1 15 7 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 166 Folder The folder containing the original item. 4947 Series The series number of the original item. Series VII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. Title A name given to the resource Memorandum: from Barclay M. Shepard with subject VA Publications of Scientific Literature on Herbicides, January 1987 https://www.nal.usda.gov/exhibits/speccoll/files/original/b677371336f0a60017b46af9dd5a1d6f.pdf a3e56005c1947ba2597cabb4591043d8 PDF Text Text Item ID Number 01868 Author Shepard, Barclay M. Corporate Author ROpOTt/ArUdO TltlB Critique of West Virginia Mortality Study Journal/Book Title Year 1986 Month/Day February 4 Color a Number of Images 36 UOSCrtytOn NOtBS ltem inlcudes critique, as well as attached 1) M. L. Neighbors Diversified Maritime Services, Inc. advertisement and 2) Vietnam-Era Veterans Mortality Study, West Virginia Residents 1968-1983, Preliminary Report, January 1986. Wednesday, July 11, 2001 Page 1869 of 1870 �FEB 04 1986 Critique of West Virginia Mortality Study The West Virginia Department of Health has recently completed a mortality study (copy attached) of Vietnam-era veterans based on the recipients of a state bonus. The State offered a differential bonus to all West Virginia residents who served in the military during the Vietnam era with a larger amount going to those who served "incountry". 41,059 in-country (Vietnam veterans) and 41,782 non-incountry (non-Vietnam) veterans received the bonus. The list of bonus recipients was matched against state vital statistic records resulting in 1225 male Vietnam-era veterans who had died between 1968 and 1983. For each deceased male veteran a copy of the Report of Separation From Active Duty (DD 214) was reviewed to determine dates and place of service. The latter was determined by receipt of at least one of the three medals awarded for service in the Southeast Asia theater of operations. In addition, cause of death information was obtained on each deceased veteran. Of the 1225 deceased veterans, 615 were in the group of Vietnam veterans and the remaining 610 were non-Vietnam veterans, i.e., veterans who served elsewhere during the same period of time. When comparing causes of death between all veterans in the group and non-veterans of similar age only those classified as accidents, poisoning, and violence were elevated among the veteran group. Deaths due to cancer were statistically the same in both groups. Other causes of death were lower in the veteran group, a commonly observed phenomenon known as the "healthy veteran effect". A stated by the authors, the study has a number of limitations which must be kept in mind when interpreting the results: "In spite of the intense publicity given to the bonus campaign, it is likely that many veterans or their survivors never applied for the bonus. Thus, those veterans who did qualify for a bonus represent an unknown proportion of the actual number of West Virginia males'who served in the military during the Vietnam era. It cannot be assumed that the proportion was similar for both [groups]. Furthermore, because the mortality tape identified only residents of West Virginia who died during the study period, deaths in that period among veterans who no longer resided in West Virginia at the time of their demise would not have been counted among the 1,225 veterans deaths ascertained. . . With respect to a comparison between in-country and era . veterans, it cannot be assumed that similar proportions of the respective candidate population qualified for the bonus or that the death rates among in-country veterans who were no longer West Virginia residents were similar to those among era veterans who were no longer residents." �There were 145 cancer deaths of which 71 were in the group of Vietnam veterans and 74 were among the non-Vietnam veterans. In comparing specific types of cancers between these two veteran groups, only Hodgkin's disease, testicular cancer, and soft tissue sarcoma were elevated in the Vietnam veteran group. In each instance, however, the number of actual cases was small, i.e., 5 cases of Hodgkin's disease, 3 testicular cancers and 3 soft tissue sarcomas. As the authors state: "These findings must be interpreted cautiously ... since ... the site- specific cancer deaths were derived from a relatively small number . . and would . therefore be subject to ... large random fluctuations". In addition to the stated limitations of the study, as pointed out by the authors, there has been no systematic review of military personnel records, except for the DD 214 reviews as noted above, to validate the Vietnam service status of the study subjects. Because of the interest and concern over the relationship between soft tissue sarcoma and exposure to the phenoxy herbicides, the authors have now requested a review of the personnel records of the 3 veterans recorded as having this diagnosis. All.three of these were reported to have occurred in the in-country veteran group. The first of these is now known to have served in Thailand, not Vietnam, and would not have been exposed to Agent Orange. This is an example of the serious effect of misclassification especially when dealing with small numbers of subjects. In addition, there has been no systematic review of hospital or other clinical records to validate cause of death information or confirm the specific cancer diagnosis. Again, when dealing with relatively small numbers, a few errors in diagnosis can significantly alter the conclusions. In summary, this study appears to have been well designed and well conducted as far as it goes. As noted by the authors, however, it has inherent limitations and additional data are needed to validate some of the conclusions. BARCLAY M. SHEPARD, M.D. Director, Agent Orange Projects Office �«J£. tLAet&Ad&Ht- 1 January 1986 ANNOUNCEMENT M. L. NEIGHBORS, DIVERSIFIED MARITIME SERVICES, INC., announces that it is now able to offer part time consultative service or representation in the Washington, DC area to additional firms or persons that are engaged or have an interest in maritime related business ventures or business involving the disposal of chemical waste. Such work may also be arranged for in locations other than the Washington DC area as mutually agreed, and on either a prime or sub-contract basis. Among services offered are: A. Maintaining continuous contact with federal agencies having jurisdiction or control over maritime or chemical waste disposal ventures, and submittal of reports on matters of client interest. Rapid "feed-back" on specific information of more urgent interest can also be provided. B. Projection of U.S. chemical waste disposal requirements, in general or with specificity. C. Assisting in the initiation of either a maritime project or a project involving chemical waste disposal (except services involving the disposal of chemical waste by incineration at sea cannot be provided until after 30 November, 1986). CORPORATE EXPERIENCE INCLUDES: Nineteen years involvement with Department of Defense vessel charters and military cargo movement contracts. Thirteen years involvement with various offices of the Environmental Protection Agency that are responsible for regulating chemical waste disposal. This work included interaction with other federal agencies and with commercial firms offering alternative types of chemical waste disposal service. Written inquiries should be addressed to M. L. Neighbors, DMS Inc., 777 Fourteenth St., Suite 747, Washington, DC, 20005. Further information may also be obtained from Mr. Neighbors at phone number 564 1568 (area code 301 if calling from outside metro area). �WEST VIRGINIA HEALTH DEPARTMENT �VIETNAM-ERA VETERANS MORTALITY STUDY WEST VIRGINIA RESIDENTS 1968 - 1983 Preliminary Report January 1986 Arch A. Moore, Jr. Governor David K. Heydinger, M.D. Director, Department of Health �Alan P. Holmes, B.S.E.E., M.B.A. Principal Investigator WEST VIRGINIA DEPARTMENT OF HEALTH VIETNAM-ERA VETERANS MORTALITY STUDY COMMITTEE Charles Bailey Assistant Director, Health Statistics Center Roy C. Baron, M.D., M.P.H. Medical Epidemiologist Edward Bosanac, Ph.D. Research Consultant John Brough, Dr. P.H. Director, Preventive Health Services Charles Conroy, M.A. Agent Orange Program Coordinator Acting Director, Community Health Services Loretta Haddy, M.A., M.S. State Epidemiologist Alan P. Holmes, M.B.A. Director, Health Statistics Center ACKNOWLEDGEMENTS Sandra Y. Pope, Administrative Assistant, Agent Orange Program Eugenia Thoenen, Publications Coordinator, Health Statistics Center Thomas N. Leonard, Programmer/Analyst, Health Statistics Center Betty Jo Berry, Secretary, Health Statistics Center We would also like to thank Col. John W. Moon and the staff of , the West Virginia Department of Veterans' Affairs for their invaluable assistance in providing data used in this study. For further information, contact Charles Conroy, Agent Orange Program Coordinator 1800 Washington Street, East Charleston, WV 25305 Telephone: (304) 348-3210 �Vietnam-Era Veterans Mortality Study West Virginia Residents 1968-1983 The Agent Orange Assistance Program, established in 1982 by the West Virginia legislature, requested the Health Statistics Center of the Department of Health to conduct a study of the causes of death among state Vietnam veterans from 1968 through 1983.* The purpose of the study was to compare the mortality pattern among veterans with that of nonveterans in order to generate hypotheses regarding any differences in the causes of death among the former. A comparison of the causes of death among veterans who served in Vietnam with those among veterans who did not serve in Vietnam was also undertaken in order to speculate whether the Vietnam experience might be associated with a distinct mortality pattern. METHODS Identification of West Virginia Veterans West Virginia residents who served in the military during the years of the Vietnam Conflict were identified from the list *The Vietnam era is generally defined as extending from 1964 until 1973. For the purposes of this study, however, only those deaths from 1968 were considered because of the small number of deaths occurring before that year, in addition to difficulties imposed by cause-of-death coding changes over the longer interval. �of applicants for a military service bonus offered by the state Department of Veterans' Affairs in 1974. To qualify for a bonus, veterans had to meet the following criteria: 1) they must have rendered active service in the armed forces at some time between August 1, 1964, and March 28, 1973, inclusive, or have been recipients of the Vietnam armed forces expeditionary medal if they saw active service prior to August 1; 2) they must have been residents of West Virginia for at least six months prior to entry into active service; 3) they must have actively served for a period of at least ninety days unless discharged because of a servicerelated disability, and 4) they must have been honorably discharged. Efforts to notify eligible veterans or their survivors about the bonus program included one national public awareness campaign conducted in November 1975 and one conducted in July 1976. Public service announcements were issued over the television networks, and notices were posted in every major newspaper in the country and organizations on service advertised networks the bonus overseas. legislation Veterans' in their publications, and some offered assistance in filing for the bonus as a promotional device in their membership campaigns. Three different bonuses were offered. Veterans who did not serve in Vietnam ("out-of-country" or era veterans) were to receive up to $300 (Type 3 bonus); Vietnam veterans ("in-country" veterans) were to receive up to $400 (Type 4 bonus), and surviving relatives of veterans who died while in the service during the period designated by the legislature were to receive �$500 (Type 5 bonus). In West Virginia, the Department of Veterans' reported a total of 86,247 initial applicants. Affairs Of those who applied for the bonus, 83,730 veterans or survivors (97%) were eligible (Figure 1). Of these, 41,782 qualified for the Type 3 (Vietnam-era) bonus, 41,059 qualified for the Type 4 (Vietnam) bonus, and 889 qualified for the Type 5 bonus. Since this was to be a study of mortality following discharge from the service, the Type 5 bonus recipients were excluded from subsequent analyses. Names of the Type 3 and Type 4 qualifiers were, entered onto a computer tape, referred to as the "bonus tape." Identification of Veteran and Nonveteran Deaths A complete listing of West Virginia resident deaths from 1968 through 1983 was prepared from records maintained by the Health Statistics Center and entered onto a "mortality tape." The names on this list were then compared with those on the bonus tape in order to identify veterans who died during this period. For deaths from 1968 through 1978, the information had to be matched by name since social security numbers were not included on the mortality tape for these years. Any possible match generated in this manner was searched by hand and confirmed by comparing the social security number on the death certificate with that on the veteran application. From 1979 through 1983, it was possible to match by social security number. �FIGURE 1 WV VIETNAM VETERAN MORTALITY STUDY SELECTION OF STUDY POPULATION 1968-83 Bonus Tape 83,730 1 1 1 In -Country Vietnam 41,059 Not-in-Country Era 41,782 No-Match Death File 41,169 Females Era 3 Nonwhite Males Era 30 MatchedDeath File Era 613 Males Era 610 White Males Era 580 No-Match Death File 40,444 Died in Service 889 MatchedDeath File Vietnam 615 Females Vietnam 0 Males Vietnam 615 Nonwhite Males Vietnam 36 White Males Vietnam 579 �There were 1,234 initial matches between the bonus tape and the mortality tape, 614 Vietnam-era (Type 3) veterans and 620 in-country (Type 4) veterans. The veterans' discharge forms (DD-214s) were then manually checked to verify their in-country status.* This review reclassification of resulted several in records, the deletion leaving 1,228 and/or deceased veterans who qualified, 613 for the Type 3 bonus and 615 for the Type 4 bonus. Three of the deceased veterans, all Type 3 bonus recipients, were female. They were excluded from the final tape; the subsequent analyses included only deceased male veterans. Of the 1,225 male veterans who died (Table 1), 1,159 were white and 66 were nonwhite (65 black and 1 Hawaiian). nonwhite veterans were Type 3 (5%) and 36 were Type 4 Thirty (6%). Because nonwhite veterans constituted a small percentage of those who died, the study combined the mortality patterns of white and nonwhite veterans. For nonveteran males, deaths were identified from the mortality tape by deleting the records of all remaining female deaths and those of the 1,225 male veteran deaths. thus four groups defined for analysis: died; (2) male Vietnam-era-only There were (1) all male veterans who (Type 3) veterans who died; *In-country status was determined by the receipt by the veteran of one of three service medals (the Vietnam service medal, the Vietnam campaign medal, or the Vietnam expeditionary medal) as noted on the DD-214. These medals were awarded to military personnel who served in the Southeast Asia theater of operations. �TABLE 1 TYPE 3 AND TYPE 4 MATCHES BETWEEN BONUS TAPE AND MORTALITY TAPE BY YEAR 1968-83 YEAR VIETNAM-ERA (Type 3) IN-COUNTRY (Type 4) TOTAL 1968 4 13 17 1969 14 16 30 1970 17 22 39 1971 16 33 49 1972 26 31 57 1973 33 22 55 1974 25 29 54 1975 50 47 97 1976 47 46 93 1977 50 40 90 1978 54 35 89 1979 53 44 97 1980 58 51 109 1981 53 70 123 1982 55 59 114 1983 56 56 112 TOTAL 610 615 1,225 �(3) male in-country (Type 4) Vietnam veterans who died, and (4) all other West Virginia males (nonveterans) who died from 1968-83. DEMOGRAPHIC PROFILE OF DECEASED VETERANS Age Distribution The average age at death was 35.3 for all veterans, 35.1 for era veterans and 35.4 for in-country veterans. Table 2 shows that the distribution of deaths by age for Type 3 and Type 4 veterans was similar. Tables 3 and 4 present the distributions of age at death by race for Vietnam-era and Vietnam veterans, respectively. Among white Type 3 veterans, the average age at death was 35.3, among nonwhites 31.3. For Type 4 veterans, the mean age at death for whites was 35.5, with 33.5 that for nonwhites. �TABLE 2 ALL VIETNAM-ERA VETERANS Age Distribution by Type of Service VIETNAM-ERA (Type 3) TOTAL IN- COUNTRY (Type 4) AGE GROUP f % % * 4 I 15-19 4 0.7 1 0.2 5 0.4 20-24 82 13.4 92 14.9 174 14.2 25-29 139 22.8 125 20.3 264 21.5 30-34 137 22.4 143 23.2 280 22.9 35-39 83 13.6 61 9.9 144 11.7 40-44 42 6.9 53 8.6 95 7.7 45-49 36 5.9 60 9.8 96 7.8 50-54 40 6.6 33 5.4 73 6.0 55-59 24 3.9 32 5.2 56 4.6 60-64 12 2.0 12 2.0 24 2.0 65-69 9 1.5 3 0.5 12 1.0 70-74 2 0.3 0 0.0 2 0.2 TOTAL 610 100.0 615 100.0 1,225 100.0 Average Age at Death 35.4 35.1 8 35.3 �TABLE 3 VIETNAM-ERA VETERANS (TYPE 3) Age Distribution by Race WHITE TOTAL NONWHITE AGE GROUPS % # % # % 1 19 4 0.7 0 0.0 4 0.7 20-24 77 13.3 5 16.7 82 13.4 25-29 131 22.6 8 26.7 139 22.8 30-34 127 21.9 10 33.3 137 22.4 35-39 79 13.6 4 13.3 83 13.6 40-44 42 7.2 0 0.0 42 6.9 45-49 33 5.7 3 10.0 36 5.9 50-54 40 6.8 0 0.0 40 6.6 55-59 24 4.2 0 0.0 24 3.9 60-64 12 2.1 0 0.0 12 2.0 65-69 9 1.6 0 0.0 9 1.5 70-74 2 0.3 0 0.0 2 0.3 TOTAL 580 100.0 30 100.0 610 100.0 Average Age at Death 35.3 31.3 35.1 �TABLE 4 IN-COUNTRY VIETNAM VETERANS (TYPE 4) Age Distribution by Race NONWHITE WHITE TOTAL AGE GROUPS % # # % t Z 19 0 0.0 1 2.8 1 0.2 20-24 87 15.0 5 13.8 92 14.9 25-29 114 19.7 11 30.5 125 20.3 30-34 135 23.3 8 22.2 143 23.2 35-39 59 10.2 2 5.6 61 9.9 40-44 51 8.8 2 5.6 53 8.6 45-49 59 10.2 1 2.8 60 9.8 50-54 29 5.0 4 11.1 33 5.4 55-59 30 5.2 2 5.6 32 5.2 60-64 12 2.1 0 0.0 12 2.0 65-69 3 0.5 0 0.0 3 0.5 70-74 0 0.0 0 0.0 0 0.0 TOTAL 579 100.0 36 100.0 615 100.0 Average Age at Death 35.5 33.5 10 35.4 �Branch of Service Review of the DD-214 forms showed that 718 (59%) of the deceased veterans had served in the army, 210 (17%) had served in the air force, 167* (14%) had served in the navy, and 120 (10%) had served in the marines (Table 5). Seventy-five percent of the in-country veterans who died had been in either the army or the marines, in contrast to 62% of the era veterans. Twenty-five percent of in-country veterans had served in either the air force or the navy, in contrast to 37% of, the era veterans. For 10 veterans, the branch of service was not recorded on the discharge forms. *Includes 3 coast guard veterans. 11 �TABLE 5 ALL VIETNAM-ERA VETERANS Branch of Service by Type of Service VIETNAM-ERA (Type 3) IN-COUNTRY (Type 4) TOTAL BRANCH OF SERVICE % * t % * % Army 340 55.7 378 61.5 718 58.6 Air Force 127 20.8 83 13.5 210 17.2 16.1 69 11.2 167 13.6 Navy 98* Marines 39 6.4 81 13.2 120 9.8 Unknown 6 1.0 4 0.6 10 0.8 610 100.0 615 100.0 TOTAL *Includes 3 coast guard veterans 12 1,225 100.0 �ANALYTIC METHODS In spite of the intense publicity given to the bonus campaign, it is likely that many veterans or their never applied for the bonus. survivors Thus, those veterans who did qualify for a bonus represent an unknown proportion of the actual number of West Virginia males who served in the military during the Vietnam era. It cannot be assumed that the proportion was similar for both Type 3 (era) and Type 4 (in-country) qualifiers. Furthermore, because the mortality tape identified only residents of West Virginia who died during the study period, deaths in that period among veterans who no longer resided in West Virginia at the time of their demise would not have been counted among the 1,225 veteran deaths ascertained. Because of these limitations, the records provide neither complete information about the total candidate population nor a comprehensive estimate of the force veterans who did qualify. the veteran and the of mortality among the With respect to a comparison between nonveteran groups, the data would underestimate the relative force of mortality among the veterans, if such a comparison were made. With respect to a comparison between in-country and era veterans, it cannot be assumed that similar proportions of the respective candidate population qualified for the bonus or that the death rates among in-country veterans who were no longer West Virginia residents were similar to those among era veterans who were no longer residents. 13 �The method of choice for a study of mortality when there is incomplete data on the population at risk is a proportionate mortality analysis. In this type of study the proportion of all deaths due to the disease(s) of interest in the study population is compared with the proportion of all deaths due to the disease(s) of interest in the comparison (referent) population. Such proportional rates do not express the risk of dying from a disease since the incidence is not measured against a population base. They simply suggest that there may be a difference worth investigating further. The validity of such a study rests on the assumption that there is no association between the study factor, i.e., veteran status, and the occurrence of other diseases. Since we cannot make this assumption, such an analysis is used to generate hypotheses or to conduct preliminary tests of etiologic hypotheses without collecting much additional data. The relationship between the proportion of deaths due to a specified cause in a study population and the proportion derived from the referent population is expressed as a proportionate mortality ratio (PMR). The PMRs in this study are standardized to adjust for selected confounding variables. When the veteran group and its subgroups were compared with the nonveteran group, adjustments were made by stratifying on age at death by 5-year intervals (15-19, 20-24, . . . etc.) and on year of death by 2-year intervals stratum, (1968-69, 1970-71, expected deaths were . . . 1982-83). For each calculated by determining the percentage the cause of death of interest contributed to all 14 �causes in the referent population and multiplying this result by the total deaths from all causes in the study population. The standardized PMR statistic (sPMR) is the ratio of the number of deaths of interest observed in the study population summed over all strata, multiplied by 100, and then divided by the expected values summed over all strata. Stratification by age only and not by year of death was done when the in-country (study) group of veterans was compared to the era (referent) group. This was done in order to avoid losing data from the study group when respective strata in the referent group had no deaths. An sPMR greater than 100 indicates that the cause of interest contributes a greater percentage of all deaths in the study population than in the referent population; an sPMR less than 100 indicates that the cause contributes a smaller percentage of all deaths in the study population than in the referent population, and an sPMR of 100 indicates that the cause of interest contributes the same percentage of all deaths in both groups. expected frequencies against confidence p-value for each cause of interest were tested the null hypothesis, i.e., proportionate mortality interval expressing The observed and structure, around the each each exact sPMR by group has the same calculating a 95% and also a one-tailed probability of finding the difference between the observed and expected frequencies. RESULTS In the period 1968 through 1983, there were 1,225 deaths among males who had served in the military during the Vietnam 15 �Conflict. Six hundred fifteen of the men served at least a portion of their duty in Vietnam (in-country, Type 4 veterans) and 610 had no experience in Vietnam (era, Type 3 veterans). For both groups combined, 716 deaths (58%) were from external causes (injury from accidents, poisoning, or violence), 237 (19%) were from cardiovascular neoplasms, 48 (4%) disease, were 145 from (12%) were nonmalignant from diseases malignant of the gastrointestinal system, 24 (2%) were from nonmalignant diseases of the respiratory system, 5 (-=1%) were from allergic, metabolic, and endocrine disorders, and 50 (4%) were from all other causes. With nonveteran West Virginia male deaths from 1968 through 1983 as a reference, Table 6 demonstrates the number of observed and expected deaths in each cause-of-death category for all veterans together and for in-country and era veterans separately. For all veterans, the observed distribution of deaths over these categories was significantly different from the expected (Chi square Goodness of Fit •» 50.2 with 6 degrees of freedom, p<10~8). Accidents, significantly poisoning, greater and proportion violence of accounted all veteran for a deaths than expected (sPMR excess), while deaths from allergic, metabolic, and endocrine conditions and from all other causes accounted for significantly smaller-than-expected deaths (sPMR deficits). For 16 proportions of all veteran cardiovascular, digestive, and �TABLE 6 ALL CAUSES OF MORTALITY Vietnam Veterans vs. Nonveterans West Virginia, 1968-83 ALL VETERANS vs. NONVETERANS IN- COUNTRY VETERANS vs. NONVETERANS ALL CAUSES °/. Accidents, Poisoning, and Violence (80E9) E0-99 716, '626.74 Cardiovascular Disease (9-5) 3049 237, '251.5 Malignant Neoplasms (140-209) sPMR (95Z CI) °/ 'E sPMR ERA VETERANS vs. NONVETERANS (95Z CI) ° / sPMR (95Z CI) (106-130) 354, '318.1 111* (100-124) 'E (106-123) 362. '308.6 117** 94 (83-107) 114, '129.1 88 (73-106) 123, '122.4 100 (84-120) 145, '142.4 102 (86-120) 71, '73.6 96 (75-122) 74, '88 6. 108 (85-136) Diseases of the Digestive System (520-577) 48, '56.7 85 (62-112) 29, '29.0 100 (67-144) 19, '27.8 68 (41-107) Diseases of the Respiratory System (460-519) 24. '29 3. 73 (47-108) 12, '16.7 72 (37-125) 12, '16.2 74 (38-129) 38* (10-96) 52** (33-77) 114** y Allergic, Metabolic, and Endocrine Diseases (240-279) All Other Causes (Residual) '19 2. 50. '29 9. 23** (7-53) 'll.2 9** (-=1-47) '06 1. 54** (40-71) 26. '68 4. 56** (36-81) 24, '61 4. Goodness of Fit X2. -50.2 odt p- 1 ' 08 *polsson p value*.05 **poisson p value£.001 �respiratory diseases, the standardized proportionate mortality ratios were less than unity when all veterans were compared with nonveterans, but the observed numbers of deaths in these categories were not significantly lower than the expected. proportion of veteran The deaths due to malignant neoplasms was similar to that of nonveterans. The pattern of death for in-country and era veterans evaluated separately relative to the nonveteran population was similar in both instances to the pattern observed for the groups combined. In a separate contrast with era veteran deaths as the standard (not shown), no difference was. observed in the overall mortality pattern between in-country and era veterans (Chi square Goodness of Fit = 7.0 with 5 degrees of freedom, p - .22). In order to evaluate more specific causes of death within the leading categories, the contrasts were repeated to obtain standardized proportionate category-specific mortality ratios for external causes (injury), cardiovascular diseases, and malignant neoplasms separately. Table 7 shows the distribution of injury deaths for veterans contrasted with nonveterans over five causes: motor vehicle accidents, non-motor-vehicle accidents, suicide, homicide, and all other external causes. Homicide accounted for a significantly smaller-than-expected proportion of the injury deaths among veterans. The standardized proportionate injury mortality ratio for motor-vehicle-related deaths among veterans was greater than 100 but was not a statistically significant 18 �TABLE 7 INJURY MORTALITY Vietnam Veterans vs. Nonveterans West Virginia, 1968-83 ALL VETERANS vs. NONVETERANS ° / sPMR (95Z CD 315, '9. 206 108 (97-121) 201, '0. 293 96 (83-110) 104 (85-125) ACCIDENTS. POISONING, AND VIOLENCE (E800-999) Motor Vehicle (E810-E825) Ron-Motor Vehicle (E800-E809, E826-E949) Suicide (E9SO-E9S9) HoBiclde (E960-E969) All Other Causes (E970-E999) IN-COUNTRY VETERANS vs. NONVETERANS 'E 111 '107.2 63. '81.5 77* (59-99) 26. '74 2. 95 (62-139) Goodness of Fit X^.--6.78 P-.15 *poisson p value-=.05 sPMR 107 (115 9-2) 100, '105.1 95 (77-116) 111 (85-144) sPMR (95Z CI) 154. '4. 105 110 (318 9-2) 101, '0. 142 97 (79-118) / '54.2 96 (72-126) 35, '14 4. 85 (59-118) 87 (45-152) (95Z CI) 161, '5. 101 ERA VETERANS vs. NONVETERANS °'E / 5 9 / '53.0 28. '02 4. 1 4 / '13.6 70* 103 (46-101) (56-173) Goodness of Fit XJ^-5.43 P-.25 °'E / 5 2 12 / '38 1. Goodness of Fit X2df-2.71 p-,61 �excess. For non-motor-vehicle fatalities, suicide, and all other causes, the expected numbers were similar to the observed. The overall pattern for veterans was not significantly different from nonveterans (Chi square Goodness of Fit » 6.78 with 4 degrees of freedom, p =.15). Separate comparisons of the in-country and era veteran populations with nonveterans similarly overall difference in the distribution reflected no of injury deaths; the ratios in each of these contrasts were similar to those observed for the combined veteran group. Among the cardiovascular causes of mortality there were no veteran deaths from either (Table 8), hypertension or rheumatic heart disease (p-=.005), fewer-than-expected veteran deaths from cerebrovascular disease (difference not significant), and more-than-expected veteran deaths due to ischemic heart disease (difference standardized not significant). proportionate cardiovascular The individual disease mortality ratios for in-country and era veterans were similar to the corresponding mortality ratios derived for the combined group. Proportionate cancer mortality ratios comparing veterans to nonveterans are shown in Table 9. veterans and respiratory the system nonveteran excess contributed population, accounted proportion of veteran cancer by In the comparison between all for deaths in-country identical to that contributed by 20 a era neoplasms significantly than of greater expected. veterans veterans. was the The virtually Melanoma of �TABLE 8 CARDIOVASCULAR DISEASE MORTALITY Vietnam Veterans vs. Nonveterans West Virginia, 1968-83 ALL VETERANS vs. NONVETERANS CARDIOVASCULAR DISEASES (390-459) Ischemic Heart Disease (410-414) Cerebrovascular Disease (430-438) °/. sPMR (95Z CI) 158. '141.5 112 (95-131) 18, '50 2. 72 (43-114) Hypertension (400-405) °65 '. Rheumatic Heart Disease (390-398) °/5.4 All Other Cardiovascular Diseases (415-429, 440-459) IN-COUNTRY VETERANS vs. NONVETERANS 61 '86 5. 0** 0** 104 *poisson p valuer .05 **poisson p value «.005 °/ 'E sPMR (95Z CI) °'E / sPMR (952 CI) / '67.7 111 (87-139) 83, '40 7. 112 (89-139) 73 (32-144) 10, '40 1. 71 (34-131) 75 8 / '09 1. - °/3.4 0* - °>1.9 0 / '30.2 103 (80-134) ERA VETERANS vs. NONVETERANS 31 - °/3.0 0* - °/3.5 0* (70-146) 30 '84 2. 106 - (71-151) �TABLH. » CANCER MORTALITY Vietnam Veteran* vs. Nonveterans West Virginia. 1968-83 IN-COUNTRY VETERANS vs. NONVETERANS ALL VETERANS vs. NONVETERANS MALIGNANT NEOPLASMS (140-209) sPHR (951 CD 135* (102-174) 123 (91-162) 462* (6-9) 1897 21, '69 2. 78 (819 4-1) 12, '. 66 182* (94-318) 79 (38-145) 6 128 (46-276) 7 123 (50-254) °>E Respiratory System "4. '31 (160-163) Trachea, Bronchus, 50 and Lung '07 4. (162) Larynx (161) Digestive Organs and Peritoneum (150-159) to to Malignant Melanoma of the Skin (172) Lymphoms (200-203, 208-209) '13 '. 10 / '12.7 Hodgklns Disease (201) /4.7 Hale Genital Organs (185-187) Leukemia (204-207) >,.7 6 /13.1 3 /0.7 % sPHR (951 CD 131* (87-187) 29, '09 2. 139* (93-199) 118 (76-174) 25. '19.5 128 (83-189) 49 2* (95-1349) 49 2* (95-1349) 77 (37-142) % 7 . 4 148 (40-378) %9 . 205* (89-406) 7 >6.2 113 (45-233) % 4 . 47 (10-136) % 4 . 208 (69-497) >/2.4 42 (1-233) 4 182 (49-461) %* . 83 (18-254) (17-100) 3 48 (10-139) V. 44 (9-129) (36-334) 2 /1.4 143 (17-508) 2 118 (5-435) (11-102) '41 /. 24 (-1-137) 3 51 (10-148) 250 (52-731) % 7 . 429* (90-1271) 200 (5-1071) 46* 129 */10 Soft and Connective Tissue (171) 3 Bone (170) 2 /K4 143 (18-531) Urinary Organs (188-189) 2 /5.6 36 (4-129) /15.6 103 (59-166) 16 / '21.2 (951 CD 10, '13.0 Brain i Nervous System (191-192) All Other Halfgnancle. 25 sPNR (911 3-4) 4 /1.2 29, '22.2 NONVETERANS 79 Oral Cavity (140-149) >3.1 °>E ERA VETERANS 40* •polaaon p value*.05 11, '14.0 /2.7 /2.2 /6.3 '05 '. V, '77 '. 0* 78 /1.7 /5.9 °OS '. V . 2 - (29-170) '. 27 ' , V 0 - 125 (3-663) 74 (10-305) 127 360-231) �TABLE 10 CANCER MORTALITY FOR VIETNAM VETERANS In-Country Veterans vs. Era Veterans West Virginia, 1968-83 OBSERVED, 'EXPECTED Respiratory System (160-163) (95Z CI) 93 (63-134) NS 110 (55-197) NS 7 280 (113-577) 0.014 5 833 (271-1945) 0.0004 222 (62-579) NS 500 (103-1461) 0.023 (12-118) 0.066 - - 29, '31.0 n Digestive Organs and Peritoneum (150-159) Lymphoma (200-203. 208-209) to Hodgklns Disease (201) POISSON p VALUE (Fisher's exact) sPMR / '10.0 '2.5 '. 06 U) Male Genital Organs (185-187) *!. /. Cancer of the Testls (186) V . Malignant Melanoma of the Skin (172) VT 46 Soft and Connective Tissue (171) \ oo Leukerolas (204-207) 3 Oral Cavity (140-149) 2 / All Others /1.9 2.4 8 / '12.7 158 (33-461) NS 83 (10-301) NS 63 (27-124) NS �the skin also accounted for a significantly greater-than-expected proportion of cancer deaths among all veterans, but the contribution of in-country veterans to this excess was trivial in comparison with that of era veterans. Deaths from leukemias and malignant neoplasms of the nervous system each occurred less frequently than expected among both veteran groups. tissue tumors, For soft a significant difference between observed and expected deaths was not found for all veterans combined. These tumors occurred only among in-country veterans and not among era veterans, however. When in-country veterans alone were contrasted with nonveterans, they had a significantly elevated standardized proportionate cancer mortality .ratio for soft tissue tumors. The contrast between in-country and era veteran cancer deaths shows the difference in the observed (3) and expected (0) soft tissue tumors for in-country veterans (Table 10). In-country veterans also have significantly elevated standardized proportionate contrasted cancer with era mortality ratios veterans. The for lymphoma difference is when more specifically attributable to Hodgkin's disease, for which there were five deaths in this group, compared with an expected 0.6. Finally, there was a statistically significant excess in the sPMR from testicular cancer among the in-country veterans. Discussion The present study demonstrates that the mortality experience 24 �among persons who served in the military during the Vietnam Conflict differs substantially from that of nonveterans. It also suggests that there may be important differences between the veterans who served in Vietnam and those who did not with respect to their cancer mortality experience. Differences in the mortality experience between veteran and nonveteran groups are influenced by a selection bias initiated at the time of induction to the military service. assure that healthy individuals In order to serve in the military, the preinduction screening process excludes persons with preexisting conditions such as diabetes and allergies, asthma, hypertension, have substantially metabolic disorders, rheumatic heart disease, and clinically apparent malignancies. veterans other lower Because of this selection, mortality rates than the nonveteran population for many years following their induction. This is known as the "healthy veteran effect." In the present study, this selection bias is the most plausible hypothesis to account for the significant sPMR deficits observed among veterans for mortality from allergic, metabolic, and endocrine disorders, all other causes, rheumatic heart disease, and hypertension. Moreover, it may also have contributed to the less prominently diminished sPMRs among veterans for cardiovascular, digestive, and respiratory diseases. While real differences in the mortality rates between veteran and nonveteran groups for selected causes are reflected 25 �in the sPMRs, proportionate they also mortality complicate the for other interpretation causes. Since of the proportionate contribution from all separate causes must sum to 100, the proportionate contributions among "healthy" veterans from causes that are not screened by the induction process become artificially inflated relative to their contribution among the "unhealthy" population. Injury, the leading cause of death for both veterans and nonveterans, played a significantly greater role among veterans, accounting for 58% of their deaths as opposed to an expected 51%. Since the study did not adjust for discrepancies in the health status between veterans and nonveterans, part of the excess in injury among veterans must be due to the relative absence of deaths from conditions that would exclude persons from military service. While an excess of these deaths araong nonveterans reciprocally diminishes the proportion of their mortality attributable to injury, there may be a real difference in life style and the propensity veterans and nonveterans. for risk-taking behavior between An evaluation of injury mortality alone, performed to eliminate distortion from the healthy veteran bias, showed only that homicide was significantly less important as a cause nonveterans. of injury death among veterans than On the other hand, while not significant, among the difference between the observed and expected number of veteran deaths from motor-vehicle accidents would suggest that this is at least one area where veterans may be at a substantially greater 26 �risk of death than nonveterans. This issue, however, and previous assertions that veterans are at greater risk of death from suicide cannot be adequately addressed by this analysis in the absence of more complete data on the populations at risk. While malignancies as a group accounted for similar proportions of veteran and nonveteran deaths, deaths from tumors of the respiratory system were a significantly more prominent cause of cancer death among veterans than among nonveterans. probable explanation for this finding would be A a greater prevalence of smoking among military as compared with nonmilitary personnel, but this cannot be substantiated from the limited information available on death certificates. In general, the pattern of death among in-country veterans from all causes, and within the subcategories of "accidents, poisoning, and violence" and "cardiovascular diseases," were similar to those observed for all veterans combined, and there were no substantial differences in the mortality patterns between in-country and era veterans for these categories. Among cancer deaths, however, there was strong statistical evidence to suggest that .Hodgkin's disease, cancer of the testis, and soft tissue tumors were more common among veterans who served in Vietnam than among veterans who did not. cautiously, however, These findings must be interpreted since the expected proportions of site-specific cancer deaths for in-country veterans were derived from a relatively small number (74) of cancer deaths among era 27 �veterans and would therefore be subject to considerably large random fluctuations. At the same time, the difference between the observed and expected numbers of soft tissue tumors among in-country veterans supports similar proportionate mortality findings study conducted in a previous by the Massachusetts Department of Public Health. Neither the Wisconsin study nor the New York study found significant differences between in-country and era veterans in the occurrence of soft tissue sarcomas. These studies, however, and the present one are limited by the absence of precise exposure data, unknown sizes of the candidate populations at risk, and insufficient follow-up time to account for latency from in-country veterans. exposures that might have been unique to Also, by including deaths from as early as 1968, the present study may have been biased against finding an excess occurrence of cancers with long latency periods. This study only suggests the possibility that the risk of death from soft tissue sarcomas, Hodgkin's disease, and testicular cancer are elevated among veterans who served in Vietnam. We are currently awaiting the records of the in-country veterans who died from these tumors in order to speculate about possible exposure histories and to generate hypotheses that may have some biologic plausibility. To take advantage of latency periods, cancer-specific proportionate mortality studies could be repeated in several years. Also, by excluding deaths that occurred in the late-Vietnam and early post-Vietnam period, and by improving ascertainment of exposure histories, studies can 28 �focus more sharply on etiologic hypotheses relating to possible exposures in Vietnam. On the other hand, since proportionate mortality studies are more useful to explore than to confirm hypotheses, it is recommended that more precise risk-assessment studies of Vietnam cohorts be performed using national data to further test the hypothesis that Hodgkin's disease, testicular malignancies, and soft tissue tumors may be important causes of cancer mortality among veterans who served in Vietnam. 29 �BIBLIOGRAPHY Dienstfrey, Stephen J., and James J. Bryne. Veterans in the United States; A Statistical Portrait from the 1980" Gensus. Washington, D.C.: Veterans Administration, 1985. "Final Toll for U.S. in Indb-China." (Sept. 24, 1973): 73. U.S. News £ World Report Kogan, Michael D., and Clapp, Richard W. Mortality among Vietnam Veterans in Mas sachuse t1s, 1972-1983. Boston: Massachusetts Department of Public Health, 1985. Lawrence, Charles E. et al. "Mortality Patterns of New York State Vietnam Veterans." American Journal of Public Health 75 (March 1985): 277-79. ' Shottenfeld, David, and Joseph F. Fraumeni, Jr., Cancer Epidemiology and Prevention. Philadelphia: W.B. Saunders Company, 1982. 30 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 069 Folder The folder containing the original item. 1868 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. Date A point or period of time associated with an event in the lifecycle of the resource February 4 1986 Title A name given to the resource Critique of West Virginia Mortality Study Subject The topic of the resource state-funded Vietnam veterans study mortality trends study criticism study protocol ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/4b6e0b217cdfbcc0568397aa68f8f4ce.pdf cdab8ab06c56a11d1a22a7ca0ad39b07 PDF Text Text Item ID Number 01669 Author Shepard, Barclay M. Corporate Author Report/Article Title Memorandum: Subject Amendments, from Barclay M. Shepard to Director, Office of Procurement, March 5, 1984 Journal/Book Title Year 000 ° Month/Day Color D Number of Images 2 Desorlpton Notes Wednesday, June 06, 2001 Page 1670 of 1688 �MAR 0 51984 Director r Aaent Orange 'Projects Vl'J! ("?!} ?—-;J201<!5, .•'s^jfkjsiii.'nfc Niuwl^r 4 tan-* rrotxrisc1.! •I;^i-xi.-^;nfc 2. ^;jiri-?!sr>nt ;iut?.S*?er 5 si'aowa, :>c. Jos^j 5* Carra reuiacx^j Or. ?t •:«. i^ut^ *» Project Otricer tor r<SA «nd r^jujtc^s A^pircw.!;!! by th<? -A* 4 L* K>r*;aruQii tor vour intorwacion. 3. ?l*as« £eel £re« to contact carry >toc^i*», 01^ ««t<anf»ion 553*3, if further I ccs Janet Ra«»iers, SPA Dr. Hiohele Flicker, VRMC Kansas City, MO Dr. Alvin Young 101611 �1 5 «* Joseph 8. Carra, Ph.D, Project Officer Exposure Evaluation Division (TS-798) Office of 'Ibxic Substances Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 Dear Dr. Carra: Amendment nwaber five (5) to our interagency agreanent (V101 (91) P-82016) was signed by the Veterans ^ministration's authorizing official on March 7, 1984. A signed copy is enclosed for your agency's records. I am pleased that you are assuming the role of Project Officer for the study. Dr. Han Rang is also looking forward to working with you. -Sincerely, BARCLAY M. SHEPAIO, M.D. \ Director Agent Orange Projects Office '] r !•' *• , /"• Enclosure . >\ cc: 10A 101B11 Elaine Jiit\ Jeffries, (91) Dr. YoungX^ Dr. Michelle Flicker, VAMC Kansas City, ¥D Dr. iSarnes, Dr. Kutz, 2PA SrrOCK?DS:jm 3/12/84 10A7B 10A7A 10A7 �Item ID Number 0167 Author Flicker, Michele ° Corporate Author RODOrt/ArtlGlO TltlO Letter: from Michele Flicker to Alvin L. Young, January 4, 1985 Journal/Book Title Yoar 000 ° Month/Day Color n Number oflmaoes 5 DOSCriptOn NOtOS Enclosures: a letter from F.D. Hileman providing results from tissue samples he analyzed for TCDD and 2 newspaper articles discussing the study and Flicker's involvement. Wednesday, June 06, 2001 Page 1671 of 1688 �Veterans Administration REFERENCE SLIP TO (Name or title-Mail routing symbol) INITIALS-DATE jf 0 o /I 2. /V 3. 4. 5. REASON FOR REFERENCE L] AS REQUESTED LJ FOR YOUR FILES 1_ 1 COMMENTS I (INFORMATION [_J PER CONVERSATION 1_ 1 CONCURRENCE I (NECESSARY ACTION I_ (SIGNATURE wJLt> VA FORM MAY 1980 (_ | NOTE AND RETURN rt&L'+--ty" k^J**^ EXISTING STOCKS OF VA FORM 3230, AUG 1976, WILL BE USED. * V.S. G.P.O. 1983-606-200 �Monsanto MONSANTO COMPANY Dayton Laboratory 1515 Nicholas Road P.O. Box 8, Station B Dayton, Ohio 45407 Phone:(513)268-3411 TWX 8 10-459- 1681 2 November 1984 Dr. Michele Flicker Veterans Administration Mail Code 11C 4801 Linwood Blvd. Kansas City, Missouri 63167 Dear Michele: I apologize for not writing sooner but it cover from the trips taken in October. I the TCDD data I had on three human tissue the past year. The results, in parts per has taken the past two weeks to rehave gone back and gathered together samples that have been analyzed over trillion, are shown below: Tissue 2275519-1 November 1983 July 1984 1.7, 1.9, 2.0 2.1, 2.0 Tissue 2275519-7 June 1983 November 1983 July 1984 9.5 9.2, 8.6, 8.0 7.4, 7.2, 6.4 Tissue 2275519-8 November 1983 July 1984 10.6, 9.5, 6.3 6.5 In interpreting these results it should, be kept in mind that the results generated in June and November of 1983 were done using a base digestion technique and a 2,3,7,8-TCDD standard prepared in our laboratory. The samples run in July 1984 were done using an acid digestion and a* 2,3,7,8-TCDD standard provided by EPA. We are currently preparing to reanalyze these tissues again using acid digestion and standards prepared in our laboratory. This should provide information as to whether the lower results obtained in July were the result of storage losses or due to the variability in the analyses and analytical standards. When these analyses are complete, I will write and inform you of the results. It was pleasant to have a chance to meet you again in Canada and if I can be of any further assistance, please feel free to contact me. Sincerely, F. D. Hileman �KC doctor Kansas City researcher is seeking final federal approval for a study to deterT\yhether,,more,dfoxin Js , iund fo|he fat tissue of Vietnam sterans! t i in*• other-a.Amerithan r.i' •:, »•• .:.. %-,.*' W-- •:• '• •-*.•,.' •--., Flicker and a reat t^e Midwest Reate want to find out exposed to Orange herbicide of the toxic chemithan the general population. Agent Orange was used exteniant. '"''•''*••"-j 7:.:>S''f;r •'" . flicker's" research, ap" by the Veterans Adminisn, could play a role in ddressing concerns of of Vietnam veterans blame dioxin for health Problems in themselves and t teir children^ including skin dis4ases, cancers and birth defects. It also would help future dioxin Agent Orange research by normal back-; dioxin in U.S.- : ,isaid..S";:'v:v . Flicker alsp is a staff phyat Veterans Hospital in s City and principal naco^nvestigator with the., ed Veterans AdmlnistraOrange Project. - *r study would look at only most toxic of the family of ixins, the type found in Agent ge and at Missouri sites minated by waste off con- • ln£ the substance. ,. {' nus is the one study that will at any differences in dioxin vels in veterans and noivVeter' Dr. flicker said. It would" ve staff of the Veterans Adtration and the Environntal t*rotectioja "Agency and Bike use *of 1J laboratories nation, including the �-V archers would use in 21,000 preserved sanv AV-v-vr> 1,000 samples, she said, are from people born '1937 and 1955. Statistibut 30 to 60 are expected 'Xin have been found in fly ash, arette smoke, charcoaled and, automobile exhaust, JSirice 1946 the most toxic dfoxIB has been a* byproduct and ofa contaminant of trichloroa chemical formerly in some cleansers and still ujted in some industrial processes. Trichlorophenol is an ingredient of Agent Orange. •Science still has not deternSined how dangerous dioxin is to '** humans. The toxin earned its reputation as the most lethal / njan-made ^chemical because a minute quantity will kill a guinea pig. Its effects on different species vary greatly, however, and hiimans appear to be among the njost dioxin-resistant animals. «Dr. Flicker noted that no resf arch^bas tied skin cancer or circulatory problems to dioxin, although an Air Force study of liffiOO fliers who sprayed Agent Orange in Vietnam ' showed higher r-ates of skin cancer and circulatory problems. The h|gher incidence could be caused because the men got greater exposure to the sun and because many of the men smoked cigarettes, she said. ! Hie probabilities are stacking u > that many veteran health problems are not associated with . dioxin, Dr. Flicker said. Veterans and seven chemical companies that produced Agent Orange reached an out-of-court, 1^0 million settlement earlier this year, with the money eventually to go to veterans who have suffered proven health VSi damage from exposure to the hfrbicide. ,.-, ;~ ,4. , b •••: \-teiS fyd seamy ••*«#-•• x* �If*** Vietnam lessons fad ns from the audience on videotape. Fall's letter showed that historians and ar* member erf the editorial staff „, Ists can confront the recent past and try to do it he dear colleague letter from the History De- well. Where they may fail in the eyes of some is in partment chairman stated the problem suc- not showing the connections between recent histocinctly: "It has come as something of a ry 'and modern events — almost always shock to many of us to discover we are now teach- guaranteed to engender controversy. The Vietnam ing students to whom the Vietnam War and the series could have used that touch. ,• social Upheaval of that era is no more than a re- Questions to the panelists and my own conversa-, *note childhood memory." tions with members of the audience, who ranged Surprising? from high school children on assignment to grandi Yes, and no. College freshmen parents, showed how much interest, curiosity and today were about'7 years old raw feelings hang on from Vietnam. One woman, ,' «when the last regular American •concerned about Hie growing U.S. involvement in -•troops pulled out of Vietnam. The war in Indochina Central America, stood to ask former Rep. Rich.-that shaped a generation and poisoned a nation's ard Boiling what the United States has learned spirit has all the relevance of the Peloponnesian from Vietnam that can be applied to the present ; War for many of today's students planning their and the future. Mr. Boiling replied that a president v :'. careers. - , • ' ' ; • ' • • ' -•'"•' '•<"* "'cannot delegate responsibility for making war and - But the national experience in Southeast Asia, peace. He added that Americans have little pathe politicizatton of foreign policy, doubts and bra- tience for long wars with no clear victory." ' vado over armed intervention, the battle to stem Suzann Settle, a Southwest High School teacher, inflation and deep concern over Agent Orange and .assigned the series to her students for extra credit. environmental degradation share a common "I see Vietnam as a trick bag," Ms. Settle said. "I source in the Vietnam era. Certainly the politics of believe we got tricked into it by our leaders.... the anti-war protest movement has its offspring in We're studying the American Revolutionary War, . t h e nuclear freeze movement and growing demon- which was not unlike Vietnam for the Vietnamese. strations against U.S.-supported military action The parallels are pretty handy right now. If we ^against Nicaragua and in Central America. have war in Central America...." Connections abound. Vietnam is relevant. One . The series of panel discussions on Vietnam over has only to be shown, as the recent panel discus- seven weeks (Oct. 2 through Nov. 13) brought sions at the University of Missouri-Kansas City on together former enemies—and no Viet Cong was on the Vietnam War attempted for the several hun- the panel. An active duty Army lieutenant colonel dred persons who attended. with two combat tours and a former enlisted man In his letter, Professor James Falls of UMKC who organized draft resistance when he returned Was calling attention to the latest in a series of from Vietnam sat at opposite ends of the panel annual panel discussions co-sponsored by the His- table the night I participated. The distance \ tory Department and the Kansas City branch of the between them was more than the several meters National Archives, the federal agency that keeps from one to the other. At one point, the Army offirecords on many aspects of the American people cer said he would not have been present with the former enlisted man a year earlier. His feelings of and their experiences. The series have shown documentary, commer- resentment to the protest movement were obvious. In another session, the present controversy over .. cial and government movies—some have been real jewels—and had discussions on World Wars I and possible effects on veterans and their offspring of II, the Korean War, the Great Depression, govern- Agent Orange, a defoliant used by the U.S. Air ment propaganda and presidential politics. Viet- Force to rid the tropical jungle of its foliage, flared nam was the freshest in terms of a national into the open. Dr. Micheie Flicker, a staff physi- r cian at the Veterans Medical Center here, had the! experience. "It isn't possible to put this into perspective," thankless task—for which she volunteered—of exsaid Alan Perry, the archivist who helped organize plaining repeatedly that no proof exists that Agent .the series. "But we have to deal with current Orange causes birth defects in veterans' children . events, even if we don't have everything. The poli- or cancer in veterans. Dr. Flicker was not believed, perhaps because cy questions raised by Vietnam still are very much with us. For instance, the phrase, 'No more Mun- some veterans need a scapegoat for their troubles ichs' (from the appeasement of Hitler before since Vietnam. Agent Orange and the Veterans AdWorld War II), was one of the rationales used to ministration may fill that role well. And so it went, from the buildup in the mid 1960s buttress the arguments to get into Vietnam." There is something very commendable about to the use of technology to fight a guerrilla enemy this outreach effort by the archives (which con- to the massive student protests in the streets at jures images of musty, handwritten documents) home. If a cardinal frustration remained from the seand the local university. In fact, Mr. Perry believes this is the only effort of its kind outside of ries, it was that there wasn't more time, more of Washington. Hours and hours were spent by Mr. the public attending, more controversial panelists Perry and Mr. Falls and others to sort through and more attention to what Vietnam means in film, TV ncwsreels and locate qualified panelists to terms of foreign policy, relations with Third World discuss these pivotal events in modern U.S. histo- nations in transition, fighting wars of indefinite ry. For the price of time only, a member of the conclusions and effects on veterans and their famipublic could gain valuable impressions and infor- lies. mation about a war Iik6 Vietnam or World War II. Mr. Perry would like to do Vietnam again in two years and hopes to preserve the discussion and •"'By Repps Hudson T � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 061 Folder The folder containing the original item. 1669 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. Title A name given to the resource Memorandum: Subject Amendments, from Barclay M. Shepard to Director, Office of Procurement, March 5, 1984 Subject The topic of the resource VA/EPA TCDD Assay ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/e60d6e0915a2c041b9cb88f357f1c009.pdf c26923e4beba70ccf43ac8c3d4b04e26 PDF Text Text Item ID Number 01496 Author Shepard, B. M. Corporate Author Roport/Arttehj TltlO Typescript: Chapter 6: The Risk of Soft Tissue Sarcoma in Veterans of the Vietnam Conflict Journal/Book Title °00° Year Month/Day Color n Numberoflmae.es 25 DOSCriptOD NOtflS This manuscript is a draft version of a chapter or section from the following book: Agent Orange and its Associated Dioxin: Assessment of a Controversy, Young, A. L. and G. M. Reggiani, eds. New York: Elsevier, 1988. This book is available in the NAL collection, call no.: RA1242 T44 A3. Tuesday, May 15, 2001 Page 1496 of 1514 �CHAPTER 6 "Perhaps the greatest fear held by veterans of the Vietnam conflict was the fear of Cancer because they had been exposed to Agent Orange" THE RISK OF SOFT TISSUE SARCOMA IN VETERANS OF THE VIETNAM CONFLICT B.M. Shepard, H.K. Rang, F.M. Enzinger, L.B. Hobson Ever since the reports by Hardell and Sandstrom (1979) , Eriksson et al. (1981) and others began to appear in Sweden in the late 1970's, the concern that exposure to the phenoxy acid herbicides increases the risk of developing one of ,.the soft tissue cancers has persisted in the minds of scientists and non-scientists alike. This concern coincided with the growing fear among many veterans of the Vietnam conflict that service in that country and especially exposure to the phenoxy herbicides used for strategic purposes during that military action posed a major risk for developing a wide variety of serious health problems. It was inevitable, therefore, that soft tissue sarcomas quickly joined the growing list of adverse health effects attributed to exposure to the phenoxj? -herbicides used in Vietnam. By far the predominant Herbicide used was code named Agency Orange. It was a 50:50 mixture of 2,4-D and 2,4,5-T, the latter containing trace amounts of 2,3,7,,8-TCDD ranging between 1 and 47 parts-per-million (ppm). The average concentration was estimated to be approximately 2 ppm. The distinction �between the active herbicidal ingredients and the dioxin contaminant as being the "causative" agent of these various health problems including the soft tissue sarcomas has remained clouded, although there is little evidence to implicate 2,4-D or 2,4,5-T alone as human carcinogens. The reports of. Hardell and his associates linking phenoxy herbicide exposure with soft tissue sarcomas and related concerns among Vietnam veterans have stimulated a series of studies in the United States designed to shed more light on this perplexing and troublesome issue. Meanwhile the concerns of Vietnam veterans in this area drew considerable attention in the U.S. Congress where the issue was heatedly debated and became the subject of a number of legislative initiatives designed to mandate additional research in this area as well as to provide compensation and special medical care eligibility for Vietnam veterans who developed one of these rare types of cancer. This chapter will provide an overview of what is known generally about this group of tumors and will summarize the results of some of the studies designed to determine if service in "'y Vietnam and herbicide exposure have increased the ' 5, risk for developing soft tissue sarcomas. "V INCIDENCE, DEFINITION AND DISTRIBUTION Soft tissue sarcomas, compared to carcinomas and other neoplasms are relatively rare tumors. It is estimated that �they account for about 1% of all cancers and are responsible for about 2% of all cancer deaths. Between 5000 and 7500 new cases are diagnosed each year in the United States. It has been suggested that there is an upward trend in the incidence of soft tissue sarcomas, but it is not clear whether this represents a true increase or whether it reflects merely better diagnostic capabilities and greater interest in this type of tumor. The average annual age-adjusted incidence rate is 2.0 to 3.5 per 100,000 population, but the rate varies not only in different age groups, but also depends upon the definition of soft tissue sarcomas and the types of neoplasms that are included among these tumors. For example, in the National Cancer Survey, retroperitoneal, mesenteric and omental sarcomas are counted among the neoplasms of the digestive system and pleural sarcomas (malignant mesotheliomas) are included among the tumors of the respiratory system. Judging from the available data, incidence and distribution of soft tissue sarcomas seem to be similar in different geographic regions of the world (Tucker and Franmeni, 1982). As the name indicates soft tissue sarcomas are usually *'"'' defined as extra-skeletal, non-epithelial sarcomas that arise chie.fXy in musple, fat or fibrous connective tissue such as tendons or ligaments and less frequently in blood vessels and nerves that serve these tissues. Consequently, soft tissue sarcomas may occur anywhere in the body, but the majority �originate in the large muscles of the extremities, the chest wall, mediastinum and retroperitoneum. Excluded are sarcomas of the brain and other major organs, such as the heart, lungs, kidneys, liver and intestinal tract. Excluded also are the tumors of the hematopoietic system, such as leukemias as well as malignant lymphomas and Hodgkin's disease (Enzinger et al. 1969; Enzinger and Weiss, 1983). Soft tissue sarcomas may occur at any age: about 15% affect persons younger than 15 years old and about 35% occur in persons 55 years or older. In general they are somewhat more common in males than in females. The age and sex incidence, however, varies among different histologic types. There is no proven racial variation, even though the annual age- : adjusted incidence rates have been reported in some cases to be higher for blacks than whites. CATION AND DIAGNOSIS On clinical examination, as well as direct visualization and palpation during surgery, soft tissue sarcomas as a group tend to display a fairly uniform picture. When examined under the microscope, however, they vary greatly in appearance and actually comprise an extremely varied and highly complex group of neoplasms rather than a single entity. At present, the classification recognizes 25 major types of soft tissue sarcoma, many of which can be further divided into one or more subtypes on the basis of their 4 �histologic characteristics. Classification and diagnosis by subtypes are essential because the clinical behavior and response to therapy frequently depend not only upon the histogenetic type but also upon the degree of cellular differentiation or grade of the tumor. The various types are named according to the predominant cellular elements and the resemblance of the tumor to normal tissue or its embryonal counterpart. Malignant fibrous histiocytoma, liposarcoma and fibrosarcoma are the most common soft tissue sarcomas of adult life; together they account for more than 50% of all cases. Rhabdomyosarcoma, neuroblastoma and extra-skeletal Swings sarcoma are the most frequent types of soft tissue sarcoma in children. Correct diagnosis of these tumors is still largely dependent on incisional or excisional biopsy in order to provide the pathologist with a specimen of sufficient size for an accurate description and identification. In recent years percutaneuous needed biopsy and aspiration have become increasingly popular as a means of diagnosing many types of neoplasms. Reliance on these techniques when dealing with this group of tumors, however, should be approached with great caution, since they provide only a minute specimen which may not be representative of the entire tumor. But even with adequate material many soft tissue sarcomas present a diagnostic dilemma, and an accurate diagnosis often requires �examination with the transmission or scanning electron microscope. techniques More recently the use of immunohistochemical in the study of soft tissue sarcomas has profoundly changed the approach to the diagnosis of these tumors and has permitted an accuracy of diagnosis unheard of only a few years ago. BEHAVIOR AND THERAPY The various types of soft tissue sarcoma differ considerably in their degree of malignancy, and identification and diagnosis of the exact histologic type and subtype are essential for predicting the clinical course of the tumor as well as selecting the best method and plan for treatment (Costa et al. 1984; Mandard et al. 1981). Despite a wide variety of therapeutic modalities, it is generally agreed that surgical resection, when possible, is still the treatment of choice for primary soft tissue sarcomas. Chemotherapy and radiotherapy serve as adjunctive forms of treatment, especially in highly malignant sarcomas. When planning definitive surgery, it is important to know as much as possible about the extent of the lesion as well as the >• •'• type and grade of the tumor. Since the extent of the tumor is not always evident microscopically, it is most important that the margins of the resection be checked by the pathologist during the operative procedure. The best chance of cure is achieved with total excision during the initial surgical �procedure. Since many sarcomas develop microscopic met- astases early in the course of the disease, the ultimate outcome of these tumors must be assessed with considerable caution and long term follow-up is essential, especially in the case of high grade soft tissue sarcomas. The outcome is much less favorable with recurrent tumors and with large unresectable tumors such as many sarcomas in the retroperitoneum (Eilber et al, 1984; Enneking, 1983; Rosenberg, 1982) . Soft tissue sarcomas occurring in childhood often respond extremely well to combination therapy with some reported cure rates as high as 80%. For this reason surgery in this age group can usually be less radical when combined with •- radiation and chemotherapy. PATHOGENESIS As with other types of malignant neoplasms, the causative factors of soft tissue sarcomas, are still for the most part unknown. The development of sarcomas from benign soft tissue tumors is rare. A notable exception to this rule is the appearaftce pf malignant neural tumors arising in neurof ibromas... .In this instance it is nearly always seen in T patients with previously determined manifestations of neurofibromas. A few causative agents and predisposing factors have been clearly established and include various physical and chemical exposures such as ionizing radiation �and asbestos as well as various inherited or acquired immunologic defects. Determination of the exact cause is often extremely difficult, because of the long latent period between the time of exposure and appearance of the sarcoma. The possible effect of multiple environmental and hereditary factors during the induction period further complicates any attempt to establish the causative agent or other circumstances (Enzinger and Weiss, 1983). Considering the extensive use of radiotherapy, radiation induced sarcomas are extremely rare and therefore the benefit of radiation in the treatment of malignant neoplasms, far outweighs the risk of developing such a sarcoma. It has been estimated that only about 1% of patients who survive 5 years following intensive radiation therapy for breast carcinoma, malignant lymphoma or other types of malignant neoplasm, develop a soft tissue sarcoma in the area of radiotherapy. Almost any type of soft tissue sarcoma may arise following radiation, but the two most common types are malignant fibrous histiocytoma and extra-skeletal osteosarcoma. There is a close relationship between the total radiation dosage and the risk' of developing a sarcoma (Halperin, et al, 1984; Kim, 1978). In addition to radiation, immunodeficiency and therapeutic immunosuppression are known to be associated with the development of soft tissue sarcomas. For example virus- induced immunodeficiency such as in the case of acquired 8 �immune deficiency syndrome (AIDS) has been recognized as causing Kaposi's sarcoma in almost 1/3 of the affected patients. The profound depression of cell-mediated immunity in these patients is the result of a defect in the T-4 inducer or helper subset of T-lymphocytes. Kaposi's sarcoma carries a high mortality rate with a median survival of 18 to 20 months. Aside from their role in the development of Kaposi's sarcoma, there is no evidence that human transmissible viral agents constitute a major risk factor in the development of soft tissue sarcomas. However, using the electron microscope, particulate material, which may represent viral fragments,; has been found repeatedly in soft tissue sarcomas. The origin and significance of this material, however, have not yet been conclusively established. Various types of sarcomas also occur secondary to therapeutic immunosuppression associated with organ transplantation, especially in renal transplant recipients. Acquired immune deficiency may also be the underlying mechanism in the development of the relatively rare angiosarcomas or lymphangiosarcomas that arise in the edematous extremity, •M , ' either secondary to radical mastectomy (Stewart-Treves Syndrome) or as a consequence of other forms of chronic lymphedema. There are only a few environmental factors that are associated with the development of soft tissue sarcomas. �About 80% of patients with pleural or peritoneal mesothelioma give a history of asbestos exposure, usually 25 years or more prior to the first appearance of this tumor. As increased incidence is found in asbestos miners as well as shipyard and other industrial workers engaged in the process of manufacturing, installing or repairing asbestos containing products such as thermal and electrical insulation, brake linings and cement tiles and pipes. Important risk factors include the intensity and duration of asbestos exposure as well as the type and submicroscopic diameter of the asbestos fiber (Selikoff et al 1964; Selikoff and Hammond, 1979). Soft tissue sarcomas have also been reported as arising in scar tissue following surgical procedures or thermal burns, in fracture sites and rarely in the vicinity of plastic or metal implants. Whether trauma per se ever leads to a sarcoma has not been clearly established, but in most instances the association with mechanical trauma appears to be coincidental rather than causative. EPIDEMIOLOGICAL TECHNIQUES USED TO STUDY THE SOFT TISSUE SARCOMA ISSI Research efforts designed and conducted to shed more light on • < •' ^ * ^*St>%, • the relationship between adverse health effects in humans and 'exposure to the phenoxy herbicides and trace amounts of the '•A '• dioxin contaminant found in 2,4,5-T have usually been in one of two general categories or types of epidemiological study design. These are case/control studies and cohort studies. 10 �Each of these types has its own strengths and weaknesses, but when taken in combination they can provide a convincing body of evidence. The case/control design is well suited for the study of rare events such as soft tissue sarcomas. Two features of such a study, however, are of paramount importance: accurate diagnosis of the disease in question and assurance of non-bias in the selection of the controls. The cohort study is probably the most widely used method to determine the relationship between exposure to a particular chemical or other environmental factor (s) and a disease or group of diseases. Using this study design, however, the rarer the outcome being studied, the larger the cohort,.must be. In this type of study the accuracy of exposure data for each member of the cohort of interest is of key importance. Again, the selection of the comparison or control cohort must be carried out with great care. The mortality experience of a group can be used to look for possible cause-and-effeet relationships between an exposure of concern and adverse health outcomes. The two commonly used analytical techniques are known as the proportionate m r a i y * ' ! ' (PMR) and the standardized mortality ratio otlt^*!? i. "• • ,-,*>:'/•?* '^' (SMR) . In general, when using the SMR one determines and r'tiSj "^. .' - -Jf •"»!* ** " compares the numbers and causes of death in a particular study group and a comparison group. This method has the potential for and the advantage of providing death rates if sufficiently large cohorts are used. 11 As with the cohort �morbidity study, the rarer the outcome, the larger the cohort must be. The PMR on the other hand cannot generally provide death rates, but can provide relative frequencies by cause of death. These relative frequencies in the group of interest, as for example a group of deceased Vietnam veterans, can be compared to those in a comparison group, i.e., veterans of the same age and sex who served elsewhere. In addition the frequencies may be compared to those known to exist for age and sex specific segments of the general population. In the case of veterans, however, the latter method of comparison is generally considered less valid since veterans represent a highly selected group of individuals and their patterns of death, especially in the first half of life are somewhat ,- different from those seen in the general civilian population. 12 �REVIEW OF STUDIES OF SOFT TISSUE SARCOMAS IN VIETNAM VETERANS VETERANS ADMINISTRATION STUDY In view of the concern raised by this issue among Vietnam veterans, a case comparison group analysis of patients treated in Veterans Administration hospitals was undertaken to determine the association between previous military service in Vietnam and soft tissue sarcomas (Rang et al. 1986). A total of 418 cases with International Classification of Disease (ICD) 171 diagnosis, i.e., malignant neoplasms of connective and other soft tissues,;; were identified by computer search of the Veterans ... Administration Patient Treatment File (PTF) for Vietnam era veterans who were hospitalized between 1969 and 1983. The PTF is a large computerized hospital data base of in-patient records which includes diagnostic and demographic information. A pathology report for each of theses 418 cases was requested from the appropriate VA hospital and a total of 394 pathology reports were received. reports were reviewed by a single VA pathologist With particular expertise in this area of cancer diagnosis. He;had no knowledge of the Vietnam service status of any of the cases. A total of 234 of these cases were determined to meet the World Health Organization (WHO) classification system for soft tissue sarcoma. 13 The �comparison group consisted of 14,931 VA hospital patients who were systematically sampled from the same Vietnam era veteran patient population from which the cases were identified. Military service information, in particular the Vietnam service status, for each STS case and control patient was obtained from a comprehensive review of the military personnel records at the National Personnel Records Center (NPRC) in St. Louis Missouri. Military personnel records were located and abstracted for all of the 234 STS cases and 13,496 of the 14,931 (90%) control patients. V Eighty six of the 234 STS cases (36.8%) had served in Vietnam. ':- 5# . whereas of the sample of 13,496 Vietnam era patients who's^t ''."*• * f personnel records were located and reviewed, 5544 (41%) had served in Vietnam. On the basis of this comparison it was concluded that no significant association of soft tissue sarcomas and previous military service in Vietnam exists among Vietnam era veterans who come to the VA hospital for inpatient medical care. The odds ratio was 0.83 with a 95% confidence interval of 0.63-1.09. In order to further strengthen the study, the tissue slides • '•; -iS1 from/all the<?a$es originally coded as ICD 171 in the PTF •«' if, were requested^$rom the VA Medical Centers. The tissue specimens f.0r 1 8 cases were located and sent to Dr. Franz '1 Enzinger at the Armed Forces Institute of Pathology for his review. During the review, Dr.Enzinger knew neither the Vietnam service status of the cases nor the VA's diagnoses. 14 �Following his review a comparison was made between his diagnosis and that of the VA Pathologist who had reviewed the pathology reports. Among the 181 cases he reviewed, he concurred with the VA diagnosis in 171 cases (94.5%): cases, STS; 73 cases, non-STS. 98 However, for 10 cases he disagreed with the VA's diagnosis: 4 cases that VA classified as non-STS, he classified as STS; 6 cases that VA determined as STS, he reclassified as non-STS. Military service information was available for 96 of the 98 ICD 171 cases that both VA and AFIP agreed to be STS cases. A record of Vietnam service was indicated on 33 of the 96 STS cases (34.4%). Comparing this proportion to the proportion of Vietnam veterans in the comparison group, no significant association of soft tissue sarcoma and previous military service in Vietnam was observed. (The odds ratio was 0.75 with a 95% confidence interval of 0.49-1.15.) U.S. Air Force Health Study A group of approximately 1260 men who conducted the Ranch Hand fixed wing, aerial herbicide spraying missions in Vietnam from 1962 through 1971 is being studied for their mortality patterns and the current health status. Cumulative mortality as of December 31, 1984, in Ranch Hand personnel revealed no death from soft tissue sarcoma (Wolf et al., 1985). Although the study did not indicate any increased mortality or any 15 �unusual patterns of death, it should not be regarded as final because of the small number of study subjects and the relatively short follow-up period. STATE STUDIES OF SOFT TISSUE SARCOMA IN VIETNAM VETERANS In four states-New York, Massachusetts, West Virginia, and Wisconsin-investigators have conducted mortality studies that include soft-tiss.ue sarcomas among the causes of death. In each study there have been relatively few cases of soft tissue sarcoma and the results in this area have not been : £ consistent. In addition to the mortality studies, a case control study of soft tissue sarcoma was conducted in New York. New York Greenwald et al. (1984) conducted a case-control study in which he identified 281 soft-tissue sarcoma cases in the New York State Cancer Registry among men who were between the ages of 18 and 29 during the period 1962-1971 and who were diagnosed between 1962 and 1980. y At the time of the study, . '•* 151 of the 281 cases were still alive and 130 had died. Using the'driver's license registration files of the N.Y. State Department of Motor Vehicles, a living male control was selected to match each of the 281 cases by being within 5years of the birth date and within the same ZIP code of 16 �residence. In addition, a deceased control was selected for each of the deceased cases. The deceased cases and the deceased controls were also matched for race, sex, the year of death, 5-year age group, year of education and health system area. Of 281 cases, 10 men had served in Vietnam as had 18 men of 281 living controls and 9 of 129 deceased controls. This carefully conducted case-control study demonstrates "no statistically significant positive association between sarcomas of soft-tissues and either service in Vietnam or military service in general." Lawrence et al. (1985) undertook a mortality study involving 1,496 male Vietnam-era veterans of whom 555 or 37% served.: ' I Vietnam and all of whom died in New York State (but outsid£ New York City) during 1965-1967 or 1970-80. Among the 555 Vietnam veterans, 2 died of cancer of connective and soft tissues and 3 of the 941 non-Vietnam veterans died from this same category of cancer. This resulted in an adjusted mortality odds ratio (MOR) for connective and soft-tissue cancers of 1.09; 95% CI of 0.18 - 6.70. In addition, the study included a comparison of mortality patterns between 4558 deceased v&terans of the Vietnam era and 17,936 nonveteran males of the same age group who had died in New York State. There were 12 connective and soft tissue cancers among the veterans and 47 among the non-veterans 95% CI 0.61 - 2.17). These (MOR=1.15: data suggest that there was no significant difference in deaths due to soft tissue sarcomas 17 �between Vietnam veterans and non-Vietnam veterans as well as between veterans and non-veterans. The small number of cases, however, make the results relating to soft tissue sarcoma of limited value. Massachusetts Kogan and Clapp (1985) in the report of a mortality study conducted in Massachusetts described their results as showing "a statistically highly significant excess of soft tissue sarcoma mortality in Massachusetts Vietnam veterans." The two veteran groups, those with service in Vietnam and those who served elsewhere were identified from a list of honorably discharged service men who applied for a state bonus and whose names appeared in the Massachusetts death registry. Vietnam service status was determined from the fact that in granting the bonus a larger amount was paid to those who served in Vietnam. The cause of death was obtained from death certificates. No verification of military service beyond the discharge certificate (DD214) was attempted. Among the 840 deceased Vietnam veterans nine deaths were believed tf&JtyidLdue to soft tissue sarcoma. Statistical calculations found that 1.02 deaths from connective and softtissue cancerrwould have been expected among Vietnam-era veterans and 1.90 deaths among non-veterans. Such differences are striking. The validity of the Massachusetts study is somewhat in 18 �question however, because verification of Vietnam service status was not attempted. The DD214 often does not show the specific place of service as Vietnam. In addition when dealing with such relatively rare causes of death as soft tissue sarcoma where the diagnosis can be difficult to make it is generally agreed that verification of the diagnosis by a pathologist with expertise in this area is necessary in order to draw valid conclusions regarding this type of cancer. West Virginia The fact that reliance on the DD214 to determine service in Vietnam may be misleading is illustrated in a mortality study of West Virginia veterans conducted by Holmes, et al. (1986). The study groups were compiled from a list of 83,730 bonusfe applicants of whom 41,059 qualified as Vietnam veterans and 41,782 as non-Vietnam veterans. The DD214 was used to determine whether or not the veteran had served in Vietnam and the cause of death was obtained from death certificates. Comparison of the bonus roster with the death register revealed that 615 Vietnam and 610 non-Vietnam male veterans had died. Among these were 3 deaths attributed to soft- tissue sarcoma.;5 and all were among veterans classified as having served in Vietnam. No soft tissue sarcoma deaths were found among the non-Vietnam veterans. Subsequent to publishing the report, the military service records of the three veterans who died of soft-tissue sarcoma were examined. One veteran was in the Navy and had served 19 �aboard ship off the coast of Vietnam, a second was stationed in Thailand, and the third served with an Army combat unit in Vietnam. Thus, only one soft-tissue sarcoma death occurred in a Vietnam veteran with actual in-country service. Wisconsin Anderson et al. (1986) issued a report of a study of Wisconsin veterans in which Vietnam service status was determined from the DD214 and the cause of death from the death certificate. Two epidemiological techniques were used: "proportionate mortality ratio" (PMR) comparing the relative number of deaths from that cause expected on the basis of experience in another, e.g., Vietnam-era veterans, or ., "standardized mortality ratio" (SMR) comparing the causespecific death rates in the two groups. A comparison of the proportion of STS deaths in 923 deceased Vietnam veterans with the same proportion in 1,571 deceased non-Vietnam veterans showed no statistically significant increase in the proportion of soft-tissue sarcoma (PMR, 147; 95% CI, 62-350). There were, however, only 5 deaths tabulated £ra»J8oft-tissue sarcoma among Vietnam veterans and the tabulated information about these cases indicated that one>man;had a,"wide-spread carcinoma", apparently misclassified as a soft-tissue sarcoma. This reduces to 4 the number of soft-tissue sarcoma deaths and further diminishes the significance of any differences. 20 �An SMR analysis comparing the deaths among Vietnam veterans with the deaths among Wisconsin, non Vietnam veterans, was based on 4 STS deaths among 43,398 Vietnam veterans and 5 STS deaths among 78,840 non Vietnam veterans. Both groups had less risk of dying from soft-tissue sarcoma when compared to the entire state of Wisconsin. Vietnam veterans had a somewhat greater risk than non Vietnam veterans but the observed elevation was not statistically significant. Discussion The absence of a consistently positive association between soft tissue sarcoma and Vietnam service might be a result of insufficient observation time since Agent Orange exposure in Vietnam. In general, it takes more than a decade for cancer to manifest itself if it is induced by a chemical carcinogen. Another possibility it that even if Agent Orange or dioxin has the potential for including STS in humans, Vietnam veterans as a group, were exposed to such small amounts that the conventional epidemiologic study cannot detect the excess risk resulting from Agent Orange exposure in Vietnam. Alternatively, there is the possibility that neither Agent Orange nor clioxin has the potential for inducing STS in humans. In conclusion, studies of STS in Vietnam veterans, in general,have not revealed a statistically significant positive association between STS and previous military service in Vietnam. 21 �SUMMARY OF SOFT TISSUE SARCOMA STUDIES OF VIETNAM VETERANS AUTHORS STUDY DESIGN STUDY POPULATION Greenwald, et al (1984) Case/Control 281 STS cases, 18-29 years old anytime between 1962-1971 in NY State Cancer Registry Odds ratio = 0.53 (95% CI 0.21-1.31) Lawrence, et al. (1985) PMR 555 NY State Vietnam veteran deaths between 1965 and 1980, exclusive 1968 and 1969 Vietnam: 2 STS/555 deaths Non Vietnam: 3 STS/941 deaths, Mortality odds ratio= 1.09 (95% CI 0.18-6.70) Kogan & Clapp (1985) PMR 840 Massachusetts State Vietnam veteran deaths 9 STS deaths vs. 1.02 expected, PMR=880 (P<0.0001) Anderson, et al (1986) PMR 923 Wisconsin State Vietnam veterans deaths 5 STS death vs. 3.40 expected, PMR= 147 (95% CI 62-350) SMR 43,398 Wisconsin State Vietnam veterans, of which 927 were dead as of December, 1984 Vietnam: 615 West Virginia State Vietnam veteran deaths between 1968 and 1983 Vietnam: 3 STS/615 deaths Non Vietnam: 0 STS/610 deaths Holmes, et al. (1986) PMR 22 RESULTS 4 STS/927 deaths Non Vietnam: 5 STS/1663 deaths �AUTHORS STUDY DESIGN STUDY POPULATION Wolf et al (1985) SMR 1260 Ranch Hand Personnel who conducted aerial herbicide spraying missions in Vietnam from 1962 through 1971 0 STS/55 deaths University of Sydney (1984) SMR 10,205 Australian Vietnam veterans, of which 260 were dead as of January, 1982 Vietnam: 2 STS/260 deaths Non Vietnam = STS/263 deaths Rang, et al Case Control 234 STS cases in the Patient Treatment File Odds ratio = 0.83 (95% CI 0.63-1.09) 96 STS cases reviewed by the AFIP Odds ratio = 0.75 (95% CI 0.49-1.15) RESULTS SMR = Standardized Mortality Ratio; PMR = Proportionate Mortality Ratio; CI = Confidence Interval 23 �REFERENCES 1. Anderson, H.A., Hanrahan, L.P., Jensen, M., et al.: 1986. Wisconsin Vietnam veteran mortality study. Wisconsin Health Department. 2. Bailey, C., Baron, R.C., Basanac, E. et al.: 1986. West Virginia Vietnam-era veterans mortality study. West Virginia Health Department. 3. Costa, J., Wesley, R.A., Rosenberg, S.A.: 1984. The grading of soft tissue sarcomas. Results of a clinicohistopathologic correlation in a series of 163 cases. Cancer 53:530. 4. Eilber, F.R., Morton, D.L., Eckhardt, J., et al.: 1984. Limb salvage for skeletal and soft tissue sarcomas. Cancer 53:2579. 5. Enneking, W.F.: 1983. Musculoskeletal Tumor Surgery, Churchill Livingstone, New York, London. 6. Enzinger, F.M., Lattes, R., Torloni, R.: 1969. Histological typing of soft tissue tumors. International Histologicalj Classification of Tumors No. 3., World Health Organization. 7. Enzinger, F.M., Weiss, S.W.: 1983. The C.V. Mosby Company, St. Louis. 8. Eriksson, M., Hardell, L., Berg, N.O., et al.: 1981. Soft tissue sarcomas and exposure to chemical substances: A case-referent study. Br. J. Ind. Med. 38:27-33. 9. Greenwald, P., Kovasznay, B.,Collins, D.N. et al.: 1984. Sarcomas of soft tissues after Vietnam service. JNCI 73(5): 1107-1109. 10. Halperin, E.C., Greenberg, M.S., Suit, H.D.: 1984. Sarcoma of bone and soft tissue following treatment of Hodgkin's disease. Cancer 53:232. 11. Hardell, L., Sandstrom, A.: 1979. Case-control study: tissue sarcoma and exposure to phenoxyacetic acids or chlorophenols. Br. J. Cancer 39:711-717. 12. Rang-, H.K., Weatherbee, L., Breslin, P.P.: 1986 Soft tissue sarcomas and military service in Vietnam: A case comparison group analysis of hospital patients. J. Occup. Med. 28(12): 1215-1218. 13. Kim, J.H.:, Chu, F.C., Woodard, H.Q., et al.: 1978. Radiation-induced soft tissue sarcoma and bone sarcoma. 24 Soft Tissue Tumors. Soft �Radiology 129:501. 14. Kogan, M.D. and Clapp, R.W.: 1985. Mortality among Vietnam veterans in Massachusetts, 1972-1983. Massachusetts Department of Public Health. 15. Lattes, R.: 1983. Tumors of soft tissues. Atlas of Tumor Pathology, Second Series, Fascicle 1 (Revised), Armed Forces Institute of Pathology. 16. Lawrence, C.E., Reilly, A.A., Quickenton, P., et al.: 1985. Mortality patterns of New York State Vietnam veterans. AJPH 75(3); 277-279. 17. Mandard, A.M., Chasley, J., Mandard, J.C.: 1981. The pathologist's role in a multidisciplinary approach for soft tissue sarcoma. A reappraisal. J. Surg. Oncol. 1.69. 18. Rosenberg, S.A., Tepper, J., Glatstein, E., et al.: 1982. The treatment of soft tissue sarcomas of the extremities. Ann Surg 196:305. 19. Russell, W.O., Cohen, J., Enzinger, F.M., et al.: 1977. clinical and pathological staging system for soft tissue sarcomas. Cancer 40: 1562. 20. Selikoff, I.J., Churg, J., Hammond, E.G.: exposure and neoplasia. JAMA 188:22. 21. Selikoff, I.J., Hammond, B.C.: 1979. Health hazards of asbestos exposure. Ann NY Acad. Sci. 330:1. 22. Tucker, M.A., Fraumeni, J.F.: 1982. Soft Tissue, in Cancer Epidemiology and Prevention; Schottenfeld, D. and Fraumeni, J.F.,: W.B. Saunders Co. 23. Wolfe, W.H., Michalek, J.E., Miner, J.C., et al. 1985. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. Mortality update-1985. Epidemiology Division, USAF School of Aerospace Medicine, Brooks AFB, Texas. 25 1964. A Asbestos � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 056 Folder The folder containing the original item. 1496 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. H. K. Kang F. M. Enziger L. B. Hobson Title A name given to the resource Typescript: Chapter 6: The Risk of Soft Tissue Sarcoma in Veterans of the Vietnam Conflict Subject The topic of the resource VA/AFIP STSS Air Force Health Study state-funded Vietnam veterans study ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/3ce8147ab1c1296e66549f53f17ce898.pdf c6e5799d8a5ce0699630a79b6833b442 PDF Text Text torn ID Number 01439 Author Shepard, Barclay M. Corporata Author RODOrt/ArtiClB Titfe Typescript: Non-Hodgkin's Lymphoma: a Brief Overview, March 31, 1987 Journal/Book Title Year Month/Day March 31 Color ° Number of Images 46 Descripton Notes Tuesday, May 15, 2001 Page 1439 of 1514 �Non-Hodgkin's Lymphoma A Brief Overview The term non-Hodgkin's lymphoma refers to a group of malignant neoplasms within the larger category of malignant lymphomas. These tumors arise from the lymphoreticular system which consits primarily of lymph nodes and collections of specialized cells in many organs including the spleen, liver, bone marrow, and portions of the gastrointestinal system. The annual incidence of malignant lymphomas in the United States is approximately 33,000 of which 25% are classified as Hodgkin's disease and the remaining 75% are called non-Hodgkin's lymphoma. The diagnosis of non-Hodgkin's lymphoma depends on a careful microscopic examination of the actual tumor tissue and frequently requires additional histo-chemical studies. There is a wide range of cell types and the appropriate classification of a particular tumor requires considerable skill on the part of an experienced pathologist. Accurate diagnosis and correct classification are very important since these determine the most effective course of treatment and the prognosis of the tumor. As is the case with many malignant neoplasms, the causative factors for this group of tumors are largely unknown. Considerable evidence does exist, however, that certain viruses which have the potential for altering the immune system play a key role in the development of certain types of non-Hodgkin 1 s lymphoma. In addition, a number of recent epidemiological studies are showing a positive association between non-Hodgkin's lymphoma and exposure to chlorophenols and agricultural chemicals such as the phenoxy acid herbicides and nitrogen-containing fertilizers. It is too early to state that this represents a definite cause-and-effect relationship, but the evidence seems to be increasing to suggest such a conclusion. Prepared by: BARCLAY M. SHEPARD, M.D. Director, Agent Orange Projects Office March 31, 1987 �ABSTRACT A population-based case-control study was conducted 1n western Washington State to evaluate the relationship between occupational exposure of men aged 20 to 79 to phenoxy acetic acid herbicides and chlorinated phenols and the risks of developing soft tissue sarcoma (STS) and non-Hodgkins lymphoma (NHL). Occupational histories and other data were obtained by personal interviews for 128 STS cases and 576 NHL cases, diagnosed between 1981 and 1984, and for 694 randomly selected controls without cancer. Among the study subjects with any past occupational exposure to phenoxy herbicides, the estimated relative risk and 952 confidence interval of developing STS was 0.80 (0.5-1.2), and of developing NHL, 1.07 (0.8-1.4). Risk estimates of developing STS and NHL associated with past chlorophenol exposure were 0.99 (0.7-1.5) and 0.99 (0.8-1.2), respectively. No increasing risk of either cancer was associated with overall duration or intensity of chemical exposure or with exposure to any specific phenoxy herbicide per se. However, estimated risks of NHL were elevated among men who had been fanners, 1.33 (1.03-1.7), forestry herbicide applicators, 4.80 (1.2-19.4) and for those potentially exposed to phenoxy herbicides in any occupation for 15 years or more during the period prior to 15 years before cancer diagnosis, -1.71 (1.04-2.8). Increased risks of NHL were also observed among those with occupational exposure to organochlorine insecticides such as DDT, 1.82 (1.04-3.2), organic solvents 1.35 (1.06-1.7), and to other chemicals typically encountered in the agricultural, forestry or wood products industries. These results demonstrate small but significantly increased risks of developing NHL in association with some occupational activities involving exposure to phenoxy herbicides, particularly for prolonged periods, and possibly in combination with other Page 2 �chemicals. They do not demonstrate a positive association between increased cancer risks and exposure to any specific phenoxy herbicide product alone. Moreover, these findings provide no evidence of increased risks of developing NHL associated with chlorinated phenol exposure or of developing STS associated with exposure to either class of chemical. Page 3 �INTRODUCTION Recent studies from Sweden (1-5) and elsewhere (6-10) have reported an increased risk of soft tissue sarcomas (STS) or non-Hodgkins lytnphomas (NHL) in association with occupational exposures to phenoxy acetic acid herbicides and/or chlorinated phenols. appeared (11-15). Negative studies of this association have also Implicated as the putative carcinogen in most of these studies is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS:1746-01-6), a trace contaminant formed during the manufacture of chemicals which are derived from alkaline hydrolysis of 1,2,4,5-tetrachlorobenzene. Of particular concern in this respect are 2,4,5-trichlorophenol and the phenoxy herbicides, 2,4,5-trichlorophenoxy acetic acid (2,4,5-T) (CAS:93-76-5) and 2-(2,4,5-trichlorophenoxy) propionic acid (Si!vex), which have been reported to be contaminated with TCDD as high as 30 ppm (16). Moreover, TCDD is the prototype of a larger series of halogenated aromatic hydrocarbons including other polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans and biphenyls, all of which share similar biochemical properties and which may also contaminate phenoxy herbicide or chlorophenol products in commercial use. Hence, concern exists regarding the possible health risks from exposure to chemical products in which any such contaminants may be present. The present study was conducted to investigate the relationship between the incidence of soft tissue sarcomas and non-Hodgkins lymphomas and past exposure to phenoxy herbicides and chlorinated phenols using a population-based case-control approach. Subjects were drawn from the male population of western Washington state, where phenoxy acetic acid herbicides and chlorophenols have been widely utilized during the past 40 years by agricultural, forestry and wood products industries. Specific emphasis was placed on identification of intervening factors or conditions which may Page 4 �influence human susceptibility to the risk of cancer in association with exposure to phenoxy acetic acids, chlorophenols or PCDDs. METHODS Acquisition of Cases and Controls From 1983 through 1985 men with either STS or NHL were identified through the Cancer Surveillance System (CSS), a population-based tumor registry that has covered 13 counties of western Washington since 1974. Men eligible to participate in the study were between the ages of 20 and 79 at diagnosis and had been diagnosed during the years 1981-1984 as having either STS or NHL, as classified histologically by the World Health Organization International Classification of Diseases for Oncology, First Revision (17). Case definitions of eligibility for STS by ICD-0 codes are 8800-8804, 8810-8813, 8830-8832, 8840, 8850-8860, 8890-8920, 8990-8991, 9040-9044, 9120, 9130, 9150, 9170, 9251, 9260, 9503, 9540-9560 and 9580-9581. Case definitions of eligibility for NHL by ICD-0 codes are 9590-9642, 9690-9701 and 9750. The CSS obtains data from all hospitals throughout a 13 county region, and essentially complete population coverage is attained. During 1983-1985 a control group without STS or NHL was also selected. Live control subjects aged 20-64 were chosen using a random digit dialing procedure as described by Waksberg (18). Because the elderly are relatively sparse in the general population, it was not economical to locate all older controls by random digit dialing. Thus, additional live control subjects aged 65-79 were chosen at random from data supplied by the Health Care Financing Administration covering social security recipients in the study area. Controls were group-matched to NHL-cases by vital status and 5-year age group with a ratio of 1.2 controls per case. Deceased controls exclusive of Page 5 �homicides and suicides were identified from non-cancer death certificates for persons aged 20-79 with a date of death occurring during the study period and with a residence within the 13-county study area. The disposition of case and control subjects according to vital status, interview outcome and pathologic review of STS is presented in Table 1. Interview Procedure All study subjects, including proxies, were interviewed in-person by experienced interviewers at a time and location of their choice. The interview lasted approximately one hour and covered the participant's residential, military and medical histories with a detailed section on occupational exposures to herbicides, chlorophenols and other chemicals prior to diagnosis or interview. Detailed information on known or suspected risk factors for STS and NHL including past history of immunosuppressive disorders, use of immunosuppressant medication or family history of cancer or immune disease, was also obtained. Additional information, including pathology, stage, extent of disease and date of diagnosis, was collected for each case from data supplied by the CSS. "Exposure" for all variables refers to that occurring prior to the date of diagnosis for the cases and prior to the date of interview for controls. The effect of recall differences on cancer risk owing to the difference in lapse time between diagnosis and interview for the cases (about 1 year) versus initial contact and interview.for controls (about 1 month) was evaluated and found to be negligible. Risk estimates among living and deceased cohorts were comparable for essentially all associations; hence, living and deceased groups were combined in all analyses. The questionnaire utilized in the interview was designed after identifying the principal occupations and activities undertaken within the study area which have involved the manufacture or use of phenoxy herbicides and/or Page 6 �chlorophenols. < Such occupations and activities were identified in consultation with local industrial and university representatives who had had long term experience with forestry, wood products and agricultural industries in the Pacific Northwest. This consultation resulted in identification of 34 specific job titles (e.g., wood products worker, herbicide applicator) and 17 specific job activities (e.g., spray weeds with phenoxy herbicides; manufacture chlorophenols) involving potential exposure to either phenoxy herbicides or chlorophenols. In addition, 14 specific phenoxy herbicide or chlorophenol preparations in common commercial use in the study area were identified. Each job title or activity was then assigned to a "high," "medium," "low" or "no" exposure category for both phenoxy herbicides and chlorophenols, reflecting the consensus of the consultant group of the likely intensity of exposure to each chemical received in that occupation. Examples of occupational activities in each exposure category are given in the tables. In the interview, cue questions referring to each specific job title, activity or chemical preparation were asked to determine whether a subject had worked in an occupation involving probable exposure to phenoxy herbicides or chlorophenols. If an affirmative response to any cue question was elicited, a series of additional inquiries was made to acquire detailed information i regarding the extent of exposure to specific chemicals of interest and the precise time intervals during which each exposure episode had occurred. Among the additional questions asked was an inquiry regarding the name and address of the supervisor or a close co-worker in each job episode where possible chemical exposure had occurred. This information was used with subject's permission to corroborate self-reported exposure to specific chemicals and to verify exposure histories in instances where the subject or his proxy was . uncertain regarding the actual exposure circumstances in that job. Paae 7 Additional �measures taken to reduce the likelihood of recall bias with respect to the reporting of phenoxy herbicide or chlorophenol exposure included avoiding a deliberate focus on these specific chemicals in the interview and conducting the interview during a period (1983-1985) of relatively low local or national media attention to the herbicide-cancer issue. The study was not advertised locally, and subjects were not made aware of the focus of the investigation except that it had broad immplications with respect to environmental factors related to cancer etiology. In coding occupational exposure to phenoxy herbicides or chlorophenols based on job descriptions, the inclusive dates during which a person was employed in any specific occupation or activity were recorded in the questionnaire. In the analysis, however, occupational exposure to phenoxy herbicides and chlorophenols was considered to have begun no earlier than 1946 and 1937, respectively, the years when these chemicals first came into widespread commercial use in the study area. The coding of each job episode held by a study subject according to intensity and duration of exposure permitted evaluation of the exposure history of each subject in terms of duration of continuous or cumulative exposure at each dose level. Thus, a complete exposure profile on each subject for each class of chemical under evaluation was obtained. Quality Control Procedures Several quality control procedures were employed to verify the accuracy of the data collected by interview. First, 145 respondents from a total of 1444 who completed interviews were randomly selected and were recontacted by telephone approximately one month after the interview date. Interview and reinterview responses to 7 questions were compared. Five of the 7 questions reflected an 88 percent or higher agreement with the original interview, and �one item had an 81 percent agreement rate. The remaining item, cups of coffee consumed per week, had a 34 percent agreement rate, although 55 percent of the discrepancies involved minor disagreements regarding the precise number of cups consumed. A second quality control procedure consisted of independent receding of a random sample of 238 coded interviews. The overall agreement rate between codes and recedes was 99 percent. The agreement rate was 98.9 percent for codes pertaining to phenoxy herbicides and 98.3 percent for codes pertaining to chlorophenols. Pathologic Review of Soft Tissue Sarcoma Case Materials Pathologic review of histologic slides and/or sections prepared from tissue blocks of STS cases was conducted in order to verify the initial diagnosis of STS. Reviews were performed by a pathologist (BK) with expertise in soft tissue tumors. For the review of STS, specimen materials were acquired from each participating hospital where the initial diagnosis of STS was made, and were then coded, and sent "blind" to the project pathologist. In all, histoligic material from 155 cases was obtained for review. Twenty percent of the slides or sections were resuomitted to the pathologist as an internal check of his first diagnosis. In a few circumstances the project pathologist disagreed with either the CSS or himself regarding the diagnosis of either STS per se or the specific histological classification of STS. In these instances a sample of the disparate slides was sent to the Armed Forces Institute of Pathology in Washington, DC for resolution of STS and/or histologic type classification. This 3 tier STS evaluation procedure resulted in retention of 45% of the STS cases in the study with histologic diagnosis as originally determined, and an additional 34« of cases retained with STS confirmed although of a different histologic classification than originally Paae 9 �made. Twenty one percent of original cases were determined either not likely to be STS, or of indeterminate pathology, and, consequently, were excluded from the study. Many of these were primary bone tumors. In light of the widely accepted high level of reliability associated with the accurate identification of NHL according to broad histologic classifications, pathologic materials from NHL cases were not reviewed for verification in this study. Statistical Methods The data analysis includes estimates of relative risks as odds ratios and their 95* confidence intervals for a number of variables of interest. The most common confounding variable was age; thus, all relationships were age-adjusted by 5 or 10-year age groups, where possible. Pooled odds ratios were calculated using the Mantel-Haenszel method (19). Test-based confidence intervals were calculated using the method of Miettinen (20). In addition, logistic regression analysis (21) was employed to evaluate the joint effect of several variables and possible interactions between chemical exposure and other potential risk factors on cancer risks. The total number of subjects represented in each analysis varies according to the rate of unknown responses; for occupational assessments unknowns were omitted from the analyses. In all other analyses unknowns were included in the "none" or "no exposure" category. The percentage of the total study population responding affirmatively with respect to specific job titles, exposures or other characteristic is presented in the Tables. "Significance" in all analyses was determined at the five percent level. Paae 10 �RESULTS Characteristics of the Study Population Table 2 presents a comparison of NHL and STS cases and controls for selected demographic attributes. The three groups were similar in most respects. Notable differences included a higher proportion of STS cases than controls among subjects in the 20-39 age group and a higher percentage of STS cases in the "other" race category. Asians account principally for this difference. Risks Related to Intensity of Chemical Exposure When estimates of relative risks of both STS and NHL were determined for various levels of phenoxy herbicide or chlorophenol exposure among the entire study population, no increasing trend nor risk estimates significantly different from unity for any exposure level were seen (Table 3). However, elevations in risk were observed for several specific occupations involving chemical exposure. Estimates of relative risks of STS and NHL for various occupations involving exposure principally to phenoxy herbicides are shown in Table 4. When viewed across job categories involving increasing levels of exposure, no clear indication of increasing risk is observed. No significantly increased risks of either cancer were seen among those in occupations involving low exposure to phenoxy herbicides, although a nearly significant 1.70 (0.9-3.1) odds ratio for NHL was observed among landscapers. Among those in medium exposure occupations, no significantly elevated risks of STS were seen. A small but significantly increased risk of NHL, 1.33 (1.03-1.7), was observed among farmers, an occupation traditionally associated with regular use of weed killers. This observation is consistent with reports from other studies which have identified agricultural occupational groups at increased NHL risk (22-25). Further evaluation of this observation with Pace 11 �regard to duration of exposure and to use of specific substances indicated that the risk of NHL increased from 1.02 (0.7-1.5) among those working as fanners from 1 to 9 years to 1.62 (0.9-2.9) among farmers with 10 to 19 years in that occupation. However, no increased risks of developing NHL were observed among those with more than 20 years as farmers, 0.92 (0.5-1.6). Additionally, there were no increased risks of NHL among farmers who reported having "regularly worked with" 2,4-D (0.68 [0.3-1.4]), 2,4,5-T (0.74 [0.3-2.1]), or phenoxy herbicides per se (0.71 [0.3-1.5]) when compared with study subjects reporting no phenoxy herbicide exposure. The estimated risk of developing NHL among farmers who reported having regularly sprayed weed killers by knapsack, tractor or aircraft was 1.13 (0.7-1.9). A risk of developing NHL equal to 1.46 (0.8-2.8) was observed among farmers who reported having worked with the specific organochlorine insecticides DDT and chlordane. In occupations associated with high herbicide exposure, none was associated with a statistically significant increased risk of developing STS. A substantially increased risk of developing NHL, 4.80 (1.2-19.4), was noted for persons who claimed to have worked regularly in jobs involving spraying of weed killers in national, state or commercial forests. However, increased risks of this magnitude were not observed among those engaged in other herbicide spraying activities or among those who worked as herbicide f emulators or applicators per se. Further evaluation of-the increased risk of NHL observed among forestry herbicide sprayers with respect to specific chemicals used and duration of exposures indicated that all forestry sprayers reported the combined use of 2,4-D and 2,4,5-T as well as various commercial herbicide preparations containing these and other chemicals. An infinite risk estimate was attained for developing NHL among forestry herbicide applicators specifically in association with phenoxy herbicide exposure, inasmuch as tnere Paae 12 �were no control subjects who served as forestry herbicide sprayers and did not use phenoxy herbicides. p = 0.004. involved. This association was statistically significant with However, only a very small number of exposed subjects (7) were The risks of STS and NHL associated with all occupations involving potential exposure to phenoxy herbicides considered together were 0.80 (0.5-1.2) and 1.07 (0.8-1.4), respectively. The risks of developing NHL associated with exposure specifically to 2,4-D and 2,4,5-T and to phenoxy herbicides in general among the entire study population were 0.73 (0.4-1.3), 0.98 (0.5-2.0) and 0.87 (0.5-1.5), respectively. Table 5 presents risk estimates of STS and NHL for various occupations and activities involving chlorophenol exposure. As in the case of phenoxy herbicides, no clear indication of increasing risks of either STS or NHL is apparent when viewed across job categories involving increasing levels of exposure to chlorophenols. Somewhat elevated risks of developing STS are suggested for lumber graders, 2.66 (1.1-6.4), and log/lumber inspectors, 4.83 (0.6-38.2), although other jobs involving comparable chlorophenol exposure offer no suggestion of substantially increased STS risks. No specific jobs involving chlorophenol exposure were associated with increased risks of developing NHL. When all occupations involving potential exposure to chlorophenols were considered together, the risks of developing STS and NHL were 0.99 (0.7-1.5) and 0.99 (0.8-1.2), respectively. Results of Supervisor/Co-worker Survey Corroboration of self-reported occupational exposure to phenoxy herbicides, chlorophenols and other chemicals was sought through telephone contact with employer supervisors or co-workers of subjects who had been employed in jobs involving potential exposure to such substances. Confirmation of subjects' responses regarding exposure was provided in , Paae 13 �essentially all instances where employers or co-workers could be reached. There were no significant differences between agreement rates for cases or controls. The ability to acquire corroborative evidence of exposure (about 802 of contacts attempted) was greatest for most recent occupations held. Risks Related to Duration of Chemical Exposure Inasmuch as cancer risks may vary with length of exposure to specific carcinogens or tumor promoting agents, it was of interest to estimate the relative risks of STS and NHL for various lengths of cumulative exposure to either phenoxy herbicides or chlorophenols. Hence, risk estimates of both cancer types for 10-year durations (1-10, 11-20, 20+) of exposure to phenoxy herbicides or chlorophenols were calculated. In this context, "exposure" refers to any level of occupational phenoxy or chlorophenol exposure during any portion of the time period since 1946 or 1937, respectively, up to the date of diagnosis (cases) or interview (controls). "Duration" refers to the total length of cumulative exposure during this time period. From these calculations, it was determined that the risk of neither STS nor NHL increased with the duration of phenoxy herbicide or chlorophenol exposure for periods of 20 years or more when all levels of exposure are considered concomitantly. Moreover, no increased risks of either cancer were seen when increasing lengths of exposure to only high levels of phenoxy herbicides or chlorophenols were considered. Evaluation of a Latency Period for Cancer Development The average latency period for a carcinogenic effect of aromatic hydrocarbons in humans has been postulated to be on the order of 15 to 30 years (26). It was, therefore, of interest to determine if exposure to either phenoxy herbicides or chlorophenols prior to an assumed latency period of 15 years before cancer diagnosis was associated with an increased risk of STS or Page 14 �NHL. For these determinations, the risks of each cancer type were calculated for two durations of cumulative exposure (1-14 and 1 5+ years) during the period between 1946 or 1937 for phenoxy herbicides and chlorophenols, respectively, and 15 years prior to diagnosis or interview. The results revealed a significant increase in the risk of NHL, 1.71 (1.04-2.8), among those with cumulative exposures to phenoxy herbicides of more than 15 years during the period preceding 15 years before diagnosis. When a 5 year latency period for cancer development was assumed, the risk of NHL among those with 15 or more years of prelatency phenoxy exposure dropped to 1.29 (0.9-2.0). In contrast, the risk of developing NHL was 2.51 (0.5-13.0) among subjects with more than 15 years of herbicide exposure prior to a 25 year assumed latency period. No increased risks of STS for either chemical or of NHL for chlorophenols were observed in relation to chemical exposure for any latency period or cummulative exposure assumption. Evaluation of Other Risk Factors for STS and NHL Since autoimmune diseases, primary immunodeficiency syndromes and other conditions which compromise immune competence may act as independent risk factors of STS or NHL, it was of interest to determine the risks of either type of cancer associated with such conditions existing prior to the year of cancer diagnosis (or interview). Table 6 presents risk estimates of STS and NHL for a number of such conditions or factors. All assessments were made from subject interviews, not from medical records. Immunosuppressant drug therapy received for any reason prior to the year of diagnosis of NHL was the greatest risk factor for either cancer. Immune defficiency in a blood relative was also associated with an increased (although non-significant) risk of NHL. In contrast, the use of corticosteroids for observed periods of use up to 29 years was not associated with an increased risk of either cancer type. Paqe 15 �Of specific note is the 1.38-fold increased risk of NHL observed in relation to a history of rheumatoid arthritis. Although not statistically significant, this observation is interesting in light of the current controversy surrounding the question of increased risks of NHL among persons afflicted with autoimmune diseases (27). Preexisting skin cancer was also associated with a slightly increased risk of both STS and NHL. Although the type of skin cancer was not ascertained in this study, several histological types of STS and NHL can have dermal manifestations which could have been misreported as "skin cancer". Among these are the soft tissue tumors, dermatofibrosarcoma (8832/3) and Kaposi's sarcoma (9140/3), and the non-Hodgkins lymphoma, mycosis fungoides (9700-9701/3). Kaposi's sarcoma was excluded from evaluation in this study, and none of those reporting skin cancer was found to have this form of STS. Among those 12 STS cases reporting a prior history of skin cancer, none was found to have dermatofibrosarcoma, and among 53 NHL cases, none had confirmed mycoides fungoides. Malaria was evaluated as a potential risk factor for STS and NHL in light of studies suggesting an etiologic association between malarial infection and the risks of developing sarcomas or lymphomas through mechanisms involving plasmodial suppression of immune defenses against malignant diseases (28,29). The risk of developing neither STS nor NHL was significantly elevated in association with a self-reported prior history of malaria alone. Finally, Table 7 presents risk estimates associated with various occupational and/or lifestyle factors which were observed in the present study to independently alter the risk of STS or NHL and which might, therefore, be considered as potential modifiers of the effect of chemical exposure on cancer risks. Of particular note is the significantly increased risk of NHL seen among men with previous exposure to organic solvents, lead or lead arsenate Paae 16 �pesticides, and welding and metal fumes. The risk of NHL was also elevated among men reporting previous exposure to the organochlorine insecticides, chlordane and DDT. Also of note is the increased risk of both STS and NHL observed among those reporting a prior incidence of chloracne. Although this condition was not clinically confirmed in this study, this observation is of considerable interest inasmuch as chloracne is an important clinical manifestation of exposure to high levels of chlorinated dibenzodioxins and furans in humans (30). The statistical association of reported chloracne with phenoxy herbicide exposure was of borderline significance (p < 0.075) in this study. Neither cigarette -smoking nor coffee drinking was a risk factor for either cancer. Not shown in Table 7 are a number of other factors or conditions which were also evaluated as potential risks factors, but for which no significant or suggestive associations with either STS or NHL were found. These include: exposure to radiation, X-rays or radioactive materials; exhaust fumes from motorized equipment; home use of phenoxy herbicides; residency near areas sprayed with weed killers; TB vaccination; consumption of multiple vitamins; eating fish caught in Puget Sound; and, use of alcohol. Logistic regression analysis was employed to estimate the potential interaction between phenoxy herbicides or chlorophenols and various other single variables appearing in Tables 6 or 7 as well as others of interest. Intervening variables for which the interaction with phenoxy herbicides or chlorophenols were determined included: organochlorine pesticides (DDT + Chlordane), lead/lead arsenate, welding or metal fumes, inherited or acquired diseases of the immune system, any prior cancer, prior skin cancer, home use of phenoxy herbicides, family history of cancer, and family history of diseases of the imnune system. All analyses were controlled for age. Results �of the logistic regression analysis for these variables confirmed the magnitude of the risks shown in Tables 6 and 7. None of the interactions between chlorinated phenol or phenoxy herbicide exposure and these variables was statistically significant, with the exception of that between phenoxy herbicides and organic solvents as a risk factor for NHL. The odds ratio for joint exposure compared with exposure to neither substance was 1.50 with a 95« confidence interval of 1.03-2.18. The odds ratio estimates from the model for exposure solely to organic solvents or phenoxy herbicides were non-significantly 1.12 and 0.85, respectively. The significance of the joint exposure in this case may be a result of the large number of comparisons made in this study or, possibly, due to a genuine synergistic effect. Positive although non-significant interactions were also observed between exposure to-either phenoxy herbicides or chlorophenols and co- or preexisting autoimmune diseases or immune deficiency syndromes when those listed on Table 6 and others (mononucleosis, celiac sprue, Sjogrens syndrome) were considered jointly. This interaction was most notable with chlorophenols where the odds ratio for joint exposure (compared with neither) was 1.40 (0.95-2.07), as compared with 0.91 (0.72-1.14) and 1.32 (0.99-1.78), respectively, for chlorophenol or immune deficiency alone. These observations are worthy of note in light of the widely held theory (31) that the etiology of malignant lyraphomas involves failure of immunoregulation in the face of a persistent stimulus for lymphocyte proliferation. In autoimmune diseases, chronic antigenie stimulation is provided by the constant exposure to self-antigens, whereas in primary immunodeficiency syndromes, recurrent infections are the likely source for antigenic stimulation. In contrast, T2DD is well recognized as a suppressant of both humoral and cell-mediated immunity in animals (32-34), and has been recently characterized as a depressant of Paae 18 �cell-mediated immunity in humans during prolonged, low-level exposure ( 3 5 ) . Immunosuppression by other PCDDs has also been described (36). The possibility that the statistical interactions, however slight, observed in this study between phenoxy herbicides or chlorophenols and immunosuppressive disorders may have biological relevance with respect to the etiology of NHL in humans, therefore, deserves further consideration. DISCUSSION The results of the present study demonstrate significantly increased risks of developing NHL among men in occupations involving farming and forestry herbicide spraying and for occupations involving.regular exposure to phenoxy acetic acid herbicides for prolonged periods. However, neither phenoxy herbicides nor chlorophenols alone appear to constitute a sufficient cause of either NHL or STS when evaluated within a population residing in western Washington state, since increased cancer risks were not observed for numerous other occupations or activities involving comparable opportunity for exposure to these substances. In this regard, the present findings are not consistent with results of studies conducted in Swedish and other populations which report consistent and substantially increased risks of both types of cancer in association with occupational exposure to specific chlorophenols or phenoxy acetic acids or to combinations of these chemicals. In consfderation of possible reasons underlying the apparent lack of consi stency between the results of Swedish studies and those conducted here and elsewto?*:, three issues which have not received major attention with regard to •Slis question include: (1) differences in the intensities or dosages of chemicals received by workers in comparable occupational activities, (2) differences in the extent of environmental (non-occupational) exposure to the ha ae 1 9 �chemicals received by the respective study populations, and (3) differences between study populations with respect to the proportional distribution of other risk factors which in combination with phenoxy herbicides or chlorophenols contribute causally to the cancers putatively associated with chemical exposure alone. In addressing the question of differences in dosages of chemicals received by workers engaged in comparable job activities, it is likely that, should the chemicals under investigation independently increase cancer risks in humans, this effect should be more apparent among persons receiving higher dosages. In considering this possibility as it pertains specifically to application of phenoxy herbicides, it is known that spraying activities, as well as work in sprayed areas, extend over substantially shorter periods of the year in Sweden than occur in western Washington, owing largely to climatic differences in the length of the growing season. Thus, Swedish workers participate in activities in which phenoxy herbicide exposure is typically consolidated within a 2-3 month period annually, during which spraying activities involving intensive herbicide exposures which extend over several consecutive weeks at a time are not uncommon (1,37). In contrast, the annual spraying season in the Pacific korthwest extends over 6 to 7 months, during which individual spraying episodes usually span only a few days at a time and may be separated by weeks or even months during which no spraying is performed. Such differences in herbicide use patterns could conceivably lead to Swedish applicators receiving appreciably higher cumulative exposures to biologically active substances than occurs among workers engaged in less intensive use patterns, as supported by several studies of this questions (38,39). To analyze this possibility quantitatively, we have employed the pharmacokinetic model developed by Gehring (40) from the oral study of 2,4,5-7 Paae 20 �in humans to calculate maximum absorbed daily dosages of herbicide received by Swedish and American workers. The workers in question engaged in activities with comparable job description, namely, herbicide applicator using tractor-drawn equipment. Calculations, based on urinary herbicide concentrations using data derived from studies of applicators under actual field conditions (37,41), indicate that the maximum daily dose of 2,4,5-T absorbed by American workers in an application operation involving 2 sprayings, 2 weeks apart, is in the range of 12 to 86 ug/kg of body weight, with a mean maximum daily dose of 45 ug/kg. In contrast, calculated maximum daily dosages received by Swedish workers, doing the same type of work but involving spraying for 3 to 4 hours/day over a consecutive 2 week period ranged from 11 to 315 ug/kg, with a mean maximum daily dosage of 90 ug/kg. Maximum daily dosages received by American workers involved in other modes of herbicide application were backpack crew, 19-104 ug/kg; helicopter crew, 17-23 ug/kg; and mixers, 12-138 ug/kg. These results suggest that maximum daily dosages of herbicides received by Swedish applicators could substantially exceed those received by American counterparts as well as those engaged in other modes of spraying operations. From the pharmacokinetic studies in humans (40) it is known that 2,4,5-T is absorbed and excreted in the urine with a half-life of about one day following a single oral exposure. Moreover, from measurements of urinary 2,4,5-T, the maximum dose which can be absorbed on repeated exposures is estimated to be about 100 ug/kg/day, with the expected maximum concentration in plasma of individuals receiving repeated daily doses reaching a plateau after 3 days of such exposure. Based on these considerations, the calculated mean maximum daily dose of 2,4,5-T received by Swedish workers under the occupational circumstances described above (90 ug/kg) would approximate that required to produce the maximum plasma Paae 21 �concentration of 2,4,5-T which could be sustained during spraying operations. Thus, Swedish applicators would experience higher sustained tissue levels during repeated frequent exposure episodes, as well as higher tissue concentrations of any PCDDs or other contaminants which would be concomitantly absorbed, than would be experienced by American counterparts, who receive lower exposures on a more sporadic basis. Although the implications of these calculations with respect to human cancer risks are difficult to estimate, they are nevertheless of interest in light of findings from recent studies of Swedish subjects (42) involving analysis of PCDDs in abdominal fat from both cases of STS and NHL as well as control subjects. These studies reported that cancer cases exposed to phenoxy herbicides 16 to 31 years previously had levels of highly chlorinated PCDDs significantly higher than control subjects unexposed to phenoxy herbicides. Interestingly, no differences in case or control TCDD levels were seen. These findings are consistent with the observations from both Swedish (2) and Danish (7) studies of increased cancer risks among persons exposed to phenoxy herbicides and chlorophenols which do not contain detectable levels of TCDD per se, but which are most likely contaminated with a variety of other chlorinated dibenzodioxins and furans (43,44), some of which have been shown to have carcinogenic potential (45,46). Moreover, the capacity of TCDD, and presumably its approximate isostereoisomers, to act as a cocarcinogen (47) and a tumor promoter (48,49) have been well characterized. These properties are highly dose-dependent. Thus, the exposure of Swedish workers to potentially higher concentrations of biologically active substances associated with the use or manufacture of phenoxy herbicides or chlorinated phenols is a consideration possibly consistent with the higher cancer risks observed in studies on such subjects. A recent study by Hoar et al (25) showing that the Page 22 �relative risk of NHL dramatically increased with the number of days of phenoxy herbicide use per year among agricultural workers in the U.S. supports this view. Differences in risk estimates observed between this and the Swedish studies might also be accounted for on the basis of variation in the extent of non-occupational exposure received by the general populations in areas where the studies were conducted. Several investigators (50,51) have recently reported widespread contamination of the general population in the United States and Canada with PCDDs and PCDFs, based on analysis of human fat samples. The findings indicate that, while higher levels of total dioxins and other contaminants may be seen in some exposed persons, there is considerable overlap in actual tissue concentrations of such substances between some persons with confirmed occupational exposures and others who are not previously known to have been exposed through job-related activities. These observations suggest that epidemiologic studies conducted in areas where the extensive use of phenoxy herbicides and chlorophenols has occurred may have inadvertently included subjects who have experienced significant exposure to the chemicals of concern outside of the occupational setting. Should this be the case, it is possible that estimates of actual risk based on recall of occupational exposures alone may be underestimated, owing to non-differential misclassification of subjects according to exposure status (52). To estimate the extent to which non-occupational exposure to phenoxy herbicides may have occurred"in the present investigation, we have evaluated data from several air monitoring studies (53,54) conducted during the spraying season in the Pacific Northwest. These data indicate that phenoxy acetic acids as well as PCDDs can be transported in the atmosphere, either as vapor or adsorbed on particles, for distances ranging from several hundred feet up Paae 23 �to a mile from the application area (54), depending on weather conditions and mode of dispersion. The maximum concentration of 2,4,5-T, for example, found in 24-hour collections from sampling stations in one study (55) was 3.4 o 3 ug/m . Concentrations of up to 10 ug/m of other phenoxy herbicides have been detected at sampling sites in agricultural regions of Washington state 3 (57). If it is assumed that a 70 kg person inhales 30 m of air per day, a person residing in the proximity of a sprayed area could conceivably receive a dosage of 2,4,5-T equal to 1.5 ug/kg/day during the spraying operation solely from atmospheric sources. These levels are on the order of 10 to 50 times less than those received from occupational sources, as described above, and moreover, are received via a different route of exposure (inhalation versus dermal), which could alter absorption rates appreciably. However, it is noteworthy that 24% of STS cases, 23% of NHL cases and 21% of control subjects in the present study responded positively to the question "Have you ever lived in an area where weed spraying was routinely done by truck or airplane?", suggesting that considerable population exposure to phenoxy herbicides and their contaminants from environmental sources could have occurred over the 40 year exposure assessment period. Eliminating subjects who reported residential or home use exposures to phenoxy herbicides or chlorophenols in the present study did not alter the estimated risks of developing STS or NHL. Hence, it is unlikely that bias due to such exposures could account for the large differences in risk estimates observed between these and the Swedish studies. Nevertheless, should phenoxy herbicides and/or their contaminants increase the risk of cancer at environmental exposure levels, or, as recently suggested, produce subclinical immune system alterations which may predispose to such risks (35), it is possible that risk estimates based solely on assessment of occupational exposures could be attenuated as a result of Pace 24 �exposure misclassification. Confirmation of this possibility awaits further investigations based on direct analysis of tissue chemical content or the development of a reliable surrogate measure of past chemical exposure. A third possible reason for a lack of consistency between the results of this and the Swedish studies may be differences between the study populations with respect to the proportional distribution of factors or conditions other than chemical exposure which contribute to the cancers under evaluation. If, for example, a specific inherited, lifestyle or environmental condition which independently predisposes to increased risks of the cancer(s) associated with chemical exposure is more prevalent among Scandinavians than among other populations, increased cancer risks could be observed in the former group, even if the prevalence of phenoxy herbicide or chlorophenol exposure were the same or even less than that occurring elsewhere. In this regard it is interesting to note in the present study that exposure to the insecticides, DDT and lead arsenate, as well as to agricultural and industrial chemicals such as organic solvents and welding/metal fumes are associated with significantly increased risks of developing NHL (Table 7). Compromise of the immune system (31), exposure to zoonotic viruses (24,57) and chronic mitogenic stimuli (24,31) have also been suggested as etiologic factors for NHL. The extent to which differences in the proportional distribution of such factors between Swedish and the local study population might account for the inconsistencies observed between the results of this and the Swedish studies cannot be currently estimated, since neither the specific conditions which modify the effects of chemical exposure on cancer risks nor their prevalence among the respective populations have as yet been identified. However, information based on interview responses from existing studies (4) indicates that Swedish populations may have had as much as twice tne frequency of Paoe 25 �exposure to DDT (5.8-7.8? versus 3.8°*. locally) as well as to total insecticides (14.6% versus 7.9%), and this higher exposure may underlie some increased risk of developing cancer, particularly NHL, independently of or in combination with the chemicals currently under study. On the other hand, the frequency of exposure to organic solvents, for which a small but significant interaction with phenoxy herbicides was observed in this study, was approximately equal (28.2% versus 29.9%) between Swedish and local study populations. Similarly, the frequency of cigarette smoking, now or ever, among Swedish and local study populations was comparable (71* versus 73%). Little or no data are available regarding population differences in nutritional, medical or other lifestyle factors which might serve as component causes of STS or NHL or which modify the effect of chemical exposures on cancer risks. The prospect that inherited factors or conditions among Scandinavians might contribute to increased risks of developing cancer in that population when exposed to the chemicals under investigation is another possibility that might account for differences in risk estimates observed. Although specific studies of this question have as yet to be accomplished, laboratory investigations have shown that the binding affinity of the TCDD receptor, as we'll as subsequent receptor-mediated events, are genetically determined and may vary considerably even among different strains of the same animal soecies (58). That such variations are also a characteristic of human geneaology is suggested by recent studies (59) which demonstrate both the presence of the Ah (TCDD) receptor in human lung as well as considerable heterogenity in the human population in regard to lung Ah receptor concentrations. Moreover, evidence of heritable differences in aryl hydrocarbon hydroxylase induction among humans (60) has been presented. Recently, a hereditary predisposition Pace 26 �for the development of STS has been described in tne study of Danish phenoxy herbicide manufacturers (7). However, no attempt has been made to determine the frequency of this condition among Scandinavian or other populations, or to investigate the extent to which the presence of such a condition could modify the effect of chemical exposure on cancer risks. In the present investigation we have taken advantage of the fact that approximately 6% of the population of the study area is of Scandinavian heritage (61) to make a crude evaluation as to the extent to which this factor (Scandinavian heritage) might constitute an increased risk of STS or NHL in association with phenoxy herbicide or chlorophenol exposure. For this assessment, the surnames of all study subjects were segregated into Scandinavian or "other" categories by a member of the University of Washington Department of Scandinavian Languages and Literature who had expertise in Scandinavian genealogy. Through this effort 169 subjects with Scandinavian surnames were identified including 15 STS cases, 66 NHL cases and 88 controls. No increased cancer risks were associated with having Scandinavian as compared with non-Scandinavian names. However, when the analysis was restricted to Scandinavians only, the risk estimates for STS in relation to past occupational chemical exposures were substantially greater than those observed among the study population as a whole both for high level phenoxy herbicide (2.8[0.5-15.6]) and high level chlorophenol (7.2[2.1-24.7]) exposures. These estimates are comparable in magnitude to those reported among subjects in Swedish (1-5) and Danish (7) studies. Moreover, the distribution of predominant histologic types of STS was comparable to that reported from the Swedish studies (2). No increased risks of NHL in relation to chemical exposures were observed among persons with Scandinavian surnames. While the assignment of Scandinavian ancestry in these studies remains �unconfirmed, the results are interesting inasmuch as they suggest that factors specific to Scandinavian descent, as opposed to residency or occupation in Scandinavian countries, may contribute to increased risks of STS when exposed to the chemicals under evaluation in this study. Further investigation of this issue may be warranted to help resolve the inconsistency between Swedish studies and those conducted elsewhere. In conclusion, the results of the present investigation demonstrate increased risks of NHL in several specific occupations in which phenoxy acetic acid herbicides are employed, as well as for prolonged occupational exposure to these substances. However, they are not consistent with results from Swedish and other studies reporting substantially increased risks of either STS or NHL associated with phenoxy herbicides or chlorophenols as sole or major component causes of these diseases. 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Cancer Res. 1986; 46:3739-3743 (60) Nebert DW, Jensen NM. The Ah locus: genetic regulation of the metabo of carcinogens, drugs and other environmental chemicals by cytochrome P-450-mediated monooxygenases. CRC Crit. Rev. Biochem. 1979; pp.401-437. (61) 1980 Census of Population, Vol 1, Characteristics of the Population, Chapter C, General Social and Economics Characteristics, Part 49 Washington, US Department of Commerce, August, 1983. �Table 1. A case-control study of soft tissue sarcoma (STS) and non-Hodgkins lymphoma (NHL) in relation to phenoxy herbicide and chlorophenol exposure in Western Washington: Subject disposition. STS Subject NHL Living Disoosition Dead Controls Living N % N % 150 - 56 - U % Dead K Living % N % Dead N : Total identified as eligible Physician refusal 20 13 Respondent refusal 43 527 - 219 - 7 13 80 15 23 11 24 1 5 3 84 622 - 288 - 9 5 15 2 9 10 51 4 0 14 Other reasons for non-interview Total Interviewed 6 4 120 80 4 7 43 77 24 5 10 5 408 77 178 81 8 476 77 219 76 I Excluded by pathologic review ' 21 18* 12 28* Excluded as non-eligible post-interview** 2 - 0 - 6 - 4 - 1 - 0 Total Subjects for analysis 97 - 31 - 402 - 174 * Percent of Total interviewed **Based on diagnosis, age, "residence or date of diagnosis. - 475 - 219 - �Table 2. Selected characteristics of 128 STS case men, 576 NHL case men (diagnosed 1981-1984) and 694 interviewed population control men (1983-1985). STS (?) NHL (?) Controls (?) Age 20-29 28.1 10.9 10.2 40-59 29.7 34.4 34.0 60-79 42.2 54.7 55.8 Less than High. School 21.1 26.3 26.4 High School graduate 76.6 72.0 70.6 2.3 1.7 3.0 White 89.8 94.4 95.1 Black 2.3 2.1 2.3 Other 7.0 3.4 2.6 Unknown 0.8 0.0 . 0.0 Education Unknown Race Annual Income Level Less than 515,000/year 25.8 28.0 24.1 $15, 000-530, OOD/year 32.8 37.3 35.2 30,000+/year 33.6 *»«••• 0 34.3 Refused 3.9 0.5 0.7 Unknown 3.9 0.7 1.7 �Table 3. Risk (pooled odds ratio) of developing STS or NHL in men aged 20-79 by estimated intensity of past occupational exposure to phenoxy herbicides or chlorophenols: 128 STS cases and 576 NHL cases (diagnosed 1981-1984) and 694 population control men (interviewed 1983-1985)in Western Washington. The percentage of the total study population in each exposure category is also presented. PHENOXY HERBICIDES EXPOSURE STS NHL CATEGORY OR (95? CI) OR ( 5 CI) 9? PERCENT STUDY POPULATION None 1.0 1.0 63.3 Low 0.56 (0.3-1.1) 0.90 (0.6-1.3) 12.0 Medium 0.99 (0.6-1.7) 0.95 (0.7-1.3) 16.5 High 0.89 (0.4-1.9) 1.24 (0.6-1.9) 8.2 CHLOROPHENOLS EXPOSURE STS NHL CATEGORY OR ( 5 CI) 9? OR ( 5 CI) 9? Pr.Rwr.KT STUDY POPULATION None 1.0 1.0 41.5 Low 0.90 (0.5-1.6) 0.97 (0.7-1.3) 16.5 Medium 0.93 (0.6-1.5) 0.92 (C.7-1.2) 31.8 High 0.93 (0.5-1.8) 0.92 (0.9-1.4) 10.2 �Table 4. Risk (pooled odds ratio) of developing STS or NHL in men aged 20-79 for specific occupations and activities involving potential phenoxy herbicide exposure: 128 men with STS and 576 men with NHL in Western Washington (diagnosed 1981-1984) and 694 population control men (interviewed 1983-1985). The precentage of the total study population in each occupation or activity is also presented. PHENOXY HERBICIDES OCCUPATION OR ACTIVITY STS NHL OR (95£ CD OR (9Si CD PERCENT STUDY POPULATION Low Exposure: landscaper 0.92 (0.3-2.8) 1.70 (0.9-3.1) 3.6 railway worker 1.14 (0.6-2.2) 1.06 (0.7-1.5) 10.7 telephone lineman 0.73 1.28 (0.6-2.6) 2.4 0.83 6.1 (0.1-3.6) Medium Exposure: gardner/grou ndskeeper 1.07 (0.5-2.2) fanner 1.25 (0.8-1.9) working in sprayed area 1.34 (0.7-2.6) 1.33 herbicide forma lator/mixer 1.24 (0.3-5.3) 1.53 (0.7-313) 2.1 herbicide applicator 1.77 (0.5-5.6) 1.33 (0.8-3.9) 2.2 spraying herbicides from backpack 0.80 (0.3-2.4) 0.82 (0.4-1.5) 2.3 spraying herbicides from tractor or aircraft 1.27 (C. 5-3.1) 1.51 (0.9-2.5) 4.9 spraying farmlands with herbicides 1.35 (0.5-2.3) 1.35 (C.8-2.4) 4.3 spraying forests with herbicides - - -- *4.80 (1.2-19.4) 1.0 spraying near utility lines or railroad tracks _ _ _ _ (0.5-1.4) *1.33 (1.03-1.7) (0.9-2.0) 30.0 8.4 - High Exposure: * D n nc 1.03 (0.3-3.1) 0.9 �CHLOROPHENOL OCCUPATION OR ACTIVITY STS NHL OR (95% CD OR (95? CD PERCENT STUDY POPULATION' Low Exposure: planer mill worker 1.55 (0.5-4.7) 1.39 (0.7-2.7) 3.1 feeder man 1.31 (0.4-4.7) 1.44 (0.7-2.81) 2.9 bander man 0.90 (0.2-4.4) 1.45 (0.6-3.4) 1.8 log/lumber inspector 4. 83 (0.6-38.2) 0.40 (0.0-3.6) "0.4 sawmill worker 0.97 (0.5-1.8) 1.03 (0.7-1.4) 15.0 wood products worker 1.27 (0.7-2.3) 0.88 (0.6-1.3) 12.0 fork lift driver in mill 1.52 (0.6-3.6) 1.44 (0.8-2.6) 4.2 lumber grader *2.66 (1.1-5.4) 0.94 (0.5-1.9) 3.1 wood preserver 0.79 (0.1-5.9) 1.64 (0.6-4.2) 1.4 manufacturer of chlorophenols 1.37 (0.4-4.3) 1.72 (0.9-3.4) 3.0 Medium Exposure: High Exposure: * P •* 0.05 Paoe 42 �Table 6. Risks (pooled odds ratio) of developing STS and NHL among men aged 20-79 with factors or conditions associated with compromise of immune competence: 128 men with STS and 576 men with NHL (diagnosed 1981-1984) and 694 population controls (interviewed 1983-1985) in Western Washington. The precentage of the total study population with each risk factor is also presented. STS RISK FACTOR Malaria NHL OR (95% CI OR (95% CI) PERCENT STUDY POPULATION 1.14 (0.4-3.1) 1.47 (0.9-2.5) 4.7 non-skin 0.88 (0.3-2.5) 1.24 (0.7-2.1) 4.8 skin 1.47 (0.7-3.1) *1.57 (1.03-2.4) 7.5 0.70 (0.4-1.1) 0.91 (0.7-1.2) 27.5 Rheumatoid arthritis 1.38 (0.9-2.2) 5.9 Low gamma or immunoglobulin 1.59 (0.5-4.6) 1.0 *10.97 (2.1-57.3) 0.7 1.51 (0.4-5.6) 0.6 Preexisting Cancer: Corticosteroids Imnunosuppressant drug therapy** Immune deficiency in a blood relative * P <0.05 ** Azathioprine, Cyclophosphamide, Chlorambucil and/or Mercaptopurine. �Table 7. Risks (pooled odds ratio) of developing STS and NHL among men aged 20-79 associated with nicellaneous occupational factors or conditions among 128 men with STS and 576 men with NHL (diagnosed 1981-1984} and 694 population controls (interviewed 1983-1985) in Western Washington. The precentage of the total study population with each condition or factor is also presented. STS CONDITION NHL OR (95* CI) OR (95% Ci: PERCENT STUDY POPULATION Insecticides: Chlordane 0.96 (0.2-4.8) DDT 1.10 (0.4-3.2) *1.82 (1.04-3.2) 1.61 (0.7-3.8) 1.6 4.0 Industrial Chemicals: Organic solvents 1.10 (0.7-1.7) *1.35 (1.06-1.7) 29.8 lead/lead arsenate 1.51 (0.9-2.6) *1.60 (1.1-2.3) 12.0 • welding/metal fumes 1.30 (0.9-2.0) *1.31 (1.03-1.7) 31.1 Chloracne 3.32 (0.8-14.0) 2.12 (0.6-7.0) 1.0 Skin blisters from chemicals 1.72 (0..9-3.2) 1.06 (0.7-1.6) 7.8 Cigarette smoking 0.93 (0.6-1.4) 0.85 (0.7-1.1) 73.5 Coffee drinking 0.49 (0.4-1.2) 1.28 (0.9-1.9) 8°.8 * P < 0.05 �Table 7. Risks (pooled odds ratio) of developing STS and NHL. among men aged 20-79 associated with micellaneous occupational factors or conditions among 128 men with STS and 576 men with NHL (diagnosed 1981-1984) and 694 population controls (interviewed 1983-1985) in Western Washington. The precentage of the total study population with each condition or factor is also presented. STS CONDITION NHL OR (95* CD OR (95£ CD PERCENT STUDY POPULATION Insecticides: Chlordane 0.96 (0.2-4.8) 1.61 (0.7-3.8) 1.6 DDT 1.10 (0.4-3.2) *1.82 (1.04-3.2) 4.0 Organic solvents 1.10 (0.7-1.7) *1.35 (1.06-1.7) 29.8 lead/lead arsenate 1.51 (0.9-2.6) *1.60 (1.1-2.3) 12.0 welding/metal fumes 1.30 (0.9-2.0) *1.31 (1.03-1.7) 31.1 Chloracne 3.32 (0.8-14.0) 2.12 (0.6-7.0) 1.0 Skin blisters from chemicals 1.72 (0..9-3.2) 1.06 (0.7-1.6) 7.8 Cigarette smoking 0.93 (0.6-1.4) 0.85 (0.7-1.1) 73.5 Coffee drinking 0.49 (0.4-1.2) 1.28 (0.9-1.9) 89.8 Industrial Chemicals: * P < 0.05 �FOOTNOTES 1. Supported by U.S. Public Health Service Grant CA-29900. 2. We are indebted to the staff of the Epidemiologic Research Unit of the Fred Hutchinson Cancer Research Center for their assistance in the conduct of this study. 3. We gratefully thank Frans M. Enzinger, M.D., Chairman, Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC, for assisting in the confirmation and histological classification of soft tissue sarcoma case materials in this study. i /! r � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1439 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. Title A name given to the resource Typescript: Non-Hodgkin's Lymphoma: a Brief Overview, March 31, 1987 Subject The topic of the resource soft tissue sarcoma lymphomas DDT health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 043 Folder The folder containing the original item. 1052 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. Description An account of the resource <strong>Corporate Author: </strong>Veterans Administration Source A related resource from which the described resource is derived Accidental Exposure to Dioxins: Human Health Aspects Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource Health-Related Problems to TCDD Subject The topic of the resource VA veteran health and hygiene Southeast Asia health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 043 Folder The folder containing the original item. 1051 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Shepard, Barclay M. A. L. Young Description An account of the resource <strong>Corporate Author: </strong>Office of Environmental Medicine, Veterans Administration Source A related resource from which the described resource is derived Human and Environmental Risk of Chlorinated Dioxins and Related Compounds Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource Dioxins as Contaminants of Herbicides: The U.S. Perspective Subject The topic of the resource herbicide damage assessment study protocol Southeast Asia veteran health and hygiene ao_seriesIII