Dependence of the Effects Caused by Acute Intoxication with 2,4-D. II. Oxidative Phosphorylation. Bromat. Chem. Toksykol. 14:169. - Poland, A.P., Smith, D., Metter, G., and Possick, P. (1971). Health Survey of Workers in a 2,4-D and 2,4,5-T Plant. Arch. Env. Health 22:316. Potter, C.L., Sipes, I.G., and Russell, D.H. (1983) Hypothyroxinemia and Hypothermia in Rats in Response to 2,3,7,8-TCDD Administration. Toxicol. Appl. Pharmacol. 69:89-95. Prescott, L.F., Park.J., and Darrien, I. (1979) Treatment of Severe 2,4-D and Mecoprop Intoxication with Alkaline Diuresis. Br. J. Clin. Pharmac. 7:111 DSW 476038.0592 I STLCOPCB4042756 112 Rappe, C.,and Buser, H.R.(1980) Chemical Properties and Analytical Methods. In: Kimbrough (Ed), Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. Elsevier/North Holland, New York. Rappe, C., Buser, H.R., and Nygren, M. (1981) Unpublished. Rappe, C., Gara, A., and Buser, H.R., (1978) Chemosphere 7:981. Rappe, C., Nygren, M., Buser, H.R., Masuda, Y., Kuroki, H., land Chen, kP.H. (1981). Identification of Polychlorinated Dioxins and Dibenzofurans in HumanSamples. Unpublished. Reggianl, G. (1982) Observations in Man. Pocchiarl, F. l(Ed), Press,New York. Toxicology of TCDD and Related Compounds: In: Hutzinger, 0., Frei, R. W., kMerlan, E., and Chlorinated Dioxins and Related Compounds, Pergamon Rihmaiki, S. Et al (1980) Report of the Advisory Group to the Finnish National Board of Health on Herbicides. Riviere, J.L. and Bach, J. (1981) Effect of Pesticides and Pollutants on Metabolism: Effect of Herbicides, 2,4-D and Paraquat, on the Cytochrome P450 System of Mice and Japanese Quail. Phytiatr. Phytopharm. 30:183. Roberts, H.J. (1983) Aplastic Anemia and Red Cell Aplasia Due to Pentaghlorophenol. South Med. J. 76:45. Roll, R. (1971) Studies of the Teratogenic Effect of 2,4,5-T in Mice. Fd. Cosmet. Toxicol. 9:671. Rose, J.Q., Ramsey, J.C., Wentzler, T.H., Hummel, R.A., and Gehrlng, P.J.(1976) The Fate of 2,3,7,8-TCDD Following Single and Repeated Oral Doses to the Rat. Toxicol. Appl. Pharmacol. 36:209. Sauerhoff, M.W., Braun, W.H., Blau, G.E., and Gehring, P.J. (1977) The Fate of 2,4-Dichlorophenoxyacetic Acid Following Oral Administration to Man. Toxicology 8:3. Smith, F.A., Schwetz, B.A., and Nitschke, K.D., (1976) Teratogenicity of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in CF-1 Mice. Toxicol. Appl. Pharmacol. 38:517. Somani, S. M., Kaka, J.S., and Smart, T.A. (1981) Disposition of 2,4-Dimethylphenol and 2,4-Dichlorophenol in Rat. Fed. Proc. Fed. Am. Soc. Exp. Biol. 40 (3PT 1): 698. Stingily, K.0. (1940) A New Industrial Dermatitis." South. Med. J. 33:1268. Suskind, R.R. (1980) ' DSW 476038.0593 STLCOPCB4042757 113 Suskind, R. R. (1953) A Clinical and Environmental Survey, Monsanto Chemical Company, Nitro, West Virginia. Report of the Kettering Laboratory, July. Suskind, R. R. (1977) Chloracne and Associated Health Problems in the Manufacture of 2,4,5-T. Report to the NIEHS/IARC Joint Conference, Lyon, France. January. Suskind, R. R., and Hertzberg.V.S. (1984) Human Health Effects of 2,4,5-T and its Toxic Contaminants. J. Amer. Med. Assoc. 251:2372. Taylor, C. B., Coffey, T., Berka.K., Iaffaldano, R., Casey, K., Haskell, W.L., (1984) Seven-Day Activity and Self-Report Compared to a Direct Measure of Physical Activity. Amer. J. Epi. 120:818-24. Telegina, K.A., and Bikbulatova, L.J. (1970) Affection of the Follicular Apparatus of the Skin in Workers Employed in the Production of the Butyl Ester of 2,4,5-T. Vestnik Derm. Ven. 44:35. Thiess, A.M., Frentzel-Beyme, R. and Link, R. (1982) Mortality Study of Persons Exposed to Dioxin in a Trichlorophenol Process Accident That Occurred in the BASF AG on November 17, 1953. Am. J. Ind. Med. 3:179. Thigpen, J. E., Faith, R. E., McConnell, E. E., and Moore, J. A., (1975) Increased Susceptibility to Bacterial Infection as a Sequela of Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Infection and Immunity 12:1319. Tillman, E. (1977) Todd, R.L. (1962) A Case of 2,4-D Intoxication. J. Iowa Med. Soc. 52:663. Toth, K., Somfal-Relle, S., Sugar, J. , and Bence, J. (1979) Carcinogenicity Testing of Herbicide 2,4,5-Trichlorophenoxyethanol Containing Dioxin and of Pure Dioxin in Swiss Mice. Nature 278:538. Treibig, G., Krekeler, H., Gossler, K., Valentin, H. (1981) Determination of the Motor and Sensory Nerve Conduction Velocity in Persons Occupationally Exposed to Pentachlorophenol. Int. Arch. Occup. Environ. Health 48:347. Truhaut, R., Vitte, G., Boussemart, E. (1952) Occupational Poisoning in the Wood Industry, Observations on Two Fatal Cases. Arch. Mai. Prof. 13:567. Tulp, M.T.M. and Hutzinger, 0. (1978) Rat Metabolism of Polychlorinated Dibenso-p-Dioxins. Chemosphere 9:761. " USEPA (1978) Draft Report of the Ad Hoc Study Group on Pentachlorophenol Contaminants. Environmental Health Advisory Committee, Science Advisory Board, Research Triangle Park, N.C. " DSW 476038.0594 STLCOPCB4042758 L14 Van Miller, J.P., Lalich.J.J., and Allen, J.R. (1977) Increased Incidence of Neoplasms in Rats Exposed to Low Levels of 2,3,7,8-Tetrachlorobenzop-Dioxin. Chemosphere 9:537. Van Miller, J.P., Marlar, R.J., and Allen, J.R. (1976). Tissue Distribution and Excretion of Tritiated Tetrachlorodibenzo-p-Dioxin in Nonhuman Primates and Rats. Fd. Cosmet. Toxicol. 14:31. Vemot, E.H., MacEwen, J.D., Haun, C.C., and Kinkead, E.R. (1977) Acute Toxicity and Skin Corrosion Data for Some Organic and Inorganic Compounds and Aqueous Solutions. Toxicol. Appl. Pharmacol. 42:417. Villanueva, E.C., Burse, V.W., and Jennings, R.W , Chlorodibenzo-pDloxins. Contamination of Two Commercially Available Pentachlorophenols. J. Agric. Food Chem. 21:739. Vos, J.G., Sterringa, T.J., Zellenrath, D., Docter, H.J., and Dalderup, L.M. (1977) TCDD Accident at a Chemical Factory in the Netherlands. Report to the NIEHS/IARC Joint Conference, Lyon, France, January. USEPA (1978) Draft Status Report. Dioxin in Industrial Sludges. Office of Solid Waste. Research Triangle Park, N.C. Wallis, W.E., Van Poznak, A., and Plum, F. (1970) Generalized Muscular Stiffness, Fasciculations, and Myokymia of Peripheral Nerve Origin. Arch. Neurol. 22:430. Williams, P.L. (1982) Pentachlorophenol, an Assessment of the Occupational Hazard. Am. Ind. Hyg. Assoc.J. 43:799. Wood, S., Rom, W. N., White, G.L., and Logan, D.C. (1983) Pentachloro phenol Poisoning. JOM 25:527. Woolson, E.A., Thomas, R. F., and Ensor, P.D. (1972). Survey of Polychlorodibenzo-p-Dioxin Content in Selected Pesticides. J. Agric. Food Chem. 20:351. Young, J.D., Ramsey,J.C., and Braun, W. H. (1981). Pharmacokinetics of 2,4,5-T PGBE Ester Applied Dermally to Rats. J. Toxicol Environ. Health 8:401. Zack, J. (1980) Zack, J.A., and Suskind, R.R. (1980) The Morality of Workers Exposed to TCDD in a Trichlorophenol Process Accident. J. Occup. Med. 22:11. Zober, A., Schaller, K.H., Gossler, K., and Krekeler, H.J. (1981) Pentachlorophenol and Liver Function. A Pilot-Study on Occupationally Exposed Collectives. Int. Arch. Occ. Environ. Health 48:347. DSW 476038.0595 STLCOPCB4042759 115 9. PEER REVIEW COMMITTEE Mark R. Cullen, M.O. Assistant Professor of Medicine & Epidemiology Director, Yale-New Haven Occupational Medicine Program School of Medicine New Haven, Connecticut George Lathrop, M.D., Ph.D. Principal Scientist Epidemiology JRB Associates San Antonio, Texas Richard Monson, M.D. Professor of Epidemiology Harvard School of Public Health Boston, Massachusetts Lynne Moody, M.D., M.P.H. Medical Officer National Institute for Occupational Safety and Health Robert A. Taft Labs Cincinnati, Ohio Robert Waldman, M.D. Chairman, Department of Medicine University of West Virginia Morgantown, West Virginia DSW 476038.0596 Ii i STLCOPCB4042760 PRELIMINARY BUDGET ESTIMATES FOR KRUMMRICH PROJECT 1) Data Gathering - 18 subjects per day by a team of 6 physicians (3 internists, 2 neurologists, 1 dermatologist) working 5 days per week and communting from Chicago on a weekly basis. (All figures assume 813 subject examination.) Physician Fees Physician Expenses Blood k Urine Test Paramedical Salaries , . Equipment Lease/Purchase Survey Research Lab Neuro Behavioral Exam Subject Reimbursement 585,360 65,800 654,000 78,750 46,300 170,000 12,810 54,000 1,667,020 2) Data analysis - assumes 18 month required for data analysis and generation of individual reports. Salary of Investigators Salary for Support Personel Office Equipment, Supplies Equifax Cohort Search Data Coding Service Consultation Fees k Expenses Peer Review 156,000 356,134 45,465 45,150 31,150 13,632 10,000 657,531 Totals: I II University Overhead 1,667,020 657,531 53,250 2,377,801 DSW 476038.0597 STLCOPCB4042761 V DEC l 9 1989 \\ Monsanto Company 800 N. Lindbergn Boulevard St. Louts, Missouri 63167 Phone: '314) 694-1000 December 11, 1989 NVIRONMENT. SAFETY & HEALTH Daniel 0. Hryhorczuk, M.D. 1515 N. Keystone Avenue River Forest, Illinois 60305 Dear Drs.` Hryhorczuk and Wallace: Thanks for your presentations to our workforce at the Krummrich plant last Friday the 1st. It appeared to us that you were successful in communicating both your findings and conclusions to the attendees at each meeting. We appreciate your efforts and are certain the plant and all of our employees feel the same. We look forward to seeing you both again in a year or so, if not sooner. Until then have a joyous holiday season and fruitful new year. Yours truly PRC/kg P. R. Conner, M.D. DSW 476038.0598 STLCOPCB4042762 Monsanto Company 800 N. Lindbergh Boulevard St. Louis, Missouri 63167 Phone: (314) 694-1000 September 28, 1988 ENVIRONMENT, SAFETY & HEALTH Daniel O. Hryhorczuk, M.D., MPH Department of Preventive Medicine and Community Health Northwestern University Medical School Chicago, IL 60611 Dear Dan: Everybody and his brother (that is to say, Friedlander, Gaffey, Garrett, Haselhorst and Leet) has reviewed the preliminary draft report, each of us taking the sections that he or she was best qualified to review. Our comments are attached. Some of the comments are editorial, some are matters of fact, and some represent our opinions or questions about the text. I hope they will be helpful to you. Some of them may affect the tables that will go into the final report. Yours sincerely, / William R. Gaffey, Ph.D. Epidemiology Director /jf cc: B.R. J.T. B.L. T.L. Friedlander w/copy of comments Garrett 11 II Haselhorst II II Leet It II II DSW 476038.0599 STLCOPCB4042763 Comments on Preliminary Draft Report Titled "Epidemiologic Investigation of the Health Status of Monsanto Employees with Past Exposure to Chlorophenols, Chlorphenoxy Acid Esters and Their Dioxin Contaminants at the W.G. Krummrich Plant in Sauget, Illinois" Pages 1-4. Acronyms are given for a number of substances (e.g. 2,4-D) and tests (e.g. BUN). They should be spelled out the first time they are used, followed by the acronym in parentheses. Page 3, first paragraph. Dr. Tillman said that these weight variations did not seem to him to be unusual. Page 4, Sec. 2.3.3. The first two sentences are a nonsequitur and should be removed. Page 5, Sec. 2.4.2. Second line. "1982" should be "1986". Third line. Something should be added to the effect that no adjustment was made for smoking because the data were not easily available. Fourth line. "investigating" should be "investigated". Sixth line. "selected" should be inserted between "with" and "subcohort". Page 6. After first sentence put (MEHI) in parentheses. Page 7, Sec. 4.2.1. No rationale for why some hypotheses are "primary" and some are "secondary". Page 9, Sec. 4.3. Here and elsewhere, proprietary names like Santobrite should be followed by TM the first time they are used, with a footnote saying that it is a registered trade mark of the Monsanto Company. 1 DSW 476038.0600 STLCOPCB4042764 Page 15, Table 4.1. 1931. S-036 should be in parenthesis. 1964. S.G. should be spelled out. Page 17, first line. The term "snift gas" should be replaced by "revaporized chlorine (known in the plant as "sniff gas")." Page 22, Table 4.2. Did the A and B operator also assist the Premium Operator? Replace question marks with an asterisk and explanatory footnote. Pages 37 and 51. The word "fines" is a generic term used here in specific senses that are not appropriate. On page 37, next to last line, replace "fines" with "materials" and on page 51, Table 4.10, in 1961, replace "fines" by "particulate products". The usage elsewhere is correct. Page 83, Sec. 4.4.1.1. Title and first sentence. Since cohorts are identified independently of outcome, and these people had to be alive to get into the study, the term "group" may be more appropriate. Definition of exposed cohort. The implication here is that chloracne alone did not qualify a person as being exposed. On page 94, Sec. 4.5.2, the opposite is implied. On page 136, Sec. 5.6, it is apparent that people were called exposed if they worked in the appropriate departments according to their work histories or if they had chloracne and stated that they had worked in the appropriate departments. In other words, the criterion for exposure appears to be different for those with chloracne and those without. Some clarification is needed here and in the other cited sections. Last paragraph. Salaried controls were not included in the main study. It might be appropriate here to explain why salaried people were included only in the pilot study. In the last sentence MEHI does not have to be spelled out. Page 85a, Table 4.17. The age ranges go over 100. In some comment needed? DSW 476038.0601 STLCOPCB4042765 Page 86, first complete paragraph. We studied the mortality experience of the whole plant, so this could not explain the difference in the percents whose vital status is unknown in the exposed and controls. The explanation seems to be that one way not to be exposed was to work for a shorter time. Therefore there were more terminations in the control group who had to be followed, therefore more persons with unknown vital status. Tables 4.17 and 4.18 vs. Tables 8.1, 8.2, 8.3. The labels "Exposed" and "Control" are used in both sets of tables, but it is clear that Tables 4.17 and 4.18 deal with "potential" or "eligible" persons while Tables 8.1 etc. deal with those who were actually examined. The labels should be different in the first set of tables. Page 91, Sec. 4.5.1, first paragraph. There were actually four sources. One was hard copies of employment records prior to MEHI. Page 96, Sec. 4.5.1.1, first sentence. No need to define the acronym MEHI. "hourly" should precede "worker" and "after 1935" should precede "at". Page 92, first five lines. Is the statement about Dr. Davis correct? Page 93, fifth line. "assigned" should replace "misclassified" Page 94, third line from bottom. Why capitalize "Department"? Page 95, Sec. 4.5.2.2. The classification by exposure department needs clarification. First, the implication is that there was no one with a mixed exposure. We know this is not true because in the succeeding tables the numbers of people in each of these categories do not add up to the "Total Exposed" given in the tables. . Second, the category "maintenance workers on the chloracne registry" must include some people (perhaps all of them) with chloracne. Therefore, in the succeeding tables, almost all of which show a fifth category called "chloracne", that category must overlap the other categories. A table showing the numbers in each group, and the numbers with mixed exposures, would be helpful. DSW 476038.0602 STLCOPCB4042766 Page 96, first complete paragraph. Reliance in self-reporting was necessary because plant records were not available for those terminated before 1970. Page 97, Sec. 4.6, last line. There is no Table 19. Page 100, Sec. 4.6.2, second line. Delete "b". Page 103, Sec. 4.6.9, third line "Sensortec" should be "Sensortex". Page 104, third line. There is no Table 4.19. Page 107, sec. 4.8.2.1, first paragraph. In item (3), should it be pointed out that the subjects, when asked, did not recall any such discrepancies? Page 108, Sec. 4.8.2.3. Should it be pointed out that the groups were randomized with respect to time of examination in order to eliminate time-of-day bias? Page 109, Sec. 4.9. If there are to be power calculations after the fact, they should be done for tests of means as well as for tests of prevalence. However, after a test has been done the power is not relevant. What is relevant are the confidence intervals that were obtained. It can happen that a test which is a priori not powerful can give a confidence interval that rules out the alternative. Page 117, second full paragraph, second and third lines. Johns, not John's and Holmes, not Homes. Page 122, last paragraph, fifth line. Insert after "to" the phrase "a six digit job class code beginning with" DSW 476038.0603 STLCOPCB4042767 Page 148, Sec. 6.5.8, third line One "n" in Marilyn. Page 122, last paragraph, eighth line. Add to the end of the sentence the parenthetical expression (this accounted for about two percent of the sample). Page 125, Sec. 5.4.1, fourth line. (83.2%) should be (83.3%) Page 136, second line. "that" should be "than". Page 142, second paragraph, fifth line. "of" should be "or". Page 143, last line. "coordinator" should be "manager". Page 145, second line. Insert the sentence - The van was also inspected by Mr. Paul Kalicki from the Illinois Department of Nuclear Protection. Page 145, Sec. 6.5.3. second line - change "coordinator" to "manager" third line - change "electrocardiogram" to "electrocardiogram/ blood pressure". Page 146, third line. After first sentence insert - At that time each one was given an ID bracelet with a 4 digit study number and the first 4 letters of the last name for purposes of quality control, but which included no indication of exposure status. Page 146, first paragraph, last line. Change "coordinator" to "manager". Add the sentence - All participants completed a final exit interview prior to leaving the examination site. Page 146, Sec. 6.5.6, fifth line. Remove "ed" from "administered". Page 148, Sec. 6.5.8, second line. Date is April 7, 1986. C DSW 476038.0604 STLCOPCB4042768 Page 149, Sec. 6.5.10, sixth line. "At" should be "A". Page 151. Should be some comment on which records were lost. Were they for people who terminated before some date? Page 154, Table 7.1. What do the initials mean? Page 157, Sec. 7.6, third paragraph. Fisher's Exact test is usually a one-sided test. Chi-square is a two-sided test. For these associations and the p-values in the regression tables, was a one-sided or a two-sided test used? Page 158, Sec. 7.6.1, first paragraph. The exposure classification, except for the chloracne category, is redundant with Sec. 4.5.2.2 and needs clarification. Page 161, Sec. 7.6.4. Chloracne as defined here is a mixture of cumulative incidence and prevalence. This implies that the investigators consider chloracne a marker for relatively heavy exposure. This is perfectly proper, but should be mentioned so that readers will not interpret the chloracne figures as being incidence or prevalence. Page 194, Sec. 8.3.1, second paragraph, third line. Phrase (2) does not seem to make sense. Page 197, Table 8.17. The number in Maintenance cannot be greater than the corresponding number in Table 8.16. One of the two entries must be incorrect. Tables 8.19, 8.20, 8.21, 8.22. Apparently Table 8.19 includes people who worked in more than one production department and therefore do not appear in Tables 8.20, 8.21, or 8.22. It would be helpful to restate in the text that Tables 8.20, 8.21 and 8.22 do not add up to Table 8.19. (The pages for these tables are misnumbered.) 6 DSW 476038.0605 STLCOPCB4042769 Tables 8.30-8.32. Pages are misnumbered. Page 232, Table 8.40 The number in "Only 236" is 278. It was never more than 260 in previous tables of the examined group. Is this an error? Table 8.50 and text. In several places in this table (Pattern Memory is one example) Department 236 did significantly worse than the controls while the other three exposure groups did very well. Because the people in 236 were a majority of the "All exposed" group the latter group also was significantly worse than the controls. The results for Department 236 and for "All exposed" are presented as if they were two independent conclusions, when in fact the latter is caused by the former. As stated, the findings for "All exposed" falsely imply that the result is pervasive in the exposed group, which it generally is not. Tables 8.51 to 8.69. What are the numbers in square brackets in the left column? DSW 476038.0606 STLCOPCB4042770 d DANIEL O. HRYHORCZUK, M.D., M.P.H. 1515 North Keystone Avenue River Forest, Illinois 60305 (312) 366-1064 Dr. Barry Friedlander Medical Director Monsanto Company 800 N. Lindbergh Boulevard St. Louis, Missouri 63167 March 26, 1990 APR 6 n Dear Dr. Friedlander: My colleagues and I wish to thank you and your staff for your careful review of our first report on the Krummrich morbidity study. Several of your suggestions regarding an executive summary, critical literature review, and choice of emphasis and wording were excellent and would indeed improve the clarity of our report. While I had taken notes regarding your suggestions at our last meeting, I would be grateful if you could transmit them to me in writing. This way I can assure that we have the opportunity to address each of your suggestions. We have sent the original version of our report to the Peer Review Committee to keep them abreast of our updates. We will similarly send them updated versions of our report as they become available. We are eager to proceed with the preparation of manuscripts for publication in peer-reviewed journals. We will of course give you the opportunity to review these articles before they are submitted. I know that we are all committed to completing this work as carefully and expeditiously as possible. I look forward to your reply at your earliest convenience. If need any additional information or have any questions, please feel free to call. g i' \r Daniel Hryhorczuk, M.D., M.P.H. DSW 476038.0607 STLCOPCB4042771 NORTHWESTERN MEDICAL FACULTY FOUNDATION. INC. January 30, 1985 222 East Superior Street Chicago. Illinois 60611 (312) 649-6940 George Roush, M.D. Medical Director Department of Medicine and Environmental Health MONSANTO COMPANY G2WG 800 North Lindberg Boulevard St. Louis, Missouri 63167 Dear Doctor Roush: We are forwarding to you the revised protocol for the "Epidemiologic Investigation of the Health Status of Monsanto Employees with Past Exposure to Chlorophenols, Chlorphenoxy Acids, and Their Dioxin Contaminants at the W.G. Krunnrich Plant in Sauget, Illinois". _ This revision incorporates many of the excellent-suggestions. of the Peer Review Committee. ' We believe that each worker will look upon the examination as a valuable benefit provided by Monsanto. We also believe that this study will be a major contribution to the scientific literature on dioxins. The study is designed to answer many of the previously unresolved questions regarding the possibility of chronic health effects in workers with past exposure to dioxins. The Peer Review Committee was unanimous in commending Monsanto. for, its sponsorship of this study. We appreciate your confidence in " selecting us to design and carry out this important research. We wish to extend our personal thanks to you and your staff for your assistance and the courtesy you have shewn us during the, design of this study. .. . - Warren Wallace, M.D JEW/W:pjw DSW 476038.0608 STLCOPCB4042772 EPIDEMIOLOGIC INVESTIGATION OF THE HEALTH STATUS OF MONSANTO EMPLOYEES WITH PAST EXPOSURE TO CHLOROPHENOLS, CHLORPHENOXY ACIDS, AND THEIR DIOXIN CONTAMINANTS AT THE W.C. KRUMMRICH PLANT IN SAUCET, ILLINOIS: STUDY PROTOCOL Principal Investigators Daniel 0. Hryhorczuk, M.D., M.P.H. Warren H. Wallace, M.D. Co-Investigators . James R. Webster, Jr., M.D. Victoria Persky, M.D. Department of Medicine Department of Preventive Medicine and Community Health Northwestern University Medical School Chicago, Illinois January, 1985 DSW 476038.0609 I STLCOPCB4042773 TABLE OF CONTENTS 1. 2. 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 3. 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 4. 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 4.2.8 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.3.9 Executive Summary PURPOSE OF STUDY BACKGROUND Plant History Products Previous Studies of Plant Population Tillman, 1977 Suskind, 1980 Zack, 1980 LITERATURE REVIEW Overview Ortho Chlorophenol Parachlorophenol 2.4-Dichlorophenol Pentachlorophenol 2.4-Dichlorophenoxyacetic Acid 2,4,5-Trichlophenoxyacetic Acid Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzofurans (PCDFs) DESIGN Study Design Ascertainment of Exposure Processes Industrial Hygiene Chloracne Registry Maintenance Employees Definition of Exposed Cohort Demographic Characteristics of the Exposed Cohort Follow-Up, Accessibility and Participation of the Exposed Cohort Internal Control Group Ascertainment of Health Status Medical History Questionnaire Reproductive History Dietary History Physical Activity Assessment Occupational and Environmental History Medical Records Review Internist's Physical Examination Dermatologic Examination Neurologic Examination 1 1 1 1 2 2 2 3 4 8 8 10 10 11 14 16 17 36 36 36 51 61 61 63 65 65 69 72 72 73 74 74 74 74 75 76 76 DSW 476038.0610 STLCOPCB4042774 Table of Contents (page 2) 4.3.10 4.3.11 4.3.12 4.3.13 4.3.14 4.3.15 4.3.16 4.3.17 5. 5.1 5.2 5.3 5.3.1 5.3.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.4 6. 6.1 6.2 6.3 6.4 6.5 6.5.1 6.5.2 6.6 6.7 7. 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8. 9. 10. Electrocardiogram Pulmonary Function Tests Chest X-Ray Quantitative Sensory Examination Nerve Conduction Velocities Neurobehavioral Testing Blood Tests Urine Tests DATA ANALYSIS Data Entry, Processing, and Storage Quality Control Analysis Classification of Exposure Classification of Disease Confounders and Effect Modifiers Demographic Characteristics Lifestyle Characteristics Chemical Exposures Effect Modifiers Statistical Tests IMPLEMENTATION Identification and Recruitment of the Study Population Development of Survey Instruments Medical Examinations Data Analysis Reports Reports to Individual Participants Final Report Timetable Human Subjects Review STUDY LIMITATIONS AND CORRECTIVE MEASURES Loss to Study Survival Incidence-Prevalence Bias Recall Bias Interviewer/Examiner Bias Misclassification of Exposure Confounding Chemical Exposures Repeated Measures Statistical Power Limitations REFERENCES PEER REVIEW COMMITTEE BUDGET 76 76 76 76 77 77 77 78 83 85 87 87 88 88 88 88 89 90 90 92 92 92 93 93 93 93 94 94 96 96 97 97 97 97 98 98 99 105 115 116 DSW 476038.0611 i STLCOPCB4042775 TABLE OF TABLES Title Page Observed and Expected Deaths (Non-White Males) 6 2 Observed and Expected Deaths (White Males) 7 3 Possible Number of Isomers of PCDDs and PCDFs is 4 PCDDs and PCDFs Reported in Phenols 19,20 5 PCDDs in 2,4,5t-T and 2,4-D 21,22 6 Summary of Acute Toxicity of 2,3,7,8 - TCDD 26 7 Toxic Effects of 2,3,7,8 - TCDD in Man 28 8 Occupational Exposures Resulting in Illness (Chlorinated Phenols) 29,32 9 Epidemiologic Studies on Carcinogenicity of TCDD 33 10 Symptomology of Yusho Cases, 1969-72 35 11 Job Descriptions Monsanto/CWU 42,43 12 Levels of PCDD in PCP, PCP-Cuts and PCP Residue 53 13 PCP Air and Wipe Samples (Dept. 236) 54 14 PCDD in Wipe Samples (Dept. 236) 56 15 Air Levels of Chlorinated Phenols (Dept 237) 58 16 Levels of PCDD in 0-CP and D-CP 59 17 Demographic Characteristics of Maintenance Workers 62 18 Exposed Cohort by Length of Exposure and Employment Status 64 19 Age Distribution of Exposed Cohort as of 1984 66 20 Comparison Between Exposed and Internal Controls 70 21 Summary of Comprehensive Medical Exam - 80,82 22 Forms for Collection, Recording and Coding of Data 84 23 Power Analysis for Dichotomous Variables 100,102 24 Power Analysis for Continuous Variables 103,104 DSW 476038.0612 STLCOPCB4042776 TABLE OF FIGURES No. 1 2 3 4 5 6 7 8 9 10 11 12 Title Page Chemical Structure Plant Geography Chlorination and Acid Scrubbing (Dept. 236) Prilling and Packaging (Dept. 8-236) Chlorination Step (Dept. 237) Overhead Layout (Dept. 237) Pre-Mix Slurry (Dept. 268) Reaction (Dept. 268) Neutralization and Filtration Estimated Follow-up, Accessibility and Participation Quality Control of Data Entry Study Timetable 9 37 39 40 44 45 47 48 49 67 86 95 DSW 476038.0613 STLCOPCB4042777 EXECUTIVE SUMMARY OF THE STUDY PROTOCOL The purpose of this study is to determine if workers at Monsanto's Krummrich Plant in Sauget, Illinois suffered any long term health effects as a result of their past exposure to chlorinated phenols, esters of 2,4-D and 2,4,5-T, and their chlorinated dioxin contaminants. The health status of the exposed employees will be compared to the health status of Krummrich employees who were not exposed to these compounds. The exposed cohort will consist of all Krummrich employees who were engaged in the production of chlorinated phenols or chlorphenoxy herbicides for one or more days between January 1, 1938 and December 31, 1983. Maintenance employees who were assigned to these areas and who developed chloracne will also be included in the exposed cohort. One thousand and fifty-five employees meet the definition of exposure of whom 221 are deceased. Four hundred and four exposed workers are expected to participate in the study. This exposed cohort will be comprised of 221 active, 106 retired, 60 terminated, and 17 other workers whose employment status is as yet unknown. One thousand seventy-seven Krummrich employees were considered to be non-exposed during this same time period. Four hundred and nine are expected to participate as internal controls. This group will be comprised of 218 active, 50 retired, and 141 terminated workers. Study participants will undergo a comprehensive medical examination, including a medical history, occupational and environmental history, reproductive history, physical examination, dermatologic examination, neurologic examination, electrocardiogram, pulmonary function tests, chest DSW 476038.0614 STLCOPCB4042778 x-ray, quantitative sensory examination, nerve conduction velocity studies, neurobehavioral testing, blood tests, and urine tests. Questionnaire items will be confirmed by medical record review. The health status of the exposed cohort will be compared to the health status of the internal controls. The strategy for statistical analysis will consist of 1) examination of crude associations, 2) stratified analysis, 3) tests for dose response, and 4) multivariate analysis. DSW 476038.0615 STLCOPCB4042779 1 1. PURPOSE OF THE STUDY The purpose of Chis study is to determine if workers at Monsanto's Krummrich Plant in Sauget, Illinois suffered any long term health effects as a result of their past exposure to chlorinated phenols, esters of 2,4,-D and 2,4,5-T and their chlorinated dioxin and dibenzofuran contaminants. 2. BACKGROUND . 2.1 Plant History The plant was established in 1907 as the Commercial Acid Company. At that time it occupied 30 acres and employed 70-100 people. Monsanto purchased the plant in 1917 to insure a supply of mineral acids. The plant was referred to as "Plant B" until 1951, when it was renamed the William G. Krummrich Plant in honor of a former plant manager. The Krummrich Plant currently occupies 329 acres and employs approximately 1100 people. The plant produces about 1 billion tons of material per year. The plant is administered by two of Monsanto's four operating companies: Monsanto Industrial Chemicals and its guest company, Monsanto Polymer Products. The Krummrich Plant is organized by the International Chemical Workers Union, Local 12. The plant is located in Sauget, Illinois, which is 3 miles southeast of downtown St. Louis. Fifteen percent of the plant's total resources in manpower, time, and money are devoted to its environmental monitoring and control program. The plant employs 2 part-time physicians and several nurses in addition to a large staff of industrial hygiene, safety, and environmental personnel. Monsanto's Corporate Medical Program provides oversight and support of the plant program, including computerization of employee exposure and medical surveillance data. DSW 476038.0616 STLCOPCB4042780 2 2.2 Products The Krummrich plant currently uses more than 75 different raw materials to produce approximately 20 different intermediate chemical products. The major raw materials include chlorine, phosphorus, benzene, sulfur, and salt. Major products include chlorinated benzenes, chlorophenols, orthonitrophenol, nitroanilines, PCl^, P0C1^ ^2^5' c^lrine sulfuric acid, chlorosulfonic acid, muriatic acid, chlorine bleaches and stabilizers, detergent materials, feed grade antioxidants, and elastomers. The manufacture of chlorophenols began in 1938. Production of pentachlorophenol was discontinued in 1978; the production of mono- and di-chlorophenols was discontinued in 1983. Esters of 2,4-D and 2,4,5-T were produced between 1960 and 1970. This plant was a producer of PCBs until 1977 when production was discontinued. 2.3 Previous Studies of the Plant Population 2.3.1 Tillman, 1977 In 1977 Dr. Ernest Tillman reviewed the plant medical records of 60 employees in the Pentachlorophenol Unit at the W. G. Krummrich Plant. The study group included all persons who were working in Department 236 in 1977 and all persons who had worked in Department 236 for 1 year or more since 1951. The lengths of exposure ranged from 3 months to 13 years. Forty-eight percent of the cases studied developed chloracne at some time while assigned to Department 236. In the majority of cases of active employees, chloracne appeared within 1 year of being assigned to Department 236. No difference in the frequency of occurrence was found on the basis of race or age. Chloracne occurred at all times between 1959 and 1977 with DSW 476038.0617 STLCOPCB4042781 3 no peak at any particular time. Seventy-seven percent of the study group made repeated comments about weight variations from one periodic examination to the next. The review of the periodic health questionnaires and physical examinations failed to identify any other abnormalities. 2.3.2 Suskind. 1980 In 1979 Dr. Raymond Suskind conducted a medical survey to determine the health status of employees of the W. G. Krummrlch Plant who had been exposed to chlorinated phenols. The study population included active employees who had worked in either Department 236 (pentachlorophenol) or Department 237 (chlorophenols). The total number of active employees who worked in these two areas was 157. One hundred fifteen persons volunteered for examination and 106 of these completed the physical examination. The medical survey included the completion of an administered questionnaire, a medical history, a dermatologic examination, and examination of other organ systems if indicated by the clinical history. Skin biopsies were done when indicated. Clinical laboratory tests included: blood Ca, P, BUN, creatinine, BUN-creatinine ratio, uric acid, fasting blood sugar, total protein, albumin, globulin, total bilirubin, direct bilirubin, SGOT, SGPT, alkaline phosphatase, LDH, cholesterol, iron, magnesium, sodium, potassium, chloride, GGT, triglycerides and lipoprotein profiles; CBC and differential*, urinalysis and urinary copro porphyrin, uroporphyrins, and creatinine. Personal medical histories were comfirmed by reviewing plant medical and personnel records. Sixty-six of 115 workers had a history of chloracne. Forty-three were found to have residual chloracne and of these cases 67.6% were mild and 32.5% DSW 476038.0618 I STLCOPCB4042782 moderate. All of the residual cases were comedonal in type, and 32.5% of those had cystic lesions as well. Five of 106 persons were found to have malar hirsutism and 12 were found to have actinic elastosis. In the analysis of laboratory data, test results were compared between employees with and without a history of chloracne or residual chloracne. While a small number of elevated total serum lipids were observed, there was no correlation between the serum lipids and the presence of chloracne. While persons with elevated triglycerides were found in both groups, there was no correlation between serum triglycerides and presence or absence of chloracne. No significant differences in levels of cholesterol, LDL, SGOT, SGPT, and GGT were found between the chloracne and non-acne groups. Urinary porphyrins could not be interpreted due to technical error. The frequency of abnormal levels of VLDL was significantly increased in those persons with a history of chloracne or with residual chloracne as compared to those who never had chloracne. There appeared to be less residual chloracne in the group with HDL levels of 45 or more than those in the group with levels less than 45. There was also significantly less chloracne found in workers who did not smoke at the time of examination than those who did smoke. 2.3.3 Zack, 1980 In 1977, The Chemical Manufacturers Association contracted with Tabershaw Occupational Medicine Associates to conduct an industry-wide epidemiologic study of workers exposed to benzene. The W.G. Krummrich Plant was one of the nine plants chosen to participate in this study. Judith Zack conducted a separate Standardized Mortality Ratio analysis of the data from DSW 476038.0619 STLCOPCB4042783 5 the Krummrich population. Her study cohort consisted of all male, hourly employees active on or after January 1, 1946 with six months or more of employment prior to December 31, 1977. Vital status was ascertained as of December 31, 1977. The population of the United States was used as the standard. Three thousand twenty-two employees fit the cohort entrance criteria, but 114 were excluded because of incomplete data. Two thousand seventy-two of the 2908 member study cohort were verified as living, 736 were identified as deceased, 702 of these by death certificate. The SMR's for white and non-white employees for specific causes of death are shown in Tables 1 and 2. There were no statistically significant elevations in SMR's observed among male Krummrich employees for any of the cause-of-death categories examined. Re-analysis of this data by work area is currently being done by Monsanto epidemiologists. Past employees of Department 236 and Department 268 (agricultural esters) have been included in NIOSH's industry-wide mortality study of workers exposed to dioxin. DSW 476038.0620 I STLCOPCB4042784 6 Table 1 Observed and Expected Deaths for Krummrich Plant Study Population Non-white Males Cause of Death 8th Rev. ICD Code Observed Expected SMR All causes of death - 001-998 225 256.87 88* All malignant neoplasms Buccal cavity and pharynx 140-209 140-149 42 44.54 94 1 1.54 65 Digestive organs and peritoneum 150-159 9 15.34 59* Respiratory system 160-163 17 13.20 129 Genitourinary organs 185-189 6 6.88 87 Lymphatic and hematopoietic tissue 200-209 6 3.02 199 Leukemia and aleukemia 204-207 2 1.09 183 Other lymphopoietic cancer - 4 1.93 207 Other malignant neoplasms - 3 4.56 66 Circulatory diseases 390-458 117 123.01 95 Arteriosclerotic heart disease 410-413 62 58.34 106 Cerebrovascular disease 430-438 25 28.01 89 Other circulatory diseases - 30 36.66 82 Respiratory diseases 460-519 4 14.90 27* All other diseases - 19 47.79 40* All external causes of death 800-998 31 25.47 122 Total Residual 12 1.16 * p <.05 Number persons observed =584 Number person-years observed = 12925.1 DSW 476038.0621 I STLCOPCB4042785 7 Table 2 Observed and Expected Deaths for Krummrich Plant Study Population-White Males Cause of Death - 8th 1Rev. ICD Code Observed Expected SMR All causes of death 001-998 All malignant neoplasms 140-209 Buccal cavity and pharynx 140-149 Digestive organs and peritoneum 150-159 Respiratory system 160-163 Genitourinary organs 185-189 Lymphatic and hematopoietic tissue 200-209 Leukemia and aleukemia 204-207 Other lymphopoietic cancer _ Other malignant neoplasms - Circulatory diseases 390-458 Arteriosclerotic heart disease 410-413 Cerebrovascular disease 430-438 Other circulatory diseases - Respiratory diseases 460-519 All other diseases - 511 98 2 17 46 6 7 2 5 20 273 201 30 42 20 41 522.43 101.76 3.54 28.45 34.76 11.01 10.58 4.14 6.44 13.42 261.06 188.14 30.60 42.32 27.90 69.49 93 96 56 60* 132 54* 66 48* 78 149 105 107 98 99 72 59* All external causes of death Total Residual 800-998 57 59.62 96 22 2,60 *p 05 Number persons observed = 2324 number person-years observed = 54509.1 DSW 476038.0622 STLCOPCB4042786 8 3. LITERATURE REVIEW 3.1 Overview The health effects of 2,3,7,8-TCDD, 2,4,-D, and 2,4,5-T have been studied extensively in recent years and are the subjects of several excellent reviews (Kimbrough, 1980; Esposito et al, 1980; Huff et al, 1980; HALTS, 1980; JRB, 1981; Clement, 1984). The occupational morbidity studies done to date suffer from inadequate characterization of exposure and lack of adequate controls. The occupational mortality studies are limited by small numbers. Very few studies have followed affected workers over time. Little is known about the health effects of exposure to PCDDs other than 2,3,7,8-TCDD. The only human data on the health effects of exposure to PCDFs comes from the outbreaks of Yusho disease in Japan and Taiwan in the past two decades (Kuratsune et al, 1972). These observations are confounded, however, by the co-ingestion of PCBs and chlorinated quaterphenyls. Acute poisoning from pentachlorophenol has been well described. Studies of chronic effects, however, have been limited to small numbers of active workers. There is very little animal data and no human data on the toxicities of the mono- and dichlorophenols. The structures of the chemicals discussed in this review are shown in Figure 1. A description of the actual manufacturing processes and re sulting exposures is provided in Sections 4.2.1 and 4.2.2. 3.2 Ortho Chlorophenol Ortho chlorophenol (0-CP) is a light amber liquid used as an intermediate in chemical synthesis. 0-CP is prepared by the direct chlorination of phenol. It is soluble in water (2.85/100 parts water), alcohol, and ether; its vapor DSW 476038.0623 STLCOPCB4042787 9 Fig.J CHEMICAL STRUCTURES OF CHLOROPHENOLS, CHLORPHENOXY ACIDS, AND THEIR DIOXIN AND DIBENZOFURAN CONTAMINANTS OH Cl Cl PENTACHLOROPHENOL 2,4-D 2,4,5-T DSW 476038.0624 STLCOPCB4042788 10 pressure is 1 mm at 12.1 C. . The oral LD^gOf 0-CP is 670 mg/kg in rats (NIOSH, 1983) and 625-750 mg/kg in chickens (Bubnov et al, 1971). Toxic effects in rats include restlessness, increased respiratory rate, tremors, and clonic convulsions. Pathologic changes in chickens include inflammatory loci in the cerebral cortex and dystrophic changes in the liver and myocardium. O-CP decreased hemoglobin content; increased alkaline phosphatase, LDH, and glutamate-oxaloacetate; and produced pathologically evident liver tissue degeneration in rats (Chung, 1978). 0-CP did not affect the immune system in rats at oral concentrations of 500 ppm (Exxon and Koller, 1983). 0-CP is fetotoxic in rats and high doses (Exxon and Koller, 1982). 3.3 Parachlorophenol Parachlorophenol (P-CP) is a white to straw-colored crystalline compound prepared by the direct chlorination of phenol. Solutions of P-CP are used as topical antiseptics. P-CP is soluble in water (2.71/100 parts water) and very soluble in alcohol and ether. The oral LD^q of P-CP is 261 mg/kg in the rat (NIOSH, 1983). Toxic effects include restlessness, increased respiratory rate, tremors, and convulsions. P-CP is irritating to rabbit eye and skin. 3.4 2,4-Dichlorophenol 2,4-Dichlorophenol (2,4-DCP) is a colorless crystalline compound prepared by the direct chlorination of phenol. 2,4-DCP is used as an intermediate in the synthesis of 2,4-Dichlorophenoxy acetic acid. It is sparingly soluble in water. (.45/100 parts water) and very soluble in alcohol and ether. DSW 476038.0625 STLCOPCB4042789 11 Somani et al (1981) studied the kinetics of 2,4-DCP in rats. 2,4-DCP was conjugated to glucuronide and other conjugates. The kidney had the highest amounts of free compound, followed by the liver and fat. The LD^q of 2,4-DCP is 580-4,500 mg/kg in rats and 1,630 mg/kg in mice (Kobayashi et al, 1972). Toxic effects in rodents include decreased spontaneous locomotor activity, loss of righting reflex, and sedation. The maximum chronic no-effect level in mice is 100 mg/kg/day (Kobayashi, 1972). 2,4-DCP in doses of .1 mg/kg is fetotoxic in rats (Konstantinova et al, 1976). 3.5 Pentachlorophenol Pentachlorophenol (PCP) is the second most heavily used pesticide in the U.S. Its major application is wood preservation. PCP is a dark-colored crystalline compound which is produced in the U.S. by the direct liquid phase chlorination of phenol (Boehringer process). PCP produced by the Boehringer process may contain 4-12% tetrachlorophenol, 1-5% hydroxychloro-diphenyl ether, 0.1% trichlorophenol, and trace amounts of PCDDs and PCDFs. Very little is known about the toxicity of hydroxychlorodiphenyl ethers. One of these pre-dioxins, 2-hydroxy-2,4,4-trichlorodiphenyl ether, has a low acute toxicity in rats, with an LD^q of about 5000 mg/kg (Williams, 1982). The sodium salt of PCP is produced by reacting pentachlorophenol with sodium hydroxide. While PCP and its sodium salt vary in their solubilities in different solvents, their toxicities are basically the same. PCP and its sodium salt are usually used as 1-5% solutions in organic solvents (PCP) or water (Na PCP). The main routes of occupational exposure to PCP are inhalation and skin contact. Skin absorption is facilitated by the presence of organic solvents or by cuts and abrasions of the skin. PCP is bound to plasma proteins. Repeated DSW 476038.0626 STLCOPCB4042790 workday exposures Co the TLV of 0.5 mg/m^ results in a maximum steady state plasma concentration of 0.5 ppm (Wood, 1983). PCP is eliminated from the plasma via distribution to the tissues, metabolism via glucuronidation and oxidation to tetrachloro-p-hydroquinone, and excretion of PCP and its metabolites in the urine and, to a lesser extent, the feces. PCP may undergo enterohepatic circulation. Elimination follows a first order, single compartment model with a half life of 30.2+4 hours in healthy human volunteers. (Braun, 1979). Elimination half lives in workers may be longer. Technical-grade PCP is irritating to the skin and mucous membranes of the eyes and upper respiratory tract. Skin irritation occurs with frequent contact to PCP solutions of 1% or stronger. Eye and respiratory tract irritation occur at PCP air levels greater than 1.0 mg/m^. Skin contact with technical-grade PCP can produce chloracne, though this is most likely due to the HCDD (and perhaps other PCDD/PCDF) contaminants. PCP produces its systemic toxicity by interfering with electron transport in mitochondria. The resulting uncoupling of oxidative phosphorylation results in an increase in metabolic heat production and hyperpyrexia. The acute oral LDjq of PCP is 40-130 mg/kg in rabbits and 27-78 mg/kg in rats. PCP contaminated with HCDD, HeCDD, and OCDD has produced hepatic effects in rats, including hepatic porphyria and increases in aryl hydrocarbon hydroxylase (AHH) and glucuronyl transferase (GGT) activity (Goldstein, 1977). Pure PCP was not porphyrogenic and produced only a slight effect on GGT activity. Technical PCP has also produced hepatocellular degeneration and necrosis in rats (Kimbrough and Linder, 1978). PCP has not been shown to be carcinogenic in DSW 476038.0627 STLCOPCB4042791 13 animals. PCP with its HCDD contaminant, however, may be fetotoxic and teratogenic <Cirelli, 1978). There are numerous case reports of acute PCP poisoning resulting from occupational exposures (Truhaut et al, 1952; Menon, 1958; Wood et al, 1983). Symptoms include hyperpyrexia, diaphoresis, tachycardia, tachypnea, weakness, nausea, vomiting, abdominal pain, anorexia, thirst, pain in the extremities, progressive coma, and death. Acute PCP poisoning may present with hepatic and renal dysfunction and metabolic acidosis with an increased anion gap. Skin absorption appeared to be the primary route of exposure in many of these cases. Sporadic cases of aplastic anemia, leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma of the skin have been reported among PCP workers, but the association with PCP exposure is not conclusive (Roberts, 1983). Chronic occupational exposure to PCP has been associated with an increased prevalence of conjunctivitis, chronic sinusitis, bronchitis, polyneuritis, and dermatitis (Baader and Bauer, 1951; Klemmer et al, 1980). Chloracne has occurred in PCP workers, but is most likely due to the PCDD and PCDF contaminants. Treibig et al (1981) found a significant decrease in sensory nerve conduction velocities in PCP production workers, but they could not demonstrate a dose response relationship. Zober et al (1981) found elevated GLDH-activities in workers producing and applying PCP. Begley et al (1977) demonstrated a significant improvement in creatinine clearance and phosphorus reabsorption in PCP wood treatment workers following a 20-day vacation. Bauchinger et al (1982) analyzed the chromosomes from peripheral lymphocytes from PCP production workers. They found a small, but significant, increase in the frequency of dicentrics and acentrics, but no significant increase of sister-chromatid exchanges. SW 476038.0628 I STLCOPCB4042792 14 3.6 2.4 Dichlorophenoxyacetic Acid 2.4- Dichlorophenoxyacetic acid (2,4-D) is a widely used post-emergent herbicide. 2,4-D is a white powder produced by reacting 2,4-dichlorophenol with chloroacetic acid in a solvent mixture of water and sodium hydroxide. The esters are produced by reacting 2,4-D with the appropriate alcohol. 2,4-D may be contaminated with Di-CDD, Tri-CDD, and 1,3,6,8-TCDD as well as with a variety of derivatives of phenoxyacetic acid and phenol, such as Bis (2,4-dichlorophenoxy) methane, Bis (2,5-Dichlorophenoxy) methane and 2,2,4,6- tetrachlorodiphenoxy methane. Most commercial 2,4-D preparations contain the ester or the salt rather than the free acid due to their better solubility characteristics. Alcohols are often used as solvents in 2,4-D formulations. The concentration of 2,4-D in commercial preparations is highly variable and may range from 1-80% (Halts, 1980). 2.4- D is rapidly absorbed from the gastrointestinal tract in healthy male volunteers with peak plasma levels occurring in 4-24 hours. The volume of distribution is .28-.29 1/kg. Elimination is first order with a plasma half life of 7-33 hours. 2,4-D is excreted in the urine as the free acid, though a small percent may appear in the urine as conjugates. (Kohli et al, 1974; Sauerhoff et al, 1977). Since 2,4 D is a weak organic acid, urinary excretion is pH dependent. Prescott (1979) increased renal clearance of 2,4-D in a case of accidental ingestion by alkalinizing the urine. Feldman and Maichbach (1974) found that 5Z of 2,4-D applied to the forearm was absorbed and excreted. 2.4-D's mechanism of toxic action has not been well established. 2,4-D may produce its neuromuscular effects by interfering with organic acid anion transport in neuromuscular tissues. (Podolak, 1981 a,b; Kim, 1981). 2,4-D has also been shown to induce mixed function oxidases in animals (Rivieri and Bach, 1981). DSW 476038.0629 I STLCOPCB4042793 15 The LD50 of 2,4-D in animals ranges from 100 mg/kg to a few thousand mg/kg depending on the form of 2,4-D and the species tested (IARC, 1977). Toxic effects are apparent after a latent period of 2-9 days and include loss of appetite, weight loss, myotonia, and muscle weakness progressing to paralysis, coma, and death. Pathological changes have been described in the gastrointestinal tract, liver, lungs, and kidneys. The free acid appears to be more toxic than the esters, and equal in toxicity to the sodium salt (HALTS, 1980). 2,4-D increased the frequency of tumors in rats (Hansen et al, 1971; but most other studies have not shown a carcinogenic effect in animals. 2,4-D is fetotoxic in high doses and may be a weak teratogen. Duffard et al (1981) demonstrated reduced hatchability and an increased frequency of malformations in chick eggs painted with 2,4-D. In a second study, painting eggs with 2,4-D resulted in postnatal alterations in the chemical composition of chick brain (Duffard et al, 1982) The LD50 of 2,4-D in man is estimated at 80-800 mg/kg. Autopsy findings from two fatal human ingestions showed acute demyellnatlon in the brain (patient with senile dementia), peripheral neuropathy, degenerative changes in the ganglion cells, hepatic necrosis, and congestion of most organs (Nielsen et al, 1965; Dudley and Thapar, 1972). Seven cases of peripheral neuropathy following dermal exposure to 2,4-D have been reported in the literature (Goldstein et al, 1959; Todd, 1962; Berkeley and Magee, 1963; Wallis et al, 1970; Halts, 1980). Signs and symptoms of a symmetric, "dying back," sensorimotor neuropathy began within 1-2 weeks after exposure. While nerve conduction times were at or slightly below the lower limit of normal, electromyography revealed denervation phenomena in the most severely affected patients. Recovery was slow with some residual deficits. DSW 476038.0630 STLCOPCB4042794 16 Epidemiologic studies of occupational exposure to the phenoxy herbicides are discussed under the section on PCDDs and PCDFs. 3.7 2,4,5-Trichlophenoxyacetic Acid 2.4.5- Trichlorophenoxyacetic Acid (2,4,5-T) was widely used as a post- emergent herbicide for controlling woody plant growth until 1979, when many of its uses were curtailed by the US EPA. 2,4,5-T is a light tan solid produced by reacting 2,4,5-Trichlorophenol with chloroacetic acid under alkaline conditions. The esters are produced by reacting 2,4,5-T with the appropriate alcohol. 2,4,5-T may be contaminated with 2,3,7,8-TCDD, HCDD, and perhaps some PCDFs. Most commercial preparations contain the ester or amine salt. The amine salts are soluble in water while the esters are emulsifiable in water and soluble in most oils. 2.4.5- T is rapidly absorbed from the gastrointestinal tract in healthy male volunteers (Matsumura, 1970; Gehring et al, 1973; Kohli et al, 1974). Rates of skin absorption vary from 0.22-1.13 mg/sq ft/hr for spray concentrations of 2-32 lb 2,4,5-T/100 gal (GRB, 1981). Elimination is first order with a plasma half life of 19-23 hours. Metabolites have been detected in animals but not in humans. 2,4,5-T propylene glycol butyl ether ester is rapidly hydrolyzed to the free acid in rats (Young et al, 1981). The LDjq of 2,4,5-T and its derivatives ranges from 100 to 940 mg/kg in various species (JRB, 1981). The free acid appears to be more toxic than the salts or esters. Acute toxic effects in animals include anorexia, vomiting, diarrhea, locomotive disturbances, and depression. Histopathologic changes are nonspecific. The mechanism of toxic action of 2,4,5-T is unknown. 2,4,5-T with less than 1 ppm TCDD produced cleft palate and growth DSW 476038.0631 ti STLCOPCB4042795 L7 retardation in mice (Roll, 1971; Hood et al, 1979). 2,4,5-T increased the incidence of tumors in C3Hf mice (Muranyi-Kovacs et al, 1976). Tumor incidence was not increased, however, in other strains of mice or in ocher animal species. The health effects observed in humans after chronic exposure to 2,4,5-T are usually ascribed to the 2,3,7,8-TCDD contaminant. There are no reported cases of acute poisoning with pure 2,4,5-T in humans. 3.8 Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzofurans (PCDFs) PCDDs and PCDFs are two series of tricyclic aromatic compounds which are inadvertantly formed during the synthesis of chlorinated phenols and their derivatives. The dibenzo-p-dioxin and dibenzofuran nuclei can hold from one to eight chlorine atoms. The numbers of possible positional PCDD and PCDF isomers are given in Table 3. Each of the 75 PCDD and 135 PCDF isomers may have different chemical, physical, and toxicological properties. As a general trend in both series, solubility in most solvents and volatility decrease with an increasing number of chlorine atoms. Levels of PCDDs and PCDFs reported in mono-, di-, and pentachlorophenols are shown in Table 4. PCDDs do not appear to be common contaminants of mono- and di-chlorophenols. The levels of PCDFs in these compounds are unknown. Hexa, hepta, and octa-dibenzo-p-dioxins and dibenzofurans have been repeatedly detected in PCP. The tetra- and penta-dibenzofuran congeners have been detected in numerous samples of 2,4,5-T. 2,4-D is frequently contaminated with DCDD, tri-CDD, and 1,3,6,8-TCDD.(Table 5). . The various PCDD and PCDF isomers vary considerably in toxic potential. The LD5QS range from 0.6-2.0 mcg/kg for 2,3,7,8-TCDD in guinea pigs to over DSW 476038.0632 STLCOPCB4042796 18 TABLE 1. POSSIBLE NUMBER OF POSITIONAL ISOMERS OF PCDDs AND PCDFs. Chlorine Substitution Number of Isomers PCDDs PCDFs monoditritetrapentahexa- 24 10 16 14 28 22 38 14 28 10 16 hepta- 24 oc'ta- 11 75 135 DSW 476038.0633 STLCOPCB4042797 STLCOPCB4042798 TABLE A. Ch lorophenol PCDDs and PCDFs Reported in o-chlorophenol., 2,4-Dich loropheno 1 and PentachIorophenol monoCDD DCDD triCDD PCDDs, ppm*1 TCDD pentaCDD IiexaCDD hept aCDD OCDD fre9o-8eo9Zfr msq Data Source Monocli loropheno 1 o-chlorophenol o-chlorophenol ND Dichlorophenol 2,4-dichlorophenol Pentachlorophenol PCP (Dowcide 7) PCP ND __ Na-PCP (1967) ND Na-PCP (1969) PCP (1970) PCP (1970) PCP (1967) PCP (1969) PCP (1970) PCP (1970) PCP (1978) Pentachlorphenate ND ND ND ND ND ND ND .-- -- PCP formulation __ PCP (technical grade) -- PCP (reagent grade) PCP (many samples PCP's (17) -- -- -- ND ND __ ND ND ND ND ND ND ND ND -- -- _. -- -- -- -- ND ND ND __ 0.037 (2,3,7,8)b __ ND ND ND Firestone et __ __ al, 1972 Esposito et al 1972 ND ND -- ND (0.5) ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND -- ND(0.1) __ __ __ -- ND -- ND -- ND ---- ND ND ND ND Firestone et Al, 1972 9 235 250 Buser, 1975 -- 10-100 100-1000 100-1000 Woolson et al. 1972 ND 14 14.5 3.8 Firestone et al, 1972 ND 20 11.3 3.3 If ND 39 49 15 II ND 35 23 ND It ND 0.17 ND ND If ND 13 47 ND ft ND 0.19 2.1 5.3 H ND 15 23 15 ft -- 19 140 432 USEPA, 1978 __ --++ Jensen and Renberg,1972 __ _. 870 50-3300 tl -- 33-42 19-24 7-11 Villanueva et al, -- 0.02-0.03 0.04-0.09 0.02-0.03 tl -- 9-27 90-135 575-2510 tl -- 0-23 -- 0-3600 tf (continue Table 4 (cont.) PCP or PCP-Na (7) mono CDF -- PCP (Dowcide 7 1970) -- PCP (Dowcide 7 1970) -- (distilled) PCP -- Na-PCP(Dowcide G 1978) -- DCDF -- -- -- -- -- Pentachlorophenol o PCP (USA) rJ PCP (USA) PCP (USA) PCP (Germany) PCP __ -- -- -- -- _ -- -- -- -- triCDF -- -- -- -- -- __ -- -- -- -- PCDDs, pptna TCDFs -- -- -- -- -- pentaCDFs -- -- -- -- -- HexsCDFs 0.03-10 4 1 .0 9-27 ND-2 HeptaCDFs 0.06-180 125 6.5 -- 1-12 OctaCDFs O 8 ------------------------------1-------------------t> >i h- Data Source > 5.5-370 Buser and q Bosshardt,1976 2500 15 USEPA, 1978 If 575-2510 \ Johnson, 1973 4-173 If PPDFs, ppm 0.9 -- <0.4 -- 0.20 4 -- 40 -- 0.20 32 30 90 0.03 13 120 80 400 0.8 70 130 80 260 1.3 55 Rappe, 1978 USEPA, 1978 Goldstein, 1977 Rappe, 1981 Buser and Bosshardt, 1976 a Key to abbreviations and symbols: ND = Not detected (minimum detection level, ppm). Other numbers in parentheses indicate year chlorophenol sample was obtained, or specific dioxin detected. -- = Not analyzed or not reported. b P resence of 2,3,7,8-TCDD confirmed but not quantitatively reported. TABLE 5. PCPDs IN 2,4,5-T AND 2,4-D Pesticide Sample 2,4,5-T (1973) 2,4,5-T Acid (1952) 2,4,5-T Ester 2,4,5-T Ester 2,4,5-T Ester (1960) 2,4,5-T Ester (1962) 2,4,5-T Ester (1966) 2,4,5-T Ester (1967) 2,4,5-T Ester (1967) 2,4,5-T Ester (1967) 2,4,5-T Acid (1964) 2,4,5-T Acid (1969) Herbicide Orange Herbicide Orange Herbicide Orange 2,4-D Ester (1980) 2,4,-D Ester (198Q) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) 2,4-D Ester (1980) MonoCDD a -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- DCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2.72 4.20 0.10 1.24 0.11 0.10 -- TriCDD -- -- -- -- -- -- -- -- -- -- -- -- '-- -- -- 0.35 2.08 1.63 0.64 1.82 0.93 0.68 -- TCDD 10.0 i.iob PCDDs ppm PentaCDD -- -- 0.50 0.05 0.40 0.95 0.10 0.05 0.22 0.18 4.8 6.0 0.12 1.1 5.1 0.23c -- -- -- -- -- -- -- -- -- -- -- -- -- -- 0.72 1.75 0.32 0.85 0.49 0. 32 -- -- -- -- -- -- -- -- HexaCDD 10.0 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- HeptaCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- OCDD -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --' -- -- -- -- -- <o CO CO o CO CoO CO h- Data Source 5 (/) Fishbein, 197 Rappe and Buser, 1980 tl 1 t| tl tf M ft It It tl M It ft It Cochrane et al, 1982 tf ft It tf ft tf It STLCOPCB4042800 DSW 476038-0 TABLE__ 5^ (cont.)__ I'CDDs i n 2,4,5-T and 2,4-D Pesticide Sample 2,4,-D Ester (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D Salt (1980) 2,4-D (1972) MonoCDD -- -- -- -- -- -- -- -- -- DCDD 0.20 -- -- 0.005 -- 0.033 -- -- -- TriCDD 0.16 0.038 0.58 0.054 -- 0.53 -- -- -- TCDD PCDDs ppm PentaCDD 0.21 -- 0.054 0.28 0.02 -- 0.21 -- -- -- -- -- -- -- -- -- -- -- HexaCDD -- -- -- -- -- -- -- -- 0.5-10 HeptaCDD -- -- -- -- -- -- -- -- -- OCDD -- -- -- -- -- -- -- -- -- Data Source Cochrane et al, 1982 ft 1 If If II H II II Wool son et al, 1972 Not detected, not tested, or not reported. ^Levels of TCDD in this and subsequent 2,4,5-T formulations are of the 2,3,7,8 isomer. CLeve.ls of TCDD in this and subsequent 2,4-D formulations are of the 1,3,6,8 Isomer. 23 4.0 x 106 mcg/kg for OCDD in mice. (Esposito et al, 1980). The LD5Q for 2,3,7,8-TCDF in guinea pigs is 2 to 4-fold higher than that reported for 2,3,7,8-TCDD (More et al, 1979). Chemical structural requirements for toxicity in both series appear to be chlorine substitutions at positions 2,3, and 7 with at least one hydrogen remaining on the nucleus. The mechanism of toxic action of PCDDs and PCDFs is still unknown. A cytosol receptor has been identified in mouse and rat liver which binds certain PCDDs and corresponds to their potency to induce aryl hydrocarbon hydroxylase activity (Huff et al, 1980). The ability of these compounds to induce aryl hydrocarbon hydroxylase correlates with their toxicity in animal studies. Iron deficiency protects mice from some of the toxic effects of 2,3,7,8-TCDD, but the mechanism of this interaction is unclear (Jones and Sweeney, 1982). The toxicokinetics of 2,3,7,8-TCDD have been studied in several species including rats, guinea pigs, and monkeys (Piper at al, 1973; Rose et al, 1976; Nolan et al, 1979; Gasiewicz and Neal, 1978; Van Miller, et al, 1976). 2,3,7,8-TCDD is moderately well absorbed from the gastrointestinal tract in most species. There are significant differences in the tissue distribution of this compound among various animal species. Following a single administration of 14 C-2,3,7,8-TCDD, the largest percentage of the dose appears in the liver in rats and in the adipose tissue in guinea pigs and monkeys. Materials other than 2,3,7,8-TCDD constitute a significant fraction of the 14 C activity in the feces, but no metabolites have yet been identified. After repeated oral dosing in the rat, a fraction of the 14 C acivity may also appear in the urine. The excretion of a single oral dose of 14 C-2,3,7,8-TCDD-in rats follows a onecompartment, open model with a half life of 31 days. DSW 476038.0638 STLCOPCB4042802 24 The toxicokinetics of other PCDDs can differ considerably from those of 2,3.7,8-TCDD. Norback (1975) studied the toxicokinetics of OCDD in the rat following chronic oral dosing: OCDD concentrated in rat liver and was excreted mainly by the urinary system with a half-life of about 3 weeks. Tulp and Hutzinger (1978) studied the rat metabolism of a series of PCDDs. They demonstrated that some PCDDs can be metabolized by hydroxylation at the lateral (2,3,7 and/or 8) positions in the molecule. When these positions are blocked by chlorine atoms, metabolism via epoxide formation is much less likely to occur. Decad et al (1982) studied the toxicokinetics of 2,3,7,8-TCDF in guinea pigs, rats, and monkeys. Gastrointestinal absorption of 2,3,7,8-TCDF was nearly complete in rats and guinea pigs. The liver was the major initial depot for 2,3,7,8-TCDF in all three species with lesser amounts in adipose tissue, skin, and muscle. Rats, and to a lesser extent, monkeys were able to metabolize 2,3,7,8-TCDF whereas guinea pigs could not. The whole body half-life of TCDF in guinea pigs, monkeys, and rats was 20, 8, and 2 days respectively. The metabolism of PCDF isomers in man may depend on the positions of the chlorine atoms on the dibenzofuran nucleus. Rappe analyzed liver samples for PCDFs from two patients with Yusho disease and compared the distribution of the isomers to that found in the ingested rice oil (Rappe et al, 1981). He found that the PCDF isomers which had apparently been excreted had two vicinal hydrogenated carbon atoms in at least one of the two rings; these unblocked positions are presumably involved in the metabolism by forming epoxides. DSW 476038.0639 STLCOPCB4042803 25 The toxic effects produced by PCDDs and PCDFs vary quantitatively and qualitatively among different species. Within a given species, the effects produced by the toxic PCDD and PCDF isomers are similar to those of 2,3,7,8- TCDD, differing mainly in the intensity of toxic effect. In all laboratory animals the lethal effect is slow and ensues days or weeks after a single dose. The spectrum of acute toxic effects of 2,3,7,8-TCDD in mice, guinea pigs, and monkeys is presented in Table 6. The most striking finding in most species is substantial loss of body fat. Involution of the thymus and testicular alterations have been observed in all species studied. Bio chemical effects of 2,3,7,8-TCDD include induction and/or suppression of various enzyme systems, changes in porphyrin metabolism, and alteration of lipid pro files. 2,3,7,8-TCDD and HCDD have produced chloracne in animals. Rats fed TCDD were found to have decreased thyroxine, free thyroxine index, glucose, and insulin levels in the serum (Potter et al, 1983). Doses of 2,3,7,8-TCDD which do not produce overt clinical or pathological changes may still be capable of causing immunosuppression. (Thigpen et al, 1975). Moore et al (1979) studied the toxicity of TCDF in mice, guinea pigs, and monkeys. The toxic effects in guinea pigs and monkeys were similar to those pro duced by 2,3,7,8-TCDD but required 2-20 fold higher doses of TCDF. Mice did not demonstrate clinical signs of toxicity at a dose of TCDF which was 23 fold higher than the TCDD LD50/30* lnterspecies variation in acute toxicity may be due to differences in detoxification metabolism (Decad et al, 1982). 2,3,7,8-TCDD increases the incidence of neoplasms in rats and mice. (Van Miller et al, 1977; Kociba et al, 1978; Toth et al, 1979). The data implicating 2,3,7,8-TCDD as a mutagen are conflicting, and it is unclear whether 2,3,7,8-TCDD acts as an initiator or a promotor. Carcinogenecity studies of other DSW 476038.0640 i STLCOPCB4042804 26 Table 6. 'Summary of Acute Toxicity Effects of 2.3,7.8-TCDDa Thymus Involution Spleen reduction (white pulp) Bone-marrow hypoplasia Liver, megalocytosis/degeneration Bile-duct hyperplasia Testicular degeneration Renal-pelvis hyperplasia Urinary-bladder hyperplasia Adrenal-cortical atrophy (Zona Glomerulus) Hemmorhage: Intestinal Adrenal Acites Cutaneous lesions Mice +-H+ + +++ + ++ - + ++ Guinea pigs +-H+ ++ + -H-f ++ ++ ++ + ++ - Monkeys (female) +++ + + - +++ N/A + - + -H-+ ^Source: Esposito, Tiernan, and Dryden, 1980 Key as follows: - no effect + mildly affected ++ moderately affected +++ severely affected DSW 476038.0641 I STLCOPCB4042805 27 PCDDs are in progress. The carcinogenic potentials of PCDFs have not been studied. 2,3,7,8-TCDD is teratogenic in mice and hamsters. The threshold teratogenic dose in mice was estimated to be 0.1 meg per day (Smith et al, 1976). 2,3,7,8-TCDD has been shown to be fetotoxic in a wide variety of species, including primates. HCDD was teratogenic in rats at a dose of 100 meg/kg per day (IARC, 1977) There is as yet no data on the fetotoxic potentials of PCDFs in animals. The toxic effects of 2,3,7,8-TCDD in man are summarized in Table7. The toxic effects most consistently observed in occupational studies are chloracne, liver dysfunction, neuropsychiatric disturbances, and abnormalities in porphyrin metabolism. Table 8 summarizes the findings of the morbidity studies of workers exposed to 2,3,7,8-TCDD to date. The few follow-up studies which have been done show resolution of gross liver dysfunction and porphyrin abnormalities following removal from exposure. (Pazderova-Vijlupkova et al, 1981; Suskind, 1984). Several of the occupational exposures occurred as the result of uncontrolled exothermic reactions during the production of trichlorophenol. A similar process accident at Seveso, Italy in 1976 resulted in widespread community exposure to 2,3,7,8-TCDD. Health effects included chloracne, primarily in children, and peripheral neuropathy in a small percent of those exposed (Pocchiari et al, 1979). The epidemiologic- studies on the carcinogenecity of TCDD are summarized in Table 9. While individual occupational mortality studies reveal no excess of cancer, the pooled data suggest an excess of soft tissue sarcoma (Honchar and Halperin, 1981). _ DSW 476038.0642 STLCOPCB4042806 28 Table 7. Toxic Effects of 2.3.7.8-Tetrachlorodibenzo-p-dioxin in Man.a Effects DERMATOLOGICAL Chloracne . Porphyria cutanea tarda Hyperpigmentation and hirsutism INTERNAL Liver damage^ Elevated serum hepatic enzyme levels Disorders of fat metabolism Disorders of carbohydrate . metabolism Cardiovascular disorders Urinary tract disorders Respiratory disorders Pancreatic disorders NEUROLOGICAL Polyneuropathies (perpheral neuritis) Lower extremity weakness Sensory impairments (sight, hearing, smell, taste) PSYCHIATRIC Neurasthenic or depressive syndromes_____________________ ^Source: Huff, Moore, Saracci, and Tomatis, 1980 _ ^Mild fibrosis, fatty changes, hemofuscin deposition and parenchymal-cell degeneration were observed in a few cases. DSW 476038.0643 i STLCOPCB4042807 TABLE 8. REPORTED OCCUPATIONAL EXPOSURES IN CHLORINATED PHENOLS RESULTING IN HUMAN ILLNESS1 Year,Place,and chemical(s) Type of exposure and no. of cases 1936 Michigan Tetrachlorophenol 2- (2-chlorophenyl) phenol Production 21 Effects on the skin Chloracne, hyperkeratosis Neurological effects Effects on the liver and serum lipids Other effects Fatigue, weight loss 1936 Mississippi Tetrachlorophenol Wood treatment 300-400 1949 West Virginia Trlchlorophenol 2,4,5-T Explosion 117 Production 111 1949 Germany Trlchlorophenol Tetrachlorophenol Pentachlorophenol Production, Industrial Laboratory 17 Chloracne,facial erythema, vesicula1 -- tlon, ulceration, hyperkeratosis, hype rpigmen ta tion Fatigue, colored urine, urinary problems, venous thrombosis Chloracne, facial erythema, hyperpigmentation, melanosis Nervousness, Hepatomegaly, ab- irritability, normal liver insomnia. function, toxic personality hepatitis, elevat change,de ed triglycerides pression, and cholesterol headache, vertigo, pain and weakness lower extrem- eties, paresis, peripheral neurci- pathy, abnormal nerve biopsy (loss of myelin) Fatigue, weight loss, weakness, decreased libido, impotence, intol erance to cold, increased sus ceptibility to infection (es pecially respir atory) Chloracne, hype rpigmen tat ion, scarring Lower extremity pain and weakness, paresis without atrophy, paresthesia, polyneuritis Abnormal liver function. cirrhosis Fatigue, severe bronchitis, decreased libido, impotence, bursi tis, myocardial damage References ( Butler, 1937 Tf CO o CO CoO ChrOt- 5in Q Anonymous, 1936: Stingily 1940 Ashe and Suskind, 1949, 1950; Suskind, 1953; Suskind, 1977 Baader and Bauer, 1951 STLCOPCB4042808 1952 Germany Trichlorophenol Production 31 1953 Germany Trichlorophenol Explosion 55 1956 France Trichlorophenol 1966 France Trichlorophenol 1956 New Jersey Trichlorophenol Product ion 17 Explosion 21 Production 29 1963 Holland Tr ichlorophenol 2,4,5-T Explosion 106 Chloracne, hyperpigmen tation Lower extremity Toxic hepatitis, pain and weak- abnormal liver ness.paresthesia, memory and con biopsy centration defi cits, sleep disturbances, hy persomnolence , abnormal psycho logical tests (apathy, dulled emotional response) Fatigue, chronic bronchitis, per sistent blepharo conjunctivitis, myocardial dam age, intolerance to alcohol Suskind, 1977 i Chloracne Sensory impair- Toxic hepatitis ment of smell,taste, hearing; tendency to orthostatic collapse, limited paresis, peripheral neuropathy, reading difficulties Fatigue, drowsiness bronchitis, laryn gitis, blepharo conjunctivitis, hemorrhagic pleuritis, myocardial damage, increased susceptibility to infect ion Goldman, 1973 Chloracne Peripheral neuropathy Toxic hepatitis, elevated tryglycerides and choles terol Dugols et al, 1956; Dugois et al, 1968 Chloracne, Clinical exam hyperpigmen tation, hy ination normal pertrichosis, acquired porphy ria cutanea tarda Chloracne, facial erythema No information Abnormal liver Right upper function, abnor- quadrant pain mal liver biopsies (parenchymal cell degeneration, fluorescence) Liver function normal Fatigue Bleiberg et al, 1964 Vos et al, 1977 DSW 476038.0 1964 USSR Tr ichlorophenol 2,4,5-T Production 128 1968 England TrIchlorophenol Explosion 79 1965-1968 Czechoslovakia TrIchlorophenol Pentachlorophenol 2,4,5,-T Production 80 1969 New Jersey Trichlorophenol 2,4,5-T 2,4-1) 1978 England TrIchlorophenol no longer in product ion Production 73 Followup of plant studied by Bleiberg (above) Followup of 41 workers In 1968 explosion (above) 41 Chloracne Headache, loss of memory, somnolence, sleeplessness, increased sweating Fatigue, joint pain, stomach pain Telegina and Bikbulatovd, 1970 <o o(o eo 2 {2 * (0 a Cloracne, faclal erythema Abnormal liver function Transient glyco suria, mild con junct Ivit is May, 1973; Jensen and Walker, 1965; Jensen et al, 1972 Chloracne, hyperpigmenta tion, hyper trichosis, scarring, ac quired porphyria cutanea tarda Lower extremity Hepatomegaly, ab- weakness and normal liver func- psin,somnolence, tion, abnormal headache, insom- liver biopsies nia, emotional (mild steatosis, and psychiatric periportal fibro- disorders, peri- sis, fluorescence) . pheral neuro- Elevated triglyc- pathy (confirmed erides, phospho- by abnormal EMG) lipids, and cholesterol Fatigue, weight loss, abnormal blucose tolerance, no evidence of myocardial or renal damage or of increased eye inflammation or respiratory in fection Jiraskek et al, 1964; PazderovaVejlupkova et al, 1980; PazderovaVejlupkova et al, 1981 Chloracne in 48, hypertrichosis in 16, hyperpig mentation in 30, no overt por phyria cutanea tarda Lower extremity No significant weakness, corre- abnormalities lation between chloracne and hypomania scale on MMPI Eye irritation, mild uroporphyrinuria in one worker Poland et al, 1971 (see Bleiberg et al, 1964) Chloracne Elevated CGT, elevated tri glycerides , elevated urinary D-glucaric acid May, 1982 STLCOPCB4042810 STLCOPCB4042811 1949 West Virginia Tr ichlorophenol 2,3,5-T 1949 West Virginia Trichlorophenol 2,4,5-T 226 Followup of plant studied by Ashe and Suskind (above) 204 Followup of plant studied by Anhe and Suskind and Moses et al (above) Chloracne 70-residual 47-by his tory Abnorma1 sensory findings in those with chloracne Chloracne in 107 Actinic Elastosis Elevated CGT in those with chloracne Decreased libido, sexual dysfunction Moses et al, 1984 n. co o 0CoO0 ChO- 5 w Q History of Cl ulcer Lower pulmonary function in exposed smokers Suskind and Hertzberg, 19^4 1976 Seveso T richlorophenol No. not given 1CMESA workers follow-up five years after explosion Elevated Aik. Pbos. Elevated urinary porphyrins Chezzi et al, 1984 a Source: Moses et al, 1984 Tabl <? 9 Epidemiologic Studies on the Carcinogenicity of TCDD.a Type and Place of Exposure Number of Cases Accidental, Monsanto, USA 228 Accidental, Boeliringer, RFC 24 Accidental, Basf, RFC 55 Accidental , Philips, Nether land 50 Acci dental, Dow Chemical, USA 60 Accidental, Spolana, Czechoslovakia 78 Accidental, Coalite, UK 79 Accidental, Chemie Werke, Linz, Austria 50 Herbicide Spraying, Sweden, Backsprayers 348 Herbicide Spraying, Finland, Backsprayers 1960 Herbicide Contamin ation, Sweden 72 Agent Orange Spraying USAF, VietNam 1242 TCDD Level of Exposure Unknown U nknown Unknown 10,000 ppb Unknown 24,200 ppb 400 ppb 140 ppb 0.00315 ppt 0.00315 ppt 0.0001 ppb 0.1 ppt 1.9 ppm Time Elapsed Since Exposure 30 years 28 years 27 years 17 years 16 years 15 years 12 years 7 years Over 10 years Over 10 years Over 10 years Over 13 years Frequency of Cancer Death No Excess No Excess Excess of Stomach Cancer No Excess No Excess No Excess No Excess Reference Zack, 1980 Krause, 1978 Theiss, 1982 Vos, 1978 Cook, 1980 Jirasek, 1978 May, 1980 Excess of Stomach Cancer No Excess No Lymphomas Excess of Lymphomas No Excess AxeIson, 1979 Rihmaiki, 1980 Hardell, 1979 Lathrop, 1983 a Source: Reggiani, 1980 34 A review of these cases revealed that several were not true soft tissue sarcomas; moreover, exposure in a few of the cases was minimal (Fingerhut et al, 1984). Swedish case-control studies of soft tissue sarcoma found an association with previous exposure to phenoxy acids or chlorophenols (Hardell et al, 1979; Eriksson et al, 1979) The Yusho cases provide our only data on the human toxicity of PCDFs. Yusho disease was caused by ingestion of rice oil accidentally contaminated with PCDFs, PCBs, and polychlorinated quarterphenyls; as such it is difficult to separate the effects of the various toxic principles. The clinical symptomatology of the Yusho cases is presented in Table 10. The Yusho oil was clearly fetotoxic. There is as yet no data on the carcinogenic potential of PCDFs in man. DSW 476038.0649 i STLCOPCB4042813 35 Table 10. Clinical Symptomology of Yusho Cases, 1969-1972.a Effects . Percent Skin Acneform eruptions, distinctive hair follicles, red plaques on limbs, dark brown pigmentation of nail, skin and mucous membranes, itching, sweating of palms. Ocular manifestation Increased eye discharge, swelling of the upper eyelids, hyperemia of- con junctives, transient visual disturb ance. Jaunidce No abnormalities of liver functions in the majority of cases. Numbness of the limbs, feeling of weak ness, spasm of the muscles Reduced sensory and motor nerve conduc tion velocity in few cases Hearing difficulties Headaches, vomiting, diarrhea Chronic Bronchitis Lower serum Ig A and Ig M. sputum PCB in the Irregular menstrual cycles Dark brown skin pigmentation of newborn, which gradually faded away, retarded growth and abnormal teeth number and shape. aSource: Reggiani, 1980 82-87% 83-88 10 32-39 9 18 17-39 40 60 DSW 476038.0650 STLCOPCB4042814 36 4. DESIGN 4.1 Study Design The design of this study combines elements of both cohort and cross sectional designs. Two historical cohorts, exposed and non-exposed, will be identified and followed to ascertain their current vital and employment status. The health status of surviving members of both cohorts will be assessed by an in-depth medical survey to determine prevalence of clinical and sub-clinical disease states. Previous incidence of disease will be ascertained by subjects' self-reporting and verified by medical record review. Differences in health outcomes between the two cohorts will be compared statistically, after adjusting for the effects of confounding variables. 4.2 Ascertainment of Exposure The departments where employees were most likely to be exposed to PCDDs include Departments 226 (Santobrite), 236 (Penta), 237 (chlorophenols) and Department 268 (agricultural esters). The locations of these departments within the plant are shown in Figure 2. 4.2.1 Processes Departments 236 (Penta) and 226 (Santobrite) The production of Pentachlorophenol (PCP) began at the Krummrich Plant in 1938. PCP was marketed in the flake form from 1939 to the late 1950's or early 1960's. At that time Penta (PCP)and Penta 60 (so called because it contained 60% PCP and 35% tetrachlorophenol) were offered in prilled form. From 1970, PCP was also offered in the 2000 lb. block form. The sodium salt of PCP (first called Santophen 20S and later Santobrite) was produced in powder, bT-j.quette, and 30% aqueous solution forms throughout its history. DSW 476038.0651 ,i STLCOPCB4042815 " "lio o T f mTS. 1 37 38 Santophen 20 P.A. (a PCP/pine oil/alcohol mixture) was only offered for a few years. The production of Na PCP was discontinued in 1972. The production of PCP and Penta 6Q was discontinued in 1978. Over the years, the chemistry for the production of Penta and Santobrite remained essentially the same. The flow sheets for the process are shown in Figures 3 and 4. Department 236 was contained in a building which has since been dismantled. Phenol, or chlorophenol fractions from the production of o-, p-, or 2,4-dichlorophenol were progressively chlorinated with subsequent increases in reaction temperature until the appropriate crystallization point was reached (for Penta, 174-182 C; for Penta 60, 145 C). Iron powder was first used as the catalyst; later, it was replaced by aluminum. Santobrite was simply the neutralization of Penta with sodium hydroxide. Flaked Penta was produced by feeding molten Penta into a container from which it was picked up on the surface of a cold rotating drum. The material was flaked off the surface as the drum rotated against a stationary blade. The material was then mechanically conveyed to a packing area where it was bagged into cylindrical fiber backs or loaded into steel drums. Prilled Penta was produced by dispersing molten Penta into fine streams using a shower head type prill plate. The molten streams would solidify by cooling with ambient air. The cooling chamber was an 8' diameter x 40' high prill tower. The prilled material would be further cooled in a Roto-Louvre cooler and would then be conveyed in a bucket elevator to a storage hopper to await packaging. The prills were packed into fiber packs or drums using a pneumatic packer. The air used for cooling passed through a Venturi scrubber where it was scrubbed with a dilute caustic solution , DSW 476038.0653 i i STLCOPCB4042817 STLCOPCB4042818 FIGURE 4 mcino o 00 41 Penta blocks were produced by pouring molten Penta info large tapered molds and allowing it to set. The material was removed from the mold by heating it with a welding torch. Penta 60 was produced in the same way as molten Penta, except that the chlorination was terminated earlier (batch temperature 153-157 C; 145 crystalization point). It was prilled in the same manner as molten Penta. A list of the job titles in Department 236 is given in Table 11. Department 237 (Chlorophenols) The production of chlorophenols began at the Krummrich plant in 1938 and continued through 1983. The principal products of this Department were o-chlorophenol, p-chlorophenol, and 2,4-dichlorophenol. P-chlorophenol was transferred to Department 239 where it was reacted with benzyl chloride to produce Santophen 1 (orthobenzyl p-chlorophenol). 2,4-dichlorophenol was transferred to Department 262 where it was reacted with chloroacetic acid to produce 2,4-dichlorophenoxyacetic acid. Chlorophenol fractions from Department 237 were also used as feedstock for production of pentachlorophenol in Department 236. The flowsheets for the production of mono- and di-chlorophenols are shown in Figure 5. The overhead layout of the work area is shown in Figure 6. Department 237 was an open area located adjacent to Department 236. The chemistry for the production of the chlorophenols appears to have remained unchanged over the years. Crude monochlorophenol was prepared by the batchwise chlorination of phenol at a temperature of 70-90 under a pressure of 2-5 psig in a Monel chlorinator. Crude mono contained 45% DSW 476038.0656 i STLCOPCB4042820 DEPT 226 2 36 04 TABLE 11 JOB DESCRIPTION Relief Foreman Chief Operator Operator Helper Day Repairman JOB DESCRIPTIONS LISTED IN THE MONSANTO COMPANY/ CHEMICAL WORKERS UNION WORKING AGREEMENTS ZS90'8E09ZP MSQ YEARS 0co0 co OcnN r0>0 O OCOn r-4 o CM H C<Or CM CO in nO m NO 00 r^. <1 On oo in ON CmM mf-4 CmO mCM in CmO mm m vinO iinn omo NmO OmN oino r-4 "v--O OmN CO vO fM vO m NO --s. CO vO 00 NO m NO t--4 r-- oo NO m <r N ooo X XX XXXXXXX X X XXX X X X X X X X X X XX XXXXXXX X X XX XXXXXXX X XXXXXXX Relief Foreman Chief Operator Repairman Operator Building i3D Operator Building BO Intermediate Op. Bldg. BD !3 Operator - Oiler Pelletizer Operator Helper Porter A Operator Bldg. BD B Operator Bldg. BD Briquette Operator 3ldg. BD Premium Operator Bldg. BD Helper Porter Santobrlte Operator Packer Helper Operator Premium Operator XXXA X XX XXXXXXXX X XXX XX XXX XX XX X X X XX X XXXXXXXXXXXXXXXX X X X X X X \r Vi X X XX XXXXXXX XXXX XX X X X X XXX XX XXXX X XXX XXX XX XXXXX XXXXXX X XXXX XXXX XXXX XXX XX XXX X STLCOPCB4042821 STLCOPCB4042822 JOB DESCRIPTIONS LISTED IN THE MONSANTO COMPANY/ CHEMICAL WORKERS UNION WORKING AGREEMENTS YEARS 8S90'8E09ZP MSQ JOB DEPT __________________ DESCRIPTION__________ m00 a* m ^S. r*. 00 n rO O O* n f-i o sr Csl sj H sr ro st C^4 <* st St U"1 St St St vO st rs sf vO st 00 st rs st O' st 00 st O' st (SI in N in st in n in in in st in vO in in in oo in vO in O' in oo m r-H rn vO vO ~~s^ r4 to vO n ao f~4 vO vO **. m to oo vO 'O SO sfst trss rs/ st rs O oo rfss 2 36 (Cont'd) A Operator B Operator Briquette Operator 237 Operator XXXX XXXX XXX XXX 237 rn st Relief foreman Operator Helper Shift Operator New Dept. Operator Old Dept. Repairman Helper Day Chief Operator XX XXXXXXXXXXXXXXXX XXX XXXXXX X XX XXXX XX XXXXXX X X X X X X X X X X X X y. x X X XXXX XXXXX X XX X x y. X X X X X X A X X X X X 2o8 Premium Operator Intermediate Operator Utility Helper XXXX X XXX X figure 5 ,# PROGRESS FLOWSHEET FOR CHLOROPHENOLS s CHLORINATION STEP DEPT. 237 ie.u 610.04 Fit,-1974 a icno o 06 co o ChOtT <0 D STLCOPCB4042823 STLCOPCB4042824 46 parachlorophenol (P-CP), 28% orthochlorophenol (O-CP), and 2% dichlorophenol (DCP). The crude material was blown with air to remove dissolved HC1 gas. The byproduct HC1 gas was piped to Department 236's clean-up systan. The crude mono was neutralized with 50% caustic and distilled in a Linde tray fractionating column. Normal cuts from this batch distillation were water, wet fractions, O-CP, dry fractions, aid P-CP. The dry fractions were transferred to Department 236 for use as raw materials in the production of molten pentachlorophenol. Crude dichlorophenol was prepared by the batchwise chlorination of phenol at 80-90 C and at atmospheric pressure. The crude material contained 85.5% 2,4-DCP, 6.0% 2,6-DCP, 0.5% O-CP, 7.8% 2,4,6 trichlorophenol, 0.1% P-CP, and 0.1% phenol. The chlorinated crude material was blown with air to remove the bulk of dissolved HC1; the remaining HC1 was neutralized with caustic. The 2,4 isomer in the crude DCP was recovered by vacuum batch distillation in a Monel fractionating column. The remaining chlorophenol fractions stripped from the crude were transferred to Department 236 for use in pentachlorophenol production. The byproduct HC1 was sent to Department 236's clean-up system. A list of the job titles in Department 237 is given in Table 11. Department 268 (Agricultural Esters) The production of the butyl, isobutyl, and isooctyl esters of 2,4,5trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D) began at the Krummrich plant in 1960 and continued through about 1970. The 2,4,5-T was shipped in from Monsanto's plant in Nitro, West Virginia. The 2,4-D was transferred to Department 268 from Department 262. The flow sheets for the pre-mix, reaction, and neutralization/filtration stages of the process are shown in Figures 7, 8, and -9, respectively. DSW 476038.0661 STLCOPCB4042825 FIGURE 7. rv.t i u 2I d tt 4, t-r rotcr,/i --'%?' T.gwvTCS !cAASS** CvNfCrM ii m moctjs nccormm ALCOHOL* TOLVENE MW >CT*ArVo*irNT'*,,1*# vC ron euc-reaction STEAM A. rnE-Mix (sumnY) DEPT.2G8 BUTYL 2,4,5-T ISO BUTYL 2,4,5-T 094.12 894.20 TANK FARM & 0 0 ALCOHOL - DTMY.CMC XOLVCMC SIOMGC Mlf CAL, JTCCL &&JaU TAMK* AAC SI'UT IHTO !, r.ALl.ON comi'ahtmcnts rxcnr' ALCOHOL TORACC Jt.SMCAIAOHS STEEL a DSW 476038.0662 FIGURE 8. u. HbAUAUN DCPT. 2G8 BUTYL 2,4,5-T 894.12 <CtoO0 o CcoO STLCOPCB4042827 FIGURE 9. CTCtOMtRTtAMtHC BnVM 3CA LO r> roM <6t MH, -- 0 [1= V. 4^^1/ IUU A l\>U/A <>n A A V/ I OKPT. 2GU A. - . . ....................... BUTYL 2,4,5-T ISO BUTYL 2,4,5-T 89 4.12 094.20 TANK FARM <o CD o co oco CND(/> Q rnoowcr sTOMae I It. ft* OAL rrtcu rnoowcr ncMot II.* CAL, 1____L 0 ntr.t. routMxj nvren* \ iA -- a _J Q?3> STLCOPCB4042828 50 The esters were produced by reacting the chlorphenoxy acids with the appropriate alcohol using a small amount of sulfuric acid as a catalyst. The materials were pre-mixed in a slurry tank, then dropped into the reactor where the sulfuric acid was added. The reactor was then set at the appropriate temperature and pressure (butyl and isobutyl esters of 2,4,5-T; 130-140 C, 580 mm Hg; isooctyl ester of 2,4,5-T; 135-140 C, 200 mm Hg.) The reaction was originally driven to completion by removing the binary alcohol/water azeotrope and, on cooling and separating, recycling the alcohol. The 1969 processes for the butyl and isobutyl esters used toluene as a solvent for increased efficiency in driving the reaction to completion and in the water/alcohol separation. When the reaction was complete, the alcohol and toluene were stripped off maintaining the reactor at 50 mm Hg and 140-150 C for two hours. The batch was then neutralized with cyclohexylamine. After filtration, the product was pumped to storage, tank cars, tank trucks, or 55 gallon drums. A list of the job titles in Department 268 is given in Table 1 1. DSW 476038.0665 I STLCOPCB4042829 51 4.2.2 Industrial Hygiene Departments 226 and 236 Chemical exposures in Departments 226 and 236 included pentachlorophenol, tetrachlorophenol, phenol, ehlorophenol fractions, chlorine, hydrochloric acid, sodium hydroxide, iron, aluminum and PCDDs/PCDFs. Repeated over exposure to phenol may result in chronic phenol poisoning. Symptoms include vomiting, difficulty in swallowing, diarrhea, lack of appetite, headache, fainting, dizziness, dark urine, mental disturbances, and possibly skin rash. Liver and kidney damage and discoloration of the skin may also occur. Chlorine, hydrogen chloride, and sodium hydroxide are irritating to the skin, eyes, and mucous membranes. Overexposure to chlorine and hydrogen chloride gas may result in tracheobronchitis and pulmonary edema (NIOSH, 1977). Exposures to the iron and aluminum powder catalysts are not likely to result in serious health effects. The toxicities of the chlorophenols have been reviewed in Section 3. The earliest information regarding the industrial hygiene conditions in Department 236 comes from a report of an inspection conducted in 1947 by the State Department of Labor's Division of Factory Inspection. The report listed several conditions which needed improving: 1) the drum flakers on the first floor of Building BD (Dept. 236) emitted considerable fumes and dust under ordinary operating conditions; 2) maintenance personnel who handled the Draco Dust Collector System were exposed to the product when the Draco bags occasionally broke; 3) employees involved in the drumming and bagging operation which was connected to the Draco Dust Collection System bagged much of the material by hand; 4) the hopper which fed the Santobrite pelletizing system was frequently blocked and was dug out by hand; and 5) the ventilation system on the Penta briquette operation was poor. A 1954 company memo acknow- DSW 476038.0666 i STLCOPCB4042830 52 ledges a chloracne problem in Department 236 which had existed for several years. In 1963 a Schneible Dust Collector System was installed in both the Fenta and Santobrite operations. On October 24, 1965 a fire broke out in one of the chlorinators. The batch in the chlorinator was in the trichlor-tetra stage. The cause of the fire was unknown. No material was lost from the chlorinator. The operators who were on duty did not appear to suffer any acute health effects. In 1967 a central fume scrubber was installed for sample hoods, tank vents, and loading areas. Monsanto began reviewing the literature on dioxins in 1970. That same, year the Medical Department established a registry of employees at the Krummrich Plant who had developed chloracne or who worked in Departments where chloracne was prevalent. In 1972 Monsanto began monitoring the dioxin levels in PCP. The levels of PCDDs in PCP, PCP-cuts, and PCP residue from 1972 to 1979 are given in Table 12. The production of Santobrite stopped in 1972. The same year special hygiene practices (showers, clothes changes, washing, cleansing housing with Seba-Nil Solution) were begun for employees who continued to produce PCP in Department 236. Environmental monitoring for PCP began in 1977. Levels of PCP in air and wipe samples are given in Table 13. All of the air samples collected between April and October of 1977 were below the TLV of .5 mg/m^. In May of 1977, MIC staff personnel conducted an environmental audit of Department 236. The audit concluded that: 1) overchlorination of PCP could potentially cause major process accidents; 2) since 1975, 40% of the DSW 476038.0667 STLCOPCB4042831 TABLE 12- LEVELS OF PCDD IN PCP, PCP-CUTS, AND PCP RESIDUE (ppm) DATE SAMPLE C1 C2 C3 C6 C5 C6 1972 6/75 8/75 6/16/79 PCP PCP PCP Blown Crude Dry Fraction Phenol Cut Para-Rich Cut PCP-Cut - (BDL) tl If It tl "3000 ppm Total Dioxini" -- (<07) (<.01) ( < 07) 11 - (BDL) It tl It It (BDL) ft ft It It (BDL) If II It ft (BDL) If It If tl (BDL) tl If II tl C7 C8 220-538 II (BDL) ft 660 690 (BDL) Ml t II If 11 If 2/28/79 3/1/79 3/2/79 3/11/79 5/11/79 6 /6 to 6/9/79 6/25 to 6/9/79 PCP Residue with Caustic It 63 260 250 260 59 190 200 1 ,600 15 66 35 1,600 3.1 6.2 5.9 610 6.7 .1 1.9 6.7 1.3 .66 5.2 .62 2.2 .08 1.3 .81 .66 .16 .16 .17 PCP Residue without Caustic (<D PCP with Caustic 2 -22 PCP Without Caustic (<01) -.52 (<D (<1) (<D 1 -5.6 .18 -1.6 (<01) (<.01) -.67 (<01) -. 11 (<01) -.016 (<D (<05) (<05) (d) (<1) (<D (<05) (<02) (<.025) (<05) (<02) (<06) A o t--*w STLCOPCB4042832 oCOo CoO 00 CoO ChO5 CO Q TABLE U. TCP AIR (mg/m3) AND WIPE (mcg/100 cm2) SAMPLES FROM DEPARTMENT 236 DATE 4/26/77 SAMPLE Personal, 8-Hour Operator tl PCP A1R *1^ (<.001) 8/10/77 10/7/77 Area, 2nd Level Outside Control Room Personal, 8-Hour Operator " " 3/77 (AH Penta Control Room) Sink Area Table Ice Box Cabinet Desk Table ' Bookshelf .026 .066 .034 .026 .025 8/77 , Sink Area Tabl e Ice Box Cabinet Desk Table Bookshe1f PCP WIPE 15.5 30.7 24.5 24.2 13.0 216 39 6.14 11.10 1.39 15.1 8.89 1.89 4.64 O) CO CO sG0O0 5 (0 o STLCOPCB4042833 personnel in Department 236 had developed chloracne; 3) the TLV and STEL for PC? were at times exceeded during the block pouring, sawing of the 1000 pound molds, and chlorinator sampling operations; and 4) serious sources of direct operator contact with the dusty product included prilling, prill bagging, bulk loading, and routine cleaning. In 1977 Monsanto instituted more stringent industrial hygiene practices (disposable dishes, midshift shower for dirty jobs). Wipe sampling (Table 13) showed a reduction in the levels of surface contamination in the Penta Control Room between March and August of 1977. Monsanto decided to shut down the Penta operation and to explore ways to further reduce the levels of product and workplace contamination. In 1978 the Penta operation was shut down. In 1979 Monsanto developed the capability to measure PCDDs with greater analytical precision. Wipe sampling of the Department (Table 14 ) revealed surface contamination with trace amounts of higher chlorinator PCDDs. That same year, Monsanto discovered that the levels of PCDDs in PCP could be greatly reduced by removing sodium hydroxide from the process (Table 12). Department 236 was not re-opened, however, and the building was subsequently dismantled. Department 237 Chemical exposures in Department 237 included phenol, o-chlorophenol, p-chlorophenol, 2,4-dichlorophenol, 2,6-dichlorophenol, 2,4,6-trichlorophenol, PCP (possibly from adjacent Dept. 236), chlorine, hydrochloric acid, and the lower-chlorinated PCDDs. The earliest record of any problem in Department 237 dates back to April 25, 1952 when an explosion destroyed a 2,4-DCP transfer pump. The DSW 476038.0670 i STLCOPCB4042834 STLCOPCB4042835 TABLE l4 . LEVELS OF PCDDs IN WIPE SAMPLES FROM DEPARTMENT 236 DATE 6/6/79 SAMPLE 2 Blower (mcg/m ) Office Wall (") Handrail (") Beam (") Wall (") C1 (BDL) II II II II C2 (BDL) II II II II C3 (BDL) It II II II C4 (BDL) 4.5 (BDL) 10 1 C5C6 (BDL) II II II II C7 400 ( BDL) II 60 (BDL) 8,000 50 14 1 40 2 58,000 9,000 1 ,800 47,060 700 5/81 Penta Purification Column 3rd Level (ng/100 cm^) - - 1 44 tl 2 34 36 Top of Column (") - - 7 61 46 16 38 Open Top Wall (") -- 19 74 46 10 36 57 punp overheated after it ran dry. The two operators who were in the vicinity did not appear to suffer any serious health effects. Chloracne does'not appear to have been prevalent in Department 237. Early company memos dealing with the chloracne problem do not identify Department 237 as a problem area. Only one of six employees who had worked exclusively in this Department was found to have questionable chloracne by Dr. Suskind in 1979. Environmental monitoring for phenol and chlorophenols began in 1977. Air levels of these chemicals in Department 237 between 1977 and 1982 are given in Table 15. None of the air levels for phenol exceeds the TLV of 3 19 mg/m . TLVs for o-chlorophenol, p-chlorophenol, and 2,4-dichlorophenol have not been established. Air levels of PCP exceeded the TLV on several occasions. Air samples for chlorine and hydrochloric acid were collected between September of 1979 and January of 1980. Air levels of HC1 ranged from .06 .32 mg/m 3 , well below the 7 mg/m 3 ceiling value. Air levels of chlorine 3 ranged from .02-.10 mg/m . One air sample collected near the chlorinator 3 showed an unusually high chlorine level of 5.4 mg/m , which is above the 3 mg/m3 TLV. In 1979 Monsanto analyzed batches of o-chlorophenol and 2,4-dichloro phenol for PCDDs. (Table 16) O-chlorophenol was contaminated with ppb levels of mono-, di-, and tri-CDDs. 2,4-dichlorophenol was contaminated with mono-, di-, tri-, and tetra CCDs. Removal of the caustic addition resulted in a marked reduction in PCDD contamination. An OSHA inspection in 1979 found 300 ppb of PCDDs (>50% 2,3,7,8-TCDD) in an ortho-crude spill, but Monsanto questioned the validity of this analysis. " DSW 476038.0672 _i ! STLCOPCB4042836 TABLE 15 . AIR LEVELS OF CHLORINATED PHENOLS AND PHENOL IN DEPARTMENT 237 (mR/m3) DATE PHENOL O-CP P-CP 3/15/77 3/16/77 3/31/77 4/14/77 3/10/78 1980 7/80 8/80 7/28/81 5/82 8/21/82 Personal, 8-Hour II II If It II It If It If ft It If It If " (Operator) i it " (Control Room) Personal, 8-Hour Samples Personal, 8-Hour , Area, Analytical Shed Personal, 8-Hour II II II Area, Shift, Control Room GLC Room .15 .12 .075 .39 .13 .21 .53 .14 .06 .16 .38 .28 .37 .03 .53 1.70 .20 .21 -.66 .73 .75 .90 .62 .67 .18 -.31 .40 -.53 .59 .10 .30 .25 .19 .93 .10 .57 . 44 .34 .27 .76 .20 .44 .40 .02 1.88 12.66 .18 .20 -.70 .1C -.14 .01 -1.5 .02 .05 -' - - -- .18 .12 -.18 .07 -.14 .19 -1.2 .24 .06 D-CP - .09 .04 .06 4.13 .06 .06 .12 .05 .23 .06 .09 .10 -.11 .15 .79 .67 .37 .19 .02 -.03 .03 -.29 .24 .50 T-CP - - 1 - (<.01) (<.01) (<.01) PCI .05 .55 .05 .50 .05 . 32 .48 .04 .05 .14 .18 . 14 .05 .15 .57 .93 2.35 1.33 1.15 4.88 5.17' - - - DSW 476038.0673 A o V STLCOPCB4042838 TABU- 16. LEVELS OF PCDDs IN O-CP AND D-CP (ppm) DATE SAMPLE 2/28 to A/16/79 0-CP With Caustic (<05) -.89 c2 (<02) -.18 C3 (<03) -. A5 CA (<.01) C5 (<05) C6 (<05) C7 (<02) h<D- 00 C<O0 8 (0 O (<05) o00 wV V o *Vw o 0CM V1 A/25/79 0-CP Without Caustic (<01) (<01) (<05) 3/3 to A/18/79 D-CP With Caustic (<02) -9.5 (<01) -29 (<.02) -13 (<02) -.19 (<02) (<05) (<10) (<10) 5/15 to 5/31/79 D-CP Without Caustic (<01) (<01) (<.01) -.25 (<.01) -.0A (< 05) (<05) (<.01) - 60 Trace amounts of OCDD were found in surface wipes of the chief operators desk and the desk in the Department 237 Control Room. It is not known whether these samples were analyzed for other PCDDs. PCDFs were not routinely measured in the samples collected for PCDD analysis. Department 268 Chemical exposures in Department 268 included 2,4,5-T, n-butyl alcohol, isobutyl alcohol, isooctyl alcohol, toluene, sulfuric acid, and cyclohexylamine. Exposures to high concentrations of the alcohol vapors may cause headache, dizziness, and drowziness. Keratitis characterized by corneal vacuoles has been reported following exposure to the vapors of n-butyl and isobutyl alcohols. Toluene is a central nervous system depressant. Prolonged, heavy over-exposure may result in permanent encephalopathy. Cyclohexylamine and sulfuric acid are skin and eye irritants. Repeated inhalation of sulfuric acid mist may lead to chronic bronchitis. The only information regarding industrial hygiene conditions in Department 268 comes from an internal industrial hygiene survey (undated) conducted in the 1960s. The report states that some dust was generated when 2,4-D was loaded into the fill hopper through the front end pay loader. 2,4,5-T was received from the Nitro plant in Lever packs; this was changed over to tote bins to reduce the amount of dust exposure during charging. The Drumming Station was not vented. The filter press was cleaned every three days. The operators who were not manually handling the material operated the equipment from an airconditioned control room. The 2,4-D and 2,4,5-T esters were apparently not analyzed for PCDDs. The levels of PCDDs in these products were probably not much different from those reported in the literature (Table 5). DSW 476038.0675 i i STLCOPCB4042839 61 4.2.3 Chloracne Registry In 1970 the Medical Department at the Krummrich Plant instituted a registry of current employees who had developed chloracne or who had worked in departments where chloracne was prevalent. Employees were examined for chloracne if they 1) worked in Department 236 or 237; 2) worked in Maintenance and had worked for more than 200 hours in the area containing Departments 236 and 237; or 3) were self-referred because of concern over chloracne. One hundred forty-five employees appear on the Chloracne Registry. Fifty-five of these were noted to have chloracne on at least one visit. Thirty-three of the employees were working in Maintenance at the time of examination. Twenty of these were noted to have chloracne. 4.2.4. Maintenance Employees In addition to the production workers in Departments 226, 236, 237, and 268, an unknown number of maintenance workers were exposed to chlorophenols, chlorphenoxy acids and dioxins in these work areas. One thousand nine hundred and forty employees held maintenance jobs between 1940 and 1980 and are presently alive according to company records. The demographic characteristics of these workers are shown in Table 17. A review of personnel and payroll records and interviews with maintenance supervisors have revealed that there are no existing records of Department assignments for maintenance workers prior to 1976. Self reporting was considered as a means for ascertaining maintenance worker exposure. Moses et al (1984) attempted this approach and found it unfeasible in their study of the Nitro plant. Fingerhut and her co-workers at NIOSH are not including Krummrich maintenance workers in the Dioxin Registry due to the difficulties in assigning exposure. DSW 476038.0676 STLCOPCB4042840 62 TABLE 17 DEMOGRAPHIC CHARACTERISTICS OF MAINTENANCE WORKERS EMPLOYED BETWEEN 1940 AND 1980. CHARACTERISTIC Employment Status Active/Temp. Inac. Terminated Retired Payroll Hourly Salaried Sex ' Male Female Unknown Race White Black Unknown Age <20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ N (Total - 1940) 741 572 627 1,629 311 1,871 68 1 1,602 317 21 2 2 37 55 72 130 146 118 272 311 312 483 Percent 38 29 32 84 16 96 4 <1 83 16 1 <1 <1 2 3 4 7 8 6 14 16 16 25 DSW 476038.0677 [ STLCOPCB4042841 63 We have decided Co adopt Che approach of Moses ec al (1984) and use chloracne as a marker of exposure for maincenance workers. These workers will be identified through a review of plant medical records. In addition we will consider any maintenance worker who appears on the Chloracne Registry as exposed. This approach is expected to identify approximately 48 maintenance workers with the highest dioxin exposures. 4.2.5 Definition of Exposed Cohort The exposed cohort in this study will consist of all past and present Krummrich employees who are alive and who meet one or more of the following criteria: 1) Hourly and salaried employees who had worked in Departments 226, 236, 237, or 268 for one or more days between January 1, 1938 and December 31, 1983. 2) Maintenance employees who appear on the Chloracne Registry. 3) Employees who were noted to have chloracne on plant medical records (with the exception of employees who were exclusively engaged in the production of PCBs or tetrachlorobenzene). The first entry criterion encompasses most of the members of the exposed cohort. One thousand seven employees worked in Departments 226, 236, 237, and 268 between 1/1/46 and 1/1/75. The identification of employees who were hired and left before 1946 or between 1976 and 1980 has not yet been completed. Two hundred twenty-one of the 1007 employees are deceased, leaving 786 survivors. The distribution of 720 of these employees by length of employment in one or more of these departments and_by employment status is given in Table 18. DSW 476038.0678 | STLCOPCB4042842 64 TABLE 18. DISTRIBUTION OF EXPOSED COHORT BY LENGTH OF EXPOSURE AND EMPLOYMENT STATUS AS OF 1/1/843 Employment Status Length of Exposure (months) <1 l-<3 >3-<6 >6-<12 >12 Active Retired Transferred within Monsanto Leaves of Absence Military Leave Other Terminations 55 33 2 4 9 35 42 24 0 7 10 47 48 39 22 33 20 55 11 14 34 43 82 65 2 8 9 30 Total 138 130 122 134 196 Total 266 177 6 29 53 189 720b Cohort limited to employees who had worked in Departments 226. 236,237, and 268 between 1/1/46 and 1/1/75. bSixty six additional employees have as yet not been classified by length of exposure DSW 476038.0679 STLCOPCB4042843 65 Thirty-three Maintenance personnel are included on the Chloracne Register indicating that they had either developed chloracne or had worked in Departments 226, 236, 237, or 268 for more than 200 hours after 1970. Company documents dated before 1970 contain lists of names of employees who had developed chloracne. An additional 15 names are expected to result from this entry criterion. The current estimate of the total number of individuals in the exposed cohort is approximately 834. 4.2.6. Demographic Characteristics of the Exposed Cohort At this time demographic Information is available on the employees who had worked in Departments 226, 236, 237, and 268 between 1/1/46 and 1/1/76. These individuals comprise about 907. of the total exposed cohort. Eighty-five percent of these workers are white, 14Z are black, and in 1Z the race is unknown. Ninety-seven percent of these workers are male. The age distribution of these workers is given in Table 19. Fifty percent are 60 years of age or older. Ninety-three percent of the workers were hourly employees and 7Z were salaried. 4.2.7. Follow-Up, Accessibility, and Participation of the Exposed Cohort The size of the exposed population which will undergo medical examination will depend on the rates of follow-up, accessibility for examination, and participation. These rates are expected to vary by employment status. The effects of these rates in determining the size of the examined cohort are shown in Figure 10. Follow-up is expected to be complete for active and temporarily inactive workers. An estimated 90Z of these workers will be accessible for DSW 476038.0680 STLCOPCB4042844 66 TABLE 19. AGE DISTRIBUTION OF THE EXPOSED COHORT AS OF 1984 AGE 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70 + TOTAL N PERCENT 13 1% 91 14 2 60 8 74 9 64 8 160 20 145 18 115 15 132 17 786 100% DSW 476038.0681 i STLCOPCB4042845 DSW 476038.0682 FI CURE 10. ESTIMATED FOLLOW-UP, ACCESSIBILITY, AND PARTICIPATION OF THE EXPOSED COHORT TOTAL EXPOSED ALIVE Iv'e EMPLOYMENT STATUS FOLLOW UP ACCESSIBLE PARTICIPATE tal Number Participating = 404 68 medical examination. In Suskind's 1979 survey of this same population, 68Z of the active employees chose to participate. A similar participation rate in the present study would result in 221 active and temporarily inactive workers. The follow-up rate for retirees is estimated at 95Z, since these workers are traceable through pension records. Over ninety percent are known to be living within 300 miles of St. Louis and accessible for examination. A participation rate of 60Z would result in 106 retirees. The follow-up rate for terminated workers is projected at 90Z. The locating of terminated workers will be performed by Equifax. An estimated 75Z are still living within 300 miles of St. Louis. Approximately 30 employees who had worked in Department 268 terminated employment at the Krummrich Plant when their area of the plant was sold to the Edwin Cooper Company. This group of employees will be especially targeted for participation in the study. A participation rate of 40Z would result in 60 terminated workers. Retired and terminated workers will receive a reasonable reimbursement for their time and travel. The follow-up rate for employees whose employment status is as yet unknown is estimated at 90Z. The accessibility and participation rates for these employees are estimated at 75Z and 50Z respectively, resulting in an additional 17 workers. A total of 404 exposed employees are expected to participate in the medical examinations. Present and past employees who choose not to participate in the study will be surveyed as to their reasons for non-participation and general health status. This information will be useful in detecting and measuring non-responder bias. DSW 476038.0683 i STLCOPCB4042847 69 4.2.8 Internal Control Group The internal control group will consist of all present and past employees at.the Kruomrich Plant who are alive and meet all of the following entry criteria: 1) Never worked in Departments 226, 236, 237, or 268. 2) Did not appear on the Chloracne Registry. 3) Were not listed on company documents as having chloracne. 4) Never worked in Maintenance. 5) Never worked in Department 239 (Sar.tophen). 6) Never worked in Department 224 (chlorinated benzenes). 7) Never worked in Department 262 (2,4-D). 8) Never worked in Department 218 (muriatic acid - chlorinated benzene). 9) Never worked in Department 246 (PCBs). 10) Never worked in Department 233 (chlorinated benzene). 11) Never worked in Department 861 (laboratory). One thousand seventy-seven employees meet the entry criteria for the internal control group. Thirty-three percent are active workers, 59Z are terminated, and 9Z are retired. Ninety-five percent are hourly employees and 5Z are salaried. Ninety-six percent are male. Seventy-eight percent are white, 11Z are black, and in 11Z the race is unknown. The demographic characteristics of the exposed cohort and the internal controls, are compared in Table 20. The exposed and non-exposed groups are similar with respect to age, sex, race, and payroll. A larger percentage of the internal controls are terminated employees. A larger percentage of the exposed cohort are retired, regardless of whether the terminated employees DSW 476038.0684 STLCOPCB4042848 70 TABLE 20. COMPARISON OF THE PERCENT DISTRIBTUIONS OF DEMOGRAPHIC CHARACTERISTICS BETWEEN THE EXPOSED COHORT AND THE INTERNAL CONTROLS CHARACTERISTIC Employment Status Active/Temp. Inactive) Terminated Retired Payroll Hourly Salaried Sex Male Female Unknown Race White Black Unknown Age <20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ Exposed (n-786) 46 28 26 91 9 97 3 <1 85 14 1 0 0 2 1 2 8 9 8 20 18 15 17 Control (n-1077) 33 59 9 95 5 96 4 <1 78 11 11 1 0 1 2 6 7 6 9 20 20 11 17 DSW 476038.0685 STLCOPCB4042849 71 are included or excluded. Overall, the two groups are acceptably comparable with respect to the major demographic variables. If we.assume similar rates of follow-up, accessibility, and participation,* an estimated 218 active, 50 retired, and 141 terminated workers are expected to comprise the internal controls. The 409 internal controls and 404 exposed result in a control:exposed allocation ratio of 1.01:1. *Thirty-three percent of non-exposed terminated workers are expected to participate in the study as opposed to 40Z of the exposed terminated workers. DSW 476038.0686 STLCOPCB4042850 72 4.3 Ascertainment of Health Status The comprehensive medical examination will ascertain the subjects' present and past health status. The incidence of past health events will be determined through the medical questionnaire and validated through medical record review. The examiners will be blinded as to the exposure status of the exposed cohort and the internal controls. The components of the medical examination are summarized in Table 21. \ 4.3.1. Medical History Questionnaire A trained medical Interviewer will administer a standard medical history questionnaire which will be a modification of the questionnaire previously used by the U.S.A.F. School of Aerospace Medicine in their Ranch Handy Study (Lathrop et al, 1983). The questionnaire will contain the following elements: 1. Current health status including any chief complaints or medical problems. 2. Past medical history, including hospitalizations for medical illness, surgical procedures, or transfusions. Specific questions will be asked about the presence of hypertension, cardiovascular, cerebrovascular, pulmonary, hepatic, intestinal, urogenital, reproductive, neurologic, mental, and psychiatric diseases. 3. Family history including health status of all first degree relatives, causes of death, hospitalizations, etc. 4. Social history including marital status (current and previous spouses), habits of alcohol and tobacco use. DSW 476038.0687 STLCOPCB4042851 73 5. Review of systems Including: a.. Constitutional symptoms of weight change, energy level, etc. b. Headaches c. Eye (vision, pain, discomfort) d. Ear (hearing, pain, discharge) e. Nasal (congestion, discharge, sense of smell) f. Mouth (lesions, dental, dysphagia) g. Respiratory (sputum, cough, dyspnea, etc.) h. Cardiac (chest pain, palpitations, PND) 1. Abdomen (pain, diarrhea, constipation, nausea, vomiting, etc.) j. Urogenital (dysuria, urgency, frequency, infection, nephrolithiasis, sexual dysfunction) k. Joints (pain, swelling, deformity) l. Neurologic (weakness, paresthesia, memory change, etc.) m. Psychologic (sleep disturbance, anxiety, depression) n. Dermatologic (rashes, blisters, sunburn, excess hair) o. Gynecologic (regularity of menses, character of flow, etc.) 6. Medication history which will include current as well as past use of prescription and over-the-counter preparations. 4.3.2 Reproductive History At the time of the medical history, permission will be sought to conduct a phone interview with current and previous spouses concerning reproductive outcomes. The Ranch Hand spouse's questionnaire will be administered by trained, medical telephone interviewers and will include questions on the number of pregnancies, their outcomes, and any congenital DSW 476038.0688 i STLCOPCB4042852 74 malformations in offspring of the subjects. Permission will be sought to verify reported congenital malformations in offspring through medical record review. . 4.3.3 Dietary History Participants will be asked to complete a three-day dietary history. They will be instructed in the completion of this diary by a trained nutritionist. 4.3.4. Physical Activity Assessment Participants will be administered a seven-day activity recall questionnaire (Taylor et al, 1984) to determine their level of physical activity. 4.3.5. Occupational and Environmental History A trained interviewer (other than those administering the other components of the medical examination) will administer a questionnaire designed to determine each of the following items as best remembered by the subj ect: 1. Job classification, duration, and duties for each position held at the Krummrlch plant. 2. Job classification, duration, and duties for all employment other than at the Krummrlch plant. 3. Description of any hobbies or other pursuits involving exposure to chemicals which might be confounding. 4. Military history (if any) with particular attention to service in Vietnam, especially Operation Ranch Hand. 4.3.6. Medical Records Review Permission will be sought for review and release of medical records from treating physicians and hospitals for purposes of confirming the DSW 476038.0689 STLCOPCB4042853 75 previously obtained medical histories. The medical records will be reviewed by registered medical record technicians. Diagnoses and procedures will be classified into ICD-9. 4,3.7 Internist's Physical Examination The general physical examination will be performed by an internist blinded to the exposure history of the worker. The examination will consist of the following: 1. General appearance and vital signs: supine and sitting blood pressure and pulse, respiratory rate, height and weight. 2. Head: shape, evidence of trauma. 3. Eyes: pupillary response, presence of conjunctivitis. Icterus. 4. Ears: hearing, appearance of tympanic membranes. 5. Nose: appearance of mucosa, purulent secretions, polyps. 6. Mouth: appearance of teeth, tonsils, mucous. 7. Neck: adenopathy, size and consistency of thyroid, range of motion. 8. Lungs: percussion, auscultation. 9. Heart: size and description of PMI, abnormalities of heart sounds, extra sounds and murmurs. 10. Abdomen: tenderness, masses, bowel sounds, liver and spleen size. 11. Genital (males): testicular size and consistency, hernias. 12. Rectal: mucosal surfaces, prostate size and consistency (males), stool hemocult. DSW 476038.0690 STLCOPCB4042854 76 13. Joints: range of motion, effusion, deformity. 14. Back: range of motion, tenderness. 15. Breasts, (females): masses, discharge. 16. Pelvic (females): cervix, adnexal tenderness or masses. 17. Peripheral pulses. 4,3.8 Dermatologic Examination The dermatologists will be trained in the diagnosis of chloracne by an internationally recognized expert in the field. The dermatologic examination will be performed and recorded in a standardized manner to permit quantitative assessment of the findings. Particular attention will be devoted to the detection and scoring of chloracne, porphyria cutanea tarda, and basal cell carcinoma. 4.3.9. Neurologic Examination A neurologist will perform a mental status examination and examine the cranial nerves, motor, and sensory systems. Reflexes and cerebellar function will be tested. 4.3.10. Electrocardiogram A trained technician will do a 12-lead, resting electrocardiogram. 4.3.11. Pulmonary Function Tests A trained techniclal will measure the subject's forced vital capacity and forced expiratory volume at one second. 4.3.12. Chest X-ray A trained technician will take a standard PA and lateral film. 4.3.13. Quantitative Sensory Examination A trained technician will quantitate the subject's perception of temperature and vibration. _ DSW 476038.0691 I STLCOPCB4042855 77 4.3.14. Nerve Conduction Velocities A trained technician, under the supervision of the neurologist, will measure the nerve conduction velocities of the median and sural nerves (one side only) using standardized methods. 4.3.15. Neurobehavioral Testing A trained technician will administer an automated neurobehavioral test battery (Baker et al, 1984) using computer terminals, which will Include the following tests: 1. Paired associate learning 2. Mood scales 3. Continuous performance 4. Vocabulary 5. Symbol-digest substitution 6. Hand-eye coordination 7. Visual retention 8. Digit span 9. Paired associate recall 4.3.16. Blood Tests Venous blood will be drawn after a 12-hour fast and distributed in the following manner: 1. 5cc of EDTA anticoagulated blood for complete blood count, differential white cell count, and platelet count. 2. 5cc of EDTA anticoagulated plasma for total cholesterol, HDL and LDL cholesterol and triglycerides. DSW 476038.0692 STLCOPCB4042856 78 3. 5cc of scrum for SMA 20 (albumin, alkaline phosphatase, bilirubin, calcium:, chloride, bicarbonate, creatine, GGT, glucose, phosphorus, potassium, LDH, protein, GOT, GPT, sodium, BUN, acid.). 4. 5cc of serum for LH, FSH, testosterone. 5. 2cc of serum for T4, T3 resin uptake and free thyroid index, TSH. 6. 3cc of serum for IgA, IgG, IgM. 7. lcc of frozen serum for CPK. 8. 4.5cc of blood drawn into blue-top tube and delivered on ice for prothrombin time. 9. 5cc of EDTA plasma for apoproteins AI, All, B, and E (Dr. Schoenfeld's laboratory). 10. 20cc of heparinized blood for lymphocyte stimulation studies (concanavalin A, phytohemaglutin, and Poke week mitogen). 11. 20cc of heparinized whole blood, 3cc of EDTA anticoagulated blood and 2 slides will be drawn for T and B cell determinations, T helper and suppressor cell ratio. 12. lOcc of serum will be frozen and banked to permit future analyses. 4.3.17. Urine Tests The subjects will be asked to provide a clean catch, mid-stream urine DSW 476038.0693 STLCOPCB4042857 79 specimen for urinalysis after which a 24-hour urine collection will be begun using a light-proof container. The 24-hour urine collection will be kept refrigerated and appropriate preservatives will be used. Aliquots will be sent for: 1. Creatine (creatinine clearance) 2. Protein (24-hour protein excretion) 3. Quantitative porphyrins DSW 476038.0694 STLCOPCB4042858 80 TABLE 21. SUMMARY OF COMPREHENSIVE MEDICAL EXAMINATION I. Medical History Questionnaire (trained interviewer) Current medical problems Past medical history Family history Social history Review of systems Medication 2. Reproductive History (telephone interview by trained interviewer) 3. Dietary History (nutritionist-instructed 3-day diary) 4. Physical Activity Assessment 5. Occupational and Environmental History (trained interviewer) 6. Medical Record Review (internist) 7. General Physical Examination (internist) 8. Dermatologic Examination (dermatologist) 9. Neurologic Examination (neurologist) 10. 12-lead EKG (EKG technician) II. Pulmonary Function Tests (PFT technician) 12. Chest x-ray, PA and lateral (technician) 13. Quantitative Sensory Examination (technician) 14. Nerve Conduction Velocities (NCV technician) 15. Neurobehavioral Testing Paired associate learning Mood scales Continuous performance " Vocabulary DSW 476038.0695 i STLCOPCB4042859 81 TABLE 21 (continued) Symbol-digest substitution Hand-eye coordination . Visual retention Digit span Paired associate recall 16. Blood Tests Complete blood count Platelet count Cholesterol HDL and LDL cholesterol ' Triglycerides Apoproteins AI, All, 3, and E Glucose BUN Creatinine Electrolytes Uric Acid Protein Albumin Bilirubin Alkaline phosphatase LDH, GOT, GPT GGT LH, FSH, testosterone CPK DSW 476038.0696 STLCOPCB4042860 82 TABLE 21. (continued) T4, T3 resin uptake, free thyroid index, TSH IgA, IgG, IgM Prothrombin time Lymphocyte stimulation studies T and B cell populations, T helper and suppressor ratio Banked serum. 17. Urine Tests Urinalysis Creatinine clearance 24-hour protein excretion Quantitative porphyrins DSW 476038.0697 STLCOPCB4042861 83 5. DATA ANALYSIS 5.1. Data Entry, Processing, and Storage Data management and analysis will be performed at the Northwestern University Medical School. The data management system will include quality control measures at each step of the process to ensure completeness and accuracy of data entry. Data entry and quality control will be facilitated through the use of standardized data entry forms. Whenever possible, original data will be recorded on the data entry forms to minimize transcription errors. A list of the original data, initial records, and data entry forms is given in Table 22. The data from each employee's health examination will be visually inspected on site for completeness,.legibility, and obvious inaccuracies. Errors in data collection or recording will be corrected on site. The data will be transported by courier to the Northwestern University Medical School for processing and storage. Results of laboratory analyses will be mailed to the School and inserted in each employee's data file. Recording of data will be performed by data entry clerks following specific procedures under the supervision of the Data Manager. Data contained in the data entry forms will be entered into intelligent terminals using an Intelligent Data Entry program. A screen image of the data entry form will appear on the CRT. Spaces will be included for entering values as they are reported on the data entry form. The Intelligent Data Entry program will have checks on range values and numeric types to trap transcription errors. Transactions from a forms entry session will be transmitted from the mini computer to the main frame over a phone line. The entry will be checked against DSW 476038.0698 STLCOPCB4042862 TABLE 22 . FORMS FOR COLLECTION, RECORDING, AND CODING OF DATA Components of Health Survey Information for Follow-up Employment Record Medical History Occupational History Reproductive History Internist's Exam Dermatologist's Exam Neurologist's Exam PFT's CXR Quantitative Sensory EKG EMG/NCV Automated Neurobehavioral Test Blood Tests Urine Tests Non-Participant Survey Original Data Personnel Record Personnel Record Face to Face Interview Face to Face Interview Phone Interview Physical Exam Physical Exam Physical Exam Flow-Volume Loop Volime-Time Graph Film Sensory Exam EKG Tracing Neurobehavioral Exam Blood Specimen Urine Specimen Phone Interview Initial Record Computer Printout Computer Printout Questionnaire Questionnalre Questionnaire Exam Form Exam Form Exam Form Computer Printout Data Entry Form Recoded Recoded Same Same Same Same Same Same Recoded Radiologist's Report Exam Form Cardiologist's Report EMG/NCV Form Computer Printout Recoded Same Recoded Same Same Lab Report Lab Report Questionnaire Recoded Recoded Same 85 the full data base on certain data items to prevent duplicate and other invalid entry. The original data will be stored and archived in the Northwestern University Medical School. Entered data will be stored on disks with archive copies to prevent inadvertant loss of the data base. 5.2. Quality Control Personnel data on employment history which is supplied by Monsanto will be checked for accuracy by comparing a 10% random sample of this data to the original personnel records. The employee's occupational history will serve as a further check on the accuracy of the personnel data. ' The most important step in the quality control of data management is the complete and accurate recording of data. Each employee's medical examination data will be visually inspected on site for completeness, legibility, and obvious inaccuracies. Transcription errors during data entry will be minimized through the use of the previously described intelligent data entry system. Duplicate and other invalid entry will be prevented by comparing each entry against the full data base. The final step in quality control will be an ongoing comparison of a 10% random sample of entries against the original data. Errors will be traced to their source and control measures taken to prevent their recurrence. Inaccurate or incomplete data will be corrected and re-entered. These quality control measures are summarized in Figure 11. Error tolerance will be set at .1%. DSW 476038.0700 i STLCOPCB4042864 86 FIGURE 11. QUALITY CONTROL OF DATA ENTRY Visual i nspection at site IntelIigent data entry system Point of entry interrogation Random sample check Identify source of error and take corrective measures DSW 476038.0701 STLCOPCB4042865 87 5.3 Analysis 5.3.1 Classification of Exposure Each individual's exposure will be classified 1) dichotomously, 2) by length of exposure, and 3) by exposure score. All three exposure variables will be treated as categorical variables. The exposed cohort will be analyzed as a whole and, where sample size permits, by individual department. In the dichotomous classification of exposure, individuals who meet one or more of the exposure criteria will be classified as exposed, and those who do not will be classified as non-exposed. As an employee's length of employment in a department increases, his exposure to the chemicals in that department is expected to increase. The length of employment will be divided into the following four intervals: 1) 0 months, 2) >0-<3 months, 3) >3-<12 months, and 4) >12 months. Classification by length of exposure will permit analyses for dose-resonse. NIOSH is currently developing a dioxin exposure score for the Dioxin Registry. The exposure score will be a numerical scale based on the department, job titles, length of exposure, and industrial hygiene data. The exposure score will be directly applicable to Krummrich employees, since employees from this plant are included in the Dioxin Registry. The exposure score is expected to be ready by March, 1985, and will be assigned to each employee without knowledge of the results of the medical examination. While the exposure score may be a continuous variable, we will treat it more conservatively as an ordinal varible with four exposure categories. Our review of the industrial hygiene and process information leads us to conclude that analyses by individual departments are warranted. While DSW 476038.0702 i STLCOPCB4042866 88 all four departments share the possibility of PCDD exposure, the mix of PCDPs was different for each department. Employees in Department 237 were exposed to the lower chlorinated dioxins, while employees in Departments 226 and 236 were exposed to the higher chlorinated dioxins. While no PCDD analyses were performed on the products from Department 268, historical information indicates that these employees were exposed to 2,3,7,8-TCDD. The departments will be categorized as 226/236, 237, 268, and Maintenance/Other. P.3.2. Classification of Disease The comprehensive health status evaluation, which includes a medical history, reproductive history, medical record review, physical examination, and laboratory tests, will generate a large number of categorical and continuous health outcome variables. The details of the medical survey are given in Section 4. The problem of repeated measures is discussed in Section 7.8. 5.3.3. Confounders and Effect Modifiers 5.3.3.1. Demographic Characteristics The potential demographic confounders in this study include age, sex, race, socio-economic status, employment status, and urban/rural residence. The internal controls are similar to the exposed cohort with respect to age, sex, race, and payroll class. The effects of confounding will be controlled through stratified and multivariate analysis. 5.3.3.2. Lifestyle Characteristics The potential lifestyle confounders in the study include smoking, alcohol consumption, physical activity, and diet. These variables will be ascertained through the medical history and controlled for in the statistical analysis. DSW 476038.0703 i STLCOPCB4042867 89 5.3.3.3. Chemical Exposures Employees at the Krummrich Plant are potentially exposed to chemicals other than the chlorophenols, phenoxy acid esters, and their contaminants. The major chemical products and intermediates are discussed in Section 2.2. The average Krummrich employee rotates from between 10 to 20 departments prior to retirement. The Krummrich Plant contains approximately 110 active and discontinued departments. Each employee will be dichotomously classified as having worked or not worked in each department. An employee will be considered as having worked in a department if he had worked in that department for a total of more than 3 months during his term of employment. A list of the chemical exposures in each department is available through Monsanto's MEHI computer system. Each significant health finding in the comparison with the internal controls will be reviewed to determine if it could be associated with chemical exposures in a department where the employee had previously or subsequently worked (e.g. tremor on neurologic exam and exposure to mercury in the Denora Cell House). If the potential for confounding exists, the extent of confounding will be determined by cross-tabulating the confounding exposure with the abnormal health finding. If confounding is present, we will re-examine the original association after adjusting for confounding using Mantal-Haenszel methods. Major abnormal findings may warrant nested case-control study. The Krummrich employees may have had exposure to chlorophenols, chlorphenoxy herbicides, and dioxins outside of their employment. These outside exposures will be ascertained through the administered questionnaire (e.g. history of farm use of chlorphenoxy herbicides). Confounding by DSW 476038.0704 STLCOPCB4042868 90 outside exposures will be controlled through the use of the aforementioned methods. 5.3.3.4. Effect Modifiers A factor which will influence the prevalence of residual health effects is the time since last exposure. The few longitudial morbidity studies of dioxin-exposed occupational cohorts have shown that several acute health effects improve with time. The time since last exposure will be considered in the multivariate analysis. Another factor which may influence our measurement of exposure is the calendar time of exposure. The industrial hygiene information suggests that the chemical exposures in Departments 226 and 236 were higher before 1970 than after 1970. There is no information to suggest a similar variation in exposure in Departments 237 or 268. The temporal variation in exposure will probably be factored into the NIOSH Exposure Score. If not, we will include it as a variable for study in the analysis of the data from Departments 226 and 236. 5.3.4. Statistical Tests The strategy for statistical analysis of parametric data will consist of 1) examination of crude associations; 2) stratified analysis; 3) tests for dose-response; and 4) multivariate analysis using SAS statistical packages. Crude associations between dichotomous variables will be examined by cross-tabulation, calculation of prevalence odds ratios, and testing for significance using Fisher's Exact or Chi Square Tests. Differences in means between continuous variables will be tested using the Student T Test. In the next step of the analysis, we will stratify on major confounding variables and calculate factor-adjusted odds ratios using DSW 476038.0705 STLCOPCB4042869 91 Mantel-Haenszel methods. Differences in means between continuous variables will be adjusted for confounding and tested for significance using analysis of covariance. Dose-response relationships between the ordinal exposure variables and dichotomous dependent variables will be examined using the test for trend. Confounding variables will be controlled using the Mantel extension. Multivariate analysis of dichotomous dependent variables will be performed using multiple logistic regression. Multivariate analysis of continuous dependent variables will be performed using multiple linear regression. Multivariate analysis of categorical dependent variables will be performed using log linear analysis. DSW 476038.0706 STLCOPCB4042870 92 6. IMPLEMENTATION 6.1 Identification and Recruitment of the Study Populations The exposed and non-exposed employees at the Krummrich Plant will be identified through 1) Monsanto's MEHI computer system; 2) the chloracne register; and 3) a review of company memoranda dealing with chloracne at the Krummrich Plant prior to 1970. The addresses of active employees are available through current personnel records. The present addresses of retirees are available through the company's pension plan. Terminated workers will be located through Equifax. Northwestern University will work together with Monsanto's Public Relations Department, and the international Chemical Worker's Union, and in recruiting Monsanto employees for the study. Active workers will be approached through the individual plants. Northwestern researchers will meet with the workers at the plants to discuss the purpose, scope, and implementation of the study. Retirees will be contacted by mail and also through existing retiree associations. Terminated workers will be contacted by mail. 6.2 Development of Survey Instruments The medical history, occupational and environmental history, and non-participant questionnaires will be developed in conjunction with the Survey Research Laboratory. The Survey Research Laboratory will also provide trained medical interviewers to administer these Instruments. 6.3 Medical Examinations Northwestern University will place a team of health professionals at the plant sites to conduct the medical examinations. An examination is expected to take 8 hours of an employee's time, including breakfast and lunch. The examination will be completed during a single 8-hour shift with DSW 476038.0707 STLCOPCB4042871 93 the exception of the 24-hour urine collection, 3-day dietary history, and spouse's reproductive history. The team will be able to examine 18 employees per day by: using a rotatlng-statlon examination system. Blood and urine samples will be processed and sent to the appropriate laboratories in dally batches. Consent for medical record review will be sought at the time of examination. The medical records will be mailed to the Department of Medicine for review by medical record technicians after the examinations have been completed. The female spouses of the study participants will be asked to consent to a telephone interview to obtain pertinent reproductive history. The telephone interviews will be conducted by trained Interviewers from the Survey Research Laboratory. 6.4 Data Analysis Data analysis is discussed in detail in Section 5. 6.5 Report 6.5.1. Reports to Individual Participants Each participant will be debriefed as to available medical findings on site upon completion of the medical examination. In addition, each participant will receive a report summarizing the results of his medical examination. The report will be prepared by the internist who examined the participant. The report will contain recommendations for further medical follow-up by the participant's personal physician when appropriate. If the participant so desires, the results of Individual tests will be forwarded to the participant's physician. 6.5.2. Final Report Northwestern University will submit a final report to Monsanto upon completion of the study. A draft of the final report will be reviewed by the DSW 476038.0708 STLCOPCB4042872 94 Peer Review Committee prior to submittal to Monsanto. The report will contain an introduction, presentation of methods, results of analyses, discussion, and conclusions. 6.6 Timetable The study is expected to take 78 weeks to complete. The duration and timing of specific tasks are presented in Figure 13. 6.7 Human Subjects Review The study is contingent upon approval by Northwestern University's Human Subjects Review Board. The major risks to participants are the discomfort of the medical examination and breach of confidentiality. The medical examination is by design non-invasive, with the exception of venopuncture. Venopuncture will be performed by a certified technician under the supervision of the examining physician. Each participant's examination results will be confidential and will not be released to other parties without the participant's signed consent. Each participant will receive a study code number which will serve as his identifier. No personal identifiers will be entered into the computer or included in the group data file. A participant may elect to have his test results sent to his personal physician. A Monsanto employee may also elect to have his test results sent to the Monsanto Medical Department in lieu of his annual medical surveillance examination. - DSW 476038.0709 STLCOPCB4042873 FIGURE 12. Study Timetable O INDIVIDUAL REPORTS SENT DATA ENTRY AND ANALYSIS ".r 7 TELEPHONE SURVEY ^ ^ ^ ^) r'v FINAL ^ REPORT QPEER REVIEW O STUDY DRAFT KRUMPRICH EXAMS ' - DEVELOPMENT OF SURVEY INSTRUMENTS IDENTIFICATION AND RECRUITMENT OF COHORTS vo Ul ' O CONTRACT SIGNED O FINAL DRAFT OF PROTOCOL O peep. REVIEW O DRAFT OF PROTOCOL ------------------------------------------ 1------------------------------------------1----------------------------------------- U-----------------------------------------1ll____________________________________ _:----------------------------------------------------------------- :------- ---------------------------------- 1_ ' 10 20 30 40 50 60 70 80 90 WEEKS 96 7. Study Limitations and Corrective Measures 7.1 Loss to Study Losses to the study may occur through 1) incomplete follow-up, 2) inaccessibility for examination, and 3) non-participation. If the losses are not random, then the study sample may not be representative of the entire exposed cohort. Losses will be especially damaging to the validity of the study if they are due to exposure and disease. For example, if exposure leads to illness, and illness results in termination, then losses due to terminations will bias the study in the negative direction. Less than 10Z of the exposed cohort are expected to be lost due to incomplete follow-up. These losses should not result in serious bias. Losses due to inaccessibility for examination are expected to be low, since 90Z of the retirees and 75Z of the terminated employees are estimated to be living within 300 miles of St. Louis. Non-participation is expected to result in substantial losses despite intensive recruitment efforts. We will compare the study sample with the entire exposed cohort on the basis of age, sex, race, payroll, work area, length of employment, and hospitalization rates while employed (available through the health insurance carrier) to determine if the sample is representative of the target population. We will also survey non-participants as to their reasons for non-participation and general health status. 7.2 Survival If exposure results in the death of the most susceptible individuals, then a morbidity survey of survivors will underestimate the strength of the association between the exposure and disease. The mortality study conducted by Zack (1980) suggests that exposures at the Krummrich Plant are not resulting in excessive mortality. DSW 476038.0711 STLCOPCB4042875 97 7.3 Incidence-Prevalance Bias Medical surveys are designed Co measure Che prevalence of disease ac the cirne Of Che survey; they are much less sensicive ac dececcing incidenc events chat may have occurred many years before. The present scudy is aimed ac measuring long-term health effects; as such, prevalence is an appropriate measure of disease frequency. The incidence of pasc events remains of interesc, however, and will be measured by 1) asking incidence-type questions on the medical hiscory (e.g. "Have you ever been hospitalized for an ulcer"), and by 2) medical record review. 7.4 Recall Bias The exposed employees will know the purpose of the scudy and may be more likely Co recall informacion on Che medical hisCory chan non-exposed employees. This source of bias will be concrolled by 1) medical record confirmacion of major healch evencs and 2) correlacing physical and laboracory findings wich medical hiscory findings. 7.5 Incerviewer/Examiner Bias The medical incerviewers and examiners may be biased in cheir measuremenc of healch scaCus if chey know che subjecc's exposure hiscory. This source of bias will be eliminaced Chrough 1) blinding Che incerviewers and examiners wich respecc Co che subjecc's exposure sCacus; 2) craining of incerviewers and examiners; and 3) use of scandardized questionnaires and physical examlnacion protocols. 7.6 Misclasslfication of Exposure Employees at the Kruimrrich Plant may be misclassified with respect to their degree of exposure due to 1) temporal changes in exposure; 2) personal DSW 476038.0712 STLCOPCB4042876 98 differences in work practices; and 3) non-documented exposures. Misclassification of exposure will bias the study in the negative direction. Our chief concern is the frequent and undocumented assignment of employees to the Utility work force which may briefly place them in an exposed work area. These exposures will be ascertained through the occupational and environmental history questionnaire. 7.7 Confounding Chemical Exposures Differences in health status between the exposed cohort and the internal controls may be due to the confounding effect of chemical exposures incurred in other departments. We will code the employment histories of Krummrlch employees to allow for statistical search for confounding. Exposures Incurred outside the Krummrlch Plant will be analyzed in a similar manner. If confounding appears to be present for major health outcomes, a nested case-control approach may be warranted. 7.8 Repeated Measures The comprehensive medical survey will provide data on a large number of health outcomes. If we set out alpha error at .05, one out of twenty will be significant by chance alone. A reduction of the alpha error would result in an unacceptably high beta error for low frequency events. The judgement of causality will not rely on statistical significance alone Associations will be judged for causality on the following criteria: 1. Statistical significance 2. Temporal Sequence: The exposure must have preceded the disease. 3. Consistency: The association should be consistent with findings from previous studies. DSW 476038.0713 STLCOPCB4042877 99 4. Strength of Association: The larger the value of the prevalence odds ratio or the greater the difference in means, the less likely the association is to be spurious. 5. Dose-Response: The frequency and severity of disease should increase as the exposure increases. 6. Specificity: Alternative causes, such as confounding by demographic, lifestyle, or outside exposure variables, have been ruled out. 7. Biological Plausibility: The association is plausible in light of existing toxicological and epidemiological data. 7.9 Statistical Power Limitations The study is limited in its statistical power to detect some associations by the size of the exposed cohort. Power analyses for dichotomous variables by size of the prevalence odds ratio are given in Table 25. Power analyses for continuous variables by the difference in means is given in Table 26. As is clear from these Tables, the sample size is adequate to detect mean differences of 10Z for most of the continuous variables and prevalence odds ratios of 2 for many of the important dichotomous variables. These estimates are conservative in that they are based on a total sample size of only 600 participants. A sample size of 800 would provide an additional 10-30Z increase in power for many of the study variables. DSW 476038.0714 STLCOPCB4042878 100 STLCOPCB4042879 TABLE 23 POWER ANALYSIS FOR DICHOTOMOUS VARIABLES BY SIZE OF THE ODDS RATIOS (EXPOSED = 328; CONTROLS = 283; a =.05) Variable History Acne II Chloracne Skin Cancer Control PrevalenceCZ.) RH3 35.2 sb 29.5 s 0.0 s 2.5 1.1 .14 .13 1.25 .37 .35 Power by ip 1.5 1.75 2 .78 .96 .99 . 76 .95 .99 .07 .11 .20 . 32 .54 Other Cancer Any Cancer s 1.2 RH 40 0o0 .06 .09 .14 . 20 .27 .14 .27 .44 .61 Hepatitis Jaundice Cirrhosis UGI Ulcer RH 4.1 RH 4.5 RH .4 S 5.5 .08 .14 .28 .45 .62 .08 .14 .29 .48 .66 .06 .07 .09 .11 .13 .08 .16 .33 .54 .72 Heart Disease RH " " Verified RH Myocardial Infarction RH " " Verified RH Coronary Artery bisease S Angina S Hypertension S 17.6 14.1 .5 .4 6.1 6.1 24.5 .12 .28 .64 .89 .98 .11 .25 .58 .84 .95 .06 .07 .10 .12 .15 .06 .07 .09 .11 .13 .09 . 16 . 36 . 58 .77 .09 .16 .36 . 58 .77 .13 . 33 .73 .94 .99 Psychosis Anxiety Other Neuroses RH RH RH .5 .5 .8 .06 .07 .10 .12 .15 .06 .07 .10 .12 .15 .06 .08 .12 .16 .20 34 .99 .99 .99 .99 5 .99 .99 .87 .99 1 .99 .59 .85 .97 .99 .97 .99 .97 .99 .98 .99 .25 .39 .99 .99 .99 .99 .55 .99 .99 .99 .99 .99 .30 .48 .25 .39 .99 .99 .99 .99 .99 .99 .99 .99 .66 .55 .99 .99 .99 .30 .48 . 30 .48 .44 .69 .66 .66 .87 TABLE 23 (continued) Variable Alcohol Dependence Nervousness/Anxiety/ Depression Decreased Libido Impotence Control RH S S S Prevalence(%) .3 11.7 15.3 11.7 Power by Y 1.1 .25 1.5 1.75 2 .06 07 .08 . 10 .11 .10 23 .53 . 79 .93 .11 26 .60 .86 .97 .10 23 .53 .79 .93 Chronic Sinusitis and Upper Resp. Disease Kidney Disease RH RH 55.7 3.5 .14 .79 .96 .99 .08 .13 .25 .40 .57 Miscarriage II Stillbirth II Birth Defects II Physical Exam Appears 111 RH 13.6 S 11.8 RH .8 S 1.3 RH 6.5 S 2.9 RH .1 .17 .49 . 92 .99 . 99 .16 .46 .89 .99 .99 .07 . 11 .19 . 30 .43 .08 .13 .26 .57 .60 .12 .32 *72 .94 .99 .09 . 20 .45 .71 . 88 .05 .06 .06 .07 .07 Chloracne 'Acne Vulgaris Hirsutism Comedones Acneiform Lesions Acneiform Scars Cysts Hyperpigmentation S S S RH RH RH RH RH 00 0.0 11.7 20.7 17.5 10.4 10.5 7.1 .10 .07 .12 . .12 .10 .10 .09 23 .53 .79 .93 10 .17 .26 .36 31 .69 .92 .99 28 .64 .89 .98 22 .49 .76 .91 22 .50 .76 .91 18 .39 .63 .81 U) 00 DSW 476038 STLCOPCB4042880 to 34 .19 . 30 .99 .99 ,99 .99 .99 .99 5 .42 .99 .99 .99 .99 . 99 .95 .99 .99 .99 .99 .99 .99 .99 .85 .98 .97 . 99 .99 .99 .99 .99 .99 .99 .99 . 99 .99 .99 .09 .11 .14 .99 .99 .76 .96 .99 .99 .99 . 99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 .99 TABLE 23 (continued) Variable Hepatomegaly Pinprick Light Touch Muscle Status Vibra tion Patellar Achilies Biceps Babinski Tremor Coordination Romberg Gai t Lab Sed Rate 40 y.o. >40 y.o. . RBCs on U/A Protein on U/A ECG <40 y.o. >40 y.o. Control RH RH RH RH RH RH RH RH RH RH RH R1I RH RH RH RH RH RH RH o 00 STLCOPCB4042881 Prevalence () .8 1.1 .06 9.6 7.5 3.6 8.8 .6 3.4 .5 .3 4.0 3.9 19.1 1. 8 .10 .09 .08 .09 .06 .06 .06 .08 .08 .12 .07 L. 25 08 Power by T 1.5 1.75 .12 .16 2 . 20 21 .47 .73 .89 18 .41 .65 .83 13 .25 .41 .57 20 .45 .70 .87 07 .12 .16 .17 13 .25 .40 .56 07 .10 .12 .15 07 .08 .10 .11 14 .27 . 44 .61 14 .27 .43 .60 30 .67 .90 .98 10 .17 .26 .36 34 .44 .69 5 .87 .99 .99 .99 .99 .99 .99 .95 99 , .99 .99 .99 .99 .34 .56 .75 .95 .99 .99 . 30 .48 .66 .19 .30 .42 .97 .99 .99 .97 .99 .99 .99 .99 .99 .76 .96 .99 i- o GO CoO to 1 Q 4.2 5.4 1.3 2.6 23.1 28.4 .07 10 . 18 .28 .39 o CO .97 .99 .07 11 .21 . 33 .46 .87 .99 .99 .06 09 .14 . 21 .28 .63 .88 .98 .07 11 .21 . 33 .46 .87 .99 . 99 .10 21 . 46 .71 .87 .99 .99 .99 .10 22 .50 .75 .90 .99 .99 .99 TABLE 24 VARIABLE Aik. Phosphatase GGT Males LDH Mai es SGOT (AST) SGPT (ALT) Males T riglycerides Glucose Urea Nit rogen Creatinine Males Total Protein Total Bi1irubin LDL HDL LH Maies FSH Males Testosterone Males T-l by RIA T-3 Uptake Ratio Free Thyroxine Index POWER ANALYSIS FOR CONTINUOUS VARIABLES BY DELTA % (Exposed=300: Controls==300) 5 JO 15 .59 .99 1 .17 .53 .86 .99 1 1 .38 .91 1 .25 .73 .97 .Mi .95 1 11 1 71* 1 1 1 1 111 .31 M .99 00 *v 0 -C" 00 .92 1 .7 1 1 1 M 73 9*t .26 7** .98 . 5* 98 1 11 111 111 Power by Delta 20 30 1 98 1 1 1 1 1 1 1 1 1 l0 1 1 1 1 1 1 1 1 104 STLCOPCB4042883 Table 24 (continued) WBC Hemoglobin HCT Platelet Count Ferritin Creatinine Clearance Delta Ammino Levulinic Acid Porphobi1inogen Copropophyrin 1 gG IgA IgM Total Protein-Urine T-Pan T-Heiper T-Suppres sor T-He1per/T-Suppressor 5 JO .85 1 11 11 11 1 1 1 . 66 1 1 .09 .22 .*3 .98 1 1 .13 .37 .69 A .93 1 .2 .6 91 .86 1 1 .28 .8 .99 .* 93 1 .86 1 1 .67 1 1 .38 91 1 .36 97 1 .56 99 1 Power by Delta X 20 30 II I1 II l0 Il .67 .95 II .91 I II .99 I II II 1I II II I1 II II 05 h- 50 75 100 CO coo tIo-. 5 w a 105 8. 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DSW 476038.0729 I STLCOPCB4042893 H5 9. PEER REVIEW COMMITTEE Mark R. Cullen, M.D. Assistant Professor of Medicine & Epidemiology Director, Yale-New Haven Occupational Medicine Program School of Medicine New Haven, Connecticut George Lathrop, M.D., Ph.D. Principal Scientist Epidemiology JRB Associates San Antonio, Texas Richard Monson, M.D. Professor of Epidemiology Harvard School of Public Health Boston, Massachusetts Lynne Moody, M.D., M.P.H. Medical Officer National Institute for Occupational Safety and Health Robert A. Taft Labs Cincinnati, Ohio Robert Waldman, M.D. Chairman, Department of Medicine University of West Virginia Morgantown, West Virginia DSW 476038.0730 i STLCOPCB4042894 PRELIMINARY BUDGET ESTIMATES FOR KRUMMRICH PROJECT 1) Data Gathering - 18 subjects per day by a team of 6 physicians (3 internists, 2 neurologists, 1 dermatologist) working 5 days per week and communting from Chicago on a weekly basis. (All figures assume 813 subject examination.) Physician Fees Physician Expenses Blood k Urine Test Paramedical Salaries , Equipment Lease/Purchase Survey Research Lab Neuro Behavioral Exam Subject Reimbursement 585,360 65,800 654,000 78,750 46,300 170,000 12,810 54,000 1,667,020 2) Data analysis - assumes 18 month required for data analysis and generation of individual reports. Salary of Investigators Salary for Support Personel Office Equipment, Supplies Equifax Cohort Search Data Coding Service Consultation Fees k Expenses Peer Review 156,000 356,134 45,465 45,150 31,150 13,632 10,000 657,531 Totals: I II University Overhead 1,667,020 657,531 53,250 2,377,851 DSW 476038.0731 STLCOPCB4042895 BATES LABEL NO. DSW 476038.0732 NOT USED STLCOPCB4042896