2 15 34 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. 075 Folder The folder containing the original item. 1954 Series The series number of the original item. Series III Subseries IV 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 Shannon, Peter Date A point or period of time associated with an event in the lifecycle of the resource 1983-12-01 Title A name given to the resource Letter: from Peter Shannon to Alvin L. Young, 9 December 1983 Subject The topic of the resource AVHS Australia international cooperation 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. 080 Folder The folder containing the original item. 2061 Series The series number of the original item. Series III Subseries IV 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 O'Toole, Brian I. Michael A. Adena Michael J. Fett Description An account of the resource <strong>Corporate Author: </strong>Commonwealth Institute of Health in the University of Sydney Date A point or period of time associated with an event in the lifecycle of the resource September 7 1984 Title A name given to the resource Australian Veterans Health Studies, The Mortality Report, Part II: Factors Influencing Mortality Rates of Australian National Servicemen of the Vietnam Conflict Era Subject The topic of the resource AVHS mortality trends ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/eb6debf974ce03cc4e2b945c807897f6.pdf b9dc095475ed57983dee2a445bd57420 PDF Text Text Item ID Number 01497 Author O'Keefe, Barry Corporate Author Report/Article TitlO Typescript: Chapter/: Soft Tissue Sarcoma: Law, Science and Logic, An Australian Perspective Journal/Book Title Year 0000 Month/Day Color Number of Images DOSCrlptOU NotOS Tnis 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. "This chapter deals with the Final Report of the Royal Commission on the use and effects of chemical Agents on Australian Personnel in Vietnam, July 1985. It is based on the transcript of the examination and cross-examination of Professor Olav Axelson and Dr. Lennart Hardell as expert witnesses concerning chemically caused cancer, their published papers and the submissions made to the Royal Commission in relation to the subject as well as the Report itself." Tuesday, May 15, 2001 Page 1497 of 1514 �CHAPTER 7 SOFT TISSUE SARCOMA Law, Scien'ce and Logic (*) An Australian Perspective Barry O'Keefe Q.C. - Sydney - Australia Introduction The Royal Commission conducted by the Australian Federal Judge, the Hon. Mr. Justice Evatt D.S.C., presented an excellent opportunity for close examination of a number of studies relied upon by some statutory agencies and others in support of claims that 2,4-D, 2,4,5-T and the contaminant dioxin in Agent Orange are carcinogenic in man and induce male-mediated birth defects. The data and methodology involved as well as the conclusions reached in such studies were able to be examined in an objective, logical and disinterested manner by a Royal Commission wellequipped to make an accurate assessement of the reliability and scientific value of such studies. (*) This chapterdeals with the Final Report of the Royal Commission on the use and effects of chemical Agents on Australian Personnel in Vietnam, July 1985. It is based on the transcript of the examination and cross-examination of Professor Olav Axel son and Dr. Lennart Hardell as expert witnesses concerning chemically caused cancer, their published papers and the submissions made to the Royal Commission in relation to the subject as well as the Report itself. �- 2- A claim made repeatedly by those who represented the members of the Australian Vietnam Veterans Association or who purported to speak on behalf of the veterans was that Agent Orange had caused and was causing cancer in Vietnam Veterans. One type of cancer in particular (soft tissue sarcoma , a generic term for several types of rare cancer), was the focus concern because of surveys of Swedish agricultural, forestry and railway workers by the Swedish investigators Axelson and Hardell. Both published several scientific papers, produced a number of documents for use in courtrooms, gave newspaper and radiointerviews and appeared on television. Both were identified in local and other media with the scientific work which was seeking to link specific cancer types with the use of phenoxy herbicides. This was more manifest in relation to Hardell. Since these studies are the main epidemiological evidence relied upon to support an association between exposure to phenoxy herbicides and an increase of the relevant types of cancer, the Royal Commission examined these data very closely. This involved not only a close examination of the background of their research but also a careful analysis of their data case by case and of their methodology. �- 3 - Epidemiological methodology - The case control study. Epidemiology is said to be the science dealing with the environmental causes of diseasesof humans as inferred from observations of human beings. Whilst the discipline of epidemiology can be used to assess the risk of individuals in a human population developing a particular disorder or to demonstrate an apparent association or lack of association between an observed health phenomenon and a given substance or substances by the mathematical testing of a possible association between the observed health phenomenon and the postulate source of that phenomenon, such a demonstration cannot of itself be used as proof of causal relationship. It merely demonstrates statistical association. This may be a true association or only an indirect or artifactual association. In this regard the problems of confounding and of bias (whether of the selection or observational kind) are important because they can invalidate the conclusions. �- 4- Observational bias may take different forms. It may be bias of the subject arising, for example, out of memory problems or it may be bias in the investigator himself. People who are suffering from a particular disease are more apt that health people to think about their condition and to try and find an explanation, for example, in exposure to various situations or agents which they believe may have caused their disease. This can affect the accuracy of the data obtained. Likewise the accuracy of data obtained may be affected by the subject having knowledge of the result which the investigator is seeking to achieve, just as it may be affected by the data collector being made aware of the object of the data collection. Positive evidence (unless due to confounding) is important. Negative human evidence may not carry, unless it relates to prolonged and heavy exposure. If however it is related and is consistent in a variety of correlation studies over time (cohort studies of exposed individuals and/or case-control studies of affected patients) negative human evidence may justify the conclusion that for practical purposes the agent may be considered as not constituting a risk to human health. In assessing the result of a particular epidemiological study the strength of the association: demonstrated, the duration and degree of exposure, the presence of a dose/response relationship, confirmation or replication of the result by others and the specific �- 5- nature of the response are all relevant factors. So too is the knowledge that the data on which the result is based are accurate. If the data on which a study is based are subject to doubt, then the conclusions of the study must be treated as doubtful at best. In proper epidemiological practice the events which generate an hypothesis should be kept separate from the events used to test that hypothesis. The case control study is one of the methods which can be used for an epidemiological study to assess cancer association and is the one which has been used by Dr. Hardell. A case control study is a retrospective study where one sample of a selected population is compared with another regarding one or more characteristics of interest. The case-control study method has become widely used and refined during the last 50 years due to the increasing importance of chronic diseases where the low incidence and long interval between cause and effect are not well suited for other epidemiological approaches. �- 6- Given the extension of case control studies it is more than ever important to recognize the limitations of the method. In the case of herbicides the case control study is an investigation of the exposure frequencies of two groups of subjects selected on the basis of their status with respect to exposure to the chemical or chemicals in question. The method is valuable because it permits us to see back through time, commencing with the effect back to a postulated cause. It has advantages in relation to other methods: it is relatively inexpensive and requires little time; it is very well suited to the study of rare diseases; it allows the evaluation of several etiologic factors both as independent and interacting causes. The method has also a number of important limitations; it is not suitable for the study of exposures which occur only rarely; it allows estimation of relative rates but not of absolute rates; and finally it is susceptible to bias. Bias, especially selection and recall bias, is the most serious potential problem in case control studies. There are many kinds of selection bias: selective admission to the group; selective survival and death; selective detection; selective response �- 7- and participation. There are other tuasis and confounding factors which can make the conclusions of a study untenable. There can also be demographic bias due to age and sex, which can be risk factors in cancer. There can be clinical bias when a person is genetically predisposed to a specific disease. There is finally the anamnestic recall bias of the interviewed subject. In this case the disease itself acts a&a stimulus which makes the subject concentrate his attention to the possibility or to the degree of an antecedent exposure. There is also the problem of defining the exposure. Taking, for example, an industrial exposure which has occurref 20 years ago and which lasted only a few days, it is extremely difficult, perhaps verging on the impossible, to assess the validity of the information. Efforts should be made to stimulate the memory of the control group of to check the statements made by both the cases and the controls. �- 8- A methological standard which is used to lesten the possibility of bias is the interview with each single member of the group. However the interviewer should be "blinded". In many studies the interviewer who inquires about whether or not the patient was exposed to the causel agent is aware of the research hypothesis or of the subject's identity as a subject or as a control. This can lead to a preconception on the fact of the interview, which is another source of bias. All these factors were thoroughly dealt with in the course of the testimony of Prof. Axel son and Dr. Hardell and considered in detail in the report of the Royal Commission. Prof. Olav Axelson In late 1971 and early 1972 Professor 0. Axelson undertook a study (first analysis) of cancer mortality amongst railway workers because of rumors of excess lung cancer mortality amongst those exposed to 2,4-D and 2,4,5-T (1). In an endeavour to determine if the rumors were justified he examined mortality amongst a cohort of 348 railway workers, inclusion in which cohort depended upon a workers having a given duration of exposure to herbicides during the period from 1951 to 1971. On analysis of the data Professor Axelson �- 9- found a total of 18 deaths from all causes compared with 20.54 expected and a total of 6 deaths from tumors compared with 4.88 expected when a zero latency period was allowed for. For tumors, therefore, the relative risk was close to unity (namely 1.2) and certainly not statistically significant. As far as deaths from lung cancer were concerned, 0.83 have been expected and 2 were found. Neither of these occurred in the sub-cohort said to be exposed to phenoxy acids and both of them (cases 256 and 257) occurred in people who have been smokers for a long time, perhaps decades. From this analysis Professor Axel son concluded that: "There seems to be a possible association between excess tumor mortality and exposure to amitrol and its combinations, especially if a latent period is considered. On the contrary in the cohort exposed to phenoxy acids and .combinations a fairly good agreement is found between the exposed and observed deaths indipendent of the latent period" (4 ). Not only did his first analysis not demonstrate an association between phenoxy herbicides and an increase in cancer incidence but Professor Axelson expressed the view that his conclusion was: "as close as one can get to a negative epidemiologically". �- 10 - After becoming aware of observations by Dr. Hardell i.e. "the first clinical report about soft tissue sarcoma and phenoxy herbicide-exposure" Professor Axelson reanalysed his data (re-analysis). Two (2) cancer cases which in his first analysis had been classified as having been exposed to amitrol were now stated to be cases in which "it is possible that phenoxy acid exposure alone may have occurred"/2 J . When these cases were reclassified in this way i.e. the possibility was converted to a fact and used as an assumption in the re-analysis, an excess of mortality from tumors was obtained amongst individuals with phenoxy acid exposure, as redefined/i) . Thus to produce an excess of -tumors in the relevant subcohort a change in classification had to be effected and the excess found in that cohort depended on only two (2) cases - the two who were re-classified. It is no doubt because of considerationssuch as these that the Axelson re-analysis concedes that: 1) "the material is unsatisfactorily small"; 2) " the exposure pattern is complex" and 3) "it is not possible to clearly select any special herbicide as carcinogenic", and they explain why the conclusion in the �- 11 - re-analysis are so nebulous in relation to the subcohort said to have been exposed to phenoxy acids: "certain indications suggest that an excess tumor mortality may also be referable to phenoxy acids", and "on the basis of these investigations it is not possible to select any special herbicide as carcinogenic but the suspicion against phenoxy acids as a group \ of preparations may have become somewhat increased". Subsequently, using the same exposure data as before, Professor Axel son followed the cohort through to October 1978 and undertook yet another analysis (update). This time, however, he introduced a latency period of 10 years and reached a conclusion which was different from the conclusion in his first analysis. There are two (2) reports of his update (£|). Whilst they are not identical both versions contain the following statement: "tumor incidence was also updated but provided little additional information. The incidence data have therefore been omitted from this presentation". The omission of the incidence data is interesting since, in his first analysis, Professor Axelson had stated that: the "tumor incidence data, however, may be more relevant than the mortality data...." �- 12 - It would seem reasonable to conclude that nothing abnormal was found in the update in relation to tumor incidence - an indicator which Professor Axel son had regarded as "more relevant" than mortality. In his update Professor Axel son concluded that: 1) "no specific type of tumor is predominating; 2) "the aspects of causal relationship are rather unclear"; 3) "those exposed in 1962 or later did not show a clear excess mortality"; 4) "this finding might be interpreted in different ways, i.e. the variety of herbicides during the early period could be of importance and/or the work conditions may have been more primitive and the herbicide handling more careless resulting in a higher degree of exposure". Thus the findings from the update do not single out phenoxy acidi . Indeed the comment in (4) above together with the discussion concerning Table I in reference (1) (below) and the absence of any other data as to the herbicides used by the Swedish railways, support the inference-1 that Professor Ayeison's work in fact exculpates 2,4,5-T. As the Royal Commission found: "At the very least, there are serious problems in his work arising from confounding factors". �- 13 - Because it has been suggested by some that Professor Axel son's first analysis, re-analysis and update in some way support Dr. Harden's later findings, they should be examined. In carrying out this examination it is desirable to look at: 1) methodological flaws; 2) the lack of expertise of those engaged in Axelson's study; 3) the inaccuracy of uncertainty of the data involving problems in the selection of the cohort, in the determination of exposure and arising from wrong diagnoses; 4) the weakness of the conclusions; and 5) the difference between the results obtained by Professor Axelson and those obtained by Dr. Harden. 1) Methological flaws In proper epidemiological practice the events which generate an hypothesis should be kept separate from the events used to test that hypothesis. As Professor Axelson himself agreed: "To my understanding there is a tendency for some statisticians to take the view that one should not use individuals or such observations that have started - yes, started the study - I would not say generated the hypothesis because that is generated from the facts as well". �- 14 - However, his study breached this basis principle, as is clear from the fact that what generated the study was an assertion of three lung cancer amongst the railway workers. One of those was subsequently excluded and leaving Professor Axelson with two cases and they were included as cases in his study. 2) Lack of expertise A questionnaire was sent out as part of the data gathering process. At the time the questionnaire was designed and sent out and at the time the data were gathered, Professor Axelson had neither university qualifications nor professional training in either epidemiology or statistics. He was not a mathematician and his only training in epidemiology was self-training - by reading books. True it is that in 1972 he attended 14 days of lectures in Finland but that, as he conceded, "did not have any effect because it came later".(5; Lack of training and experience may well explain the absence of a written protocol for the study as well as the absence of any formal development of a plan in which the design and purpose of the study and how it would be carried out were detailed (6). �- 15 - 3) Inaccuracy of the data Inaccuracy of the data about exposure can affect the correctness of the conclusions in a study in which exposure to a given substance is the variable. The collection of the data which were used for the first analysis was undertaken at a time there was a good deal of controversy in Sweden about the use of phenoxy herbicides, particularly 2,4,5-T, and a lot of adverse publicity both in the newspapers and on television (7). In addition, rumors were current about an association between cancer and use of such herbicides by railway workers (8). Thus the climate in the communitiy generally and in the study population in particular raises a serious question of possible information bias. This possibility was conceded by Professor Axelson in his evidence to the Royal Commisison. The problem was heightened amongst railway workers by the distribution of questionnaires, in which the first question was : "Have you experienced any health problems which you relate to herbicides?" (9). The questionnaires were sent first to the Chief Physician of the Swedish Railways. From him they went to the various districts in the railway network and then from each district to the men of that district (10). Professor Axelson did not know �- 16 - who had actually filled out the questionnaires (|O). However, it is clear that they went to the bulk of the workers who were included in the cohort as well as to others. All of those to whom the questionnaires went had asked for health check-ups, as appears from Professor Axel son's evidence both before the Royal Commission and the EPA (1980) deposition. The questionnaires were distributed at the very time when lists of the workers said to have been exposed to herbicides in the period 1951 to 1972 were being compiled, or had been requested from, the Swedish railways. An examination of a copy of the questionnaire (3) reveals that no information was sought concerning the extent of exposure to any particular herbicide or chemical and that the instructions which formed part of the questionnaire did not differentiate between different herbicides, all of which were grouped together as "weed and brush killers". In view of the form of the instructions which appeared at the head of the questionnaire, and the first question in it, it is not surprising that Professor Axelson conceded that it was: "fairly clear what the investigation was all about" and that: " we did not camouflage that at all", �- 17 - Despite the fact that the distribution of the questionnaires at such a sensitive time was likely to have exacerbated the problem of recall bias, the information obtained from them in relation to exposure was not used (10). The cohort was in fact compiled from exposure information derived from lists supplied by the Swedish railways. Thus the problem of information bias was made more severe by the adoption of a procedure which produced no countervailing positive or beneficial effect on the study. It took a nember of attempts to compile the study cohort. In the first attempts information as to exposure was sought from the Swedish railway authorities. They provided information in lists which were the result of a "joint assessement of exposure from the railway company and from the trade union representatives". That first or basic set of lists proved to be of little use "because we got in material which was fai'r/y bad from some districts", and "therefore we repeated the whole procedure once more". So instructions were given for the compilation of another set of lists: "At least in this respect, because we had a bad experience there from the first attempts,., we had to be more detailed in the second one before we gave up". �- 18 - There has been therefore a first set of lists from the Railways which were rejected because they were inclomplete and inconsistent, due to differences in the various data provided from different districts. A second set of lists was then compiled and in respect of that Professor Axelson made some mechanical exclusions i.e. everybody who had only exposure up to and including 45 days. The manuscript submitted by Professo Axelson to the Health Board of Occupational Safety and Health became the subject of media publicity. This led to a number of persons coming forward claiming that they should have been in the study. This new group of claimants who came forward to the Railways led to the compilation of a third set of lists. In the compilation of the second set of lists there were instances in which the union insisted that the names of particular workers be added and, after discussion, addition were made for this reason. The lists were then signed as "mutually agreed" between the railways and the unions, although they probably included the names of workers who did not appear from the rail ways' records as persons who had been exposed for 45 days or more. �- 19 - How many of the workers fell into this category was and remains unknown. The employees at the Swedish railways who gathered the material had not training in data collection. The potential for inaccuracy created by this circumstances was compounded by the fact that the exposure was determined by the people compiling the list looking at the salaries that were paid to the various workers, from those salaries deducing what work tasks were undertaken by the various workers and then implying what exposure they could have had. The process involved in the collection of exposure data was conceded by Professor Axel son to be "a sort of guessing". The extend to which any particular person may have been exposed was "guesstimated". Professo Axel son agreed during the examination that in the railway records there was no indication in relation to any individual of any particular preparation or preparations of a chemical nature which were in fact involved in his job. Thus the compilation of the lists relating to exposure was fraught with problems. No checking of exposure was ever undertaken by Professor Axel son or his assistants. The data which were provided in the second and thrird sets of lists were accepted with "not even a spot check in relation to one or some random number", and "..except �- 20 - for excluding persons who are (sic) exactly 45 days of alleged exposure and some accidental inclusions of those who were under 45 days (Professor Axelson) took no part in the selection of the cohort" In these circumstances it is understandable that Professor Axelson did not attest the accuracy of the exposure data. Professor Axel son's reservations about the accuracy of the data are highlighted by his decision to "modify the cohort selection basis after the data had been gathered" by increasing it from a minimum of 45 days exposure to a minimum of 46 days of exposure. This modification of the basis of selection of the cohort was regarded by the Royal Commission as being perhaps somewhat naive, As indicated above the data relating to phenoxy herbicide exposure used in the first analysis, the re-analysis and the update were obtained from the lists supplied by the Swedish railways. These lists categorised potential exposure under three headings namely, Group A, Group 0 and Group F. Professor Axelson said that 'A1 in the Group A heading stood for amitrol. However, an examination of his document (10) shows that a number of specific herbicides are referred to by name under and included within that heading. �- 21 - The heading for Group 0 was "other herbicides". The heading for Group F was said by Professor Axel son to stand for "phenoxy acids". However it turned out that this was not so. It emerged that Group F was "all brush killers". Professor Axelson conceded that the word "brush killers" meant all chemicals of that the description. The description "brush killers" is not apt for 2,4-D and is certainly a category much wider than phenoxy herbicides. Therefore the fact that a person was included in the lists under the heading of Group F did not mean he had been exposed to phenoxy acids even if it be accepted (for the sake of argument) that it meant anything in relation to exposure to a herbicide. It could mean, for example, that the worker was exposed to a phenoxy acid in combination with another herbicide or other herbicides or that he had no exposure to phenoxy acids at all. This latter possibility was accepted by Professor Axelson as was the fact that : "The exposure data did not come from the men claiming to be exposed", "it came from railway officials which may or may not have had personal knowledge of exposure of any individual", "in conjunction with union people who may or .may not have personal knowledge of any such expsure", "and it was derived substantially by way of inference from the category of employment revealed by the employment record". �- 22 - It should be noted that the herbicides which fell within Group F included Primatol D43, Totalex extra, Uridal and MPCA ( None of these contains 2,4-D, 2,4,5-T or TCDD. Ino. Table included in his publication (1) on the exposure of the railway workers Professor Axel son reported the total quantity of specific herbicides "consumed" in 1957-1961 on the Swedish railways over the whole of Sweden. The records did not reveal any use of certain of these herbicides for some of the years 1957 to 1961 inclusive. Professor Axelson sought to avoid the consequences of the implication of this absence of evidence of use of phenoxy herbicides by saying that the word "consumed" really meflnt "purchased from suppliers" but not necessarly used in any given year. However the word "used" which appears in the •footnote to the Table is clearly a synonym for "consumed" and not for "purchased". It is difficult to understand Professor Axelson's reason for including the Table in his study unless he were of the belief that it showed the amount of herbicide actually "consumed" i.e. "used" throughout Sweden by the Swedish railways in the years against which entries are made. Either the Table (and the records on which it was based) indicated the amount of herbicides used in the years dealt with or it does not. If the records do so indicate, then they are de_structive of the conclusions set out in the update. If they do not in fact so indicate then there are two further possibilities, namely Professor Axelson either believed �- 23 - that they did so indicate of he did not so believe. It is unconceivable that he did not believe that Table (and the relevant records) showed what the heading said it showed. If he did not so believe, the inclusion of the Table in his study would amount to a gross departure from the proper standards of scientific honesty. However, even accepting that he did believe the contents of the Table to be accurate (although his oral testimony indicates that they are not accurate) this very situation highlights the loose, untrained and unexperienced approach which was involved in the study and emphasizes the totally unsatisfactory nature of his exposure data. The significance of Professor Axel son's change of stance in relation to this matter prompted the Royal Commissioner to ask: "THE COMMISSIONER: I mean, I am rather shattered to find that in that Table there that I have studied in some depth - to find that it has got nothing to do with the price of fish if I may use a colloquial!ism of this country. I had assumed the men had been exposed, or there was potential exposure, to that amount of that chemical and I find I am wrong in making such an assumption?". "A-Yes". Professor Axel son admitted in his answer that the Table does not tell explicity the exposure of the men in question. �- 24 - A little later, however, Professor Axelson said that the records "reflect indirectly at least how much of herbicide that was used" The Table sKo»o$that no herbicides containing 2,4,5-T or any substance that could potentially contain 2,3,7,8-TCDD were used by the Swedish Railways prior to 1963. When Professor Axelson undertook the updating of his data he ascertained that two cases (Nos. 268 and 334) which had previously been classified as having cancer ("f ) had not had their diagnoses of cancer confirmed by the National Central Bureau of Statistics (3). These cases were therefore excluded from the update (3) on the grounds of misdiagnosis. The proposition that error in diagnosis can be quite important in a study in which the numbers involved are small is clearly applicable to the work of Professor Axelson. The "other exposures*1 of the workers involved in the analysis, the reanalysis and the update were unknown (3)- In this regard the update expressely stated that: "It should be made clear that the recognized exposure have been mixed with other unknown exposures; unfortunately there is no possibility of sub-dividing the material in this regard" (3). �- 25 - The Royal Commission observed in relation to Professor Axel son's work that: "It was carried out by untrained and inexperienced people; there was no protocol; it was based on a cohort, the selection of which was completely outside the control and supervision of those conducting study; no responsibility for the accuracy of the exposure data was accepted; those conducting the work used data the accuracy of which they themselves doubted; the data on which the work was based were inaccurate"; and then conluded that: "(a) it was carried out by untrained and inexperienced people; (b) there was no proper protocol; (c) exposure data were obtained in a climate of considerable controversy about the very subject of the study; (d) the questionnaires distributed made apparent to the subjects the purpose of the information sought; (e) in a number of cases the data relating to exposure were little more than a guess; (f) persons who were counted as having been exposed to phenoxy acids may not have any such exposure; (g) the number and extent of confounding factors was unknown; (h) there was inaccuracy in diagnosis data." 4.- Weakness of the conclusions The three conclusions reached by Professor Axelson in relation �- 26 - to the effects of phenoxy herbicide exposure are different. The first is negative. The second raises a fairly nebulous possibility if a particular assumption as to exposure is adopted. The third is dependent on small numbers, involves a lack of specificity and the accuracy of the exposure data is questionable. On their own these considerations would be adequate to justify the conclusion that Professor Axel son's work does not make any real contribution in relation to the problem of whether there is an association between exposure to phenoxy herbicides and the incidence of cancer. But such considerations do not stand alone. There are other factors within Professor Axelson's material which support the conclusion just expressed. In his first analysis Professor Axelson used a maximum latency pariod of 5 year. In his later analysis he changed the latency period to 10 years so as to bring it "more in line with standard epidemiological approaches". Such a period "seemed to be a reasonable latency or induction period" according to Professor Axelson. After being questionned at length Professor Axelson agreed that if he had adopted the same latency period in his first analysis as he had in the update, the total number of tumors observed in the cohort said to have been exposed to �- 27 - phenoxy acids and combinations would be reduced from five (5) to three (3) viz. Cases 173, 328 and 388 - the only cases who had both the potential for exposure to phenoxy acids and combinations as well as the necessary minimum latency period. This reduced number of three (3) is to be compared with 2.83 expected: "And the relative risk then is 1.06 which is insignificant in any case." This conclusion would flow through to the re-analysis (2). When a minimum latency period of 10 years is adopted and the consumption data set out in Professor Axel son's publication are accepted as correct, the number of tumors observed in the so called "phenoxy acid" sub-cohort in the update is reduced to three (3) compared with 3.14 expected (1). The relative risk is then 0.95. Whilst the figure of 3.14 for the number of tumors expected would need some reduction, the extent of the reduction could not, according to Professor Axelson, be calculated from the data available. Although he was not able to agree that the adjustment would probably result in a figure of between 2.22 and 2.44 (Relative Risk of 1.35 and 1.22) such figures can fairly be derived from the data presented and are a reasonable indication of number of tumors to be expected. �- 28 - As can be seen from Table I there is only one instance (Case 328 \- cancer of the prostate) in which the first exposure occurred after 1963. TABLE I (*) Case first year of exposure No. assigned by Axelson 127 1957 172 1958 173 1958 268 1960 317 1958 328 1967 388 1961 113 1960 In the original analysis, the re-analysis and the update the numbers from which the relative risks for the subcohort said to have been exposed to phenoxy acids and combinations were calculated are small and the existence of an excess depends (*) From Reference No. 1 �- 29 - entirely on the classification as to exposure which is assigned to given cases. However, as the Royal Commission found, "the exposure data are inadequate, unreliable and non-specific" Its final word in relation to the value of his work is worthy of note. The Royal Commission concluded that: "because of number of faults, together with the extent of uncertainty or error in the data, Professor Axelson's doubful positive conclusions * should be given little or no weight". Jr^ Lennart Ha.rdell The relevant studies undertaken by Dr. Lennart Hardell in relation to the effects of herbicide exposure on various populations in Sweden are as follows: 1) the North Sweden Study concerning the incidence of soft tissue sarcoma (X-^/12,1$, 11+, Js). 2) the South Sweden Study also concerning the incidence of soft tissue sarcoma 3) the Malignant Lymphoma Study 4) the Nasopharyngeal Cancer Study (19); �- 30 - 5) the Colon Cancer Study (I3>) which had as its essential purpose the verification of the conclusions in the studies referred to in paragraph (1), (2) and (3) above (2.0). Before undertaking his North Sweden study Dr. Hardell published the preliminary clinical observations which had caused him to undertake that study in North Sweden (2A}. These clinical observations had been made during the first three (3) months after he had gone to the Umea Regional Hospital in 1976. A like course was taken by him prior to undertaking his malignant lymphoma study (22). Since Dr. Hardell's studies constitute the main body of epidemiological evidence which supports an association between exposure of humans to phenoxy acids and an increased incidence of soft tissue sarcoma and malignant lymphoma they will be examined in some detail. However, as Judge Weinstein noted in his judgment of 8 May, 1985 in the Agent Orange Product Liability Litigation, Hardell's studies "were widely recognised as flawed" (Gibbs et al.y Dow et a!. U.S. District Court, Eastern District of New York MDL 381 at page 48). This statement by Judge Weinstein adopts the conclusion of Mr. Justice Nunn in the Nova Scotian case of Palmer & Ors v Stora Kopparbergs Bergslags Aktiebolag trading as Nova Scotia Industries £tl983j 60 Nova Scotia Reports (2d) 271) in which His Honour referred �- 31 - to the Harden studies as "unacceptable as proof of the results claimed" and found "that they cannot be taken at face value" (supra at page 352). 1) The Nort Sweden Study In August 1977 Dr. Hardell reported on clinical observations either made by him in his first three (3) months at the hospital or deduced from the earlier hospital records. These related to seven (7) initial and two (2) other instances of soft tissue sarcoma found amongst persons said to have been exposed to phenoxy herbicides during the 10 or 20 years preceding diagnosis and observed in the Oncological (Cancer) Centre at the Umea Regional Hospital between 1970 and 1976 (23). He treated the initial seven (7) of these cases as "a series1.1 In this first report (24) Dr. Hardell states that between 1970 and 1976 a total of 87 patients with malignant mesenchymal tumors (soft tissue sarcomas - STS) had attended the Umea Oncological Centre. Fifty five of these (68%) were men and of these 43 were still working. Nine (9) of the men who were still working were forestry workers, four (4) worked in agriculture and forestry and six (6) at saw mills or in the pulp industry - a total, of 19 or 42.2%. Such a mix of occupations is not surprising in view of the geographic situation of Umea in Sweden's North and extent to which �- 32 - forestry, activities associated with forestry and, to a lesser extent, agricultural pursuits are undertaken in the region , In the report of his clinical observations concerning the seven (7) initial cases Dr. Hardell states that "the exposure was quite massive in all cases" (21) and that the exposure of five (5) of them was "direct" (2.1). In his North Sweden study these seven (7) initial cases are described as "a series of patients with soft tissue sarcomas and massive exposure to phenoxy acids" (2lj). Examination of the histories of these patients as ascertained by Dr. Hardell shows that these statements are far from accurate. His use of the word "massive" in fact reveals a good deal about his approach to exposure data as also, perhaps, does the form of his editing of the case histories of the seven (7) cases extracted from the hospital records. Case I had sprayed with 2,4,5-T for barely one week in 1963 and 1964, two weeks in 1965, one month in 1966, one month in 1967 and 2 weeks in 1968. He was diagnosed as suffering from STS in 1976. Adopting, as both Professor Axelson and Dr. Hardell did, a minimum latency period of ten years the relevant exposure for Case I should be taken as that arising from something less than three weeks of herbicides spraying. The longer the latency �- 33 - period adopted the less the relevant exposure, falling into nil if 15 years is adopted. Case 2 sprayed for 3 weeks in each of three or four summers during the 1950's and 1960. He was diagnosed as suffering from STS in 1976. Thus his exposure was a maximum of twelve weeks spread over twenty years. Case 3 was diagnosed as suffering from STS in 1976. His only association with herbicides was that "thousand of litres of phenoxy acid" were stored for about eleven months each year in the workshop in which he was employed. Some of these had been "stored partly in open containers" so that he could smell the material and it is stated that he "had also handled the preparation". In what circumstances or for what period the containers were left open (e.g. whether this was only when they were being handled), the extent and manner of handling of "the preparation" (singular) by the patient, what "the preparation" handled was or what the "phenoxy acids" (plural) were is not revealed. Similarly whether or not the man was wearing gloves or other protective clothing when he handled herbicide is not stated' in the report and remains unknown. Such an absence of detail itself suggests that there was no great extent of exposure. Since Dr. Hardell saw his patient and appears to have taken a part in his extended treatment the data must have been known to �- 34 - Dr. Hardell and, if substantial, surely would have been revealed by him either in one of his publications or in the course of his evidence to the various tribunals before which he has testified. This has never been done, indeed Dr. Hardell was unable to supply any further details about these relevant matters although he was expressly afforded such an opportunity. However it is known, that case No. 3 never sprayed and that this case was classified as unexposed when Dr. Hardell undertook his North Sweden study (24). Case 4 was exposed to unspecific phenoxy acids for about twenty days per annum in the years between 1961 and 1966. As the date of his diagnosis is not stated, the precise extent of his relevant exposure cannot be calculated. However, taking the date of Dr. Hardell's observations (i.e. 1976) as the latest date of diagnosis, the maximum relevant period would appear to be low. If 15 years is adopted as the latency period the relevant exposure of this case falls to nil. Case 5 was exposed to herbicides for a total of six weeks in 1945 and 1946. The nature of those herbicides is not revealed but having regard to the fact that 2,4-D and 2,4,5-T were introduced into Sweden after 1950 it is improbable that such early exposure would have involved phenoxy acids, Case 5 did spray phenoxy �- 35 - acids for two weeks in each of the years 1960 to 1968. He was diagnosed as suffering from STS in 1974. Adopting a latency period of ten years, his relevant exposure is that arising from a maximum of eight weeks spraying spread over four years. His relevant exposure falls to nil if a latency period of 15 years (or more) is adopted. Case 6 was diagnosed in 1972 as having STS. The only evidence that he had any exposure was that "over 4-5 summers in the fifties... he cut and removed grass along the verges sprayed by the Highway Department" and that "he had worked and lived in forests sprayed with phenoxy acids" (2-1). In Dr. Hardell's report of this case neither the relationship between the time of cutting of the grass and the time of herbicide spraying nor the actual herbicide/s involved is revealed. However, it is unlikely that 2,4,5-T would have been used for grass killing since it is unsuitable for such a purpose. It is used for trees and for woody, tree-like growth. It is also inherently improbable that the grass would have been cut before such herbicide sprays as had been used would have had time to take effect. There is no point in spraying herbicide on grass an4 then immediately cutting the grass. This conclusion was accepted by Dr. Harden, �- 36 - Dr. Hardell also admitted that as far as the possibility of exposure of this man as a result of having lived and worked in the forest was concerned, he did not know the relationship between his place of residence and the location where spraying occurred, or the relationship between the time of spraying and when he worked in the forest. Nor did Dr. Hardell have any data as the whether the case was ever actually been in contact with the substances which had been sprayed or as to when and how often the spraying had occurred. In addition there was nothing to indicate that the man in question had carried out spraying himself, indeed it was not suggested that he had ever done so. Case 7 was diagnosed as having STS in 1970. However symptoms had been manifest in mid-1969. His only association with phenoxy acids was that he "had worked in forests up to 1970" (21) where "he carried out thinningin the phenoxy acids prayed areas from 1956 to the beginning of the 1960's (21). Whilst it is hardly likely that he would have been carrying out thinning immediately after spraying had taken place, the report is silent about any such temporal association and Dr. Hardell was unable to provide any further information on this subject in the course of his evidence before the Royal Commission. The only other possible source of exposure for this patient was that he had worked "in conjuction with spraying a few years later" (21). What this involved remains �- 37 - obscure as does the description of the spray or sprays used. There may in fact have been no exposure whatsoever. However, deficient as it is, the information set out above in relation to this man was agreed by Dr. Hardell to be "... a fair summary of the total information you were able to get about exposure of this man". Once again, if a 15 years latency period is adopted, this man would have no relevant exposure. From the foregoing it can be seen that it is doubtful whether there was any exposure of Cases 3,6 and 7 and that, insofar as there may have been any exposure at all, it was minimal at most. If a latency period of 15 years is adopted then Cases 1, 4 and 5 would also be excluded because of absence of relevant exposure. Dr. Hardell's description of the extent of exposure of the cases include in the series as "massive" and "quite massive" was found by the Royal Commission to be both "inaccurate" and "highly emotive". It is the language of the advocate rather than the language of the detached scientist. In his role as advocate Dr. Hardell manifested a readiness to adapt his evidence in the light of cross-examination. His description of the exposure of the initial seven (7) cases referred to in his clinical observations (21), the special meaning �- 38 - he ascribed to the word "massive" in his Agent Orange deposition, his realization in the course of giving evidence that this created problems for him and his change in position when it was clearly demonstrated that he had been inaccurate in his description of the extent of exposure, all demonstrate his approach. A ban on the use of 2,4,5-T was imposed in Sweden (25) in or about April 1977. This was done for reasons which were political rather than scientific. At that time phenoxy herbicides were the subject of intense debate and there was grave concern amounting to alarm about 2,4,5-T (25), indeed so great was the intensity of the controversy in the North of Sweden that it led to accusations that an academic from the Umea area, Professor Rappe, was a liar because he defended the use of Hormoslyr, one of the constituents of which was 2,4,5-T (2S). It was against such a background that Dr. Hardell's clinical observations were published. With the active co-operation of Of, Hardell they received widespread publicity (2&). He gave a number of newspaper and radio interviews and also appeared on television ( ) . He was increasingly identified in local and other £) media as involved in the scientific work which was seeking to link specific cancer types with the use of phenoxy herbicides (29). �- 39 - He became a prominent figure of the then current controversy. (25,26,27,28,29,30). The publicity which he and his clinical observations received and the extent to which he was identified with the controversy concerning phenoxy herbicides are relevant in relation to the problem of information bias in his studies. Because of the extent and heat of the controversy which surrounded the use of phenoxy herbicides in Sweden, information bias was always likely to be a problem, however,thi's problem was accentuated by Dr. Hardell's involvement and prominence in 4n£- controversy. Thus a climate which was already unsuitable for epidemiological research in relation to the possible association between phenoxy herbicides and cancer was made even worse by Dr. Hardell's actions. Indeed, it was admitted by him that at the material time there were "very few topics in the environmental debate... discussed as much as phenoxy acids. The debate was concerned with both the possible carcinogenic properties and the teratogenic properties" (24). �- 40 - Dr Harden recognized that in a climate which was already conductive to information bias "it would be most undesirable for a researcher who was going to undertake a study to do anything that would exacerbate or make worse the situation which existed at that time". However that is precisely what he did. Not only did he give newspaper interviews, appear on radio and television and pose for photographs, he also took part in public meetings and generally ensured that his work was put before the Swedish public. A number of criticisms of Dr. Hardell's studies have been advanced!. These include: 1) the inclusion within the studies of • the data which generated the hypothesis which the studies were intended to test; 2) information bias as a result of: a) selective recall by the cases because of the prevailing publicity and other factors including a preliminary phone call from Dr. Hardell; b) a difference in the completeness of the histories of exposure s of cases when compared with those of controls; c) interviewer bias arising out of the fact that the interviewers knew the purpose of the various studies; 3) inadequate and unsatisfactory exposure data; 4) methological problems arising from: �- 41 - a) the inadequacy of the instructions for the telephone interviewer; b) the form of the questionnaires which required only "Yes" of "No" answers and gave no opportunity for a "Don't know" reply or for explanations (25, 30, 31). c) the use of the Oncological Centre's letterhead and the requirement that the questionnaire be returned to the Centre at Umea: 5) the linking by the results of 12 different histological types of sarcoma with exposure -- a unique and improbable situation, the previous highest link being three (3) sites in human (See Palmer & Qrs v Stora Kopparbergs Bergs lags Aktiebolag at page 307) ; 6) the presence of confounding factors for which no adjustment was, or could on the available data be made. After a lengthy and careful examination of the evidence the Royal Commission concluded that "each of these criticisms is validly applied to Dr. Hardell's North Sweden Study and most of them also apply to his later studies". Dr. Hardell 1 s North Sweden Study was a case control study of 52 male patients aged from 26 to 80 years. Each had been diagnosed as suffering from soft tissue sarcoma and all had been treated at the Umea Oncological Centre between 1970 and 1977. Each case was matched for sex, age and town of residence with four (4) controls. Dr. Hardell then contacted all subjects by �- 42 - telephone. This was followed by a letter and a printed questionnaire (32,33). The letter was signed by Dr. Hardell and was on the letterhead of the Umea Onclogical Canter (24). The questionnaire was headed "Umea Regional Hospital Oncological Centre" (33). North Sweden is a fairly sparsely populated area and although Umea is a relatively small place (80-90.000 people) it is a centre for the north. Its hospital is a specialist hospital dealing with cancer and is the only such hospital in the north of Sweden. All soft tissue sarcomas would be referred to it and so its cancer section would be well known to the people of the region. Although a proper application of the principles of epidemiology requires that hypothesis generating data and hypothesis testing data be kept separate, Dr. Harden included the hypothesis generating cases in his North Sweden Study. There were 13 patients with soft tissue sarcoma included in the Study as exposed cases. At least six (6) of these were drawn from the seven (7) initial cases in the hypothesis generating material referred to in Dr. Hardell's clinical observations (21). The number drawn from the hypothesis generating data and included amongst the exposed cases in the study may well havebeen as high as eight (8) from the nine (9) cases referred to in his published clinical observations (21). �- 43 - Of the initial seven (7) cases who were clearly included in the Study onl} one (1), namely Case 3, was treated as unexposed. Thus six (6) out of 13 of the exposed cases, and possibly as many as eight (8) of such cases, were derived from the hypothesis generating data. In view of this the Royal Commision found that: "The first criticism of Dr. Hardell's studies is clearly justified in re]ation to the North Sweden Study". In addition to the publicity which preceded Dr. Hardell's North Sweden Study and his prominence in the debate which was then raging about phenoxy herbicides; every case "had already been if treated in the Department of Oncology at the University of Uinea, so the fact that the letter accompanies the questionnaire as well as the questionnaire itself were linked with the Oncological Centre at Umea is highly material. The questionnaire: a) specifically referred to Hormoslyr in question 10, 14 and 28; b) included seven (7) questions out of a total of 31 which were either concerned with the spraying of herbicide a herbicide; nominated �- 44 - c) contained 20 questions which expressely referred to exposure to some form of chemical or chemicals; d) included as its remaining questions, eight (8) which were concerned only with occupation or place o-f work, one (1) which dealt with medical details, one (1) which asked about cigarettes and one (1) at the end of the questionnaire, namely question V, which gave the subject an opportunity to add any "additional information", i An examination of the questionnaire clearly shows that its major concern was with exposure to chemicals, the emphasis being on herbicides, particularly Hormosylr (2,4,5-T). In the context of the then current controversy about 2,4,5-T the subject matter of the inquiry by Dr. Hardell would have been patent to anyone who received the letter and questionnaire and even more obvious to those who had been treated at the Onclogical Centre at Umea. Having regard to all these considerations it is perhaps not surprising that Dr. Hardell finally agreed that: "there could be a recall bias which probably is in our study" and that the Royal Commission decided that : "clearly information bias taints the study..." �- 45 - The question of exposure to phenoxy herbicides had been expressly raised with each of the patients referred to in the clinical observations (21) and the diagnosis of cancer and its associations with the patient's history of exposure discussed in detail with the patient. In taking the history the connection between the patient's cancer and its exposure to phenoxy herbicides was said to have been "probed". At least one of those initial cases "spontaneously told me (i.e. Dr. Harden) about his work as a forestry man and that he constantly talked about spraying within the occupation". No such probing or volunteering of association can be found in relation to the controls. Each questionnaire revealed the name of the relevant patient when it went out. Numbers were assigned to the cases only after interviews had taken place. The telephone interviewer (Miss Damber) had no written instructions in respect of the interview and Dr. Harden had no direct knowledge of her mode of questionning. It appears that she was not experienced in such studies. The exposure data relating to the cases included in the story were described by the Royal Commission as "both unsatifactory and inadequate". In the first instance the statement about exposure contained in the study says that: "Exposure to phenoxy �- 46 - acids of chlorophenol was admitted by 36.5% of the patient group..." (24). However, the words "phenoxy herbicides do not appear in the questionnaire. For the purposes of the Study exposure was defined by Dr. Hardell as including "working in a freshly sprayed moist area". However, whether a person had worked in such an area of1 had "wet contact" was not asked in the questionnaire (24). The only question which touched upon this subject was question 14 that asked whether a person had "worked in treated area". However Dr. Harden conceded that the answer to this question did not inform as to whether the area had been sprayed five minutes, five days or five months before the exposure had occurred. It is clear from the use of the seven (7) original cases referred to in the clinical observations (21) that no uniform approach to exposure was maintained (e.g. see above regarding Cases 6 and 7 in the clinical observations). In addition Dr. Hardell said that questionnaires were sent to the employers of all those cases and controls who had been working in forestry i.e. 50 persons in total (16) and "we could only get answers from twenty persons since c'ne employers did not keep the records". As a result the information was regarded by Dr. Hardell as "weak data and nothing I can set up on a scientific basis and argue about". �- 47 - Some of the data on which the North Swedish Study is based are included in a paper which was published in 1979 (l6). This paper is very revealing since the additional data relating to exposure and the substances involved can be analysed to some extent. It is not possible, however, to relate the numbers assigned to the cases in that publication with those assigned in Dr. Hardell's clinical observations (21). Dr. Hardell was unable to do this when he gave evidence and, although the material was going to be forwarded by him to the Royal Commission, it was not forthcoming. What is known is that at least six (6) of the original seven (7) cases and possibly as many as eight (8) of the initial nine (9) cases observed by Dr. Hardell were included as exposed cases in the North Sweden Study. The North Sweden Study contains details relating to the 13 soft tissue sarcoma cases who are said to have been exposed to phenoxyacetic acids, It. is worthwhile looking in more detail at six of these cases, namely Cases 160, 180, 390, 490, 510 and 520. In cross-examination it emerged that Case 390 had only two (2) days of exposure at some time between nine (9) and 19 years prior to diagnosis. This occurred while he was mist blowing with a chemical the nature of which was undefined but was perhaps 2,4-D. �- 48 - 2,4-D does not contain 2,3,7,8-TCDD. Case 160 was stated in the Study to have seven (7) days exposure 19 years prior to diagnosis. However, it emerged that the only information available about the exposure of this case was that he had worked as a supervisor and whilst so working he had either sprayed the material himself or had got it on himself or on his clothes. It should be noted that if only two (2) cases had been wrongly included in this sample the findings would not be statistically significant, i.e. the result depends on a claimed excess of only two (2) soft tissue sarcomas. Cases 390 and 160 could properly be treated as unexposed. In addition it is worthwhile looking at some of the cases who were included in the Study and to examine their latency periods: 1.- Case 180 was said to have had seven (7) days of exposure to MCPA alone at some time between 13 and 15 years before the study. MCPA does not contain 2,3,7,8-TCDD. 2.- Case 490 had a latency of between five (5) and 10 years. 3.- Case 510 had an exposure of five (5) months "somewhere between 3 and 9 years before the date of diagnosis". The maximum latency period for this case was thus nine (9) years, a period saic| to be "improbably short". �- 49 - 4.- Case 520 had a latency period which was between eight (8)and - 12 years, Thus in relation to the 13 "exposed" cases included in the Study the Royal Commission pointed out that: a)"at least six (6) and perhaps as many as eight (8) formed part of the hypothesis generating data; b) three (3) had either doubtful or minimal exposure; c) one (1) had a clearly inadequate latency and another one (1) of even two (2) had a latency period which was barely adequate." Dr. Hardell did not dispute that of the 13 cases included as many as eight of them could be cases he had referred to in his clinical observation and that in two (2) cases (Case 490 and 510) had a latency period significantly less than that usually attributed to soft tissue sarcoma and the same is probably true for Case 520. Thus even adopting a 10 years latency period, 10 or even 11 of the 13 cases could properly be excluded on grounds of wrong classification or as irrelevant to the question of causation. Looking at a best case (from Dr. Hardell's point of view) exclusions would not be fewer than: - six (6) because they formed part of the hypothesis generating data; �- 50 - - one (1) because of no real evidence of exposure to phenoxy herbicides; - one (1) with a latency period which was clearly inadequate. There are then only five (5) cases remaining if a 10 years latency period is adopted and fewer if a 15 year period is adopted. Five (5) cases would not give rise to a result which was statistically significant. If the proper principles of epidemiology were applied and the initial 7 (7) cases referred to in the clinical observations (2j) were excluded from the Study it was admitted by Dr. Hardell that the relative risk would fall "to something just below 3'! Dr. Hardell did not have material from which the precise figure could be calculated. However he offered to forward copies of relevant data to the Royal Commission. This was not done so his claim has not been able to be verified. The above reduction in the relative risk is achieved by eliminating only one (1) of the sources of error in the Study, namely the inclusion in the study of the hypothesis generating data. However, even the reduced figure is still influenced by the effects of subject recall bias, interviewer bias and the presence of confounding factors for which no adjustement has been made in the Study. �- 51 - Another matter which is worthy of note is that exposure to phenoxyacetic acids alone cannot be determined although Dr. Harden asserted in the report of his study that he had analysed "exposure to phenoxy acids alone" (24), and obtained a relative risk of 5.3 in relation to such exposure. It is apparent both from the Study itself and from Dr. Hardell's oral testimony that no such analysis was done. The study states that: "It is impossible... to assess the effects of the individual chemical substances separately since practically all patients may have been exposed to chlorinated dioxins as well, including tetrachlorodibenzodioxin (TCDD)... and also to other compounds" (24). In that part of Dr. Hardell's publication in which the results of the so-called analysis of "exposure to phenoxy acids alone" are set out (24) persons who had also been.-exposed to chlorophenols are included. In this context it should be remembered that Dr. Hardell claims that exposure to chlorophenols is associated with a relative risk for soft tissue sarcoma of 6.6, so such exposure constitutes a confounding factor of importance. Yet another consideration which is relevant to the accuracy or adequacy of the exposure data on which the study is based is the unsuccessful attempt to verify exposure to particular substances with employers, the results of which were: "uncertain �- 52 - and difficult to evaluate. Records of individual working manuals had not been kept, and the answers were mainly based upon reminescence. Replies from the employers were obtained for 20/50 persons involved" (14). Thus the exposure data for the 13 cases said to have been exposed to phenoxyacetic acids alone depend very much on the outcome of the interviews for which there were no written instructions and which were carried out by a lady who had had no a prior experience whatsoever in conducting interviews for epidemiological studies. An examination of the effect of interview on rejection of study subjects and on relative risk assessement (see Tables II and III below) reveals that the relative risk of the cases when compared with controls more that doubled after interview. There is also a marked disparity in the effect of interview on the percentage of controls rejected when compared with cases - nearly 4:1. Thus not only is there justification for the criticisms which assert that the circumstances gave rise to the possibility of interviewer bias, but Dr. Hardell's own later analyses provide material which, the Royal Commssion found "suggests that this, in fact occurred". All cases were given the suffix 0. Controls were given suffixes of 1, 2, 3 or 4. The consequence was that those classifying the subjects in the study "knew just by lookina whether a person was a case or a control" - yet another avenue for information bias. �- 53 - A preliminary classification of the subjects was carried out by Or. Hardell and his assistant and then discussed with others. These included Professor Axel son. The classifying process was carried out with knowledge of the numbers which had been assigned to the subjects who were to be classified, so "there was no question as to classification being blind" For some deceased subjects that fact that their next of kin who washed their clothing said that the clothes of the deceased smelt was sufficient to result in them being classified as exposed, The Study itself admits the presence of a number of confounding factors such as: diesel oil - about which there was insufficient information for a proper evaluation, and other pesticides - about which no information was available (\fc). It is relevant to the problem of confounding to note that Dr. Hardell conceded that none of the 13 exposed cases of soft tissue sarcoma in the study were exposed to phenoxyacetic acids alone. One of the 13 had high grade of exposure to chlorophenols and Dr. Hardell was unable to say how many had been exposed to organic solvents, but he conceded that a number had been and that no calculation whatsoever could be made about the effect of organic �- 54 - solvents because no data were available on them. It is interesting to note the limited conclusion to which Dr. Hardell came as a result of his North Sweden Study. These are set out in the Royal Commission Report. The Royal Commission noted these, commented upon the fact that Dr. Hardell was influenced by an anxiety to prove the integrity of his study and concluded that: "The North Sweden Study is open to criticism and... that is is rightly regarded as flawed and unacceptable as proof of the result claimed". 2.- The South Sweden Study Following the completion of his North Sweden Study, Dr. Hardell undertook an investigation into "the potential effects of MCPA, 2,4-D and the analogous phenoxy propionic acids" all of which were widely used in agriculture in the southern areas o£ Sweden (16) The study was commenced in February 1979 and;as in the case of the North Sweden Study, the data gathering took place in the spring, with the telephone interviews for this particular study ben conducted in May/June 1978. The study involved 110 patients diagnosed between 1974 and 1978 as suffering from 12 different types of soft tissue sarcoma (16). These were matched with 219 controls. �- 55 - The gathering of exposure data involved advance contact with people by telephone, then sending them a nine page questionnaire and later supplementing the information derived from the responses by means of selective telephone interviews of these respondents who had worked in agriculture, forestry or horticulture during the relevant period. In some instances (unspecified) the interviewer also contacted employers, neighbours and others "to elucidate possible exposure" (16). Exposure to phenoxy acids of less that one day was not considered nor was exposure within five (5) years before the year of diagnosis i.e. a latency period of only five (5) years was adopted. As an aside it is worth referring to the Swedish railway workers dealt with in thi's'Study - in relation to whom it is stated that: "the embankments of the Swedish State Railways have been sprayed mainly with amitrol, but pesticides including phenoxy acids have also been used. It is not possible to determine completely all the substances to which individuals had been exposed, despite contact with the people themselves, their workmates, or their employers. Therefore, railway workers who reported exposure to pesticides were regarded as unexposed to phenoxy acids". (16). This is to be contrasted with the approach adopted by Professor Axelson in his Study (A). �- 56 - Eighty five (85) of the 100 cases (i.e. 77,3%) were not exposed to any phenoxy acids of chlorophenols. Of the remaining 25, seven (7) are said to have been exposed to phenoxy acids other than 2,4,5-T and 11 to chlorophenols alone. This left only seven (7) cases who were exposed to 2,4,5-T as well as to other phenoxy acids and other known and unknown chemical substances, included amongstmwhich were organic solvents. Based upon these seven (7) cases and one control Dr. Harden calculated the point estimate of the relative risk of exposure to 2,4,5-T and other phenoxy acids as 17.0 (16). The Royal Commission regarded this as "an extraordinary figure" and "so far out of step as to lack credibility". Relative risks in the South Sweden Study (16) were stated to be as follows: - exposure to phenoxy acids or chlorophenosl: 53; - exposure to all phenoxy acetic acids: 6.8; - exposure to all phenoxy acetic acids excluding 2,4,5-T: 4.2; - exposure to chlorophenols alone: 3.3. An examination of a different print of South Sweden Study (15) is revealing. It includes material which does not appear in versions of the same study published elsewhere (11 - 16). �- 57 - In the publication under examination (15) Dr. Hardell concedes that "when exposure data are collected via questionnaires and interviews a certain possibility exists that the cases will have a greater interest in the questions than the healthy controls do". This concession is not included in later published versions of the Study. Also, for a reason which is unexplained, the results reported in the two versions differ. Thus in Table 6 to reference 15 the relative risk amongst agriculture/ forestry workers exposed to phenoxy acids is calculated at 6.4 based upon 13 cases and five (5) controls. On the same data i.e. 13 cases and five (5) controls, a relative risk of 5.7 is reported in Table 7 of reference 16. The very conclusion of the study would seem to reflect a concern, even a reservation, on the part of Dr. Hardell about the accuracy of the results because, despite the high relative risk reported, the conclusion is expressed in very guarded terms: "this investigation has indicated that exposure to phenoxy acids and chlorophenols might constitute a risk factor in the development of soft tissue sarcomas" (13). Except for the fact that no hypothesis generating data were included in the South Sweden Study, the problems with and criticisms which can be levelled at it are similar to those dealt with in relation to the North Sweden Study. In addition, �- 58 - the media publicity which the North Sweden Study attracted in Sweden is likely to have accentuated the problem of information bias. Having examined the South Sweden Study and the author's testimony about it, the Royal Commision was of the view that the study "has properly been widely regarded as flawed, unacceptable as proof of the results claimed and such that it cannot be taken at face value" 3.- The Maiignant Lymphoma Study In January 1979 Dr. Hardell published his preliminary clinical findings relating to 17 male patients who were suffering from malignant lymphoma (2*2.). As a result of the findings he undertook his third study, the Malignant Lymphoma Study. In it Dr. Hardell deals with 169 patients aged between 25 and 85 who were diagnosed in the period from 1974 to 1978 . <«» &u$Wr«£ from either Hodgkin's Disease or non-Hodgkin's lymphoma. The cases included the 17 patients referred to in the preliminary findings who formed the group from which the hypothesis to be tested was generatepf(22), Cases were matched for sex, age, place of residence and year of death with a total of 338 controls. �- 59 - Information about exposure to various chemicals including organic solvents, chlorophenols and phenoxy acetic acids was obtained by questionnaire. However, there were severe problems about identifying the substances to which any individual had been exposed. Indeed Dr. HardeH conceded in cross-examination that he could not present any separation of figures which showed the number of cases exposed to phenoxy acid alone. On Dr. Harden's analysis of the data the relative risk for exposure to phenoxy acetic acids or chlorophenols was 6.0', to phenoxy acetic acids 4.8 and to chlorophenols 4.6 (18). However, in view of the concession-above it is difficult to understand how the relative risk of 4.8 was calculated, or to know what it really means. A fivefold increased risk of malignant lymphoma was found for those exposed to phenoxy herbicides and chlorophenols. The increased risk for those with high grade exposure to chlorophenols was eightfold and threefold for those with low grade of exposure . An increased risk was also found for those exposed to organic solvents. The study did not reveal any difference between the risk of Hodgin's Disease and non-Hodgkin's lymphoma despite the fact �- 60 - that Hodgkin's Disease seems to occur in two peaks, one affecting the young and one affecting the old and there is thought to be some viral; association in the etiology of Hodgkin's Disease, at least as far as the younger group is concerned. Whilst the etiologies of Hodgkin's Disease and non-Hodgkin's lymphoma appear to be different, Dr. Hardell (18) does not differentiate between the two. He groups them together and, in addition, includes lymphomas which are unclassifiable. At page 10 of reference 18 it is stated that "exposure to phenoxy acid was analysed separately excluding all persons who had high grade exposure to chlorophenols". However, this is just not correct, because Dr. Harden agreed in crossexamination that a number of them may have been exposed to low grade chlorophenol and five (5) of them had been exposed to high grade chlorophenol. Table 3 to reference 18 had a heading which was held by the Royal Commission to be "inaccurate and misleading". It reported on cases and controls exposed to phenoxy acids after those exposed to chlorophenols were excluded. However a number of the persons included in the Table had low grade exposure to chlorophenols and five (5) had high grade exposure. �- 61 - Thus the relevant data is not looking at those cases which were exposed only to chlorophenols. It includes cases who were exposed to phenoxy acids, fourteen (14) who were exposed to a low level of chlorophenols and five (5) instances of exposure to a high level of chlorophenols. Dr. Hardell was also asked about the subdivision of cases as reported in label 5 to reference 18 . That table is headed "Exposure to organic solvents in cases and controls after matching was dissolved and those exposed to phenoxy acids (F) or with high grade exposure to chlorophenols (K) were excluded, assuming there was no joint exposure". Exposure to organic solvents was characterized as low grade (1) and high grade (2). In Table 5 there are 23 cases who had both phenoxy acid exposure and high grade chlorophenol exposure. Dr. Hardell could not say how many cases were exposed just to phenoxy acids and nothing else. This was despite the fact that Dr. Hardell "set out in this paper to examine the relationship between phenoxy acid exposure and lymphoma". In addition, he did not publish a figure in respect of phenoxy acid exposure alone. He said in his testimony that he had carried out such an analysis but that he had no submitted it for publication. The result was not produced to the Royal Commission although Dr. Hardell was afforded an opportunity to do so. His published conclusion �- 62 - namely: "The present investigation... suggests... that exposure to organic solvents, chlorophenoly and/or phenoxy acids constitutes a risk factor for the incidence of malignant lymphoma", certainly gives no scientific support for the proposition that phenoxy acetic acids cause malignant lymphoma. It can thus be seen that not only is the Study misleading in the form in which some of its data are presented but there are also very serious, multiple confounding factors which have not (and cannot) be adjusted for. The Study is also subject to the same criticisms as the North Sweden Study, including the fact that hypothesis generating data were used in it. No one has been able to replicate the findings in Dr. Harden's studies relating to soft tissue sarcoma and malignant lymphoma and the results of his three studies are contrary to the findings obtained by others. This absence of replication, the absence of specific outcome (i.e. 12 types of soft tissue sarcoma, non Hodgkin's malignant lymphoma and Hodgkin's Disease), admitted information bias, the presence of significant confounding factors which are not adjusted for, the unrealibility of the exposure data and the other factors detailed above led the Royal Commission to conclude that "the statistical associations asserted by Dr. Hardell are suspect" and that it could not "accept them as �- 63 - supporting an inference of causal connection between soft tissue sarcoma, malignant lymphoma and exposure to phenoxy herbicides". 4.- The Nasopharyngeal Cancer Study In 1981-82 in conduction, inter alia with Professor Axelson, Dr. Hardell undertook a case-control study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. The Study (('•J) dealt with 71 patients (being 44 cases of nasal cancer and 27 of nasopharyngeal cancer) who were aged between 25 and 85 years, who had been reported to the Swedish Cancer Registry in the years 1970-1979 and who were resident in the three most northern counties of Sweden at the time of diagnosis. These cases were matched with 541 controls. A questionnaire which was identical with that used in previous studies was sent to the cases, or the next-of-kin of deceased cases. It is claimed by Dr. Hardell that the Study in question "follows the methodological design" of the previous studies undertaken by him. The controls had been used in earlier studies in North Sweden, but no further contact was made with them for the purposes of this Study. On analysis of the data "no significant association was found" between the cancers of interest and phenoxy herbicides �- 64 - Dr. Hardell claimed that this Study could be used as a verification of previous studies. However, despite the assertion that this and previous studies used the same procedures, there are a number of differences between the procedures for the Nasopharyngeal Cancer Study and those used in Dr. Hardell 's earlier studies. In the Nasopharyngeal Cancer Study: a) no contact was made by telephone with the cases before they received the questionnaire; b) there was no publicity linking phenoxy herbicides and nasal cancer at the time the study was undertaken and the debate about phenoxy herbicides had no doubt abated with the banning of 2,4,5-T in 1977; c) no hypothesis generating cases were included amongst the cases examined in the Study; d) the interviewer who made telephone contact with the cases was "blind", since the questionnaires for this study were mixed with identical questionnaires from the Colon Cancer Study The existence of differences in the procedures adopted for this Study means that it cannot be used as a verification of the earlier studies. The fact that a negative result was obtained in relation to exposure to phenoxy herbicides may even be �- 65 - regarded as further evidence supporting the criticisms advanced in respect of Dr. Hardell's first three (3) studies. It is also of interest to note that, contrary to what had been done by Professor Axelson in his study of Swedish Railway workers, employees of the Swedish Railways who were reported as exposed to pesticides: "were considered unexposed to phenoxy acids, since the type of preparation could not betstablished with certainty". In summary therefore it can be said that the Nasopharyngeal Cancer Study not only produces a negative result in relation to phenoxy herbicide exposure but it may even reinforce the criticisms of Dr. Hardell's earlier studies. 5.- The Colon Cancer Study The Colon Cancer Study (l2>) Involved 157 male colon cancer patients who had been extracted from the Swedish Cancer Registry and were resident in northern Sweden. Each was sent a questionnaire and interviewed. The group which had been used as a control group for the studies previously carried out by Dr. Hardell in relation to soft tissue sarcoma and malignant lymphoma was used as the control group for this �- 66 - study, but not further contact was made with the controls. The results show no difference in the incidence of colon cancer amongst those exposed to phenoxy acids and it is argued by Dr. Hardell that this verifies that there was no information bias in his earlies studies. There are, however, differences in the methodology for the Colon Cancer Study when compared with the earlier studies. For example the cases were not telephoned by Dr. Hardell before they receive a questionnaire,'the interviewer did not have knowledge either of the object of the Study or of the classification of patients (as the interviewer in the previous studies had) and there had been no publicity linking colon cancer with phenoxy herbicides. In the course of his testimony, Dr. Hardell was shown a document which had been produced by him in Washington in the 1980 EPA proceedings as a true analysis of his previous studies. This document shows that before interviews were conducted: - in the North Sweden Study, 28.8% of the 52 cases of soft tissue sarcoma (i.e. 15 cases) had originally been classified as exposed and 13.6% of the 206 controls (i.e. 28 controls) had been so classified; - in the South Sweden Study, 16.4% of the 110 cases of soft tissue sarcoma (i.e. 18 cases) had been classified as exposed and 4.6% of the 209 controls (i.e. 10 controls) had been so classified; �- 67 - - in the Malignant Lymphoma Study, 24,9% of the 169 cases of soft tissue sarcoma (i.e. 42 cases) had been classified as exposed and 11% of the 335 controls (i.e. 37 controls) had been so classified. After interview 13 cases and 14 controls classified as exposed remained in the North Sweden Study,. In the South Sweden Study 14 cases and a mere five (5) controls remained after interview. In the Malignant Lymphoma Stdy 41 cases remained after interview but only 24 controls. These results are set out in label II below. TABLE II EFFECT OF INTERVIEW ON REJECTION OF STUDY SUBJECTS North Sweden STS Study South Sweden STS Study Malignant Lymphoma Study Controls - Before Interview „„ 10 37 Controls - After Interview ,. 5 24 Reduction Cases - Before Interview Cases - After Interview Reduction Comparative) Effect of ) interview ) Controls ) v. ) Cases ) 50% 35% 50% 15 18 42 13 14 41 13% 3.8:1 22% 2.27:1 2.1% 16.66:1 �- 68 - The differential effect of the interview on cases and controls is both obvious and telling. At the very lowest, it "is at least suggestive of interviewer bias" as the Royal Commission put it. A comparison of documents tendered to the Royal Commission shows that the percentage of exposed cases in the Malignant Lymphoma Study in the former version is 24.9. However, in a later one it is shown as 27.2% (13). When this difference was pointed out to Dr. Hardell he said that this change had taken place after he had been cross-examined in the EPA proceedings and that the change was effected because he "must have overlooked some exposure (sic) ones which he had not noticed before". Dr Hardell then conceded that by changing that figure he had built up the relative risk from 2.7 to 3. That such a mistake should have had escaped not only him but also the four people who had gone through the data concerning the Malignant Lymphoma Study is curious to say the least. Dr. Hardell explained the difference by saying that "different criteria for exposure were discussed. The first part says all phenoxy acid exposure and that means exposure that has been notified somehow in the questionnaire or by interviews, but during the evolution of the exposure it has turned out that these people are not exposed". �- 69 - However, when pressed on his answer he admitted that this explanation was wrong since th,e document in question was dealing with information derived from questionnaires alone, unadjusted by any value judgements made in the assessement process and unaffected by the results of the interview i.e. not taking into account the effect of interview. When data derived from the questionnaires alone are used, a point estimate for the relative risk revealed by the study is 2.6 compared with 5.3 when the effects of ther interviews are taken into account. If for each of Dr. Hardell's first three (3) studies a comparison is made between the point estimates obtained using data from the questionnaire alone and the point estimates obtained when the effects of the interviews on the data are taken into account, the relative risks are: 2.6 for the North Sweden Study - compared with 5.3 as published; 4.1 for the South Sweden Study - compared with 6.8 as published; 2.7 for the Malignant Lymphoma Study - compared with 4.8 as published. If the data are changed in the way which a comparison of tendered documents reveals, the figures becomes 3 compared with 4.1 for the Malignant Lymphoma Study. �- 70 - TABLE III RELATIVE RISKS - EFFECT OF INTERVIEW North Sweden South Sweden STS Study STS Study Malignant Lymphoma Study RR* - Before Interview 2.6 4.1 2.7 RR - After Interview 5.3 6.8 4.8 Increase in RR following Interview 103.8% 65.8% 77.1 *Relative Risk (References 21, 34, 18, 20) When Dr. Hardell was cross examined on Table I of the Colon Cancer Study, the heading to which is "Exposure Frequencies to Phenoxy Acids", he conceded that these cases were not exposed only to phenoxy acids but some cases also had exposure to chlorophenols and organic solvents. At this point it is relevant to return to the 13 exposed cases of soft tissue sarcoma included in the North Sweeten Study. Dr. Hardell agreed that none of the cases were exposed to phenoxy acids only. One of them in fact had high grade chlorophenol exposure and there was an unknown number who had low grade chlorophenol exposure and whilst Dr. Hardell was unable �- 71 - to say how many were exposed to organic solvents, he agreed that some of them were. Although Dr. Hardell claimed that organic solvents had been / excluded from the analysis of the North Sweden Study (>M) when he was asked to clarify this he referred to a passage at page 715 of reference 12 . However, this passage makes no reference to organic solvents. When this was pointed out to Dr. Hardell he said they were included "with the emulsifiers which contain organic solvents In the end, however, he conceded that organic solvents had not been dealt with in the paper . It is also clear from Dr. Harden's cross-examination that the heading to Table IV in the North Sweden Study (11) is not accurate when it refers to exposure to "phenoxy acetic acids only" since the persons included under that heading were exposed to chlorophenols and to organic solvents as we!1. It is not possible to make any calculation about or allowance for the confounding effect of exposure to organic solvents. Dr. Hardell was then asked about information bias as a result of which response from the subject may be inaccurate and differ between case to control and he said that the existence �- 72 - Of a controversy and of publicity may have influence on the interviewer with consequent difference in classification of the cases. This interview could influence the result and lead to a distortion in the risk ratio. 5) Inconsistencies between Axelson and Hardell a) Hardell claims that there is an increased risk of soft tissue sarcoma and malignant lymphoma both of the Hodgkins and non-Hodgkins types from exposure to pehnoxy herbicides. In Axel son's work there were no cases of soft tissue sarcoma or of non-Hodgkin's lymphoma found and only one case of Hodgkin's Disease. b) It is claimed that Hardell's work indicates specificity in the type of tumor produced by phenoxy herbicide exposure namely, soft tissue sarcoma and malignant lymphoma. However, in his update Axelson concludes that: "no specific type of tumor can be considered as predominating". (3) c) Hardell asserts relative risks in excess of 4 for the association of cancer and phenoxy herbicide exposure. In Axelson's first analysis nis finding in relation to the "phenoxy acids and combination" subcohort wasqs. close to a negative as one can get. In his re-analysis, even when �- 73 - the exposure classification was changed for two (2) cases so as to produce an excess of tumors observed over those expected in the subcohort exposed to phenoxy acids and combinations, the relative risk was still only 1.6 and not statistically significant. In his update the relative risk when properly determined (i.e. with exclusion of wrong diagnoses, adoption of a ten years latency period and using the data detailed in Table I to reference 3> ) lies close to unit and is certainly not statistically significant. Thus far from supporting Dr. Hardell, Professor Axelson's work and his conclusions are different from and, destructive of Dr. Hardell's conclusions. The Axel son Technique Both Dr. Hardell and Professor Axel son sought to rely upon a mathematical calculation undertaken by Professor Axel son in an endeavour to demonstrate that the procedures adopted by Dr. Hardell in his early studies did not give rise to information bias (35, 36). Dr. Hardell was asked about the Axelson Technique and from his cross examination on this topic �- 74 - it emerged that the Axel son technique depends upon a number of assumptions: 1) both cases and controls will have like recall on the subject of exposure and such recall will be accurate; 2) the classification of workers into categories of agriculture and forestry (AF) on the one hand and other occupations (0) on the other hand is accurate; 3) there will be an equality of incidence in the soft tissue sarcoma amongst the unexposed members of the AF group and the 0 unexposed members of the group; 4) there is no other factor which operates in one group and does not operate in the other. It would seem that the technique assumes the result sought to be proved. Certainly, as Professor Allan Smith pointed out "there seems to be little basis for the assumption that there would be differential recall as between cases and controls". In addition Professor Smith stated that it is possible on a theoretical, i.e. mathematical basis "that diminution due to recall bias in the proper number of unexposed cases employed in agriculture or forestry could be compensated for and masked by an increased incidence of the disease amongst the workers in agriculture or forestry not exposed to phenoxy herbicides but exposed to other �- 75 - environmental factors prevalent in their industry". Professor Smith also expressed the view that there was "little value to be found in the application of the Axelson technique especially in relation to the South Sweden Study" and that such technique was "not a reliable indicator of the absence of recall bias in that Study". This view was accepted by the Royal Commission. CONCLUSION The conclusion of the Royal Commssion in relation to the Hardell studies is worth setting out verbatism since it is in marked contrast to the way in which one statutary agency in the United States has recently dealt with in the same studies: "...absence of replication, the absence of specific outcome (i.e. 12 types of soft tissue sarcoma, non-Hodgkin's malignant lymphoma and Hodgkin's Disease), admitted information bias, the presence of significant confounding factors, the unreliability 1 of the exposure data and the other factors detailed above all indicate that the statistical association asserted by Dr. Hardell are suspect. TheCommission cannot, on the balance of probability, accept them as supporting an inference of causal connection between soft tissue sarcoma, malignant lymphoma and exposure to phenoxy herbicides." �- 76 " . . . the Commission does not accept the Hardell studies as proving, on the balance of probabilities, any causal association between Soft Tissue Sarcoma and Lymphoma and exposure to 2,4-D, 2,4,5-T, and TCDD." The conclusion of the Australian Royal Commission in relation to the Hardell studies is congruent with the judicial conclusions reached in relation to those same studies in the United States in the Agent Orange Product Liability Litigation (Gibbs et al. versus Dow et al.: U.S. District Court, Eastern District of New York MDL 381/14; 1985, Weinstein C.J.) and in Canada in the forest spraying litigation (Palmer & Ors versus Stora Kopparbergs Bergslags Aktiebolag trading as Nova Scotia Industries, 1983, 60 Nova Scotia Reports, 2d, 271; Nunn J.). It is also significant that others have not confirmed Dr. Hardell's findings. The epidemiologic studies on soft tissue sarcoma and cancer risk among agricultural and forestry workers as well as factory workers with exposure to the relevant herbicides or their manufacturing processes which have been carried out in Sweden (42,43,44), in Finland T45, 46), in New Zealand (47,48,49,50,51), in the United States of America (52,53,54,55,56,57,58,59,60,61,62,63,64) and in the United Kingdom (65,66,67,68,69) have not confirmed Ilardell's results. The Hardell Studies should now be laid to rest. Perhaps an appropriate epitaph is that written by the eminent epidemiologist Sir Richard Doll, of Green College, Oxford. In a letter (70) written to Hon. Mr. Justice Philip Evatt, the Australian Royal Commissioner, on December 4, 1985, he gave his view on Hardell's studies as follows: "your review of Hardell's work with the additional evidence obtained directly from him at interview shows that many of his published statements were exaggerated or not supportable and that there were many opportunities for bias to have �- 77 - been introduced in the collection of his data. His conclusions cannot be sustained, and, in my opinion, his work should no longer be cited as scientific evidence." �-73LIST OF REFERENCES 1 AXELSON, 0. and Sundell, L. Herbicide Exposure. Mortality and Tumor Incidence. An Epidemiological Investigation On Swedish Railroad Workers. Work Environ. Health. Vol. 11 (1). 1974; pp 21-8. 2 AXELSON, 0. and Sundell, L. Phenoxy Acids and Cancer. Translated for EPA and revised in accordance with comments by Dr. Axelson. Lakartidningen. Vol 74. 1977. pp 2887-8. 3 AXELSON, 0. et al. Herbicide Exposure and Tumor Mortality: An Updated Epidemiological Investigation oh Swedish Railroad Workers. Scand. Jnl. Work Environ. Health. Vol. 6 (1). Mar. 1980; pp 73-79. 4 AXELSON, 0. Sweden. Document. Document Digest 1974 Railroad Workers Study 1974. 23 pages. 5 Axelson, Olav. Curriculum Vitae & List of Publications 13.8.84, 9 pages. AXELSON, 0. EPA Transcript. In the Matter of the Hearing-of 2,4,5-T and Silvex. The Dow Chemical Company, et al. 7.7.80. Washington pp 8821-9100 and Appendices. Evidence of Prof. Olav Axelson. R.C. Transcript 3375 and see for example FOLKBLAD. Copy of Swedish Newspaper No. 190. Torsdag 18 August 1977 and English translation labelled Clipping 9. Umea doctor with the cancer report. 2 pages. See reference 1 at p. 21 and see for example FOLKBLADET. Copy of Swedish Newspaper. Torsdag 18 August 1977 and English translation labelled Clipping 10. The doctor who investigates the cancer cases. 4 pages. AXELSON, 0. Sweden. Questionnaire in Swedish to all railroad workers in the cohort under study headed "Document Digest" 4 pages. (i) �-79- 10 11 AXELSON, 0. Sweden. Document Digest 1974. Railroad Workers Study, 1974. 23 pages. ERIKSSON, M. et al. Soft-tissue Sarcomas and Exposure to Chemical Substances: a Case Referent Study. British Journal of Industrial Medicine, Vol. 38, 1981: pp 27-33. 12 HARDELL, L. & Sandstrom, A. Case-Control Study: Soft Tissue Sarcomas and Exposure to Phenoxyacetic Acids or Chlorophenols. British Jnl of Cancer 1979. Vol. 39 pp 711-717. 13 HARDELL, L. Relation of Soft Tissue Sarcoma, Malignant Lymphoma and Colon Cancer to Phenoxy Acids, Chlorophenols and other Agents.Scandinavian Jnl. of Work, Environment & Health. Vol 7, 1981 pp 119-130. 14 ERIKSSON, M. et al. Soft-Tissue Sarcomas and Exposure to Chemical Substances: A Case Reference Study. British Jnl. of Industrial Medicine, Vol. 13, 1981. pp 27-33. la ERIKSSON, M. Hardell, L. Ber<j, N.O. MolU-r, T. Axelson, 0. Case Control Study on Malignant Mosoncliyiiial Tumors of Soft Tlssuo and Exposure to Chemical Substances translated for EPA. Originally in Ukartdningen Vol, 76, 1979. |jp 3872-75. 16 HARDELL, L. et al. Malignant Lymphoma and Exposure to Chemicals, especially Organic Solvents, Chlurophenols and Phenoxy Acids: A Case-Control Study. British Jnl. of Cancer 1981. Vol 43. pp 169-176. 17 18 19 HARDELL, L. et al. Malignant Lymphoma and Exposure to chemicals especially Organic Solvents, Chlorophenols and Phenoxy Acids. Case Control Study in Br. Jnl. of Cancer Vol. 43, 1981, pp 169 HARDELL, L. et al. Malignant Lymphoma and Exposure to Chemical Substances especially Organic Solvents, Chlorophenols and Phenoxy Acids in Lakartidningen Vol. 77 (4), 1980. pp 208-210. HARDELL, L. et al. Epidemiological Study of Nasal and Nasopharyngeal Cancer and their Relation to Phenoxy Acid or Chlorophenol Exposure. American Jnl of Industrial Medicine 3, 1982. pp 247-257. �20 HARDELL, L. On the Relation of Soft Tissue Sarcoma, Malignant Lymphoma and Colon Cancer to Phenoxy Acids, Chlorophenols and other Agents. Scand. J. Work Environ. Health 7; 119-130; 1981. HARDELL, L. Clinical Observations regarding Malignant Mesenchymal Tumors, in Lakartidningen (the Doctor's Journal) No. 33 of 1977 pp 2753-2754 (Study 1 in Green Book). 21 22 HARDELL, L. Malignant Lymphoma of Histiocytic Type and Exposure to Phenoxyacetic Acids of Chlorophenols. Lancet, Vol. 1 (8106) January 1979: pp. 55-56 23 HARDELL, L. Epidemiological Studies on Soft-Tissue Sarcoma and Malignant Lymphoma and Their Relation to Phenoxy Acid of Chlorophenol Exposure. Umea, Univ. Press, 1981. 139 pages. 24 HARDELL, L. & Sandstrom A. Malignant Tumors and Exposure to Phenoxy Acids of Chlorophenols (Case Control Study). Br. J. Cancer: 39; 711-17; 1979. 25 26 SWEDEN. Swedish Telex of 16.8.77 - Stockholm 27 SWEDEN. Newspaper. Vasterbottens-Kuriren, 18.8.77. Undersokningen Pekar pa Samband Men ar Inget Bevis. 28 FOLKBLAD. Copy of Swedish Newspaper No. 190. Torsdag 18 August 1977 and English translation labelled Clipping 9. Umea doctor with the cancer report. 2 pages. 29 FOLKBLADET. Copy of Swedish Newspaper. Torsdag 18 August 1977 and English translation labelled Clipping 10. The doctor who investigates the cancer cases. 4 pages. �• 31 AXELSON, 0. Umea Regional Hospital, Northern Sweden Questionnaire B. Undated 12 pages. 32 AXELSON, 0. Umea Regional Hospital, Northern Sweden, Questionnaire A, Undated 11 pages. 33 SWEDEN. Oncology Centre. Questionnaire in Swedish from Regionsjukhuset I Umea (Northern Sweden). Undated. 8 pages. 34 ERIKSSON, M. Hardell, L. Berg, N.O. Holler, T. Axel son, 0. Case Control Study on Malignant Mesenchymal Tumors of Soft Tissue and Exposure to Chemical Substances translated for EPA. Originally in Lakartdningen Vol. 76, 1979. pp 3872-75. 35 AXELSON, 0. Some comments on the Swedish Experiences from Studies of Cancer and Exposure to P.henoxy Acid Herbicides and Chlorophenols - largely an extension and updating of a presentation by 0. Axel son, Hardell at a conference on Health Hazards of Chlorophenols in Vancouver, May 16-17, 1984. 25 pages 36 37 AXELSOH, 0. A case-referent epidemiology. Environmental note on observational bias in studies in occupational health Scandinavian Jnl. of Work & Health 6, 1980, pp 80-82. Smith A.H.: Outline of additional testimony of 25.9.1984. 6 pages. (iv) �-82- 38.r Cole, P. Direct testimony of Dr. Philip Cole Before the Environmental Protection Agency of the United States of America. In Re: The Dow Chemical Company, et al, FIFRA Docket Nos. 415, et al. (Exhibit 860) Appearance Date: November 6, 1980. 39.- Anonymous. Further review of the safety for use in the U.K. of the herbicide 2,4,5-T, Advisory Committee on Pesticides, Ministry of Agriculture, Fisheries and Food (December 1980). 40.- Rt. Hon. Peter Walkers, M.P., Minister of Agriculture, Fisheries and Food, In: Advisory Committee on Pesticides; Report on Phenoxy Acid Herbicides. London: Ministry of Agriculture, Fisheries and Food, February 7, 1983. 41.- Cook, R.R. Soft Tissue Sarcomas: Clues and Caution. Tucker, R.E., Young, A.L. and Gray, A.P., Eds. Human and Environmental R|sks of Chlorinated Dioxins and Related Compounds. New York: Plenum, 1983. pp. 613-618. 42.- Eklund G.: Does occupational exposure to chemical pesticides increase the risk of cancer. Weed and plant protection conferences. Uppsala, Sweden, 1983. pp 6-12. 43,-Wiklund K, and Holm I.E.: Soft Tissue Sarcoma risk in Swedish agricultural and forestry workers. Journal of National Cancer Institute. In press. 44.- Stenbeck G., and Wiklund K.: Multiple myeloma in Swedish agricultural workers. Int. Journal of Epidemiology. In press. 45.- Riihimaki, V., Asp, S, and Hernberg, S. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid herbicide applicators in Finalnd. Scandinavian Journal of Work Environment and Health 8:37-42, 1982 46.- Riihimaki, V., Asp, S., Pukkala, E. and Hernberg, S. Mortality and cancer morbidity among chlorinated phenoxyacid applicators in Finland. Chemosphere, Vol. 12. No. 4/5. pp. 779-784, 1983! 47.- Smith A.H., Fisher D.O., Giles H.J. and Pearce N.: The New Zealand Soft Tissue Sarcoma Case-Control Study: Interview Findings Concerning Phenoxyacetic Acid'Exposure. Presented at 3rd International Symposium on Chlorinated Dioxins and Related Compounds, October 12-14, 1982, Salzburg, Austria. �-8348.- Smith A.H., Fisher D.O., Pearce N.E. and league C.A.: Do Agricultural Chemicals Cause Soft Tissue Sarcoma? Initial Findings of a Case-Control Study in New Zealand. Community Health Studies 6: 114-119, 1982. 49.- Smith A.H., Pearce N.E., Fisher D.O., Giles H.J., league C.A.: Soft Tissue Sarcoma and exposure to phenoxy herbicides and chlorophenols in New Zealand. I.N.C.I. 73; 1111-17, 1984. 50.- Smith A.H., Pearce N.E.: Update on Soft Tissue Sarcoma and Phenoxy herbicides in New Zealand. 5th International Symposium on chlorinated dioxins and related compounds. Septmber 16-19, Bayreuth, F.R.G., 1985. v 51.- Pearce N.E., Smith A.H., Howard J.K., Giles H.J.: Case Control Study of non Hodgkin's Lymphoma and exposure to phenoxy herbicides, chlorophenol, fencing work and meat employement. British Journal of Indutrial Medicine. In press. 52.- Zack J.A. and Suskind R.S.: The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process. Journal of Occupational Medicine 1980: 22:11-14. 53.- Ott M.G., Holder B.B. and Olson R.D.: A Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5'Trichlorophenoxyacetic Acid. Journal of Occupational Medicine 1980; 22:47-50. 54.- Cook R.R., Towsend J.C. and Ott M.G.: Mortality.Experience of Employees Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Journal of Occupational Medicine 1980; 22:530-532. 55.- Zack J.A. and Gaffey W.R.: A Mortality Study of Workers Employed at the Monsanto Company Plant in Nitro, West Virginia. Environmental Science Research 1983; 26:575-591. 56.- Suskind R.R.: Long Term Health Effects of Exposure to 2,4,5-T and/or its Contaminants. Chemosphere, Vol. 12 No. 4/5, p 769, 1983). 57.- Cook R.R. and Cartnill J.B.: Soft Tissue Sarcoma and Dioxins. Putting the data onto perspective. Symposium on public health risk of dioxin. October 19-20, 1983, New York, N.Y. 58.- Fingerhut M.A., Halterin W.E., Honchar P.A., Russel W.O.: Review of exposure and pathology data for seven cases reported as soft tissue sarcoma among persons occupationally exposed to dioxin-contarninated herbicides. Symposium on public health risks of the dioxins. October 19-20, New York, N.Y. (vi) �59.- Fingerhut M.A., Halperin W.E., Honchar P.A., Smith A.B., Groth D.H., Russel W.O.: An evaluation of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States. Scand. J. Work Environ Health 1984; 10(5): 229-303. 60.- Milham S.J.: Herbicides, Occupation and Cancer. Lancet 1; 1464-65, 1982. 61.- Zack J.A. and Suskind R.R.: The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident. Journal of Occupational Medicine 22: 11-14, 1980. 62.- Cook R.R., Towsend J.C., Ott M.G. and Silverstein L.G.: Mortality Experience of Employees Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Journal of Occupational Medicine 22: 530-532, 1980. 63.- Cook R.R.: Dioxin, Chloracne and Soft Tissue Sarcoma. Lancet 1: 618-619, 1981. 64.- Zack J.A. and Gaffey W.A.: A Mortality Study of Workers Employed at the Monsanto Company Plant in Nitro, West Virginia. Tucker R.E., Young L.A. and Gray A.P., Eds. Human and Environmental Risks of Chlorinated Dioxins and Related Compounds. New York: Plenum, 1983. pp. 575-591. 65.- Balarajan R., Acheson E.D.: Soft tissue sarcomas in agriculture and forestry workers. Journal of Epidemiology and Community Health 1984; 38:113-116. 66.- May G.: TCDO: A Study of Subjects 10 and 14 years After Exposure. Chemosphere, Vol. 12, No. 4/5, pp 771-778, 1983. 67 Coggon D. Acheson E.D.: Do phenoxy herbicides cause cancer in man? Lancet: 1; 1057-1059; 1982. 68 Gallagher R.P. Threlfall N. J.: Cancer and occupational exposure to chlorophenols. Lancet 11; 48; 1984. 69 Olsen J.H. Mbller Jensen 0.: Nasal cancer and chlorophenols. Lancet 1 1 ; 47-48; 1984. 70 Doll Richard: Director, Imperial Cancer Research Fund, Cancer Epidemiology and Clinical Trials Unit, Green College, Oxford, U.K.; Letter to Hon. M. Justice Philipp Evatt, Australian Royal Commission on the use and effects of chemical agent on Australian personnel in Vietnam. Page of this volume. � 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. 1497 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 O'Keefe, Barry Title A name given to the resource Typescript: Chapter 7: Soft Tissue Sarcoma: Law, Science and Logic, An Australian Perspective Subject The topic of the resource AVHS 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. 075 Folder The folder containing the original item. 1942 Series The series number of the original item. Series III Subseries IV 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 Nairn, Jean Evelyn Harding Description An account of the resource <strong>Corporate Author: </strong>Commonwealth Institute of Health, University of Sydney, Australia Date A point or period of time associated with an event in the lifecycle of the resource 1983-07-01 Title A name given to the resource Australian Veterans Health Studies: Pilot Study Report, Volume II: An Analysis of the medical findings and morbidity in the Pilot Study Subject The topic of the resource veteran health and hygiene AVHS 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. 038 Folder The folder containing the original item. 0858 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 Lee, Charles Source A related resource from which the described resource is derived The Medical Journal of Australia Date A point or period of time associated with an event in the lifecycle of the resource June 30 1979 Title A name given to the resource Dioxin (Dilemma)? Subject The topic of the resource dioxin AVHS herbicide regulation 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. 070 Folder The folder containing the original item. 1888 Series The series number of the original item. Series III Subseries IV 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 Kameron, A. J. Description An account of the resource <strong>Corporate Author: </strong>W. D. Scott and Company Date A point or period of time associated with an event in the lifecycle of the resource 1981-04-01 Title A name given to the resource Australian Veterans Herbicide Studies: Overview of the Proposed Studies on the Effects of Exposure to Herbicides on the Health of Australian Vietnam War Veterans Subject The topic of the resource AVHS study protocol congenital birth defects veteran psychological health 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. 036 Folder The folder containing the original item. 0786 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 Jessop, D. S. Source A related resource from which the described resource is derived Senate Date A point or period of time associated with an event in the lifecycle of the resource November 25 1982 Title A name given to the resource Standing Committee on Science and the Environment: Report on Pesticides and the Health of Vietnam Veterans Subject The topic of the resource AVHS government liability 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. 071 Folder The folder containing the original item. 1904 Series The series number of the original item. Series III Subseries IV 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 Jessop Description An account of the resource <strong>Corporate Author: </strong>Commonwealth of Australia, Senate, Standing Committee on Science and the Environment Date A point or period of time associated with an event in the lifecycle of the resource February 5 1982 Title A name given to the resource Reference: Pesticides Inquiry (Official Hansard Report), Melbourne, Friday, 5 February 1982. Subject The topic of the resource Australian Parliamentary hearings health effects veteran psychological health AVHS 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. 071 Folder The folder containing the original item. 1903 Series The series number of the original item. Series III Subseries IV 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 Jessop Description An account of the resource <strong>Corporate Author: </strong>Commonwealth of Australia, Senate, Standing Committee on Science and the Environment Date A point or period of time associated with an event in the lifecycle of the resource February 4 1982 Title A name given to the resource Reference: Pesticides Inquiry (Official Hansard Report), Melbourne, Thursday, 4 February 1982. Subject The topic of the resource Australian Parliamentary hearings health effects dioxin AVHS 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. 070 Folder The folder containing the original item. 1899 Series The series number of the original item. Series III Subseries IV 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 Jessop Description An account of the resource <strong>Corporate Author: </strong>Commonwealth of Australia, Senate, Standing Committee on Science and the Environment Date A point or period of time associated with an event in the lifecycle of the resource December 8 1981 Title A name given to the resource Reference: Pesticides Inquiry (Official Hansard Report), Tuesday, 8 December, 1981. Subject The topic of the resource Australian Parliamentary hearings health effects pesticide regulation AVHS 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. 034 Folder The folder containing the original item. 0695 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 Hall, Peter Ben Selinger Source A related resource from which the described resource is derived Nature Date A point or period of time associated with an event in the lifecycle of the resource July 23 1981 Title A name given to the resource Letter to the Editor: Australian 2,4,5-T Subject The topic of the resource dioxin AVHS 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. 080 Folder The folder containing the original item. 2062 Series The series number of the original item. Series III Subseries IV 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 Forcier, Lina H. Malcolm Hudson Michael J. Fett Description An account of the resource <strong>Corporate Author: </strong>Commonwealth Institute of Health in the University of Sydney Date A point or period of time associated with an event in the lifecycle of the resource September 7 1984 Title A name given to the resource Australian Veterans Health Studies, The Mortality Report, Part III: The Relationship Between Aspects of Vietnam Service and Subsequent Mortality Among Australian National Servicemen of the Vietnam Conflict Era Subject The topic of the resource AVHS mortality trends 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. 079 Folder The folder containing the original item. 2060 Series The series number of the original item. Series III Subseries IV 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 Fett, Michael J. Margaret Dunn Michael A. Adena Brian I. O'Toole Lina Forcier Description An account of the resource <strong>Corporate Author: </strong>Commonwealth Institute of Health in the University of Sydney Date A point or period of time associated with an event in the lifecycle of the resource September 7 1984 Title A name given to the resource Australian Veterans Health Studies, The Mortality Report, Part I: A Retrospective Cohort Study of Mortality Among Australian National Servicemen of the Vietnam Conflict Era, and an Executive Summary of the Mortality Report Subject The topic of the resource AVHS mortality trends ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/2f079846877c4349c6f09e2beb20fe29.pdf 2f14b6260585640f7557acb72da2bea2 PDF Text Text Item D Number 0193 Author rott M J ° Corporate Author ROpOrt/ArtlOlO TltlB Australian Veterans Health Studies: Morbidity Study: Protocol for a Morbidity Survey of Vietnam Veterans and Controls Journal/Book Title Year 1982 Month/Day December 13 Color Number of Images 12 DeSCriptOU NotBS Cover sheet says, "A protocol was prepared for this study, but it was never carried out. The protocol is attached, and is a public document." ° Thursday July 26, 2001 Pago 1930 of 1957 �Australian Veterans Health Studies Morbidity Study A protocol was prepared for this study, but it was never carried out. The protocol is attached, and is a public document. �PROTOCOL FOR A MORBIDITY SURVEY OF VIETNAM VETERANS AND CONTROLS Written by: Dr M.J. Fett MB, BS (Hons), B Med Sc (Hons), MFH Consultant: Dr J.D. Mathews MD, BS, FRACP, PhD Director of Studies: Professor R.J. Walsh MB, BS, FRACP, FRCPA, FAA Date: 13 December 1982 �Ac k i iow ] c no front s The following people have provided specialist advice and information in their respective fields: Piof<:.;or G. Andrews - Psychiatry Dr S. Henderson - Psychiatry Profersor R. Kalucy - Psychiatry Professor J. McLeod - Neurology Dr C. Smith - Associate Professor C. Tennant - Psychiatry Dr K. Kalsh - Neuropsychology Professor Khitrod - Hepatology Psychiatry Many AVHS staff members have made contributions to this protocol. Among them are Drs A. Long, G. Nairn, E. Harding, B. O'Toole, Mr C. Fung, Mr I. Adams, Mr N. Kendrick and Ms J. Busby. This protocol was typed by Mrs J. Charles, Mrs S. Foster and Miss A. Micallef. �TABLE OF CONTENTS Page J. SUMMARY 1.1 1 Rationale for this Study of Morbidity Descriptive Hypotheses to be Tested 1 2 1.4 Summary of Study Design 3 1.5 1.6 2. Background 1.2 1.3 Cancer Morbidity to be a Separate Study Relationship to Other Studies 3 4 PACKGROUND TO PROBLEM 5 2.1 Stimulus to Study 5 2.2 Possible Effects of Phenoxy Herbicides and 2.3 2.4 3. Related Subr-tances Corlist Syndrome and Other Psychosocial Effects of War Service Effects Related to Specific Concomitants of War Service 5 10 13 BACKGROUND TO STUDY DESIGN 15 3.1 3.2 3.3 15 15 3.4 Rationale for Study of Former National Servicemen Enlistment and Training of National Servicemen Factors Influencing Selection of National Servicemen for Vietnam Service Comparability of Veteran and Non-veteran National Servicemen 3.5 3.6 3.7 3.8 Duration of National Service in the Army National Service Intakes Sources of National Service Cohort Data Base Verifying the Completeness of National Service 3.9 Determining the Accuracy of the National Service Cohort Rationale for Morbidity Study Subjects Being a Subset of Mortality Study Subjects Rationale for Subjects being N.S.W. Enlistees Only Subject Selection Obtaining Subject Addresses Areas to be Investigated Implications of Pilot Study Results Rationale- for Using MEDICHECK Health Screening Centre Rationale for Method of Measuring Morbidity Physician Assessment Rationale for Number of Subjects Index of Herbicide Exposure Index of Combat Exposure Army Dossier Data Held on Each Subject Cohort 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.27 3.18 3.19 3.20 3.21 3.22 16 19 20 21 21 23 24 24 25 27 28 29 31 32 34 42 44 47 49 50 �Page 4. STUDY PROTOCOL 54 4.1 4.2 4.3 55 56 59 4.4 4.5 4.6 4.7 4.8 4.9 4.10 5. Subject Selection Obtaining Current Address Methods of Obtaining Compliance for Medical Examination Outline of Design of Medical Examination Design of Examination Procedure for Subjects Information from Wife/Female Partner Follow-up of Non-Complying Subjects Follow-up of Non-Complying Wives/Female Partners Pilot Testing of Medical Examination Verifying Data in Medical Records 61 63 70 73 76 77 78 79 5.1 5.2 5.3 6. ADDITIONAL INFORMATION FROM ARMY SOURCES 79 79 80 CARD Dossier Central Medical Record Psychology Record Cards ' DATA ASSESSMENT AND ANALYSIS 81 6.1 6.2 6.3 6.4 6.5 81 82 91 93 97 Data Acquisition and Verification Adequacy and Utility of Morbidity Study Data Hypotheses to be Tested Outcome Measures to be Used Principles of Statistical Analysis References APPENDIX 1: APPENDIX 2: 105 SPECIFIC HYPOTHESES AND POWER CALCULATIONS PULHEEMS ARMY HEALTH RATING �1. PUKVARY 1.1 Background^ At the request of the Commonwealth Department of Veterans' Affairs, a study group was established in January 1980 to investigate the suggestion that herbicide exposure in Vietnam was responsible for health problems reported by Vietnam veterans and their families. The investigations, initially known as "Australian Veterans Herbicide Studies", are administered by the Commonwealth Institute of Health. In October 1981, the terms of reference were widened to include all disabilities related to Vietnam service, and not just those which might be due to herbicide expor.ure. In May 1982, the study group was renamed the "Australian Veterans Health Studies" (AVHS). 1.2 Rationale for This Study of Morbidity Comments from Vietnam veteran groups have led to suggestions that there is an increased illness rate among veterans, particularly in the following areas: psychological health, behaviour, liver, gastrointestinal system, skin and neurological system. There have also been claims of an increased incidence of cancer amongst veterans, and of marital and reproductive problems affecting veterans and their wives and offspring. The rationale for this study is to use information on current health and past medical treatment of veterans and their wives to test some of these claims. To achieve this it is proposed to follow-up and examine medically 5,000 former national servicemen who enlisted in NSW (3,000 veterans, 2,000 controls) and obtain reproductive histories from their wives/female partners. The results will be assessed to see whether the disabilities for veterans are more frequent than for national servicemen who did not go to Vietnam (controls). �In the event that, disabilities are more frequently found in veterans than in controls, additional data will be analysed to decide whether the excess disabilities are best explained in terms of the physical or social sequelae of combat stress, and/or in terms of herbicide exposure and/or in terms of individual differences which antedated the Vietnam experience (See Sec 3.4) . The rationale for restricting this study to national servicemen is explained in detail in Sec 3.1. 1.3 E^c.rJp.VLY? Hypotheses to be Tested The null hypothesis is that there is no difference in the frequency of disabilities between Vietnam veterans and controls (national servicemen who did not go to Vietnam) . This null hypotheses will be tested against each of the following alternative hypotheses: (i) That social and behavioural disabilities (unemployment, separation, divorce, motor accidents, alcohol abuse) are more frequent in veterans than in controls. (ii) That anxiety, depression and other psychiatric disabilities are more frequent in veterans than in controls. (iii) That disorders of the nervous system (including neuropsychological disorders) are more frequent in veterans than controls. (iv) That liver disorders are more frequent in veterans than controls. (v) That gastro-intestinal disorders are more frequent in veterans than controls. (vi) That skin disorders are more frequent in veterans than controls. (vii) That infertility, miscarriage or death or disability of children have been more frequent in the families of veterans than in the families of controls. �1.4 FuTu-nary of _Study _p_esiqn Veterans and controls will be former national servicemen who enlisted in those intakes from which veterans were chosen (from June 1965 to February 1971), who served at lear.t 13 weeks, and who were discharged alive or survived for 2 years after enlistment. , From the group of former national servicemen who enlisted in N.S.W., 3,000 veterans and 2,000 controls will attend a central examination site in Sydney. The medical examination will consist of an in-depth medical questionnaire, neuropsychialric testing, biochemical testing of blood and urine, and physical examination and health assessment by a doctor. Following this examination, certain subjects will undergo more detailed psychiatric and neuropsychological assessment (see Figure 1, chapter 4). Any subject with illness requiring treatment or urgent investigation will be referred back to his local doctor. Any subject with a suspected disability which requires further investigation for research purposes will be referred to an appropriate specialist, either immediately (option A) or after interim data analysis (option B). The wives of veteran and control subjects will be interviewed, to seek information about the health of any children of the subject, and about the outcome of all pregancies. 1.5 Cancer Morbidity Not Addressed by This Study This morbidity survey is not ideally suited to examining the incidence of cancer (see section 3.19) . �1.6 Kplat KMiship to Other Studies Separate studies have investigated the relationship of Vietnam service to birth defects in offspring (Case-Control Study of Congenital Anomalies and Vietnam Service), and are investigating mortality (Retrospective Mortality Study of Vietnam Veterans and Controls Revised Protocol). �2- BACKGROUND^ TO PROBLEM 2.1 St_im_u 1 u r, Jto_St udy In 1979 Vietnam veteran groups reported that there was an excess of veteran morbidity due to gastrointestinal, neurologic, skin and psychiatric disability and cancer, above that expected in a group of previously healthy young men. This supposed excess was attributed, by some veterans, to exposure to Agent Orange herbicide during Vietnam war service. Health effects other than morbidity are addressed in other documents (Case-Control Study of Congenital Anomalies and Vietnam Service Report, Mortality Study protocol). While the claimed effects of Agent Orange have yet to be substantiated, it has become apparent that several other environmental exposures, both in Vietnam and back in Australia, could be causally related to any increase in disability f in veterans. Among these exposures are non-phenoxy herbicides (e.g. cacodylic acid), insecticides, infectious tropical diseases and malaria prophylaxis, experiences of social dislocation and warfare, alcohol, tobacco and other drug consumption, and the experiences of homecoming, readjustment and re-establishing a satisfactory life style (Boman, 1982). 2.2 Possible Effects of Phenoxy Herbicides and Related Substances 2.2.1 General Literature Review The 'Review of Literature on Herbicides, Including Phenoxy Herbicides and Associated Dioxins1, (U.S. Veterans Administration 1981) summarises the known and suspected health effects of herbicides, and the gaps in current knowledge. study of Vietnam veterans are: Points of relevance to a morbidity �TCDD (Dioxin) o TCDD has been an important contaminant of 2,4,5-Tr and it has not always been possible to distinguish between the effects of the two substances. o Chloracne is the most consistently reported health effect of TCDD exposure in huir.ans. o Neurasthenia, a series of subjective complaints including irritability, fatigue and insomnia, has been reported after many industrial accidents and exposures, o Other neurological disorders (as peripheral neuritis) and hepatic disorders (as hepatomegaly) have been reported after several of the exposure incidents. o Porphyria cutanea tarda and gastrointestinal problems have not been commonly reported and seem to be associated with long-term exposure. o TCDD is a limited cumulative toxicant; cumulative effects of doses administered within a month of each other have been observed in animals, but not for doses administered beyond about one month, o The subacute effects of TCDD are porphyria and depletion of blood cells; these effects are not observed after acute doses, o In animal studies TCDD appears to act secondarily or indirectly in enhancing the carcinogenicity of other components (usually unidentified). 2,4-D, 2,4,5-T o Both 2,4-D and 2,4,5-T are cleared rapidly from the blood after they are absorbed, with half-times for plasma clearance in humans of 12-23 hours. �o Neither 2,4-D nor 2,4,5-T has been shown to accumulate in animal fat. o 2,4-D and 2,4,5-T are not cumulative toxicants. o In animals the cause of death from lethal doses of 2,4-D or 2,4,5-T is unknown; both compounds produce several non-specific effects, such as mild weight loss. o 2,4-D produces neurotoxicity in humans and animals, and 2,4,5-T produces neurotoxicity in animals. o Animal studies have not produced conclusive evidence that 2,4-D, 2,4,5-T, cacodylic acid or picloram are carcinogenic. o The effects of acute exposure to 2,4,5-T in humans are unknown. o There is no positive information on the carcinogenic potential in humans of diquat, diuron, dalapon, bromacil, picloram, and tandex and on 2,4-D, 2,4,5-T, or TCDD, (except in the case of concomitant exposure to trichlorophenol or other herbicides). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Kan: Volume 15 gives the following effects of TCDD, 2,4-D and 2,4,5-T as having been described in humans: TCPD chloracne porphyria cutanea tarda hyperpigmentation and hirsutism liver damage raised serum hepatic enzyme levels disorders of fat metabolism disorders of carbohydrate metabolism cardiovascular disorders �urinary tract disorders respiratory disorders pancreatic disorders polyneuropathies lower extremity weakness scnr.orial impairment (sight, hearing, smell, taste) neurasthenic or depressive syndromes 2,4-D hyperthermia and tachycardia nausea, vomiting, diarrhoea anorexia and gastralgia increased salivation sweet taste in the mouth abdominal pain fatigue, malaise headache sensation of drunkenness peripheral neuropathy paralysis somnolence muscular weakness, twitching skeletal muscle damage severe leg pains joint swelling increased blood cholesterol abnormal serum protein �chloracne liver disorders neurological changes behavioural changes fat metabolism disorders signs of porphyria cutanea tarda gastrointestinal symptoms headache hypomania neurasthenic syndrome The effects listed have generally been observed in subjects after recent chemical exposure, and the pattern of effects varies between reports. 2.2.2 Possibility of Carcinogenic Risk in Man Soft-tissue sarcoma and lymphoma are suspect as outcomes of exposure to phenoxy herbicides or associated substances (Hardell and Sanstrom, 1979). The work of Hardell has received some support from reports of at least four cases of soft-tissue sarcoma which have occured in workers involved in the manufacture of phenoxy-herbicides (Hardell and Ericksson, 1981; Honchat and Halperin, 1981). Several other studies of the effects of herbicides on cancer mortality have failed to demonstrate an effect (Axelson and Sundell, 1974; Riihimaki et al, 1978) and no excess mortality has been demonstrated following the 1976 Seveso dioxin disaster (Regianni, 1980), although the latent period is short. �2.3 ?f?:Tll''?t._?ynF'?c?TTic!!:. ^nj-LPth.?1 Psychospcijl Effects of War Service There are no published epideroiologic studies of the effects of Vietnam service on the psychological adjustment of Australian soldiers, nor on their subsequent readjustment to civilian life; however, literature indicates three main areas of psychopathology in U.S. veterans: post traumatic stress disorder; depression; alcohol and substance abuse disorder (review by Boman, 1982; symptoms after DSM III). 2.3.1 ?9.st..~?.r_fiu!!!ati5: Stress Disorder Symptoms: Re-experiencing of the trauma; numbing of responses to or reduced involvment with the external world; hyperalertness, sleep disturbance, guilt about surviving; memory impairment or trouble concentrating. 2.3.2 Depression of various types Symptoms: Anorexia, weight loss or gain, increased appetite; sleep disturbance, psychomotor agitation or retardation; feelings of worthlessness; loss of interest, loss of energy, fatigue; complaints or evidence of decreased ability to think; recurrent thought of death or suicide; suicide attempt. 2.3.3 Alcohol and Substance Use Disorder Symptoms: Alcohol or drug consumption causing impairment in social or occupational function, with or without tolerance or withdrawal. 10 �2.3.4 Othc- r_ Psy chospci a 1_ Disorders Three other classes of disorder seem possible in view of media reports of the health of Australian Vietnam veterans. These are: anxiety disorders; adjustment disorder with anxious mood; somatization disorder (symptoms again taken from DSM III). Anxiety Disorders Symptoms: apprehension, fear or terror; dyspnoea, palpitations, chest pain or discomfort; choking or smothering sensation; dizziness, vertigo or unsteady feelings; feelings of unreality, paraesthesias, hot and cold flushes; sweating, faintness, trembling or shaking; fear of dying, going crazy or doing something uncontrollable. Adjustment Disorder with Anxious Mood Symptoms: as for anxiety disorder, with nervousness, worry or jitteriness predominating. Somatization Disorder Symptoms: Sickly: Believes that he or she has been sickly for a good part of his or her life. Conversion or pseudoneurological symptoms: Difficulty swallowing, loss of voice, deafness, double vision, blurred 11 �visionf blindness, fainting or loss of consciousness, memory loss, seizures or convulsions, trouble walking, paralysis or muscle weakness, urinary retention or difficulty urinating. Gastrointestinal symptoms: Abdominal pain, nausea, vomiting spells, bloating (gassy), intolerance (e.g. gets sick) of a variety of foods, diarrhoea. Psychosexual symptoms: For the major part of the individual's life after opportunities for sexual activity: Sexual indifference, lack of pleasure during intercourse, pain during intercourse. Pain: Pain in back, joints, extremities, genital area (other than during intercourse); pain on urination; other pain (other than headaches). Cardiopulmonary symptoms: Shortness of breath, palpitations, chest pain, dizziness. Other psychiatric abnormalities may occur, but the number of affected individuals will probably be very small. 12 �2.4 Ii(f_e.£tE_Rc3at_ed _to_Sppci_f ic Con corn Habits of War Service 2.4.1 Alcohol Use Because of combat stress and the social changes consequent on Vietnam service, it is likely that the consumption of alcohol by Vietnam veterans will prove to be higher than that in non-veterans. This would lead us to expect that there could be a greater incidence of alcohol related disability in veterans than in controls, as has been reported in other army and veteran populations (Mathews 1976). It is also necessary to consider the possibility that some of the personal qualities which are associated with being a "good soldier" (e.g. vigour, initiative, aggression) may show an intrinsic (genetic) correlation with the propensity to drink more alcohol (Mathews, 1981) . if this were the case, then any association of alcohol use with veteran status could be partly consequent on the processes of veteran selection. It will be possible to test this hypothesis in the morbidity study, as data on alcohol consumption will be collected from subjects. 2.4.2 Cigarette Smoking and Other Drugs Similar considerations apply to cigarette consumption. A particular attempt will also be made to identify any morbidity which could be attributable to illicit drug usage. 2.4.3 Infectious Diseases It is likely that Vietnam veterans have been at greater risk of several infectious diseases (e.g. malaria, hepatitis, melioidosis, strongyloidiasis), although there is no specific evidence to suggest that this has contributed to any disability in the post-Vietnam period. 13 �Tuberculosis might also be more prevalent in veterans, because of the greater exposure in Vietnam, and the greater susceptibility associated with a history of social disintegration and alcohol abuse. However, because of the efficacy of treatment, it is unlikely that there will be any subjects with tuberculosis. Because of the social dislocation of the war experience, venereal disease may also be more prevalent in veteran than in control cohorts. 14 �3 - 3• * J^CKJSROUND TO ST_IJDY_ DESIGN Rationale for Study of Former Kational Servicemen In studying the effect of Vietnam service on subsequent risk of disability, a group of subjects who served in Vietnam (veterans) is required, along with a comparison group of subjects who did not serve in Vietnam (controls). The veterans and controls should have been as similar as possible at the point in time at which the veterans departed for Vietnam. Specifically, the distribution of age, health status and socio-economic status (SES) should be similar between veterans and controls. Former national servicemen are considered to form a group most closely satisfying these requirements and consequently the study will be restricted to this group. At present it is considered that it would be too difficult to * define an appropriate control group for those Vietnam veterans who were in the regular army. If further investigation were to be performed, it may prove feasible to identify acceptable groups of veterans and controls among the regulars, but even so it would still be highly desirable to perform the study with national servicemen for two reasons: firstly, national service veteran and control groups would, in all probability, still be more comparable than groups of regulars, and secondly, within regulars the health effects of Vietnam service could be obscurred by the deleterious health effects of peace-time army service (see above). 3.2 Enjy.?j-!n±nt_A"d Training of National Servicemen Nineteen year old Australian males were required to register for national service (National Service Act 1957-1971), and those with birth dates selected by ballot were required to present for medical examination and interview by the Department of Labour and National Service. 15 Those accepted were required �to enlist in the army within the next few months, unless deferrment (educational, medical reasons) or exemption (clergyman, conscientious objector) was obtained. Then followed an enlistment medical examination. Some men volunteered for national service independent of the ballot. They had to reach the same medical standard as ballotees. These men can only be identified by examination of individual, dossiers. After enlistment followed 10 to 12 weeks of recruit training, then allocation to corps and 12 weeks Initial Employment (corps) training (except Infantry). The member was then posted to his service unit. Generally, between 6 months and 1 year after enlistment the veterans were sent to Vietnam for a 1 year tour of duty . » 3.3 Factors Influencing Selection of National Servicemen for Vietnam Service Selection for Vietnam service was based on whether an individual had been allocated to a unit which was subsequently selected for Vietnam service. Very few if any national servicemen were prevented from serving in Vietnam for medical conditions and the interval between enlistment and posting to Vietnam (less than 1 year) was insufficient for life-threatening conditions to develop in a significant number of national servicemen which would result in exclusion from Vietnam service. Many factors influenced the selection of a national serviceman for service in Vietnam. Those currently known to the Study Team are as follows: 16 �a) Indi_y ijdua 1^ Soldi^e£_E__I_nf luence Completing form NS24, giving details of education, special skills and t r a i n i ng. Completion of a "dream sheet1 which recorded desires to serve in particular corps. It is believed that in a considerable proportion of cases these preferences were recorded on the psychology record cards, which are available. It is thought to have been common knowledge which units were going to Vietnam in the next couple of years, and therefore a national serviceman could steer himself toward a corps which was more or less likely to be sent to Vietnam. Additionally, the field corps (Artillery, Armoured, Infantry, Engineers, Signals) were known to be the most dangerous. Volunteering for a reinforcement unit. Expressing a desire to serve in Vietnam. Performing in a sufficiently unsatisfactory manner so as to be regarded as unsuitable for Vietnam service. A fear of combat, or conscientious objection to the Vietnam war or combat. Lack of physical fitness becoming apparent during basic training but not necessitating discharge; lack of psychological fitness for combat service, as evident on enlistment testing or as determined by his commanding officer. 17 �An accident resulting in injury prior to posting to Vietnam, but not necessitating immediate discharge (due to its minimal severity or the need for prolonged medical treatment). Family circumstance, such as illness, social problems etc. resulting in the national serviceman being granted leave without pay or being posted to a base near home, precluding Vietnam service. b) Army influence Requirement lists. These listed the manpower requirements of corps and units. The allocation boards attempted to match 'dream sheets' to 'requirement lists', probably with varying success. The 49/51 rule. The Army maintained Vietnam service unit strength at 51% regulars or above, although it appears from 1968 onwards the lack of available regulars meant that the ratio sat on 49% national servicemen and 51% regulars. A national serviceman's superiors regarding him as unsuitable for Vietnam service. It is probable that these factors, while influencing Vietnam service, would also influence subsequent morbidity and mortality. The number of national servicemen who sought or avoided Vietnam service is not known. 18 �As this problem is one of confounding, its role may be evaluated, at least in part, at the data analysis stage once the requisite data has been obtained from the army. It appears possible to identify individuals transferring into or out of Vietnam bound units by searching through individual personnel dossiers. The proportion of national servicemen who became veterans is similar across all States of enlistment (see Table 3.1) although anecdotal evidence indicates that some units were comprised mainly of enlistees from certain States. OLD NSW vie SA- WA TAS NT Total subjects enlisted in State 14% 32% 30% 10% 10% 4% 0% % of subjects who are veterans 43% 42% 39% 40% 42% 44% Table 3.1 Origin of subjects by State of enlistment, and % veterans of subjects enlisted in each State. 3.4 Comparability of Veteran and Non-Veteran National Servicemen As indicated in the previous section, there is ample evidence that the decision to send a national serviceman to Vietnam was not random. In the absence of random allocation, it is likely that even before the Vietnam experience, those who eventually went (veterans) would have differed, in several important respects, from those who did not go to Vietnam (controls). 19 �This view is supported by evidence that veterans differed from controls in educational level and in scores on the SDI psychological scale at induction. In as much as these pre-Vietnam differences between veteran and control national servicemen are measurable, they can be treated as potential confounding factors. At the stage of analysis of results it will be possible to see whether factors such as education and psychological type are related to outcome, and if so, to make statistical adjustments to minimise the effects of the confounding. However, it is important to emphasise that because of (undetectable) errors in the measurement of these confounding factors, such statistical adjustments will always be incomplete. Furthermore, no statistical treatment could ever allow for the effects of confounding factors which are unmeasured (and possibly unsuspected). 3.5 Duration of National Service in the Army Discharge occurred after 2 years service (reduced to 18 months in 1971) unless discharge occurred early for extraordinary reasons (medically unfit, exceptional hardship, change of Government) or late (retention for medical treatment, voluntary prolongation of service). An analysis of 'discharge reason1 by 'duration of service1 for those intakes with veterans revealed that 53% of discharges as 'medically unfit1 occurred in the first 3 months, 67% by 6 months and by 12 months 80% of all such discharges had occurred (see Table 3.2). For 'expiration of term1, 0% occurred in the first 12 months, 29% in 13-24 months, 65% in the 25th month, and 5% after 25 months. The 5% of discharges after 25 months service may be due to errors in enlistment and discharge dates or retention of servicemen in 20 �the Army for medical treatment or voluntary prolongation of service. The reasons for those delayed discharges will be explored by manual searching of the CARD dossiers. Reason for Discharge % Discharged in Time Interval of Duration of Service 0-3m 7-12 m 13-24 m 25m + 4m- 6m Total No. 100% 0% 0% 14% 19% 4% 10% 0% 0% 13% 22% 13% 22% 29% 0% 15% 19% 23% 23% 70% 100% 5% 6% 52% 42% 40829 Other 0% 0% 53% 34% 6% 3% Total 5% 2% 3% 27% 63% 49881 Expiration of term Exceptional hardship Medically unfit Unsuitable, non-discipl. Unsuitable, disciplinary 63 3661 874 316 4138 Table 3.2 Reason for Discharge by Duration of Service 3.6 National Service Intakes Department of Defence Army Manning Reviews divide national service enlistments into 4 intakes each year. Each intake lasted up to 2 weeks, and they occurred in January, April, July and September. A minority of enlistments occurred in the other months, and for the purposes of this study an intake consists of all national servicemen who enlisted in 1 of the above months or enlisted in the month on either side of that month. 3.7 Sources of the National Service Cohort Data Base The following information is available from the army for current and former servicemen: Service number Surname Given names 21 �Date of birth Date of enlistment Marital status at enlistment Educational status at enlistment Occupation at enlistment Religion Nun-iber of dependents Place of birth Army health classification at enlistment Postings Dates of postings Date of discharge Discharge reason Army health classification at discharge » Medical record and psychology record data Other To date, two army sources have been used to provide data about national servicemen in the Vietnam period. These are the Central Army Records Office (CARD) and the Melbourne Regional Computer Centre (MRCC), both located in Melbourne. MRCC An MRCC-supplied computer file contains most of the above data for most study subjects. However, it has several major short-comings. Firstly, it contains initials, not given names (which are required for obtaining subject addresses) and does not contain postings data, medical or psychology data, or other miscellaneous service history data. Secondly, preliminary examination indicates that the data it contains are less accurate than those in the CARD 22 �dossier. As discussed below the first match to obtain addresses will be computerised: matching study subjects' MRCC-file derived names (surname, 2 initials) and date of birth with the Australian Electoral Register. It is proposed to overcome the problems of MRCC file inaccuracy by returning all unmatched subjects names and d.o.b. to CARO for manual verification and addition of 2 given names (CARO contains dossier records for all current and former servicemen). Where corrections have been made, the subjects will be matched with the Australian Electoral Register again, and the residue not matching will be sought in other registers. CARO In addition to the above limitations, the MRCC file does not indicate veteran/control status, and neither dates nor names of Vietnam postings. These are contained on a computer file held by AVHS compiled from data manually extracted from individual CARO dossiers. While this file does have 2 given names for all veterans, it only gives data for 17% of controls. There is evidence of misclassification of veteran/control status, probably less than 1%. 3• & Verifying the Completeness of the National Service Cohort The completeness of the cohort has two aspects: firstly, whether we know of the existence of all of the national servicemen, and secondly, whether we have complete details on those known. This work has already been performed as part of the Mortality Study. All national servicemen have been identified, and the data listed in 3.7 above is present in at least 98% of cases. 23 �3• 9 P?i.cJ.?r?r1 Ln.9 _yi£.^Jr-SmiacV °* the Nationa 1 JSe r_vi£e_ Cohort Generally, data on the MRCC file will be used for the purposes of the Morbidity Study, as this is the only file with complete coverage of national servicemen. The CARD computer file has much greater coverage of veterans than controls and is therefore a biased source. The MRCC - CARO match was used to determine the error rates in the MRCC data in the following way: If an inconsistency emerged in the MRCC - CARO match the origin of this inconsistency was determined. This involved checking that the computerised CARO data were correctly entered, and, if so, that they were correctly transcribed from the original CARO dossiers. The remaining discrepancies were corrected by referral to army personnel dossiers. 3.10 Rationale for Morbidity Study Subjects Being a Subset of Mortality Study Subjects Mortality Study subjects comprise all former national servicemen who saw service in Vietnam, and all other national servicemen from those intakes which also included veterans who stayed in the army at least 13 weeks. The 13 week minimum army service criterion is proposed for several reasons: Initial recruit training lasted from 10 to 12 weeks and the majority (53%) of discharges described as "medically unfit" occurred during this time. Recruit training therefore acted as a further screening procedure to identify and discharge these persons not suitable for army service. By the end of recruit training those remaining in the army would be considered suitable "material" for selection for Vietnam service. A minimum service duration of 13 weeks for subject selection therefore ensures that subjects, both veterans and controls, had an adequate health standard at the time of enlistment. 24 �This rationale for defining mortality study subjects applies equally to morbidity study subjects. Since all 48,600 national servicemen fulfilling the above criteria will be selected for the mortality study and only 5,000 need be studied for the morbidity study, the morbidity study subjects can be a subset of mortality study subjects. Vietnam service generally commenced 9 to 12 months after enlistment. Therefore servicemen discharged between 10 weeks and 9 months after enlistment were not eligible to become veterans. Nevertheless, they will be included, because their exclusion would prevent investigation of the relationship between morbidity and the factors associated with early discharge. If morbidity is found to be related to a history of early discharge in the control sample this will provide evidence of the magnitude of the effects on morbidity that can arise from differences which are not related to the Vietnam experience. If necessary, these 'short service1 controls could be excluded from the analysis at a later stage, to allow comparisons of morbidity to be made in veterans and controls with similar duration of army service. 3.11 Rationale for Subjects Being N.S.W. Enlistees Only To enhance the logistic feasibility of the morbidity study it is proposed to select subjects who enlisted in N.S.W. N.S.W is chosen as it is the most populous State and the study team is physically located in Sydney, within 200 kilometers of approximately 85% of the State's residents. N.S.W. enlistees who have moved interstate will be sought and encouraged to participate. N.S.W enlistees who have emigrated from Australia will be deemed to be unavailable until they return to Australia. 25 �The assumption underlying this state of enlistment approach is that a large majority of N.S.W. enlistees are still living in the State. This assumption has been examined by matching former national servicemens1 names and dates of birth with the Australian Electoral Register of July 1981 (see Table 3.3) and tabulating the State of residence on the register. Approximately 6,000 veterans and 9,000 controls enlisted in N.S.W, many more than required for the morbidity survey (see sec. 3.19) . Veteran 3515 6155 2728 4971 % of Names Matching 78% 81% % of Names Not Matching (b) Number of Names Sought Number of Names Matching (a) Control 22% 19% State Distribution of Names Matching with Australian Electoral Register. Table 3.3 State of Residence of N.S.W. Enlistees. 1981 Electoral Register State Veteran Control NSW 88% 91% VIC 2% 2% OLD 6% 5% SA, NT 2% 1% WA 2% 1% TAS 0.4% 0.4% 12% Not in NSW 26 9% �The results in Table 3.3 are likely to be the best possible expectation of reality ar> the 19-23% not matching on the Australian Electoral Register may be more evenly spread across Australia or overseas. In addition, errors in the Electoral Register State of residence due to delays in entering change of address data are likely to over-represent N.S.W. since N.S.W. enlistees started out there. Nevertheless, the result is encouraging, and also suggests that confining the medical examination facilities to N.S.W. may be the most economical way of executing the study. N.S.W. enlistees are comparable to enlistees from other states in terms of distribution across corps, proportion of veterans overall, and proportion of veterans within each year of enlistment. » An alternative approach is to select current N.S.W. residents irrespective of State of enlistment. There would be the potential for major bias, in that mobility after Vietnam service could be strongly correlated with morbidity, and, in terms current State of residence, differ among the States (e.g. mobile people heading to Qld and NT). 3.12 Subject Selection To be eligible for subject selection, a former national serviceman must fulfil the following requirements: (i) Served in the Army at least 13 weeks, to ensure uniform enlistment health status (see section 3.10); (ii) Be enlisted in an intake from which Vietnam veterans were subsequently drawn. (iii) Intakes after February 1971 contain no veterans; Be enlisted in N.S.W. (see section 3.11). 27 �The pool of former national servicemen fulfilling these three criteria will be stratified by veteran/control status and enlistment intake. With regard to the total number of veterans required (see section 3.19), random selection of a constant proportion of veterans within each intake will be made. For every intake from which veterans have been selected, 2 controls will be randomly selected for every 3 veterans. This will ensure that both the structure of ages and chronologic years of army and Vietnam service are similar for veterans and controls. 3.13 Obtaining Subject Addresses Inviting subjects to a medical examination requires knowledge of their current address. * Initially, address will be obtained from the Australian Electoral Register, (probably 80%) and drivers licence registers (a further 10-15%). Follow-up data from the Mortality Study would be useful in this regard. Additional negotiation will be required to obtain addresses from licence registers. However, in the Pilot Study it was found that only 87-90% of subjects could be located using a known Electoral Register address. It is proposed therefore, that when a morbidity study subject is unable to be located through an address obtained via the mortality study, additional address searching will be carried out. Since all subjects will be sought in the Australian Electoral Register and computerized licence registers, there will be no additional search requirement for these sources. Additional searching will involve manual drivers licence registers (Vic, Qld) the latest Electoral Register microfiche, commercial 28 �credit bureaux, telephone books and Telecom customer files, and Social Security records, if available. It is probable that 10% of morbidity subjects will have to be sought in this way. This second stage searching, specific to the morbidity study requirement for current addresses, will be carried out concurrently with the medical examination field work, as the failure to contact a subject will only become evident at this stage. If available, the current Australian Electoral Register tape will be used as the initial source of the addresses of subjects. Addresses, once obtained, will be held on computer file to facilitate the control and monitoring of subject contact and participation. 3.14 Areas to be Investigated Veterans have expressed concern about the health of themselves and their offspring in several areas. However, confining investigation to these areas alone would ignore many areas of disease which might have arisen from service in Vietnam, and which might, at a later stage, become significant to the veterans. 3.14.1 Veterans Areas of Concern Birth defects - see Case-Control Study of Congenital Anomalies; Death from a variety of causes - see Retrospective Mortality Study; Cancer - to be investigated in part via the Mortality Study; Abnormalities of behaviour (eg outbursts of rage); Substance abuse (eg excessive use of alcohol, tobacco, illicit drugs, prescription drugs); Relationship difficulties (eg divorce, social disabilities); Psychiatric disorders (eg depression, anxiety); Reproductive disorders (eg miscarriages, infertility); 29 �Liver disorders; Gastrointestinal disorders; Neurological disorders of both the C.N.S. and P.N.S.; Skin abnormalities. 3.14.2 Morbidity Related to Concomitants -of War Service. - ._ Corcbat injuries, disability and crippling Psychiatric disorders (see sec. 2.3): Post-traumatic stress disorder Substance abuse: alcohol - gastrointestinal ulceration, liver disease, hypertension, degeneration of nervous system and heart, psychoses tobacco - chronic obstructive pulmonary disease, respiratory tract infection, cardiovascular disease, cancer miscellaneous drug dependencies Depression and anxiety disorders: wide variety of concomitant symptoms Somatization disorders: wide variety of concomitant symptoms affecting nervous system, gastrointestinal system, cardiopulmonary system, psychosexual functioning Infectious diseases Only four diseases endemic to Vietnam could (arguably) still affect veterans: Melioidosis Strongyloidiasis Syphilis Tuberculosis 30 �All other infections will have either spontaneously resolved or become sufficiently florid to necessitate treatment and cure. Although vivax malaria can persist in a latent phase for long period of time it is not considered that this could be a significant cause of morbidity. 3.14.3 Morbidity Implicated in Herbicide Literature Occupational studies of the long term effect of human exposure to chlorinated phenols have revealed cases of soft tissue sarcoma, and the Swedish case-control studies, suggest that phenoxy herbicides could cause soft tissue sarcoma and lymphoma (Hardell and Sandstrom, 1979, see also section 2.2). 3.15 Implications of Pilot Study Results The Pilot Study has provided information about the value of many aspects of methodology which have been considered in the planning of this morbidity protocol. Information from the Pilot Study will also be used in the planning of detailed procedures if this present protocol is approved in principle. Briefly, the pilot study results show that: o telephone and face to face interviews were more expensive ($100 and $95 respectively) than self-administered questionnaires ($60) posted to the home o response rates were higher for telephone and face to face interviews than for self-administered questionnaires o veterans responded to the request for an interview more frequently than controls o self reports on army unit, subunit, corps and veteran status are likely to be useful 31 �o self reports on posting dates and operations in Vietnam are unlikely to be useful o sell reports on exposure to chemicals in Vietnam are unlikely to be useful o self reports on exposure to chemicals at work and home are more likely to be useful - - o cigarette smoking was reliably reported o the use of alcohol was reliably reported, but with the instrument used drinking frequently was less reliably reported o false positive and false negative rates for conditions reported in the medical history were high, especially for conditions occurring more than one year prior to interview o separation of the medical history and physical examination meant that the examining physicians were hindered by a lack of contextual clues in making judgments about morbidity in the subjects studied o morbidity was detected in both veteran and control subjects; target conditions based on subjective responses were found at highest frequency o the psychology tests used were insensitive in detecting psychopathology o a proportion of the reports from wives on miscarriages, birth defects and handicaps in children could not be confirmed. The implications of these findings have been considered in more detail elsewhere in this protocol. 3.16 Rationale for Using MEDICHECK jte a1th Screening Centre Comprehensive medical evaluation of several thousand men requires complex logistical arrangements. The MEDICHECK Centre in Sydney has extensive experience in processing large numbers of people through a medical evaluation procedure. As the majority of subjects will be living in or near Sydney, �compliance will he maximized by having the examination site in Sydney. MF.DICHECK is convenient, as it is located in the centre of Sydney, close to public transport. Detailed evaluation of the comparative economics of MEDICHECK versus AVHS established centres has not as yet been performed. However, initial indications are that MEDICHECK compares favourably with Pilot Study costs. Apart from economics, there are other advantages of using MEDICHECK: 1. The use of MEDICHECK facilities would significantly reduce the time required to commence the medical examination of subjects and would therefore bring forward the date of reporting of the morbidity survey. 2. The experience and skill of currently employed staff ensures maximum •• - efficiency in subject processing, even at the commencement of examinations. 3. MEDICHECK uses a computer-guided VDU-type questionnaire which is acceptable to clients, does not permit invalid or inconsistent answers, and does not require staff to administer. (It is constrained by permitting only yes/no answers and will therefore be supplemented by a pencil and paper instrument when more complex responses are required). 4. Facilities and staff are in place for blood pressure measurement, electrocardiogram, chest x-ray, pulmonary function, audiogram, anthropometric and biochemical evaluation. The Centre operates it own biochemistry and microbiology laboratories, and participates in a standards programme supervised by the College of Pathologists of Australasia. 33 �/ 5. The entry of all data onto computer files is the routine method of data handling, and will increase the efficiency of the morbidity study. While the use of MEDICHECK is indicated for the above reasons, certain additions and modifications to the usual programme will be made to ensure quality control of critical items {eg blood presure measurement) -and-to ensure that additional items of data of particular interest to the morbidity study are collected. These are discussed below. 3.17 Ra t_ionale for Method of Measuring Morbidity Additions to the usual MEDICHECK programme are required to meet the requirements of the morbidity study. The data to be collected by the usual MEDICHECK evaluation and those to be collected by additional sections of the examination are listed below, along with their rationale (see section 3.14). 3.17.1 VDU Questionnaire. Item Rationale Marital status Veterans, war service Job satisfaction block War service Financial status/problems Veterans, war service Sleep/worry Veterans, war service Depression and state of mind Veterans, war service, TCDD, 2,4-D, 2,4,5-T Drinking habits War service Smoking habits War service Exercise War service Tablets War service Bereavements and family history Confoundin- variable Coronary symptoms War service, TCDD 34 �Leg pain symptoms War service, TCDD Hoart beat/hypertension War service, TCDD, 2,4-D Breathlessness, numbness, varicose War service, TCDD, 2,4-D, 2,4,5-T veins Ankle oedema symptoms War service, TCDD Lung problems and diseases War service, TCDD Abdominal diseases and history Veterans, Vietnam service, TCDD, 2,4-D, 2,4,5-T Veterans, war service, TCDD, Sexual problems 2,4,5-T VD and U/G history, infections, War service, TCDD operations Joint & muscle pains/arthritis War service, 2,4-D Neurological symptoms Veterans, war service, TCDD, 2,4-D, 2,4,5-T Skin disease and allergies Veterans, war service Vision and eye problems TCDD, 2,4,5-T Ear, nose and throat problems 2,4-D Tropical diseases Veterans, Vietnam service Infections and miscellaneous Veterans diseases 3.17.2 Components of the AVHS Questionnaire Self Report of Current Conditions and Symptoms At reception, all subjects will be asked to list all current medical conditions and symptoms, to indicate a grading of severity (from 1-trivial to 5-incapacitating) and to give a duration for each complaint. This data is being sought in addition to questionnaire data for several reasons: 35 �to identify intercurrent and trivial illness which may affect pathology tests (e.g. white cell count) to permit an unprompted description of the subject's problems, which may reveal unsuspected or unconventional symptomatology to improve the accuracy of clinical judgements made by the doctor about the subject's health. Pencil and Paper Questionnaire Item Rationale (see section 3.14) Occupation, employment Veterans Education Veterans Social and behavioural functioning Veterans, war service Marital and offspring history Veterans, war service Wife/partner identification Veterans, war service Social desirability questions Confounding variable Reasons for Vietnam/non-Vietnam Confounding variable service Combat experience Explanatory variable Combat injuries Explanatory variable Alcohol and tobacco consumption War service - diary of past week Other drug consumption, including tea and coffee War service Medical and hospital consultations Confirmation of reports - reasons, when, duration, name and address. Confounding variable Herbicide exposure in Australia 36 �3.17.3 Neuropriychjatric Screening Test Rationale Interview: Veterans, war service present state examination post-traumatic stress disorder interpersonal relationships psychological well-being AVHS schedule of life events: Eysenck Personality Inventory Army Self Description Inventory Symbol-Digit Modalities Test Supra-Span Digit Learning Test Trail Making Test Nelson Adult Reading Test Army Speed and Accuracy Test. 3.17.4 Pathology and Other Tests Rationale Test Electrocardiogram War servicer TCDD Chest x-ray Vietnam service: tuberculosis Spirometry War Service Hearing War service Anthropometry War service 37 �Rationale Test Blood: Glucose, lipids TCDD, 2,4-D, 2,4,5-T Uric acid Alcohol related, 2,4-D Liver enzymes Veterans, Vietnam service, TCDD 2,4-D Haematology Alcohol, Vietnam service Hepatitis B serology Vietnam service Strongyloides, melioidosis, Vietnam service and syphilis serology Drug screen War service Urine 3.17.5 TCDD, 2,4,5-T Physical Examination Item Rationale Skin Veterans, Vietnam service TCDD Hepatosplenomegaly War service, TCDD, 2,4-D Neurological screen Veterans, war service, TCDD, 2,4-D, 2,4,5-T Thoracic auscultation War service, TCDD, 2f4-D Legs - vascular, reflexes, sensation Veterans, war service, TCDD, 2,4-D Blood pressure War service, TCDD, 2,4-D Auditory canals and tympanic Confounding variable in membranes hearing testing In addition, the examining doctor will have the questionnaire responses for each subject, and will elicit additional historical details and additional examination findings as indicated by the 38 �history. He will then record all physical signs found and make clinical judgements as to the presence or absence of particular conditions (see section 3.14), and record other diagnoses suggested by the data. Later, when test results are available he will have the opportunity to modify or add to his clinical judgements. 3.17.6 Hicrarchica1 Struetun; One component of the on-site medical examination will be conducted on a sample of subjects only. This is the phase 2 neuropsychiatric evaluation. This area is of particular importance to veterans and relates directly to the putative effects of both war service and herbicide exposure. It is therefore desirable that detailed evaluation be carried out in this area. As this will require 1 hour of additional testing per subject, it is not feasible to evaluate all subjects without reducing the total number of subjects studied. A random sample of 10% of all subjects plus subjects with high scores on the neuropsychiatric screen will undergo additional testing. This allows for accurate diagnosis of those with suspicious scores on the screening test, and the evaluation of the random sample of non-high scorers will enable inferences to be made about the prevalence of psychopathology in the total sample. 3.17.7 Referral Policy 3.17.7.1 Referrals Indicated for Medical Reasons Any subject with illness requiring treatment or urgent investigation will be referred back to his local doctor, with a brief note from the MEDICHECK physician explaining the problem and asking for follow-up information. Subsequent investigation and treatment would be arranged by the local doctor. 39 �With the prior approval of each subject, a summary of the complete evaluation will be sent to his local doctor. 3.]7.7.2 Pp_tigns__fgr Referrals Indicated for Research Reasons For some subjects, although there may be no indication for treatment or urgent investigation, there may be symptoms and/or signs which cannot be explained without specialist consultation or referral. There are two alternative methods for obtaining the opinions of nodical specialists in regard to subjects who are thought by the examining doctor to be suffering from a medical condition that the doctor is not able to diagnose accurately. The first alternative (option A) is to confine specialist examination to the 3 areas of particular concern to veterans and of significance in relation to herbicide exposure. gastroenterology and neurology. These are dermatology, For this option, if the examining doctor is of the opinion that the subject has a condition in any of the 3 areas of interest which the doctor is not able to diagnose accurately the subject will be referred to co-operative specialists for full clinical evaluation at AVHS expense. The results of the clinical evaluations of all subjects referred would then be available at the time of data analysis. The second alternative (option B) is to perform the standard medical examination on all subjects prior to referral of any subjects, and at the stage of analysis, if the data suggested that veterans were suffering from particular forms of disability more frequently than controls, selected veterans and controls would be referred to the 40 �appropriate specialists. This appioach has the advantage that there is no prejudgement of areas requiring specialist assistance, thereby throwing the net wider to catch unexpected areas of morbidity; specialist evaluation (and consequent expenditure) is confined to those areas in particular need of investigation; the number of subjects to be investigated is much more readily controlled-than vould be the case with a comparatively open-ended referral system; referral is confined to those subjects that, on full consideration of all data, have inexplicable disabilities. Difficulties are that in the interval between initial examination and subsequent referral some subjects will have changed addresses, and therefore all subjects will be required to notify the Study of all changes of address; subject motivation may have waned, resulting in lower compliance rates. Option B will also delay the completion of the study. In both option A and option B specialist reports would be made available to the Study. 3.17.8 Questionnaire jor Wife/ Female Partner Considerable anxiety has been experience by veterans in relation to decreased fertility and abnormal reproductive outcomes. The separate Case-Control Study of Congenital Anomalies has addressed part of this area, but not infertility, death or disability of offspring, or miscarriages. These will be investigated using a structured telephone interview with the current and previous partners. 41 Attention will be confined to �women who have cohabited with the subject for at least 12 months (or who became pregnant while cohabiting for a lesser period). If contact cannot be made by telephone, a home visit will be made to all wives who live in a capital city, otherwise a postal questionnaire will be sent, to be completed at home. There is no requirement for the partner or children to be present at the examination site, as all abnormal pregnancy outcomes will be verified through medical records. For any treatment received in relation to these outcomes, the year of treatment and name and address of the doctor or hospital will be obtained, to allow verification of the data supplied. For all children biologically fathered by the subject the following data will be sought (from the most recent child, back in time): Sex and birthdates *» Difficulties with any pregnancies Disabilities or death of any of the children. Additional data will also be obtained: Miscarriages leading to curettage in hospital Mothers date of birth. 3.18 Physician Assessment Based on a retrospective assessment of Pilot Study data, two AVHS physicians made judgments about the presence and absence of a number of target conditions, taking into account the symptoms, physical signs and results of special tests. This work has also been incorporated in the Pilot Study Report. The following recommendations can be made about the need for physician assessments in the proposed morbidity study: 42 �(i) An assessment by a physician has high face validity, provided that it is based on a contextual analysis of symptoms, signs and results of special tests. Therefore, in the proposed study each subject should have a brief interview (15 minutes) with a physician, working in the MEDICHECK environment, who will: o assess the results of the MEDICHECK and pencil and paper questionnaires o ask additional direct questions o carry out a physical examination o record judgments about: the quality of the history the presence of designated signs the presence of designated conditions - o other morbidity re-assess his judgments when the results of special tests have been made available. (ii) No case can be made for separating the assessment of the history from the assessment of signs and special tests. (iii) To minimise subjective bias in physician judgments, objective indices should be sought, wherever possible, to support the judgments based on the assessments of symptoms and signs. • For example, to precisely document the prevalence of peripheral neuritis in veterans and controls, a "council of perfection" would be to recommend that clinical examination and nerve conduction studies by • a trained neurologist be carried out on (a) all subjects with symptoms and signs suggestive of peripheral neuritis and (b) a random selection (e.g. 1 in 20) of subjects. 43 �However/ such an option is probably precluded by considerations of cost and acceptability to subjects. The lessei option, i.e. of referral on the basis of suspected signs alone, would be less informative because of the subjective nature of neurological signs when elicited by a physician who is not a practised neurologist. (iv) Ideally, the physicians who carry out the 15 minute interviews and assessments at KEDICHECK should have post-graduate training as physicians (i.e. FRACP qualifications or MRCP) or general practitioners (FRAOGP), and they should be specially selected for the purpose of this study. (v) The exact protocols and proformas for the recording of physicians judgments will be finalised after consultation between MEDICHECK physicians and AVHS physicians. 3.19 Rationale For Number of Subjects The number of subjects to be examined is influenced by several constraints: o The need to complete examinations in 12-18 months to allow the submission of a report in an appropriate time frame, o The total number of subjects available that fulfil the criteria outlined above, o The need for the study to have sufficient power to detect moderate relative risks for conditions of interest possibly associated with Vietnam service. o The need to have sufficient numbers of veterans to test the hypothesis that variables such as combat exposure, herbicide exposure and corps, are predictive of morbidity -within the Vietnam cohort. 44 �Approximately 120 subjects could be examined per week, for a total of 5,760 in a 48 week period. Taking into account delays introduced by not being able to locate subjects at known addresses, and initial failure of some subjects to keep examination appointments, a more realistic total in one year is probably 5,000 subjects. As approximately 6,000 veterans and 9,000 controls enlisted in N.S.W., total numbers available are adequate. For 5,000 subjects, maximum study power is achieved when the numbers of veterans and controls are equal (2,500 of each). Increasing the number of veterans studied to 3,000 (to increase power in relation to explanatory variables within the veteran group) and reducing the number of controls to 2,000 reduces the power of veteran/control comparisons by 4%, a minimal loss. The effect on study power of further increasing the number of veterans is shown in Table 3.4. Table 3.4 Effect of Veteran/Control Ratio on Power. Veterans Controls 2,500 2,500 0% 3,000 2,000 4% 3,500 1,500 16% 4,000 1,000 36% Loss of efficiency Therefore, it is proposed to examine 3,000 veterans and 2,000 controls. 45 �Foi selected conditions of particular interest, the minimum relative risk that would be detected (80% power, P(1) = 0.05) is shown in Table 3.5. The expected prevalence rates are mostly derived from complaints of controls in the Pilot Study. A more detailed table is given in Appendix 1. Table 3.5 Minimum Relative Risks Detectable as Statistically Significant with 3,000 Veterans and 2,000 Controls Condition Estimated prevalence Anxiety Sleep difficulties Depression Temper outbursts Hypertension Numbness and tingling Dizziness Loss of strength Severe acne Burning /itching of skin Persistent rash Minimum Relative Risk 10% 16% 10% 20% 1.2 1.1-1.2 1.2 1.1-1.2 5% 5% 7% 5% 1.3-1.4 1.3-1.4 1.2-1.3 1.3-1.4 3% 13% 13% 1.3-1.4 1.1-1.2 1.1-1.2 Up to 100 deaths are anticipated to have occurred since discharge (18 months to 2 years post enlistment) in this cohort of 7,000. These will be detected via the mortality study. A minimum detectable relative risk of 1.4 for the common conditions of interest indicates that 5,000 is a satisfactory number of subjects. Rare * conditions such as melioidosis, strongyloidiasis and syphilis will, if significant causes of morbidity among veterans, have much larger relative risks than 1.4. Lack of adequate general population prevalence rates makes power estimation impossible. Rare manifestations of common exposures such as 46 �alcohol (eg Korsakow's psychosis) are not of relevance here, as there are much more common manifest ions that will allow evaluation of veteran/control differences arising from any differences in patterns of alcohol use. Any infrequent but distinctive effect of Vietnam service or herbicide exposure might be provisionally identified on clinical grounds even if its frequency was not statistically increased in veterans (e.g. 6 cases in veterans, none in controls). For instance, there would be only 2 or 3 cases of a condition with the incidence of multiple sclerosis in this group of 5,000 men. This study will not specifically investigate cancer incidence for the following reasons: i. The study would have very low power to detect veteran/control *• differences due to the infrequency of cancer in this young age group, ii. The mortality associated with cancer would reduce the number of subjects giving a past history of cancer, iii. Subjects with cancer may not be sufficiently well or motivated to present for medical examination, iv. The long latent period for developing cancer. 3.20 Index of Herbicide Exposure 3.20.1 Objective Determination of Herbicide Exposure Determining individual herbidide exposure in Vietnam from spraying mission and troop movement data is considered in other reports (Adams et al., 1981). 3.20.2 Subjective Reports of Herbicide Exposure The relationship between subjects reporting of herbicide exposure and morbidity will be difficult to interprete for several reasons: 47 �The events occured 12 to 17 years ago and therefore recollection is likely to be inaccurate. At the time the spraying was taking place the soldiers did not know what chemicals were being sprayed. It may be anticipated that as a result of the publicity surrounding the issue and the desire for compensation those subjects with morbidity will be more likely to recall being sprayed independent of whether they were actually sprayed. It may be possible to analyse this latter problem, one of recall bias, by determining the relationship between current morbidity, reported exposure to herbicide and the likelihood of herbicide exposure determined by the HOPPS programme. In spite of this potential bias it is important to collect and assess the utility of subjective reports » of herbicide exposure. 3.20.3 Quantity of Herbicide Sprayed Each Year The volume of herbicide sprayed in the RANCH HAND programme in Phuoc Tuy in each year of the Vietnam War is known (Table 3.6). Table 3.6 Annual Herbicide Usage in Phuoc Tuy Province by Agent According to HERBS Tapes 1965-1971 Amount of RANCH HAND herbicide sprayed in Phuoc Tuy (in thousands of litres) Year Agent Orange 1965 1966 1967 1968 1969+ Total White 90 200 490 240 140 570 "~ • * 1020 Blue ^^ ^ - 50 • 710 48 50 Total 90 200 680 810 " 1780 �Thus the chronologic year of service in Vietnam is useful as an explanatory variable, although herbicide usage and level of combat are probably highly correlated. 3.20.4 Exposure to Herbicide in kustralia If herbicide exposure does have a measurable effect on morbidity, the relationship between herbicide exposure in Vietnam and current morbidity is potentially confounded by herbicide exposure in Australia. Therefore data will be sought from subjects on occupational exposure to herbicides. 3.21 Index of Combat Exposure American literature suggests increased prevalence of war-related disorders amongst those troops closest to the 'front-line1 of combat (Penk et al., 1981). In analysing relationships within the veteran group it is therefore important to assess the degree of combat or danger to which veterans were subjected. This will be done in several ways: 1. Chronologic Year of Vietnam Service. The risk of death or wounding as a function of year of Vietnam service will be determined and used as an explanatory variable. 2. Corps Subject's Corps will be used as an explanatory variable, as some Army Corps (Engineers, Infantry, Armoured, Artillery, Signals) engaged in contact with the enemy, and other did not. 3. Subjects Injured in Combat The Central Medical Record of each subject will be reviewed 49 �and the presence of any combat injuries recorded, along with their nature, cause and duration of hospital treatment (see section 3.22.2). 4. Casualty Rate of Units (Combat Index) With "Casualty Reports' (the completeness of which is not yet known) and Vietnam Unit postings data, the incidence of combat wounds and deaths will be compiled for all Units, if feasible. With data on each subject's Vietnam postings from his CARD dossier (see section 3.22.1) the risk of combat injury and death will be calculated for each subject. 5. Subjective Combat Exposure Figley (1980) has developed a questionnaire which quantifies combat exposure, which he has validated on a small sample. Only minor modification is required to make it applicable to Australian Vietnam veterans. Only veterans will be asked to complete this instrument, as it is not applicable to controls. 3.22 Army Dossier Data Held on Each Subject The personal (CARD) dossier, Central Medical Record and psychology record cards together contain a wealth of information about almost every aspect of a serviceman's period of service. This material is potentially available, is not subject to recall bias, and constitutes a valuable source of baseline data for each subject, enabling comparisons of veterans and controls at the time of enlistment and during the period of service. are outlined below. 50 More specific uses of these data �For all 5,000 subjects it is proposed to extract certain data from these records for UKO in the analysis and interpretation of findings from the medical examinations and to compare the enlistment and Army service characteristics of subjects who present for examination with those who do not. The extraction of these data therefore need not precede the medical examinations, but will be concurrent. 3.22.1 CARP Dossier Data to be extracted: Verification of veteran/control status Verification of Vietnam postings for veterans. Disciplinary proceedings Promotions Volunteer/bal lotee The CARD dossiers of all current and former members of the army are held in the Central Army Records Office (CARD) in Melbourne, except for those of serving Officers (Military Secretary's Office, Canberra). These data will be used to derive each subject's risk of combat injury or death (Sec. 3.21), and to see if ability in the army or disciplinary problems are related to current morbidity and social and psychological functioning. 3.22.2 Central Medical Record; Data to be extracted: 1. From enlistment medical examination: Weight, height Significant past medical history PULHEEMS rating (Army fitness ratings, see Appendix 2). 51 �2. Hospital admissions: Type of disease Duration of admission Residual disability 3. From discharge medical examination: PULHEEMS Theso data will be used to determine to what extent current morbidity existed at the time of army service, or has arisen subsequently. 3.22.3 Psychology Record Card Three types of data will be extracted from the psychology record card: i. Enlistment psychology test results. The comparison of these test results between veterans and • controls, and with scores obtained when retesting subjects 10 to 15 years later, will permit valuable comparisons of veteran and control subjects both prior to and after army service. The relationship between test scores and subsequent morbidity is also of interest, ii. Corps preferences expressed by recruits. The preferences for corps reflects the desire of a member for combat (e.g. prefers Armoured, Infantry, etc) or non-combat (e.g. Ordnance, Catering, Band, Transport) roles, and are therefore potentially valuable explanatory variables in analysing the relationship between desire for Vietnam service and subsequent morbidity. The completeness of these data is adequate, although not 100%. 52 �iii. Referral for Psychological Opinion. The referral of a soldier for psychological evaluation may bear significantly on current morbidity and therefore such data will be obtained. Data from all three types of records will be transferred directly onto a data entry sheet for ease of computer entry and analysis. 53 �STUDY PROTOCOL 4. The outline of the design of the Morbidity Study is shown in Figure 1. Figure 1. Overall Plan of the Morbidity Study Development and testing of examination procedures (Section 4.9) Subject selection (Section 4.1) I I Subject location and invitation (Figures 2 and 3) V Search Army records (Section 5) Subject examination (Figure 4) reception questionnaires testing physical examination detailed testing of a sample Record data Specialist r e f e r r a l Option A Section 4.5.11 Partner/wife location (Figure 5) Verification of medical data (Section 4.10) I J \ Data entry (Section 6.1) Specialist r e f e r r a l Option B Data analysis (Section 6.2-6.5) Report findings 54 Partner interview (Section 4.6) �4.1 Subjcct Selection 4.1.1 Definition of Veteran Status A Vietnam veteran is a national serviceman who served at least 13 weeks who went to Vietnam within two years of enlistment during the period of the war, irrespective of the duration of Vietnam service, and who was discharged alive or survived for two years after enlistment. 4.1.2 Definition of Control Status A 'control' subject is a national serviceman who served at least 13 weeks, who did not go to Vietnam but was drafted in an intake from which national servicemen were sent to Vietnam (June 1965 to February 1971) , and who was discharged alive or survived for two years after enlistment. 4.1.3 Process of Subject Selection Former Vietnam war period national servicemen only; N.S.W enlistees only; Date of original enlistment February 1971 or before; Served at least 13 weeks; Discharged alive or survived for 2 years post enlistment, whichever occured first; Randomly select a uniform proportion of veterans from all intakes to yield 3,000 veterans; Randomly select 2 controls for every 3 veterans from each intake (to yield 2,000 controls); Randomly allocate veterans and controls to 10 blocks, each with 300 veterans and 200 controls; �Blocks of subjects are invited to participate sequentially until 5,000 subjects have been examined. For the subjects within each block selected, full measures will be taken to maximize the participation rate (see section 4.3). 4.2 Obtaining Current Address Current addresses will be sought only for the 5,000 subjects selected. 1. Current serving member of the army. Address from CARO and serving unit. If not a current serving member, go to stage 2. 2. Subjects names matched with computerised registers: Current Electoral Register, and N.S.W drivers licence register, and S.A. drivers licence register, and N.T. drivers licence register, and Tas drivers licence register, and (possibly) W.A. drivers licence register. If a name matches and an address(es) is found, it is stored on the study subject file. If no match occurs go to stage 3. 3. Subject whose names are unmatched after stage 2: Names matched with manual registers: QLD drivers licence register, and Vic drivers licence register, and Immigration and Ethnic Affairs 'arrivals and departures' microfiche. If a name matches and an address is found it is stored on the study subject file. Note; Matching in stages 1,2, and 3 has been performed in the Mortality Study. 56 �4. Subjects whose names are unmatched after 3: Names matched with: Commercial credit bureaux and Criminal Records Bureau (if available), and Department of social Security files (if available). If a name matches and an address is found it is stored on the study subject file. 5. If an address if found, yet subsequent tracing fails to locate the subject, the name will be matched with those registers in stages 2,3 and 4 not yet used for that name. This stage can only occur after an attempt at initial contact has been made. 6. Once an address has been found, telephone books and Telecom will be consulted to obtain a home telephone number if required. » See Figure 2 for plan for obtaining subject addresses. 57 �Fiaurc 2 Name_ & D.O.B. "t-'~ f ' • Not Currently Serving in Army -. ^ Currently Serving in Army^^ I Address exact match Computer Search of Computerised Matching Sources: \ ^ A D D R E S S Elect. Roll/Mot. Req. I no match 1 f Manual Search of r>mnmi4-ni- { r.~.A -r*A computer i sea ana Manual Motor Registries F I L E I noTO£i4"f'V'i Ilw Ilia Ui^ii SEARCH " Immigration & ^^ Ethnic Affairs j n ; arrived: address available not listed Army Record: Parents/N.O.K. ^ parent(s) ^ ^ N.O.K. Address ^ 1 UrM-4- al 'i t-\f List 1 SEARCH alive Reaistrar(s) General ^ name change ^ Initiate Search ™" using New Name »o name change 1 Other: V.A. n SEE FURTHER k PROCEDURES PROTOCOL Cr\r* i A 1 Qof^ DOC laX DCt, . Corr. Serv. Def. Forces H. Corp 58 �4.3 Methods of Obtaining Compliance for Medical Examination 4.3.1 Contact Procedures For each address obtained, a sequence of contacts will be made until an appointment is made for the subject to attend for examination (see Figure 3). A record will be kept of all attempts made to contact each subject. For subjects living in the country, telephone calls will be substituted for personal visits. Stage 1. Sequence until contact made: 1st mailing - introductory letter followed by an appointment card. 2nd mailing - letter plus appointment card. Telephoning (if possible) Personal visit to enlist participation. If no contact has been made with the subject go to stage 2A. If contact has been made with the subject but he has not presented for medical examination, go to stage 2B. Stage 2A Seek new address, firstly by visiting or telephoning the most recent address found on register searching, and then if no contact is made, seek another address on the registers (see section 4.2, stage 5). Stage 2B Contact subject again by telephone and make another appointment. If 2nd appointment not kept, or no telephone contact possible, make personal visit to arrange appointment if the subject is a capital city resident. If the subject still fails to attend, see section 59 4.7. �Figure 3 1 H3*? Subject Contact Procedures KNOWN ADDRESS Mail 1 1 Contact Participation Contact Participation Contact Participation no contact 1 no contact 1 I 1 Home Visit no contact Seek New Address 60 �4.3.2 F_i ni a nc_i_a 1. ..Compe n ca t_i on Full economy class return fares for travel between home and the examination site by taxi, country train or aeroplane will be paid to all subjects. Full compensation for lost earnings will be provided to the subject or his employer upon receipt of appropriate documentary evidence. 4.3.3 A_dd_i_ti_ona_l Means of Maximizing Compliance A covering letter signed by the Minister for Veterans' Affairs will be sent to all subjects, mentioning that the investigation is supported by the leaders of the major political parties, the Returned Servicemen's League and the Vietnam Veterans Association of Australia, if such endorsement can be obtained. Advertisements and feature articles and programmes in the public media would be • valuable. 4.4. Outline of Design of Medical Examination All subjects presenting for examination will undergo:- V.D.U. questionnaire Pencil and paper questionnaire Neuropsychology and psychiatric screening tests Blood and urine testing Electrocardiogram, lung function test, chest x-ray, hearing and vision test, height and weight measurement Physical examination and evaluation by a doctor See Figure 4 for plan for medical examination. 61 �Figure 4 Plan For Medical Examination Reception identification list of current complaints Blood and urine specimen collection NEDICHECK Questionnaire (administered using Visual Display Unit) Pencil and paper questionnaire I Neuropsychiatric screening Additional tests: ECG, CXR, spirometry, ht and wt, audiogram, visual acuity 1 t I Checking of incomplete or inconsistent responses Physician examination and assessment Neuropsychiatric evaluation Discharge 62 �High scorers on the neuropsychiatric screen plus a 10% random sample will undergo detailed neuropsychiatric testing. Under option A subjects with suspected undiagnosed gastroenterologic, dermatologic or neurologic conditions will be referred to appropriate co-operative specialists for full clinical evaluation. Under option B, any referrals for specialist opinion for research purposes will depend upon the results of initial analyses of the morbidity profiles of veterans and controls (see 4.5.11). The current and previous wives/female partners will be interviewed by telephone, and failing that will be interviewed at home or sent a pencil and paper questionnaire, to be returned by mail. Subjects who are located but do not present for examination will be asked to complete as much of the questionnaire (all pencil and paper) as possible, and give a blood and urine sample. Subjects will be referred to their local doctors for management, where indicated on clinical grounds. 4.5 Design of Examination Procedure for Subjects MEDICHECK 4.5.1 component Recept ion Name taken and identified on subject list. yes Given written request to answer all questions as honestly and completely as possible. no Given form to describe (unprompted) all current complaints, with severity and duration. 63 no �MED1CHECK component 4.5.2 Blood and Urine Samples taken yes Blood tests: Biochemistry Glucose, lipids, electrolytes, urea, creatinine yes Liver enzymes, serum protein yes Drug screen* - benzodiazepines, salicylate no Alcohol* no Microbiology VDRL Screen* no Melioidosis and strongyloides serology* no Hepatitis B serology*: no 1. Core antibody - indicator of past infection. 2. Surface antigen if core antibody (+) - indicator of current infection. 3. Be antigen if surface antigen (+) - indicator of infectiousness. 4. Surface antibody if surface antigen (-) - indicator of resolved infection. Contractual arrangements with additional laboratories will be required for these tests. 64 �MEDICHECK component Harmatology Hb, MCV, MCHC yes WCC, ESR yes Platelet count ' " yes Urine tests Culture yes 'Dipstix1 chemical testing - Hb, protein, glucose, bilirubin, pH yes Additional serum for storage 4.5.3 no MEDICHECK Questionnaire yes Questions in Yes or No format, will cover the following areas: Marital status Job satisfaction block Financial status/problems Sleep/worry Depression and state of mind Drinking habits Smoking habits Exercise Tablets Bereavements and family history Coronary symptoms Leg pain symptoms Heart beat/hypertension Breathlessness, numbness, varicose veins 65 �MEDICHECK component Ankle oedema symptoms Lung problems and diseases Abdominal diseases and history Sexual problems VD end U/G history, infections, operations Joint & muscle pains/arthritis Neurological symptoms Skin disease and allergies Vision and eye problems Ear, nose and throat problems Tropical diseases Infections and miscellaneous diseases » The questionnaire will take up to 40 minutes to complete. 4.5.4 AVHS Questionnaire no Pencil and Paper Questionnaire: Occupation, employment Education Marital and offspring history Wife/partner identification Reasons for Vietnam/non-Vietnam service Combat experience Combat injuries Alcohol and tobacco consumption - diary Chemical exposure in Vietnam Exposure to noxious substances 66 �MEDICHECK component Other drug consumption including tea and coffee Medical and hospital consultations - reasons, when, duration, name and address. Medical record release Herbicide exposure in Australia 4.5.5 Keuro-Psychiatric Screen Interview by clinical psychologist, assessing psychiatric no pathology using the Present State Examination (PSE) , assessing post traumatic stress disorder, interpersonal relationships, and psychological well-being. Tests of psychological functioning, given to all subjects: AVHS schedule of life events Eysenck Personality Inventory Army Self Description Inventory Symbol-Digit Modalities Test Supra-Span Digit Learning Test Trail Making Test Nelson Adult Reading Test Army Speed and Accuracy Test. 4.5.6 Additional Tests Electrocardiogram yes Chest x-ray yes Spirometry yes Audiogram yes Visual acuity yes Height and weight yes 67 �While these tests are being performed, the AVHS questionnaire and ncuropsychiatric screen will be checked for completeness and consistency of answers, and the neuropsychiatric tests will be scored, to determine whether the subject needs further psychiatric or neuropsychological testing as a 'high scorer1. If incomplete or inconsistent answers are detected, the interviewer will ask the subject to correct his answers at the end of the 'Additional Tests' section. 4.5.7 Doctors Examination and Evaluation The examining doctor will have the results of the MEDICHECK questionnaire and the AVHS questionnaire, and will seek further information from the subject to guide his/her clinical formulation of the subject's morbidity. Physical examination will be directed toward arriving at a conclusion about problems suggested by the questionnaires and the history. In addition, examination will be directed toward detecting abnormalities in the following areas: Skin Hepatosplenomegaly Neurological screening examination Thoracic auscultation Legs ~ vascular, reflexes, sensation Blood pressure Auditory canals and tympanic membranes (to facilitate interpretation of audiogram) 68 �Blood pressure measurement and ear examination could be performed by technicians. The doctor will then record all physical signs found and his clinical impression in the form of differential diagnoses, with confidence ratings. Three days later, when the results of pathology tests are available, he will have an opportunity to reassess and modify or add to his list of possible conditions. 4.5.8 Detailed ^euro-psychiatric Assessment. Subjects who are "high scorers' on the neuropsychiatric screen plus a 10% random sample will undergo detailed neuropsychiatric assessment consisting of both pencil and paper tests: Hostility Questionnaire Spielberger Anxiety Scale Depression Questionnaire. 4.5.9 Specialist Referral Two options have been identified with respect to specialist referral: Option A; If, in the opinion of the examining doctor, a neurological or gastroenterological condition is suspected, he will be referred to specialists who have agreed to co-operate with AVHS. The specialist will carry out a full evaluation as warranted by the subject's symptoms and signs. If, in the opinion of the examining doctor, a subject has an unusual skin condition, or if any doubt exists about the diagnosis of a skin 69 �condition, the subject will be referred to a dermatologist for consultation. Option^ B; At the stage of data analysis the frequencies of disabilities will be compared for veterans and controls. If, after adjusting for the relevant confounding variables (e.g. alcohol consumption in the case of liver disease), an apparent excess in veterans is evident, the affected veterans and controls will be identified on the subject file. Within this group, samples of veterans and controls with no obvious clinical explanation for their examination findings will be referred to the appropriate specialist for full clinical evaluation. The arrangement between AVHS and specialists will provide for a full report to be sent to AVHS with regard to every subject referred. 4.5.10 Local Doctor Referral If, in the opinion of the examining doctor a subject has a condition requiring treatment he will be advised to consult his local doctor immediately. With the prior approval of each subject, his medical report (including specialist reports, if applicable) will be sent to his local doctor. 4.6 Information From Wife/Female Partner 4.6.1 Definition A partner will be any woman who has cohabited with the subject for at least 12 months, or who became pregnant while cohabiting for a lesser period. Thus each subject could have more than one partner. 70 �4.6.2 Ver_if_ication of Address All subjects will be asked to provide the full names, dates of birthf telephone numbers and current addresses of their partners, if known. For partners where the address is unknown, it will be sought on the Electoral Register microfiche, and then telephone number sought in telephone directories (see Figure 5). 71 " �4.6.3 Figure 5 J Plan for Partner Follow-up KNOWN ADDRESS Telephone Participation Contact J no contact 1 J Participation Mail no contact Home Visit.. Seek Participation Contact 1 no contact 1 Seek New Address 72 �4.6.4 Questionnaire A structured telephone interview will seek the following information, for the most recent pregnancy and then for any other pregnancies going back in time: Mothers date of birth. Outcome of pregnancy Difficulties with the pregnancy. (If yes, year and name of treating doctor or hospital). Miscarriages leading to curettage in hospital. (If yes, year and name of treating doctor). For each child biologically fathered by the subject: sex and birthdate Congenital anomalies or death (If yes, year and name of treating doctor) . A medical record release will be sent to participating partners for signature and return by mail. 4.7 Follow-Up of Non-Complying Subjects 4.7.1 Additional Strategies for Obtaining Compliance. If a subject fails to present for examination after 3 appointments have been made, or, if at an earlier stage he expresses a desire not to present for examination, he will be contacted at home and a modified health evaluation performed. This contact will be by telephone if the subject lives in the country or personal visit (initially) if the subject lives in Sydney, or the capital city of another State. 73 �ESllow-up of Non-Complying Subjects Figure 6 Appointmont made Appointment kept End of follow-up ^.Appointment kept End of follow-up Appointment not kept i J 2nd and 3rd appointment made Appointment not kept State capital city resident Able to be contacted by telephone? Country . resident \ No Yes >me visit to .e appointment X \ Telephone interview Appointment kept i Appointment not kept Pencil and paper questionnaire 1 \ Returned? End of follow-up T 1' / 7 / Yes, / / End of End of follow-up follow-up No "< 2nd questionnaire sent I Home visit for interview and sample collection Returned? No End of follow-up Reminder letter 4 End of follow-up �4.7.2 He a 1J h Evaluation Modified for Home Administration. List of current complaints VDU questionnaire in pencil and paper format AVHS questionnaire Neuropsychiatric screen Reasons for reluctance to co-operate If nurse available: Blood samples Urine sample Blood pressure measurement 4.7.3 Hierarchy of Data to be Sought Data will be elicited in a particular order so that if the subject becomes reluctant to continue at any point the most critical data will have been gathered. A suggested sequence is given below but this will be modified in the light of experience with initial home interviews. Order of precedence: Blood pressure measurement List of current complaints Combat exposure (veterans only) Reasons for Vietnam/non-Vietnam service Sleep/worry Depression and state of mind Drinking habits Smoking habits Tablets Marital status 75 �Job satisfaction Medical and hospital consultations Medical record release Neuropsychiatric screening Social adaptation Family coherence Behavioural Education Occupation, employment Neurological symptoms Abdominal diseases and history Skin diseases and allergies The remainder of the MEDICHECK questionnaire The remainder of the AVHS questionnaire Blood samples Urine sample 4.8 Follow-up of Non-Complying Wives/Female Partners 4.8.1 Additional Strategies for Obtaining Compliance Partners not able to be contacted by telephone will be visited at home if residents of a State capital city, and failing that, will be sent a pencil and paper questionnaire. Partners failing to return a questionnaire will be sent another, and then a reminder letter. 4.8.2 Suggested Hierarchy of Data to be Sought Order of precedence: Sex and birthdate of all children Death of children 76 �Miscarriages leading to curettage in hospital Difficulties with pregnancies Mother's date of birth For each occurrence: when name and address of institution or treating doctor Medical record release 4.8.3 Data Not Able to be Obtained All data not obtained due to poor compliance will be coded to indicate this. 4.9 Pilot Testing of Medical Examination The components of the routine MEDICHECK evaluation that are being retained will not require specific pilot testing. The AVHS questionnaires for subjects and wives/partners will be tested on a small sample of men and women (not study subjects) prior to the commencement of the medical examinations to detect and overcome any ambiguities or problems which might arise during questionnaire administration. The sources of men and women for pilot testing have not yet been determined. The physician assessment will be pilot tested by MEDICHECK doctors prior to commencement of AVHS medical examinations, and the comments provided by the doctors used to modify both the physical examination protocol and the documents used to record clinical findings and judgments. Following this, it is intended to operate the examination centre for a 1 or 2 week period initially, to determine how long the various components of the examination take, how many subjects will keep a first appointment and to 77 �discover any logistic or organizational problems. This examination period will be followed by a 1 or 2 week break, while solutions are found to the problems revealed by the initial run. Following this, the examination centre will commence full scale operation. 4.10 Verifying Data in Medical Records All medical data volunteered by subjects or partners that is accompanied by the name of a treating doctor or hospital and signed release form will be verified. A letter giving the reported complaint and time of occurence will be sent to the relevant doctor or hospital with a request for substantiation of the condition and for the provision of more accurate or clarifying information. The verified data will not be used to replace data volunteered by the subject* but will be retained for complementary analyses. 78 �5. ADDITIONAL DATA FRQM_ARMY ^SOURCES 5.1 Caro Dossier Verification of: Dates of birth, enlistment, discharge Veteran/control status Corps Civil education Vietnam postings data Obt a in: Australian posting data Special courses completed Disciplinary offences Promotions Volunteer/ballotee 5.2 Central Medical Record Verify: Enlistment and discharge PULHEEMS (Army health rating APPENDIX 2) Obtain: From enlistment medical examination: Weight, height Significant past medical history PULHEEMS Hospital admissions: site (e.g. Vietnam, Australia) 79 �type of pathology (trauma - combat/non combat, sexually transmitted disease, other infection, drug induced, psychiatric, other stress-related,) duration of admission From discharge medical examination: PULHF.EMS 5.3 P_sychology Record Cards Obtain: All test results Corps preferences - 1st, 2nd, 3rd. Referrals - reason (application for course or promotion, disciplinary problem, psychological problem). - date. 80 �6 • 6.1 DATA ASSESSMENT AND ANALYSIS HaJr.£L Acqui si t ion and Vertical ion Baseline information from the MRCC tape has been checked for logical inconsistencies, and where possible, for inconsistences with the CARD tape. As error emerged, they have been checked against original dossiers in CARO. Follow-up information, including last known address will be stored on computer disc file and verified against the original source documents. This information will be used as a basis for a master file which will be used to record the appointment and compliance history of each subject. A parallel file will be developed for the corresponding information on wives and female partners. Combat exposure information will be derived from manual searching of army records, and the reliability of coding, punching and verification will be established during pilot studies and spot checks of the final data set. Verification of veteran/control status is essential. For some individuals on the MRCC tape there were logical inconsistencies - eg "veterans" with periods of service which were far too short for them to have served in Vietnam. This suggested that there are errors on the tape, either in relation to veteran status and/or in relation to duration of army service. All inconsistent records have been checked manually and manual spot checks will be made of other "self-consistent" computer records to assess the accuracy of the remaining information on the MRCC tape. 81 �Furthermore, if at the time of interview there is a conflict between the reports of the subject ("I went to Vietnam") and the computer record ("he is a control"), the details will be returned to CARD for clarification. Final data will be coded according to the correct (CARO) classification. Interview information will be obtained from computerised MEDICHECK records, from AVHS pencil and paper questionnaire, from psychiatric questionnaires, neuropsychology assessments and physician assessments. The reliability of coding, punching and verification will be established during pilot studies and spot checks of the final data set. 6.2 Adequacy and Utility of Morbidity Study Data 6.2.1 Comparability of Follow-up of Veterans and Controls As shown in Table 3.3, there is suggestive evidence that the proportion of NSW veterans found on the Electoral Register (78%) is less than the proportion of controls (81%); furthermore, of those found on the register, the proportion of veterans presently living outside NSW, (12%) was greater than the proportion of contols (9%). These differences may reflect differences between veterans and controls in relation to socio-economic factors, employment and social mobility. It should be noted that the men who will be most difficult to trace (namely those men who are single, divorced, separated, itinerant, unemployed, or alcoholic) are most likely to be at greatest risk of disability. Thus in order to minimise any bias between veteran and control families arising from incomplete follow-up, it will be 82 �important to reduce the number of untraced men in both groups to an absolute minimum. Some idea of the magnitude of bias arising from incomplete follow-up could be obtained by looking to see how the morbidity of each veteran and control subject varies with the amount of follow-up required to trace him (i.e. was his address found in a primary, secondary or other source) . 6.2.2. Complicance Rates for Veteran and Control Subjects Even if the follow-up is adequate for both veteran and control subjects (e.g. 95% or more followed to their most recent address), the results of the morbidity assessments could still be biased if there were a difference between veteran and control rates of compliance with the interview. The most likely bias would be for veteran subjects with a disability to be more compliant than control subjects with a disability. After maximising the compliance rate, the magnitude of any residual bias could be assessed by comparing the morbidity profiles of veteran and control subjects according to whether they attended the first, second or third appointment. These data can also be compared with the (incomplete) data obtained from non-compilers at a home interview. If the morbidity patterns do vary according to level of compliance (appointment) then this can be adjusted for (at least in part) during the analysis of the results. 83 �6.2.3 Subjectivity of Self Reported Information A major source of potential "bias" is that self reports from veterans are likely to be influenced by an expectation of disability which is greater than that of non-veterans. This tendency, whether it is conscious or sub-conscious, could be so general that it could lead to quite marked differences between veterans and controls in the prevalence of symptoms related to many different disabilities. The potential for such bias will lead to major problems in the interpretation of all subjective information collected in the course of this morbidity study. Similar problems of interpretation have been encountered in assessing the symptoms of "effort syndrome" and "combat syndrome" in servicemen from previous wars, and in assessing symptoms associated with "compensation neurosis" after injury at work or in road accidents. There are several approaches to this problem of interpretation. It may be appropriate to accept the reality of the symptoms, as such, and to explain them as being consequent on the psychogenic stimulus (of the war). This interpretation is, of course, more plausible if the symptoms can be identified as components of a depressive syndrome, an anxiety reaction or if they can plausibly be identified as somatic equivalents of psychogenic origin. In some circumstances the physical findings may support a functional diagnosis (eg tachycardia, sweating and hyperventilation if otherwise unexplained), and in other circumstances the functional origin of symptoms is supported by their 84 �pjpomorphic or protean nature, and by their failure to fit an organic syndrome. However, the functional or psychogenic origin of symptoms should only be accepted after steps have been taken to exclude an organic or biologic basis for the symptoms. An organic basis can be suggested by the pattern of symptoms: thus if a veteran complains of chronic productive cough, shortness of breath on exertion and give a history of heavy smoking, we would be justified in suspecting the presence of chronic obstructive airways disease. This could be confirmed by physical examination or by objective testing. The presence of dissimulation or malingering might be suspected if there were a constellation of plausible symptoms, together with an absence of supportive objective signs. In some subjects it may be possible to suspect dissimulation if there is a high score on the social desirability scale administered as part of the psychological assessment. However, in general it will be necessary to assume that all symptoms are real, to analyse the contexts in which the symptoms are found, and to look to the epidemiological data, the physical examination and objective tests to provide clues about the physical disabilities which may underlie the symptoms. In the context of this study, the analysis of subjective information is made easier by the fact that we are not necessarily required to make judgments about the physical bases of symptoms in individual veterans; it will suffice to show that in veterans as a group, such 85 �and such a symptom complex is associated with objective signs of disease significantly more often than in similar groups of control subjects. For those symptom complexes which are not supported by objective measures, the symptoms might be provisionally identified as being of functional or psychogenic origin. However, if these symptoms are found to be more frequent in veterans, and specifically if they are correlated with measures of combat exposure or herbicide exposure, then they can plausibly be regarded as real effects of war service. Certainly, if any functional syndrome is associated (see 6.5) with a measurable outcome which is more frequently observed in veterans (e.g. more frequent divorce) then it should probably be counted as one of the real hazards of army service. 6.2.4 Objective Measures Several objective measures are available. For example, lung function testing will provide an objective test for chronic obstructive airways disease, biochemical tests on plasma will provide objective evidence of abnormalities of liver function and help to detect heavy drinkers. Objective tests are also available for the detection of past hepatitis B infection and for the detection of past syphilitic infection. Neuropsychological tests for the detection of brain damage and neurophysiological test of nerve function can also be regarded as objective. The importance of these objective tests is not that they will provide a definitive medical diagnosis in their own right, but rather that they can provide independent support for disabilities which might be 86 �suspected from the pattern of symptoms and from signs reported by the examining physician. As argued in the previous section, although this objective support might not be evident in every case with symptoms, it should be sufficient to show whether, as a group, veterans symptoms are significantly associated with objective measures more often than in similar groups of control subjects. Because of the importance of objective measures, and because of the need to make inferences about the whole population of veterans and controls, we have argued that objective measures should be included either: (i) for all veterans and controls, or (ii) for randomly selected veterans and controls, plus those who have a clinical indication or those who fail a screening test. 6.2.5 Face Validity of Medical Diagnosis Made by a Physician Medical diagnoses made by a physician must be accorded face validity, because the practice of diagnosis is defined in terms of the judgment of the physician. This is not to say that a judgment of a physician is necessarily reliable and objective, but as it is based on a contextual analysis of symptoms, physical signs and the results of special tests (gestalt), it provides an assessment of the meaning of the data which can be obtained in no other way. Nevertheless, because a physician's judgments are subject to error, it is important to consider the possibility that there may be a systematic bias in diagnostic accuracy between veteran and control subjects. Such a bias could invalidate any conclusions which were 87 �based on physician judgments. To minimise this bias in the pilot study, a decision was made to "blind" the physician carrying out the physical examination to the veteran status of each subject and to the results of the medical history (and vice versa). As a result, the judgments made by the physicians were out of context, and they were less helpful than might otherwise have been expected. It would be unwise to separate the assessments of symptoms and physical signs in the proposed morbidity study, although it would be desirable to try to maintain "blinding" of the physician to the veteran status of each subject during the examination. However, regardless of the precautions taken, it is unreasonable to suppose that the physician will always remain ignorant of the veteran status of each subject; accordingly it will be impossible to always exclude physician bias as an explanation for (minor) differencies in the frequency of certain diagnoses in veteran and control groups. This conclusion is not as gloomy as it sounds, in that it will be possible to test some of the medical diagnoses made by the physician against objective data which are free from bias. For example, suppose that on the basis of physicians' dignoses, the frequency of alcoholic liver disease appears to be higher in veteran than in control subjects. This difference could be real, or it could be a result of a systematic bias in the physicians assessments. However, if the objective tests of liver function show more abnormalities in veterans than controls, this would suggest that the difference in diagnostic frequency reflected a real difference in disease frequency, and not just a diagnostic artefact. 88 �On the basis of this example, it might be argued that it would be wise to discard the physicians' judgments and to rely on objective tests alone. Such a policy would be misguided, for several reasons: (i) Objective tests are not available for all organ systems. (ii) Although objective tests can identify the organ system involved (eg liver), additional information is usually neded before an aetiological diagnosis can be made. (iii) Physician judgments are based on contextual clues, and on an "intuitive" synthesis of the available information. It is not possible to automate this synthetic function of the physician, if only because of the difficulty of capturing and codifying all the observations upon which his judgments are based. Any attempt to use the physician merely as an "observer" would be misguided, because it is impossible to separate "observation" from "theory" (contextual analysis and selective aquisition of data to test provisional diagnoses) in the course of medical diagnosis. (iv) The face validity of physicians judgments is widely accepted, both in the medical and in the lay mind. Thus a study which ignored the opinions of physicians could lack credibility in the eyes of the community. 6.2.6 Data From Wives and Female Partners Data from wives and female partners will be obtained via telephone, face-to-face interview or written questionnaire to assess pregnancy outcomes, birth defects and children's health. The data will suffer from subjective bias and selective recall, and even if there is no 89 �real difference, these results could suggest that there is a greater frequency of disability in the families of veterans than in the families of control subjects. Several strategies can be used to assess the validity of these subjective responses. The first is to verify the reported medical condition or event (eg stillbirth, birth defect, curettage for miscarriage) with the medical attendant or hospital authorities. This procedure is adequate as far as it goes, but it suffers from the defect that it is not possible to verify an event which has been forgotten or not reported in the first place. Thus, even using an outcome criterion such as hospital admission for miscarriage, it will not be possible to exclude the possiblity of selective bias in recall between veteran and control wives. The potential for biased will be even greater for those (early) miscarriages which did not result in a hospital admission. Hospital admissions occuring after 1978 are also likely to be subject to bias because of the publicity, from 1979 onwards, surrounding the alleged effects of herbicides. There is less likely to be bias for hospital admissions occuring before 1979. For those outcome conditions which leave a more or less permanent trace (eg surviving children with birth defects or spasticity) the validity of the wife's responses could be assessed, in part, by arranging for a follow-up medical examination of the children affected. This could undoubtedly confirm the diagnoses in the (most severly) affected children, but it would not exclude the possibility 90 �of bias in the initial reporting. For example, it is plausible that there would be less incentive for the wife of a control subject to report the presence of a disability in one of her children, and such a child, if unreported, would be missed from the follow-up study. 6.3 Hypotheses to be Tested 6.3.3 Descript ivc Hypotheses The null hypothesis is that there are no differences in the frequency of disabilities between Vietnam veterans and controls (national servicemen who did not go to Vietnam). This null hypotheses will be tested against each of the following alternative hypotheses: (i) That social and behavioural disabilities (unemployment, separation, divorce, motor accidents, alcohol abuse) are more frequent in veterans than in controls, (ii) That anxiety, depression and other psychiatric disabilities are more frequent in veterans than in controls, (iii) That disorders of the nervous system (including neuropsychological disorders) are more frequent in veterans than controls, (iv) That liver disorders are more frequent in veterans than controls, (v) That gastro-intestinal disorders are more frequent in veterans than controls, (vi) That skin disorders are more frequent in veterans than controls, (vii) That infertility, miscarriage or childhood disability or death have been more frequent in the families of veterans than in the families of controls. 91 �6.3.2 Actiological Hypotheses In the event that one (or more) of these disabilities is more frequently observed in veterans (or their wives and offspring), it will be necessary to explore the causal basis of the difference(s) observed. The following hypotheses need to be considered: (i) That for self-reported symptoms or disabilities, an apparent excess in veterans (or their wives) might be caused by bias between the subjective responses of veteran and control subjects. (ii) That an excess of some disabilities in veterans might be caused by non-comparability of the original groups of veterans and controls (eg in age, education, socio-economic status, and predisposition to subsequent disability), (iii) That an excess of some disabilities in veterans night be caused by the physical and psychosocial sequelea of war service and combat stress, (iv) That an excess of alcohol abuse in veteran, itself attributable to war service, might contribute to any observed excess of social, behavioural and physical disabilities, (v) That an excess of some disabilities might be caused by herbicide exposure in Vietnam, (vi) Than an excess of other disabilities (e.g. tuberculosis, strongyloides, VD) might be caused by other aspects of Vietnam service. 92 �6.4 Outcgmc_Measures_ to be Used 6.4.1 Keed for Simplicity As the protocol calls for the collection of a large amount of information, it is essential to specificy, a priori, a simple set of outcome measures which can be easily used to test the principal hypotheses of interest. Such a scheme is outlined in Table 6. It can be seen that most emphasis is placed on those outcome measures which are valid and unambiguous, potentially relevant and reliably measured. Consequently, at the primary stage of analysis most attention will be paid to objective measures, to physician assessments and to subjective self-reports using psychiatric scales which have been well validated. 93 �Table 6 Major Outcome Measures and Covariates To Be Used In Testing Principal Alternative Hypothesis ALTERNATIVE HYPOTHESES Veterans will show an increased frequency of: 1. Social disability MAJOR OUTCOME MEASURES MOST IMPORTANT CONFOUNDING FACTORS AND COVARIATES (in additions to age, Vietnam exposures to combat, herbicides, etc.) Employment/unemployment Level (status) of employment Pre-enlistment education level, Pre-enlistment psychological assessment Ever married/single Divorced, separated/Presently married Frequency of marital disputes Number of children Religion Substance use and abuse Alcohol use (GGT, urate, MCV) Cigarette use Teas and coffee use Other drug use Marital stutus S.E.S. Behavioural disability Uncontrollable rages Motor accidents Fighting at hotel/football etc Sexual problems Marital disability 2. Psychiatric disability SDI score O mfc• b • Marital Status S «E • S • Alcohol consumption 5 • £• • o • Depression (Hamilton scale) Anxiety (Spielberger) Present state examination Prevalence of psychoactive drug use Scores and components 3. Neur©psychologic disability Symbol digit substitution Scores S.E.S Trail making tests and Alcohol consumption Supra-span digit learning components Nelson adult reading test 4. Neurological disability Physician assessment of - peripheral neuritis & nerve conditions studies - other neurological disability Nerve conduction deafness Alcohol Occupation history (Patency of external ear) 5. Liver disease Liver enzymes Physician assessment of liver disease Alcohol consumption Hepatitis B 94 �6. Cardiovascular disability Blood pressure ECG abnormalities - individual items and components Physician assessment - angina Cigarettes Alcohol - myocardial infarction - stroke - palpitations Plasma cholesterol 7. Infectious disease Hepatitis B virus serology Tuberculosis - CXR report Melioidosis antibody titre Strongyloides antibody titre Venereal disease - VDRL 8. Gastrointestinal disease Physicians assessment irritable bowel syndrome - diarrhoea - ulcerative colitis 9. Skin disorders Physicians assessment 10. Other symptoms A. Symptom complexes, specified jj priori, which are potentially relevant to particular outcomes (above) B. component or factor analyses of symptoms to define their latent structure. These components can then be used as outcome measures to look for differences between veterans and controls. Alcohol consumption Veteran wives partners have an increased frequency of; 1. Infertility Complaints of inability to conceive No. of pregnancies No. of live-born children 2. Miscarriage Verified miscarriage resulting in hospitalization prior to 1979. 3. Birth defects spasticity Verified birth defect and/or spasticity in child born prior to 1979 4. Stillbirth Verified still birth 5. Health disability in surviving children Verified hospitalisation of child prior to 1979 95 �6.4.2 Need for Date Reduction Some of the outcome measures are simple and unambiguous (eg marital status). Others, such as the psychiatric scales contain numerous items which measure several different components, are relevant to psychiatric disability. The dimensions of these more complex outcome measures can be reduced by calculating, for each individual studied, a score on each of the known components. These component scores (e.g. for depression, anxiety and somatic symptoms) can then be used as measures to test for any differences in outcome between veteran and control subjects. In other situations (e.g. with the neuropsychology tests) it may be more appropriate to use the data obtained in the study (from pooled cases and controls to avoid bias) to define the components of interest. Component scores in the reduced number of dimensions can then be used to test for any differences between veterans and controls. 6.4.3 Approach to the Analysis of Subjective Self Reports Interpretation of subjective information presents many problems, and in sec. 6.2.3 some guidelines are given which should be helpful. In particular, it will often be wise to discount any disabilities for which the symptoms are not supported by objective data or physician assessments. In some circumstances (Table 6) it will be possible to define, a_ priori, those self-reported symptoms which are deemed to be relevant to particular outcomes (e.g. the questions defining coronary heart 96 �disease). Scores on these symptom patterns can then be used as outcome measures which should be complementary to those based on objective measures or physician assessments. Another approach is to use the self-reported information itself to explore the factors or components giving rise to the observed variation. Thus it should be appropriate to subject the entire response matrix to factor and/or component analysis. If "expectation of disability" or "response bias" is an important cause of variation in response pattern (i.e. if many people tend to say yes to many symptoms) then this would be reflected in the identification of a "disability factor" which loads for most of the questions. The residual factors or components would then help to identify patterns of symptoms which are not simply due to "general disability" or "response bias" but which are likely to be more useful as potential outcome measures. 6.5 Principles of Statistical Analysis 6.5.1 The Problem The major objective of the analysis is to examine the relationship of the several outcome measures to veteran status, to measures of exposure in Vietnam, and to those explanatory covariates which may be confounded with Vietnam service or with exposure while in Vietnam. The interpretation of morbidity study results would be moderately straghtforward if the allocation of national servicemen to Vietnam service had been completely at random (rather than being haphazardly selective, as was the case), if there had been no mortality while in Vietnam, and if there were no selective compliance with the proposed 97 �interview schedules. If this were the case, then any observed differences between the veteran and control subjects could be interpreted, at least in a very general sense, as being caused by the Vietnam experience. On this view, even the most subjective of self reported symptoms (see Sec. 6.2.3) could be attributed to the Vietnam experience acting through functional or psychogenic processes or through a (conscious or subconscious) desire for compensation. Unfortunately, because of non-random allocation to Vietnam, selective mortality and the likelihood of selective compliance, the veteran and control subjects studied will differ for reasons which may not be logically consequent on Vietnam service; therefore, much of the statistical analysis will be directed towards examining the effects of the variables which are confounded with Vietnam service. This will allow assessment of the effects of Vietnam service on outcome to be made which have been adjusted for the effects of confounding variables. 6.5.2 Basic Approaches to Analysis Because of the non-experimental design, it will be most appropriate to fit regression models to the data, using the outcome measures as the dependent variable. For those situations where the outcome variable is qualitative and binary, it would be appropriate to use a logistic regression model (Cox, 1970; Breslow and Day, 1980) , and for those situations where the outcome variables is quantitiative, the basic approach will be that of standard multiple regression (Draper and Smith, 1966). 98 �The advantage of the regression approach is that it provides a flexible method for dealing with confounding and for estimating the main effects (and interactions) of explanatory variables. This is achieved at the cost of making assumptions about linear effects and about the distribution of residuals. As required, these assumptions can be tested or relaxed at a later stage of the analysis. In some situations it may be appropriate to fit mixed models for the analysis of covariance to allow for the effects of factors which are related to outcome but which have random rather than fixed effects (Sokal and Rolf, 1972). In other situations, with qualitative outcome data and qualitative explanatory variables, it would be appropriate to use log-linear models for the analysis of multidimensional contingency tables (Bishop et al, 1975; GLIM manual - Baker and Nelder, 1978). For those outcome measures which are measured on random samples (because of the hierarchical design) the analyses will be modified accordingly. Special procedures will be developed to use data from the "random" samples and the "extreme value" samples to make efficient estimates about the distribution of the outcome measures over the entire population studied and to find the most efficient procedures for testing fcr differencies in outcome related to veteran status. 6.5.3 Confounding variables can be regarded as (nuisance) variables which have (potential) effects on outcome, and which are •accidentally" correlated with the main factor of interest (veteran status) and logically independent or antecedent in the causal chain. 99 �For example, age is likely to be confounded with veteran status in the present study. Thus because morbidity will be higher in older men, there could, due to confounding, be an artefactual association between morbidity and veteran status. - The appropriate analysis is to first fit a model which includes only the confounding variable(s) (age) and then to fit the factor of interest (veteran status). The test for improvement in fit then provides a measure of the significance of the factor after allowing for the effect of the confounding variable. In practice, it will be necessary to allow for the effects of a number of confounding variables, although care is needed to ensure that variables which are secondary to veteran status are not treated as if they were confounding variables. Effects of interactions can also be estimated. For example, consider the hypothesis that any effect of Vietnam service on subsequent morbidity was greater in men who where older at the time that they went to Vietnam. This hypothesis can be tested by first fitting the main effect of age at time of service (as a confounding variable) and then fitting the main effect of veteran status; the third term (age x veteran status interaction) will provide a test of the required hypothesis. At least in principle, it is also possible to allow for non linear (quadratic) effects of covariates. 100 �6.5.4 Strategy of Model Fitting After the descriptive stage has been completed, it will be important to first fit a model vhich includes all necessary confounding terms (age, educational attainment, religion etc) without regard to veteran status, exposure indices etc. It also seems plausible to allow some degree of overfitting for these confounding variables. Next it will be appropriate to fit (sequentially) the effects related to Vietnam service (veteran status, time in Vietnam, combat exposure) and to retain any significant effects in the model. Thirdly it will be appropriate to look for interactions of these service related variables with the (confounding) explanatory variables (eg age x Vietnam service). 6.5.5 Incompleteness of Adjustments for Confounding Factors If there is an apparent effect of Vietnam service on morbidity which is partly removed when confounding factors are fitted beforehand, it will be necessary to seriously consider the possiblity that the Vietnam effect might have been removed completely if it had been possible to measure the confounding factor(s) more precisely (R. Peto, 1973). For example, if a pre-Vietnam measure (eg psychological assessment at induction) were found to be predictive of outcome and also to be confounded with veteran status, then it might be found to "explain away" a considerable proportion of any effect of Vietnam service. As there is always considerable error associated with the measurement of such psychological scales, it can be argued that a more precisely measured scale might have "explained away* a greater proposition of the observed effect. This qualitative argument could 101 �be made somewhat more precise if data were available on scale reliability and validity. 6.5.6 Problems Arising from Non-orthogonality and Confounding It is important to remember that there may be particular problems in elucidating the significance for outcome of factors-vhich-are confounded with Vietnam service. For example, national servicemen were selected for Vietnam service (either by the army or by themselves), so that veterans will differ from controls for a number of factors, only some of which will have been measured. Consider a factor which is measurable and has been measured (e.g. psychological scale at army induction); furthermore, suppose that Vietnam service is selected partly on the basis of this factor ("they » make good soldiers"). Given this state of affairs, how are we to interpret the relationships between Vietnam service, the "confounding" factor, and outcome? The problems arises, in part, because the measured factor is, in one sense, a cause of Vietnam service, and hence some of the outcome which might be attributable to Vietnam service would, in any convential analysis, be partly attributed to the measured factor because it is a logically prior "confounding" factor and should be fitted first. Thus if we simply adopt the policy of fitting only main effects and of fitting the confounding effect first, we could increase the risk of a Type II error (i.e. of missing a real effect of Vietnam service). To minimise the risk of such Type II errors it will be important to always examine the interaction terms between Vietnam service and each of the "confounding" factors which have a significant main effect on 102 �outcome. For example, we would always be interested to know whether, after adjusting for main effects of Vietnam service and (say) the confounding (psychological) factor, there is a significant 2 way interaction effect on outcome. If there is such a significant interaction, then we are justified in concluding that both factors have real (causal) effects, even though the main effect of Vietnamservice may appear to be non-significant. Thus by fitting such interaction terms it is possible to reduce the Type II error rate with respect to detection of effects related to Vietnam service. It might be argued that an alternative strategy would be to fit the effect for Vietnam service before that for the confounding factor, or at the least to allow the effects to compete with each other at the same stage of model-fitting. Although these issues are complex, it is generally agreed that if the aim of the analysis is to make inferences about attributable (causal) risk, there is usually no justification for fitting first that factor which is logically (and/or causally) secondary. Thus in the context of the present example, we would not usually be justified in fitting the effect for Vietnam service before fitting an effect for a factor (e.g. psychological scale at induction) which is logically prior to Vietnam service. In other words, although it is plausible to postulate that a psychological factor could influence the probability of Vietnam service, it is much less plausible to postulate that Vietnam service could influence psychological measures measured at army induction (i.e. well before the process of selection for Vietnam service began) . 103 �6.5.7 Approach to the Testing qf_Aeti_ological Hypotheses Thus in developing statistical procedures for testing aetiological hypotheses, it is important firstly to impose a causal ordering on the explanatory variables, and secondly to see whether, after allowing for main effects of confounding variable and Vietnam service, the interaction terms also have significant effects on outcome. If the interaction terms are significant, this provides further evidence for rejecting the null hypothesis in relation to Vietnam service. 104 �References Adams, I.M., Hehir, P.J., Byth, K., Charlesworth, N., Mears, A. Report on the Feasibility of Establishing an Index of Exposure to Herbicides for Vietnam Veterans. (Confidential document) Australian Veterans Herbicide Studies, November 1981. American Psychiatric Association. Diagnositic and Statistical Manual of Mental Disorder, ed. 3., Washington, D.C, 1980. Army Manning Review 1973-74, Department of Defence, Canberra. Axelson, O. and Sundell, L. Herbicide exposure, mortality and tumour incidence. An epidemiological investigation on Swedish railroad workers. Work Environment Health, 11, 21-28 (1974). Baker, R.J. and Nelder J.A. The GLIM system release 3. Generalised linear interactive modelling. Numerical Algorithms Group, Oxford, (1978). Bishop, Y.M.M., Fienberg S.E., Holland, P.W. Discrete multivariate analysis: Theory and practice. MIT Press, Cambridge, (1975). Boman, B. Review: the Vietnam veteran ten years on. Aust. N.2. J. Psychiat. 1982; 16:107-127. Breslow, N.E. and Day, N.E. Statistical methods in cancer research. I. The analysis of case-control studies. IARC Scientific Publications No. 33 (Lyon) , (1980). Case-Control Study of Congenital Anomalies and Vietnam Service. (Confidential document) Australian Veterans Herbicide Studies, April, 1982. Cox, D.R. Analysis of binary data. Methuen, (1970) . Draper, N.R. and Smith, H. Applied regression analysis. Wiley, N.Y., (1966). Fett, M.J. Retrospective Mortality Study of Vietnam Veterans and Controls. Revised Protocol. (Confidential document). Australian Veterans Health Studies, May, 1982. Figley, C.R. and Stretch, R.H. Vietnam Veterans Questionnaire. manuscript. U.S. Veterans' Administration, (1980). Unpublished Hardell, L. and Eriksson, M. Soft-tissue sarcomas, phenoxy herbicides and chlorinated phenols. Lancet, j_i, 250, August 1, (1981) . Hardell, L. and Sandstrom, A. Case-control study: Soft-tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br. J. Cancer, 39, 711-717, (1979). Honchat, P.A. and Halperin, W.E. 2,4,5-T, trichlorophenol and soft tissue sarcoma. Lancet, \_, 268-9, January 31, ( 9 1 . 18) International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: Some fumigants, the herbicides 2,4-D and 2,4,5-T, chlorinated dibenzodioxins and miscellaneous industrial chemicals. 15, 41-299, (1977). 105 �Ma thews, J.D. Alcohol use as a possible explanation for socio-economic and occupational differentials in mortality from hypertension and coronary heart disease in England and Wales. Aust. N.Z. J. Med., j>, 393-397, (1976). Ma thews, J.D. Genetics and alcohol: Implications for human disease. N.Z.J. Med. n, 109-114, (1981). Aust. National Service Act 1951-1971, The Commonwealth of Australia. Penk, K.E., Robinowitz, W.R., Roberts, E.T., Patterson, M.P. , Dolan, M.P. and Atkins, H.G. Adjustment differences among male substance abusers varying in degree of combat experience in Vietnam. J. Consult. Clin. Psychol. , 4:9, 426-437, (1981). Peto, R. 1973, (Personal communication). Reggiani, G. Acute human exposure to TCDD in Seveso, Italy. J. Toxicol. Environ. Health, Jj, 27-43, (1980). Riihimaki, V., Asp, S., Seppalainen, A.M. and Heinberg, S., (1978) Mortality study of persons exposed to dioxin after an accident which occurred in the BASF on 13th November 1953. Working paper for the Workshop-on Long-term Hazards of Polychlorinated Dibenzodioxins and Polychlorinated Dibenzofurans. International Agency for Research on Cancer, Lyons, January 10-12. Cited in Kimbrough, (1980). Scientific Advisory Committee Report. (Confidential document) Australian Veterans Herbicide Studies, February, 1981. Sokal and Rolf. Biometry. Freeman, San Francisco, 1972. The PULHEEMS System of Medical Classification. Medical Pamphlet. Department of Defence (Army Office), Canberra, 1978. U.S. Veterans' Administration. Review of literature on herbicides, including phenoxy herbicides and associated dioxins. Volume I, Washington D.C., 1981. 106 �APPENDIX 1 SPECIFIC HYPOTHKSES AND POWER CALCULATIONS The null hypothesis is that there are no differences in the frequency of disabilities between Vietnam veterans and controls (national servicemen who did not go to Vietnam). These null hypotheses will be tested against the alternative hypotheses that each outcome listed in Table 1 is more frequent in veterans than controls. In interpreting Table 1 the following points should be borne in mind: (1) Smaller numbers of study subjects (sample sizes) than those given have the consequence of increasing the minimum size of an effect (the relative risk) that can be detected, that is, of reducing the sensitivity of the study to detect veteran/control differences. (2) In the process of adjusting for pre-Vietnam and other differences in the veteran/control group (for example, differences in marital status at enlistment), the study becomes less sensitive than shown in Table' 1. The data in Table 1 are therefore 'best possible case1 data, where no adjustment for veteran/control differences is required. (3) Many of the putative effects of Vietnam service appear to be related to particular aspects of Vietnam service (e.g. combat). Since it is unlikely that all veterans would be exposed to the factor of importance (e.g. combat), the number of truly 'exposed1 veteran subjects may be considerably below the total number of veteran �subjects. This further reduces the power of the study to detect veteran/control differences below those shown in Table 1. This consideration is the rationale for selecting veterans to controls in a 3 to 2 ratio, thereby permitting more powerful comparisons between veterans at different levels of exposure to possible causal variables for a given sample size, and at the same time reducing only slightly the sensitivity of veteran-control comparisons. It is not currently possible to perform power calculations within the veteran group, as the distribution of potentially causal variables among veterans is not yet known. �• I Outcome Source Estimated prevalence (limits) 2,500 subjects Rel. risk Min VN-caused detectable cases detectable/1000 Cancer (i) 1% 2.23 Husculoskeletal Arthritis/rheumatism Muscular aches & pains (h) (a) 3% 10-30% 1.65 1.16-1.32 Infectious Disease Syphilis (VDRM+) ) Melioidosis Strongyloidiasis (a) , ( j ) (k) , (1) (P) 0.5-1% 1-3% 1% in vets 5 , U U U siJD^eci-t. 12 Min VN-caused cases detectable/1000 Rel. r i s k detectable Min VN-causod cases detectable/1000 1.83 8 Rel. risk detectable 5 1.63 4 1.45 19-28 1.11-1.23 2.23-2.90 1.65-2.23 2.23 6-8 8-12 1.83-2.24 1.45-1.83 8 8 14-20 1.34 1.09-1.18 6 11-16 1.63-1.94 1.34-1.63 1.83 4-5 5-8 5 1.63 3-4 4-6 4 Medical Treatment Hospitalised in last 12 months Medication taken in last 2 days (h) 14% 1.26 22 1.19 16 1.14 12 (h) 37% 1.14 30 1.10 21 1.08 17 Reproductive Relative infertility (a) 5% 1.48 14 1.33 10 1.26 8 Social and Behavioural Never married Divorced Currently unemployed Recent accident (h) (h) (n) (b) 13% 2.5% 4% 6% 1.28 1.74 1.55 1.43 22 11 13 16 1.19 1.50 1.38 1.30 15 8 9 11 1.15 1.39 1.28 1.23 12 6 7 8 3-16% 1-19% 1.24-1.65 1.22-2.23 12-23 8-25 1.17-1.45 1.15-1.83 8-16 5-17 1.13-1.34 1.12-1.63 6-13 4-14 0.5% 1-2% 3-10% 2.90 1.83-2.23 1.32-1.65 6 8-10 12-19 2.24 4 5-7 8-14 1.94 1.43-1.63 1.18-1.34 3 4-5 6-11 Psychiatric (o) Depression Anxiety (0) Severe personality disorder (a) (a) ,(p) Psychosis j Alcoholism (100gms+/d) (g) Smoking: see Respiratory * 1.53-1.83 1.23-1.45 Table 1. Prevalence of Outcomes of Importance with Minimum Relative Risks Detectable as Statistically Significant and the Minimum Number of Vietnam-Caused Cases per 1,000 subjects that would be Detected with Power of 80% at PJJ_J 0.05 for Sample Sizes of 2,500, 5,000 and 18,000 subjects. �Outcome Kervous system Clinical peripheral neuropathy Neu r opsy cholog ica 1 abnormality Hearing abnormality Frequent headaches Skin Severe acne Fungal infections Liver Cirrhosis Hepatitis B(+) aerology Abnormal liver function tests Source Estimated prevalence (limits) 2,500 subjects Min VN-caused Rel. risk detectable cases detectable/1000 5,000 subjects Rel. risk Min VN-caused detectable cases detectable/1000 Rel. r i s k detectable 1.63-1.94 ( 2 ) , (a) 0.5-1% 2.23-2.90 6-8 1.83-2.24 4-5 (3) (3) (4),(b) 5% 5% 3-4% 1.48 1.48 1.33 1.33 1.55-1.65 14 14 12-13 10 10 8-9 (a) (a) 3% 4% 1.65 1.55 12 13 1.38-1.45 1.45 1.38 8 9 3-4 1.26 1.26 8 8 6-7 1.28-1.34 1.34 1.28 6 7 1.85 2-4 3 10 1.26 8 1.26 1.18 1.63 1.56-1.63 10 14 5 5-7 1.43-1.63 8 11 4 4-5 14 1..33 10 1.26 8-10 1.56-1.83 5-7 1.43-1.63 (a) (c) 0.1-1% 0.6% 2.70 3-8 6 (3) 5% 1.48 (a) (a) (b) (d) 5% 10% 1% 1-2% 1.48 1.32 2.33 (3) 1.83-4.3 2.11 14 1.33 1.33 1.23 1.83 1.83-2.23 14 19 8 8-10 5% 1.48 (e) 1-2% 1.83-2.23 (b) (f) 0.1% 0.6% 6.3 2.7 Respiratory Smoking currently Asthma Abnormal pulmonary (g) 40-46% (h) 2-4% 1.11-1.13 1.55-1.83 function tests (3) 5% 1.48 Cardiovascular Hypertension Receiving medication for hypertension Symptoms of ischemic heart disease ECG abnormality Min VN-caus«?d cases detectable/1000 % 2.23-6.3 2-5 4 Gastrointestinal Persistent vomiting Persistent diarrhoea Abdominal pain Peptic ulcer 8,000 subjects V. 3 ' 6 30-31 10-13 14 4.3 2.11 1.08-1.09 1.38-1.56 1.33 2 4 22 7-9 10 1.63-3.5 3.5 1.85 1.06-1.07 1.28-1.43 1.26 8 4-5 2 3 17 5-7 �Notes (1) The power calculations have been performed using the following parameters: o veteran to control ratio of 3 to 2 o the 'relative risk detectable1 is the minimum relative risk that would be statistically significant at the level ?„* 0.05, with power of 80% o (2) the excess cases in veterans are derived from the relative risk detectable and the veteran to control ratio of 3 to 2. Pilot Study prevalence data have been used only where other data have not been obtainable, since the validity of Pilot Study data is limited. The prevalence rates cited are for veteran and control subjects combined. (3) For this measure an abnormal (positive) result is defined as that result above which only 5% of the normal population resides. * (4) All data are for the appropriate age and sex group. Sources of Prevalence Data (a) Pilot Study, Australian Veterans Health Studies. (b) Australian Health Survey 1977-78 Recent Illness. ABS. (c) (d) Nelson (1975) Health Care Surveys Gosford/Wyong/Illawara 1975. ABS, HC NSW. (e) Australian Health Survey 1977-78. ABS. (f) Personal Communication: Dr T. Ireland, Director of Research, Medicheck Centre. (g) Alcohol and Tobacco Consumption Patterns. (h) (i) Social Indicators. No. 3. 1980. ABS. Cancer in NSW Incidence and Mortality 1977. NSW Cancer Registry. (j) Personal Communication: A. Lee, Serologist, NSW Red Cross Blood Transfusion Service, (k) Clayton et al (1973) . (1) Kishimoto et al (1971). (m) (n) Gilbert et al (1968). Labour Statistics 1980 Australia. (o) (p) Reynolds and Rizzo (1979). Goldberg (1972). ABS. February 1977. ABS. �References Australian Bureau of Statistics. Alcohol and Tobacco Consumption Patterns. February 1977. ABS Catalgoue No. 4312.0, Canberra, 1978. Australian Bureau of Statistics. Australian Health "Survey 1977-1978. ABS Catalogue No. 4311.0, Canberra, 1979. Australian Bureau of Statistics. Labour Statistics 1980 Australia. ABS Catalogue No. 6101.0, Canberra, 1980. Australian Bureau of Statistics. Social Indicators. No. 3. 1980. ABS Catalogue No. 4101.0, Canberra, 1980. Australian Bureau of Statistics. Australian Health Survey 1977-1978. Recent Illness. ABS Catalogue No. 4318.0, Canberra, 1981. Australian Bureau of Statistics and Health Commission of New South Wales. Health Care Surveys in Gosford-Wyong and Illawarra areas of NSW. 1975. AB^S Catalogue No. 4305.1, Sydney, Clayton, A.J., Lisella, R.S. and Martin, D.G. 1976. Melioidosis: A Serological Survey in Military Personnel. Milit. Med. 3J3 : 24-26, (1973). Gilbert, D.N., Moore, W.L.f Hedberg, C.L. and Sanford, J.P. Potential Medical Problems in Personnel Returning from Vietnam. 68 t 662-678, (1968). Review. Ann. Int. Med. �Goldberg, D.P. The Detection of Psychiatric Illness by Questionnaire. Institute of Psychiatry Maudsley Monographs No. 21. Oxford University Press, London, 1972. Kishimoto, R.A., Brown, G.L., Blair, E.B. and Wenkheimer, D. Melioidosis: Serologic Studies on US Army Personnel Returning from South East Asia. Milit. Med. 3j> : 694-698, (1971). Nelson, M. immunology and Epidemiology of the Hepatitis B (Australia) Antigen. PhD thesis. Unilversity of New South Wales, 1975. New South Kales Central Cancer Registry. Cancer in New South Wales Incidence and Mortality 1977. Health Commission of New South Wales, Sydney, 1981. Reynolds, I. and Rizzo, C. Psychosocial Problems of Sydney Adults. Commission of NSW and Medicheck Referral Centre. 1979. Health �APPENDIX 2 PULHEEMS ARMY HEALTH RATINGS The following tables outline the basis of the PULHEEMS ratings, and are extracts from "The PULHEEMS System of Medical Classification1, 1978. NOTES ON THE PULHEEMS QUALITIES 15. a. P - Physical Capacity. This indicates general physical development, potential capacity to acquire a high level of physical stamina, capacity for hard work. b. U - Upper Limbs. This indicates the functional use of hands, arms, shoulder girdle and upper spine. Htyere there is a degree of incapacity which would limit general physical capacity the U assessment will also affect the P assessment. c. L - Lower Limbs. This indicates the functional efficiency of feet, legs, thighs, pelvis, lumbar spine, ankle, knee and hip joints. As with the U assessment the L assessment may also affect the P assessment. d. H - Hearing Acuity. This indicates hearing acuity only. Diseases of ear are to be assessed under the P quality. e. EE - Eyesight. This indicates visual acuity only. Diseases of the eyes are to be assessed under the P quality. f. M - Mental Capacity. This is difficult to assess on the basis of a single medical examination. Some guidance is given by: (1) (2) School record and post-school occupational record; (3) g. Impression given on interview with regard to alertness and intelligence; Selection test results. S - Emotional Stability This is also difficult to assess on the basis of a single examination. There are no tests of temperament or personality available to estimate emotional stability. Reliance must be placed on careful history taking, including family background and employment record, and physical examination. �DEGREES OF PULHEEMS QUALITIES 16. There are nine degrees of qualities but not all of these are in use. The following table shows the degrees used under each quality. U 17. H M The broad correlation between degress of P, U, L, M, S, and functional capacity, combatant capacity, climatic restriction, is as follows: Degree Function Capacity Combatant Capacity Above Average Full Climatic Restriction None Non tropital Average None Non tropical Below Average None Non tropical Markedly Deminished Restricted Serve in Australia Note: The restriction "Service in Australia" applies only to P 7 and not to U7 or L7, Under P, U, L, E, M, S « medically unfit for. any form of service. � 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. 073 Folder The folder containing the original item. 1930 Series The series number of the original item. Series III Subseries IV 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 Fett, M. J. J. D. Mathews R. J. Walsh Date A point or period of time associated with an event in the lifecycle of the resource December 13 1982 Title A name given to the resource Australian Veterans Health Studies: Morbidity Study: Protocol for a Morbidity Survey of Vietnam Veterans and Controls Subject The topic of the resource AVHS study protocol morbidity trends 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. 075 Folder The folder containing the original item. 1944 Series The series number of the original item. Series III Subseries IV 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 Davidson, Lindsay Description An account of the resource <strong>Corporate Author: </strong>Commonwealth Institute of Health, University of Sydney, Australia Title A name given to the resource Family Health Survey: Questionnaire (Male), Strictly Confidential and Family Health Survey: Questionnaire (Female), Strictly Confidential Subject The topic of the resource AVHS veteran health and hygiene data collection ao_seriesIII