1 15 86 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. 029 Folder The folder containing the original item. 0483 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R. H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 1 1981 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants Subject The topic of the resource health studies industrial exposure human exposure veteran health and hygiene 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. 051 Folder The folder containing the original item. 1357 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R. H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 18 1983 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants Subject The topic of the resource health studies human exposure veteran health and hygiene industrial exposure ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/b5a1cdf71121edc4ae4ac1b2dbfb57fe.pdf f4a4f9a983def9e0b95c6ce4295856c7 PDF Text Text Item ID Number 01394 Author Beljan, John R. Corporate Author American Medical Association, Council on Scientific Affa Roport/Artldo TltlO The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants: an Update, 1984, Technical Report Journal/Book Title Year 1984 Month/Day October 1 Color n Number of Imauos 58 DOSCrlptOU NOtflS See items 483 and 1357 for earlier versions. Thursday, May 03, 2001 Page 1394 of 1403 �Reprinted by the Veterans Administration with permission of AM A THE HEALTH EFFECTS OF "AGENT ORANGE" AND POLYCHLORINATED DIOXIN CONTAMINANTS: AN UPDATE, 198* American Medical Association Chicago, Illinois �THE HEALTH EFFECTS OF "AGENT ORANGE" AND POLYCHLORINATED DIOXIN CONTAMINANTS: AN UPDATE, 198* Technical Report Prepared by the Council on Scientific Affairs' Advisory Panel on Toxic Substances John R. Beljan, MD, Chairman Nelson S. Irey, MD Wendell W. Kilgore, PhD Kazuo Kimura, PhD, MD Raymond R. Suskind, MD Jaroslav 3. Vostal, MD, PhD R.H. Wheater, MS, Secretary Environmental and Occupational Health Program October 1, 1984 American Medical Association Chicago, Illinois �Contents Preface Acknowledgements 1 Introduction Historical Perspective Summary of AMA's 1981 Report Chemistry of Dioxins General Structure 2,3,7,8-Tetrachlorodibenzo-p-dioxin Formation of Chlorinated Dioxins Occurrence of Chlorinated Dioxins In 2,4,5-T (2,4,5-Trichlorophenoxy Acetic Acid) In Chlorophenols In Hexachlorophene Decomposition of Chlorinated Dioxins Analysis Extraction Detection Toxicological Evidence of a Health Hazard in Animals General Discussion Mutagenicity Oncogenicity Teratogenicity Reproductive Effects Studies of Human Populations Introduction Vietnam Veterans (Studies Complete or Partially Complete) Ranch Hand Program CDC Birth Defects Study Estimate of Vietnam Troop Exposure VA Agent Orange Registry Agent Orange Biopsy Registry of the Armed Forces Institute of Pathology Single Case Reports Of "Dedrumming" Personnel Australian Birth Defects Study Vietnamese Epidemiologic Study Vietnam Veterans (Studies in Progress) VA Identical Twin study (Vietnam Experience Twins Study, VETS) Vietnam Ground Troops Study VA Mortality Study VA Case-Control Study of Soft Tissue Sarcoma VA Retrospective Study of Dioxins and Furans in Adipose Tissue Australian Mortality Study State-Sponsored Programs Workplace Exposures Monsanto (Nitro, West Virginia) Dow Chemical (Midland, Michigan) Diamond Alkali (New 3ersey) 2 d56:contents (revd. 5-29-85) 4 6 7 8 9 10 13 14 15 16 18 19 20 21 22 23 24 25 �BASF AG (Ludwigshafen, Germany) NV Philips (Netherlands) Spolana (Czechoslovakia) Coalite (United Kingdom) Vertek Chemical (Jacksonville, Arkansas) NIOSH Dioxin Registry NIEHS-IARC International Phenoxy Herbicides Registry Isolated Exposures to TCDD Exposed Herbicide Users Swedish Railway Workers Other Swedish Workers Finnish Railway and Forestry Workers New Zealand Birth Defects Study Long Island Railroad Birth Defects Study General Population Seveso, Italy Times Beach, Missouri Missouri Pilot Study St. Louis, Missouri (Trucking Employees) Alsea, Oregon Review of Alsea II by Oregon State University Review of Alsea by FIFRA's Scientific Advisory Panel Review of Alsea II by Others Canadian Review of TCDD's Health Hazards Cancer Studies . CDC Selected Cancers Study NIOSH Soft Tissue Sarcoma Study NCI Case-Control Study of Lymphoma and Soft Tissue Sarcoma New Zealand Soft Tissue Sarcoma Case-Control Study Finland US, Pacific Northwest New York State Michigan State Department of Public Health Italy Denmark Immunological Response to TCDD In Animals In Humans Conclusions 26 27 28 29 31 32 33 34 35 36 .38 39 40 • 41 References R-l Appendix List of States with Vietnam Veteran Commissions or Programs A-l d56:contents (revd. 5-29-85) �The Health Effects of "Agent Orange'1 and Polychlorinated Dioxin Contaminants: Update, Preface This report represents the second comprehensive study by the American Medical Association on the subject of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a topic that has been of considerable interest to the lay public and the medical community alike. In late 1980, the AMA's Council on Scientific Affairs directed its Advisory Panel on Toxic Substances to review and assess the available scientific information on Agent Orange and its associated contaminant, TCDD, and to develop objective information based on their findings. The outcome in October 1981 was a broadly accepted and widely distributed publication entitled, "The Health Effects of 'Agent Orange' and Polychlorinated Dioxin Contaminants." A summary version of the Panel's report also appeared in the 15 October 1982 issue of the Journal of the American Medical Association (JAMA). In brief, The Panel found that, "In spite of the voluminous data on the biological effects of the phenoxy-type pesticides and their associated chlorinated dioxins, which oftentimes co-exist as contaminants of the pesticide formulations, there is still very little substantive evidence for many of the alleged claims that have been made against these compounds. The most serious of these allegations assert that Agent Orange, or compounds of a like nature, have caused malignant tumors, spontaneous abortions and birth defects. Although data from studies on experimental animals tend to support some of these claims, it is not certain that animal data are extrapolatable to man. No laboratory animal can fully substitute for man; we must, therefore, depend on the results of ongoing epidemiologic studies on persons who are known to have been exposed." In the interim following publication, there has been a disquieting and continuing controversy both here and abroad over the long-term consequences of exposure to TCDD. The concern has not been limited to the military who served in Vietnam, but it has also extended to countless nvimbers of the general population who were believed to have been exposed to TCDD in the careless and oftentimes unwitting disposal of toxic wastes. Inasmuch as several important human epidemiologic studies have been underway since 1981, the AMA's House of Delegates called for an update of the Council's original report. Once again, the same Panel of experts was called upon to review the new studies, to consider the more recent and relevant scientific information, and to issue its conclusions and recommendations. Acknowledgements In the process of review, a number of principal investigators who were involved in ongoing human studies were invited to meet with the Panel and to brief it on the progress or results of their work. We are, therefore, indebted to the following persons and organizations for their cooperation: Ralph R. Cook, MD (Dow Chemical USA); H. Denny Donnel, MD, MPH (Centers for Disease Control); Marilyn A. Fingerhut, PhD (NIOSH); William R. Gaffey, MD (Monsanto Co.); Sheila Hoar, ScD (National Cancer Institute); Richard E. Hoffman, MD, MPH (Missouri Division of Health); Renate Kimbrough, MD (Centers for Disease Control); George D. Lathrop, MD (US Air Force); Vern May, PhD (Dow d57:update (revd. 5-29-85) - page 1 �Chemical USA); D. Franco Merlo (Department of Epidemiology, National Cancer Research Institute, Genoa, Italy); Kenneth W. Sell, MD (National Institutes of Health); Barclay M. Shepard, MD (Veterans Administration); Robert F. Willis, PhD (Chairman, Joint Health and Welfare Canada/Environment Canada, Expert Advisory Committee on Dioxins); Alvin L. Young, PhD (White House Office of Technology Policy). Introduction Historical Perspective Phenoxy herbicides were introduced into commerce and agriculture in the mid-40s with the advent of 2,4-D, followed by 2,4,5-T in 1948. Both were used extensively and uneventfully in the control of woody and broadleaf vegetation in croplands, forests, rights-of-way, and turf until 1969, when public concern was raised over the human health hazards of 2,4,5-T and/or its contaminant, TCDD. As this concern mounted, the Secretary of Agriculture suspended applications of the herbicide in areas where humans might encounter greatest exposure to TCDD. In 1971, the Environmental Protection Agency (EPA) initiated cancellation proceedings against certain other uses of 2,4,5-T. This notice was subsequently withdrawn, and EPA initiated a plan to develop necessary data for their decision-making processes. In April 1978, EPA issued a notice of Rebuttable Presumption Against Registration (RPAR), an intensive benefit/risk review to ascertain the desirability of continued registration and unrestricted use of 2,4,5-T. One year later, the RPAR process was interrupted by an emergency ban on the use of 2,4,5-T in pastures, forests, rights-of-way, home gardens, and for aquatic weeds and other applications, excluding its use on rangeland and rice fields. This suspension was prompted by reports of spontaneous abortions in humans in Alsea, Oregon attributed to use of herbicides by the US Forest Service. Two studies done by the EPA—Alsea I and Alsea II—were criticized severely for insufficient evidence to support the alleged claims. Inasmuch as the EPA believed that silvex (or 2-2(2,4,5-trichlorophenoxy)propionic acid) was related closely to 2,4,5-T and also apt to be contaminated with TCDD, the Agency suspended silvex as well. During the US involvement in Vietnam, herbicidal mixtures of 2,4-D, 2,4,5-T, picloram, and cacodylic acid were widely employed as defoliants; these mixtures were variously identified as Agents Orange, White, Blue, Purple, Pink, and Green. The most widely used was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T; early formulations of the agent were heavily contaminated with as much as 47 ppm (a weighted mean concentration of 1.98 ppm) of 2,3,7,8-TCDD (Young et al, 1978). After termination of defoliation operations in Vietnam in 1970, two reports by Dr. Ton-That Tung (1971, 1973) linked Agent Orange with increases in liver cancer, abortion, and birth defects. Although hard scientific evidence for that conclusion was lacking in Tung's reports, a variety of other studies clearly demonstrated that TCDD was extremely toxic to laboratory animals. A large number of US personnel in Vietnam who may have been exposed to herbicides are greatly concerned that Agent Orange could be responsible for the deleterious health effects that they and their offspring are experiencing. As a consequence, a class action suit was filed in 1979 against five herbicide manufacturers (Dow Chemical, Monsanto, d57:update (revd. 5-29-85) - page 2 �Hercules, Diamond Shamrock, and Thompson-Hayward); the suit was extended to "all American servicemen whose health has been damaged because of contact with Agent Orange." The companies, in turn, filed a third-party action against the US government, passing the responsibility for alleged harm to the government for its "negligent misuse" of the chemicals. A similar class action suit was filed in January 1981 against the Veterans Administration and the Department of Defense. Some 2.4 million Vietnam veterans, including 1,200 Operation Ranch Hand personnel, and 20 civilians involved in destroying surplus Agent Orange, are presumed to have been exposed. The news media have stated that potential "plaintiffs" will exceed 2.5 million people and suggest that 40,000 veterans may become ill or die; an additional 2,000 or more children also will suffer "catastrophic" birth defects. More than 1,250 lawyers from 150 law firms in the United States have been involved in the litigation as of 1980 (Elson, 1980). The suit was scheduled to go to trial in Brooklyn, New York in May 1984. The corporation defendants, however, came to an out-of-court agreement; without admitting culpability, they set aside $180 million for distribution to claimants and their respective heirs. An equitable means for assessing and awarding damages remains to be established. Many persons are not satisfied with the outcome and may still seek redress in the courts. Meanwhile, the veterans, their heirs, and the general public anxiously await medical evidence that will either support their allegations of harm from the chemical or prove convincingly that dioxin has no serious health consequence. To date, at least 579 industrial workers are also known to have been exposed to TCDD. The first of several accidental releases of TCDD during the manufacture of 2,4,5-trichlorophenol (TCP) or 2,4,5-T occurred in 1949; a larger number of employees were also exposed to the manufacturing process from 1948-69. A suit has been filed against the Monsanto Chemical Company on behalf of former Monsanto employees and representatives of deceased persons who worked in the company's Nitro, West Virginia plant. One of the first large-scale exposures of the general population to TCDD occurred near Seveso, Italy in 3uly 1976; the compound was released accidentally at the ICMESA (Industrie Chimiche Meda Societa Anonima) trichlorophenol synthesis plant. Approximately 500 acres of surrounding countryside were contaminated to varying degrees. Some people in the most highly contaminated area became ill immediately, while others experienced chemical burns of the skin, abdominal pain, and internal hemorrhage. Although there were deaths of small animals and vegetation, there were no documented human deaths. Approximately 511 of the 736 evacuees were allowed to return to their homes within a year (Homberger, 1979). Meanwhile, cleanup of the contamination in Seveso has been completed. Seven-million cubic feet of the dirt were scraped from 115 acres and sealed in a reservoir outside the town. All houses in the immediate area were destroyed and the area planted with trees; former residents have been forbidden to return to their former homesites (Anon, 1984). In the early 1970s, dioxin-conlaminated waste oil was widely applied to certain areas of Missouri to suppress dust, most notably near the town of Times Beach and at three horse arenas in Lincoln County. Reports were to follow of animal deaths and complaints of human illness that sparked a national concern, which was further fueled by the news media: the town of Times Beach was purchased by the government, other extensively contaminated sites were discovered in eastern Missouri and elsewhere in the US, and new rule-making by the EPA was established for the disposal of dioxin-contaminated wastes. Meanwhile, several reports from Scandinavia indicated a possible link between exposure to dioxin and cancer, especially soft tissue sarcomas. These reports were soon followed by discovery of a number of soft tissue sarcomas among an industrial population in the d57:update (revd. 5-29-85) - page 3 �US. An apparent increase in the number of deaths due to connective tissue cancers among white women was then perceived in the Midland, Michigan area; this news received wide publicity by environmental groups when dioxin contamination was discovered in the Tittabawassee and Saginaw Rivers, Saginaw Bay, and the grounds of Dow Chemical Company. The Michigan Department of Health investigated the situation, the outcome of which is presented below. In May 1983, a representative action was brought by several Nova Scotian residents against a forest industry company that operated in their area. Plaintiffs were seeking an injunction that would prevent the company from further spraying of 2,4-D, 2,4,5-T, and mixtures thereof. A major part of the documentary evidence and testimony of environmentalists and medical experts related to the alleged adverse health effects of these compounds and dioxin. Quoting from the opinion of the trial judge (Nunn, 1983), who denied the injunction for lack of evidence that the spray operation constituted an unreasonable risk to health: "...on the whole of the evidence, where risk to health is claimed in any study, the circumstance has been one of massive exposure and such are not of significant probative value in light of the actual low possible exposure here. ...most of the more highly publicized studies in these situations are regarded in the wider scientific community as flawed...particularly...the Alsea II study. Where risk to health might be expected, for example, ...at Seveso, which caused a massive dioxin exposure, none have found. ...the evidence of risk assessments clearly indicates that any risk here in Nova Scotia, if, indeed, there is a risk at all, is infinitessimally small and many, many times less than one in a million...(whereas,) the risk of cancer to a smoker is 1 in 800, and for a non-smoker continuously in the same room with smokers it is 1 in 100,000...this court is of the opinion that these spraying operations can be carried out in safety and without risk to the health of the citizens of the province. (Nunn DM: Judicial decision in the trial of Palmer et al vs Stora Kopparbergs Bergslags Aktiebolag (or Nova Scotia Forest Industries), Supreme Court of Nova Scotia (15 Sep 1983)). The general public continues to be concerned about the possible adverse health effects of dioxin, especially those of a long-term nature; eg, cancer, birth defects and reproductive abnormalities. However, this concern is best addressed by scientific facts, not fanciful conjecture. Summary of AMA's 1981 Report Before discussing newer developments, it would be well to review the salient points of the 1983 report. * Agent Orange, as used in Vietnam, was a 50:50 mixture of the n-butyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), together with a minor amount of the free acid 2,4,5-T (1% of the total mixture) and varying amounts of the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). * Commercial formulations of 2,4,5-T, as well as silvex (or 2-2(2,4,5-trichlorophenoxy)propionic acid) may contain TCDD as a contaminant. At one time, the amount of TCDD was as much as 70 ppm; present methods routinely produce levels below 0.01 ppm. TCDD may form as a by-product in the synthesis of 2,4,5-trichlorophenol (a precursor of 2,4,5-T). It may also be produced by the pyrolysis of certain chlorinated compounds in industrial or municipal wastes and d57:update (revd. 5-29-85) - page 4 �.by the burning of vegetation that has been sprayed with the chlorinated phenoxy acid herbicides. Note that 2,4-D, a phenoxy herbicide closely related to 2,4,5-T, is not normally contaminated with TCDD. * In addition to the marked variations in the sensitivity and susceptibility of animal species to all toxic substances, there are significant differences between some of the toxic effects of TCDD in experimental animals and the human experience; thus, the animal data cannot be translated directly to man. * One of the more pronounced biological effects of TCDD, as well as a number of other chlorinated aromatic compounds, is a tendency to cause chloracne in certain animals and man. This skin disease is, in fact, regarded as the clinical marker for TCDD exposure. Systemic disorders in man from exposures to TCDD are unlikely to occur in the absence of chloracne. Such signs and symptoms as impaired liver function, nephropathy, gastroenteritis, myopathy, neuropathy, and central nervous system manifestations have been reported after exposure to large amounts of TCDD; however, they have not been progressive and have always cleared with time (the nephropathy and myopathy have not been proven). * Other toxic effects of TCDD in experimental animals appear as pathological effects in the liver, peripheral nerves, and hematopoietic and reticuloendothelial systems. TCDD is a very powerful enzyme inducer. In addition to altering normal enzyme activity, it may potentiate the harmful action of other toxins or even render an otherwise innocuous agent toxic. * TCDD promotes car ci no genesis or induces cancer in some strains of rats and mice. In contrast to other chemical carcinogens, however, this carcinogenicity is always accompanied by considerable systemic toxicity. By itself, 2,4,5-T does not presently appear to be a carcinogen, nor has it been shown to cause genetic changes in any animal species. * A consensus of studies utilizing high prenatal doses of 2,^,5-T with 0.1 ppm or less of TCDD showed cleft palate in mice (but no other species) and embryotoxicity in the mouse, rat, hamster, sheep, monkey, and rabbit. TCDD does induce genetic changes by the Ames test with S. typhimurium and E. coli. However, dominant lethal and cytogenetic evaluations in rodents do not confirm that such changes also occur in other animals, especially man. * While 2,4,5-T and 2,4-D pesticides have been used in agriculture, forest management, and commercial and residential landscaping for over 30 years, there is still no conclusive evidence that they and/or TCDD are mutagenic, carcinogenic, or teratogenic in man, nor that they have caused reproductive difficulties in man. * Both 2,4-D and 2,^,5-T undergo rapid decomposition in the soil and are, therefore, of little environmental concern. TCDD does persist in soil longer than 2,4,5-T but, in general, ... in the presence of ultraviolet light, it breaks down rapidly when present as a thin film on plants, water, and the surface of soil. (Its half-life in deep soil is now known to be much longer than one year.) d57:update (revd. 5-29-85) - page 5 �Chemistry of Dioxins General Structure Of late, the term "dioxin" has been applied—though incorrectly—to any of a number of polychlorinated dibenzo-p-dioxins and more specifically to 2,3,7,8-tetrachlorodibenzo-p-dioxin (or "TCDD" as it is usually but inappropriately called for brevity). More precisely, a dioxin is any of a group of dibenzo-p-dioxins whose structure consists of two benzene rings interconnected by two oxygen atoms as shown below: Dioxins differ only in the nature and position of their substituents; ring positions 1 through 4 and 6 through 9 can be occupied by hydrogen or halogen atoms, or various organic radicals. Theoretically, there can be 75 different chlorinated dioxins; 40 different chloro- isomers have been prepared and identified to date (Buser, 1975; Buser et al, 1978; Poland et al, 1972; Bolton, 1978), while five others have been identified but not separated from their accompanying compounds (Buser, 1975; Buser et al, 1978; Rappe, 1978). Dow Chemical Company has synthesized all 22 tetrachloro (TCDD) isomers (US EPA 1980). 2,3,7 ? 8-tetrachlorpdibenzo-p-dioxjn Of the 22 tetrachlorodibenzo-p-dioxins, the 2,3,7,8- isomer—wherein chlorine has been substituted for hydrogen in the 2,3,7 and 8 positions in the dibenzo-p-dioxin structure shown above—has received the most attention because of its adverse health effects in experimental animals and its potential hazard to humans. It is structurally represented as: TCDD 2,3,7,8-TCDD is a colorless, crystalline solid at room temperature, chemically stable and extremely lipophilic. It is only sparingly soluble in water and most organic liquids. Some of its physical properties, along with those of 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD), another chlorinated dioxin with twofold symmetry, are listed in Table 1 (Crummett et al, 1973; International Agency for Research on Cancer, 1977). d57:update (revd. 5-29-85) - page 6 �Table 1 — Physical Properties of Two Chlorinated Dioxins, 2,3,7,8-TCDD and 1,2,3,4,6,7,8,9-Octachlorodibenzo-p-dioxin (OCDD) Property 2,3,7,8-TCDD Empirical formula C OCDD c12cigo2 12H4C14°2 Percent by weight C O H Cl 31.3 7.0 44.7 9.95 1.25 44.1 61.7 322 459.8 305°C 130°C Above 700°C Above 700°C 1.* g/liter 0.72 — _ 1.83 g/liter Molecular weight Melting point Decomposition temperature Solubility o-Dichlorobenzene Chlorobenzene Anisole Xylene Benzene Chloroform n-Octanol Methanol Acetone Dioxane Water 1.73 3.58 0.57 0.37 0.048 0.01 0.11 -— 0.2 ppb 0.56 — _ 0.38 Adapted from the US Environmental Protection Agency (1980). Formation of Chlorinated Dioxins One route to the formation of chlorinated dioxins begins with certain chlorinated organic chemicals. 2,4,5-Trichiorophenol, for example, can condense to form a phenoxyphenate or substituted diphenyl ether (a "predioxin") (Buser, 1978; Jensen et al, 1972; Moore, 1979; Nilsson et al, 1974) as shown here: cl ONa Cl cl CH^OH NaOH 1,2,4,5-tetraehlorobenzcne ClCH 5 CO.>Na Cl Cl 2,4,5-trich'orophenoI I TCD0 d57:update (revd. 5-29-85) - page 7 Cl 2,4,5-T �"Predioxins" have been found in waste sludges and commercial products, as well as in some products of laboratory scale reactions (Jensen et al, 1972, 1973; Arensault, 1976). Chlorinated dioxins also can be formed during the combustion of various substances. For example, Olie et al (1977) reported the occurrence of chlorinated dioxins in the fly ash and flue gases of municipal incinerators in the Netherlands, while Buser et al (1978) found chlorinated dioxins in fly ash from a municipal incinerator and in an industrial heating facility in Switzerland; the levels ranged from 0.2 ug/g to 0.6 ug/g of ash. Buser (1979) also reported that chlorinated dioxins were formed by the pyrolysis of chlorobenzenes in the presence of air. Other studies have shown that chlorinated dioxins are to be found in cigarette smoke, fireplace soot, and in the burning of wood (Dow Chemical Company, 1978; Nestrick et al, 1982). Occurrence of Chlorinated Dioxins acid) The levels of TCDD in drums of Herbicide Orange placed in storage in the US and in the Pacific before 1970 varied from 0.1 to 47 ug/g (Firestone, 1978). Since Herbicide Orange was formulated as a 1:1 mixture of the butyl esters of 2,4-D and 2,4,5-T, it is conceivable that the levels of TCDD in individual 2,4,5-T formulations for agricultural and residential use in the 1960s could have been as high as 100 ug/g. After the enactment of government regulations, the amounts of TCDD in 2,4,5-T formulations should be less than 0.1 ug/g. In C hi or ophenol s The most important use for chlorinated phenols, such as pentachlorophenol, 2,3,4,6-tetra-, and 2,4,6-trichlorophenols, is as a preservative of wood. These chlorophenols can contain a variety of contaminants, including polychlorinated di ben zo-p- dioxins (PCDDs) as well as dibenzofurans (PCDFs) (Nilsson et al, 1978). There can be several positional isomers of PCDDs and PCDFs, and since the relative ratios of PCDF to PCDD depend on the particular route of synthesis for the chlorophenol in question, the ratio of PCDFs/PCDDs can range from about 1 to greater than 20. Usually the level of 2,3,7,8-TCDD is relatively low, although a Scandinavian preparation of 2,4,6-trichlorophenol contained 0.5 ppm of 2,3,7,8-TCDD (Rappe et al, 1979). In Hexachlorophene Hexachlorophene is a bactericide and, like 2,4,5-T, is synthesized from 2,4,5-trichlorophenol. However, after extensive purification, the amount of 2,3,7,8-TCDD in hexachlorophene is usually less than 0.03 ug/kg (Rappe et al, 1979). Decomposition of Chlorinated Dioxins Photodegradation, or photolysis, is the process whereby chemical bonds are broken by means of photons of light. As applied to chlorinated aromatics, such as chlorinated dioxins, photodegradation usually proceeds by progressive loss of chlorine to create a free-radical, or a loss of chlorine through a nucleophilic displacement in the presence of a solvent or substrate molecule. According to Crosby (1982), three requirements must be met if degradation is to proceed: 1) light energy must be absorbed by the compound, 2) light of the appropriate wavelength must be available at a meaningful intensity, and 3) a source of excess reducing agent (proton donor) must be present, inasmuch as the reaction involves reductive dechlorination. d57:update (revd. 5-29-85) - page 8 �There is clear experimental evidence to show that dioxins may be photodegraded in the environment by natural sunlight. The maximum absorption of ultraviolet light for chlorodioxins is in the range of 290 to 320 nm; 2,3,7,8-TCDD absorbs maximally at 307 nm. Crosby et al (1971) studied photolysis rates of 2,3,7,8-TCDD dissolved in methanol using both natural and artificial sunlight of 100 mW/cm intensity and at the absorption maximum of 2,3,7,8-TCDD. Complete photolysis to less chlorinated dioxin isomers occurred in 24 hours under natural sunlight, while 6 hours of artificial light destroyed almost 50% of the original 2,3,7,8-TCDD. Irradiation had no effect on a crystalline water suspension of 2,3,7,8-TCDD. Apparently the crystalline state may prevent the loss of chlorine or abstraction of hydrogen atoms (Plimmer, 1978). On the other hand, irradiation reduced the dioxin content of a benzene solution of 2,3,7,8-TCDD added to water and stabilized with a surfactant (Plimmer et al, 1973). Crosby (1971) also found that, when 2,3,7,8-TCDD was applied to dry or moist soil, irradiation caused no change after 96 hours. In addition, no degradation occurred when the substance was applied to a glass plate and irradiated for up to 14 days. When Crosby et al (1977) exposed on glass petri dishes thin layers of Herbicide Orange containing 15 ppm of 2,3,7,8-TCDD to summer sunlight, approximately 60% of the TCDD disappeared after 6 hours. A commercial herbicide composed of butyl esters of 2,4-D and 2,4,5-T and 10 ppm 2,3,7,8-TCDD was exposed in the same manner; after 6 hours, only about 30% of the initial TCDD content remained. Herbicide Orange was also applied to excised rubber plant leaves and to the surface of Sacramento loam soil and then exposed to sunlight; no TCDD was detected on the leaves after 6 hours at an application rate of 6.7 mg/cm 2 of leaf surface, while about 30% remained after 6 hours when applied at 1.3 mg/cm . About 90% of the TCDD remained after 6 hours when the dioxin was applied to soil at a rate of 10 mg/cm . According to the authors, partial shading of the lower layers by soil particles accounted for the lesser degree of photolysis. Analysis Extraction Since 2,3,7,8-TCDD has been found in a variety of substances, a number of different extraction procedures have been developed to separate the compound from its substrate and to reduce the sample volume to a manageable size. Generally, these procedures take place in either a neutral or highly basic (alkaline) medium. Contaminants, such as polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) isomers, are frequently present in the extracts in relatively high amounts compared to the likely amount of 2,3,7,8-TCDD. It is now possible to isolate and quantitatively determine 2,3,7,8-TCDD in the presence of the other twenty-one tetrachloro- isomers. The basic extraction procedures were developed first for the detection of 2,3,7,8-TCDD in environmental samples (Baughman et al, 1973 a,b; Crummett et al, 1973). After digestion with alcohol and a strong base, a sequence of extractions with various organic solvents (eg, ethanol, petroleum ether, methylene chloride, hexane) separates the TCDDs from the alkaline mixture. The resulting extracts are combined, washed with distilled water and a strong acid, then treated to remove any traces of water and passed through one or more chromatographic columns for the partial removal of contaminants. The neutral extraction procedure was developed primarily to avoid a possible base-catalyzed formation of chlorodioxins within the mass spectrometer. In this process, developed by O'Keefe et al (1978) and modified by Albro et al (1977), the sample is first d57:update (revd. 5-29-85) - page 9 �extracted with hexane; the extract is then passed through a series of chromatographic columns—the first being magnesia-Celite 545, followed by an alumina minicolumn, and finally a Florisil minicolumn. The Florisil column is eluted with methylene chloride and the product then condensed for analysis. This technique is particularly effective for fish tissues and human milk. Detection Technological advances in analytical chemistry permit the detection of dioxin concentrations at least as low as one part per trillion (1 ppt). However, relatively few analytical laboratories are capable of identifying, much less quantifying, individual isomers at such a low level. Then too, regulatory agencies can only speculate as to the safest levels that should be allowed for human exposures. Most of the current methods for the detection of 2,3,7,8-TCDD employ gas chromatography (GC) and/or mass spectrometry (MS) and even tandem mass spectrometry (MS/MS). Other procedures—electron spin resonance spectroscopy (ESR), lowtemperature phosphorescence emission spectroscopy (LTE), and ultraviolet spectroscopy (UV)~have been used, but their usefulness is limited by poor selectivity and sensitivity. For the present, a combination of gas chromatography and mass spectrometry (GCMS)--both low- and high-resolution—is used almost exclusively for the detection and quantitative analysis of TCDDs. In the low-resolution scheme, fragment ions at nominal mass: energy ratios (m/e) of 320 and 322 are monitored and measured as the TCDDs emerge from the gas chromato graph. To differentiate these compounds from those with nearly identical mass, such as pentachlorinated biphenyls, high-resolution mass spectrometry can distinguish the dioxin component with an exact mass of 321.8936. Toxicological Evidence of a Health Hazard in Animals General Discussion 2,3,7,8-Tetrachloro-dibenzo-p-dioxin is still considered to be one of the most powerful poisons for lower animals and the most toxic of all tetrachloro- isomers. The large differences in acute toxicity among animal species have not been satisfactorily explained; toxicity levels for higher animals, such as the dog, are estimated to be between 300 and 3000 ug/kg of body weight (BW) (Schwetz et al, 1973). Acute toxicity symptoms develop after a latent period of 7 to 10 days; the animals experience a rapid loss in body weight and depletion of adipose tissue. The loss of body mass is only partially related to the reduced food intake~"wasting syndrome." The final mechanism responsible for death is unknown, but the general clinical appearance of the animals suggests general exhaustion of energy reserves (McConnell et al, 1978). Significant reduction in the size of the thymus dominates the postmortem findings in all animal species (Buu-Hoi et al, 1972; Gupta et al, 1973; Vos et al, 1973), but the animals do not die from infection secondary to immune suppression (Greig et al, 1973). Pathological changes in other organs are characteristic for a given species; eg, hepatic lesions are striking in mice, rats and rabbits but relatively minor in guinea pigs, monkeys, cattle and horses. The organ manifestation may be related to the distribution of the compound in the body; mice and rats retain several times more of the compound in the liver, while guinea pigs have much lower concentrations in this organ (van Miller, 1976). Mucosal changes, particularly cellular hyperplasia or metaplasia, have been observed in the gastric, intestinal, and urinary tracts of primates and cattle but were not reported in d57:update (revd. 5-29-85) - page 10 �the rat, mouse, and guinea pig. Similar hyper plastic epidermal changes~ie, chioracne—are the most characteristic lesions observed in exposed human populations. Corresponding lesions do not, however, appear in many laboratory species; ie, rats, hamsters, guinea pigs. In mice, characteristic epidermal changes occurred in hairless strains but not in the ordinary laboratory or wild types of animals i(lnagami et al, 1969; Knutson et al, 1982). It is interesting to note that the absence of the hair follicle is not a prerequisite for the skin changes; the symptoms were not produced by TCDD directly applied to areas without hair (ear) in laboratory mice (Poland et al, 1982). Local application of TCDD did produce characteristic changes in the ear of the rabbit (Kimmia et al, 1957; Vos et al, 1971). Specific epidermal changes also have been observed after systemic administration in rabbits and primates (Allen et al, 1977; McNulty, 1977; McConnell et al, 1978; McNulty et al, 1980, 1981). The presence of TCDD increases keratinization in epidermal cell tissue cultures in spite of the simultaneous partial inhibition of DNA synthesis. This observation suggests that TCDD can stimulate differentiation of human epidermal cells in culture (Osborne et al, 1984). The exact mechanisms by which TCDD produces its toxic action are still unknown. Biochemical studies indicate that TCDD is a very potent inducer of aryl hydrocarbon hydroxylase (AHH), as well as the mixed-function oxidases and the cytochrome P.-450 (P-448) enzymes of the liver, lung, placenta, and kidney of the mouse and rat. However, Poland et al (1982) do not believe that the induction process is directly responsible for TCDD's toxicity; they attribute the pleiomorphic clinical symptomatology to the presence of an intracellular receptor with high binding affinity for TCDD and other aromatic hydrocarbons (Ah locus) (Nebert et al, 1972). Poland et al (1976) identified a stereospecific TCDD receptor in the hepatic cytosol of laboratory mice. The receptor has a maximum binding capacity of approximately 8 x 10 TCDD mol/mg of cytosol protein, or approximately 5 x 10 TCDD binding sites per cell. The receptor binds other aromatic hydrocarbons with enzyme induction properties, but the binding affinities in these instances are only 1/3 to 1/30 that for TCDD. Enzyme-inducing compounds other than aromatic hydrocarbons do not compete for this particular receptor. The receptor is a high-molecular-weight protein that serves as a carrier in the nuclear uptake of TCDD (Carlstedt et al, 1979; Greenlee et al, 1979; Okey et al, 1979, 1980; Weaver, 1980). Once within the nucleus, the TCDD receptor complex binds to a specific set of genes in the Ah locus, which initiate the production of RNA responsible for the synthesis of new cytochrome P-45Q enzymes. Since the hepatic receptor affinity and the enzyme induction potency of individual TCDD isomers correspond to their LD5Q and since the presence of the Ah locus is necessary for expression of TCDD toxicity, Poland et al (1982) have postulated that the TCDD response is mediated by its binding to the induction receptor. However, the sole presence of the Ah locus, although essential, is not sufficient for the full expression of toxicity. Many tissues respond to TCDD by enzyme induction but not all with an adverse reaction and, while animal species vary widely in their sensitivity to TCDD, they do not differ in their liver receptor concentration or affinity. The authors suggest that TCDD can induce enzymes in all tissues that contain the receptor, but activation of an additional battery of genes to control the expression of a fully developed toxic response only occurs in some tissues. The composition of these additional genes may vary in different tissues but their presence is essential for the manifestation of TCDD toxicity; thus, enzyme induction may be only a secondary sign not directly related to the toxicity of TCDD. d57:update (revd. 5-29-85) - page 11 �Analytical assays were developed for the quantification and characterization of the TCDD cytosolic receptor (Gasiewicz et al, 1982; Mason et al, 1982; Gasiewicz et al, 1984); they confirm that the hepatic cytosolic receptor in the Sprague-Dawley rat is similar to the one described in the "responsive" genetic strains of mice (Poland et al, 1976). Genetic strains that are nonresponsive to TCDD toxicity have very low or unmeasurable levels of the receptor in the liver (Poland et al, 1976; Okey et al, 1979; Gasiewicz et al, 1982). High concentrations of the receptor are localized in the liver, lung, intestine, and kidney, which produce the highest levels of induced AHH activity in all tested animal species (Nebert et al, 1969). Gasiewicz et al (1984) reported that the receptor concentrations in the liver and lung of the Sprague-Dawiey rat rapidly increase after birth then decline after 21 days of age; levels in the thymus, on the other hand, remain constant between 2 and 70 days. In the adult rat, the thymus contains the highest concentrations of the receptor. Recent laboratory data indicate that the thymic epithelium and its differentiation is the primary and most sensitive site of TCDD toxicity. Administration of TCDD produced genetically dependent thymic atrophy in mice (Poland et al, 1980) and suppressed a variety of lymphocytic functions (Voss et al, 1973; Faith et al, 1977; Faith at al, 1979). Clark et al (1981) found that thymic generation of cytotoxic lymphocytes (CTX) is particularly sensitive to inhibition, since it occurs at a dose level that is 10 to 100 times lower than the dose required for enzyme induction in the liver (weekly dose of 0.001 ug/kg BW). However, TCDD is not toxic when added directly to a culture of thymic cells, and an indirect mechanism was postulated for its suppressive effects on the immune system (Knutson et al, 1980; Clark et al, 1981). Mason et al (1982) reported the presence of TCDD cytosol receptor in the murine thymus, and Clark et al (1983) suggested that TCDD produces immunosuppression by acting on the differentiating process of lymphoid cell population within the thymus rather than on mature immunocompetent cells in the peripheral lymphoid organs. Recently, replacement of peripheral lymphocytes in the irradiated bone marrow of mice with a genetically different sensitivity to TCDD indicated that the immunosuppressive effect of TCDD on the thyrnic generation of allospecific cytotoxic T-lymphocytes (CTL) is predetermined by the sensitivity of the radio-resistant tissue of the host, not by the grafted lymphomyeloid cells. Although the impaired generation of CTL was accompanied by increased activity of suppressor T-cells, the authors concluded that TCDD acts indirectly through receptors in the thymic epithelium rather than on the lymphomyeloid tissue (Nagarkatti et al, 1984). Their results were confirmed by Greenlee et al (1984), who co-cultivated thymocytes with thymic epithelium in the cell culture. Subsequent treatment with TCDD altered the capacity of the thymic epithelium to support the intrathymic differentation of T-lymphocytes. Since the symptoms of TCDD toxicity resemble manifestations of thyroid dysfunction— eg, loss of body weight, alopecia—the role of the thyroid gland in mediating the toxicity of TCDD has been suggested (Bastomsky, 1977; Neal et al, 1979). However, Gasiewicz et al (1980) observed unchanged mortality in euthyroid rats given the lethal dose of TCDD and maintained at constant or increasing body weight by parenteral nutrition. In contrast, administration of the same lethal dose resulted in no mortality in athyroid (thyroidectomized) animals in spite of the fact that their body weight losses were not different from the TCDD-treated euthyroid animals. Supplementation of thyroidectomized animals with thyroid hormone (T4) brought mortality to the level of the control group 31 days after injection (Rozman et al, 1984 a) but to only one-half of the control group at 90 days (Rozman et al, 1984 b). Triiodothyronine (T3) was equally effective (Scheufler et al, 1984). d57:update (revd. 5-29-85) - page 12 �The whole body half-life of TCDD is between 20 and 30 days in the rat (Rose et al, 1979) and guinea pig (Gasiewicz, 1979; Nolan, 1979), and 10 to 12 days in the hamster (Olson et al, 1980). Differences in the rates of elimination cannot completely explain differences in toxicity: guinea pigs and rats have identical half-lives but their susceptibilities to TCDD (LDtQ ) are different. The discrepancy is more striking in the Syrian hamster whose elimination rate is nearly the same as that of the guinea pig and rat but its resistance to TCDD toxicity is larger by several orders of magnitude. Similarly, the accumulated body burden of TCDD does not seem to be related to toxicity, for the Syrian hamster can tolerate up to 5,000 ug of TCDD per kg of tissue without signs of liver toxicity. Some investigators think that the more resistant animal species, such as the beagle dog, convert TCDD to metabolites at a higher rate (Poiger et al, 1982). Weber et al (1981) found the toxicity of the crude canine biliary metabolite to be at least 100 times lower than that of TCDD. The detoxification process occurs primarily through hydroxylation and methylation of the tetrachloro- molecule to the trichloro- metabolite and finally cleavage of one or both ethereal bridges in the dioxin molecule (Poiger et al, 1982). TCDD metabolites, however, differ among individual animal species; for example, different biotransformation products were identified in the laboratory rat (Poiger et al, 1982). Olson et al (1983) found that most of the metabolites in the hepatocytes, bile, and urine of the Syrian hamster are glucuronic acid conjugates; the 1-hydroxy derivative of the tetrachloro- isomer was the most abundant metabolite in the hepatocytes. Administration of P-45Q cytochrome inhibitors, such as SKF-525, slightly decreased the metabolic rate of TCDD (Neal, 1983). This is consistent with previous findings wherein pretreatment with enzyme inducers decreases the lethality of TCDD, but administration of P-450 blockers increases it (Beatty et al, 1978). Mutagenicity No conclusive evidence of mutagenicity has been observed in microbial assay studies of TCDD. Of more relevance to man are the results on mammalian cells--ie, HeLa; Balb3T3, normal mouse fibroblasts; SV101, virus (SV^O)-transformed 3T3 mouse fibroblasts; human foreskin fibroblasts and normal human lymphocytes (Beatty et al, 1975). There was no significant growth inhibition in the cell cultures, nor were there discernible ultrastructural changes under electron microscopy. Rogers et al (1982) examined the mutagenicity of TCDD in L-5178Y mouse lymphoma cells. Doses of 0.1 to 0.5 ug TCDD/ml induced significant mutations in the methotrexate-, excess of thymidine-, and thioguanine-selection systems. No induced mutations were noted in the ouabain or cytosine-arabinoside systems. The authors concluded that mutagenic effects of TCDD show similarities with proflavin and other acridines, its genotoxicity being exerted by DNA intercalation (Wassom et al, 1978). In baby hamster kidney cells (BHK cell transformation system), 2,3,7,8-TCDD was also positive, the dichloro- and trichloro- isomers were weakly positive, and the octachloroand unsubstituted dioxins were negative; unfortunately, the authors provided no specific information on the test concentrations (Hay et al, 1983). Tests for chromosomal aberrations in bone-marrow cells of laboratory rats were negative after a single administration of TCDD (Green et al, 1975) but positive after 13 weeks of chronic dosage (Green, 1977). Similarly, single doses of TCDD did not induce dominant lethal mutations (Khera et al, 1973). d57:update (revd. 5-29-85) - page 13 �It may be concluded that the positive data on the mutagenic activity of TCDD are isolated in the literature and refer mainly to high TCDD concentrations in closed laboratory systems. The positive findings contrast sharply with data of Poland et al (1979) who examined the in vivo covalent binding of TCDD to rat liver macromolecules using minimal levels of TCDD to interact with DNA. Although 18% to 64% of the administered dose accumulated in the liver, virtually all of the deposited radioactivity was extractable. Only 6 pmol of TCDD per mol of nucleotide residuum was associated with the DNA. This represents a binding level that is four to six orders of magnitude lower than that of most chemical carcinogens, and it contradicts the probability that covalent binding of TCDD to DNA and subsequent somatic mutation is responsible for the oncogenic potency of TCDD. Oncogenicity Several investigators have examined the tumor-initiating and -promoting potencies of TCDD on mouse skin. DiGiovanni et al (1977) found little or no tumor-causing or tumorpromoting properties of TCDD, and Berry et al (1978, 1979) found an inhibitory effect on skin tumors in mice. In contrast, dermal application of TCDD was carcinogenic in Swiss-Webster mice (NTP Rept 80-32, 1980); the females had integumentary fibrosarcomas, while results from the males were inadequate. Poland et al (1982) tested the capacity of TCDD to promote tumor formation in the skin of hairless and haired HRS/3 inbred mice, which have a genetically different sensitivity for TCDD. The authors found a powerful promoting effect of TCDD in the "responsive" hairless mouse but not in the resistant heterozygote (haired) strain. This effect was 100 times stronger than that of tetradecanoyl-phorbol acetate (TPA). It is important to note that TCDD produces acneiforme changes in the skin of a hairless mutant that are identical to those observed in human skin (Knutson et al, 1982). In 1982, the International Agency for Cancer Research (IARC) reviewed all studies in which TCDD was tested orally in mice and rats and dermally in mice; the agency declared that the evidence for TCDD's carcinogenicity in animals was sufficient (IARC, 1982). The experimental evidence came primarily from two sources: 1) chronic feeding studies where only the highest administered level (0.1 ug TCDD/kg BW per day) produced an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue in the Sprague-Dawley rat (Kociba, 1973, 1978), and 2) studies by the National Toxicology Program (NTP) in which TCDD given by gavage was carcinogenic in the B6C3F1 mouse; hepatocellular carcinomas were observed in both sexes of mouse but only female mice and male rats developed follicular cell thyroid adenomas (NTP-Rept 80-31). The positive initiating effects of TCDD in the chemical carcinogenesis process conflict with indications that neither TCDD nor its metabolites form covalent adducts with cellular DNA. Poland et al (1979) found no significant DNA binding in vivo after administration of radioactive labeled TCDD; similar results were reported for in vitro TCDD binding (Piper et al, 1973; Vinopal et al, 1973; Ghiasuddin et al, 1975; Rose et al, 1976; Nelson et al, 1977). Pitot et al (1980) tested TCDD's potential for promoting hepatocarcinogenesis following partial hepatectomy and a single initiating dose of diethylnitrosamine (DEN); TCDD was thereafter administered subcutaneously at two levels every two weeks for seven months. The higher dose (1.4 ug/kg BW) produced five hepatocellular carcinomas, whereas the animals treated only with DEN had no carcinomas and only a few enzymed57:update (revd. 5-29-85) - page 14 �altered foci. The authors concluded that TCDD is a potent promoter of hepatocarcinogenesis. Similar conclusions were reported in TCDD promotion studies on the skin of the "responsive" strain of the HRS/3 hairless mouse (Poland et al, 1982). Teratogenicity 2,4,5-T containing 30 ppm of TCDD in two strains of mice (C57BL/6 and AKR) and one strain of rats, produced increased incidences of cleft palate in mice and cystic kidney in the rat (Courtney et al, 1970); when comparably dosed with a sample containing only 1 ppm of TCDD, teratogenesis was not evident (Emerson et al, 1971). A gavage dose in the rat of 0.125 ug/kg/day from the 6th-15th days of gestation showed only a slight effect that was much pronounced at the level of 0.5 ug/kg/day (Sparschu et al, 1971). In utero exposure of mice to TCDD during the final half of the gestation period produced fetuses with poorly developed lymphatic systems and fatty infiltrates in the liver (Neubert et al, 1973). Prenatally, TCDD causes hydronephrosis, which according to Gibson (1976), may be only a sign of delayed maturation and not permanent damage inasmuch as the test animals were taken by cesarean section. Gibson did find altered PAH transport from kidney slices of neonate animals even where there was no evidence of a lesion; the significance of these data in the adult is unknown. TCDD also caused postnatal hydronephrosis in a suckling pup whose foster mother had been dosed beforehand with the compound (Moore et al, 1973). A low proportion of kidney abnormalities also was found in the rabbit; Giavini (1982) considers the kidney to be the target organ of TCDD's effect in many animal species. No other severe teratological effects from TCDD have been described in the literature. Reproductive Effects It is still unclear whether TCDD affects spermatogenesis in lower animals (Wassom et al, 1977, 1978) and primates (Allen, 1979) by a direct action on testicular parenchyma or only secondarily as a result of cachexia produced by the high level of exposure. The maternal and embryofetal toxicity of TCDD is comparable among the various species; eg, 0.1 ug/kg BW was a "no effects" level in the mouse (Smith et al, 1976), rat (Sparschu et al, 1971), and rabbit (Giavini et al, 1982). Pregnant female rabbits were treated orally with 0.1, 0.25, 0.5, and 1.0 ug TCDD/kg BW on the 6th to 15th days of gestation. No abortions occurred at the lowest dose of 0.1 ug/kg; two, five, and three dams aborted at the higher doses of 0.25, 0.5 and 1.0, respectively. The high abortion rate was ascribed to severe maternal toxicity and the incidence of total resorptions, which increased at the higher doses. No living fetuses were found at term in the group with the highest exposure. No external malformations occurred, and histological examination did not reveal any signs of teratogenicity (Giavini et al, 1982). More recent data (McNulty, 1983) on pregnant Rhesus monkeys treated with 0.2, 1.0, and 5.0 ug TCDD/kg BW between 20 to 40 days of pregnancy revealed no increase in abortion rate or maternal toxicity from the lowest dose. At 1.0 ug/kg BW, however, there were three abortions out of four animals. Maternal toxicity symptoms were recorded in 50% of the animals and one out of four mothers died. Abortions and maternal deaths occurred in all animals fed 5.0 ug/kg BW. Inasmuch as the Rhesus monkey seems to be particularly sensitive to TCDD and the administered doses greatly exceeded the potential levels of d57:update (revd. 5-29-85) - page 15 �environmental exposure, the pharmacokinetics of TCDD during pregnancy—particularly the transfer of the toxin to placenta and fetus—must be investigated further. The fetuses were reported dead before the abortion, with no abnormalities except for small changes in the sebaceous glapds. Studies of Human Populations Introduction The most significant information about the acute and long-term effects in man of Agent Orange, 2,4-D, 2,4,5-T, and their toxic contaminants is provided by the clinical, epidemiological, and pathological studies of the personnel who handled and sprayed the defoliant in Vietnam, as well as those who dedrummed the defoliant at the close of the conflict. The populations that were most heavily exposed were industrial workers exposed during routine manufacture and use, and in several instances when the reaction process went out of control. These workers provide critical information regarding the acute, chronic, and long-term effects of the parent herbicides, as well as their contaminants, especially 2,3,7,8-TCDD. Approximately 18 distinct industrial populations of record have been exposed, and several of these as a result of such "runaway" reactions. In some instances, workers have beeen exposed both to a trichlorophenol runaway reaction as well as the routine production and use of trichlorophenol. In both situations, 2,3,7,8-TCDD has been the major toxic contaminant. Another source of data is workers who formulated or sprayed 2,4,5-T or were exposed to areas where the herbicide had been applied. This chlorophenoxy compound, later known to contain varying amounts of TCDD, was widely used from 1948 - 1970 in large scale farming, family gardens, forest management, and weed control along roadsides and railroad rights-of-way. A gauge of the extent of such human exposure in the US is provided by the production figure in 1964 for domestic use alone—9.8 million pounds. Recently, both scientific and lay communities have become concerned about contamination of the environment by the inappropriate use and disposal of the phenoxy herbicides and of TCDD-containing materials, such as in Missouri. As a consequence, pilot studies have been carefully designed to determine the health effects of TCDD and its related compounds in at least one heavily contaminated area. In studies of all populations, the critical components are proper design of the study, carefully defined population cohorts, and suitable controls. It should be recognized, however, that in the study of industrial populations, which are likely to be the most heavily exposed, it is often not: possible to satisfy completely the requirements for randomization, for percent participation, or for knowledge of exposure levels. This is particularly true for long-term follow-up investigations. Vietnam Veterans (Studies Complete or Partially Complete) —Ranch Hand Program According to Lathrop et al (1984), the personnel who filled the tanks and flew the missions in Operation Ranch Hand are currently the most relevant human population for study. The purpose of the Ranch Hand (RH) program, an ongoing, two-phase, highly sophisticated epidemiological investigation of this population, has been to determine whether there are long-term health effects from occupational exposure to Agent Orange and other herbicides during military service in Vietnam. The matched cohort design in a nonconcurrent prospective setting has incorporated mortality, morbidity, and follow-up studies on 1,174 Air Force "Ranch Hand" personnel who were involved in the actual spray d57:update (revd. 5-29-85) - page 16 �operations; these men are being compared to a matched control group of Air Force C-130 cargo personnel who had no exposure to Agent Orange. The first phase, a mortality study (USAF, 1983) published 30 3une 1983, has shown no unusual findings that can be attributed to the herbicide, though the number of deaths is not substantial at present. The second phase of the study, released in February 1984, is designed to determine morbidity incidence. The 270-page report is a myriad of detailed findings, including investigations of many of the major categories of disease and of most of the human organ systems; such as malignancies, neurological and psychological assessments, fertility dysfunction, and evaluations of hepatic, dermatologic, cardiovascular, immunologic, hematologic, pulmonary, renal, and endocrine functions. Considered a baseline, it too has shown no definitive clinical endpoints, such as soft tissue sarcoma, porphyria cutanea tarda, or chloracne. Information has been derived from two sources: 1) a specially designed questionnaire given to the 2,706 respondees, who were about equally divided between the RH group and its controls, and 2) a physical examination on a total of 2,269 individuals, again about equally divided between Ranch Hand personnel and controls. Positive findings included significantly more minor birth defects (eg, birth marks) in the RH group compared to the controls. The fertility and reproductive results are preliminary, based largely upon subjective self-reports that await medical record and birth certificate verification. Although an excessive number of neonatal deaths and physically handicapped children occurred in the RH group, the data—from unverified subjective questionnaire reporting—must be confirmed from medical records and birth certificates. A large number of basal cell carcinomas of the skin were reported in the RH group, but these data were not adjusted for sunlight exposure, the recognized primary cause of these cancers. A more complete analysis of this data is planned for the first follow-up examination. Although biochemical differences between the RH and control groups existed, the results were still within normal limits. Negative findings indicated that there were no significant differences between the RH and control groups with respect to the occurrence of systemic cancers; clinically significant blood abnormalities; or cardiovascular, renal, pulmonary, hepatic, and neurologic effects. Among the exposed, the absence of chloracne, soft tissue sarcomas, and porphyria cutanea tarda was noted. Periodic follow-up examinations—at 3-, 5-, 15-, and 20-year intervals—will be compared to the baseline information. The preliminary nature of this report is repeatedly emphasized. Many of the group differences were based largely upon recall or elicited through the questionnaire and subjective data; although a subtle effect of differential reporting is suggested, the data have not been fully evaluated. Additional work on the baseline data is still required, including data-base refinement, establishment of follow-up examination requirements, and collaboration with other dioxin research projects. While it is premature to accept these findings as conclusive, they "should be reassuring to Ranch Handers" because "no major clinical health problems" have surfaced and the men are "overall (in) good general health for (their) age." On 11 February 1985, the US Air Force released a second mortality report (Wolfe et al, 1984). Like the first mortality study, which appeared in 3anuary 1983, this report did not reveal any statistically significant differences in the number of deaths between the d57:update (revd. 5-29-85) - page 17 �Ranch Hand group and its comparison members. Ranch Hand officers and flyers had slightly lower death rates and RH ground personnel had a slightly higher death rate than their respective comparisons; none of the differences was statistically significant and there was no apparent relationship between exposure and mortality. Compared to US white males, the RH officers and enlisted men, as well as their comparisons, are living significantly longer than expected; the pattern is similar to the patterns of the DOD retirees and civil service personnel. There is presently no evidence of increased mortality in persons exposed to herbicides during the Ranch Hand operations in Southeast Asia. Though the elapsed time has been sufficient for the development of clinically significant conditions, it may still be too early to see the development of conditions that might be attributable to herbicide exposure. —CDC Birth Defects Study Aimed at determining if there is any possible association between Vietnam service and subsequent male parentage of congenitally malformed offspring, this case-control study by the Centers for Disease Control was based on the experiences of parents of selected babies born during 1968 through 1980. From among 13,000 live- and stillbirths registered with the Metropolitan Atlanta Congenital Defects Program (MACDP), 7,133 cases with serious or major birth defects according to the International Classification of Disease, 8th revision (ICD-8), were chosen; a serious defect was defined as being associated with premature death, the cause of a substantial handicap, or the need for surgery or extensive medical care. These cases were matched with 4,246 controls according to race, year of birth, and hospital of birth. The results (Erickson et al, 1984) provide "strong" evidence that Vietnam veterans are at no greater risk than other men for siring babies with all types of serious structural birth defects combined. The evidence for Agent Orange-associated risks is weak; if there is any risk from exposure, it is either small or it is limited to select groups of veterans or to specific types of defects. There is no explanation for the likely association between Agent Orange exposure and spina bifida, cleft lip with or without cleft palate, or congenital neoplasms; these associations may be an element of chance or the result of some unknown bias or uncontrolled confounding factor. —Estimate of Vietnam Troop Exposure In an effort to evaluate the possible toxic effects of the dioxin in Agent Orange on Vietnam veterans, Stevens (1981) calculated a minimum toxic dose (MTD) from animal and human data, an intake transfer factor (from human data), and from data on the spraying operation of Agent Orange in Vietnam, he calculated the fraction of the MTD to which a soldier would have been exposed. The calculation of the MTD (0.1 ug/kg) was based on primate studies of TCDD exposure and human studies of Yusho oil contaminated with tetrachlorodibenzofuran (TCDF). The average intake transfer factor (1:2,050) was based on the calculation of data from an individual exposed to TCDD in a Missouri horse arena and approximately 75 individuals exposed in zone A of Seveso, Italy. From available information on the spraying operation (Operation Ranch Hand) in Vietnam, it was calculated that a 70 kg man would have been exposed to 1/14,000 of the MTD, or 0.1 ug/kg. Thus, if a veteran had been exposed to 8 ug of TCDD/m2/day/one year tour of duty, his cumulative intake would have been 1.4 ug, or 0.02 ug/kg. This amount, Stevens concluded, could not be responsible either for the veterans' alleged systemic illnesses or the birth defects in their offspring. Interlaboratory analyses for 2,3,7,8-TCDD in the adipose tissue from Vietnam veterans indicated a correlation between the degree of exposure to Agent Orange and the tissue levels of TCDD. For example, the "heavily" exposed subjects had the highest levels of TCDD--greater than 20 ppt (Gross et al, 1984). d57:update (revd. 5-29-85) - page 18 �—VA Agent Orange Registry The Registry was established by the Veterans Administration in 1978 as an index to the records of those Vietnam veterans who have come to the VA for Agent Orange-related examinations. It is essentially an extract of the veteran's complete records: his name and address, examination center, brief information about military service, estimated herbicide exposure, and elements of the findings of the physical examination. Besides serving as a means of identifying and contacting the veteran about developments and the possible need for further testing, it also provides a means of detecting health trends and other characteristics about the group. Inasmuch as the information is supplied voluntarily, any comparisons that are made are not statistically valid. As of 31 December 1983, there were 130,220 initial examinations and 31,471 follow-ups. Thus far, there is no unusual morbidity or mortality associated with either Vietnam service or Agent Orange exposure. There have also been attempts to compare the distribution of malignant neoplasm cases in the Registry with a reference population. Subjects in the SEER (Surveillance Epidemiology End Results) program, representing about 10% of the entire US population and being fairly representative agewise, have been selected for reference; from these, the number of malignant neoplasm cases diagnosed between 1973-1977 among US males of ages 25 to 39 is expected to include most Vietnam-era veterans. As yet, there have been no significant differences in the proportion of cancers of various sites and the proportions of soft tissue sarcomas and skin cancer, though some differences—marginal, yet statistically significant—were noted for lymphomas and cancers of the buccal cavity and pharynx (Shepard, 1983; Shepard et al, 1983). —Agent Orange Biopsy Registry of the Armed Forces Institute of Pathology The Agent Orange Registry (AOR), in the Department of Environmental and DrugInduced Pathology of the Armed Forces Institute of Pathology (AFIP), was begun in 1978. Its objective is to attempt to establish whether or not there is a link between Vietnam exposure to Agent Orange and the current illnesses of these veterans. Any unusual features in the findings would suggest the need for further study. A linkage might be suggestive if there were such unusual features based on past experience with some environmental diseases that have had rather selective anatomic targets and a rather limited number of induced diseases (eg, asbestos and mesothelioma, vinyl chloride and hemangiosarcoma of the liver). To date, the AOR has been unable to show any unusual disease patterns, including cancer. Biopsy and autopsy specimens for the Registry project are received primarily from the Veterans Administration and Armed Forces. Two phases will be carried out: Phase I is to collect and evaluate the morphologic findings of veterans or active duty personnel who served in Vietnam during 1962-1973, while Phase II will be concerned with veterans or active duty personnel who had not served in Vietnam and who will serve as a matched control set for cases in Phase I. The Phase I group is being closely scrutinized for: 1) any clustering or peaks that represent similar organ-diagnosis combinations, 2) any clustering of pathologic findings that are unusual for a site or organ, and 3) any unusual age of occurrence for a particular diagnosis. As of March 1983, pathologic diagnoses and demographic data have been tabulated on 1,200 veterans who had service in Vietnam. Over 300 different diagnoses, involving 84 different organs or anatomic sites, were made. d57:update (revd. 5-29-85) - page 19 �No clusters of medical significance have appeared; in other words, there have been no persistent patterns of adverse health effects. Two clusters of relatively trivial lesions—lipomas (79 cases) and epidermal inclusion cysts (96 cases)--were noted, but both were benign and of no serious prognostic significance. The relatively large incidences of these lesions may be due to their superficial locations in or on the skin; being visible or palpable, there is more concern to have them removed. Six cases with unusual features occurred singly, not as diagnostic clusters: 1) mucinous adenocarcinoma of the colon with unusual features; 2) adenocarcinoma of the jejunum with metastases, in which both site and age were unusual for a 37-year-old black male; 3) large cell undifferentiated carcinoma of the lung, probably primary in the lung, unusual for age 31; 4) anaplastic adenocarcinoma of the lung (diagnosed in 1978) and welldifferentiated prostatic carcinoma (diagnosed in 1980); metachronous malignancies—the only metachronous combination out of the total 1,200 cases—two tumors of different histologic types and different sites and types; 5) carcinoma of the prostate (age 44) at an unusually young age; and 6) gonadoblastoma of the testis, sarcoma of the epididymis, and metastatic carcinoma of the inguinal lymph node. These 1,200 cases in the Agent Orange Registry have failed to reveal "unusual" features of apparent significance, which may be a premature conclusion because: the small number of cases may not reflect rare yet significant events, and environmental factors, which may produce unusual lesions in unusual sites, also may be associated with the more common lesions in common sites. In order to guard against missing the more common lesions, the AOR is now entering Phase II. A matched set of control cases is being developed, having as a major criterion, "no service in Vietnam." These cases will come from the same VA hospitals and from the same time period (ie, 1978-1984) as the bulk of cases in Phase I, and will be matched by age, sex, and race. The anticipated size of the Phase II groups will be about 4,000 cases. —Single Case Reports Isolated cases of soft tissue sarcoma (STS) among non-Ranch Hand veterans from Vietnam who were exposed to Agent Orange have been reported (Sarma et al, 1982; Schacter et al, 1984). Whether the STS cases are related to service in Vietnam or other unrelated events is yet to be determined. —of "Dedrumming1 Personnel Approximately 200 civilians were assigned by the military to destroy the contents of about 40,000 55-gallon drums (2.22 million gallons) of surplus Agent Orange at the close of the Vietnam war. In addition to environmental monitoring during this operation, pre- and postexposure physical examinations, including x-rays, neurological examinations, and extensive clinical chemical tests, were performed on all workers. Military personnel revealed no apparent physical effects (Young et al, 1978). —Australian Birth Defects Study An extensive survey of Australian veterans was conducted to examine the impact on birth rates of those who served in Vietnam. Entitled "Case-Control Study of Congenital Anomalies and Vietnam Service (Birth Defects Study)," it is the first such study of its kind to be completed. Included in the study population were Vietnam veterans, contemporary Army personnel who had not been in Vietnam and members of the community who did not serve in the Army during this period. The records of 34 hospitals d57:update (revd. 5-29-85) - page 20 �and four cytogenetic laboratories were used to identify 8,517 subjects with birth defects and an equal number of matched controls, which consisted of healthy infants that were delivered in the same hospitals. The size of each group was reduced to 127 infants with defects and 123 normals when the service records of the fathers were taken into account (Donovan et al, 1983). No association between exposure and adverse pregnancy outcomes was found, and the risk of siring a malformed child was no higher for either the Vietnam or the non-Vietnam veteran than for other Australian males, including the National Service and Australian Regular Army Vietnam veterans (Armstrong, 1983; Lipson, 1983; Minister of Veteran Affairs, 1983). —Vietnamese Epidemioiogic Study A major Vietnamese epidemiological study has been described in the news section of Science magazine. Among some 40,000 families in North Vietnam, there was reportedly an increased incidence of congenital abnormalities in the offspring of fathers exposed to herbicides during the Vietnam war. In addition, children born of South Vietnamese women who were directly exposed to the spraying are said to have a suggested increase in birth defects, including neural tube defects, deformities of the sensory organs and limbs, Siamese twins, and cleft lip. No definite link between Agent Orange spraying and the anomalies has been ascertained (Norman, 1983). Vietnam Veterans (Studies In Progress) —VA Identical Twin Study (Vietnam Experience Twins Study, VETS) Still in the design phase, this series of complex comparisons of identical twins may make it possible to establish whether or not Vietnam service has affected morbidity. The mental and physical health status of the subjects will be surveyed by means of a five-day battery of psychological, physiological, and biochemical tests. The study will be conducted by the VA's St. Louis facility; examinations are to be done under contract. The VA has requested the Medical Follow-up Agency (MFUA) of the National Academy of Sciences' Commission on Life Sciences to develop the registry to be used in this project. MFUA has maintained a comparable registry since 1967 of 15,000 male pairs of twins from the WWII US Armed Forces, from which useful epidemiologic studies on schizophrenia and diabetes have been obtained. It is hoped that the new registry will also be about 15,000 strong. The VA wants about 600 pairs of twins: 100 pairs in which both twins served in Vietnam, another 100 in which neither served there, and 400 pairs in which only one served in Vietnam. A computerized list of candidates is to be furnished by the Department of Defense, state twin registries, birth records of certain states (ie, those that paid a bonus to their Vietnam veterans), VA in-patient hospital records, and VA compensation and pension records. Once compiled, the registry will be useful for future investigations into the relationships between genetic and environment and disease (CLS Lifelines :2, Spring 1984). NRC expects to complete the entire registry early in 1987. —Vietnam Ground Troops Study The VA was directed by Congress in January 1979 (PL 96-151) to conduct an epidemiologic study of Vietnam ground troops who may have been exposed to Agent Orange and to determine if there have been long-term effects from such exposure. The scope of the investigation was later expanded (PL 97-27 of November 1981) to include other factors, such as medications and environmental hazards or conditions, in the Vietnam experience. In January 1983, the Congress designated the Centers for Disease d57:update (revd. 5-29-85) - page 21 �Control to conduct the work for the Veterans Administration under an interagency agreement. CDC proposes two retrospective cohort studies and one case-control study. One cohort of male US Army veterans of Vietnam conflict is to be compared with male Army Vietnam-era veterans who did not serve in Vietnam—hereafter referred to as "Vietnam Experience" study; the other cohort will be male Vietnam veterans who differ in their probable level of exposure—to be referred to as the "Agent Orange" study. Each of the two cohort studies will have mortality assessment, health interview, and clinical and laboratory assessment. The case-control study is to evaluate the risk of contracting STS and lymphoma among Vietnam veterans—designated as the "Selected Cancers," or "Sarcoma/Lymphoma," study—and will be limited to males of draftable age during the Vietnam conflict and to veterans from all branches of the military. This study will involve a health and exposure interview. Malaria was the most significant medical complaint in Vietnam; by 1970, neuropsychiatric disorders became the second leading disease. Diarrheal, skin, and venereal diseases were also significant (US DHHS, 1983). Inasmuch as this will be a massive piece of research, consisting of interviews and physical examinations of several thousand veterans, its rate of progress cannot be predicted. However, CDC expects to have final reports for the Agent Orange and Vietnam Experience Studies completed by 30 September 1988 and for the Selected Cancers Study by 30 September 1989 (US CDC, 1984). Females should be studied separately, inasmuch as they would require different sampling strategies and emphases in interviews and medical examinations. Furthermore, too few women were involved for any meaningful case-control study (US DHHS, 1983). —VA Mortality Study This work, begun in 1982, is analyzing death certificates for rates and causes of death of some 60,000 deceased Vietnam veterans and comparing the data with those of nonVietnam veterans. By the end of 1984, the collection and coding of data should be completed, at which time the analytical phase can commence. —VA Case-Control Study of Soft Tissue Sarcoma Individuals with soft tissue sarcomas, as drawn from the files of the Armed Forces Institute of Pathology, will be compared to those without such tumors, taking into account service in Vietnam and probable exposure to Agent Orange. As of March 1984, 221 hospitals have agreed to cooperate in providing two matched controls for each case of sarcoma, one of which is to be a neoplastic disease other than STS. The study is expected to be completed in 1986. —VA Retrospective Study of Dioxins and Furans in Adipose Tissue Since 1970, the Environmental Protection Agency (EPA) has been collecting human adipose tissue from the general population to be analyzed for residues of certain pesticides and polychlorinated biphenyls (PCBs). The bank of approximately 8,000 samples contains specimens from approximately 524 males born between 1937 and 1952, the Vietnam veteran age group. It is highly probable that many of these men served in the military during the Vietnam era and very likely that some actually served in Vietnam. The veteran status, especially Vietnam service status, for each will be established from military and VA databases. Chemical analyses of these specimens for selected chlorinated dioxins and dibenzofurans will provide data on background levels of 2,3,7,8-TCDD in the US male population and will determine if duty in the military or d57:update (revd. 5-29-85) - page 22 �service in Vietnam has affected the levels of TCDD in adipose tissue. —Australian Mortality Study According to a three-part retrospective study by the Australian Commonwealth Institute of Health, which compared the death rates among 19,209 Vietnam-era veterans with 26,957 non-Vietnam veterans, the Australian Vietnam veteran is not dying at any faster rate than his counterpart who did not serve there; nor are the causes of death from diseases that have been suggested as being linked to phenoxy herbicides. Neither was there a statistically significant difference in the rates from soft-tissue sarcoma or nonHodgkin's lymphoma (US VA, 1985). These findings are similar to those of earlier ones reported in 1983. —State-Sponsored Programs Nineteen states—identified in the Appendix—currently have commissions or programs designed to assist their residents who were Vietnam veterans. The activities of these commissions and programs vary considerably, from registries to university-based clinical studies. Workplace Exposures —Monsanto (Nitro, West Virginia) A process accident, or "runaway reaction," in the manufacture of 2,4,5-T occurred in the Monsanto Chemical plant at Nitro, West Virginia in March 1949. Those employees involved in the clean-up and repair of equipment experienced acute symptoms that were characterized by skin, eye, and respiratory tract irritation, headache, dizziness, and nausea. Soon after the accident and on three occasions during 1949-1953, Ashe and Suskind (1949, 1950) and Suskind (1953) examined 12 of the workers who were severely affected with chloracne; an additional 26 persons with chloracne who were not connected with the accident were examined in 1953. The most frequent clinical symptoms were acneiforrn lesions followed by severe muscle pains in the upper and lower extremities, shoulders, and thorax; fatigue; nervousness and irritability; decreased libido; dyspnea; vertigo; and intolerance to cold. In addition to one case of sensory loss in the foot, there were four instances of hepatomegaly and other signs of liver impairment. Upon re-examination of several of the above workers in 1953, there was marked improvement in the skin lesions and a general subsidence of the noncutaneous symptoms. Some persons had persistent but inexplicable complaints of pains in the back and lower extremities, nervousness, excess fatigue, and dyspnea. Of the 122 persons identified as having had chloracne following the accident in 1949, 121 were selected for a cohort mortality study (Zack et al, 1980). The results of the standardized mortality analysis revealed that the 32 actual deaths (from all causes) were less than the 46.41 expected deaths; this SMR of 0.69 was the only statistically significant value among the collected data. Nor was there any apparent excess of deaths from malignant neoplasms or circulatory diseases. Of the nine deaths from malignant neoplasms, five were due to lung cancers—four of them in cigarette smokers—three were from neoplasms of the lymphatic and hematopoietic tissue; one was a rare form of skin cancer, a fibrous histiocytoma, which can be classified as a soft tissue sarcoma. A clinical epidemiological follow-up study of 367 current or former employees of the plant was reported by Suskind et al (1984). The two cohorts in this investigation consisted of 204 subjects who were clearly exposed to the 2,4,5-T process at some time from 1948-1969, and 163 subjects with no exposure to 2,4,5-T. Clinical evidence of d57:update (revd. 5-29-85) - page 23 �chloracne persisted in 53% of the exposed subjects, while no cases of chloracne were observed in the unexposed group. An association was found between the persistence of chloracne and the presence and severity of actinic elastosis of the skin, as well as between exposure and a history of gastrointestinal ulcer. Pulmonary function values of exposed workers who currently smoked were lower than values for unexposed workers who currently smoked. There was a greater frequency of low HDL cholesterol values among those with persistent chloracne. No significant differences were detected between the exposed and nonexposed groups for abnormal laboratory values of alkaline phosphatase, SCOT, SGPT, and GGPT. There were also no differences in these same parameters between the exposed who never had chloracne and those who had chloracne currently or in the past. And finally, there was neither evidence of increased risk of cardiovascular disease, hepatic disease, renal damage, central nervous system (CNS) or peripheral nervous system disorders, reproductive disorders, or birth defects nor differences in nerve conduction velocity measurements. A health survey in 1979 by Moses et al (1984) of 226 current or former employees at Nitro between 1948 and 1977 found a history of chloracne in 52% of the 226 workers; the mean duration for residual chloracne was 26 years. An increase of abnormal gammaglutamyl transpeptidase (GGT) was reported, with a higher mean GGT in those with chloracne compared to those without. There was a statistically significant decrease in "sensation to pin prick" in 11 of 60 subjects with current or past chloracne but none in the 34 who never had chloracne. No mention is made of age differences or other factors that could account for this finding. —Dow Chemical (Midland, Michigan) Ott et al (1980) examined the mortality experiences of a group of 204 workers who had been exposed to 2,4,5-T during its production from 1950-1971. Many of the workers were also potentially exposed to a number of other chemicals during this period. Only 19 episodes of acute exposure were noted during 1954-1970, which consisted largely of irritant exposures to the eyes and skin. No cases of chloracne or porphyria cutanea tarda were evident, and mortality of this limited sample was stated to be comparable to that of US white males, as well as to the "background mortality experience" at this location. A mortality study of 61 employees who had been engaged in the production of trichlorophenol and who had been accidentally exposed in 1964 to TCDD did not disclose an elevated mortality rate; there were four actual deaths from all causes vs 7.8 expected. Overall cancer deaths were elevated (3 vs 1.6 expected), but no particular tumor type predominated. None of the findings was statistically significant (Cook et al, 1980). Of these workers, 49 developed chloracne. The three cancer deaths (identified as an adenocarcinoma, a fibrosarcoma, and a glioma with metastases) were slightly above the expected number (3 vs 1.6), but they could not be ascribed to any predominant tumor type or particular organ/tissue site (Cook et al, 1980). In another Dow study, information was obtained from an interview questionnaire of 715 wives of men who worked in the Michigan division. It revealed no statistically significant differences in occurrences of miscarriages, stillbirths, and fetal deaths or malformations. The two groups (ie, 370 wives of men with exposure to TCDD and 345 controls, wives of men without possible exposure) were matched closely for husbands' dates of hire. Nine variables were considered to be potential confounders in some or all of the analyses: maternal age, birth control method, conditions during pregnancy, complications in labor and delivery, medications or treatments during pregnancy, alcohol consumption, smoking during pregnancy, gravidity and mother's occupation. Most of the analyses considered the conceptus as the observational unit. If a conception occurred prior to the worker's dioxin exposure, the corresponding conceptus was classified among d57:update (revd. 5-29-85) - page 24 �the "unexposed" control group. Thus, of the 1,503 total conceptions of the 370 wives, only 737 occurred after their husbands' first exposure and constituted the "exposed" conceptuses. The remaining 766 conceptuses (ie, 1,503 - 737) were combined with the 1,274 occurring among wives of the "never exposed" employees; also, 9 induced abortions within the latter group were excluded, giving a total of 2,031 "unexposed" conceptuses (Cook et al, 1983; Townsend et al, 1982). In a report on the findings of a cross-sectional medical and morbidity surveillance of employees considered potentially exposed to TCDD from 1976-1978, few differences between cohorts were noted. An increased frequency of radiographically documented ulcer and other digestive diseases was reported in the cohort of workers who were engaged at some time in the production of 2,4,5-T and who probably had low exposure to TCDD. These effects did not occur in the "high" exposure group, which indicates that dioxin is not likely associated with digestive effects (Bond et al, 1983). —Diamond Alkali (New Jersey) Porphyria cutanea tarda (PCT), of varying degrees of severity, and elevated urinary uroporphyrins were discovered in 11 of 29 workers exposed to 2,4-D and 2,4,5-T during the manufacturing process; they were examined because of chloracne (Bleiberg et al, 1964). Hyper pigmentation was more prevalent in Negroes and was said to vary in degree according to the severity of chloracne. The degree of hirsutism was related to the severity of chloracne. Of 26 workers whose urine was tested for uroporphyrins, eight had elevated uroporphyrins and 19 had chloracne. Three of those with elevated uroporphyrins had no chloracne. The porphyria cutanea tarda was assumed to be chemically induced as a result of damage or insult to the liver and not of genetic origin. The skin manifestations of PCT—ie, epidermal fragility, vesiculobullous eruptions—occurred on areas of the face, ears, and hands that were exposed to sun or pressure. A follow-up of Bleiberg et al was made in the same plant by Poland et al (1971) on 73 male workers. Moderate to severe chloracne was prevalent in only 13 out of 73 (18%) of the cases; again, it varied in degree and was accompanied by scarring, hyperpigmentation, hirsutism, and eye irritation. There was no evidence of porphyria cutanea tarda and only one case of uroporphyrinuria. The authors have inferred that porphyria cutanea tarda and chloracne are independent syndromes, although they may have the same etiologic agent. There was either no acne or only minimal lesions in 82% of employees. Occurrence of chloracne, likewise, was not significantly greater in Negroes than whites, and was seemingly not related to job location or duration of employment (hence, level of exposure); cardiovascular findings were unremarkable except for three persons with a history of myocardial infarction. The porphyria observed by Bleiberg also was observed in a heavily exposed population in Czechoslovakia. It has never been seen in populations exposed to trichlorophenol or 2,4,5-T processing alone. —BASF AG (Ludwigshafen, Germany) In 1953, seventy-five workers in a trichlorophenol plant were exposed to reactor products during an accident and its subsequent cleanup. Most of them suffered chloracne; 42 suffered severely and 21 of these persons also had systemic damage to internal organs or CNS disturbances. Polyneuritis, impaired senses, and liver damage were most prominent. In 1978, a mortality study was conducted on the cohort: Of the 17 deaths (from 11 to 25 were expected, depending on the choice of control population), six were due to cancer (three from stomach cancer), five from cardiovascular diseases, one from cirrhosis of the liver, and one from urogenital disease; all other deaths were either accidental or suicidal (Huff et al, 1980). No miscarriages or abortions were reported among the wives of exposed employees who were still at work in the plant (IARC, 1977). d57:update (revd. 5-29-85) - page 25 �A mortality study was conducted by Thiess et al (1982) 27 years after the trichlorophenol process accident at the BASF AG plant. The exposed group of workers (74), matched by age and date of entry into the factory, was compared with two internal groups and three external groups. Although there were relatively few reported deaths, malignant neoplasms were consistently above expectation but beyond chance only for stomach cancer, which has a latency of 15 years. ~NV Philips (Netherlands) In this 1963 explosion at a 2,4,5-T plant, 106 workers were probably exposed to TCDD (or related polychlorodibenzofurans). The two operators were exposed to TCDD largely by way of inhalation. Other workers, who were either part of the regular adjoining work force or were part of the clean-up and rebuilding crews, were outfitted in protective gear; they may have had only dermal contact. Chloracne occurred in 44 persons. Liver damage was not apparent, but there were a few complaints of fatigue. Of the eight deaths, one was from a pancreatic tumor and one was due to a myocardial infarction (at age 69); five other deaths also could have been from infarctions. —Spolana (Czechoslovakia) 3irasek et al (1973, 1974) have reported from Czechoslovakia on what is probably the most thoroughly documented group of exposed workers. From 1965-1969, 78 persons were affected by their contact with the sodium salt of 2,4,5-T, the butyl ester of 2,4,5-T and pentachlorophenol; 76 of them developed acne (sic), hypertrichosis, and hyperpigmentation. Complaints included fatigue, weakness and pain in the extremities, sweating, and headache; many had polyneuropathy. Clinical findings revealed hepatomegaly, porphyria cutanea tar da, and increases in ALA and alkaline phosphatase (Suskind, 1980). The tenyear follow-up of 55 workers by Pazderova-Vejlupkova et al (1980, 1981) emphasized the nonuniformity of TCDD's effects on individual organs and the development of illness that affects virtually every important organ system. Complete recovery is rare, except for anxiety and depression, and persistence of impaired metabolism of fats and carbohydrates can be a major cause of premature arteriosclerosis. Children who were born to exposed individuals were not adversely affected. —Coalite (United Kingdom) The Coalite episode, which occurred in Derbyshire, UK in April 1968, was first described by May (1973). This also involved an overheated reactor used to synthesize TCP; the explosive rupture of the kettle was accompanied by detonation of the released glycol and chlorobenzene vapors. Seventy-nine cases of chloracne were initially recorded; many were severe but resolved within four to six months. There was no evidence of depression, weight loss, malignancies, or liver, kidney, or cardiac impairment. The epidemiological survey of 1977-1978 covered only 41 of the 90 exposed workers and revealed some abnormalities in blood chemistry and immune function. There were no chromosomal abnormalities in the circulating lymphocytes. The levels of serum cholesterol and triglycerides were elevated, while the gamma-glutamyl transpeptidase was abnormally high. Both IgD and IgM were lower than the controls. Twenty-nine of the original 41 workers were re-examined, but immune globulins were not measured. No statistically significant differences between groups were reported when chromosomal aberration and sister chromatid exchange studies were performed on blood samples of workers who were exposed, possibly exposed, or not exposed to TCDD (Blank et al, 1983). Sell (1983) reviewed for AMA's Advisory Panel on Toxic Substances a report on the outcome of an industrial accident at the Coalite plant. In his opinion, there were no immunologic differences between the three groups of workers; ie, 1) those exposed to d57:update (revd. 5-29-85) - page 26 �TCDD and with chloracne, 2) those exposed to TCDD but without chloracne, and 3) those who were unexposed and had no chloracne. —Vertek Chemical (Jackonville, Arkansas) This plant was involved in the production of 2,4,5-T and 2,4,-D since 1957. The recent discovery of toxic wastes leaking from drums stored above ground at the plant led to a health survey in 1979 of 190 current or former workers. Nerve conduction velocity (NCV) measurements were done on 55 workers who were prescreened for a negative history of diabetes, neurological disease, or excess alcohol consumption; all 55 were considered to be at risk for exposure to phenoxy herbicides. There were no concurrent exposures to other possible neurotoxic agents in any of the 190 workers, although prior exposure to such agents was reported in nine workers and prior exposure to 2,4-D was reported in two. The control group was similarly prescreened and found to have had no significant exposure to neurotoxic agents. NCV measurements of the median motor, median sensory, and sural nerves were performed without knowledge of a subject's employment history. Limb temperature also was measured. Slowed NCV in one or more nerves was reported in 46% of the study group compared to 5% of the controls. The conduction velocities of the median motor and sural sensory nerves were significantly slower in the study group vs the control group. In addition, slowed sural sensory velocity correlated significantly with duration of employment (Singer et al, 1982). It is appropriate to note that neurologists and neurotoxicologists regard NCV measurements as a useful research procedure when carried out in connection with a thorough neurological examination. The ambient conditions and technical skill requirements, however, are such that it has limited use as a field study examination. —NIOSH Dioxin Registry The National Institute for Occupational Safety and Health has established a dioxin registry to analyze causes of death among workers at 14 manufacturing sites for dioxincontaining products (Fingerhut, 1984a). The Registry was established in late 1979 to identify male workers exposed to substances such as TCP, 2,4,5-T, silvex, and pentachlorophenol that might contain polychlorinated dioxins and to describe the processes for manufacturing these compounds. The first use of the Registry data is a mortality analysis, which is expected to be completed in 1985. In this mortality study, a subcohort of persons who had chloracne will be analyzed separately. One value of the Registry is its exposure matrix, which will characterize exposure conditions for the specific processes and will then delineate both high- and low-exposure populations. The factors that will be taken into account in the exposure matrix include the product, the process, the operating conditions, temperatures and solvents, job duties, and analyses of dioxin concentrations in products. A strict definition of exposure has been utilized. The Registry includes only production workers assigned to the processes of interest, maintenance personnel assigned to those departments and clean-up workers or others identified by the companies as being involved in process accidents and who may not have their work assignments documented. The Registry has already identified 6,000 production workers at 14 companies. The quantity and quality of the records, which date back as far as the 1930s, vary tremendously; included are personnel records, payroll records, union records, medical records, insurance records, workers' compensation records, and Social Security records. --NIEHS-IARC International Phenoxy Herbicides Registry In 1981, the National Institute of Environmental Health Sciences of the NIH initiated d57:update (revd. 5-29-85) - page 27 �support for a feasibility study on the development and maintainence of an international registry—exclusive of the USA—of phenoxy herbicide-exposed populations. The populations were to include production workers, formulators, and users. Workers' records and environmental data from' more than 25 plants are under consideration. Some European countries are reluctant to release their health and environmental data, and there are still questions about the pooling of data from different sources and the assembling of a sufficient number of records for an estimate of excess frequency of outcomes. —Isolated Exposures to TCDD Oliver (1975) described three laboratory workers who were exposed to "pure" TCDD. Two of the three had typical chloracne. All had abnormal serum cholesterol levels but without porphyria. Two had gastrointestinal symptoms, one complained of blurred vision and impaired muscular coordination, and another complained of "neuralgia of the left thigh." Two years after the exposure, two of the men experienced personality changes, neurological disturbances, and hirsutism. Exposed Herbicide Users —Swedish Railway Workers The first study of this group, who had worked with both phenoxy acid (2,4-D and 2,4,5-T) and arnitrole herbicides (Axelson et al, 197*0, indicated that amitrole was probably solely responsible for an excess of tumors. A case-control analysis of the data later revealed the possibility of a masked tumor-inducing effect of the phenoxy acids (Huff et al, 1980). —Other Swedish Workers Follow-up on an earlier line of investigation led Hardell and coworkers to additional cases of soft tissue sarcomas, which again seemed related to occupational exposures to phenoxy acids or chlorophenols. Malignant histiocytic lymphomas* were clustered among a group of hospital admissions in Sweden from January to September 1978; 14 of 17 patients were in occupations that utilized phenoxy acids or chlorophenols (eg, forestry, wood and paper mills, farming). Inasmuch as both 6-fold tumor increases (Hardell, 1977, 1979) were attributed to impurities, such as TCDD, a case-control (case-referrent) study by Eriksson et al (1981) was launched; their objective was to confirm the previous findings and to clarify whether the impurities were causative. The new risk ratio (5.7) for soft tissue sarcomas from exposure to phenoxy acids or chlorophenols was of the same order of magnitude as before; furthermore, a risk ratio of 4.2 was obtained for other phenoxy acids that are free of dioxins, such as MCPA, 2,4-D, mecoprop, and dichlorprop. In a review of the occupational histories of patients with malignant lymphomas, Olsson et al (1981) reported a possible relationship between non-Hodgkin's lymphoma of the skin and exposure to phenoxy acids. In another investigation by Hardell et al (1981), exposure to organic solvents, chlorophenols, and/or phenoxy acids resulted in a relative risk factor of 4.1 for malignant lymphoma compared to a risk factor of 0.9 in the unexposed control group. These results seem to indicate an increased risk for malignant lymphoma in workers exposed to phenoxy acids, chlorophenols, or organic solvents. * Neoplasm sites included frontal sinuses, bladder, ileum, retroperitoneal, parotid and submandibular areas, femur, and groin. d57:update (revd. 5-29-85) - page 28 �Yet another investigation by Hardell et al (1982) reported a sevenfold increase in the incidence of nasal and nasopharyngeal cancers, particularly among woodworkers, due to chlorophenols. Cabinet makers, with no exposure to chiorophenols, had a doubled (but insignificant) risk of nasal cancer. Exposure to phenoxy acids resulted in a doubled (but insignificant) risk of nasal and nasopharyngeal cancer. Analysis of geographical clusters of malformations in Sweden failed to identify any one etiological factor responsible for the clustering (Ericson et al, 1983). —Finnish Railway and Forestry Workers A similar group of 30 workers in Finland, who were exposed to TCDD-containing herbicides, will be compared to a matched control group to see if there are any longterm effects from their exposures. Thus far, no differences are apparent (Huff et al, 1980). —New Zealand Birth Defects Study Smith et al (1982b) surveyed by questionnaire the pregnancy outcomes of 548 New Zealand professional sprayers and their wives, who were also occupationally exposed to phenoxy herbicides, comparing them with a control group of 441 agricultural contractors. Inasmuch as the authors' preliminary results showed little difference in rates of congenital defects between cases and controls, this study redefined the extent of exposure by subdividing the group of sprayers; there was still no suggestive evidence that 2,4,5-T adversely affected pregnancy outcomes. Although the men had an increased risk (1.19 times) of siring children with defects, the wives' risk of miscarriage was only 0.89; the differences were not statistically significant and no other effect on the women's reproductive cycle was apparent. The several inherent sources of bias in the study were explained, but even when they were excluded the results were unchanged. —Long Island Railroad Birth Defects Study In 1979, NIOSH investigated a reported excess of birth defects among the children of about 1,400 maintenance workers of this New York railroad who were exposed to 2,4,5-T. Of 170 live births in the study, there were less than the expected number of all combined major defects but a significant excess of minor defects. The latter, however, is believed to be due to diagnostic bias (Honchar, 1982). General Population —Seveso, Italy Inhabitants In 1976, an explosive release of TCDD from a trichlorophenol reactor at the ICMESA plant occurred in the vicinity of Seveso, Italy. This is the largest single population—over 37,000 persons—to have been potentially exposed to varying doses of this compound. Two years after the incident, the acute and mid-term, health effects were assessed; mild chloracne, mainly in a small group of children, healed quickly. Subclinical peripheral nerve impairment was reported; there also was liver involvement but without apparent functional disorders. Immunoresponse was not altered nor was susceptibility to infectious diseases increased (Reggiani, 1979). This incident has been described more fully in AMA's 1981 report. The long-term epidemiologic survey of the 220,000 residents of the Seveso area is expected to go on for many years. A progress report emphasized the preliminary nature of the findings and reiterated the above conclusions of Reggiani (Pocchiari et al, 1979; Huff et al, 1980). Except for the skin, no organs or body functions were impaired. No derangement of gestation, no fetal lethality and loss, no gross malformations, no growth d57:update (revd. .5-29-85) - page 29 �retardation at term, and no cytogenetic abnormalities have yet occurred. Analysis of the livers of 144 sheep which died in the Seveso area following the accident disclosed that tympanism was the cause of death, not TCDD (Anon, 1980). The primary biological effect on the inhabitants was skin irritation, largely as the result of alkali mist. However, up to the end of a year and over a six-month period, about 200 cases of chloracne were identified, primarily among children. It is interesting to note that no cases of chloracne were observed among the ICMESA workers either prior to or following the accident, including workers involved in clean-up operations. Spontaneous abortions and birth defects were monitored by the Birth Defects Registry (established in 1978), but except for hemangiomas and benign neoplasms, the data did not show an association between malformations and TCDD exposure. A controlled study of children with chloracne was not completed because too few of the affected children wished to participate. An Occupational Health Surveillance study was established soon after the accident and a large amount of data was collected between 1976-1980; however, the "lack of adequate study designs" and the difficulties in coping with "prevailing clinic characteristics" precluded any definitive conclusions. Nevertheless, the high incidence of "abnormals" in the liver function test declined markedly during the four-year surveillance period. Neurologic studies by the Clinica del Lavoro Luigi Devoto of Milan revealed only three or four cases of suspected neuropathy in which either the motor or sensory nerve conduction velocity was reduced. These findings and "subclinical signs of neuropathy" in 16 other subjects could not be evaluated properly because there was no control group and no information on alcohol intake and history of diabetes. In late 1980, a cross-sectional study was designed to evaluate hepa toxic and neurotoxic effects in 188 ICMESA workers compared to an unexposed control group of 305 workers from the metallurgical and mechanical industries outside the Seveso area. The battery of laboratory tests included lung function tests (FVC, FEV), SPE and ulnar nerve electromyography, SCOT, GGT, alkaline phosphatase, total bilirubin, cholesterol serum level, triglycerides, total serum protein and electrophoresis, prothrombin time, hematocrit, hemoglobin, WBC and differential, and total urinary porphyrin. No statistically significant differences between the two groups were found. Thus, five years after the accident, no significant adverse health effects were detected in the ICMESA workers. Likewise, both the mortality study and Cancer Registry have yielded very little conclusive information, though eight cases of soft tissue sarcoma were found in the group of 222,000 residents living in the buffer zone outside of the more highly contaminated zones A and B. Merlo (1983), who was associated with the Seveso data analysis group from 1979-83, said that, "... knowledge of the TCDD health effects comes from animal studies and human occupational exposures occurring during the manufacture of trichlorophenol. Shortterm effects have been identified. Long-term effects are still under study. Unfortunately, due to the lack of proper studies in the early phase of the 'Seveso Program,1 reevaluation of these data— such as has been done with Hiroshima and Nagasaki records— has to be excluded. Only well designed epidemiologic studies carried out carefully will enable us to draw conclusions about the occurrence of d57:update (revd. 5-29-85) - page 30 �chronic health effects and their relationship with TCDD exposure." Tenchini et al (1983) performed a cytogenetic analysis of maternal and fetal tissues from induced abortions in TCDD-exposed and nonexposed women. They found a statistically significant increased incidence of aberrant cells and a greater number of aberrations per damaged cell in the dioxin-exposed group vs controls. While some effect of maternal exposure to the toxic agent cannot be ruled out, variations in cell culture growth are more likely to be the cause of the observed cell changes. —Times Beach, Missouri The Centers for Disease Control (CDC) was called in by the State of Missouri to find an explanation for the unusual occurrence of animal deaths and reports of family illness near a horse riding arena in Missouri (Donnel et al, 1983; Kimbrough, 1983). In 1973, the toxic agent was identified as TCDD, which was later traced to TCDD-contaminated stillbottom waste from a TCP process in Verona, Missouri. It seems that, in 1971, approximately 29 kg (64 pounds) of TCDD-contaminated waste from a chemical plant in southwest Missouri was mixed with waste oils and applied to soil for dust control at 241 sites in the eastern part of the State. At one site, the Shenandoah horse stables, as much as 35,000 ppb of TCDD was measured in the soil. In addition to several other horse arenas, there was an urban residential area with a population of 2,100, later referred to as "site-21," or "Times Beach." The situation in this town came to light when a flood struck the major portion of the town and led to a near-total evacuation of the community. As early as 1971, the unpaved streets of the town also had been sprayed with TCDD-contaminated oil. Soil samples taken in the aftermath of the flood from both the shoulder of the road and the ditches contained TCDD. While they did not have the greatest degree of TCDD contamination in Missouri, they reached a peak of 98 ppb. Since there was no established rationale or methodology in Missouri for determining "safe" levels of TCDD in soil, the Missouri Department of Natural Resources (DNR) in collaboration with CDC and EPA reviewed environmental sampling data and the Remedial Action Marker Plan (RAMPS); they jointly recommended appropriate strategies for intervention. Hence, on 23 December 1982, CDC advised that the evacuated residents of the town should not return to their homes until additional samplings were carried out. Contaminated Times Beach soils were given by gavage to guinea pigs and rats by McConnell et al (1984) to determine the degree of bioavailability of dioxin on soil. A characteristic clinicopathologic syndrome developed in the guinea pig, AHH was induced in the rat and both species of animals had TCDD in their livers. Hence, TCDD in soil was believed to have a "high biological availablity after ingestion." Kimbrough has cited the bioavailability of TCDD to be as much as 30% to 50% of the original amount contained on the soil matrix. CDC based its risk assessment on a "decision of prudence" and several assumptions that were presumed to be in the best interests of the public's health and safety. One such assumption was that a child would be most vulnerable to the contamination and might ingest as much as 1 to 10 g of soil. Thus, from the chronic animal toxicity data of Kociba and the National Toxicology Program, the safe human dose was judged to be in the picogram range, and "1 ppb of dioxin in soil is a reasonable level at which to begin consideration of action to limit human exposure for contaminated soil" (Kimbrough et al, 1984). (The EPA has meanwhile published a methodology for estimating human exposure and cancer risk associated with five different pathways of exposure to 2,3,7,8-TCDD contaminated soil (Schaum, 1984).) The Missouri Department of Health and CDC decided, after a review of animal data and consultation with other health professionals, that there would be a risk of developing d57:update (revd. 5-29-85) - page 31 �"adverse health effects" if there were continued residential exposure to soil having more than 1.0 ppb of TCDD. The two agencies then went on to initiate four public health actions in January 1983 that would provide: —health education of the medical and public health communities, as well as the general public, regarding current understanding of health effects of dioxin exposures; —dermatologic screening clinics for the general public; —a registry for potentially exposed individuals; approximately 2,000 interviews were conducted; and —the design and implementation of a "highest risk" cohort. —Missouri Pilot Study An investigation by questionnaire of two groups of residents was conducted; one group of 68 persons was at risk, having been exposed agriculturally to dioxin, while the control group of 36 had little or no history of exposure. Both were matched by age; sex; socioeconomic status; history of alcohol, tobacco, and pesticide usage; and according to their relative proportion of work in a hazardous occupation. The medical examination included separate neurologic and dermatologic examinations and a broad range of laboratory tests, one series of which was intended to assess cell-mediated immunity. An initial review of data did not indicate any statistically significant differences between the high-risk and low-risk study groups. No consistent indications of increased disease prevalence was found in the dioxin-exposed group, although there was an apparent trend of urinary tract abnormalities and some immune function changes (T^:Tg cell ratios were less than 1.0). Functional tests of the immune system did not indicate any overall abnormalities. No cases of chloracne or porphyria cutanea tarda were reported. Follow-up studies were recommended (Donnel et al, 1983; Webb et al, 1984). And finally, the authors of the report entitled "Missouri Dioxin Health Studies," (published by the Missouri Division of Health and CDC in collaboration with St. Joseph's Hospital of Kirkwood, Missouri and St. Louis University Hospital) stated that, "... it is conceivable that uptake of dioxin from contaminated soils was generally less than estimated for this study group or that chronic exposures to environmental TCDD have actually induced little or no adverse health effects as measured in this study." The Missouri Department of Natural Resources has meanwhile added to its registry of uncontrolled hazardous waste sites three new locations that are contaminated with dioxin: Minker-Stout and Lacy Manor sites in Jefferson County and Erxleben site in St. Louis County. —St. Louis, Missouri (Trucking Employees) A recent survey of present and former workers employed at trucking terminals that had been sprayed for dust abatement with TCDD-contaminated oil disclosed a 59-year-old man with a sarcoma and porphyria cutanea tarda (PCT). A truck driver for 21 years, he had worked at one of the contaminated terminals for several years; he also was exposed to TCDD while unhooking trailers in the terminal. The PCT improved with treatment; however, in February 1983, a sarcoma in the proximal right femur and pelvis involving the adjacent soft tissue was diagnosed. It was not possible to determine whether the tumor originated in the bone or in the soft tissue (Hope et al, 1984). d57:update (revd. 5-29-85) - page 32 �—Alsea, Oregon In the Alsea basin of Oregon, 2,4,5-T and silvex were used on a seasonal basis to eradicate unwanted vegetation from forest lands. In 1978, there was some concern that such spraying was responsible for a number of spontaneous abortions in the area. All told, 13 miscarriages were reported from nine women. As a result of much publicity and public concern, the EPA conducted a study—Alsea I—to assess the facts and to determine whether the spraying was indeed responsible. EPA concluded that there was no relationship between the spraying and the incidence of miscarriage; the rate was within the expected limits. The study was harshly criticized because the exposures were not documented and the statistical treatment was improper. Thus, Alsea II was begun in October 1978, to study a much larger area and population than Alsea I and to compare miscarriages within the first 20 weeks of pregnancy with the spraying of 2,4,5-T. A high probability of an elevated miscarriage rate shortly after spraying was reported to the press, but this claim was proved to be without merit. review of conducted al, 1979). contended Alsea II by Oregon State University—A critical analysis of Alsea II was by an interdisciplinary team of Oregon State University scientists (Wagner et It did not support any of EPA's conclusions in the Alsea II study. The team that: there was no control population in the study; data on miscarriages were unreliable and inaccurate; medical practices were profoundly different in the three areas under consideration; information on use of 2,4,5-T was inaccurate and incomplete; variations in hospitalized miscarriages expectations; in all the areas were well within differences existed in topography, climate, and demography; data collection was incomplete and failed to account for patterns of and differences in medical practice among areas. The panel termed the EPA's hospitalized spontaneous abortion indices (HSAI) values to be unreliable because: there was substantial variation in the magnitude of the HSAIs for any one month among the six years, and the peak HSAI in June was due to a single large excursion only in 1976, while the seasonal cyclic peaks were consistent with random variations. Furthermore, alleged increase in the use of 2,4,5-T was actually due to more complete collection of spray data; there was no statistically significant cross-correlation except for the apparent increase in the June HSAI—deletion of the single June 1976 HSAI value removed the significant correlation; and d57: update (revd. 5-29-85) - page 33 �the HSAI increase in 3une 1976 was identified only with a location where human exposure was least likely to have occurred. Hence, according to the OSU panel, there was: no significant correlation between 2,4,5-T use and the HSAI, and EPA's study was seriously flawed because of incomplete and inaccurate data. review of Alsea by FIFRA's Scientific Advisory Panel—This panel of the Federal Insecticide, Fungicide and Rodenticide Act reviewed the evidence and found neither immediate nor substantial threat to human health or the environment when silvex or 2,4,5-T was applied to rice, rangeland, orchards, or sugarcane and when used for certain non-crop purposes. review of Alsea n by others—Lamm (1979) also declared the Alsea II study to be epidemiologically unsound and the report useless. Both statistically and epidemiologically, the report does not support any relationship between herbicide spraying and miscarriages. Lamm (1980) has since claimed that only four of the ten women cited by EPA in the Alsea II study underwent spontaneous abortions; the remainder were hospitalized for other reasons. New Zealand's Allan H. Smith (1979) termed the Oregon study of highly doubtful validity. Robinson (1979) of Australia emphasized that the EPA information in no way confirmed a hazard to human health from 2,4,5-T when it was used in a careful manner and according to label instructions on the container. A comprehensive review by the Australian Department of Health (1977) concluded that there was no evidence that 2,4,5-T caused human birth defects. Canadian Review of TCDD's Health Hazards Canada's Expert Advisory Committee on Dioxins has evaluated the available published information and concluded that: Epidemiological data on the effects of dioxins on Canadian populations, when taken in isolation, are insufficient to prove any significant association with disease. Considering that it is impossible to prove the absolute safety of a substance—not to mention the multiplicity of dioxin sources and its mixtures with other chemicals, and the small size of the Canadian population—additional epidemiological studies solely on a Canadian population would be unlikely to provide a definitive identification of dioxin-associated diseases. Therefore, risk assessments associated with dioxin exposure must rely on world-wide epidemiological data in conjunction with toxicological studies on laboratory animals. Similarities between the signs and symptoms in humans and laboratory animals justify the concern about human exposure to dioxins; hence, a "virtually safe dose" for 2,3,7,8-TCDD was calculated from animal data. The corresponding dose for a one-in-a-million lifetime risk of cancer in humans ranged from 0.02 to 0.07 pg/kg (mean = 0.03) of body wt/day. Another estimate of cancer risk assumed a dose threshold, for humans was estimated to be between 0.2 and 1 pg/kg of body wt/day, based on dividing the "no observed effect level" (or NOEL) from animal studies by an arbitrary safety factor, usually 5,000 or 1,000. d57:update (revd. 5-29-85) - page 34 �The potential risks of adverse effects on human reproduction were also evaluated from animal data, inasmuch as epidemiological data on reproductive toxicity and teratogenesis were of such poor quality that no association could be determined. Fetotoxicity and teratogenicity in laboratory animals occurs at doses near those which cause maternal toxicity. A 1000-fold safety factor was arbitrarily applied to the NOEL for reproductive effects in animals, thereby resulting in an "acceptable daily intake" of 1 pg/kg of body wt/day. This estimate is not much higher than the level to which some high-risk groups in Canada are exposed (Willis, 1983). Cancer Studies CDC Selected Cancers Study See under "Vietnam Veterans (Studies in Progress), —Vietnam Ground Troops Study." NIOSH Review of Reports of Soft Tissue Sarcoma and Dioxin Exposure in Seven Chemical Workers According to Fingerhut (1983), the first suggestion of an association between these tumors and TCDD began with clinical observations in Sweden in 1977 and two published studies of Hardell and others. Four separate studies of industrial populations were then reported in the United States in 1980. The mortality analyses, which were conducted by Monsanto and Dow epidemiologists, included workers exposed during process accidents as well as during the uneventful processing of TCP to 2,4,5-T. The authors indicated that there was no excess of mortality due to dioxin exposure. Honchar and Halperin (1981) reviewed the studies and noted that of the total 105 deaths, three were reported to be due to soft tissue sarcomas—a frequency of 2.9%, which contrasts with 0.07% for the general population. Subsequently, a fourth person from the Dow cohort was reported to have STS (Cook, 1981), and Johnson et al (1981) and Moses et al (1981) provided case reports of three additional cases of soft tissue sarcoma in chemical workers. Fingerhut and others (1984b) undertook an effort to evaluate the accuracy of reports of dioxin exposure and soft tissue sarcoma pathology in these seven chemical workers. Tissue specimens of the persons with alleged soft tissue sarcomas were examined by two STS pathologists, Dr. Franz Enzinger at the Armed Forces Institute of Pathology and Dr. William Russell. Of the four cases in the Dow and Monsanto cohorts, whose causes of death were derived from death certificates, only two were found to have soft tissue sarcomas, and these two also had chloracne. The three other individuals were confirmed as cases of soft tissue sarcoma, but one was a truck driver who had been a clerk and maintenance worker but with no recorded assignment to dioxin-contaminated processes. The other two cases were a father and son. The son was never assigned to a dioxincontaminated process during his 2.5 years of employment before he died; the father, a utility worker who worked for 11 days in the pentachlorophenol process area, had a generalized liposarcoma. This review of seven cases neither affirmed nor rejected the association alleged by the Swedish workers because there was no adequate comparison group that could be used. In this country, we have no mortality rates for soft tissue sarcomas that are based on pathologic review of tissue specimens; the only available rates are derived from death certificates. According to a review by Percy et al (1981), the death certificate does not accurately estimate the diagnosis of STS. The authors, from NCI's Biometry Branch, have shown that only around 50% of STS cases list STS on the death certificates, while only around 50% of the death certificates listing STS also have a corresponding diagnosis d57:update (revd. 5-29-85) - page 35 �from hospitals during 1970-1971, 252 reported soft tissue sarcomas, but only 54.8% of these were confirmed by pathologists of soft tissue sarcomas. On the other hand, only 56.3% of the pathology diagnoses of soft tissue sarcoma were recorded as such on death certificates. There are several other dilemmas in the study of these tumors: Not only is the death certificate inadequate as a source of diagnostic information, but the tumors are often misclassified because of the anatomic-based rules for the International Classification of Disease (ICD) System. For example, if a sarcoma occurs in either the stomach or liver, it will not be classified under ICD-171 for soft tissue sarcoma but as a tumor of the stomach or liver. Only 60% of the histological diagnoses of STS in the Swedish studies are listed under ICD-171, the remaining 40% are in other ICD categories. Fingerhut and others (1984b) suggest that the diagnosis of the original pathologist may not be accurate; thus, experts in soft tissue pathology may be needed necessary to confirm original diagnoses. Additionally, the histological subtypes of STS are difficult to diagnose. Among the above seven cases reviewed by expert pathologists, there was agreement by the experts that five were soft tissue sarcoma. However, the experts themselves disagreed on the subtypes subtypes for two persons. A causal relationship between soft tissue sarcoma and dioxin exposure has not yet been confirmed or excluded. Since the incidence of soft tissue sarcoma in the general population is very low, most of the study designs require a very high relative risk for the sarcoma to be detected (Coggen et al, 1982). NCI Case-Control Study of Lymphoma and Soft Tissue Sar com a According to Hoar (1983), the first disclosure of herbicide-related cancers was that of Swedish railroad workers exposed to amitrole, 2,4-D and 2,4,5-T, which showed elevated rates of cancer incidence (Axelson et al, 1974). Next in line were the case-control studies by Hardell and his collaborators wherein associations were described between phenoxyacetic acid or chlorophenol exposure and soft tissue sarcomas (STS), nonHodgkin's lymphomas (NHL), and Hodgkin's disease (HD). Risks for all three cancers were increased five- to sixfold, irrespective of the presence of polychlorinated dibenzodioxins or dibenzof urans as contaminants. A five- to sixfold increase in risk is a remarkable finding for epidemiologists; furthermore, such an increase is of especially great concern because there is widespread potential for exposure to phenoxyacetic acids and chlorophenols. Apart from their use as herbicides, these compounds act as blue-stain retardants in lumber, as slime control agents in cutting oil fluids and in the paper and pulp industry, as wood preservatives, and as water-proofing agents for leather and textiles. Thus, if the epidemiologic associations suggested by the Swedish research are proven to be causally related, these agents could be responsible for a large share of STS, NHL, and HD cases in the United States. The National Cancer Institute (NCI) consequently is comparing herbicide exposure among reported cases of soft tissue sarcoma and lymphoma in Kansas; subjects have been matched with a control group of similar age, sex, and county of residence. The work is expected to be completed in late 1984 or early 1985. NCI has considered various approaches for further investigations. Cohort studies of pesticide applicators are underway. A duration-related association between lung cancer and employment as an applicator has already been reported by Blair et al (1983). Unfortunately, these cohorts are far too small for conclusive evidence in a disease as d57:update (revd. 5-29-85) - page 36 �rare as STS. A case-control study of STS, NHL, and HD with particular attention to herbicide exposure was planned, with concentrated effort on agricultural uses; for example, on wheat, corn, sorghum, soybeans, alfalfa, and pasture land. Inasmuch as herbicides are often accompanied by extremely heavy applications of insecticides, which could confound the results of the study, the choice of crop was narrowed down to wheat. Wheat requires a large amount of herbicide but comparatively little insecticide and fungicide application. Kansas, a major wheat-producing state, was chosen as the site for the study. The herbicide most commonly used there has been 2,4-D; nevertheless, substantial amounts of 2,4,5-T also have been used in addition to a number of other chemicals. According to a 1981 report of the Ohio Agricultural Research and Development Center entitled "Pesticide Use on Major Crops in the North Central Region," about 5.2 million pounds of 2,4-D and 1.3 million pounds of 2,4,5-T were applied in 1978—amounts far greater than in any of the other North Central states. Kansas also has a population-based cancer registry, from which figures for cancer incidence can be obtained without having to rely on death certificates; as noted above, the reporting of sarcomas and lymphomas on death certificates is known to be extremely inaccurate. The study population consists of white males, aged 21 and older, who have been diagnosed with STS, NHL, or HD during residence in Kansas. From 1976-1982, there were 200 with STS and 173 with HD; a sample of 200 was selected from those diagnosed with NHL during 1979-1981. The control group consists of white males from the general population of Kansas. Three controls were selected for each case, matched on age (+_ 2 years) and vital status. Controls for live cases, aged 65 years or older, were selected from the Medicare file; controls aged 64 years or younger were selected by random-digit telephone dialing. For deceased members, the controls were selected from Kansas state mortality files, with an additional match on the year of death; excluded were those persons whose cause of death was STS, NHL, HD, a malignancy of an ill-defined site (ICDA code 195), homicide, or suicide. In the case of deceased subjects, the next-of-kin were interviewed. One-half of the STS and NHL and one-third of the HD cases died before the study could be initiated. The same controls are intended to be used for comparing the three different series—ie, sarcomas, NHL, and HD cases—thus, only 1,008 controls are needed instead of approximately 1,700. Seventy men who were diagnosed with colon cancer in 1981 were chosen as a "cancer control series" in order to evaluate the possibility of recall-bias among cancer patients. Pathology specimens are being reviewed to confirm the diagnosis of STS, NHL, or HD, which is important because these conditions are difficult to diagnose accurately; also, the original pathologists used a variety of schemes for categorizing the tumors into subgroups. Not only are consistent diagnoses a requisite, but there must also be agreement on the subgroup terminology. Subgroups may be important with respect to etiology; some subgroups may be associated with herbicide use, while others may not. After about 45% of the specimens had been reviewed, it was noted that some cases belonged to other series in the study—a so-called NHL is actually an HD or an HD should be an STS. Then too, a few instances of malignancies have been found that are not eligible; for example, one multiple myeloma was considered to be benign and an STS was rediagnosed as nodular fasciitis. If the number of such misclassifications is large enough, it may be possible to evaluate observation- and recall-bias in these situations with conditions that may be unrelated to herbicide exposure. d57:update (revd. 5-29-85) - page 37 �Each telephone interview has taken from about 25 minutes to one hour. Corroborative evidence of the self-reported herbicide exposure will be obtained from farm suppliers by asking them about the kinds of crops grown and the purchases of herbicides and insecticides. Such verification is an important step, giving a crude evaluation of potential observation-bias—a criticism of the Swedish studies. All interviews and verification were to have been completed in the early part of December 1983. The data were to be analyzed by computer and reported by summer of 1984. New ZealandI Soft Tissue Sarcoma Case-Control .Study In addition to the Swedish studies, a case-control study of STS has been reported by researchers from New Zealand, where phenoxy herbicides were used extensively for many years. A preliminary report by Smith et al (1982a) found no association between soft tissue sarcoma and the use of phenoxyacetic acid pesticides. None of the persons with soft tissue sarcoma in the study had worked as a licensed herbicide applicator. In this study 102 males with STS, as indicated from the New Zealand Cancer Registry between 1976-1980, and 306 controls (with cancers other than STS) were matched by age and year of registration. The 102 STS cases, or their next-of-kin, and "other cancer" controls were interviewed by telephone for information concerning their occupations. No excess of STS was seen in the category for agriculture and forestry (odds ratio = 1.03, 90% confidence limits = 0.9, 1.8); farmers showed a slight excess of 1.45 (0.8, 2.7) despite extensive use of phenoxy herbicides, but this excess may be due to misclassification. Neither complete work histories nor histories of actual herbicide use are available. Although misclassification of exposure status may dilute the risk estimates, the amount of misclassification cannot explain the differences between the Swedish and New Zealand studies. Lifetime work histories for 82 of the New Zealand STS cases and their 92 controls with other types of cancer were taken by telephone. The results of the interviews showed a 60% increase in risk of STS if the probable or definite exposure to phenoxy herbicides for more than one day occurred at least five years prior to the cancer registration; there was a 30% increase in risk if exposure was at least a total of 5 days and occurred more than 10 years prior to registration. Increases in risk for chlorophenol exposure were 50% and 60%, respectively. Little control for potential confounding factors was done (Smith et al, 1984). Finland No deaths from STS or lymphomas were revealed from a survey of mortality data on 1,926 herbicide sprayers employed from 1955-1971, although exposures were admittedly low and of short duration (Anonymous, 1983; Riihimaki et al, 1982). US, Pacific Northwest In the Pacific Northwest, there is a case-control study of approximately 280 STS cases, 540 NHL cases, and 125 liver cancer cases, all diagnosed between 1980-1983. The cases originated in 13 counties in western Washington state, where phenoxy herbicides and chlorophenols are used extensively in agriculture, forestry, and the wood products industry. Cancer incidence data are available from a population-based cancer registry. Approximately 1,100 subjects were selected by random-digit dialing to serve as controls for each of the three types of cancer. In-person interviews of cases and controls, or their next-of-kin, were used to collect detailed residential and occupational histories and other risk factor information. Information on geographical area and extent of herbicide d57:update (revd. 5-29-85) - page 38 �application will be combined with the residential histories to construct exposure indices. Occupational exposures will be ranked and given an exposure index value. The estimated time of completion is 1985. An update was provided by its principal investigator (Milham, 1982), who concluded that the mortality patterns of 200 white males, ages 20 and above, from 1950-1979 do not support a link between soft tissue sarcomas, Hodgkin's disease, and non-Hodgkin's lymphornas and exposure to phenoxy herbicides or chlorophenols. Several herbicide-related studies have been conducted in New York State. One of these was of 281 males diagnosed with STS during 1962-1980 and who were between 18 and 29 years of age during 1962-1971. A living control was selected for each case from drivers' license registration files matched on age, sex and place of residence. For each deceased case, a second deceased control was obtained from the New York State mortality files, matching year of death, age, years of education, sex, race and health systems area. Cancer deaths were excluded. The telephone interviews with the subjects or their nextof-kin focused on exposure to herbicides while in military service; other factors, such as occupation, histology and anatomic site of the tumors, were also examined. No statistically significant association was found between STS and Vietnam service or military service in general, or any other variable that could relate to herbicide exposure (Greenwald et al, 1984). Another investigation (Lawrence et al, 1985), using the mortality odds ratio (MOR), compared the causes of death among New York State veterans who had served in Vietnam with those of that era who had not served there. The study group excluded New York City and consisted of 1,496 Vietnam-era veterans, 555 of which had been in Vietnam. The highest MORs involved "non-motor vehicular injuries of transport" (2.18), other accidents and burns (1.37) and homicide (1.59); no association was shown between herbicide exposure and cause of death. A high and increasing death rate due to connective tissue cancers among white women was observed in 9 widely dispersed Michigan counties. For Midland County, the location of a Dow Chemical facility, a total of 13 deaths due to these cancers occurred over a period of 20 years, but there were none among white women during 1980 and 1981. In some instances, the onset of the disease had begun before the subjects had moved to Midland; then again, it is unclear whether the apparent increase was real or an artifact of death certification and coding. A case-control study will include all patients with a biopsy-proven diagnosis of STS from 1970-1983 -with the exception of mesotheliomas— in the specified eight counties. Three hospital patients without a history of cancer will be selected as controls for each case, matching on sex, race, and five-year age period. Interviews will cover occupational and residential history, smoking habits, hobbies, medical history, family history of malignancy, and diet. The report is estimated to be completed by October 1985. A preliminary finding by the Michigan Department of Public Health in 1983 did not establish a link with any factor in the environment, including TCDD. Though there were increases in mortality due to connective and soft tissue cancers in some of the 28 other US counties where TCDD might occur as a result of chemical manufacturing, as compared to other counties that were suspected of being devoid of the contaminant, there was no predominant pattern of excesses. One might expect a predominant excess d57:update (revd. 5-29-85) - page 39 �if TCDD were responsible. Italy A case-control study of 100 cases of STS identified from hospital pathology department logs from 1981-1983 and 300 controls is being conducted in three counties where phenoxy herbicides have been used in the growing of rice. Both sexes will be included due to the large number of women who have worked in the rice fields. Two controls per case will also be identified from the pathology logs and will be matched on sex, age, and province of residence; other cancer patients have been excluded. A second control group for cases from larger towns will be drawn randomly from the general population and from death records. A reasonable completion date is 1985. Denmark First, there will be a cohort study of workers at a plant where phenoxy acids have been produced since 1947. Workers from newer plants may also be included. After its completion, a case-control study of STS similar to the Swedish studies is planned. Imrnunological Response to TCDO In Animals Sell (1983) reviewed for AMA's Advisory Panel on Toxic Substances the available literature that might pertain to TCDD's effect on the immune system. It is known that rats and mice develop atrophy of the thymus gland when fed even "safe" doses of TCDD; their T-cells become cytotoxic, and eventually the animals die. T-cells, or T-lymphocytes, are the "policemen of the immune system" and are involved in the regulation of the immune system. Antibodies are identified according to the function of the T-cells and B-cells or their subsets. It is important to learn why these cells are activated. The most sensitive immune system test is based on the production of cytotoxic T-lymphocytes. Immunosuppresive drugs, such as cyclosporine, interfere with interleukin-2 and inhibit the growth of T-helper cells. Published data from animal, studies, however, are meager and conflicting, which makes their interpretation difficult. For example, the administered dose, usually dissolved in acetone, often may be given with no indication of what the animal actually received. Nevertheless, an NIH study on mice given high doses of TCDD (5 ug/kg of body wt, or 0.1 ug/mouse) for 270 days revealed no defects; moreover, an examination of the thymus, spleen, and lymphocytes revealed no abnormalities, and their antibody response was satisfactory. In Humans Information about TCDD's action on the human immune system is even more scarce, although imrnunologic research has been carried out by the National Institutes of Health since 1976. According to Sell, there is presently no conclusive evidence that TCDD adversely affects the human immune system. Reggiani reported earlier (Arch Toxicol (Suppl 2):291-302 (1979)) that immunoresponse was not altered nor was susceptibilty to infectious diseases increased among the inhabitants of Seveso, Italy. Sell also reviewed a report on the outcome of an industrial accident at the Coalite plant in Bolshover, England. In his opinion, there were no imrnunologic differences between three groups of workers; ie, 1) those exposed to TCDD with chloracne, 2) those exposed d57:update (revd. 5-29-85) - page 40 �to TCDD without chloracne, and 3) those who were unexposed and had no chloracne. Conclusions The studies to date on the human health effects of Vietnam exposures to Agent Orange do not reveal a clear relationship between serious illness and exposure. A number of important studies are still in progress; until they or others that may be deemed necessary are completed, no final conclusions can be drawn. Workplace exposures, on the other hand, have involved components of Agent Orange, especially 2,4,5-T and its contaminant TCDD, and represent a different level of biologic experience. Definable and measurable effects on specific organ systems can be described for acute, subchronic, and long-term exposures. Chloracne is the marker for biologically effective exposure in humans, and it may persist for as long as 30 years. A wide range of adverse reactions in animals has been observed, which are speciesdependent. For example, the guinea pig is most sensitive to TCDD, while the hamster is one of the least sensitive. Adverse reactions in animals include thymic atrophy in all species, induction of hepatic enzymes in the mouse and rat, and teratogenicity and reproductive effects in rodents and non-human primates. Except for chloracne, however, TCDD has not demonstrated comparable levels of biologic activity in man; that is to say, no long-term effects on the cardiovascular and central nervous systems, the liver, the kidney, the thymus and immunlogic defenses, and the reproductive function -in the male, female or offspring—have been demonstrated. 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Food Cosmet Toxicol 1981; 19:57-65. Merlo F: Adverse health effects in human populations exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso; an update. Presentation at meeting of AMA's CSA Advisory Panel on Toxic Substances, 13 December 1983. Michigan Department of Public Health: Evaluation of Soft and Connective Tissue Cancer Mortality Rates for Midland and Other Selected Michigan Counties Compared Nationally and Statewide, 4 May 1983. Milham S 3r: Herbicides, occupation and cancer. Lancet 1982;I:1464-1465. Minister of Veterans' Affairs: Case-control study of congenital anomalies and Vietnam service (birth defects study). Australian Government Publishing Service, January 1983. Moore 3A, Gupta BN, Zinkl 3G, et al: Postnatal effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo~p-dioxin (TCDD). Environ Health Perspect 1973;5:81-85. Moore JA: A pesticide. Science 1979;203(4382):741-742. 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Food Cosmet Toxicol Vinopal JH, Casida 3E: Metabolic stability of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian liver microsomal systems and in living mice. Arch Environ Contamn Toxicol 1973;1:122-132. Voss JG, Beems RB: Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol Appl Pharmacol 1971; 19:617-633. Voss JG, Moore 3 A, Zinkl 3G: Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals. Environ Health Prespec 1973;5:149-162. Wagner SL, Witt 3M, Norris LA, et al: A Scientific Critique of the EPA Alsea II Study and Report. Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, 1979. Wassom 3S, Huff 3E, Loprieno N: A review of the genetic toxicology of chlorinated dibenzo-p-dioxins. Mutation Res 1977/78;47:141-160. Weaver D, Amos A, Tierney B, et al: Interaction of DNA with cytosolic 3-methylcholanthrene binding proteins from either rat or mouse liver. Carcinogenesis 1980; 1:481486. Webb K, Ayres S, Slavin R, et al: Results of a pilot study of health effects due to 2,3,7, 8-tetrachlorodibenzodioxin contamination - Missouri. MMWR 1984;33(5):5461. Weber H, Poiger H, Schlatter C: Acute oral toxicity of TCDD metabolites in male guinea pigs. Toxicol Lett 1982;!*: 117- 122. Willis RF: Canadian review of human and animal studies and dioxin sources as a basis for recommendations on government regulations. Presentation at meeting of AMA's CSA Advisory Panel on Toxic Substances, 13 December 1983. Wolfe WH, Michalek 3E, Albanese RA, Lathrop GD, Moynahan PM: Project Ranch Hand II. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides; mortality update - 1984. USAF School of Aerospace Medicine, Brooks AFB, 10 December 1984. Young AL, Calcagani 3A, Thalken CE, et al: The Toxicology, Environmental Fate and Human Risk of Herbicide Orange and its Associated Dioxin. USAF Occupational and Environmental Health Laboratory, Technical Report No. TR-78-92, Final Report, Brooks Air Force Base, Texas, 1978. d57:reprefs (revd. 5-24-85) - page R-10 �List of States with Vietnam Veteran Commissions or Programs California California Division of Veterans Affairs P.O. Box 1559 Sacramento CA 95814 (916) 445-9518 Connecticut Vietnam Veterans Herbicide Information Commission Veterans1 Office Southern Connecticut University 501 Cresent Street New HavenCT 06515 (203 297-4329 Georgia Agent Orange Program Georgia Department of Human Resources 47 Trinity Avenue, S.W. Atlanta, GA 30334 (404)656-4764 Hawaii Agent Orange Program Hawaii Department of Health P.O. Box 3378 Honolulu, HI 96801 (808) 548-8705 Indiana Agent Orange Program Department of Veterans' Affairs 707 State Office Building Indianapolis, IN 46204 (317)232-3910 Iowa Agent Orange Program Iowa Department of Health Lucas State Office Building Des Moines IA 50319 (515) 281-8220 Kansas Agent Orange Program Kansas Department of Health/Environment Forbes Field Topeka, KS 66620 (913) 862-9360 Maine Bureau of Health State House, Station 11 Augusta, ME 04333 (207)298-3201 Agent Orange Program 100 Cambridge Street 10th Floor, #1001 Boston, MA 02202 (617)722-1107 Massachusetts Minnesota d57:states (revd. 5-29-85) - page A-l Agent Orange Program Department of Veterans' Affairs Veterans Service Building (612) 297-4217 St. Paul, MN 55155 �New Jersey (609)984-7397 Agent Orange Program Ohio Board of Regents 30 East Broad Street Columbus, OH 43215 Ohio Agent Orange Commission Broad Street Bank Building 1*3 East State Street Trenton, NJ 08608 (614)466-6000 Oklahoma Agent Orange Assistance Program Oklahoma Department of Health P.O. Box 53551 Oklahoma City, OK 73152 (405) 271-4200 Oregon Agent Orange Program Department of Veterans' Affairs Veterans Service Division 700 Summer Street, N.E., Suite 150 Salem, OR 97310-1270 (503)378-6839 Pennsylvania Vietnam Herbicides Information Commission Pennsylvania Department of Health P.O. Box 8380 Health and Welfare Building, Room 912A Harrisburg, PA 17105 (717) 787-1708 Rhode Island Agent Orange Commission 242 Prairie Avenue Providence, RI 02907 (401)521-6710 Agent Orange Program Texas Department of Health 1100 West 49th Street Austin, TX 78756 (817)458-7251 Texas West Virginia Agent Orange Program West Virginia Department of Health Office of Community Health Services 1800 Washington Street East Charleston, WV 25303 (304)348-3210 Wisconsin Agent Orange Program Wisconsin Department of Health & Social Services Division of Health P.O. Box 309 Madison, WI 53701 (608) 266-1253 * . . GOVERHMEIB IKIHTING OFFICE : 1985 0 4 1 8 0 3 6 1 BS -6-9/55 d57:states (revd. 5-29-85) - page A-2 � 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. 052 Folder The folder containing the original item. 1394 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R.H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 1 1984 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants: an Update, 1984, Technical Report Subject The topic of the resource health studies human exposure industrial exposure veteran health and hygiene 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. 030 Folder The folder containing the original item. 0503 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 Bogen, Gilbert Source A related resource from which the described resource is derived Journal of the American Medical Association Date A point or period of time associated with an event in the lifecycle of the resource November 30 1979 Title A name given to the resource Letter to the Editor: Symptoms in Vietnam Veterans Exposed to Agent Orange Subject The topic of the resource health effects health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 050 Folder The folder containing the original item. 1321 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 Bogen, Kenneth Geraldine M. Carr Description An account of the resource <strong>Corporate Author: </strong>Science Policy Research Division, Congressional Research Service, Library of Congress Date A point or period of time associated with an event in the lifecycle of the resource May 12 1981 Title A name given to the resource Agent Orange: Veteran's Complaints Concerning Exposure to Herbicides in South Vietnam Subject The topic of the resource dioxin health studies risk assessment veteran health and hygiene 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. 049 Folder The folder containing the original item. 1274 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 Budd, M. L. N. S. Hayner H. E. B. Humphrey J. R. Isbister H. Price M. S. Reizen G. Van Amburg K. R. Wilcox Jr. Description An account of the resource <strong>Corporate Author: </strong>Centers for Disease Control (CDC) Michigan Department of Public Health Source A related resource from which the described resource is derived Morbidity and Mortality Weekly Report Date A point or period of time associated with an event in the lifecycle of the resource April 7 1978 Title A name given to the resource Polybrominated Biphenyl Exposure - Michigan Subject The topic of the resource human exposure health studies ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/bb3b2e854afbbc1197cdafdddc181e61.pdf 6e9735a9c96a014fc47e12c23a1c99ff PDF Text Text Item ID Number 00578 Author Custis, Donald L Corporate Author Report/Article TltlB Typescript: Statement of Donald L. Curtis, M.D., Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, Before the Subcommittee on Oversight and Investigations, Committee on Veterans' Affairs, House of Representatives, September 15,1982 Journal/Book Title Year Month/Day Color Number of Images DeSCrlptOII NotOS n 20 Alvin L Your| gfiled tnis item under the category "Human Exposure to Phenoxy Herbicides and TCDD" Tuesday, February 20, 2001 Page 578 of 680 �I. ; - i «PV ' u, - , > ..v?../.^J^T.of, , .,,, ' .' •. , DONALD L.CUSTIS.M.D., 1 1 . -., ' CHIEF MEDICAL DIRECTOR, T *V DEPARTMENT OF MEDICINE AND SURGERY { V ( , , * ir:^TER/^ ^^WAT!9N ^*> ^;-( , _ * ,v ^ f r '."-•,' ^BEFORE THE , t SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS, COMMITTEE ON VETERANS'AFFAIRS HOUSE OF REPRESENTATIVES September 15, 1982 < I * > * » , / f 1 < r "t ', » * '1 t, *<t i* " ' t V ' * • > ' ' . * ' '*' '» .1 Mr. Chairman and Members of the Committee: f tv t"*, s Good morning. 1 » < '» •> *.» , v ' . On behalf of the Veterans Administration, we are pleased to have the Opportunity to appear before you today to provide an update on the status of both VA's Agent Orange-related activities and the Readjustment Counseling Program. We are continuing efforts to resolve the complex medical and scientific questions concerning Agent Orange. In the interim, we are providing medical care and treatment, as well as information to Vietnam veterans. We believe that a great deal of progress has been mode in both areas since we last appeared before this committee on May 6, 1981. Mr. Chairman, we are aware that both the Agent Orange issue and readjustment to civilian fife remain key concerns for many Vietnam veterans. A great deal still needs to be done to resolve both of these concerns. Let me reemphasize, however, that the Veterans Administration has never lost sight of the special needs of the Vietnam veteran. �2. \ V,, . *?fr Aoent Oronge Program T \rT* • l " * w ' ' *;/- . IT?- ; \ <;«v " , ^ ' * On June 30, 1982, Robert P. Nimmo, Administratpr approved a revised Department of Medicine and Surgery program of Agent Orangerelated activities. The most significant activity which was approved is a pilot study as a preliminary to the full epidemiological study provided for by Congress. Other major efforts included are the Vietnam veterans identical twin study, a mortality study, and specially-related research projects. Approval was also given for the establishment of the Agent Orange Projects Office within the Department of Medicine and Surgery. This office will coordinate and monitor a variety of epidemiological projects. Efforts are now underway to identify key epidemiologic staff who will be responsible for these efforts. The core staffing will consist of an Epidemiologist, Biostatistician, Statistical Programmer, Health Science Specialist for Quality Assurance, on Administrative Assistant and supporting clerical staff. In addition, approval was given for continuation and improvement of the Agent Orange Registry, chloracne activities, a follow-up to the literature analysis, a monograph series, establishment of a Vietnam service indicator in the Patient Treatment File (RTF), and a retrospective study of dioxins and furans in human adipose tissue. STATUS OF VA EPIDEMIOLOGY STUDY; The epidemiology protocol submitted to the VA by the UCLA School of Public Health on April 29, 1982, has now been reviewed by the VA Advisory Committee on Health-Related �3. Effects of Herbicides, the Agent Qronge Working Group (AOWG) and the Office of Technology Assessment. The protocol is currently being reviewed by a committee of the .Academy of Sciences (MAS). The VA has been advised that HAS is now in the jes of this review process. It |s expected that the report will be completed and > '' - , f\ forw.a/jted to. tjh$ Veterans Administration shortly* Following incorporation of the .yarjous ^eYlewers/ comments, we will solicit bids for a contract for the conduct of a pilot * * * » ' *-, study. We anticipate having that solicitation in place before this December. " i ' «u The purpose of the pilot.study w|U be to permit us to "fine-tune" the protocol for the conduct of the frjll-^cale epidemiology study which will study a population of approximately 18,000 veterans. The pilot study has become the focal point of recent activity by the VA, the Army Agent Orange Task Force (AAOTF) and the AOWG. < The AOWG has appointed a subcommittee of its Science Panel to establish procedures for cohort selection for the epidemiology pilot study. The VA has brought in bipstatistica) consultants to work with this subcommittee and with the AAOTF. The Subcommittee is now in the process of preparing its final report to the Science Panel. Health Care Tr« Veterans, Administration is implementing the medical core and treatment provisions of Public Low 97-72, the "Veterans' Health Care, Training, and Small Business Loan Act of 1^81." Shortly after the law was signed, interim guidelines for the implementation of » ' .. these provisions were issued to all VA health care facilities. Those guidelines were also '- . . •• . ' "-' • „ - ' • ' -i ' • ' , - • 'f- ' ' . . y published In in the Federal Register on December 5, 1981, to provide Vietnam veterans and the general public with the opportunity to comment. �. • . . . . . . . . . , . Under the provisions of the guidelines, each veteran who served in the Republic of • ' ' . . ' .' . <>.. ".'•.-' • • . . - . . • . - ; .'" ' • ' • , . : - , • • Vietnam and who requests VA medical care Is being provided a complete medical history, physical examination and appropriate diagnostic studies/When it is determined that a condition exists requiring treatment, the responsible staff physician makes a determination as to whether the condition resulted from a cause other than the specified exposure to Agent Orange. The guidelines include a description of those conditions which I determined cannot ordinarily be considered to be due to such exposure. • ' * .' . •: • ' . - . . • : 'i - - ' -' •• • • Ultimately, it is left to the treating physician to exercise professional judgment in determining whether the veteran should be provided care under this authority. Agent Orange Registry '• -• • • . , - • ' ' -:• ;••• ' • ' - : •>' : . ' • : • . • • ' . ft. .:• ' : .'• r. " : ':• Since the initiation of the Agent Orange Registry in 1978, approximately 91,000 veterans • • " • • - . . • • • ' f ', • have received an Agent Orange examination at VA health care facilities. The VA has provided approximately 20,000 follow-up examinations for Agent Orange. The basic registry process involving a comprehensive physical examination, completion of a questionnaire and informing the veteran of the results of the examination verbally and in writing, are continuing to be followed by all health care facilities. The monthly report, transmitted by VA health care facilities and compiled at VA Central Office, is still an effective tool in measuring the numbers of examinations (initial and follow-up) being performed at the facilities and the number of pending examinations. * . The4 Environmental Medicine Office is continuing to monitor the numbers of pending examinations to assure that the veteran is provided the Agent Orange examination and related treatment in a timely manner. Facilities reporting •Vjut-of-line" situations, that .:.'••• ' -., r •• . . -.SV' '.;• • .:. • r ' . ' - " ' '.• , is, facilities with examinations pending more than 30 days or having more than 50 . , ' ' . . ' • ' . • • * • * .-- ; ' • • - k •'»•.'• ' : •'•••• • • ; : ' • : • '•"•"'• .-;.^'< • .•• '••(•• examinations pending during any reporting period ore contacted by program officials at �5. V^A Central Office and directed to'take Immediate action to reduce the number of pending examinations to comply with Central Office guidelines. •ij^iSj,.^ i H i' 1 ^ t~ ** s £ i I* r ^- / 5 *** ' w ^5 t tsT^^j)*'^ £, { ij T** ' J$ ^ ~*** ** i, ' * * 'Improvements In our registry procedures will enable the VA to match Agent Orange Registry records with records of hospitalization in the Patient Treatment File (PTF) system so that correlations can be made regarding the types of diagnoses Vietnam V '» * ! « ' » ' • * f > «' s '« 1' ii»'l»'J* H ' ' " • !' veterans are fpresenting forf treatment at VA health care facilities. t » -si j f *' *A* The VA is cooperating with the Department of Defense with regard to Agent Orange examinations for active duty personnel. Instructions will be mailed to all VA health care facilities for processing an active duty service member's request for an examination and for processing the forms. The results from this examination will be entered into the Agent Orange Registry. Twins Study j\ " \" / < • < ' < • >' • • '. The VA has recently given approval for the development of a comprehensive protocol i that will involve studying identical twins. The proposed study would involve identical twin veterans where one twin served In Vietnam during the period of Herbicide Orange spraying and where the twin sibling did not serve in Southeast Asia. This study will be designed to investigate whether the current psychological and physical health of Vietnam veterans was adversely affected by their military experience in Vietnam. Veterans Administration researchers at our St. Louis VA Medical Center have proposed the study and ore currently developing the protocol. We would anticipate that If the protocol survives the scrutiny of appropriate scientific reviews, we will launch into the physical examinations of some 450 pairs of identical twins in late 1983 and should have an initial report of findings by October 1984. .. : .c T i, • . *.- • ' . i j > . ..••„• / • • : . - •" • .- • i •• ' . .• . . .•" i '• ..'-•• •: '.. �Vietnam. yeteranJAortality Studies • • • , . . . • < ••"••. '^^-t&ffi&S^ ":"' . ' "•'.'.• ' " A carefully-designed and well-executed mortality analysis of Vietnam" veterans will provide background to many questions raised by the Agent Orange exposure issue in particular as well as the possible health effects of service in Vietnam in general, the Vietnam Mortality Study is designed to analyze and compare cteatH rates arid cause-ofdeath profiles of veterans with service in Vietnam and comparable veterans with no service in Vietnam. The studies will use existing computer records to assemble a cohort of veterans and . ' . . - • • ' • ' • • "'"-. v",/;.•••• ' • ' ' : ; - • • • " '"*!'•••'•;.-j '•• ,. . •,. . -•(.•'•i-- ' ': , • ' : ; ' - • : : ••*, determine their mortality experience. It should be noted that the mortality studies will provide mortality information which may prove useful primarily in suggesting areas for further scientific study. These mortality studies will be conducted by researchers at the Veterans Administration Central Office in Washington, DC. The collection and coding of death certificates and the abstracting of military records will be done by VA contractors. We are currently evaluating submitted proposals and hope to sign contracts for these efforts shortly. It is anticipated that it will take approximately two years to complete the mortality studies. Retrospective Study of Dioxins and Furons in "Adipose Tissue of Vietnam-Era Veterans The Environmental Protection Agency has been collecting adipose tissue from the U.S. general population. This National Adipose Tissue Bank was initiated in 1968 and now contains specimens from approximately 6,000 individuals. Represented within this bank is adipose tissue from approximately 3dO males born between 1938 and 1952. It is estimated that �7. approximately 200 of these males may have served in the U.S. military during the ,'i&V&<'-iU^,'"Ti£l^ Vietnam"erei and that as many as 70 may have lervecl in Vietnam. . ~ : fef M%fi^^ ••'^'" •^'^•: "We are currently developing an agreement by which the VA would support an interogency iludy to be conducted at theJ^PA 6ioxin Laboratory in Bay St. Louis, Mississippi. This K^:!>!M?^ V*n^ ' - . - • '--'">;?"<^ ^•••'^('' will be a retrospective study of chlorinated aioxins and furans in human adipose tissue. The study is designed to establish 'background levels of 2, 3, 7, 8-TCDD in the U.S. male population. In addition, this study may serve as a means of determining whether service in the military and especially in Vietnam has had an effect on the levels of TCDD in the ^.J^'i ' - JM > , ! < , > « f?''V«, ' • * , * < " '»f i *> ' ' ' '"^ ' adipose tissue. if' „ \t r < i t ?. '«V * * ' ' V i , * I" •' ^v i » " ' " ' The proposed effort would involve a jointly-funded program between the VA and EPA to & £*_ 1 • f - y * * * 1 ! A 3 " i *.* ! i # ^ ^ develop the research protocol and appropriate sampling and analytical methods. The actual analyses of the human tissues will be costly and time consuming. Data should be forthcoming within two-three years. « ,» ^ < ••••• • .; ' •' ' ; • : • • • • Chloracne Activities The review of skin conditions to identify questionable cases which may be chloracne is •' • •'•-••':'••-:• ':,'•: '• .•'•: : i--> v 'v.'' : -'.';. ; • ' continuing. •'' ' .'•;• •.' , ." ' : . . •'•... Over 3,200 Rating Decision Sheets on skin condition claims have been reviewed by VA Central Office physicians. The medical records of questionable cases were reviewed by a dermatologist consultant at the Washington VA Medical Center who tentatively identified 12 cases requiring a further clinical review which will include a . • ; r': : ' : ' -•-' •• : ' v -••-.'••• • • • physical examination of those individuals. ••-.-. ' .. • I .>.. . • . . • • • • • . : • . < • ! : ( : • ' ; : - . t / V K - ''• We are now In the process of making arrangements for the physical examinations, •,i i ' ; • . ' » - • • : ' . . - - ' • ;•;•:'./ . ; - , ' : .-• including dermatology examinations, of these individuals at selected non-VA clinics. I r-:. ^.;-,;-:;- •;;£..;•;<*'^'.-^^V^/v^^U-' ^ ' J ^ v »^ .-•»:•-•:.: • }• • r.f-- ':.< ?'• •". . '•'•'• : 0, anticipate that these examinations will be conducted during October. >, •"••"..<. ,<' �8. •-• • ••>..-"•' •- "Tt '• '-,.'• , V i '% • }.- >• J t ;»•-< We intend to continue our review of Rating Decision Sheets provided by VA Central ' Office Compensation and Pension Service to determine possible chlorocne cases and recommend selected claimants for special dermatojogical examination. Additionally, we will review and analyze Agent Orange Registry data relating to types of skin conditions being reported by participants. -.- •• ••.-..•• ' ', * ' ij. i • i< < f ' ' I am confident that our current emphasis on chloracne-related activities will assist us in more effectively identifying and treating skin conditions which may be the result of exposure to Agent Orange. Vietnam Service Indicator for Patient Treatment File The Patient jreatment File (PTF) maintained by the Department of Medicine and Surgery has great potential for epidemiological research related to Vietnam veterans. A major problem with this automated, file is that there has been no entry to identify those veterans who actually served in Vietnam. .' • . " -s" The establishment of such an indicator, in most instances, will require a hand search of the individual veteran's service record. This would best be accomplished by a contract with an organization which has a proven record of expertise with this type of effort. ' ' " . " . ' \ We intend to conduct a study to determine the feasibility and cost of obtaining a V A - K - - . . . . . . . . • •- ; •-.•!•• , ., - ' . ' - • " , • . . • • • . - • . - . - • • • • ' • • • • • • • "• : ; . veteran's service history. Based upon the results obtained, we will then decide whether to obtain this information for all Vietnam-era veterans in the PTF. �Speciolly-Solicited Reseorch Activities *r* c-r— j ^ r i r~ ~ Medical Research Services has recently approved 10 new Agent Orange research studies f *" t •* that will investigate the impact on basic biological processes of low levels of exposure to Mfr ? * **T^ * * * ' . . - components of Agent Orange. Two other ongoing studies address these issues also. The Studies include analysis of the impact of Agent Orange components on: o Over cell function '" t, v I j -I f ii s jr. 0 ( f Skin cell chemistry relating to chloracne o * Neurobehavioral function ' •, t f * > « '«!, ' . -x V » " • ' The basis of the design( of each of these biological studies includes exposing a test ........ "' . ' *• i , biological system to one or more components of Agent Orange, and subsequently •3 • '••?*••.! . ; ' ; : ^ ;, - £*.••:'•:* •- ' ' * *"'• 'f.\::t^ ;'r' •••'• '.':. • , . . : . . , . . _ • measuring abnormalities of biological function. ~f\ -^ " - ' ; • . • • • • . . . . • • " ••'<-. : : ': •";'• ;"i.-!:^^;-,y V-' '.•.'•*' . i r . . . y ' v < - . , •.. •X^:.;{j,4;:>:.-- .--s ,; ; v/* -• ... ',,:?;;•,'',.;.-; ;.y>/. N j i : ^ :.-.;-v:: rn :•.• ..' • The chemicals used in these experiments which are the main component parts of Agent '• ''.'• ' '- • ' ' l ' * : ' • U. :••"'.'• V-",> •/"•!•»:•''«•" yV'-C-V;! • :.!Vi''.'>V '.-;. ' ,: ',' ? (• ':•:' : '•''•••'.'•l^..? ' ! ' • - • • . ; ' • ' ' < - . . „ ' .''"fi'v •'. v i* -<i '.^ Jl'*'!*,'* i'-. ' t •'. '. - ' '• " '' Orange are: 2.4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichiorophenoxyocetic " ; s- {. . .-' : * -i 'i .; f i -^ . ,. ; V-. ' 5 • * ^ , - ; , : • ^VU-i. 'i .^ . , . . . . acid (2,4,5,-T). In addition to these chemicals, Agent Orange (and some other herbicides used less frequently in Vietnam) contained varying amounts of a contaminant commonly referred to as TCDO (dioxin) which will also be a focus of studies to determine whether and how delayed toxicity is manifested after low-dose exposure. Such studies may provide clues for clinicians as to what medical tests would best identify delayed, toxic effects, if any, of exposure of veterans to herbicides in Vietnam. The biological systems thought to be affected by exposure to TCDD are: 6 Liver function; When animals are exposed to TCDD and related compounds, these chemicals are stored in the liver and produce acute liver damage. It ]' • . . ^- �10. would appear likely that any delayed harmful effects of exposure to low closes of »uch compounds would be manifested by subtle changes fn the biochemistry •«f the liver. Seven of the funded research studies will investigate the delayed impact of exposure to Agent Orange components and the contaminant TCDD on various aspects of liver cell functions in a variety of •'•'".-.• species. t' o ' ' , " ,- ' • ' , ,' • -.. . ' . • - - • -• ;, • • . ' .• •. . .' .. • . . .' • . • .. •. • . . •• -, . Skin: Chloracne is the one documented effect of low-dose exposure to Agent Orange in humans. One study will analyze the underlying biochemical events that lead to ch lor acne in a mouse model and in human tissue culture cells. o the nervous systems: Acute accidental poisoning with TCDD in man has led • j- ' •- • • • ' ? ' ' ' • ' • ' . " ' • • • •- '•• • • .' • .'•*•*"' • .' • ' r< . i . , . .' - ';j f to a variety of usually-acute neuromuscular abnormalities. Four studies will ; •.. V. • - • ; , , - , - • : • • ••' > i . , • . •• •' ' •'• • •'• , '. ' " *iiV : • ' ' • ; ' • • systematically investigate the effect of the components of Agent Orange on neuromuscular function, sleep and behavior in a variety of animal models. A new effort to solicit and support research on the special health problems facing Vietnam veterans has just begun. The Research and Development Office has sent forward to all VA medical facilities a solicitation for research studies dealing with disorders affecting Vietnam veterans and their families. It is anticipated that a significant number of new studies submitted in response to this solicitation will be supported in Fiscal Year 1983. • • - • - - • . • • > ' • . .. .- - - / : - i : Monograph Series - .-•. ' >,••• -•• "' .;«:. -:.-, ..,-. • ;•;.. • „ • ' • • ;, •• /• :/: • • . , . • * ' - . " ; • • , • Funding has been provided during FY 1982 for the preparation of a monograph series designed to provide useful scientific information on environmental factors that may have affected the'health of military personnel serving in Vietnam. �II. -&#!^^^ ore planned on the following subjects: Monographs :^/ri;* •'wf1^^ Literoture Anolysis • -|V.i.' :,. . chloracne, birth defects and genetic ' ../; ' --;.-N.-:-••--t^:. .... .::•.., . ',-v;v. ' ' v:• ^l^^fc^^^V^^ ;.«:4^;-;;utf,^*^feM]tt^:^ ..,.. : Mr. Chairman, as you may know, the comprehensive literature review of worldwide scientific literature on Agent 6range and other phenoxy herbicides used in Vietnam has *'•:•'."'', • ;•»' . • ' • ' • ' • ' - ' - - . . • • • . been completed in accordance with the provisions of Public Law 96-151, ... ' .-., . ;,. .. •.. . ,. , - • . '.',•;..•: .-<*..• - v.-',,..-...'., •;•''; - • : . .. , .-,, . . . . . . . We have .!••.; ' distributed this two-volume report (which includes an annotated bibliography and analysis of1,200i scientific papers)^widelyWithin imeVA. Copies have also been provided .to rnembers of the White-House established Agent Orange Working Group, the Advisory Committee on Health-Related Effects of Herbicides, the National Academy of Sciences, the Office of Technology Assessment, the Departments of Agriculture and Defense, Surgeon General of the U.S. Air Force, Library of Congress, the Centers for Disease Control and other individuals, organizations, and scientific research groups. The successful completion of this review represents a step forward on the Jong road to understanding the complex health issues related to the use of herbicides. It will undoubtedly serve as an invaluable scientific resource which will assist scientists and others in identifying areas suitable for additional research. We jntend to periodically update this report and to augment it with a detailed critical assessment of all publications addressing herbicide exposure with particular emphasis on health consequences in humans. It is estimated that about 400 publications have appeared since October 1981. A critical review of these recent reports is needed in -•,•••• •.•;,!'.. • • :*> .:.-•=..-.'-, : --•:. • :•• ••-:,,".^;„. •!:^f,'.-.. : --:--r-' -• •• ' , ' order to keep this effort current. The Veterans Administration will take necessary steps to ensure that the literature review and analysis remains as current as possible. �12. Armed Forces Institute of Pathology (AFIP) The Veterans Administration Is continuing to cooperate with the Armed Forces Institute of Pathology in providing biopsy and autopsy materials for analysis to the Institute. This special registry was established in 1978 with the purpose of analyzing tissue samples to determine what diseases Vietnam veterans are suffering from, as reflected in biopsies or The VA has repeatedly emphasized the importance of the AFIP Registry and will continue to urge VA health care facilities to send pathological material obtained from any Vietnam veteran. . ; v: Education Activities Mr. Chairman, our environmental physicians, as Agent Orange coordinators at our major VA health care facilities, remain the key link in examining and advising the veteran concerned about exposure to Agent Orange. In order to ensure that these health care staff remain completely abreast of the latest developments, nationwide conference calls ore held on a regular basis. When required, special conference calls are scheduled on significant developments requiring their immediate attention. In addition to the conference calls, relevant Agent Orange-related literature is periodically sent to the immediate attention of environmental physicians. Staff support within the Environmental Medicine Office is available to assist in the explanation of .specific documents. or to answer questions which may be raised by the information received from VA Central Office. �13. Environmental physicians ore encouraged to participate in important scientific meetings : '• " --• , - * • • I<in Ag«nt Orange and other environmental substances in order to keep abreast of scientific «nd medical developments. Members of our own VA Central Office staff * i played a key role In the planning and organizing of an "International Symposium on ' ,, . - < ' " * •. , .Chlorinated Dioxins and Related Compounds" which was held in Arlington, Virginia, on October 25-29, 1981. On October 12-1 A, 1982, Or. Barclay M. Shepard, my special assistant, and Dr. Alvin L. Young will actively participate in the "3rd International t * Symposium on Chlorinated Dioxins and Related Compounds" which will be held in Salzburg, Austria. ) hove been advised that several of our environmental physicians are /also planning to attend. Through such participation I am confident that our health care 'ftaff will remain professionally current with the latest findings on the short and longrange effects of Agent Orange and other environmental substances. VA Public information Activities As part of our effort to inform Vietnam veterans, their families, and other concerned individuals and organizations about Agent Orange and the assistance provided by the VA, we produced and distributed to all VA field stations a videotape entitled "Agent Orange: '< A Search for Answers." '* • , While a recent internal survey indicated that many thousands of people have viewed the program on television or in numerous groups of individual showings, we are encouraging grepter use of the film. ' : ' ' We are very pleased to report that this videotape has received considerable acclaim from critics. The Health Education Communication Association and the Network for Continuing Medical Education presented an award of merit to the VA for Outstanding �14. i t, . . - , . , • . : , . ' ; • ,.'•;••• /.',•• . , -••• . ' ' • " ' •••'. ochievement in the use of television for education in the health sciences." The International Television Association (ITVA) awarded its Golden Reel of Excellence for the vltteotape's "highly-effective form of communication, which helped Ifie user ,>;;l>i';•• ,: • ' •''•••. • ••'.\ . ..:•••: ..• •'•'•>>.'.w ft)$-.;::, •';''•:i.?W^'ify^.-lc-1'; •^i~::*';p-^*i^>\}•:*£,•: f ';"• ;•:-. • organization better achieve its stated goals." the program also was cited by ITVA for • • .-. : • . • • ' • • • • •:-,•• . ' • . : -;;:.,- ''fe v -!i;-v;-fjK^:i^^^':^ ; i.-3. : ';^ ^ : |pv»v v !^».••;>:•'/•; i;.i^l;/,.;,< • ' . : . creativity, innovative techniques, and high-production value. In addition, the program also received an Emmy Award from the National Academy of television Arts and Sciences. We are delighted by this recognition and encourage all interested individuals to view this program. * The VA takes seriously its obligation to keep veterans informed about Agent Orange. We have also pursued other avenues to provide information and education to concerned Vietnam veterans and their families and VA employees on matters related to Agent Orange. . Early this year, an automated mailing list was developed from the Agent Orange Registry. In June, letters were sent to these veterans along with the first two of a new series of printed information material on Agent Orange. One of these pamphlets was devoted primarily to Public Law 97-72. A third pamphlet has been issued and a fourth is ,-, • .. . i, . :. - . , .. . -<:•...... - • ' ;.-. ••;.:..•:•:; . - ....-• , , • • ••-< ' , . - . . . - . . . ' -•• r • • . .-=.-. in production. VA officials have participated in public seminars, news media interviews and other public forums dealing with the subject of Agent Orange. 5,. ;/. ..-• ' • • " ' : . . , • : • • • < • ; ' • • • :;c;.-x •' • •'••... •''-• • .'.' • • • • • ;.?; • • "':-'-•. •+-*\v • • . • ' • - <•;,.', VA Liaison with State Agent Orange Activities At the present time, 18 states have initiated programs directly related to the Agent Orange issue. The VA is continuing its efforts to maintain an effective, ongoing �15. J » ' , ,,• , " • . . ' ; . ' • relationship with each of these state programs. One of the prime responsibilities of our Agent Orange Research and Education Office is to insure that current and accurate information regarding VA Agent' Orange-related activities is disseminated on a timely * * * <, ' '] ' ' 1 ' r -t " . ' ' • ' • '•' basis to the various states,' as well as to veteran service organizations, government agencies, and interested parties. We consider }t to be an essential part of our program to * - "' " I • ••" ; • insure that the veteran population as a whole, and those who serve them at all levels, are fully Informed both with regard to the current body of knowledge regarding the possible adverse effects of dioxins, as well as the status of VA Agent Orange programs. V" - ': ;' " ' i'V* ' ' ^ .1 ,""'.'' To this end, the VA has provided the states with copies of all pertinent Agent Orange materials and we have extended to officials from all of these states an open invitation to attend the VA Advisory Committee meetings. Several of the states sent delegations to ' . ' • • , - ' ' , • . ' ' ' ' / ' . " . . . ' • •" . . -i, • the meeting held on August 31. The efforts are of a continuous nature and are beneficial to all concerned parties. As new states become involved in the Agent Orange issue, VA will include them in its information exchange program. White House Agent Orange Working Group (AOWG) We are pleased to report that the Veterans Administration is continuing to play an active role in the White House Agent Orange Working Group and its Science Panel. This committee was established in July 1981 when the Interogency Group to Study the Possible Long-Term Health Effects of Pnenoxy Herbicides and Contaminants was expanded and elevated in status to the Cabinet Council level. �$"' 16. .v *>, The AOWG brings together policy officials and scientists from throughout the federal : • r _, " >;'.,,, •." , . - • - r • " - . . • ' .'. *-*.-.- . . - • • • . . : -.'•• •-•-v.%»*i. . :..;'"'<• •',;••'',•• ;...•,>•', ,.v >"'•'; :" ••" • • ', ' ; ,.• • •••"•• ' '" establishment to identify ongoing research activities on Agent Orange and related (*• " matters and to develop and organize the means to carry out additional needed scientific \ - research. £ * '> > • • • • •'-••'• ••••• •'/•>»• :•:•;-: ; :V r -i;y :••.;•>. K .-.i:-'7'-:%tf^H-:f:/ v,;. ':• -V^ i'. •:. v^,...:. ,1,-,^ ,-U-' . ^ , j v . i ;, ^ 4.,t!,s.; ' The Department of Health and Human Services (DHHS) is the lead agency in the working / group. • ' •• - . • . • • • • • • • : . , . . . - \ ; . . • ' . • - ' • • • . . : -/->,,^,,'f'- . • ; . • ' . . : = . ;..- :•,., I',.,,--;.:,.., i.! ,- y - ,. : In addition to DHHS and VA, the AOWG includes representatives from the Departments of Defense, Agriculture, and Labor, Environmental Protection Agency, • •• •' •'• • . ' •••'•- • ; • • : • : • •••::.'=• ' : • . . ' . •^ • Office of Management and Budget, Council of Economic Advisors, Office of Science and Technology and Office of Policy Development. The AOWG has been very helpful to the VA in the review of our planned epidemiological study, mortality study, and other important research efforts. Through the AOWG mechanism, the VA also has been able to contribute to the success of Agent Orange research efforts conducted or sponsored by other federal departments and agencies. The more important of these research efforts are the U.S. Air Force's "Operation Ranch Hand" study and the Centers for Disease Control's Birth Defects Study. We view our participation as vital to the scientific process and as fully consistent with > • • • • . . ••>.>-:•,.-,..••. , , .-•:,•,.•,, ,-,. ;.;.,:•:,,-,. .•.',.:;-..,,*•.•••?>•• •..;:.1,^., v -, , ( . ••, •.-•:;... u: ,...,....,. the President's goal of ensuring "... that the full resources of the federal government . .-,,. .. ,.„,.,..;-x > •:.i,r-: *•: ' ' - y ...!.ys. .•-. . ; are available to support the working group's continuing efforts." i. Advisory Committee on Health-Related Effects of Herbicides This committee, established in 1979, continues to meet quarterly at VA Central Office for the purpose of assembling and analyzing information which the VA needs to formulate medical policy and procedures on"the complex questions surrounding veterans' herbicide exposure. �17. During recent meetings the committee has discu&sed the VA epidemiological study and herbicide Ijterdture review,' the VA-*olicited in-house research program regarding Agent 1 /• ^ , iilj Orange and Agent Blue, the VA mortality study, international dioxin symposiums, the Air Force t^ealth'Study, the CDC Birth Defects &udy, the proposed VA Twin Study/the * * ' * , t r AFIP Agent Orange' ftetfistry, the VA rVioribg/aph series, and many'btheir-research f- *-, ' . activities and rrtottersdf concern to Vietnam veterans dnd scientists searching for answers to the (difficult qUeirfions1 raised oi>obt'the possible human health effects of herbicides. "'>•• : ':'':';".>-v,-;'1, ^^v^-i^^'^^^^'^f^^V^^Sv!^?;'-/.1''' • ; . • • " ' ' : ; ' : - ' • ' ! • ;••• "•< '- ; .-'-'^ • ' • " : ""; ' %- • The committee 'has been particularly helpful in advising the VA on the literature review and the epidemiological study. The literature review, published October 1981, was the subject of several sessions and considerable time and attention have been devoted to a critique of the proposed epidemiological study design. Verbatim transcripts are prepared and made available to appropriate government offices and interested organizations and individuals. A copy of each transcript also is sent to all environmental physicians. ; ;:; Policy Coordinating Committee In recognition of the importance of the Agent Orange issue, the Administrator has reorganized and elevated in status the Policy Coordinating Committee (PCC) which was * * • . . . . . ' thCjAgency's central coordinating point for Agent-Orange related activities. The PCC develops policy for review and approval by the Administrator. It now is composed of the top leadership of the major departments and staff offices within the VA. Mr. Everett Alvarez, Jr., Deputy Administrator, chairs the PCC. �18. I wish to conclude this port of my testimony on Agent Orange, Mr. Chairman, by again expressing the total commitment of the Veterans Administration to attempting to resolve the many issues relating to Agent Orange. Although there is no way that we, or anyone, can guarantee that ultimate and conclusive answers will be found to the extremely-complex medical and scientific issues stemming from the use of the defoliant Agent Orange in Vietnam, nevertheless, we will continue to vigorously pursue the search for those answers. These efforts will center not only on our own research initiatives, but will be closely interfaced with the intensive research now underway by other federal, public and private institutions. Readjustment Counseling The Vietnam-era Veterans Readjustment Counseling Program has seen a number of important developments in recent months. In January, the Veterans Administration vested responsibility for this program in a new independent professional service—the Readjustment Counseling Service—and established that service on the same administrative level as Medical, Surgical, Nursing, Prosthetics, etc. A new program director was appointed by the Administrator of Veterans Affairs on February 10, 1982, following an intensive and thoughtful search and selection process. The±new Director of the Readjustment Counseling Service, psychiatrist, Arthur S. Blank, Jr., M.D., too Vietnam veteran and has been psychiatric consultant to the program since its earliest planning stages in 1979. �19. A^third leadership jnitjative ^was taken on Jun? |f, 198?, when a new position was created, C^hief pf^CpMn^eling Services, andean «*per4t clinician Dr. Raymond M. Scurfield from the Brentwood VA Medical Center was hired for this position. w Underscoring the significance » the^., A^n^jr^is^rator attaches to _the Readjustment / rj Counseling Program Is ;|he establishment |n November 1981 of a high-level Agency wide ' °" < i stee/ing commijtee tp.monitpr the^program, , , j-f ^ Improving the management. and^prganlzatjpn. :of the Vet Center Program has been one of our top priorities. In addition to augmenting our Central Office program management group, we have taken steps to strengthen the offices of pur six Regional Coordinators who oyers.ee. Vet Center operations in tl)eir .respective regions. During the developmental phase of the program, each of these important offices was staffed by a Regional Coordinator and a single secretary. Each Regional Office now has an Assistant Coordinator for Administrative Services, and we are further strengthening the Regional Coordinators' staffs with the appointment of an Assistant Coordinator for Clinical Services and an additionalI secretary. From an organizational standpoint, the most important development of recent months has been the publication of a new program circular, which clarifies lines of authority and responsibility. It contains several key elements: ~a. The responsibilities of the Director and the Readjustment Counseling Service ;.•.:../ ' • . . ' • . • ' • ' • ' • . - : • ' ' , • :•*'•' '"'•.•'• '• ' " .- • .;• •'.••'•'.". •- .-• • ... . •;.'..".••,.«: ."..:.. Staff In Central Office for overall supervision and management of the program are . spelled out. The Director and his staff have direct operational control of the Vet Center system through the Regional Coordinators and, within Central Office, ,„ report to the Deputy ACMD for Professional Services and to the Chief Medical Director through the Associate Deputy Chief Medical Director. �20. b. The responsibilities of the Regional Coordinator's staff are also clarified. We have established clear lines of authority and responsibility from Vet Centers to the . : • ' 'V ;•-• . :,-. ••^vi^'-,-.^.. • Regional Coordinator's staff to the Readjustment Counseling Service in Central Office. The Regional Coordinators are responsible for selection and all supervision , of the Team Leaders, and the program director is responsible for selection and all supervision of the Regional Coordinators. We have also spelled out the relationship (. • • $ * " > " " - ' '•- ^ ' between Vet Centers and their local VA Medical Center parent facilities. The : . •• • . ' • • - ; - . ..." '• -: •':"' •i •;:'. > . "••;]'.•?•'. V •;•'•'. •,'• •' • circular directs that the parent VA medical center is responsible for providing the Vet Center all required support services. On professional matters, the medical center's role with respect to the Vet Center operations is to be consultative and collaborative only. ; ' ' 'TV ' . •: . ' . . . . ' . . • \- ' ; ' ' • • ' '•• , . .. ..'''.- -•'. ' '. :,.' - ;• . . . . . As part of our reconstituting of the management and organization of the readjustment counseling program, we have instituted financial and accounting procedures which track all program funds and maintain their earmarked character at the local level. 1 '• • •• ''• ' * . . ' • ••' ' " • ' • ' , • • ' • ' ' ,• • ' • , i ' ' t * ' ' '• ' • . . ' ':• . * • • ' • " ' .'*• . ' • ' > - ' , ' . ' •' .• : • -. . ' *• . • " . " . . - . " " As you know, Mr. Chairman, we have also established a mechanism to contract with private sector providers to furnish readjustment counseling services to Vietnam-era - ' '. ^ ' . . . • ' ' ' • • -• • ~ • . . . veterans who do not have access to one of our Vet Centers. We are using a decentralized model with a contracting committee at each of 122 medical centers. The contracting committee includes two members of a Vet Center staff in each instance. As of August 31, over 300 contracts had been awarded. We are currently evaluating the quality and effectivenss of this new mode of service delivery. £ " • • ' . _ _ That concludes my statement, Mr. Chairman. I will be pleased to answer any questions you or members of the committee may have. � 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. 031 Folder The folder containing the original item. 0578 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 Custis, Donald L. Title A name given to the resource Typescript: Statement of Donald L. Curtis, M.D., Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, Before the Subcommittee on Oversight and Investigations, Committee on Veterans' Affairs, House of Representatives, Septe Subject The topic of the resource VA Agent Orange Registry health studies AOWG ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/bcc6c17157f0a97a565050a554e38d09.pdf 5eb7456a98e018827f84bdc312ff1a75 PDF Text Text Item ID Number °0589 Author Davis, Miriam Corporate Author Tne Llbrar y of Congress Congressional Research Servic Report/Article TltlO Agent Orange: Veterans' Complaints and Studies of Health Effects, Issue Brief Number IB83043 Journal/Book Title Yeer Month/Day Color March 3 n Number of Images 19 DeSCrlptOU NOtOS Alvin L. Young filed this item under the category "Human Exposure to Phenoxy Herbicides and TCDD" Tuesday, February 20, 2001 Page 589 of 680 ��AGENT ORANGE: VETERANS' COMPLAINTS AND STUDIES OF HEALTH EFFECTS ISSUE BRIEF NUMBER IB83043 AUTHOR: Miriam Davis Environmental Health Fellow Michael Simpson Science Policy Research Division THE LIBRARY OF CONGRESS CONGRESSIONAL RESEARCH SERVICE MAJOR ISSUES SYSTEM DATE ORIGINATED 03/03/83 DATE UPDATED 03/03/83 FOR ADDITIONAL INFORMATION CALL 287-5700 0304 �CRS- 1 IB83043 UPDATE-03/03/83 I ISSUE DEFINITION From 1962 to 1971 the United States Air Force (USAF) sprayed various herbicides (chemicals that kill plants) in South Vietnam. The purpose of the spraying was to defoliate jungle growth and to destroy enemy crops. The most extensively used of these herbicide mixtures was known as Agent Orange, which is an equal mix of two common herbicides called 2,4,5-T and 2,4-D (2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid). A contaminating chemical present in the mixture in small amounts was TCDD (2 , 3 , 7 , 8-tetrachlorodibenzo-para-dioxin) , or simply "dioxin." Dioxin is a contaminant produ-ced in the manufacture of 2,4,5-T. Its toxic effects to some laboratory animals are well known, yet its effects on humans are not fully understood. Since 1977, veterans have attributed a number of illnesses to Agent Orange exposure, including skin conditions, cancer, fatigue, nervousness, numbness in the extremities, vision and hearing impairments, birth defects in children, and other ailments. Veterans have urged the Veterans Administration (VA) to provide for medical treatment of these disorders and many have filed for disability compensation. Under P.L. 97-72, the Veterans' Health Care, Training, and Small Business Loan Act of 1981, Congress directed the VA to furnish medical care to Vietnam veterans, irrespective of age and financial status, for any condition which might possibly have resulted from exposure to Agent Orange. However, disability compensation for the veterans' illnesses has been denied unless it can be shown that the disabling condition began during the period of service. This criterion of "service connection" effectively denies claims for any latent disorder arising from military service. Until a rigorous scientific link between Agent Orange exposure and the health problems of the veterans can be established, the Veterans Administration will probably continue to deny the majority of veterans' requests for disability compensation. The VA and other Federal agencies are sponsoring a variety of research efforts to investigate the connection between Agent Orange and veterans' health problems. Recent congressional interest has focused on the transfer of responsibility from the VA to the Centers for Disease Control for the legislatively mandated epidemiology study of Vietnam veterans' health problems. The following questions continue to surround the debate effects of exposure to Agent Orange: over -- What are the adverse health effects of Agent Orange, and what studies are being conducted to answer this question? -- How much and what kind of scientific evidence is required to prove the right to disability compensation for _the veterans? -- On whom does the burden of proof lie to establish the link between Agent Orange exposure and adverse health effects? the health �CRS- 2 — IB83043 UPDATE-03/03/83' What constitutes fair treatment of the veteran until the scientific studies are concluded? BACKGROUND AND POLICY ANALYSIS History The USAF operated its herbicide spraying program in South Vietnam until the late 1960s when the National Cancer Institute released animal studies which showed that the herbicide 2,4,5-T caused birth defects in mice. At the same time, newspapers in Vietnam began to report health problems, including birth defects, in rural populations which had been exposed to herbicides. As the USAF was winding down its herbicide spraying program, it was also recognized that the military supplies of 2,4,5,-T contained amounts of dioxin suspected of being hazardous. The dioxin, which occurs as'a contaminant in the manufacture of 2,4,5-T, has been found to be highly toxic to animals. In fact, the birth defects previously attributed to 2,4,5-T exposure are now thought possibly to be related to the contaminating dioxins. The average levels of dioxin in the military Agent Orange were about 2 ppm. There were even greater concentrations of dioxin in other military herbicides less frequently used in South Vietnam: approximately 32.8 ppm in Agent Purple, and 65.6 ppm in Agents Pink and Green. In October 1969, the Air Force first restricted the use of Agent Orange to areas remote from populations; then it stopped all airplane spraying of Agent Orange in early 1970'and all helicopter spraying of Agent Orange by 1971. All remaining Agent Orange stocks were gathered and stored at naval facilities in either Gulfport, Mississippi, or Johnston Island in the Pacific until they were incinerated at sea in 1977 during the PACER HO project. The total amount of herbicides sprayed in South Vietnam from January 1962 to February 1971 was about 107 million pounds, according to a USAF report. Approximately 276,000 gallons of Agents Green, Pink, and Purple were sprayed in South Vietnam prior to 1965 when they were replaced by Agent Orange. Approximately 11 million gallons of Agent Orange were then sprayed in South Vietnam -- making it the most widely used herbicide of the war. Ninety percent of Agent Orange was sprayed on 2.9 million acres of inland forests and mangrove forests for defoliation, 8% was sprayed on enemy crops for crop destruction, and the remaining 2% was sprayed around base perimeters, cache sites, waterways, and communication lines. The Department of Defense initially maintained that only a limited number of U.S. military personnel could be positively identified as having been exposed to Agent Orange i'n South Vietnam (i.e., the crews of aircraft that were used to spray herbicides). However, following the publication of a 1979 General Accounting Office (GAO) report documenting ground troop exposure, the DoD has acknowledged that greater numbers of ground troops were exposed to Agent Orange through the USAF spraying program. Most recently, the DoD has attempted to arrive at an exposure index for individual ground troops. The American Medical Association has reported that about -2.4 million Vietnam veterans may have been exposed to herbicides. This figure includes ground troops, 1,200 flight crewmen who were responsible for the spraying under Operation RANCH HAND, and 200 U.S civilians who were involved in destroying the excess quantities of Agent Orange at sea. Details about U.S. personnel exposures are presented in the following section. �CRS- 3 IB83043 UPDATE-03/03/83 V Following reports of various health problems in some 'Vietnam ^veterans widespread concern about the possible health effects of Agent Orange was expressed. Many veterans have filed claims for disability compensation with the VA, basing their claims on Agent Orange effects. In 1979, a group of veterans initiated a class action suit against herbicide manufacturers for negligence and product liability. The manufacturers include Dow Chemical, Monsanto, Hercules, Diamond Shamrock, and Thompson-Hayward. This litigation is still in progress depending, in part, on the outcome of federally sponsored studies of the health effects of Agent Orange. Chemical manufacturers filed a third-party suit in 1980 against the U.S. Government that was later dismissed by a New York Federal District Court. Personnel Exposed to Herbicides. The early trials that were conducted in South Vietnam to improve aircraft spray systems were performed by the USAF Special Aerial Spray Flight Division at Langley Air Force Base, Virginia. During late 1962 and early 1963, the Crops Division at Fort" Detrick and the USAF Armament Laboratory at Eglin Air Force Base, Florida, were also involved in efforts to improve spray system components in support of Operation RANCH HAND. Most of the personnel involved in the actual handling of herbicide drums were Vietnamese. However, a USAF flight mechanic or crew chief was responsible for ensuring that each aircraft was properly loaded and that the spray systems were functional. Each herbicide aircrew consisted of a pilot and copilot, a flight mechanic, and a spray unit. The aircrews were frequently joined by South Vietnamese and U.S. observers. As noted in a USAF report: "within the aircraft, it was not uncommon to have herbicide leakage from around the numerous hose connections joining the spray tank and pumps with the wing and aft spray booms. In hot weather, the odor of herbicide within the aircraft was decidedly noticeable" (Young et ai., 1978: 1-18). It .is also suspected that, due to destruction of the tanks by enemy fire, crew members were acutely exposed to herbicides. In an effort to determine which ground units were'exposed to Agent Orange after it had been deposited on the ground, the Army Agent Orange Task Force and the American Cancer Society are attempting independently to correlate ground unit location with the location of aerial spraying missions. The USAF has data on 6,542 herbicide spraying missions that took place between August 1965 and February 1971 on its HERBS computer tape. These data were compiled on a mission-by-mission basis from reports and files in various offices in the U.S. and South Vietnam. After evaluating the HERBS data in a 1974 report, the National Academy of Sciences (NAS) concluded that the data accounted for approximately 86% of all herbicide operations in South Vietnam, and that "despite certain recognized deficiencies," the HERBS tape is "areliable source for an assessment of the major part of the herbicide operation in South Vietnam" and "is the best and in fact the only available comprehensive computation of the major part of the herbicide operations conducted in the Vietnam war." Since this NAS evaluation, the Army Agent Orange Task Force has been in the process of expanding the scope of the HERBS data to incorporate other herbicide sprays -- including perimeter base spraying and any unplanned dumping of herbicides from U.S. aircraft' that were under enemy attack. Despite this relative confidence in the location of the aerial and some ground spraying missions, it is difficult to determine which particular ground troops in. a given location were actually exposed and to what extent they were exposed. Although aerial spraying apparatus was' designed to �CRS- 4 IB83043 UPDATE-03/03/83 deliver the herbicide in a specified manner to reduce dispersion, no such standardized equipment was used for perimeter base spraying or other non-aerial delivery modes. Furthermore, additional troops may have been exposed in areas for which military records are incomplete. For example, not all information is available on helicopter operations flown by the Vietnamese Air Force before 1968. Thus, attempts to model the conditions of exposure in order to determine individual or group exposure levels are jeopardized by the lack of verifiable exposure information. When the DoD suspended all use of Agent Orange in South Vietnam, the USAF was 'left with an inventory of 2.22 million gallons in two locations, in Vietnam and in Gulfport, Mississippi. In April 1972, the stocks in South Vietnam were transported to Johnston Island in the Pacific for storage. Problems began to arise in both U.S and Pacific locations concerning leakage from the drums. After exploring a number of options, the USAF decided to dispose of the Agent Orange by burning it at high temperatures at sea. This operation was performed in 1977 with permission from the EP'A. About 110 USAF personnel from the Air Force Logistics command and about 100 civilian employees hired by a contractor were involved in the destruction process. Environmental monitoring of the transfer operations was performed by members of the USAF Occupational and Environmental Health Laboratory. Extensive environmental monitoring of the test incineration procedures was performed. Certain physical parameters of the actual incineration process were monitored. Physical' examinations of personnel involved in the actual incineration procedures, administered both before and after these procedures, revealed no adverse health effects. Health Effects of Dioxin and Phenoxyherbicides There are as yet no conclusive scientific studies on the long-term human health effects of Agent Orange exposure. In their absence, an understanding of health effects must rely on animal and/or human occupational exposure studies of dioxin and phenoxyherbicides. The following paragraph summarizes what is known about the health effects of these constituents of Agent Orange. Workers exposed to high concentrations of dioxin and/or 2,4,5-T (as well as other chemicals) are commonly found to have a painful skin condition known as chloracne. Chloracne can appear weeks to months after initial exposure and in some cases persists up to many years after exposure. Chloracne, however, can result from exposure to other chlorinated compounds besides 2,4,5-T. Studies of exposed workers have indicated a variety of other health problems; yet, there is not enough information at this time to establish a cause and effect relationship between phenoxyherbicides and these disorders. Soft-tissue sarcoma, a form of 'cance.r/ has been reported among Swedish workers who were exposed to phenoxyherbicides. Reports from a variety of sources associate dioxin and herbicide exposure with stomach cancer, neuromuscular weakness, liver enlargement, and liver enzyme abnormalities. Birth defects were first reported in South Vietnamese refugees living in North Vietnam, but, due to the difficulty of conducting studies in a war-torn country, the research on these reports was widely believed to be improperly executed. In animal studies, only certain strains of pregnant mice exposed to dioxin show fetotoxicity and birth defects in offspring. Exposed male mice do not have deformed offspring. Current Use. The EPA has registered 2,4-D for widespread domestic use on such crops as corn, grain, and sugar cane, as well as on non-crop areas; 2,4,5-T is currently used on rangelands, rice fields, and industrial vegetation sites, whereas approval for its other domestic uses -- forests, �CRS- 5 IB83043 UPDATE-03/03/83 rights-of-way, pastures' -- was suspended by the EPA in 1978. registered use of '2,4,5-T depends on negotiations that began in 1979 Dow Chemical and the EPA. Future between Herbicides 2,4,5-T and 2,4-D are commercially available either alone or in combination. The combination mixture (under Dow's Trademark, Esteron) differs from Agent Orange primarily in the level of dioxin. Existing Dow inventories of 2,4,5-T contain less than 0.1 parts per million (ppm) dioxin, whereas previous formulations of 2,4,5-T used in Agent Orange contained about 2 ppm dioxin. Although standards for dioxin levels in 2,4,5-T have not been officially set by the EPA, the EPA's Science Advisory Committee recommended in 1971 a level of 0.1 ppm. Veterans' Complaints and Veterans Administration Efforts Veterans who believe they have been exposed to Agent Orange have complained of a variety of illnesses for which they seek 'medical treatment and disability compensation. These illnesses include: skin conditions, cancers, nervousness, numbness in extremities, vision and/or hearing impairments, birth defects in their offspring, and reduced libido. Veterans have also complained about the paucity of scientific information available on the health effects of Agent Orange and about the sluggishness with which the VA has responded to their concerns. Specifically, the General Accounting Office (GAO) has recently reported that over half of the veterans responding to their questionnaire were dissatisfied with the amount of information they had received from the VA about Agent Orange. To fill the perceived information gap, various State 'governments, including New York and New Jersey, have attempted to disseminate information on Agent Orange to State veterans. < The VA maintains that it outset by initiating health exposed and by implementing description of the research has responded to veterans' concerns from the programs to identify veterans who may have been research projects on health effects. A detailed projects is provided later in this brief. Since 1978 the VA has provided a physical examination for Vietnam veterans who thought they were exposed to Agent Orange. The VA maintains a registry of all the veterans who have come to VA hospitals and health care facilities for the exam. The registry also contains information collected during the examination. As of Dec. 1, 1982, 101,721 veterans had received the initial exam, and about 80% of the records had been coded into the computer. The idea behind the registry is to determine whether veterans have a higher incidence of particular diseases. GAO auditors have investigated the effectiveness of the v Agent Orange examination program. The findings are summarized in an October 1982 report, "The V A ' s Agent Orange Examination Program: Actions Needed To More Effectively Address Veterans' Health Concerns." The report is 'critical of the exam for being incomplete, poorly designed, and for being administered by physicians who were not familiar with the reported health effects of Agent Orange. In an appendix to the report, the VA challenges these findings by citing improvements that 'have taken place since the evaluation; however, the GAO disagrees with the VA rebuttal in the same appendix. The GAO report is also critical of the registry because it cannot be used to determine the incidence of specific illnesses among veterans -- a major purpose for which the registry was supposedly designed. Medical Treatment: P.L. 97-72. Before the enactment of P.L. 97-72 in �CRS- 6 IB83043 UPDATE-03/03./83 1981, 'veterans who complained of Agent Orange-related illnesses were in a ranking of the lowest priority for medical treatment at VA hospitals. This is because these illnesses were defined as not being "service-connected." To have qualified at all for this treatment at this low-priority level, the veteran had to be destitute. The "Veterans' Health Care, Training, and Small Business Loan Act of 1981" (P.L. 97-72) elevated Vietnam veterans' priority status for treatment at VA hospitals for any Agent Orange-related problem. Veterans who complain of such problems are now considered for treatment irrespective of age or finances with the same priority status as former prisoners of war and ahead of veterans with "non-service connected" conditions. The Vietnam veterans' contention of exposure is acceptable in the absence of evidence to the contrary. It is the duty of a '"responsible staff physician (to) make a determination as to whether the condition resulted from a cause other than the specified exposure." To aid the staff physician, the VA has developed guidelines which identify conditions that are not considered to be related to Agent Orange exposure (Federal Register, Nov. 17, 1982). The VA contends that P.L. 97-72 is being implemented successfully, yet veterans' advocates and State Agent Orange commissions allege that veterans are uninformed about the new legislation and that treatment is still difficult to obtain at certain VA medical centers. The VA has initiated a new system to monitor the impact of P.L. 97-72 on Vietnam veterans' medical treatment. P.L. 97-72 also extended the readjustment counseling program for Vietnam veterans for another three years. The counseling programs are currently located in "Vet Centers," which are distinct from VA medical facilities. Disability Compensation. As of Jan. 3, 1983, veterans had filed 16,102 disability claims with the VA for disorders they attribute to Agent Orange exposure. The vast majority of these claims have been denied because they are not considered as being "service connected." The policy of the VA is that a disability is considered "service-connected" if it arises during or is aggravated by military service. "Service-connection" establishes temporal correspondence with military service, not causation, as the determinant for disability payments. Chronic conditions arising before discharge or within one year after discharge are presumed to be "service-connected." The policy implies that for a veteran to receive disability payments for ailments possibly related to Agent Orange exposure, it must be proved that the condition first appeared during the service or within a year of discharge. This precludes disability for latent disorders because "service-connection" criteria cannot be met. The VA acknowledges that the skin disorder, chloracne, is causally related to Agent Orange exposure. On Apr. 15, 1980, in a statement before the House Veterans.1 Affairs Subcommittee on Medical Facilities and Benefits, former VA administrator Max Cleland said that "the relationship between accidental human exposure to Agent Orange constituents and the development of long-term illnesses other than chloracne remains speculative at present." Even though the VA does view chloracne as an immediate effect (acute effect) of Agent Orange exposure, the basis for awarding disability stems from the occurrence of chloracne during the service. Temporal coincidence with active duty is the major criterion, irrespective of cause, for chloracne or any other veteran complaint. The total of 1237 (15.3%) claims which were granted were awarded primarily for skin conditions (94%) and for cancer, psychiatric, and neurological conditions (6%), among others. �CRS- 7 IB83043 UPDATE-03/03/83 The VA denied 6,824 claims after there was a confirmed diagnosis of the disease for which the veteran had filed a claim. The denied claims fall into the following categories: 4091 for various skin conditions; 2432 for nervousness and headache, or fatigue; 907 for paralysis or numbness; 791 for gastrointestinal or genito-urinary conditions; 487 for malignancies which include leukemia, lymphoma, melanoma, and Hodgkin's disease; 359 for impaired sexual activity; 463 for eye, ear, nose, a-nd throat pathology; 289 for lung conditions; 247 for cardiovascular conditions, and 146 claims denied for miscellaneous conditions. (Since each claim could fall into a variety of different categories, the category figures do not equal 6,824.) The VA policy is that the resolution of disability claims for conditions that are now defined as "non-service connected" (and therefore denied) will depend on the results of scientific studies which are described below. Since it is expected that these studies will take years to complete, the Chief Medical Director of the VA, Dr. Donald Custis, has testified at a hearing of the House Veterans Affairs Subcommittee on Investigations and Oversight on Sept. 15, 1982, that "It may well be that the Congress cannot wait for scientific answers in the short term, in which case it may well be that the sociopolitical aspect of this problem will have to be addressed." Current...._or. Proposed Studies of ^Health Effects Many branches of the Federal Government are conducting research on the health effects of Agent Orange and phenoxyherbicides. Research efforts range from large-scale epidemiology studies of Vietnam veterans to studies of cancer among Kansas residents exposed to herbicides. The following paragraphs provide an overview of research efforts at the Department of Defense, the Veterans Administration, and the Department of Health and Human Services. The impact of the following studies on VA disability policy is not clear; the VA has not established any formal criteria for how their policies might be altered by scientific findings. Due to the recent transfer of the legislatively mandated epidemiology study of Vietnam veterans and to the interest which this study has generated all along, it will be discussed first. E p i de m i o 1 o g y Study. The large epidemiology study of Vietnam veterans exposed to Agent Orange, mandated by P.L. 96-151 in December 1981, has been the focus of much of the debate over the health effects of Agent Orange. P.L. 96-151 directed the VA to perform the study of long-term health effects among veterans using' a protocol that was subject to approval by the congressional Office of Technology Assessment (OTA); in addition, the OTA director was given the task of monitoring the progress of the study. The protocol was reviewed by the OTA, the VA advisory group on the health-related effects of herbicides, the science panel of the Agent Orange Working Group, and the National Academy of Sciences. P.L. 97-72 allowed for future expansion of the scope of the study. The implementation of the study was delayed until October 1982, at which time the responsibility for conducting the study was transferred from the VA to the Centers for Disease Control (CDC). The transfer was accomplished following letters to the VA from the Veterans Affairs Committees of the House and the Senate. The letters expressed concern over the lack of progress on the study and concern over the VA's credibility with the veterans; consequently, the VA was urged to relinquish the. study to an independent research body. While the VA acceded to this request, former VA Administrator �CRS- 8 Nimmo'attributed the delay of the protocol review process. study IB83043 to legal UPDATE-03/03/83 challenges and to the On Jan. 18, 1983, the CDC formally accepted responsibility for the study in a written agreement with the VA. Under the agreement, the VA is to provide the CDC with $3 million to fund the study, yet the CDC is assured of autonomy in its design and implementation. The project will actually consist of two studies, one on the health effects of Agent Orange and the other on the health effects of the Vietnam experience. The study' designs are expected to be ready for OTA review in April 1983. Preliminary reports suggest that the veterans under study will be divided into three groups (cohorts) — one group made up of those who were likely to have been exposed to Agent Orange, another group constituting those who were unlikely to have been exposed, and a final group of veterans who did not serve in Vietnam and who were not likely to have been exposed. The DoD'is assisting the CDC in establishing criteria for assigning an individual veteran to a particular group. The selection process will depend on the use of DoD records ' of ground troop movements relative to herbicide spraying. Completion of the study is expected by the end of 1987. Department of Defense. The Air Force is conducting "The Ranch Hand Study," an epidemiological study of personnel exposed to herbicides during the Air Force's aerial spraying program in Vietnam (Operation Ranch Hand). These personnel were members of flight crews involved in the handling and/or spraying of herbicides, and they were presumed to have been heavily exposed. This study population of 1,260 personnel is being compared to a control population consisting of unexposed flight crew members. The purpose of the study is to determine whether Ranch Hand flight crews suffered adverse health effects compared to the control population. The study consists of three parts: a mortality study; a morbidity (disease) study which includes birth defects in offspring; and a follow-up period of physical examinations at specific intervals (up to 20 years) from the onset of the study. Information for the morbidity and follow-up portions is collected by questionnaires administered in the homes of the participants and by extensive physical and psychological tests. These data are collected by the independent contractors Louis Harris and Associates and Kelsey-Seybold Clinic, respectively. Before data collection began in 1980, the entire study protocol had been reviewed by the University of Texas School of Public Health, the U.S Air Force 'Science Advisory Board, the Armed Forces Epidemiological Board and the National Academy of Sciences. The initial phases of mortality and morbidity data collection were completed in December 1982. For the morbidity study, participation in the questionnaire and physical examination has been very high (greater than 95%) and an interim report is expected by the summer of 1983. The findings of the mortality study (due to be released early in 1983) suggest that there are no differences in the number of deaths between the Ranch Handers and controls. Periodic reassessment of the mortality findings are planned throughout the 20-year study by the Air Force School of Aerospace Medicine. While the Ranch Hand Study is expected to provide some valuable information about the population of herbicide sprayers, the applicability of the Ranch Hand Study to the experience of ground troops has been questioned. For example, the herbicide exposure conditions are thought to differ between the two groups. The Ranch Handers were heavily exposed at sporadic intervals (repeated acute exposures) and the exposure was through the skin, through inhalation, and through ingestion. After the missions, the flight crews were �CRS- 9 IB83043 UPDATE-03/03/83 required to shower. While the extent and mode of ground troop exposure are less certain, it is likely that the mode of ground troop exposure was primarily due to skin contact and to inhalation. The duration of ground troop exposure was likely to be for longer periods due to operational movements through contaminated areas. Thus, because the exposure conditions of Ranch Hand personnel did not mimic those of ground troops, the general relevance of the Ranch Hand study is not certain. One of the criticisms raised by the National Academy of Sciences in their May 1980 review of the Ranch Hand protocol was that adverse health effects were not likely to be found because the sample size was too small and the follow-up period was too short. In response, the Air Force did extend the follow-up period to 20 years; nevertheless, the problem of sample size makes it unlikely that the study will detect certain cancers that are relatively rare. The impact of Agent Orange exposure on the incidence of these rare cancers (e.g., soft-tissue sarcoma and non-Hodgkin's lymphoma), may be most appropriately determined by the case control sutdies in New York State and at.the National Cancer Institute. V e t e r ans Adm i n i s t rat ion. The Veterans Administration intends to spend $6.7 million of the total 1983 medical research budget of $163 million for projects on the health effects of herbicide exposure and, more generally, the health effects of combat duty in Vietnam. The majority of these research dollars ($4.2 million) is destined for the epidemiology study of Vietnam veterans, a mortality study, and an identical twin sibling study. Due to congressional pressure, responsibility for the conduct of the epidemiology study has been transferred from the VA to the CDC. Funding for the epidemiology study, however, will continue to be provided by the VA. Both the mortality and the twin study address the impact of the Vietnam experience rather than Agent Orange in particular. The purpose of the mortality study is to examine the cause-of-death and the death rate in Vietnam veterans by comparison to veterans who did not serve in Vietnam. The idea is to determine whether military service in Vietnam has resulted in different death profiles since the end 'of the war. Computer records will provide the information, and this information will be collected and coded by contractors for the VA. The project is expected to be finished by 1985. The Identical Twin Study, -also sponsored by the VA, is designed to determine whether the current psychological and physical health of Vietnam veterans has been adversely affected by their service. In this study, a group of VA researchers in St. Louis is attempting to study 450 pairs of identical twins; one twin served in Vietnam during the period of herbicide exposure, whereas the other twin was not stationed in Southeast Asia. Initial findings of this study are expected by October 1984. The VA has also established the Chloracne r Task Force to identify veterans with skin conditions and then to see if . there are bona fide cases of Chloracne within this group. Thus far, a dermatologist who is serving as a consultant at the Washington VA office has found 12 tentative cases of Chloracne which require further investigation. Another VA research activity is a study of dioxin in the fat tissues of veterans. In conjunction with the EPA, the VA intends to find out whether Vietnam veterans have higher levels of dioxin in their fatty tissues than non-Vietnam veterans. Background levels of dioxin in the U.S. male population are also to be analyzed. To detect dioxin concentrations in the fat, tissue is removed surgically from the abdomen and the sample .is analyzed on gas chromatography/high resolution mass spectrometry instruments. �CRS-10 IB83043 UPDATE-03/03./83 l Department of Health and_ Human Services: Centers for Disease C o n tr o1/B irth Def e_c t Stu dy. An ambitious epidemiology study is underway in Atlanta to find out if Vietnam veterans show an increased risk of having children with birth defects. Using the case-control method, CDC researchers are interviewing 7000 parents of children with birth-defects and 3000 parents whose children are normal. The interview process is used to establish the military history of the parents. This information will be analyzed to determine wheth'er parents who served in Vietnam are at greater risk of producing children with birth defects. Already one-half of the interviews has taken place, with initial findings expected by September 1983. Sponsors of the study are DHHS, VA, and DoD. DHHS: National Cancer^ I n s t i t u t e / Can c e r Study. Epidemiologists are investigating a Kansas population for the relationship between herbicide exposure and various cancers. The research question is: do such cancers as soft tissue sarcoma and various lymphomas result from herbicide exposure? Kansas residents are considered a good population for studying herbicide exposure because in this wheat-growing State herbicides are used much more often than insecticides. In other States, herbicides are frequently used in combination with insecticides, which are also implicated in producing cancer. Insecticide exposure would confound the results of such a cancer study. Preliminary results of this study are anticipated by the'fall of 1983. DHHS; National Institute of^Occupational Safety and Health/Dioxin Worker Registry. NIOSH is compiling a ' registry of workers involved in the manufacture "of 2,4,5-T and related compounds because these compounds contain dioxin as a contaminant. Worker exposure records on 3000-5000 individuals, compiled from all 12 U.S. sites of production, will go back to the 1940s. T'he purpose of the registry is to establish whether the mortality rates are higher in this,population of exposed workers than in a comparable group in the U.S.population. The protocol has been reviewed by an independent university-affiliated group of scientists, and the analysis of the findings is due by 1985. Role of State Commissions or Advisory Groups Several States have established their own agencies in response to veterans' complaints of Federal inactivity on the Agent Orange question. Although these organizations vary in structure, their functions are essentially similar: to identify State Vietnam veterans and to provide and coordinate various social services for these veterans. For example, various State commissions disseminate information on Agent Orange and assist in scheduling Agent Orange examinations at VA medical centers. Those States which have commissions or programs on Agent Orange are as follows: California, Connecticut, Georgia, Hawaii, Illinois, Kansas, Maine, Massachusetts, Minnesota, New Jersey, New York, Oklahoma, Ohio, Pennsylvania, Texas and West Virginia. (Wisconsin's program has been discontinued.) Some .of these States are funding their own research programs aimed at answering questions on the health effects of Agent Orange. In the "spring of 1983, New York is due to release findings of a study on the incidence of soft-tissue sarcoma among State veterans relative to other State inhabitants. Soft-tissue sarcoma has been implicated as a possible long-term health effect of herbicide exposure. New York State has also undertaken a mortality study to see if death rates are higher among Vietnam veterans than other State residents of the same age group. �' I CRS-11 IB83043 UPDATE-03/03/83 The New Jersey State Commission on Agent Orange has a variety of pro-jects underway. One task has been to assemble information on a bacterial infection called Melioidosis, which may have afflicted veterans who were exposed to the bacterium while in Vietnam. The Commission is beginning a project to determine whether blood tests can be reliably used to measure dioxin levels. Blood tests would obviate the need for more expensive and painful surgical procedures now performed for this purpose. In addition, the New Jersey Commission on Agent Orange distributes pamphlets on how to fill out VA disability claims forms. The role of the State commissions is growing to include advocacy for State veterans. State representatives have testified at congressional hearings and at the VA advisory committee meetings to bring attention to veterans' complaints. At the Nov. 30, 1982, meeting of the VA advisory committee on the health-related effects of herbicides, the spokesperson for State agencies endorsed legislation that would establish the presumption of a "service-connection" for chloracne and soft tissue sarcoma "so that veterans' disability claims for these disorders would be awarded. Because of the lack of State funds, some of the State commissions are no longer active and others are i.n jeopardy. State commissions have requested Federal funds on the grounds that they assist in the administration of VA programs such as the scheduling of Agent Orange examinations and informing State veterans about Agent Orange exposure. Previous Congressional Ac^tipn As previously discussed, two major pieces of legislation have been enacted in the 96th and 97th Congresses- to provide for Vietnam veterans' medical care and to mandate studies of the health effects of Agent Orange: P.L. 96-151, The Veterans' Health Programs Extension and Improvement Act of 1979; and P.L. 97-72, Veterans' Health Care, Training and Small Business Loan Act of 1981. The 'legislative proposals of the 96th and 97th Congresses were generally directed to the status of disability claims that are now denied by the VA because they are not considered as "service-connected." In Representative Daschle's proposed 97th Congress bills, H.R. 7146 and H.R. 7110, the presumption of service connection would have been legislatively established N for soft-tissue sarcoma and chloracne, respectively. The presumption of service connection would have permitted veterans with these disorders to collect disability payments because the conditions were presumed to have arisen during the service. Two other 97th Congress bills, H.R. 523 (Rep. Roe) and H.R. 2297 (Rep. Downey), were designed to provide a presumption of service connection for all chronic conditions specifically related to Agent Orange exposure which appear later than one year, after discharge. Existing law requires that disabling conditions only appearing before discharge or within one year after discharge are presumed to have arisen during the service. Finally, a number of bills were introduced to transfer the conduct of the epidemiology study from the VA to the Department of Health and Human Services. This was accomplished -- although non-legislatively -- with the transfer of responsibility to the Centers for Disease Control in the DHHS. LEGISLATION H.R. 209 (Long) Requires the Secretary of Health and Human Services to arrange for an �CRS-12 IB83043 UPDATE-03/03/83 independent epidemiological study of persons exposed to the chemical dioxin, used in the h.erbicide known as Agent Orange. Introduced Jan. 3, 1983; referred to Committee on Energy and Commerce. H.R. 212 (Long) Amends Title 38, United States Code, to waive the one-year limitation on claims for compensation "frojn the Veterans Administration for disabilities and diseases incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxyherbicide known as Agent Orange or other phenoxy herbicides. Introduced Jan.3, 1983; referred to Committee on Veterans Affairs. H.R. 331 (Roe) Amends Title 38, United States Code, to waive the one-year limitation on claims for compensation from the Veterans Administration for disabilities and diseases incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxy herbicide known as "Agent Orange" or other phenoxy herbicides. Introduced Jan. 3, 1983; referred to Committee of Veterans Affairs. H.R. 462 (Applegate) Amends Title 38, United States Code, to waive the one-year limitation on claims for compensation from the Veterans Administration for disabilities and diseases incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxyherbicide known as Agent Orange, or other phenoxy herbicides. Introduced Jan. 6, 1983; referred to Committee on Veterans Affairs. H.R. 509 (Hammerschmidt) Amends Title 38 of the United States Code to provide that progressive muscular atrophy or amyotrophic lateral sclerosis developing a 10 per centum or more degree of disability within seven years after separation from active service during a period of war shall be presumed to be service connected. Introduced Jan. 6, 1983; referred to Committee on Veterans' Affairs. H.R. 1135 (Downey) Amends Title 38, United States Code, to waive the one-year limitation on claims for compensation from the Veterans Administration for disabilities and diseases incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxy herbicide known as Agent Orange, or other phenoxy herbicides. Introduced Feb. 1, 1983; referred to Committee on Veterans Affairs. H.R. 1382 (Downey) Provides that any award by the Veterans' Administration of compensation for a disease or disability in a veteran resulting from exposure to Agent Orange shall be retroactive to the date the veteran first applied to the Veterans' Administration for compensation for such disease or disability. I n t r o d u c e d _ F e b . 10, 1983; referred to Committee on Veterans' Affairs. �CRS-13 IB83043 UPDATE-03/03/83 '*. i S. 374 (Specter) A m e n d s Title 38, United States Code, to provide a presumption of service connection for the occurrence of certain diseases in veterans who were exposed to phenoxy herbicides while serving in the Armed Services in Southeast Asia during the Vietnam era. Introduced Feb. 2, 1983; referred to Committee on Veterans Affairs. HEARINGS U.S. Congress. House. Committee on Interstate and Foreign Commerce. Subcommittee on Oversight and Investigations. Agent Orange: exposure of Vietnam veterans. Hearing, 96th Congress, 2d session. Sept. 25, 1980. 249 p. Involuntary exposure to Agent Orange and other toxic spraying. Hearings, 96th Congress, 1st session. June 26 and 27, 1979. 256 p. U.S. Congress. House. Committee on veterans' Affairs. Ad Hoc Subcommittee on Hospitals and Health Care. Legislation to improve medical programs administered by the Veterans Administration (H.R. 2157, H.R. 2953, and H.R. 2999). Hearing, 97th Congress, 1st session. Apr. 28, 1981. 54 p. U.S. Congress. House. Committee on Veterans' Affairs. Subcommittee on Medical Facilities and Benefits. Herbicide "Agent Orange." Hearing, 95th Congress, 2d session. Oct. 11, 1978. 62 p. Oversight hearing to receive testimony on Agent Orange. Hearing, 96th Congress, 2d session. Feb. 25, 1980. 121 p. ._ _, oversight hearing to receive testimony on Agent Orange. Hearing, 96th Congress, 2d session. July 22, 1980. 459 p. Scientific community report on Agent Orange. Hearing, 96th Congress, 2d session. Sept. 16, 1980. 145 p. U.S. Congress. House. Committee on Veterans' Affairs. Subcommittee on Oversight and Investigations. Current status of Agent Orange studies. Hearing, 97th Congress, 1st session. May 6, 1981. 385 p. Federal Agent Orange activities and the vet center program. Hearing, 97th Congress, 2d session. Sept. 15, 1982. 164 p. U.S. Congress. Senate. Committee on Veterans' Affairs. Agent Orange update and appendix: Agent Orange activities (part II) . Hearing, 96th Congress, 2d session. Sept. 10, 1980. 1368 p. Oversight on issues related to Agent Orange and other herbicides. Hearing, 97th Congress, 1st session. Nov. 18, 1981. 500 p. �CRS-14 IB83043 UPDATE-03/03,/83 VA health resources and program extensions and appendix: Agent Orange activities. Hearing, 96th Congress, 1st session, on S. 741 and S. 196. Apr. 10, 1979. 462 p. Veterans' Programs Extension and Improvement Act of 1981. Hearing, 97th 'Congress, 1st session, on S. 26 (titles II and III, only), S. 380, S. 458, S. 636, S. 689, S. 872, S. 914, S. 921, and related bills. Apr. 30, 1981. 685 p. Vietnam veterans' readjustment. Hearings, 96th Congress, 2d session. - F e b . 21, Mar. 4, and May 21, 1980. Part 2. 595-2082 p. i ADDITIONAL REFERENCE SOURCES American Medical Association. Council on Scientific Affairs. Health effects of "Agent Orange" and dioxin contaminants. 1981. 37 p. Boffey, Philip. Agent Orange: Despite spate of studies, slim hope for answers. New York Times, 1982. 24 p. Cookson, Clive. "Emergency" ban on 2,4,5-T herbicide in U.S. Nature, v. 278, Mar. 8, 1979: 108-110. Galston, Arthur W. Herbicides: V. 29, Feb. 1979: 85-90. a mixed blessing. Bioscience, International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: 2,5,5-T, v. 15, Aug. 1977. JRB Associates. Review of literature on herbicides, including phenoxy herbicides and associated dioxins. Washington, Veterans Administration, 1981. 2v. National Research Council. The effects 1 of herbivcides in South Vietnam: Part A. Summary and conclusions. Washington, National Academy of Sciences, 1974. AD-774-749. 398 p. National Research Council. The effects of exposure to Agent Orange on ground troops in.Vietnam. Washington, National Academy of Sciences, 1982. 24 p. New Jersey State Commission on Agent Orange. 1982. 54 p. Legislative Report. Reggiani, G. Toxicology of TCDD: short review of its formation, occurrence, toxicology and kinetics, discussing human health effects, safety measures and disposal. Regulatory Toxicology and Pharmacology, v. 1, 1981: 211-243. Rosenblatt, Jean. Compensating victims of toxic substances. Editorial Research Reports. v. 11, Oct. 1982: 759-772. Tung, T.T., T.K. Anh, B.Q. Tuyen, D.X. Tra, and N.X. Hugen (1971). Clinical effects of massive and continuous utilization of �'V* 1 CRS-15 -* ». U.S. IB83043 . defoliants on civilians. . . . Vietnamese Studies, 29: . UPDATE-03/03/83 . 53-81. General Accounting Office. U.S. ground troops in South Vietnam were in areas sprayed with herbicide orange. Nov. 16, 1979. FPCD-80-23. VA's Agent Orange examination program: auctions needed to more effectively address veterans' health concerns. Oct. 25, 1981. HRD-83-6. Young, Alvin et al. The toxicology, environmental fate and human risk of herbicide orange and its associated dioxin. The Surgeon General, U.S. Air Force, Washington, D.C. Oct. 1978. �APPENDIX A LISTING OF FEDERAL ORGANIZATIONS ON AGENT ORANGE January, 1983 I. Cabinet Council on Human Resources Agent Orange Working Group (AOWG) Chairman: James Stockdale (HHS) Alternate: Bart Kull Members: HHS, VA, DoD, Dept. Agriculture, Dept. Labor, EPA, ACTION Agency, OMB, OSTP, Council of Economic Advisors, Dept. State (OTA- Observer Status) Activities: Moniter and coordinate Federal Research activities on health effects of Agent Orange. Science Panel: Dr. Vernon Houk (CDC) II. Veterans Administration Advisory Committee on Health Related Effects of Herbicides Chairman: Dr. Barclay Shephard (VA) Members: VA, Veterans Groups, FDA, CDC, EPA, Army Medical Corps, Dept. Agriculture, NIH, private universiites Activities: Advise Administrator of VA on health effects of Agent Orange Agent Orange Projects Office Acting Director: Dr. Barclay Shephard (VA) Members: In-house administrative and research staff, Dept. of Medicine and Surgery, VA Activities: Coordinate and moniter epidemiology projects at VA on Agent Orange and related research effortsAgent Orange Policy Coordinating Committee Chairman: Everett Alvarez, Jr. (VA) Members: In-house staff involved in medical information and medical claims. Activities: Review VA policy to make recommendations on Agent Orange issues to the administrator of the VA. III. Department of Defense Army Agent Orange Task Force (AAOTF) Chief: Richard Christian (Army) Members: Army, Navy, Air Force, Marines, and civilian staff Activities: Provide VA with information from military records for the research projects on Agent Orange. � 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. 032 Folder The folder containing the original item. 0589 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 Davis, Miriam Michael Simpson Description An account of the resource <strong>Corporate Author: </strong>The Library of Congress Congressional Research Service, Major Issues System Date A point or period of time associated with an event in the lifecycle of the resource March 3 1983 Title A name given to the resource Agent Orange: Veterans' Complaints and Studies of Health Effects, Issue Brief Number IB83043 Subject The topic of the resource VA health studies legislation 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. 032 Folder The folder containing the original item. 0592 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 DeHart, Roy Source A related resource from which the described resource is derived Aviation, Space, and Environmental Medicine Date A point or period of time associated with an event in the lifecycle of the resource 1982-05-01 Title A name given to the resource Guest Editorial: Herbicide Orange Health Effects Subject The topic of the resource Ranch Hand health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 033 Folder The folder containing the original item. 0645 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 Ferry, D. G. L. R. Gazeley I. R. Edwards Source A related resource from which the described resource is derived Proceedings of the University of Otago Medical School Date A point or period of time associated with an event in the lifecycle of the resource 1982 Title A name given to the resource 2,4,5 - T Absorption in Chemical Applicators Subject The topic of the resource dioxin herbicide properties health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 086 Folder The folder containing the original item. 2155 Series The series number of the original item. Series IV 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 Finch, James A., Jr. Description An account of the resource <strong>Corporate Author: </strong>Missouri Dioxin Task Force Date A point or period of time associated with an event in the lifecycle of the resource October 31 1983 Title A name given to the resource Final Report of the Missouri Dioxin Task Force including Appendices Subject The topic of the resource herbicide damage assessment health studies decontamination clean-up standards https://www.nal.usda.gov/exhibits/speccoll/files/original/c2c00f58fb4fdfa7f0fc2780aaf14d95.pdf d35a4b78d3f7300ed12152d0000b90e0 PDF Text Text Item e Number 02233 Author Fitzgerald, Edward F. Corporate Author Report/Article Titto Typescript: Summary of Binghamton State Office Building Medical Surveillance Program: Design and Implementation, [nd] Journal/Book Title Year Month/Day Color Number of Images D 5 Descrlpton Notes Thursday, September 20, 2001 Page 2288 of 2293 �SUMMARY OF BINGHAMTON STATE O F F I C E B U I L D I N G MEDICAL SURVEILLANCE PROGRAM: DESIGN AND IMPLEMENTATION Prepared by Edward F. Fitzgerald, PhD, and Susan" J. Standfast, MD, New York State Department of Health Protocol A plan was established in June, 1981, to help assess the health consequences of the Binghamton State Office B u i l d i n g (BSOB) fire, which occurred on February 5, 1981. It was proposed to extend and follow-up p r e l i m i n a r y efforts conducted by the Broome County Health Department soon after the fire. The New York State Department of Health administers the BSOB Medical Surveillance Program and implements the protocol. The supervision and d i r e c t i o n of the program, howevsr, is the r e s p o n s i b i l i t y of the National I n s t i t u t e of Occupational Safety and Health (NIOSH). The plan e n t a i l s a multi-stage process contigent upon an i n d i v i d u a l ' s probable level of exposure. Anyone who entered the BSOB on or after the date of the fire was requested to have a series of laboratory tests performed. Physical examinations and interval medical histories were a d d i t i o n a l l y conducted on those persons who remained in the BSOB for at least 25 hours. Laboratory tests were, al so offered as a p u b l i c service to those not in the BSOB since the fire, but who had s i m i l a r tests performed per order of the Broome County Health Department in February or March, 1981, because they felt that they nevertheless may have been exposed to contaminants from the BSOB. The rationale for this schema is the b e l i e f that if health problems did occur as a result of exposure to PCB, d i o x i n , or dibenzofurans released by the fire, they would most probably be apparent among persons who actually entered the BSOB, since contamination was largely an i n t r a - b u i I d i n g problem. The l i k e l i h o o d of contamination should also increase w i t h duration of exposure, so the most intensive efforts are focused upon i n d i v i d u a l s who were in the BSOB for 25 or more hours. A d d i t i o n a l consideration is being given to a more sophisticated index of exposure, one which w i l l incorporate measures of intensity (e.q., use of protective gear, date of exposure, floor and location of exposure) as well as duration. The laboratory tests were performed at Binghamton General Hospital (BGH), which is operated by United Health Services, Inc (UHS). They involve a serum biochemistry profile of 20 analyses. Included were 1 i v e r function tests linked to PCB exposure in the literature (e.g., SCOT and GGPT), t r i g l y c e r i d e s , and a variety of other procedures. A complete blood count with platelets and d i f f e r e n t i a l was also conducted. These tests are nearly identical to those ordered by the Broome County Health Department and performed at BGH on most of the 'program participants soon after the fire. They w i l l provide for the examination of change in physiologic processes over time. �The interval medical history cons i sted of the person's responses to a nurse-administered questionnaire of 3^ symptoms which he or she may have first experienced since the date of the fire. I l l u s t r a t i v e items included skin rash, headaches, swollen eyelids, and other problems which may be related to- PCB exposure, in addition to control items. The physical examination was performed at Wilson Memorial Hospital in Johnson City by licensed physicians board-certified or e l i g i b l e for certification in internal medicine or family practice and employed by UHS. It focused upon the skin, since chloracne and other dermatologic conditions have been linked to PCB exposure in the literature. The nervous system was also carefully examined, because PCB's may have neural and sensory effects. The other organ systems, however, were a 1 so reviewed to complete the examination and to reassure the i n d i v i d u a l . The attending physician was encouraged to make recommendations or referrals for any conditions he detects. Referrals for dermatologic or neurologic disorders which the attending physician felt may be related to exposure to contaminants from the BSOBweremade to specialists provided by NIOSH and the New York State Department of Health. Al 1 other referral s were made through the workers ~personal physician. The consulting physician for dermatologic conditions was Dr. Steven Cohen. He is associated with the Occupational Skin C l i n i c of the Yale University School of Medicine, and is well experienced in the diagnosis of chloracne and other skin lesions associated with PCB exposure. Dr. Jeffrey Ribner is a board-certified neurologist who maintains a practice in Binghamton, and he provided neurologic consultations. The protocol also provides for the determination of serum PCB levels. Serum wassaved from all persons in the program and w i l l be sent to Hazelton Raltech, Inc., in Madison, W l , a laboratory well-equipped and q u a l i f i e d in the detection of PCB in human blood. The type of PCB under investigation is Aroclor 1254, since this was the type contained in the transformer f l u i d which was released, and the f ype idencified in the soot retrieved from the BSOB for testing. Samples of serum saved from those drawn in February and March, 1981, w i l l also be sent for analysis together with the follow-up samples to provide for an investigation of change in serum PCB levels over time. All samples w i l l be labelled so that the laboratory is unaware of when they were drawn and the patient's exposure status. Control samples w i l l be added without the laboratory's knowledge to provide q u a l i t y assurance, and all analyses w i l l be conducted d u r i n g the same time period. This assessment of serum PCB levels w i l l provide important objective evidence of exposure, and w i l l be examined in relation to self-reported exposure, laboratory test results, and c l i n i c a l findings. Program Participants The most recent enumeration revealed that the target population consists of 521 i n d i v i d u a l s (Figure 1), This total represents an increase of 42 from the original estimate of '479. Three hundred and eighteen of this number actually entered the BSOB during or after the fire. The remaining 203 persons were predominately those who worked in the adjacent City and County Office B u i l d i n g s and felt that they were exposed through secondary sources. �One hundred and eighty-five of the 318 persons who had entered the BSOB remained there for at least 25 hours. This group included approximately 47 employees of the New York State Office of General Services who were involved in the i n i t i a l clean-up, approximately 33 private electricians who removed and replaced the destroyed transformer, and 48 professional p o l l u t i o n control wo'rkers. The latter group are routinely exposed to .toxic substances as a function of their occupation. Data w i l l be collected from these i n d i v i d u a l s by their employer (New England Pollution Control Company), and analyzed separately from the other persons in the program. The effective size of the target population is therefore reduced to 473The 33 firemen who extinguished the fi.re were also considered e l i g i b l e for p h y s i c i a l examinations. Although they were not in the BSOB for 25 or more hours, they were exposed soon after the PCB's were released from the transformer oil and w h i l e the chemicals were in a v o l a t i l e state. The unique nature of their exposure warranted their inclusion in the group receiving physical examinations. Conduct of Examinations, Histories, and Labortory Tests The program officially began in September, 1981, with the receipt of budget approval for five staff positions and for maintenance and operation. The worker l i s t s were reviewed and updated. Copies were sent to each person's employer to notify the organization of the program and to assure that the l i s t s were complete. NIOSH and New York State Department of Health representatives held an informational meeting in Binghamton to instruct the panel of examining physicians on the c l i n i c a l effects of PCB exposure. Certified letters were sent to the workers informing them of the arrangements and asking them to take part. The l i s t s of workers were sent to the hospital to arrange for appointments, and the first persons were scheduled for October 30, 1981. The majority of physical examinations, interval medical h i s t o r i e s , and laboratory tests were completed by the end of January, 1982. The numbers of examinations and h i s t o r i e s currently performed are 139, and, for the laboratory tests, the number is 430. These totals represent 94% and 91%> respectively, of the persons e l i g i b l e for these services. A d d i t i o n a l efforts were made to contact the non-participants and to g a i n their cooperation. Saturday appointments have been offered to persons who were unable to v i s i t the hospital for the necessary procedures during the week. Seven of 14 dermatology and two of three neurology consultations have been performed. Serum samples are currently being prepared for shipment to Hazelton Raltech for PCB analyses. Conduct of Interviews All persons in the program are also being interviewed. The information collected includes sociodemographic characteristics, pervious medical problems, tobacco and alcohol consumption, medication currently used, and a l l e r g i e s . The main purpose of the interview, however, is to gather data concerning the exposure status of each i n d i v i d u a l . They are asked whether �they entered the BSOB on or after the date of the fire, and if so, the dates of their entry, the length of their stay, and their activities. They are also queried concerning the floors of the BSOB they v i s i t e d , the use of protective gear, and l i k e l y routes of exposure. S i m i l a r questions are posed concerning the surrounding C i t y and County B u i l d i n g s and parking garage. The interview additionally contains the patient's report of previous or subsequent chemical exposures. This information is necessary to update, standardize, and extend s i m i l a r data gathered by the Broome County Health Department last February and March. Those who received physical examinations were interviewed in Johnson City as they arrived for their examination and interval medical history. The remaining patients are interviewed by telephone from Albany. Approximately 250 interviews have been completed to date, or more than 50% of those e l i g i b l e . P u b l i c Servi ces Copies of the results are sent to the personal physicians of the persons in the program. The workers are sent letters asking them to contact their physician and discuss the significance of the findings. Informational brochures concerning the program and the health effects of PCB's and dioxin are enclosed with t h i s correspondence. Persons without a physician a re'referred to'the Broome County Health Department. The New York State Health Department's Communications Office has compiled a binder of materials relating to all aspects of the BSOB Project (cleanup, medical surveillance, environmental sampling, animal toxicity experiments, etc.), which is made a v a i l a b l e to the p u b l i c at l i b r a r i e s , the SUNY campus, and other locations. Meetings have been held with the Broome County Medical Society and other groups to inform them of the program. A New York State Department of Health representative travels to Binghamton from Albany twice a week to serve as a liason between the community and the State Health Department and to answer quest-ions concerning the program. Data Management and Analysis The physical examinations, interval medical histories, and laboratory tests (including those conducted last winter by the Broome County Health Department) have been coded, keypunched, and placed on computer tapes. E d i t programs are being developed to detect errors in processing, logical inconsistencies, duplicate or missing records, and other problems. The interviews that have been completed are currently being coded and w i l l shortly be ready for entry into the computer. A plan to analyze the data is being developed for N I O S H , and w i l l be implemented by the New York State Department of Health as soon as possible upon receipt, sd �Figure 1 Possible Exposure (N - 521) Exposure I n s i d e BSOB (N = 318) Exposure Outside BSOB (N = 203) L i Follow-up Blood Screen Durat ion < 25 Hrs, (N = 133) Follow-up Blood Screen Durat ion > 25 Hrs. (N = 185) Follow-up Blood Screen Physical Exam � 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. 090 Folder The folder containing the original item. 2288 Series The series number of the original item. Series IV 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 Fitzgerald, Edward F. Susan J. Standfast Title A name given to the resource Typescript: Summary of Binghamton State Office Building Medical Surveillance Program: Design and Implementation, [nd] Subject The topic of the resource BSOB health monitoring health studies NIOSH https://www.nal.usda.gov/exhibits/speccoll/files/original/166a877e1bf030dcaa423c05a3719e0b.pdf 681110039e22d9a0e4971ceb7786c4b3 PDF Text Text Item D Number 02269 Author Gleit Alan ' Corporate Author Report/Article Tltte Typescript: Draft Summary Report of the Medical Surveillance Program for the Binghamton State Office Building Decontamination Project, August 7,1985 Journal/Book Title Year 000 ° Month/Day Color Number oflmaflss D 55 Doscrlpton Notes Thursday, September 20, 2001 Page 2269 of 2293 �DRAFT Summary Report of the Medical Surveillance Program for the Binghamton State Office Building Decontamination Project Prepared for Versar New York, Inc. By Alan Gleit, Ph.D. Versar, Inc. P.O. Box 1549 6850 Versar Center Springfield, Virginia 22151 Arnelle 6. Cohen, M.S. Biometric Research Institute, Inc. 1401 Wilson Boulevard Arlington, Virginia 22209 Kenneth H. Chase, M.D. Washington Occupational Health Associates, Inc. 1120 - 19th Street, N.W., Suite 410 Washington, D.C., 20036 August 7, 1985 �Table of Contents I. Introduction 1 II. Materials and Data Sources 2 A. B. Study Population Health Data 2 2 C. Exposure Data 4 III. Methods and Procedures 7 A. Exposure Classification 7 B. 9 Statistical Tests C. Methods for Reviewing Clinical Data Statistical Results 14 A. IV. 11 14 Descriptive Statistics B. Correlation Analysis 16 C. 16 Cumulative Effect of Potential Exposure D. Regression Analysis 19 E. Discussion of Clinical Data 19 V. Conclusion 24 VI. References 26 Tables Appendix: Normal Ranges �I. INTRODUCTION As a result Binghamton State polychlorinated of a transformer Office Building biphenyls (PCBs), and tetrachlorodibenzofurans fire on (BSOB) 5 February was 1981, contaminated tetrachlorodibenzodioxins the with (TCDDs), (TCDFs) apparently produced by the action of the fire on the transformer fluid. With the discovery of TCDD and TCDF, the initial cleanup effort was halted, the building was shut down as of 26 February 1981, York and an expert panel was convened by the New State Department of Health on 3 April to define the conditions under which clean-up activities building could occur. BSOB decontamination and eventual re-occupancy of the The worker medical surveillance program of the project forms a part of the health and safety plans resulting from the recommendations of this panel. The purpose threefold: of the medical surveillance (1) to determine the medical suitability in the BSOB cleanup, program has been for participating (2) to periodically monitor the health status of members of the cleanup crew, both present and future, and (3) to assess the efficacy values for of the health and safety PCS blood levels and plan by establishing pertinent clinical baseline parameters-'-. The objectives of this analysis are: 1. To describe and summarize data collected during the medical surveillance program for the cleanup of the BSOB. 2. To assess the health status of workers at risk of hazardous exposure during the cleanup. 3. To evaluate the efficacy of the protective equipment and safety procedures used hazardous exposure. to minimize potentially �-2II. MATERIALS AND DATA SOURCES A. Study Population All persons entering required the BSOB as workers to participate in the medical participation includes an entrance or visitors have been surveillance examination, program. bi-monthly Such interval evaluations, an annual examination, an exit examination and a follow-up evaluation. All participants are identification numbers based project. focuses This report on male. their on Individuals are affiliation with those employees who assigned the overall were in the building during the earliest phase of the cleanup, i.e. 29 September 1981 The through 31 December 1983, when potential exposure was greatest. total number of participants for whom both exposure data and medical data were available during this time period is 193: 24 Versar, 23 Office of General Services, 139 Allwash contract workers, 3 Broome County personnel, and 4 individuals designated as visitors. The suitability of each worker determined at the entrance to participate in the program is examination. Potentially disqualifying conditions for participation in the BSOB cleanup include: dermatitis, associated liver with disease, or and aggravated other by conditions potentially alcoholism, thought hazardous to be exposures. Primary consideration was given to conditions that could interfere with the ability to use protective equipment under non-sedentary work conditions. B. Health Data All health data are collected at the examination site, either in Washington, D.C. York. or at Wilson or Lourdes Hospital in Binghamton, New Blood chemistries are analyzed at one of three labs, depending on the examination site: Bionetics laboratory, Wilson laboratory, or Lourdes laboratory, respectively. Plasma PCB specimens are split and �-3shipped to each of the following labs: Professional Clinical Laboratories (PCL) in Wilmington, Delaware and Biomedical Reference Laboratories (BRL) in Burlington, North Carolina. The normal ranges from these labs for PCB, SCOT, SGPT, GGTP, triglycerides, and HDL cholesterol a standard set of Kenneth Chase of (WOHA). Dr. Chase cholesterol are shown in Appendix A. Results are recorded on forms, as described below, and transmitted to Dr. Washington Occupational Health Associates, Inc. then delivers the forms, in batches, to Biometric Research Institute, Inc. (BRI). BRI has developed a system of processing forms that results in an accurate and consistent data set. All forms are processed in batches. Each batch is reviewed manually and any necessary coding is done. The batch of forms is then keypunched and machine-verified. After keypunching, the data are listed by computer and data coordinators check keypunching against the original form to identify keypunching errors. Errors identified in the visual check are corrected in the computer file. The objective of this first phase of data processing is to ensure data are entered into the computer exactly as recorded on the original forms by the physician. The second phase of data processing involves computer listings of the data to identify missing or out-of-range values. These listings are reviewed at WOHA and the corrected copy is returned to BRI. Resolutions are entered into the system and the computer file is updated. This data bank contains all available information from the entrance, interval, annual, exit, and follow-up exams. and The entrance examination includes a complete medical, reproductive occupational/environmental history as well as a comprehensive physical examination. Baseline laboratory parameters include a complete blood count with differential and platelet count, urinalysis, chemistry profile (modified SMAC 20), chest x-ray, pulmonary function tests, EKG, and plasma PCB level. �-4All participants evaluations. or not scheduled for bi-monthly interval These evaluations include a determination as to whether there evaluation, are a has been any determination unusual as to exposure the since presence the of any previous unusual or unexplained symptoms, a determination as to the presence or development of any pertinent dermatologic findings, and liver function '(alkaline phosphatase, total bilirubin, SCOT, SGPT, GGTP). tests Plasma PCB levels are drawn on every other interval examination. Annual examinations consist of all tests performed at the interval evaluation plus repeat pulmonary function tests and a chest x-ray. Exit evaluations include all of the procedures described under the interval evaluation but in addition include serum triglyceride, cholesterol and HDL cholesterol levels and plasma PCB level. A follow-up examination is performed approximately three months following the exit examination and is identical in scope except that plasma PCB levels are not included. Another source of data for evaluating the potential health effects of participating incident in reports". the decontamination Workers were project required to includes complete a "medical medical incident report if they were feeling ill or if they felt that any of their symptoms were potentially associated with their work in the BSOB. The safety officer on site, who co-signed these reports, was responsible for noting any signs of skin contamination as well as any other corroborating signs of illness. C. Exposure Data As part of the overall health and safety plan, a comprehensive industrial hygiene monitoring program was developed by Versar to assess �-5contaminant control and worker exposure during the decontamination of the BSOB. These data are summarized and discussed in more detail in periodic reports published by Versar2. Industrial hygiene air samples and periodically wipe samples have been determine PCS levels. surfaces and collected and analyzed to Sample selection sites were chosen to represent locations inside the BSOB with a high probability of contamination or potential worker exposure. According industrial to Versar hygiene (Revised sampling 26 January program has 1983 indicated report), that the "the overall level of control and containment of contamination is quite effective." "The concentration of PCBs in the air within BSOB ranges from 0.3 to ug/m3 2.3 for the upper floors of the samples with measurable concentrations except for one sample taken from the 18th floor men's room in September 1982." fire occurred, 3 ug/m )." A shows report Only "the basement mechanical room, where the consistently dated 18 collected in the subbasement higher levels (as 1983, states that July high as air 5.6 samples area had PCB concentrations of 0.43 and 3 0.48 ug/m . Routine wipe samples collected in selected areas depicted only one problem area — up by the floor near the wash water dump — November of "samples collected 1982. from The the July floors contain PCB-1254 in the expected 1983 of range batch the which was cleaned report subbasement states and that Floor-1 of concentrations for these areas." In addition, as part of a monitoring program jointly conducted by Versar and the New York State Health Department Center for Laboratories and Research, "air times the within dibenzofurans, 2,3,7,8-TCDF samples collected BSOB have been dibenzodioxins concentration from and at 15 distinct locations and/or analyzed for various o j biphenylenes ". twelve locations chlorinated "The sampled average when the �-6- building's internal air circulation system was operative was 15.0 ± 3.6 pg/m3". Eadon et al.3 developed a system for estimating 2,3,7,8-TCDD equivalents, and determined that the relative toxicity for air samples containing mixtures of chlorinated dioxins, furans and biphenylenes to be equivalent to about 14 pg/m3 of 2,3,7,8-TCDD. This value was within the range of suggested guidelines for re-entry into the building, as established by the risk assessment of Kim and Hawley . An additional, but unquantifiable source of potential exposure data, is "exposure incident reports" filed by Allwash employees. Workers were required to report all incidents of potential direct contact with contaminated soot as well as any malfunction of their protective equipment (e.g., tear in tyvek suit, tear in glove, or loss of respirator seal) to the on-site health and safety officer. These reports were then sent to Washington, D.C. where they were included in the employee's permanent folder. It was anticipated that working in sometimes cramped areas with bulky cleanup equipment would occasionally result in a tear or dampening of the employee's disposable tyvek suit. The usual procedure was to temporarily "break out" of their garmets, undergo appropriate personal decontamination and cleaning if necessary, and then change into a new suit and resume work. Workers were not penalized or discouraged from filing these reports so it is felt that this source of data is a fairly reliable means for evaluating the efficiency of the protective equipment and safety procedures. �— 7— III. A. METHODS AND PROCEDURES Exposure Classification When attempting to classify workers by potential occupational exposure to hazardous substances, it is preferable to assess individual exposure status rather than grouping employees by crude indices of exposure, such as general job titles or place of employment. especially that the This is desirable if industrial hygiene monitoring data suggests opportunities or routes of potential exposure differ significantly between workers. In their initial status report for the BSOB medical surveillance program, the State of New York and NIOSH investigators created an exposure index score which was computed as a multiplicative function of five factors: location in BSOB, type of activity, whether or not protective clothing was worn by workers, number of hours in the BSOB, and the actual PCB air levels on various dates in the BSOB-*. Each factor was weighted by a number reflecting its relative magnitude, as determined from studies in the literature, with "number of hours in the BSOB" being the most significant factor. The feasibility of developing a similar index for workers involved in the Versar medical surveillance program was investigated by on-site toxicologists and industrial hygienists. The following factors mitigate the ability to create a similar exposure index in this study population: (1) unlike the initial cleanup crew, all workers were required to wear full-face respirators and protective clothing when in the building in addition to taking other precautions to minimize potential exposure-'-; (2) PCB air levels documented during this time period (i.e., 9/81 - 12/83), were much lower than those during the initial fire fighting and immediate cleanup phase^; and (3) although there may be qualitative differences in the nature and opportunity for �-8- PCB exposure between individual workers or specific job duties, workers in this study were known to rotate on various teams on a daily and weekly basis and individual job assignments were not available to confidently group workers on this basis. As part of the medical surveillance and safety program administered by Versar, the total number of hours actually spent in the building was collected on everyone who entered the BSOB. After careful consideration, this measurement was determined to be the best available indicator of potential exposure. Differential exposure due to type of activity is accounted for by performing all analyses on two subsets of the population. One group (N=129) is composed of the Allwash contract employees, workers who have the greatest likelihood of contact with contaminated soot by virtue of their cleanup activities (e.g. scrubbing ceilings, vacuuming fireproofing, etc.). The second group (N=64) is comprised of all "other" participants in the cleanup project, namely Versar, O.G.S., Broome County personnel, visitors, and 10 Allwash employees working in a supervisory capacity. The individuals in this subset are predominantly supervisors or short-term visitors whose exposure to potentially toxic substances per hour spent in the building is likely to be less than that of the Allwash employees. Examination of the frequency distribution of number of hours in the building indicates that reasonable cut-off points can be identified to represent different exposure categories. The Allwash employees for whom complete PCB data was available (100/129) were used to determine these cut-offs. They were then applied to the two subsets of the population for statistical analysis. �-9- The population naturally divides itself into three groups as depicted in the histogram shown in Figure 1. These groups have the following ranges: Group I, 0-400 hours; Group II, 401-979 hours; and Group III, 980-3500 hours. These ranges hold true for the distribution of Allwash workers, as well as Other participants (see Figure 2 and 3); however, a substantial number of participants in the 200-500 hours range did not have complete PCB data. For the purpose of statistical analyses, the "least-likely" exposure category will form Group I, Group II will be comprised of the "less-likely" exposure group and Group III will represent the "most-likely" exposure category. The distribution of exposure category by study subset is depicted in Table 1. Within each subset, approximately 50% of the population falls into the lowest exposure category. Table 2 shows the distribution of study participants by job classification and exposure category. B. Statistical Tests Adopting similar procedures to those utilized by the New York State Health Department investigators, some analyses will preserve the original scaling of hours spent in BSOB, while other analyses will utilize the distinct exposure categorizations. The advantage of the first approach is that it maintains the interval nature of the data which is desirable for assessing time trends and dose-response relationships. Categorization of potential exposure status by hours in BSOB allows the use of group means to estimate the significance of differences between potential exposure status, PCB blood levels, and biochemical parameters. The data have been analyzed as follows: (1) descriptive statistics; (2) correlation analysis; (3) possible cumulative effect of potential exposure; and (4) regression analysis. Descriptive statistics Descriptive statistics have been calculated to provide an overview of the characteristics of the study population as a whole, as well as by exposure category (as defined above). This stage of analysis �-10includes frequency distributions of variables such as age, dermatogical symptoms, and history of alcohol abuse. The chi-square test of association was used to assess significant differences between exposure groups. Plasma PCB values, biochemical parameters, and other continuous variables being analyzed have been tested for normality. Whenever appropriate, log transformations of the data have been used. If neither the original data nor the transformed data approached a normal distribution, nonparametric methods were applied. Correlation analysis In order to evaluate whether potential exposure to PCB contaminated soot had subclinical effects on liver function, plasma PCB levels were compared to the three most sensitive liver function tests, i.e., SCOT, SGPT and GGTP. The normal distribution and nonparametric correlation coefficients between plasma PCB levels and each of these parameters were analyzed for Allwash employees and Other participants separately. Correlation coefficients and probability values were tabulated using the latest time interval possible. Cumulative effect of potential exposure The cumulative effect of potential exposure in the BSOB was assessed in the following manner. All analyses described were performed twice: once for the subset of Allwash workers only, and once for the subset of Other employees. This analysis compared baseline values to values on the last exam, whether interval or exit, for each particular subject by exposure category. Because of the small number of Other employees, particularly in Group II, Group I and II were combined for statistical purposes. Ideally, Group II should have been �-11combined with Group III, but because of the potential exposure in Group III it was decided to report on them separately. Thus, for each parameter considered, five distinct groups of individuals were analyzed (three Allwash and two Other). The last visit date varies considerably within the population; however, this method is most likely to assess the highest cumulative dose. The null hypothesis being tested is that the difference between the baseline and final test means in each exposure category equals zero. The mean differences of each group were statistically compared using paired t-tests. Another analysis of the cumulative effect of potential exposure evaluated possible differences in the final examination (interval or exit) values for various parameters for the three groups of Allwash employees and for the two groups of Other employees. The null hypothesis being tested is that the mean level of the groups are all equal. The analysis was performed both parametrically (Analyses of Variance) and nonparametrically (Wilcoxon). Regression analysis Possible time trends in the PCB and biochemical measurements as a function of the length of time t that individuals spent in the BSOB were evaluated. For each participant, the final interval or exit values were used as a proxy for the values when last in the building. Linear regression was performed to determine measurements were related to the time t. C. whether these final Methods for Reviewing Clinical Data The most reliable means of monitoring potential health effects is prompt recognition and reporting of signs and symptoms of illness, both by the worker himself in the form of self initiated medical incident �-12reports (with appropriate follow-up) and by the examining physician at the bi-monthly interval examination. This method identifies all cases of frank toxicity as well as most cases of immediate concern, such as grossly abnormal biochemical tests and any cases of elevated plasma PCB levels. As mentioned previously in the discussion of the medical surveillance program, Dr. Chase periodically monitors summary reports of all clinical data. During this process, employees with moderately or significantly altered biochemical tests can be identified and notified for further evaluation. Two employees who were identified as having significantly altered liver function tests are discussed in section IV. Individual records of all 129 Allwash workers employed between 29 September 1981 and 31 December 1983 were reviewed and the symptoms and signs listed on the medical incident reports were summarized. The frequency of these symptoms can only be crudely compared to those listed at the time of baseline examination because unlike the initial survey, all workers were not asked a standard set of questions at a given point in time. Instead, workers were instructed to complete a medical incident report if they felt ill. Although in most cases, these symptoms can reasonably be presumed to be associated with the circumstances of their employment on the day the report was filed, it is also necessary to keep in mind that Allwash employees, like everyone else, develop seasonal colds and are involved in non-work related accidents. These conditions could be aggravated by being garbed in a full-body tyvek suit all day while working under sometimes environmentally stressful circumstances. Similarly, individual records of all 129 Allwash workers were examined, and all exposure incident reports were reviewed and summarized. The safety officer on-site who was responsible for signing off on exposure incident reports was obligated to note on the report if �-13he saw evidence of coverall or skin contamination. The distribution of Allwash employees filing exposure incident reports was then examined by exposure category in an effort to determine if workers who quit or spent few hours in the BSOB may have experienced more intensive circumstances of exposure. These workers may have filed more incident reports or may have reported more instances of direct contact. Alternatively, it would reasonably be expected that workers who were employed longer would naturally encounter more opportunities for protective equipment failure. This comparison would also investigate whether multiple exposure incident reports were filed by few or many workers. Many previous studies have demonstrated a positive correlation between plasma PCB levels and age, length of employment (or exposure) and intensity of exposure among workers exposed to PCB fluids.6>?>8 jn lieu of personal PCB air levels, the relationship between the frequency of exposure incident reports filed by Allwash employees was compared to the PCB blood level. The hypothesis being tested is that those workers who filed more exposure incident reports should have higher plasma PCB levels. The chi square test was then used to test for a statistically significant difference. In an effort to identify those individuals thought to be at highest risk of potential exposure, all Allwash employees who filed twenty or more exposure incident reports were identified. Their latest interval or exit laboratory tests were then examined to determine if there was any evidence of liver toxicity in those individuals who presumably were at highest risk for direct contact with contaminated soot. �-14IV. STATISTICAL RESULTS The results will be presented in five sections as described in the rationale: (A) descriptive statistics; (B) correlation analysis; (C) analysis of the cumulative effect of potential exposure; (D) regression analysis; and (E) discussion of clinical data. For Section A through D, the results for Allwash employees and Other employees are presented separately. measurements In addition, were several two participants whose liver function levels of magnitude larger than any others were excluded from all analyses other than the descriptive statistics so they would not skew the results. These two cases are discussed in Section E. A. Descriptive Statistics The age distribution of Allwash employees (Table 3) reveals a relatively young population, with 88 percent less than 35 years of age. Only 2 percent of Allwash employees are 45 or older. This pattern is generally maintained among individuals in the middle and upper exposure categories, in which 50 percent of the population is 15 to 24 years old and 100 percent are younger than 45. Group I, representing workers who are least likely to be exposed to PCBs, is more diverse, having fewer people under 25 (36%) and over twice as many people age 35 or older (18% vs. 7% and 3%) than does Group II or III. Among Other employees (Table 4) most people were 25 to 44 years of age (64%) with 14 percent under 25 and 22 percent age 45 or older. The largest variation among exposure categories occurs in Group II in which all eight employees small number of (100%) are under employees under 25 35. Group I has a relatively (3%), but distribution is consistent with that of Group III. the overall age �-15- The distribution of age by exposure category among Allwash employees from whom exposure category was assessed (i.e., those with complete PCB data) is similar to the subset of total Allwash employees. This distribution is depicted in Table 5. As mentioned previously, all employees were asked to complete a detailed questionnaire at their entrance exam, before entering the building, which focused on conditions thought to be associated or aggravated by potentially hazardous exposures. It should be noted that chloracne, a specific dermatological condition requiring a tissue specimen and histological diagnosis that has been associated with exposure to chlorinated hydrocarbons, was grouped with "acne" on the original baseline questionnaire. Positive responses to this question do not necessarily imply that some workers had documented chloracne at the time of beginning work in the BSOB. Furthermore, it should be appreciated that mere reporting of ever having a history of liver hepatitis or dermatitis were not disqualifying conditions if they were not active at the time of physical examination. Baseline symptoms reported by the employee or examining physician were tested, using Chi-square, for any association with exposure category. No significant (p < .05) associations were found, i.e., the groups were about the same prior to entering the BSOB. Among Allwash employees, the most commonly self-reported symptoms at the entrance exam (Table 6) were acne or chloracne in Group I (18%), thickening in Group II (25%), and both skin irritation or burning and acne or chloracne in Group III (18%). The baseline symptoms most frequently reported at the entrance exam by the physician (Table 7) were thickening in Group I (25%) and rash in Group II (32%) and III (26%). Among Other employees, rash was the most frequently self-reported symptom at the entrance exam in Group I/II (17%). In Group III, rash was tied with skin irritation or burning and acne or chloracne at 17 �-16- percent each (Table 8). Rash was the symptom most frequently reported by physicians at the entrance exam in both exposure categories (Table 9) with 22 percent in Group I/II and 30 percent in Group III. The case records of Allwash and Other employees in Group II and III who reported history of any hepatic-related problems were evaluated to assess their impact on the results. The presence of conditions was not controlled for in the remaining analyses very employees those few reported these problems and these because who did, experienced them many years ago without recurrence. All participants reporting any unusual exposure or breach of safety regulations, adverse health effects, or abnormal findings were identified. The frequency and nature of these complaints are summarized in the discussion of clinical data. B. Correlation Analysis Plasma PCB levels (separately analyzed at PCL and BEL laboratories) were tested for correlation with the three biochemical parameters SCOT, SGPT, and available time interval. GGTP. Data were used from the latest The possible association of these parameters was evaluated using the normal Pearson correlation coefficient as well as the nonparametric Spearman correlation coefficient. results were statistically significant (p < None of the .05). C. Cumulative Effect of Potential Exposure The difference statistically analyzed the following between (paired parameters: baseline and final measurements t-test) within each exposure group for plasma PCB (analyzed at PCL Lab and Lab), SCOT, SGPT, GGTP, triglycerides, cholesterol and HDL. on the entrance exam was was subtracted from the value BRL The value on the latest interval or exit exam; therefore, when the mean difference is positive, the value of the parameter increased over time and when it is negative, �-17the value of the parameter decreased over time. The results are depicted in Tables 10 a & b to 17 a & b. The entrance and last exam means are based on all available data; the mean difference is based on results from the paired t-test, and so, may include fewer observations. PCBs Baseline and final values for plasma PCB levels were compared to normal ranges obtained from the laboratories. All values were within the normal range; most values were at or below the minimal detection limits. The ranges and means of PCB values for Allwash employees by exposure group are as follows: Exposure, lab Entrance Exam Range (Mean) Last Exam Range (Mean) Group I, Pa Group I, BRL 0 - 15 (5.85) 3 - 13 (5.09) 5 - 1 6 (5.44) 3 - 9 (4.83) Group II, PCL Group II, BRL 5 - 9 (5.19) 3 - 9 (4.19) 5 - 5 (5.00) 3 - 6 (3.44) Group III, PCL Group III, BKL 5 - 8 (5.09) 3 - 1 1 (4.30) 5 - 8 (5.12) 3 - 8 (4.24) Plasma PCB values from the PCL Laboratory did not exhibit any significant differences between baseline and final measurements. Of the five average differences, however, three are negative, one is "zero," and only one is positive (Group III Others) from baseline to final measurements. Plasma PCB values from the BRL Laboratory showed one significant difference (Group I/II Others). All five of the average differences were negative and two values (Allwash Group I and II) were close to significantly (p = .06) negative. Thus, in general, plasma PCB levels decreased for individuals in this study though, on average, not significantly. �-18Other Biochemical Parameters Average baseline and final values for selected blood chemistry parameters were compared to normal ranges obtained from the hospitals. The group means for the liver enzyme parameters SCOT, SGPT, and GGTP were always well within the normal range. Triglyceride levels were slightly high for Group III Allwash employees (both baseline and final) relative to the Bionetics Laboratory scale but were normal for the Lourdes and Wilson Hospital scales. Both baseline and final cholesterol levels were slightly high for Other employees (Groups I/II and III) relative to the Bionetics Laboratory scale but were normal for the two hospital scales. ranges. The HDL levels were all within the normal Values for SCOT, SGPT, triglycerides, and HDL did not exhibit any significant differences between baseline and final measurements. Average levels sometimes went up and sometimes went down. GGTP levels changed significantly for Group III employees (both Allwash and Others) as well as for Group II Allwash employees. Individuals with high exposure, on average, had much lower values at the end than at the beginning (mean difference of 12.83 and 9.53 lower). The differences for the other two groups did not exhibit any consistent pattern. In general, GGTP levels decreased for study participants, especially for those with medium or large exposure. Cholesterol employees. levels changed significantly for Allwash Group I Allwash individuals with low exposure, on average, had much lower (average decrease 9.44) cholesterol values at the end than at the beginning. Also, the averages for all groups of Allwash employees went down. Group III Others also decreased while Groups I/II Others groups of Allwash employees went down. Group III Others also decreased while Groups I/I1 Others remained the same, on average. Thus, in general, cholesterol levels declined for all study participants. �-19Analysis of variance and Wilcoxon tests were performed on the final measurement values for PCBs (from both labs), SCOT, SGPT, GGTP, triglycerides, cholesterol, and HDL to determine whether the mean levels for the different exposure groups were the same. The only significant ANOVA was for Allwash employees for PCBs from the BRL Lab. Furthermore, the mean levels do not vary linearly with length of exposure. The only significant Wilcoxon Rank Sum Test result was for GGTP among Allwash employees. In addition, the means decrease as exposure increases. D. Regression Analysis To assess possible time trends in the PCB and biochemical data, linear regression models were run using time in the BSOB as the independent variable and final PCB levels (from both labs), SCOT, SGPT, and GGTP as dependent variables. The only statistically significant slope occurs for GGTP among Other employees (slope=-0.0003) showing a slight decline in its level with time spent in the BSOB. Two other values are almost significant (p=.07 level): these are for PCBs (BRL Lab) for Others (slope=-0.0006) and SCOT for Others (slope=0.002). All four slopes for PCBs are negative, both slopes for SCOT are positive, and both slopes for GGTP are negative (one is significant). E. Discussion of Clinical Data The frequency distribution of symptoms reported by Allwash employees on the medical incident reports is summarized in Table 20. The two most prevalent findings were complaints of feeling nauseous and reports of blunt trauma and minor bruises. The latter findings are not atypical of any group of industrialized workers. Because the same individual could have filed more than one report, or could have listed more than one chief complaint on the same medical incident report, the true prevalence of these symptoms among all workers within a particular �-20- exposure group cannot be determined. feeling nauseous among 34 workers The reporting of 35 cases of in Group III may be attributed to working longer hours under environmentally stressful conditions or may be a manifestation of toxicity. the cumulative effects of low level chronic In order to adjust for the differences in time spent in the BSOB as well as differences In the size of the populations, a crude index of the average number of reported cases per hour spent in the BSOB was calculated and used to compare across groups. By dividing the number of cases of feeling nauseous in Group I and III (6 and 35) by the average number of hours spent in the BSOB for these same groups (184 hrs. and 1757 hrs.) it was determined that there were .033 cases per hour reported for Group I compared to .020 for Group III. The results of similar calculations are shown in parentheses in Table 20. This would suggest that spending longer time in the BSOB, and therefore presumably at higher risk of potential exposure, is not associated with a higher incidence of ill symptoms. in which the Group musculoskeletal pain. III reports per hour were necessarily The only instance clearly higher was Most of these cases were due to low back pain possibly associated with long hours in the cramped work conditions at the BSOB. The frequency distribution of all sources reported summarized by in Allwash Table employees 21. in Clearly, exposure the of equipment failure incident most frequent reports is source of "equipment failure" was tear in the outer layer of a glove or tyvek suit. If these incidents did not occur during a time when the worker was actually involved in cleaning up of contaminated soot or were not associated with evidence of skin or coverall contamination, then they were listed as such in the incident report. There were, however, a total of 44 reported incidents involving the loss of a tyvek suit seal and a total of 40 cases of a torn glove, all with evidence — dampened or soiled skin — of of skin or coverall contamination. usually In all these cases, however, workers underwent immediate decontamination procedures and no cases of unresolving contact dermatitis or chloracne �-21- have been reported. Table 21 also demonstrates that, in general, Group III workers filed more reports in total; however, the number of reports per hour spent in the BSOB was not higher. Table 22A demonstrates that individual workers more likely individuals to file multiple exposure incident in Group III were reports. Nineteen in Group III filed 11 or more exposure incident reports. Again, this occurrence is probably a reflection of the greater number of hours spent in the BSOB. In order to investigate the relationship between PCB blood levels and length of potential exposure, PCB blood levels were compared to the frequency of reporting potential contact with contaminated soot (Table 22b). There is no evidence to suggest that the group of workers at highest risk of exposure levels. more to contaminated soot had higher plasma PCB To investigate this further, all those workers who filed 20 or exposure interval incident or exit summarized in exam Table reports were identified PCB blood levels 23. and All laboratory and their latest liver function studies values were within normal limits. As mentioned previously, two Allwash employees were identified who had grossly abnormal exit examinations. indicates these liver enzyme measurements at the time of their Careful evaluation of these individuals' cases that their work in the BSOB was probably not a cause for abnormalities. Unfortunately, neither of these two workers reported for their three month follow-up exam, so it is unknown whether these enzyme levels have since returned to normal. Employee number one is a 22 year old white male who had his entrance examination in January, 1982, and first entered the building in February, 1982. At that time his liver enzyme measurements well within IU/liter). the normal ranges (SCOT of were 17 lU/liter and SGPT of 13 There was no indication at that time of any liver problems. Values for these liver enzyme measurements remained relatively constant on the interval examinations on 24 March, 26 May, 3 August, and 28 �-22September 1982. The employee last entered the BSOB in November 1982. During the time the employee was actively working in the BSOB he filed numerous minor exposure incident reports, most of which were for torn gloves and tyvek suit tears. During his March examination he did report that there had been one incident in which he felt there was potential for exposure. The exposure report for this incident stated that charcoal and water had entered the employee's tyvek suit around the wrists and that "some irritation was noted around the left wrist and lower left abdomen, but subsided after showering". The examining physician reported slightly red and swollen eyelids at the employee's March interval examination but his exam was otherwise unremarkable. The employee denied any subsequent instances of possible exposure on his next three interval examinations as well as at the time of his exit examination. employee did During his exit examination on 12 January 1982 the complain of itching and skin irritation which the examining physician at that time described as dermatographia. Liver enzyme measurements at this time were markedly elevated: SCOT 307 IU/1, SGPT 480 IU/1 and GGPT 184 IU/1. Plasma PCB blood levels as measured by the Wilmington and Burlington laboratories were 5 and 3 ppb, respectively. In view of the low PCB blood levels and no report of possible direct contact with soot for at least 9 months prior to developing these liver enzyme elevations, it is unlikely that these abnormalities are the result of any hazardous exposures while working in the BSOB. Elevated liver enzymes in this ratio are, however, suggestive of infectious hepatitis which the employee could developed in the 2 months since his last employment in the BSOB. have Employee number two is a 21 year old white male who had his entrance examination in February, 1983, and first entered the building in February. At that time his liver enzyme measurements were well within the normal ranges (SCOT of 23 IU/1). There was no indication at that time of any liver problems. Values for SCOT remained relatively constant on the interval examinations in March and May 1983. Incidents �-23- with dust in his mask and torn gloves were reported at the May, 1983, interval examination. At that May examination the physician reported no abnormal findings (including liver abnormalities). the building in July, 1983. He last entered At the exit examination in August, 1983, the value for SCOT jumped by a factor of fifteen to 446 IU/1. The employee's and Burlington plasma PCB laboratories levels as measured by the Wilmington were 5 and 7 ppb, respectively. Although the employee did report possible contact with some "dust" at the time of the exit examination, low plasma PCB levels and the absence of any history of substantive exposures make it unlikely was exposed to any hazardous substances. that this employee Significantly elevated SCOT and slightly elevated SGPT liver enzyme values in the absence of any other abnormal liver function tests (e.g., bilirubin, alkaline phosphatase, GGTP) is frequently seen as a response to short term binge alcohol comsumption. �-24- V. CONCLUSION In conclusion, the results for specific biochemical parameters are summarized and an overall explanation of the findings is presented. Table 19 summarizes the statistically significant results. o PCBs (PCL Lab); The t-test indicated that in general there was a tendency for the serum values to decline from baseline to final examinations. The regressions indicated a general decline of values with length of time in the BSOB. o PCBs (BRL Lab); The results are similar to those found using the BRL data but in this case are more pronounced and sometimes significant. o SCOT; In general, the regressions indicated a slight rise in values as the length of time increased in the BSOB. The t-tests offered no clear pattern for possible changes within groups. o GGTP; The t-test indicated a general trend for GGTP values to decrease from baseline to final examination with significant decreases for the high and medium exposure groups. The regression analyses also indicated a general trend (significant for Others, suggestive for Allwash) for lower final examination values for those with more hours in the BSOB. Finally, the nonparametric Wilcoxon test showed a significant decline in average GGTP values for the Allwash employees with time spent in the BSOB (grouped data). �-25o Cholesterol; The t-test, in general, showed declining levels from baseline to final examinations (significantly lower only for low exposure Allwash employees). o SGPT, Triglycerides, HDL; Nothing even suggestive can be said regarding these biochemical parameters based on our analysis. When evaluating the significance of these results, the following must be considered. First, even though there were statistically significant findings, they may be of limited clinical importance due to the fact that the mean level for every group and every parameter were well within normal ranges. Second, the transfer of these results to other populations may be limited by the fact that the Allwash employees (and to a lesser extent, the Other employees) were younger and healthier than the average profile for American adult males. Third, all statistical tests were performed at the 5% level so that chance alone would dictate finding about 5% of the comparisons significant if there were no real effects. In conclusion, among the employees in this study for whom protective equipment and safety procedures were used to minimize potentially hazardous exposure, the health status of the workers was not substantially affected, overall, by potential exposure to the toxic contaminants in the BSOB. �-26- VI. REFERENCES 1. Versar New York Inc., 1981. General health and safety plan for cleanup of Binghamton State Office Building. 2. Versar New York Inc., 1983. Revised Summary Report. Industrial hygiene monitoring to assess contaminant control and potential worker exposure during cleaning of the Binghamton State Office Building. 3. Eadon G, Aldous K, Hilker D, O'Keefe P and Smith R. 1983. Chemical data on air samples from the Binghamton State Office Building. Unpublished data by the Center for Laboratories and Research, New York State Department of Health. 4. Kim NK and Hawley J. 1983. Revised risk assessment: Binghamton State Office Building. Draft document by the Division of Health Risk Control, New York State Department of Health. 5. Fitzgerald EF, Melius JM, Standfast JJ, Janerich DT, Beckerman BS and Youngblood LG. 1983. Status report for the Binghamton State Office Building Medical Surveillance Program. Division of Community Health and Epidemiology, New York State Department of Health. 6. Smith AB et al. 1982. Metabolic and health consequences of occupational exposure to polychlorinated biphenyls (PCBs). British Journal of Industrial Medicine, 39:361-369. 7. Maroni M et al. 1981. Occupational exposure to polychlorinated biphenyls II, Health Effects. British Journal of Industrial Medicine, 38:55. 8. Chase KH, Wong 0, Thomas D, Berney BW and Simon RK. 1982. Clinical and metabolic abnormalities associated with occupational exposure to polychlorinated biphenyls. Journal of Occupational Medicine, 24:109-114. �Figure 1 H I S T O G R A M OF NUMBER OF HOURS IN BSOB FOR A L I W A S H EMPLOYEES W I T H PC8 D A T A (N=100) FREQUENCY BAR CHART FREQUENCY Group I t 1 2 0 0 0 0 3 0 0 4 0 0 Group II 5 0 0 6 0 0 7 a 0 0 0 0 Group 9 0 0 1 i i n 0 0 0 0 1 2 0 0 III 1 3 0 0 1 4 0 0 1 5 1 t> 0 0 0 0 1 1 7 0 0 8 0 0 1 9 0 0 2 0 0 0 EXPTIME MIDPOINT 2 1 0 0 2 2 0 0 2 3 0 0 2 4 0 0 2 2 5 6 0 0 0 0 2 7 0 0 2 8 0 0 2 9 0 0 3 0 0 0 3 1 0 0 3 2 0 0 3 3 3 3 0 0 4 0 0 5 0 0 �Figure 2 HISTOGRAM OF NUMBER OF HOURS IN BSOB FOH ALLWASH EMPLOYEES <N=129) FHEQUENCY BAR CHAPT FREQUENCY Group III Group I 30 15 10 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0 9 0 0 1 0 0 0 1 1 1 2 1 1 1 3 5 0 0 0 0 4 0 0 0 0 0 0 1 6 1 n 7 0 0 0 1 1 ft 0 0 9 0 0 2 0 2 1 2 2 0 0 0 0 0 0 E/PTIME MIDPOINT 2 3 0 0 2 4 0 0 2 5 0 0 2 2 6 0 0 7 0 0 2 8 0 0 2 9 0 0 3 0 0 0 3 1 0 0 3 2 0 0 3 3 0 0 3 3 4 5 0 0 0 0 �Figure 3 HISTOGRAM OF MUMdER OF HOURS IN BSOR FOR OTHER EMPLOYEES (N=64) FREQUENCY BAR CHART FREQUENCY Group I Group II Group III 30 20 15 .10 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 H 9 0 1 2 3 < t b b 7 8 ' 3 0 1 2 3 4 5 O O O O O O O O O O O O O -O O O O O O O O O O O U O O O O O O O O O O o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o EXPTIME MIDPOINT �Table 1 Distribution of Exposure Category by Study Subset Subset EXPOSURE CATEGORY Allwash with PCB Data // () % Total Allwash // () % Other # () % Group I 46 (6 4) 67 ( 52) 33 (52) Group II 20 (20) 28 ( 22) 8 (12) Group III 34 (4 3) 34 ( 26) 23 (6 3) (100) 129 (100) •64 TOTAL 100 (100) , �Table 2 Distribution of Study Participants By Job Classification and Exposure Category JOB CLASSIFICATION EXPOSURE CATEGORY SUBSET Allwash N GO OTHER Other N () % Versar TOTAL N (%) N () % O.G.S. N () % Misc.* Supervisory N () % N (%) Group I 67 ( 52) 33 ( 52) 100 ( 52) 15 ( 62) 9 ( 39) 2 ( 20) 7 (100) Group II 28 ( 22) 8 ( 12) 36 ( 19) 4 ( 17) 3 ( 13) 1 ( 10) 0 ( 0) Group III 34 ( 26) 23 ( 36) 5 ( 21) 11 ( 48) ( 70) 0 ( 0) (100) (100) 7 (100) TOTAL //(%) 129 (100) 64 (100) 57 ( 29) 193 (100) 24 * Includes 3 Broorae County personnel and 4 visitors 23 7 10 (100) �Table 3 Age Distribution of Allwash Employees by Exposure Category Exposure Category Age (Yrs.) Group 11 Group I () % // # Total Group III () % (%) if f () % 15-24 24 (36) 14 (50) 17 (50) 55 . (42) 25-34 31 (46) .12 (3 4) 16 (47) 59 (46) 35-44 10 -2 ( 7) 2 0 1 ( 0) .0 ( 3) 1.3 2 (0) (10) 45-54 (1?) ( 3) ( 2) 55-64 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) >65 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) TOTAL 67 (100) 2S (100) 34 (100) 129 (100) �Table 4 Age Distribution of Other Study Participants by Exposure Category Exposure Category Age (Yrs.) Group II Group I // () % 15-24 1 ( 3) 25-34 9 35-44 Group III () % // 0 Total () % // () % (12) (8 8) 7 (30) 9 (14) (27) 1 7 5 (22) 21 (33) 14 (43) 0 ( 0) 6 (26) 20 (31) 45-54 5 (15) 0 ( 0) . 3 (13) 8 (12) 55-64 3 ( 9) 0 ( 0) 2 (9) 5 ( 8) >65 1 ( 3) 0 ( 0) ( 0) 1 ( 2) TOTAL 33 (100) 8 (100) 0 23 (100) 64 (100) �Table 5 Age Distribution of Allwash Employees by Exposure Category for Those with Complete PCB Data Exposure Category Age (Yrs.) Group I () % // 15-24 15 25-34 21 35-44 9 45-54 1 Group 11 // ( 33) 11 a) ( 55) Total Group III () % // 17 16 43 ( 43) ( 46) 55-64 0 9 ( 20) 0 0 ( 2) 0 ( 0) >65 0 ( 0) 0 ( 0) 0 ( 0) 0 ( 0) TOTAL 46 (100) 20 (100) 34 (100) 100 (100) ( 45) ( 45) ( 0) 1 ' ( 50) () % // ( 0) 0 ( 47) 46 ( 3) 10 ( 0) 1 ( 0) 0 ( 0) 0 ( 1) ( 0) ( 10) �Table 6 Frequency Distribution of Baseline Symptoms Reported by Allwash Employees According to Exposure Category EXPOSURE CATEGORY SYMPTOMS Group I (N=67) # (%) Group II (N=28) # (%) Group III (N=34) # (%) Skin irritation or burning 9 (13) 6 (21) 6 (18) Rash 6 ( 9) 3 (11) 3 ( 9) 12 (18) 6 (21) 6 (18) Thickening 9 (13) 7 (25) 4 (12) Hyperpigmentation 3 ( 4) 3 (11) 2 ( 6) Nail discoloration 2 ( 3) 0 ( 0) 2 ( 0) 12 (18) 9 (32) 5 (15) Acne or chloracne Other dermatologic symptoms Eye irritation or burning 4 ( 6) 1 ( 4) 3 ( 9) Eye discharge 2 ( 3) 0 ( 0) 2 ( 6) Swelling of eyelids 0 ( 0) 0 ( 0) 0 ( 0) Other ophthalmic symptoms 2 ( 3) 2 ( 7) 1 ( 3) Any history of liver dysfunction 2 (3) 0 ( 0) 0 ( 0) Any history of hepatitis 2 ( 3) 0 ( 0) 0 ( 0) Any history of yellow jaundice 2 ( 3) 0 ( 0) 0 ( 0) Any history of alcohol abuse 1 ( 1) 1 ( 4) 2 ( 6) Other hepatic symptoms 2 ( 3) 0 ( 0) 2 ( 6) Persistent body odor 1 ( 1) 0 ( 0) 0 ( 0) History of hyperlipidemia 1 ( 1) 0 ( 0) 0 ( 0) History of cancer 2 ( 3) 0 ( 0) 0 ( 0) �Table 7 Frequency Distribution of Baseline Physical Findings Reported by Physician for Allwash Employees According to Exposure Category EXPOSURE CATEGORY PHYSICAL FINDINGS Erythema Rash Group I (N=67) # () % 1 12 Group II (N=28) # (%) Group III (N=34) // () % ( 1) 2 ( 7) 2 ( 6) (18) 9 (32) 9 (6 2) Chloracne 0 ( 0) 1* ( 4) 0 ( 0) Hyper pigmentation 7 (10) 1 ( 4) 1 ( 3) 17 (25) 8 (9 2) 4 (12) ( 9) 1 ( 4) 4 (12) 23 (68) Thickening Nail discoloration Other dermatologic findings 6 36 (54) 19 (8 6) Conjunctival Infection 3 ( 4) 1 ( 4) 0 ( 0) Eye discharge 0 ( 0) 0 ( 0) 0 ( 0) Swelling of lids 0 ( 0) 0 ( 0) 0 ( 0) Jaundice 0 ( 0) 0 ( 0) 0 ( 0) Hepatomegaly 1 ( 1) 0 ( 0) 0 ( 0) Other hepatic findings 0 ( 0) 0 ( 0) 0 ( 0) *This case was not confirmed by histological diagnosis or by a dermatologist. �Table 8 Frequency Distribution of Baseline Symptoms Reported by Other Employees According to Exposure Category EXPOSURE CATEGORY SYMPTOMS Group I/II (N-41) ; Group III (N-23) # # () % () Z Skin irritation or burning 5 (12) 4 (17) Rash 7 (17) 4 (17) Acne or chloracne 5 (12) 4 (17) Thickening 1 ( 2) 0 ( 0) Hyperpigmentation 1 ( 2) 0 ( 0) Nail discoloration 1 ( 2) 0 ( 0) Other dermatologic symptoms 5 (12) 2 ( 9) Eye irritation or burning 4 (10) 0 ( 0) Eye discharge 1 ( 2) 0 ( 0) Swelling of eyelids 1 ( 2) 0 ( 0) Other ophthalmic symptoms 3 ( 7) 1 ( 4) Any history of liver dysfunction 0 ( 0) 0 ( 0) Any history of hepatitis 1 ( 2) 0 ( 4) Any history of yellow jaundice 1 ( 2) 0 ( 0) Any history of alcohol abuse 0 ( 0) 0 ( 0) Other hepatic symptoms 0 ( 0) 0 ( 0) Persistent body odor 1 ( 2) 0 ( 0) History of hyperlipidemia 0 ( 0) 0 ( 0) History of cancer 0 ( 0) 1 ( 4) �Table 9 Frequency Distribution of Baseline Physical Findings Reported by Physician for Other Employees According to Exposure Category EXPOSURE CATEGORY PHYSICAL FINDINGS Group I/II (N=41) // (%) Group III (N-28) # (%) Erythema 5 (12) 1 ( 4) Rash 9 (22) 7 (30) Chloracne 0 ( 0) 1* ( 4) Hyperpigmentation 2 ( 5) 1 ( 4) Thickening 3 ( 7) 6 (26) Nail discoloration 4 (10) 0 ( 0) 19 (46) 4 (17) Other dermatologic findings Conjunctival Infection 2 ( 5) 2 ( 9) Eye discharge 0 ( 0) 0 ( 0) Swelling of lids 1 ( 2) 1 ( 4) Jaundice 0 ( 0) 0 ( 0) Hepatomegaly 0 ( 0) 0 ( 0) Other hepatic findings 0 ( 0) 0 ( 0) *This case was not confirmed by histological diagnosis or by a dermatologist, �Table lOa Plasma PCB Levels by Exposure Category for Allwash Employees Exposure Category Plasma PCB Level (Lab=PCL) Group I Group III 5.85 (62) 5.44 (41) -0.29 Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II 5.19 (27) 5.00 (19) - 0.26 5.09 (33) 5.12 (33) 0.03 Table lOb Plasma PCB Levels by Exposure Category for Other Employees Exposure Category i Plasma PCB Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p <0.05 **p < 0 . 0 1 tAnalysis of Variance p <.05 ttWilcoxon p <.05 6.64 (33) 5.97 (29) - 0.90 Group II Group III 5.75 (8) 5.25 (8) - 0.50 4.96 (23) 5.43 (23) 0.48 �Table lla Plasma PCB Levels by Exposure Category for Allwash Employees Exposure Category Plasma PCB Level (Lab=BRL) Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference 5.09 ( 4 6) 4.83 (46) t -0.73 Group II 4.19 (27) 3.44 (18) t -0.94 Group III 4.30 (33) 4.24 (33) t -0.06 Table lib Plasma PCB Levels by Exposure Category for Other Employees Exposure Category Plasma PCB Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p <0.05 **p <0.01 t Analysis of Variance p <,.05 ft Wilcoxon p < . 0 5 6.52 (33) 5.62 (29) -1.48 Group II Group III 5.25 (8) 4.50 (8) -0.75 5.36 (22) 4.57 (23) -0.86 �Table 12a SCOT Levels by Exposure Category for Allwash Employees Exposure Category SCOT Level Group I Group III 27.62 (67) 26.94 (67) -0.68 Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II 26.78 (27) 24.67 (27) -2.11 25.39 (33) 27.03 (33) 1.64 Table 12b SCOT Levels by Exposure Category for Other Employees Exposure Category SCOT Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p < 0 . 0 5 **p< 0.01 tAnalysis of Variance p <.05 ft Wilcoxon p <.05 Group II Group III 23.33 (33) 25.18 (33) 1.85 21.44 (8) 22.00 (8) 0.56 23.46 (23) 27.26 (23) 3.80 �Table 13a SGPT Levels by Exposure Category for Allwash Employees Exposure Category SGPT Level Group I Group III 26.33 (66) 26.66 (67) 0.42 Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II 24.56 (27) 21.56 (27) -3.00 19.39 (33) 22.09 (33) 2.70 Table 13b SGPT Levels by Exposure Category for Other Employees Exposure Category SGPT Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p< 0.05 **p< 0.01 tAnalysis of Variance p <.05 ttWilcoxon p <.05 Group II Group III 27.96 (33) 24.67 (33) -3.29 19.31 (8) 20.50 (8) 1.19 21.55 (23) 22.70 (23) 1.14 �Table 14a GGTP Levels by Exposure Category for Allwash Employees Exposure Category GGTP Level Group I 27.47 (61) 31.15 (67)tt 4.20 Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group 11 33.38 (26) 27.89 (27)tt -5.88* Group III 33.70 (30) 20.48 (33)tt -12.83* Table 14b GGTP Levels by Exposure Category for Other Employees Exposure Category GGTP Level Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p <0.05 **p < 0.01 tAnalysis of Variance p <.05 ttWilcoxon p <.05 Group I Group II Group III 25.88 (32) 22.30 (33) -3.50 17.30 (8) 19.00 (8) 1.70 26.53 (20) 16.87 (23) -9.53** �Table 15a Triglyceride Levels by Exposure Category for Allwash Employees Exposure Category Triglyceride Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II Group III 122.19 (67) 116.91 (32) 14.03 104.63 (27) 73.29 ( 7) -15.14 153.33 (33) 153.27 (15) 19.20 Table 15b Triglyceride Levels by Exposure Category for Other Employees Exposure Category Triglyceride Level Group I Entrance Exam Mean (N) . Last Exam Mean (N) Mean Difference *p <0.05 **p <0.01 tAnalysis of Variance p <.05 ftWilcoxon p <.05 113.27 (33) 109.13 ( 8) -14.50 Group II 75.88 (8) 57.50 (4) -16.25 Group III 131.57 (23) 113.17 ( 6) -2.50 �Table 16a Cholesterol Levels by Exposure Category for Allwash Employees Exposure Category Cholesterol Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II 190.57 (67) 179.03 (32) -9.44* 172.89 (27) 165.14 (7) -15.00 Group III • 193.00 (33) 189.35 (17) -7.12 Table 16b Cholesterol Levels by Exposure Category „ for Other Employees Exposure Category Cholesterol Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p <0.05 **p <0.01 t Analysis of Variance p <.05 tt Wilcoxon p <.05 Group II Group III 218.82 (33) 199.50 ( 8) -6.75 199.75 (8) 200.00 (4) 15.00 207.30 (23) 201.17 ( 6) -9.33 �Table 17a HDL Levels by Exposure Category for Allwash Employees Exposure Category HDL Level Group I 49.10 (67) 49.22 (32) -1.88 Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference Group II 51.04 51.14 -5.43 (27) ( 7) Group III 50.76 (33) 64.82 (17) 14.41 Table 17b HDL Levels by Exposure Category for Other Employees Exposure Category HDL Level Group I Entrance Exam Mean (N) Last Exam Mean (N) Mean Difference *p <0.05 **p <0.01 tAnalysis of Variance p <.05 ttWilcoxon p <.05 Group II Group III 47.54 (33) 48.75 ( 8) 0.54 54.50 (8) 55.25 (4) 2.50 51.46 (23) 47.17 ( 6) -1.67 �Table 18a Summary of Regression Analysis for Allwash Employees Parameter PCB (PCL lab) PCB (BRL lab) SCOT SGPT GGTP Sample Size Intercept 92 96 126 126 126 5.33 4.56 26.29 24.77 31.39 Slope -0.0001 -0.0002 0.0003 -0.0006 -0.0054 Table 18b Summary of Regression Analysis for Other Employees Parameter PCB (PCL lab) PCB (BRL lab) SCOT SGPT GGTP *p < .05 Sample Size 59 59 63 63 63 Intercept 5.88 5.55 23.99 23.03 . 22.25 Slope -0.0003 -0.0006 0.0021 0.0005 -0.0031* �Table 19 Summary of Statistically Significant Results (p < .05) Name of Test Paired t-test Subset and Parameter Sample Size p Value Allwash, Group I, Cholesterol Allwash, Group II, GGTP 32 .0483 26 .0230 Allwash, Group III, 30 .0133 Others, Group I/II, PCS (BRL) 37 .0374 Others, Group III 20 .0001 97 .0257 GGTP GGTP Analysis of Variance Allwash, PCB (BRL) Wilcoxon Rank Sura Allwash, GGTP 127 .0333 Regression Others, GGTP 63 .0424 �Table 20 Frequency Distribution of Symptoms Reported by Allwash Employees on Medical Incident Reports* According to Exposure Category EXPOSURE CATEGORY SYMPTOMS t Group I (* *) # Group II (**) # Group III (**) Dermatological : skin irritation/itching acne/rash 0 1 ( 0) (.005) 1 0 (.002) ( 0) 2 2 (.001) (.001) Ophthalmological : eye irritation/burning 2 (.011) 3 (.005) 9 (.005) Respiratory: dyspnea chest pain congestion sore throat 0 0 0 0 ( ( ( ( 0) 0) 0) 0) 1 1 0 0 (.002) (.002) ( 0) ( 0) 3 3 4 3 (.002) (.002) (.002) (.002) 2 9 (.011) (.049) 3 0 (.005) ( 0) 4 33 (02 .0) (.019) 0 ( 0) 0 ( 0) 25 (.014) 1 6 2 3 1 0 (.005) (.033) (.011) (.016) (.005) ( 0) 3 6 2 3 4 0 (.005) (.009) (.003) (.005) (06 .0) ( 0) 9 35 1 5 14 2 (.005) (.020) (.001) (.003) (08 .0) (.001) Musculoskeletal : lacerations/ abrasions blunt trauma/bruises and minor accidents musculoskeletal pain Other : dizziness/lightheadedness nausea/vomiting abdominal pain heat stress/diaphoresis headache palpitations *More than one report may be included for the same individual. **Number of reports divided by average number of hours in BSOB for each group: 1=184, 11=634, 111=1757. �Table 21 Frequency Distribution of Sources of Equipment Failure Reported by Allwash Employees on Exposure Incident Forms* According to Exposure Category EXPOSURE CATEGORY Group I (* *) Group II # (**) TYPE OF EQUIPMENT FAILURE # Tear in Tyvek Suit with Little Likelihood of Skin Contact 17 (02 .9) 30 (.047) 74 (02 .4) Dampening or Soiling of Tyvek Suit with No Break in Seal 11 (00 .6) 15 (04 .2) 70 (00 .4) 6 (.033) 12 (.019) 26 (.015) 18 (08 .9) 48 (06 .7) 128 (.073) 6 (.033) 12 (.019) 22 (.013) Malfunction of Respirator ( . . , loss of seal) ie 16 (.087) 25 (.039) 60 (04 .3) Accidental or Deliberate Removal of Respirator 10 (.054) 19 (00 .3) 26 (.015) 1 (05 .0) 1 (.001) Tear in Tyvek Suit with Evidence of Skin Contact Tear in Outer Layer of Glove Tear in Glove With Evidence of Skin Contact Reported Safety Violation with No Potential for Direct Contact 0 ( 0) Group III # (* *) *More than one report may be included for the same individual. **Number of reports divided by average number of hours in BSOB for each group: 11=634, 111=1757. 1=184, �Table 22a Distribution of Allwash Employees Filing Exposure Incident Reports According to Exposure Category Number of Allwash Employees Number of Exposure Reports Filed Group I Group II Group III 5 60 15 5 6 - 10 6 10 11 11 - 30 1 3 19 0- Table 22b Relationship Between PCS Blood Levels* and Frequency of Exposure Incident Reports Filed by Allwash Employees PCB Blood Level (ppb) Frequency of Reported Potential Contact ND - 5 6-10 10-16 39 18 1 Occasionally (6 - 10) 12 9 0 Frequently (11 - 30) 17 4 0 Rarely (0 - 5) *PCB blood levels are the highest values reported by either laboratory at the time of exit exam or most recent interval exam. �Table 23 Summary of PCB Blood Levels and Liver Function Tests for those Individuals Filing More Than Twenty Exposure Incident Reports ID # # of Hrs. in BSOB ALK. PHOS. BILI SCOT SGPT GGTP PCB (PCL) PCB (BRL) _ 3097 2157 44 1.1 22 18 25 3145 759 72 0.5 23 15 16 5 4 3159 2726 42 0.6 33 39 12 - 3 3217 1912 44 0.7 22 18 12 - - 3269 1349 49 0.4 21 15 9 - 3 3289 1574 46 0.7 20 9 11 6 — 3 �Appendix A Normal Ranges for Selected Biochemical Parameters Parameter Bionetics Wilson Lourdes PCL PCB (ppb) N/A N/A N/A 0-20 0-30 SCOT (IU/1) 7-46 8-36 8-44 N/A N/A SGPT (IU/1) 0-50 2-32 3-38 N/A N/A GGTP (IU/1) 8-37 0-42 15-85 N/A N/A 10-150 47-180 20-200 N/A N/A 120-200 150-250 150-250 N/A N/A 30-65 - 25-58 N/A N/A Triglycerides (mg/dl) Cholesterol (mg/dl) HDL cholesterol (mg/dl) BRL � 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. 089 Folder The folder containing the original item. 2269 Series The series number of the original item. Series IV 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 Gleit, Alan Arnelle G. Cohen Kenneth H. Chase Title A name given to the resource Typescript: Draft Summary Report of the Medical Surveillance Program for the Binghamton State Office Building Decontamination Project, August 7, 1985 Subject The topic of the resource BSOB health monitoring health studies 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. 0691 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 Gunby, Phil Source A related resource from which the described resource is derived Journal of the American Medical Association Date A point or period of time associated with an event in the lifecycle of the resource August 17 1979 Title A name given to the resource Plenty of Fuel for Agent Orange Dispute Subject The topic of the resource dioxin health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 034 Folder The folder containing the original item. 0692 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 Gunby, Phil Source A related resource from which the described resource is derived Journal of the American Medical Association Date A point or period of time associated with an event in the lifecycle of the resource April 6 1979 Title A name given to the resource Dispute Over Some Herbicides Rages in Wake of Agent Orange Subject The topic of the resource EPA litigation health studies ao_seriesIII