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/7x2V?/" ['..ut! 'ir^j OfCtiV? ub No i ;1 a Mortality Analysis of Employees *'- Engaged in the Manufacture of oi t'oai ". . vr. 2,4,5-TrichIorophenoxyacetic Acid ; hydro Am !no M. G. Ott, M.S.; B. B. Holder, M .D .; and R. D. Olson, B.S. c Therehave been tew published reports regarding surve/7- Only limited epidemiological investigations of em lance of individuis occupationally exposed to 2,4,5-tri- ployees exposed to 2,4,5-T have been conducted.1 * In chlorophenoxyacetic acid (2,4,5-T)The present study ex 1971, Poland et aP reported results of a health survey of amined the mortality experience of 204 persons exposed to 73 male employees in a 2,4,5-T and 2,4-dichlorophenoxy- 2,4,5-T during its manufacture from 1950 to 7977. length acetic acid (2,4-D) manufacturing plant This survey was a of employment in iob assignments within the 2,4,5-Tpro follow-up-of studies published by Bleiberg et aP in 1964 cess area ranged from less than one year to a maximum of on 29 employees in the same plant An important-finding approximately ten years. Efforts to minimize 2,3,7,8-tetra- in the follow-up was evidence of varying degrees of acne chkxodibenzo-p-dtoxin (TCDD) contamination of - the tn 48 of the 73 employees. The term "chloracne" was . product resulted in nondetectable concentrations using a employed to describe the moderate to severe lesions [method o f detection developed in 7966 that was sensitive observed for 13-(18%) of the individuals. No evidence of ^il.,part per million. Within the scope o f this mortality abnormal excretion of uroporphyrins was found in the ^fvy^no adverse effects were observed with respect to follow-up study, in contrast to the findings of the original Vccupaiional exposure to 2,4,5-T or its feedstock, 2,4,5-tri- study. Also, in their summary the-authors stated that yxhJorophenol. markedly less evidence of toxicity was found in other organ systems, such as the liver, than was reported in previous studies. Although not judged to be explanatory * - I of differences in toxicity seen from the earlier work, n 1976 Muranyi-Kovacs et aP published results of a TCDD contamination of the process-starting m aterial, .&oassay of 2,4,5-trichlorophenoxyacetic acid (2.4,5-11 for 2.4.5- trichloropftenol (TCP), had been reduced from 10-25 -..^ rc,'l?gen*c *tY- The 2,4,5-T.' .which contained less than ppm to 1 ppm six months before the second survey. No ^ P^ parts per million (ppm) of 2,3.7,8-tetrachlorodibenzo- detailed industrial hygiene measurements o f 2,4,5-T or -^P^HMin (TCDD), was found to produce a significant in- TCDD levels in the work environment were provided. non-incidental tumors (diagnosed during life or The present study examines the mortality experience of '/-.causing the death of the animal) in C3HF mice, but not in a cohort of 204 employees engaged in the manufacture o f. -^ Yll/G mice. Both groups of m ice had been fed 80 ppm 2.4.5- T. A revf&v of health examination findings o f' on a daily basis until death. Previously, consider- phenoxy herbicide workers in this plant was discussed in a .. ..^ v a r ia tio n between species had been demonstrated in paper by Johnson.1The current survey compares mortali ' - f excretion of 2.4.5-T.1 An earlier screening ty due to specific causes with that of the corresponding .-^woaisay study by Innes et al* was not positive for U.S. white male population, and with results of other mor --tomorigenicity in two hybrid strains of mice fed 60 ppm tality studies conducted at this company location. ,h U 5 -T in their diets. The authors of the 1976 bioassay arti- cle, aware of the kinetic studies and paper by Innes. sug gested that additional testing of 2,4,5-T was needed A hvo-year feeding study in rats was conducted in Midland. Michigan (Kociba et aP). Concentrations of up to 30 mg of 2,4,5-T per kilogram per day did not induce any treat^nt-related tumors. History of Process and Industrial Hygiene Measurements The commercial production of 2,4,5-T in the company began in March 1950. with the original process being operated continuously until it was permanently shut/ down in May 1971. In 1% 7. a second operation was' developed which employed different personnel and t V Md>cil Dipjrtm cnl, Dow CKf-mic*! U S A Mtdljod. Ml which has continued in production. Personnel from the Schenkci ^ ^ 1 o( Occupational Medicine/Vol. 22. No. 1/January 1980 47 second process were not included in the present stubecause of the shorter latency period, and because this more recent process is for the manufacture of esters of 2,4.5-T without isolation of the acid. The departmental unit under which the original process was first organized also was responsible for manufacturing a variety of other products, ranging from styrene-butadiene latex to her bicides such as 2,4,5-trich lorophenoxypropion'C acid and 2-methyi-4-chlorophenoxyacetic acid. Thus, many of the individuals included in the present study were potentially exposed to numerous other substances during their employment with this unit. The 2.4,5-T was manufactured, by reacting sodium monochloracetate with the sodium salt of TCP, the salt being prepared by adding caustic-to TCP. This was fol lowed by conversion to the acid. Ah'additional step, not considered part of the process but taking place in the same building, was esterification of 2,4,5-T with pro pylene glycol butyl ether or with isooctyl alcohol. Contin uing efforts were made to minimize TCDD contamination in the 2.4,5-T plant by proper control of a separate plant which produced the TCP later used in die 2,4,5-T process. In 1970 wipe testing, using a combined gas chromatog raphy and mass spectrometry method sensitive to approx imately 1 pgjsample, depending upon interferences, failed to detect TCDQ in the 2,4,5-T wort area. The 2,4,5-T pro cess was specifically run by a crew of four operators: a reactor operator, a salt wheel operator, an acid wheel operator, and a dryer operator. The reaction portion of the process in which the sodium salt of 2,4,5-T was produced was nearly a closed system. During the subsequent wheeling operations, the sodium salt was converted to the acid. The 2,4,5-T dust levels found in the plant were believed to have resulted primarily from finishing operations where the end product was dried and fed through a hammer m ill. An industrial hygiene survey of the process was con ducted in 1969, at which time 50 area and breathing zone samples were collected, using a midget impinger contain ing isooctane, at a flow rate of 22 liters per minute. The samples were subsequently analyzed by gas chroma tography for TCP, 2,4,5-T, and 2.4-D. Concentrations of 2,4,5-T or its sodium salt ranged from < 0.1 mg/m1to 6.2 mg/m1. Estimated time-weighted average (TWA) concen trations for the three compounds by fob classification are shown in Table 1. Concentrations of these substances were relatively similar for three of the Job classifications: Table 1. -- Tfot-Wtiglrted Average Expcsnrs Estimates for 2,'4,5-T Proctss Based on 50 Samples of Up ta five Minutes Duration and Hmo Studies for Each Job, 1969. Job Reactor operator Salt wheel operator Acid wheel operator Dryer operator TCP 2,4,5-T" ' 2,4-0 (mg/m1) (mg/nt1) (mg/m')t 2.1 0.6$ <0.4 2.1 0.5$ <0.4 9.7 0.2 <0.4 1.6 0.5 <0.4 PnxJud specifications foi 2.4.5-T m 1966 called lor a maximum ol 1 ppm TCDD. the sensitivity ot the method ol dtection. In 1972. the maximum was towered to 0.1 ppm TCDD t Highest possible values using levels ot delect ton as real values $ Present in work environment as sodium salt reactor operator, dryer operator, and salt wheel operator The acid wheel operator was exposed to lower 2.4.5-T levels and higher TCP concentrations. The 2,4-D measure ments are maximum levels. This product was dried o c c i. sionally in the building where 2,4,5-T was made. f Dust levels in the finishing area often were high enough to be noticeably irritating. Unacclimated industrial hygienists reported sensory responses such as nasal irrita tion, sneezing, and a bitter taste from exposure levels of approximately 0.1 mg/m* of 2,4,5-T or less than 4 mg/m1 of TCP, or both. A review of medical visits from 1954 to 1970 among the 204 men in this study revealed 19 episodes associated with acute exposure to 2,4,5-T or its esters. All exposure reported involved eye or skin contact, with the mild to moderate responses apparently resulting from the irritating effects of the materials. Six of the ex posure episodes occurred while the men were working as ester operators rather than directly on the 2,4,5-T process. The esters of 2.4,5-T are believed to exert toxicological ef fects similar to those of the acid, after adjustments for the molecular weight of the ester itself. Method of Analysts The employees included in the study were determined by a two-stage procedure. The first step was the identifi cation, from annual census lists covering the period January 1951 through January 1971, of all persons who had worked in the department under which the process was organized. The second step was a review of the com plete work history for each individual to determine those who had had experience on any of the' four jobs of in terest These employees constituted the population of concern. This method of selecting th exposed populatic/ insured that all employees who worked continuously for at least one year in the 2,4,5-T work area were included, but could have missed some personnel who worked in the exposure area for shorter periods of time. A crew of eight to 12 men operated the 2,4,5-T process on a daily basis. The flow of employees in and out of the department over the 21-year period resulted in 204 men having worked for one or more months on at least one of the four jobs involved. The mortality experience of these men was compared, by the indirect method, with thahftf* the U.5. white male population (five-year age intervals) for the years 1952.1957,1962, 1967 and 1971. The vital status of former employees was traced initially through the Social Security Adm inistration. Subsequently; verification of vital status has been obtained through-con tact with the individual or with relatives who could 'ac count for the former employee's vital status. < Table 2. -- Vital aod Employment Status of 204 Workers Exposed to 2,4,5-T as of December 31, 1976. Vital and Employment States Tt>UI group Still employed Retired Deceased (company records) Let! employment other than through retirement Deceased Known alive Follow-up through 1976 incomplete No. cf Workers 1 204 121 18 9 1V 51 3 48 Mortality Analysis ol Employees Engaged in the Manufacture ol 2,4.5-T/Ott, Holder, and Olso Hor Tibi 3. -- Duration of Exposure by Dito First Exposed Among 204 Employe Exposed to 2,4,5-T. .S-T ure- **a- Dito Exposuri Begin Durttlon at Exposure* Total <1 Yur 1-2 Yura 3-4 Y u ri 5+ Y u ri ugh trial ritas of 'Jm 1 Total 1950-54 1955-59 1960-54 1965-69 1970 + 204 157 30 58 30 17 45 36 6 51 44 4 35 32 3 15 15 0 9 5 2 2 0 0 6 6 1 1 0 0 4 to * Fifty-nine ol the 204 employees worked as ester operators lor Irom <1 up to 77 months (11 ol these employees hid worked for at leisi one year 19 r its as esier operators). The exposure durations as ester operalors. or while employed in other capacities within the production department, were not included m the table since exposure iniensiiies had not Been esdmated act. In this analysis, exposure is expressed Gnly in terms of Tables 4 and 5 summarize mortality by duration of ex ting length of employment on the four jobs of'primary con posure and by interval since first exposure. In Table 4, - ex- cern. Exposure durations do not take info account the . observed deaths were increased over expected only for g as unmeasured exposures to 2,4.5-T or to esters of 2,4.5-T en the cause of death category "external causes" (6 observed .ess. countered on other jobs within the production depart vs. 3.7. expected). Three deaths in this category were due I ef* ment One job did involve exposure to esters of 2,4,5-T, to separate automobile accidents, none of which took the and several other jobs may have required filling in on a place while the individuals were employed on jobs involv day-to-day basis for the operators in the four classifica ing 2,4,5-T exposure. One death was the result of a non tions of interest, as well as other duties with minimal ex industrial fire, and the remaining two deaths were :rved ntifiriod vho cess om* K)$e f in- posure. Since many of the employees in the 2,4,5-T study "'* worked on a number of jobs within the department the durations of exposure are conservatively estimated. Sixty of these employees re also known to have worked in a styrene-butadiene latex plant organized within the pro duction department. Thus, the persons included in the present study have been exposed to a variety of chemical compounds during their employment ot Results n The vital and employment status of the 204 workers ex ror posed to 2,4,5-T and its sodium salts are shown in Table 2. ded. .Fift^three of the 56 former employees have been traced i the , ..trough personal contact with the individual or with suicides of former employees which occurred more than ten years after exposure, had ceased. The single observed malignancy death in the cohort to date was due to a respiratory malignancy which was discovered in a 63-year-old retiree who had been exposed to 2.4,5-T for eight years and who had a past history of smoking up to two packs of cigarettes per day. The trerxi Of deaths with respect to interval since first exposure follows a pattern which we have observed in other studies at this company location.' The most favorable'mortality-experience occurs in the early years after first exposure, followed by a relative increase com pared to general- population mortality. We have inter preted these findings to indicate a preselection effect due cess the nen e ot >ese :t of /als) /ita! ugh itly , co ac- i'sorpeooe who currently knows him. For three persons r'vfcaj status was verified at least through 1973, but not tfttfcigh 1976, by personal contact or by social security checks. Two former employees had died as of the end of 1976 and nine deaths were observed among individuals followed through employment and retiree records. . ;; The distribution of employees by duration of exposure by date first exposed is shown in Table 3. More than * the men had worked fot less than 12 months in : *1^;;*nvolving defined exposure. None of the men were .. OJjpsed to 2,4,5-T over a working lifetim e. ^Medical records of employees were reviewed for ; ^wdence of chloracne or of porphyria cutanea tarda, to initial employment or transfer of individuals in a state of good health, which becomes less important both as the interval since employment increases and as the employees become older. Comment At the exposure concentrations of TCP and of 2,4,5-T (1966 product specification called for <1 ppm TCDD in the final product) experienced by the workmen in this study, no adverse mortality effects have been observed in association with the work environm ent Within the scope of this limited survey, m ortality has been favorable com pared to that of U.S. white m ales, and also compares well right indicate exposure to TCDD. No case of with the background m ortality experience at this ; v$Pr?CI>e or of porphyria cutanea tarda was found. manufacturing location.' The mortality comparisons Ison Table 4. -- Observed and Expected* Deaths Among 204 Employe Exposed ts 2,4,5-T, by Cause and Duration of Exposure, 1950-1976. W & C im e ot Death Category Ail causes Total malignant neoplasms Diseases ol cardiovascular system Extern al causes (accidents and surcides) All other causes Total Expos Croup Observed Expected 11 20.3 1 3.6 4 9.1 6 37 0 3.9 Duration of Exposera <1 Y u r Total Exposure Observed Expected 6 13.3 0 23 1 5.6 5 2.8 0 26 1 + Years Total Exposure Observed Expected 5 7.0 1 1.3 3 3.5 el 0.9 0 1.3 * Expected numoers ol deaths based on U.S white male monaliiy mes Jnjmalof Occupational Medicine/Voi. 22. No. 1/January 1980 49 T ib fe 5. -- Observed in d Expected* D u t t is Amoftfl 204 Em ployees Exposed to 2 ,4 ,5 -T , b y C iu s e end Interval Since First Exposure, 1850-1976. Cause ol Death Category All causes Total malignant neoplasms Oiseases ol cardiovascular system External causes (accidents and suicides) All other causes Interval Since Fksr Exposure i <10 Years 10-14 Years 15-19 Years, 20 + Years Observed Expected Observed Expected Observed Expected Observed Expected 3 6 6 0 4 7 4 4.6 4 4.4 0 1.0 0 0.9 0 0.8 1 0.9 0 2.3 0 2.2 3 2.3 1 2.3 3 2 0 0 0.8 1 0.5 2 0.4 0 1.3 0 0.8 0 1.0 0 0.8 * 'Expected numbers o! deaths based on U.S. while mate mortality rates presented in Tables 4 and 5 are point estimates and. as such, do not directly reflect imprecision in. the estimates due to small sample size. Confidence interval and power calculations may be carried out using the data provided in the tables and tabulations of the Poisson distribution. Alternately, the largest SMR or relative risk that is consis tent with the observations may be stated. For example, the probability .of observing less than two deaths due to malignant neoplasms 15 or more years after first exposure Cone actually observedl when, in fa c t the true relative risk is two, is about 15% . If the true relative risk were four, the probability of observing less than two deaths would be 0.01. Because of questions raised by recent animal toxicological studies, mortality surveillance of this limited employee population will be continued. The mor tality surveillance of other populations which have had past exposure to 2,4,5-T is recommended. References 1. M uranyi-Kovacs 1. Rudali G , and Imbert J: Bfoasjay _of 2.4.5- lrichlorophenoxyacetic acid for carcinogenicity in m ice. 8r I Cancer 33.626-633. 1976. 2. Cehring PJ. Kram er C C . Schwetz B A et a l: The fate of 2.4.5- trichloropHenonacetic acid (2,4.5-T) following oral adm inistra tion to man,' Toxicol Appl Pharmacol 26:352-361,1973. 3. Innei JRM. Ulland BM. Valerio M G, et a l: Bioassay of pesticides and' industrial chem icals for tum origenicity in m ice; A prelim inary note. } Natl Cancer Inst 42:1101-1114,1969. 4. Kociba RJ, Keyes D C , LHowe RW. et a l: Results of a two-year chronic toxicity and oncogenic study of rats ingesting diets containing 2,43-trichIofopheftoryacetic acid (2,4,5-T). Food Cosmet Toxicol 17:205-221.1979. 5. M e lson O and Sundell L : Herbicide exposure, m ortality and tumor incidence: An epidem iological investigation'- o n, Swedish railroad workers.* Work Environ Health 11:21-23,1974. 6. Poland AP. Smith D. M etier C , and Posskk P: A health survey of workers in a 2,4-D and 2,4.5-T p lan t Arch Environ Health 22:316*327. 1971. 7. Bleiberg |, W allen M, Brodkin R! et al: Industrially acquired por phyria. Arch Dermatol 89:739-797. 1964. fl. fohnsotrJE: The public health im plications of widespread use of the phenoxy herbicides and picloram . 6o-Science 21:899-905; 1971. 9. Ott M G. Holder BB. and Gordon H L Determ inants of m ortality in an industrial population. } O ccup M ed 18:171-177,1976. Skilb Productive Capital The 1979 recipients of the Nobel Prizes for economics are W . Arthur Lewis, of Princeton University, and Theodore W . Schultz of the University of Chicago. Schultz revived interest in human capital. He emphasized the extent to which the welfare of nations and individuals is determined by the amount of capital they have in the form of the productive skills of human beings, which has been acquired by invest ment in education, training, research and experience. The second main idea associated with Schultz is the insistence, based on observa tion, that the behavior of people of all kinds, not only graduates of the Harvard Busi ness School but also Indian villagers, can be explained on the assumption that they make rational and efficient use of the resources and information they. have. i -- From "Nobel Winner Dexh With People, Not Theory' by Herbert Seen, n The Proburgh ftecs, October 28.1979. SO Mortality Analysis of Employees Engaged in ` "e Manufacture ol 2.4,5-T/Ott. Holder, and Olson