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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 094 Folder The folder containing the original item. 2384 Series The series number of the original item. Series IV Subseries IV Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Source A related resource from which the described resource is derived Settimana 3 Date A point or period of time associated with an event in the lifecycle of the resource 1984-03-01 Title A name given to the resource Il Verde Degli Alberi Lungo Vai Vignazzola Subject The topic of the resource health studies ecological recovery https://www.nal.usda.gov/exhibits/speccoll/files/original/cad3267cb5be106cd2eadd6b51b80537.pdf 144a9fe99edccaec58d3ce77c9e660f3 PDF Text Text ItomD Number °2292 Author Corporate Author Report/ArtlGlB TltlB Form: BSOB Medical Surveillance, NYS Department of Health Journal/Book Title Yeer Month/Day Color Number of Images D 6 Dascrlpton Notes Thursday, September 20, 2001 Page 2292 of 2293 �7 BSOB MEDICAL SURVEILLANCE NYS Department of Health Section II. Interval History Patient's Name_ ss# Employer Date of Birth: Date of Exam: During the past 8 or 9 months, since your first exposure to the Binghamton State Office Building (BSOB) after the fire, (Feb. 5, 1981), have you have any of the following: YES NO UNKNOWN (If yes, provide specific details on comment page) 1. Excessive weight loss (10 Ibs. or more) 2 . Excessive weakness 3. Changes in coloration of the skin p D D Itching of the skin 4. a 5 . Thickening or scaling of the skin f 6 . Acne 7. Inflamation of sweat glands 8. Rash or dermatitis 9 . Headaches 10. Dizziness 11. Discharge or infection of the eye 12. Swelling of eyelids 13. Burning or pain in eyes a D a p p 14 . Changes in vision 15. Frequent coughing 16. Trouble with breathing 17. Heart trouble 18. Loss of appetite 19. Pain in abdomen 20. Nausea or vomiting 21. Changes in bowel habits Jaundice Hepatitis or liver problems CC-323 a a P a p a a D Q P a a a a a a a a a p p a a a P n p a p a a a a a a a D D D a a a a a D d a a D p p p a a �ss# Patient's Name Interval History (continued) YES NO UNKNOWN (If yes, provide spec ifi details on comment page 24. Trouble with urination 25. Abnormality in menstrual cycle (female only) 26. Pregnancy (females and wives of male workers) 27. Difficulty becoming pregnant (females and wives of males) ^ 8 2 . Numbness in the extremities 29. Muscle pain >^30. Clumsiness of movement 31. Hearing difficulties 32. Nervousness or sleep problems 33. Cancer of any type 34. Other noteworthy symptoms or illnesses Please specify • BSOB - DOH p.2 CC-323 D Q n a n a n D a P D a a a a D a LJ a a a D r•*» D n n n a D a n D a �SS# COMMENT PAGE Patient's Name (1) Complaint Number (2) Describe the Complaint in Greater Detail (3) Duration of Complaint From (Month - (4) Was Patient Seen by a Physician To Year) Yes N (Month Year) n °n If yes - A. Name of Physician B. Physician's Address C. Was a Diagnosis Established Yes No If yes, what was the Diagnosis D. Was Patient Hospitalized If yes, Name of Hospital Addre s s Date of Admission BSOB - DOH - P.3 CC-323 Yes No Don ' t Recall �BSOB MEDICAL SURVEILLANCE - DOH Section III. PHYSICAL EXAMINATION Patient's Name:__ Employer: .. - ; - _Social Security #: , Date of Birth: Date of Exam: (a) Height (in.) (b) Weight (Ibs.) (d) Pulse (e) Resp. (f) BP (g) Visual Acuity R General Appearance: Nl d (c) Temp. or Distressed Female { jWhite Black [] ~ Other Skin - specify-if the following are present Yes No Yes No a. Erythema P. g. Hyperpigmentation D Q D b. Rash h. Thickening Q P D c. Acne-like lesions D i. Nail discoloration p P D 'd. Depigmentation Q p j. Jaundice m e. Inclusion cysts k. Spider angiomata p D D f. Petechiae Q j-j 1. Ecchymosis p nu Other p Spec i fy: • Abn n a a a a If yes for a-m, specify location and describe in detail: Nl n Abn n 4. Eyes Yes a. Conjunc. injection b. Eye discharge c. Swelling of lids d. Abnormal pigment e. Other n Nl n Abn 5. Liver and Abdomen a. Hepatomegaly b. Tenderness c. Other masses BSOB-DOH- p-4 CC-323 P P P P .. P No P P P P P Yes No P P P P P P Specify: cm. liver span Specify:_ �Physical Exam (Continued) Patient's Name NL D a a Social Security # Abn C3 6 Neurological a a a . Gait b. Muscle strength - specify if decreased: 'Yes No I. Distal wrist extensors Q Q II. Ankle/toe Dors/Flexors III. Deltoids D IV. Hip Plexors D V. Hip Extensors Abn. c . Abnormal movements Specify : Abn a a a n D a a a R R R R a a a B a L a a p .* n L 0 L "Q d . Coordination fl n a P R Specify: Nl Abn a Q e. Reflexes: Biceps, Triceps, Patellar, Achilles, Bafoinski indicate on diagram (0-absent, 1-sluggish, 2-*ctive, 3-very active, 4-clonus) Nl Abn f, P a Sensory system - specify if decreased I. II. III. IV. No Cranial nerves - specify any abnormalities Nl a Yes Touch P Pin Prick D Vibration (ankle) Q Position (great toe) m If yes for I-IV, . specify location DDDD ' Q BSOB-DOH- p-5 cc-323 Ra R a R R a a sfi L LD n �Patient's Name . Social Security #: Physical Exam (Continued) Nl I—I Abn I—i 7. Head and neck - specify abnormalities: I—I i—I 8 D CH 9> D D 10. j~J Q 11. Heart Q [D 12. Back CD D 13. Extremities ' *}odes leasts Lungs 14. Genitalia (pelvic exam, optional) 15. Rectal Yes No D D D D 16. Recommendations and/or referrals D D b. " c Examiners,Signature Comments: BSOB-IDOH p,6 CC-323 � 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 2292 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/. Title A name given to the resource Form: BSOB Medical Surveillance, NYS Department of Health Subject The topic of the resource BSOB PCBs health studies survey https://www.nal.usda.gov/exhibits/speccoll/files/original/9a40182060c8221148d270c09a67141c.pdf 6d25ad4eae1cc8b2c351e8e150ee996c PDF Text Text Item D Number 02291 Author Corporate Author Report/Article TltiO Form: Binghamton State Office Building PCB Screening, [nd] Journal/Book Title Year Month/Day Color Number of uneoes D 5 Descrlpton Notes Thursday, September 20, 2001 Page 2291 of 2293 �BINGHAMTON STATE OFFICE BUILDING PCS SCREENING () 1 Record # JJ_ J_ (2) Card # J__ J_ 1 2 (4) 3 Date: Mo. Day (3) ID # 4 Yr. 9 10 11 12 __ ; 5 6 7 8 (5) Exposure Status 13 14 15 I WOULD LIKE TO BEGIN BY ASKING YOU SOME BASIC QUESTIONS ABOUT YOURSELF. BACKGROUND INFORMATION (6) Name (7) Soc. Sec. (8) Home address (9) Home phone: ft ^ 16 17 18 19 20 21 22 23 24 (10) Work address (11) Work phone (12) Employer (13) Job title (14) Job description (15) Date of birth Mo Code 25 26 27 Day 28 (16) 29 Yr. 30 31 32 33 Marital Status (read choices to respondent) 1 » Currently Married 2 = Currently Divorced 3 => Currently Separated 4 =* Currently Widowed 5 « Never Married 8 = Don't Know (DK) 9«=No Response (NR) 34 (THE INTERVIEWER COMPLETES THE NEXT TWO QUESTIONS C16 and 17) WITHOUT ASKING THE RESPONDENT.) (17) Sex 1 = Male 2 =» Female 35 (18) Race 1 • White 2 « Black 3 « Hispanic 4 - Other 36 THE NEXT SET OF QUESTIONS DEALS WITH YOUR ACTIVITIES IN OR AROUND THE BSOB AT THE TIME OF THE FIRE (FEBRUARY 5, 1981) AND AFTERWARDS. �EXPOSURE (If yes, complete below. ( 9 Were you in: 1) Total f of Times 88=DK 99=NR 1 = Yes 2 = No 8 = Don't Know (DK) 9 =>. No Response ( R N) (a) The BSOB (including its basement and 37 sub-basement) Q H (b) City Building (including its basement and sub-basement) 57 If nof DKf or NR, skip to 20.) Total # of Hours 888=DK 999=NR 000=Less than 1 First Date Mo. Day ?r. 88=DK 99=NR Last Date Mo. Day Yr. 88=DK 99=NR Code Activities 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 (ID) Keypuncher - Start new card: 0 1 ( ) County Building c (including its basement s sub-basement) 1 2 0 3 2 4 5 6 7 8 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 (d) Garage 29 Level 1 2 3 4 (Ask e only if answers a through d are no.) .st = 1s"" Floor (Ground) = Basement = Sub-basement . » Combination 8• = DK (e) Only exposed to materials outside the buildings 50 51 52 53 54 55 56 57 58 59 60 61 49 9 = NR 62 63 64 65 66 67 68 69 �ID - 3- (If respondent was in BSOB, complete below. (20) If not, skip to 23.) What sections of the BSOB were you in? Floor 19=»Base 88»DK Boom/Location Code 20«Sub-B. 99=NR (a) 70 71 72 73 74 75 76 77 (b) (ID) Keypuncher - Start new card: 0 1 1 2 0 3 3 4 5 6 7 8 (0 11 12 9 10 (21) Did you wear protective gear while you were in the BSOB? 1 » Yes 2 - No 8 « DK 9 » NR 13 (If yes, complete below. If no, DK, or NR, skip to 22.) Code (a) Type of gear:_ 1415 (b) How often did you wear this gear while in the BSOB? (Read choices to respondent.) 1 = Always 2 « Usually 3 « Sometimes 4 = Rarely 8 = DK 9 « NR 16 (22) Additional information regarding possible routes of exposure would also be helpful... For example, despite protective gear or other precautionary measures, do you believe that you may have been exposed for any reason through the: 1 = Yes 2 - NO 8 » DK 9'» NR (a) Skin 17 (b) Oral 18 (c) Nasal 19 (d) Eyes 20 Specify: (e) Other 21 �- 4- (23) ID Did you have any chemical exposures prior to the BSOB fire? 1 « Yes 2 • No 8 - DK 9 « NR _^ 22 (If yes, complete below. If no, DK, or NR, skip to 24.) Code Type of Exposure 23* 24 Earliest Yr. of Exposure 88-DK 99-NR Latest Yr. of Exposure 88-DK 99-NR 2T26 (24) 27 28 Have you had any chemical exposures outside the BSOB since the fire? 1 » Yes 2 • NO 8 « DK 9 « NR 29- (If yes, complete below. If no, DK, or NR, skip to 25.) Code Type of Exposure 30 31> Latest Date MO of Exposure 88*DK 99«NR (25) Day 32 33 Yr. __, 34 35 36- 37'" IN ORDER TO COMPLETE OUR STUDY, I ALSO NEED SOME INFORMATION CONCERNING YOUR MEDICAL HISTORY AND HEALTH HABITS. MEDICAL HISTORY Before the time of the BSOB fire, did you have any of the following health problems? 1 = Yes 2 » No If yes, complete below. If no, DK, or NR, skip to 26.) 8 « DK 9 • NR Date of Dx Code Specify Month Year 88=DK 99=NR (a) Tumor or Cancer 38 55 56 57 58 59 60 61 63 64 6 " 66" 5' 67 68 69 70 (e) 51 52 53- 62 (d) 47 48 49 50 54 (c) 43 44 45 46 (b) 39 40 41 42 71- 72 73 74 Ts 76~77 Liver Problem Neurological Problems Skin Problems Unusual loss of wt. of 10 Ibs. or more Keypuncher - Start new card: £_ 1__ 0_ 4_ 1 2 3 4 (f) 5 6 7 8 Code Other medical problems 10 11 12 13 �- 5- (26) ID _ Do you take any drugs or medication on a regular basis? 1 <» Yes 2 9 8 m DK No NR Code 17 18 19 20 If yes, specify: (27) Do you have any allergies? 1 » Yes 8 - DK 2 9 No NR ,2.1 If yes, specify5 HEALTH HABITS (28) Have you ever smoked any of the following tobacco products? (If yes, go to corresponding section of 29. jf no, DK, or NR, skip to 30 ) 1 = Yes 2 • No 8 • DK 9 « NR (b) Cigars (a) Cigarettes (29) (c) Pipes 26 25 27 Do you currently smoke: (If yes, complete below. Amount If no, DK, or NR, skip to 29.) 00 - Less than 1 *• of Years Cigarettes/Day 31 32 29 30 1 » Yes 2 » No 8 = DK 9 - NR (a) Cigarettes 28 Cigars/Day (b) Cigars 33 34 35 36 37 39~ 40 41 42 Bowls/Day (c) Pipes 38 (If response is a fraction, round u£ to nearest whole number.) (30) Have you ever used any of the-following"alcoholic beverages? 1 » Yes 2 • No (a) Beer 8 « DK 9 = NR (b) Wine 43 (31) 44 (If yes, go to corresponding section of 31%) (If no, DK, or NR, skip to 3ZJ (c)Liquor/ Mixed Drinks 45 Do you currently use: 1 - Yes 8 « DK 2 » No 9 a NR (a) Beer 46 (b) Wine (If yes, complete below. -amount 00 == Less than 1 12 oz Bottles, Cans ; or Glasses/Wk 47 48 If no, DK, or NR, skip to 32) # of Years 49 50 4 oz Glass/Wk 51 (c) Liquor/ Mixed Drinks 56 52 53 54 55 57 58 59 60 Drinks with ih oz liquor/wk (If respondent is a fraction, round up to nearest whole number.) (32) THIS CONCLUDES OUR INTERVIEW. THANK YOU VERY MUCH FOR YOUR TIME AND EFFORT. DO YOU HAVE ANY QUESTION I MAY HELP YOU WITH? � 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 2291 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/. Title A name given to the resource Form: Binghamton State Office Building PCB Screening, [nd] Subject The topic of the resource BSOB PCBs health studies survey 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 085 Folder The folder containing the original item. 2154 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/. Description An account of the resource Corporate Author: Missouri Department of Social Services, Division Health Date A point or period of time associated with an event in the lifecycle of the resource October 16 1983 Title A name given to the resource Two letters, a press release and the Executive Summary of the Progress Report: All items in regards to the Missouri Dioxin Health Studies and dated October 16, 1983 Subject The topic of the resource Missouri Dioxin Study human exposure health studies https://www.nal.usda.gov/exhibits/speccoll/files/original/dc80f0e2697784f922fac44cf29999c8.pdf 25c9af408e6744bd9775c9c9f4e62794 PDF Text Text °1483 Item ID Number Author Corporate Author ROpOTt/ArtiClO Title Typescript: Statement of Dr. Philippe Shubik, Senior Research Fellow, Green College, Oxford University Journal/Book Title Year 000 ° Month/Day Color Number of miaous n 19 Descripton Notes Tuesday, May 15, 2001 Page 1483 of 1514 �Statement of Dr. Philippe Shubik Senior Research Fellow Green College Oxford University Ecclesiastes 3:22 Wherefore I than that a for that is to see what perceive that there is nothing better, man should rejoice in how own works: his portion: for who shall bring him shall be after him? Ecclesiastes 2:1 Then I looked on all the works that my hands had wrought, and on the labour that I had laboured to do: and, behold, all was vanity and vexation of the spirit, and there was no profit under the sun, Ecclesiastes 8:1 Who is as the wise man? and who knoweth the interpretation of a thing? a man's wisdom maketh his face to shine, and the boldness of his face shall be changed. �The historical background of a role for chemical carcinogenesis in toxicology The knowledge that chemical compounds or mixtures of them might cause cancer originates from clinical studies of occupationally exposed groups. The classic instance quoted frequently in textbooks concerns the discovery that chimney sweeps in England in the 18th century developed cancer of the scrotum from prolonged exposure to soot begun in early youth. This observation by the English surgeon of note, Percival Pott, stimulated many experimental studies at the end of the 19th century and the beginning of the 20th. Various research workers tried to reproduce this disease in laboratory animals by painting solutions of soot and the related coal tar on different laboratory animals. They were uniformly unsuccessful until two Japanese research workers, Yamagiwa and Itchikawa persisted in their studies and continued to paint coal tar on the skin of the rabbit ear for many months. These workers were not only persistent but were fortunate to have chosen the right tissue in the right animal. The factors involved in the success of this study have influenced the design and interpretation of many of the routine studies undertaken since that time. It is realized that it is often difficult to obtain a positive finding even with a chemical known to cause cancer in man. The dose, the route of application and the species used as well as the length of the experiment are" crucial factors in obtaining a valid result. During the period between the discovery of the cancer causing effects of coal tar and 1946 the subject of chemical carcinogenesis was largely confined to two major areas of investigation. Firstly instances of occupational or so-called iatrogenic (drug or treatment) induced cancers were investigated both in human populations and the laboratory. Thus the causation of human bladder cancer in the aniline dye industry was finally elucidated when it was found initially that the chemical 20napthylamine caused the same type of cancer to occur in the dog; this time the positive finding took up to 7 years of administration of very large doses of the chemical to achieve. This finding determined the future course of much of the testing; the species, the time of the experiment as well as the very high dose required added other factors to be taken into account in determining the validity of studies. In the instance of the coal tar observations it was found that a single compound polycylic hydrocarbon, called benzo(a) pyrene seemed to be the principle component responsible to the cancer producing effect. (Subsequent �- 2 studies have shown that it is probably that this is only one of several similar compounds with this property; these many years later this area still requires more work). It became apparent that this compound usually abgreviated to B(a)P was ubiquitous in the human environment. It occurs as the result of combustion of organic matter and is found in small quantities in polluted atmospheres, cigarette tobacco tars, charcoal broiled meats, etc. The significance of these lower levels in the causation of human cancer is anyone's guess. In fact these so-called lower levels are, in the instance of the charcoaled meats in the range of several parts per million; with newer analytical methods this would be considered to be a high level. Common sense contemplation tells us that atmospheric pollution as seen in modern urban environments is not a major factor in the current epidemic of lung cancer; cigarettes are unequivocally a (if not THE) major factor; yet there is usually more available B(a)P in the polluted atmospheres. Other cancer causing chemicals identified in the smoke of the cigarette seem to be more likely candidates. Indeed there are a large range of potent animal carcinogens present in cigarette smoke including representatives of several different chemical classes and radio-active particles. Thus in the instance of the best established human carcinogen affecting the general population the research worker is faced with a mass of information and has not yet been able to sort out the mechanism or precise factor(s) concerned. In this instance it is, of course, possible to control the disease by stopping smoking of cigarettes; it is not, however, possible to introduce a "safe" cigarette with any degree of confidence. Other practical aspects of research into the other causes of cancer involved the demonstration that certain medical procedures such as the use of certain diagnostic procedures such as the use of a radioactive material, Thorotrast, used for outlining parts of the body to be x-rayed caused local cancers; naturally occurring hormones were found to be able to cause certain kinds of cancer in animals and this correlated well with observations in the human. In the late 1920's a major event to have a considerable effect on this era was the discovery that a food additive known as "butter yellow" (chemically p-dimethylaminoazobenzene [dab]) could give rise to liver cancers when fed to rats. This finding was particularly influential in the development in the 1940's of routine testing of food additives for possible cancer producing effects in animals. Butter Yellow (dab) was no longer permitted for use even though there was no evidence that it had had any effect on the cancer incidence in man. �- 3 In the instance of a deliberately added food additive no one wishes to know whether or not it was a human carcinogen; it was felt more prudent to assume that it might be potentially hazardous and to get rid of it. Since the use of this compound was not particularly important economically this posed none of the problems encountered later. Indeed this same dye was used to colour chemical smoke for military purposes and it was said by the late Dr. W.C. Hueper of the U.S. National Cancer Institute on several occasions but without published figures that no occupational hazard had been observed from massive exposure to this compound in the U.S. arsenal. Even if this were the case few would have advocated reintroducing this compound in the U.S. arsenal. Even if this were the case few would have advocated reintroducing this compound in the food supply. A second key incident was the testing of a proposed pesticide then called 2-acetylaminofluorene in rats for a two year period by a series of research workers in the U.S. Department of Agriculture's research facility. This compound proved to be a new kind of cancer producing agent giving rise to many cancers in many different organ sites. As time has gone on this chemical has proved to be an invaluable tool for the research worker. However the impact of this study was to result in the beginning of long term routine testing of food additives and pesticides notably in the U.S. regulatory agencies. This leads us into the next era starting in the 1940's and I will deal with this later. The second major approach taken to research into chemical compounds causing cancer subsequent to the discovery of the effects of coal tar components was a major effort to try and understand how these compounds worked. Needless to say this effort continues and above all things it must be borne in mind when considering the practical aspects of cancer control that we still do not understand and the mechanisms of action of a single causal factor of cancer and do not understand~iEhe nature of cancer.Theories abound and some are based on enough facts to be useful guidelines for preventive measures. Studies into this field between 1920 and the end of the 2nd World War took three distinct approaches; first a series of compounds closely related to those first discovered (B[a]P, or dab) were synthesized by able chemists and tested in animals usually by painting them on the skin or injecting them subcutaneously in the first case or feeding them in the second instances. It was hoped that a clear cut relationship between chemical structure and biological activity would be established and that, from this, a mechanism of action would be obvious. This logical idea was doomed to failure. For these two decades it was firmly believed that only a very few types of chemical structure had the capability of giving rise to cancer and the older cancer research workers were quite �- 4unprepared for the great onslaught when many new types of compound were demonstrated to have somewhat similar activity. The second approach was to study the metabolism or these established cancer producing agents in animal systems. The studies revealed that some compounds seemed to have to be changed into other forms before they became active; this type of study which is painstaking and long term still continues and a large body of knowledge has been accumulated which has both practical implications to control and can be counted upon to play a major role in the eventual understanding of mechanisms. The third approach was the investigation of biological and pathological factors affecting the process of cancer induction. For example one scientists, Deelman, in the 1920's found that he could greatly augment the effects of skin application of coal tar by incising the skin simultaneously. The healing would appeared to enhance the cancer producing effects. This and a variety of other studies resulted in the demonstration that at least for cancer induction in the skin it seemed likely that a multiphased process was involved. This has led to many studies on so-called "Initiation" and "Promotion." Other factors were found to inhibit the action of these compounds and studies led to the discovery of many of the modern chemotherapeutic drugs now in use. Much of this work was stimulated by the discovery that mustard gas (also known to be able to induce cancer) could inhibit cancer induction. Many efforts were made to study the effects of different routes of administration of chemicals and it was found that this was of great significance; certain compounds active on the skin had no apparent effect when administered by mouth and visa versa. It was observed that many experimental rodents developed tumours in the untreated state and that chemicals could be seen sometimes to have a dual effect - both inducing local cancers at the site of administration and "augmenting" the incidence of some of these "spontaneous" cancers. The distinction between these two effects still puzzles the research workers and poses a major problem in the assessment of modern cancer bioassays in practical terms. This early era involved the discovery that changes perhaps equatable with cancer - could be produced in tissue cultures. The knowledge that many species differences existed was noted with interest and formed the basis for interesting discoveries into mechanisms of action later on. A discovery made accidentally by Oppenheimer at the end of this first era, that inert plastics implanted under the skin of rodents �- 5 caused cancer, gave rise to great confusion which, in truth, has never been dissipated. All the theories of chemical interactions being essential for the production of cancer seemed to require revision. At the same time it became apparent that certain results attributed to specific chemicals might, in fact, be quite non-specific and only a result of the physical nature of the material. SUMMARY The first era of the scientific study of chemical carcinogens spanning the period from 1918 to the end of the Second World War established a large base of knowledge that several groups of chemicals could be shown to be responsible for cancer in man and that these cancers could in most instances be reproduced in animal models. The first inroads into understanding of mechanisms of action were made. At the same time a series of other chemicals were found to be capable of inducing different kinds of cancers in animal systems. It started to be apparent that this characteristic of chemicals was not as limited to a few types of chemical structure as originally appeared. The different end points possible in bioassays introduced complexity that had not originally been anticipated. THE PRESENT ERA For the purposes of this discussion the present era will date from the end of the Second World War, although in truth major changes started taking place about 10 years later. The first area of concern about the effect of chemicals, and particularly new chemicals as potential causes of cancer centered around the food additive and pesticide problem. More food additives and more widespread use of pesticides that resulted in residues in food appeared during this era than perhaps altogether before that time. Initially these chemicals were tested in a bioassay that was designated as a 2 year chronic toxicity test. This test was undertaken using the rat as the principal species although some tests were done in mice. It was presupposed that this test would uncover a variety of possible chronic effects and there was no special emphasis placed on this test as one for carcinogenesis. The well known toxicologists, Barnes and Denz from the U.K. believed such tests to be of little value and felt that a subacute test of three months, if conducted properly, would reveal the majority of toxic effects. Indeed their views eloquently expressed in a review article in 1953 in advance echoed some of our more modern attitudes. �- 6 In the course of some of the earlier chronic toxicity tests undertaken by the U.S. Food and Drug Administration many subsequent findings were predicted. D.D.T., for example, was found to be productive of liver tumours in mice; this was not considered to be of practical importance at that time since the tumors were all benign and only malignancies were thought to be of relevance. A variety of other food additives were found to augment or induce various tumors in rodents and some were banned as a result. By the 1960fs it had become apparent that the primary use of the chronic toxicity test was as a test for carcinogenesis and a survey of the literature reveals that little else was detected in such studies. In revising the Food Additives regulations in the 1960's the U.S. Congress took the far reaching and unusual step of singling out carcinogenesis as a special form of toxicity that required the regulatory agency to ban a compound. The freedom of the regulator to make a value judgement was removed. The regulation known as the Delaney amendment says, in effect, that any food additive found to give rise to cancer in man or in animal tests using an appropriate route of administration shall not be used. This drastic regulation was enacted after a considerable debate; a major factor in its adoption was research undertaken in Germany by Druckrey and his co-workers that had concluded that chemicals causing cancer acted by a mechanism that was different from other chemicals. Whereas the cumulative effects of the majority of chronic toxic effects were a result of an accumulation of the chemical in question the effects of cancer causing chemicals were visualized as an accumulation of irreversible changes in the cells. There were several reasons for believing this to be the case. The practical result of such a view of mechanisms was that no tolerance level for such chemicals could be determined; any dose whatsoever could be visualized as one that produced an irreversible cellular change that potentially could lead to cancer. Although there is much validity in some of the deductions drawn from some of these experiments it is also apparent that tolerance levels for carcinogens are likely to exist. Additionally the requirements of the Delaney amendment assume tests for carcinogenesis to be much more easily interpretable than is in fact the case. Since 1957 numerous bioassays of chemicals for cancer induction have been made and it is now quite apparent that many of these results are extremely difficult to assess. �- 7 In summary the Delaney amendment represents a gross over-simplification; any detailed re-examination of this legislation now would require a much more explicit statement on the details of the animal studies. The testing of food additives is emphasized since it preceded the other uses of such tests and set the stage for the use of these bioassays for chemicals of general environmental interest, as well as extending the procedures used for evaluating the potential toxicity of drugs. A comparison of the problems associated with the toxicity of drugs and of environmental contaminants illustrate almost opposite ends of the spectrum in several regards. The drugs are almost invariably administered in relatively high biologically active doses whereas the environmental contaminants are usually present at very low levels - often at levels that have only recently become detectable because of the numerous advances in analytical chemistry that have taken place. There is often little or no knowledge of the effects of these very low doses; they can only be inferred by theoretical extrapolation from studies undertaken at much higher doses. On the other hand the effects of the drugs are often found at levels quite comparable with those used under therapeutic conditions. Drugs, however, are usually visualized as useful, sometimes life saving, agents; environmental contaminant chemicals, on the other hand are only seen as undesirable. It is, therefore, the case that many drugs that are clearly potential cancer producing chemicals (some even with evidence obtained from human studies) are permitted for use whereas some other chemicals, often pesticides, resulting in contamination of the environment as parts per billion levels only have been banned. One of the clearest examples of this perhaps anomalous situation is the instance of the oral contraceptives where initial findings that liver tumors were induced on enhanced in experimental rodents was considered irrelevant to human health on the-basis that the endocrine physiology of the rodents was not similar to the human. Subsequent epidemiological studies revealed that these liver tumors did, in fact, occur in women taking these drugs, albeit at very low incidence. This finding has been ignored by regulators on the basis that the benefit of the oral contraceptives outweighs this level of risk. It may well be that this is an appropriate decision to have made for society and unfortunate that such leeway is not available in other instances. �- 8 The bioassay of chemicals for possible carcinogenic activity has proceeded particularly in the U.S. both in the regulatory areas where food additives, pesticides and drugs have largely been tested by manufacturers in order to obtain the necessary rights to market these products. These requirements are commonly applied in a similar manner on a world wide basis and many of these studies are carefully reviewed by committees of the WHO and FAO such as the Joint Expert Committee on Food Additives (JECFA) and the corresponding committee on pesticide residues (JMPR). Both these committees review procedures regularly and set approved levels for use of these chemicals. Although not bound in any way by such rigid and codified procedures as those in inherent in the U.S. food laws the philosophy inherent in the "Delaney amendment" has considerable influence on the decision making of these international bodies. More recently there has been a tendency to review this attitude and there is now a clear desire to try and introduce a more scientific and flexible judgement into these approaches. The National Toxicology Program (N.T.P.) of the U.S. has introduced another dimension into this problem. In this program selected chemicals are, in essence, "screened" for cancer induction in set tests in mice and rats; no account is taken of use conditions in many of the tests performed so far; thus the route of administration is not necessarily determined by use conditions and dosage rarely takes use conditions into account. This approach has resulted in the accumulation of much data showing some effect or another on tumor incidence in rodents and the practical significance of this data has been hotly debated. The assessment of such tests will be discussed at greater length in the next section. It is said that the protocols for these N.T.P. tests are to be modified and to be made more relevant to use conditions in the future. SUMMARY Certain specific product categories are now routinely tested for carcinogenicity according to planned protocols. Other more generalized long term animal tests are carried out notably in the U.S. in large scale "screening" programs. Many of the results obtained have been exceptionally difficult to interpret in practical terms. �- 9 Research patterns in chemical carcinogenesis: 1945-date The first part of this era was concerned with following up leads obtained in the three preceeding decades. Many new classes of chemical carcinogen were discovered. Some of these were more readily amenable to biochemical and molecular biological study and thus more in-depth investigation of the interaction of these compounds with cellular components has become possible. Also newer techniques of cell biologists involving the use of tissue cultures and of bacterial systems have played an increasingly important role in such studies. So far many of these interesting studies have not played a major role in understanding the meaning of the practical bioassays but it is not difficult to visualize a situation in which much of this research may well play a role in elucidating practical problems in the near future. Since the early part of this century Bovari's theory that cancer may be the result of a somatic mutation has been considered possible. In the past decade a series of techniques have been introduced for detecting mutations in various bacterial and other systems. There have been those who have wished to correlate this effect with chemical carcinogenesis; more recently of such correlations have been shown to be less and less predictive, A great deal of experimental work has been undertaken to expand the concepts of "initiation" and "promotion" but so far few basic mechanisms have been elucidated. CURRENT VIEWS ON CRITERIA FOR EVIDENCE OF CARCINOGENICITY OF CHEMICALS Criteria for assessing evidence for the carcinogenicity of chemicals were reviewed by a panel of the National Cancer Advisory Board of the U.S. in 1977. In its introductory statement this group stated that "The criteria that are described are guidelines and not rigid, universal criteria. The complexity of the problem dictates that the evaluation of potential human hazards of a given agent must be individualized in terms of the chemical and metabolic aspects of that agent, its intended use(s), the data available at the time the decision must be made, and other factors pertinent to the case under consideration. Each case must considered on its own and the criteria appropriate for one agent may not necessarily apply to another." This general statement of philopophy was accepted as still valid by a more recent committee which has addressed the same problems in an effort to update the situation. The report of this committee that I had the privilege of chairing will be published in the journal Science within the next few weeks and a preprint of the article has been made available to the Royal Commission. �- 10 This article deals with problems in assessing evidence derived from (1) Human studies, (2) Long term bioassays in animals, (3) Short-term tests, (4) Mechanisms of carcinogenesis, (5) Problems in extrapolation of experimental data, (6) the overall assessment process. The last section of this report is felt to be particularly pertinent to present discussions and is recorded below: The Overall Assessment Process Chemical carcinogenesis is a rapidly moving field, and great quantities of data have been accumulated during the past decade. Even though an individual experiment may yield only suggestive information, this information may be of considerable importance when considered together with other data. Clearly, when the primary source of data comes from epidemiological studies in man, it may be possible to evaluate a chemical and institute scientifically-based preventive measures. However, even in the instances where data are available from humans, the data must be supplemented with information from other sources before a conclusion can be reached. For example, toxicological evaluation of carcinogenicity has classically relied upon long term in vivo studies as the primary source of data. Such studies have been performed in a routine manner, and evaluations have followed predetermined formulas. This rote method is rapidly giving way to evaluations that take into account findings from vitro tests, metabolism studies, and biometric analyses as well as any other available information. One of these methods alone cannot produce a reliable estimate of a chemical's risk to man, but taken together they provide an estimate with a high level of confidence. Carcinogens act via different mechanisms, which results in their having different magnitudes of risk to man. Even though there is no basis for the exact extrapolation of risk from experimental animal to man, current advances, if exploited to the fullest, can provide a basis for distinguishing the degrees of risk from different carcinogens. The scientific criteria should be reviewed often, and scientific advances should be fully adopted. The scientific criteria should be reviewed often, and scientific advances should be fully adopted. The scientific characterization of human risks from carcinogens involves the evaluation and integration of data from nany disciplines. It requires scientific impartiality to review all appropriate data, both negative and positive, including statistical estimations of low-dose response. Quantitative characterization of human risk requires scientific experience and judgement. Because of the strengths and �- 11 weaknesses of the data to be evaluated in the assessment of human risk and the complexity of the problem, case-by-case analysis is most appropriate. Although it would perhaps be most reliable to quote extensively from this report in other areas certain specific matters can be dealt with in summary. Thus the report concurs with the findings of a recent IARC worker who concluded that although the distinction between carcinogens found to be mutagenic in short term tests and those that are not in most interesting it does not yet serve a purpose to divided carcinogens into genotoxic and non-genotoxic types. This does not preclude the use of knowledge of mechanisms in the evaluation of specific carcinogens. In certain situations, the particular mechanisms of action of some carcinogens provide guidelines for preventive measures. These situations include carcinogenic effects directly related to the hormonal changes caused by certain compounds and carcinogenic effects in the bladder caused by compounds that induce bladder calculi. These carcinogenic effects can be dealt with differently from those of compounds that induce cancer without the apparent intervention of other physiological or pathological factors. In spite of the inability to derive a generic classification of carcinogens, chemical carcinogens can, in principle, be divided into two types. One type gives non-threshold dose responses, is stochastic in mechanism, and has some probability of producing carcinogenic effects at any dose. The second type gives threshold dose responses and, theoretically, has a noeffect level. A few chemicals can be placed, provisionally, in one category or the other; but for the bulk of chemical carcinogens, we are currently unable to discern in which compartment they fall. By dealing with chemicals case-by-case and by studying mechanism, we can look forward to doing better than this. Individual Compounds 2, 4 dichlorophenoxyacetic acid (2,4-D) 2,4-D was reviewed by the IARC in 1977 (1) and again in 1982 () 2 . It is reported that there were studies in mice employing a combination of gavage and dietary administration. ( ) The 3 butyl, isopropyl and isoctyl esters were also studies. These 1969 studies used high doses and lasted 78 weeks. These studies were deemed to be inadequate as result primarily of the small numbers of animals used. It should be noted, however, that this was part of a large study of many pesticides; one group in this study recorded positive findings with DDT and this was considered to be an adequate demonstration of carcinogenicity. �- 12 Osborne-Mendel rats were fed for two years with diets containing 4,25,125,625 or 1250 mg/kg 2,4-D ( ) This study 4. has been variously reported. The original authors must be awarded a prize for recording one of the most confused and contradictory conclusions in the literature, namely "When tumor incidence was analysed statistically a higher incidence of tumors occurred in male rats fed 2,4-D at 1250 ppm, and a trend toward increased tumor formation with log dose in the female rats was noted. The raw data, however, support the pathological interpretation that a carcinogenic effect of 2,4-D has not been shown." I would concur with this second sentence rather than the IARC viextf that carcinogenicity "could not be evaluated." It should be noted that this study by Hansen et al has been re-recorded in a most unusual and unorthodox manner by Reuber (5). This paper is presented as if it were original data; it is, however, merely a re-evaluation of the previous study that concludes that carcinogenic effects were, indeed, seen in several different organ sites. These conclusions are not supported in any way by the data. In one other study random bred rats are recorded as having been fed one dose level; no increased tumor incidence is recorded but this study cannot be interpreted on the basis of recorded information. (4) In the 1969 (3) study mice were tested subcutaneous injection using doses of 215 mgm/kg/body weight in dimethyl sulphoxide and observed for 78 weeks. This study was negative. I believe that this negative finding must be viewed with interest in the context of the controversial reports of sarcoma occurrence in man. It cannot be denied that additional animal data using contemporary standards might be useful in the instance of this compound. Apparently such data will be forthcoming. As matters stand it would be my conclusion that 2,4-D should be classified as non-carcinogenic in animal systems, and therefore unlikely to be in humans. 2,4,5-trichlorophenoxyacetic acid 2,4,5-T was reviewed by the IARC in 1977(1) and 1982(2). It was tested in a 1969 mouse study by a combination of gavage and dietary administration (3) and was not found to be carcinogenic. Identical comments made above for 2,4-D apply to the evaluation of this study. A further mouse study (6) is made difficult to critique because of inadequate reporting by the authors and the use of less commonly used strains of mice. The authors report that 2,4,5-T was found to be non-carcinogenic when administered orally to mice of the XVII/G strain at levels of 80 ppm in the diet. The 2,4,5-T was said to contain 0.05 ppm of several dioxins that are listed. �- 13 On the other hand it is reported that there was a significant increase in tumor incidence in C3HF mice in this same study. This contention is virtually impossible to check since the tumors are classified into incidental tumors and non-incidental tumors for purposes of evaluation. It is then concluded that the incidence for non-incidental tumors is significantly increased whereas the incidence of incidental tumors is not. There is no precise listing in this paper of which tumors were placed in which category and this statistical manipulation of the data cannot be checked. My personal conclusion from reviewing the data is that this was an entirely negative study. In this instance, perhaps, it is safest to conclude that this study does not add anything of consequence one way or the other. A parallel subcutaneous injection study in mice to that recorded for 2,4-D was undertaken. The 2,4,5-T was also administered as a single dose of 215 mg/kg body weight in dimethyl sulphoxide and the mice observed for 78 weeks. This study was again negative. It is repeated continuously in IARC and other reports that the evidence from studies with 2,4,5-T is inadequate and does not permit a negative conclusion on carcinogenicity. Whilst it is undoubtedly true that additional data might permit a more definitive conclusion to be drawn the available data certainly cannot just be dismissed. In my view it indicates that it is most unlikely that any further studies would find 2,4,5-T to be carcinogenic. Having regard to the limited resources for testing for carcinogenesis by long term animal investigations, I do not think this compound should be accorded research priority over the many others requiring much more urgent evaluation for public health purposes. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) There are three recorded studies claiming to demonstrate some degree of carcinogenicity in TCDD. In the first of these studies Kociba et al (7) reported that Sprague Dawley rats were fed on diets providing 0.1.0.01 or 0.001 micrograms/kg/day for two years. At the highest level of feeding they report an increased incidence of hepatocellular carcinomas, and squamous cell carcinomas of the lung, nasal turbinates, hard palate and tongue. At the median level of 0.01 only lesions described as hepatocellular nodules were observed. At the lowest level no toxicity or neoplasms were reported. The authors of this paper draw attention to the toxicity observed at the highest level and suggest that this may have had an effect on the carcinogenic effects observed. �- 14 In a bioassay reported from the U.S. National Toxicology Program (N.T.P.)(8) Osborne Mendel and B6C3F1 mice were given TCDD by gavage for 104 weeks. The compound was administered in a corn oil-acetone vehicle at doses of 0.01, 0.05 and 0.5 micrograms/kg/week to rats and male mice and 0.04, 0.2 and 2.0 micrograms/kg/we to female mice. It is reported that male rats developed a significantly increased incidence of follicular cell adenomas of the thyroid in the high dose group only and that female rats developed an increased incidence of hepatocellular carcinomas was significantly increased at the two highest dose levels. The peer-review panel of the NTP was most critical of the interpretation of this study and concluded that the liver and thyroid tumors could well be attributed to the hepatoxicity induced. It was also pointed out that the analysis of the significance of the mouse liver tumors had not taken into account the high levels of similar tumors reported in historical controls of this strain of mice. It is my view that an objective analysis of the NTP study must dismiss it as flawed in design and interpretation. It is surprising to note that the peer review group haveing been scathing in their criticism finally agrees with the view that this study has demonstrated the compound to be carcinogenic. I would be unable to draw a similar conclusion. The comparison of the NTP test and the Kociba et al study is made difficult by the different modes of administration, different strains of rat etc. It is difficult to dismiss the findings of the Kociba study but one is puzzled by occurrence of the tumors in the respiratory epithelium (lungs, nasal sinuses, tongue) and their total absence in the NTP study. It might be that there is a greater local exposure in the diet study and it would be interesting to know this. The discrepancy between these two studies demands added investigation. The third study is an NTP study (8) in mice in which TCDD was applied repeatedly to the skin of mice alone or following a single initiating dose of the carcinogen 7,12-dimethylbenz(a)anthracene. The doses used were 0.005 micrograms per application in the females and 0.001 micrograms per application in the males; acetone was the vehicle. The higher doses female mice are said to have developed a significant number of fibrosarcomas. Once again, as in the previous study, the NTP group was exceptionally critical of this study. The portion of the study in which DMBA was administered first is disregarded since no DMBA control alone was used. There was a dispute amongst the reviewers as to the validity of the contention that a significant number of fibrosarcomas had in fact been induced. One reviewer felt that this finding should be �- 15 "interpreted with caution" and that "an assessment of human risk cannot be made." I would concur completely with this review and do not believe that the data in this study provides an adequate foundation for concluding that TCDD is a carcinogen in this model system. TCDD has been tested in a variety of so-called two stage studies as both an "initiator" or as a "promoter." I do not believe that these studies have provided any information of practical significance to the assessment of TCDD as a potential carcinogen. Conclusion In spite of considerable effort long term experimental results obtained with TCDD present a confused picture. Only one study has provided positive results that appear to be incontravertible (7) but in view of the lack of confirmation of this finding additional studies are required using the same conditions as those employed in this study. The Dow study even though not confirmed by NTP (perhaps as anxious to confirm it as Dow was unhappy to conclude as it did) must until explained leave TCDD in the very suspect compartment. Picloram (4-amino-3,5,6-trichloropicolinic acid) This compound was assayed in a standard U.S. National Cancer Institute bioassay using Osborne Mendel rats and B6C3F1 mice. The rats were given 744 or 372 mgm/kg/day and the mice fed either 640 or 320 mg/kg/day. Only the female rats were reported to have had an increased incidence of benign liver tumors. M. Reuber has reported that on re-reviewing this study that there was an increased incidence of various malignant tumors. The recent review of this literature by Clements Associates, Inc., takes issue with the techniques used by Reuber in selecting his material. It is not possible for me to take a stand in this instance without additional information. In view of the other characteristics of picloram - namely that it appears not to be metabolized it seems unlikely that it will prove to be carcinogenic in the study that is now apparently underway. Judgement of the potential hazard from this compound should await the completion of the new study. Cacodylic acid - Dimethylarsinic acid Althouth the only term study on this compound was undertaken in 1969 by Innes et al (3) and has been deemed inadequate, the compound was reported as negative. The particular study must be viewed in the context of this overall study in which several other compounds which including DDT were reported to have been carcinogenic. �- 16 From a biochemical standpoint cacodylic acid seems most unlikely to be carcinogenic since it is a detoxification product It would be quite inappropriate to equate the possible activity of this compound with the inorganic arsenicals said to be carcinogenic in man. Malathion This compound has been bioassayed in the U.S. by mouth in rats and mice and has been pronounced non-carcinogenic. The only suggestions to the contrary have not been based on any data. It would seem most unlikely that this compound poses a potential carcinogenic hazard, and in my opinion its use as an insecticide will cause no cancers in veterans. DDT DDT induces liver tumors readily in mice and less so in rats and not at all in hamsters. There is a considerable amount of work on the metabolism of this compound encouraged by these interesting species differences. There is a great deal of frustration present in many of the toxicologists that several decades after the introduction of this widely used, persistent and easily detectable compound, no one is prepared to say whether or not it has proved to be safe in man. My view is that if hazard were present there should have been some indication of it by now. Efforts to mount studies in which levels of DDT in human fat are related to tumor incidences have foundered. One can do no more than have a common sense opinion in this instance; my personal view is that it is most unlikely that DDT is a human health hazard in any respect. Dapsone-4,4'-sulphonylidianiline Of all the compounds included in the list for discussion at the Royal Commission I would select Dapsone as the most likely compound to pose a potential carcinogenic hazard. This compound is an aromatic amine which has been found to give rise to mesenchymal tumors of the spleen and thyroid tumors in rats. The exposure levels are of a much higher order of magnitude from those encountered in dealing with herbicides or pesticides. I recommend an epidemiological study of those individuals exposed to this drug in Vietnam and a control from who went to Vietnam who received other therapy. �- 17 On present data I am unable to say whether dapsone is actually carcinogenic in humans. I was unable to locate any pertinent data on the possible carcinogenicity or paludrine or primaquine and have no additional comments. Chlordane This is another representative of the group of compounds giving rise to hepatomas in mice; data in rats is inconclusive. No epidemiological evidence is available. This compound is in my view unlikely to be carcinogenic in humans. Dieldrin This chlorinated hydrocarbon, although more acutely toxic than DDT, presents similar problems from the standpoint of carcinogenesis. It enhances the incidence of hepatomas in mice but is apparently inactive in rats and hamsters. Lindane This chlorinated hydrocarbon again gives rise to hepatomas in mice; evidence in other species is said to be inconclusive. It is in my opinion unlikely to be carcinogenic in humans. Diazinon This compound has been tested in a U.S. National Cancer Institute bioassay and pronounced negative for carcinogenicity in rats and mice. I have been asked to speculate on the matter of possible synergism between the various herbicides, pesticides, drugs and possible environmental factors on any potential cancer producing effects that may have occurred. I can only respond that I have no knowledge of any studies that would suggest that any of the agents involved have ever been evaluated in any combinations to examine this possibility. Neither am I familiar with any studies that would suggest theoretically that such a possibility exists. It should be remembered that the two unequivocally established carcinogens to which Vietnam veterans were exposed were cigarette smoking and sunshine. In addition it is my understanding that a certain number of soldiers were exposed to Hepatitis B virus which can certainly be considered to be at least a co-factor in the occurrence of hepatocellular carcinoma. The possible exposure of troops in Vietman to the naturally occurring carcinogen, Aflatoxin, a product of fungal contamination and prevalent in Southeast Asia should also be considered. �- 18 REFERENCES 1. IARC Monographs Vol 15. 1977 2. IARC Monographs Supplement 4.1982 3. Innes, J.R.M. et al Journal of the National Cancer Institute 42.1101-1114. 1696 4. Hansen W.H. et al Toxicology and Applied Pharmacology 20. 122-129. 1971 5. Reuber M.D. 31.203-218. 6. Muranyi-Kovacs I, Rudali, G., and Imbert, I., Brit. J. Cancer 33.626-633. 1976 7. Kociba R.J. et al 46.279-303. 1978 8. National Toxicology Program Technical Reports 209 and 201 The Science of the Total Environment 1983 Toxicology and Applied Pharmacology � 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 056 Folder The folder containing the original item. 1483 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/. Title A name given to the resource Typescript: Statement of Dr. Philippe Shubik, Senior Research Fellow, Green College, Oxford University Subject The topic of the resource cancer risk assessment health studies herbicide toxicology 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 055 Folder The folder containing the original item. 1460 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/. Title A name given to the resource Typescript: Scientific Issues and Agent Orange Exposure Subject The topic of the resource dioxin health effects AOWG 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 055 Folder The folder containing the original item. 1455 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/. Title A name given to the resource Typescript: Chapter 3: Studies Evaluating Human Exposure to Phenoxy Herbicides Subject The topic of the resource health studies safety protective clothing 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 055 Folder The folder containing the original item. 1452 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/. Description An account of the resource Corporate Author: Industry Task Force II on 2,4-D Research Data Date A point or period of time associated with an event in the lifecycle of the resource 1990-01-01 Title A name given to the resource Public Concerns About 2,4-D Cancer Claims and the Facts Subject The topic of the resource health studies industrial exposure agricultural exposure ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/46a5af2134a93a9f98e75e7238bb90bd.pdf 4c434b009ebd99c7e4cbf602add31c97 PDF Text Text Item 10 Number °1438 Author Corporate Author Canadian Centre for Toxicology, Guelph, Ontario RODOrt/ArtlClB TltlB Typescript: Expert Panel Report on Carcinogenicity of 2,4-D, March 23,1987 Journal/Book Title Year 000 ° Month/Day Color n Number of Images & Descriptor! Notes Tuesday, May 15, 2001 Page 1438 of 1514 �EXPERT PANEL REPORT ON CARCINOGENICITY OF 2,4-D March 23, 1987 Canadian Centre for Toxicology, Guelph, Ontario, Canada �1. SUMMARY AND EVALUATION The herbicide, 2,4-Dichlorophenoxyacetic commercially in Canada during the 1940's. forestry, agriculture, rights-of-way. well. turf maintenance acid (2,4-D) was introduced It is widely used as a herbicide in and for weed control in parks and It has extensive applications in the home and garden market as Several formulations of 2,4-D are registered for use in Canada, normally as the amine salt or as esters of the acid. The total volume of 2,4-D sold in Ontario during 1986 was approximately 500,000 kg active ingredient. Concern over the safety of 2,4-D first arose in the 1960's when it was recognized that certain Although chlorinated 2,4-D formulations were contaminated with dioxins have been identified as contaminants dioxins. in 2,4-D products and formulations, current Canadian regulations allow only low concentrations (<10 ug/L) to be present. chlorodioxin has not been identified, nor would it products and formulations. products Moreover, the highly toxic 2,3,7,8-tetrabe expected in 2,4-D The dioxins that have been identified in 2,4-D and formulations (2,7- or 2,8-dichlorodioxin, 1,3,7- or 1,3,8-tri- chlorodioxin, and 1,3,6,8- or 1,3,6,9-tetrachlorodioxin) are not considered highly toxic (Ontario Ministry of the Environment, 1985). N-nitrosodimethylamine, a carcinogenic nitrosamine, also has been detected at low levels in certain samples of commercial 2,4-D particularly when nitrite was added as a rust inhibitor. The levels detected have ranged from 0.3-5 mg/L in the formulated product. A risk assessment on nitrosamines in 2,4-D conducted by the U.S. National Academy of Sciences indicated that the amounts found in 2,4-D formulations pose, at most, a negligible risk to human health. Pharmacokinetic studies conducted on 2,4-D in experimental animals and humans indicate that 2,4-D is absorbed via all routes of exposure. It appears that 2,4-D is distributed widely among the tissue of the body; the highest concentrations are found in parenchymal and excretory organs. There is no evidence that 2,4-D is metabolized to reactive intermediates which might bind to tissue macromolecules such as DNA. In all mammals examined, including humans, 2,4-D is rapidly excreted in the urine, largely unchanged in chemical form, though a small but variable amount may be conjugated in the kidney prior to excretion. These conjugated forms, which are highly polar and rapidly excreted, would be expected to be even less toxic than 2,4-D. The available pharmacokinetic studies indicate that there is a proportional and constant relationship between exposure, uptake and urinary elimination of �2,4-D in workers exposed over several state pharmacokinetics. days and who have achieved steady These studies further indicate that, in workers who use 2,4-D regularly, the amount excreted in the urine over a 24-hour period is a reliable measure of the absorbed systemic dose. This finding facilitates the measurement of dose received by workers employed in occupations involving 2,4-D exposure. Exposure studies have been conducted on 2,4-D in Ontario or in areas with similar climate and use pattern. These indicate that hydro-line workers may be exposed to the 2,4-D in amounts from 0.005 - 5 mg/person/spraying day. Exposure in this setting is highly variable and depends upon the nature of the work performed (mixer-loader, sprayer, flagger, etc.) and the extent to which precautionary procedures are followed and protective gear is worn. Commercial lawn applicators were found to receive a daily dose of approximately 0.3 mg/person/spraying day while farmers were estimated about 0.5 mg/person/spraying day. differences in spray to receive Variation between these groups is due to equipment, terrain and to the degree operators come into contact with concentrated formulations. to which the The latter is the most probable reason for the low levels of exposure in commercial lawn applicators who were reported to take appropriate precautions when mixing the formulation. Genotoxicity studies on 2,4-D have included in vitro studies in bacteria, yeasts and cultured mammalian cells. In yiyp genotoxicity studies have been conducted in rats, mice, hamsters and Drosophila. In addition, some limited studies have been carried out in humans exposed occupationally to 2,4-D. The results of tests conducted in in vitro systems indicate that 2,4-D is not mutagenic in Salmonella or |L coli; however, some conflicting data have been reported in B^ subtilis. carcinogenicity. There is an This test correlates poorly, isolated report that if at all, with 2,4-D "fluid" induced unscheduled DNA synthesis in human fibroblasts; however, no such effects were noted in more definitive studies in human embryonic lung cells and cultured rat hepatocytes. No information was given on the composition of the 2,4-D "fluid" and thus the significance of this positive report cannot be evaluated. It has been reported that 2,4-D induced mutations in yeast but positive effects were noted only below pH 4.5, leading the authors of these studies to conclude that effects were dependent entirely on pH of the culture media. There are studies indicating that 2,4-D produces sister chromatid exchanges (SCE's) in cultured human lymphocytes but not in hamster embryo cells. �The significance of these findings in questionable in light of the fact that several in vivo studies involving rats, mice, hamsters and humans have not shown any effects on SCE's in lymphocytes or bone marrow cells when 2,4-D was administered by appropriate routes at up to toxic doses. SCE's in vitro cannot be viewed as reliable predictors of In addition, carcinogenicity. There is one report that 2,4-D induced chromosomal aberrations in mouse bone marrow cells; however, the significance of this finding is questionable because the animals were given a dose corresponding to the LD5Q. Conflicting data exist on the mutagenic activity of 2,4-D in Drosophila. Unstable strains appear to show weakly positive effects while more stable strains appear to be resistant even at very high dietary concentrations (e.g. 1,000 ppm). A micronucleus test and a dominant lethal assay conducted in mice at doses of 100-125 mg/kg produced negative results. In summary, in vitro studies on the genotoxicity of 2,4-D, in some cases, produced conflicting 2,4-D produces results, however, there is no convincing evidence that mutagenic effects when it is tested in in vivo systems. Overall, the pattern of responses observed in both in vitro and in vivo tests indicates that 2,4-D is not genotoxic. The carcinogenicity of 2,4-D has been studied in two recently completed, long-term cancer bioassays, conducted in the United States under the auspices of the Industry Task Force on 2,4-D Research Data. In one study, groups of male and female Fischer 344 rats were given 0, 1, 5, 15, or 45 mg 2,4-D(acid, 97.5% pure)/kg body weight/day for 2 years. The results of this study indicated an increased incidence of brain tumours (astrocytomas) in male rats of the high-dose group. No treatment-related increase in brain tumours was noted in female rats or at any other site in either males or females. The incidence of brain tumours in male rats treated at the high dose was significantly incidence increased in the high compared to concurrent untreated dose group also exceeded controls. The that of tumors observed historically in untreated male rats of the same strain. While it is not possible to discount this evidence for carcinogenesis, the characteristics generally attributed to a brain carcinogen were not present in this experiment. There was no evidence of decreased tumor latency, the increase was limited to high-dose males, no preneoplastic lesions such as gliosis were present in treated animals, all tumors were solitary, and the tumors in treated animals were not more advanced (anaplastic) than generally seen in control animals. �Considering this, the Panel concludes that there is insufficient evidence to be certain that the brain tumors were related to 2,4-D exposure. This conclusion is supported by the large body of negative genotoxicity data on 2,4-D. In addition, there is no evidence to indicate that 2,4-D forms reactive intermediates in the liver or other tissues or forms adducts with DNA. In the industry-sponsored 2,4-D mouse study, groups of male and female B6C3F1 mice were treated with the compound at dose levels of 0, 1, 15 or 45 mg 2,4-D(acid, 95% pure)/kg body weight/day in the diet for 106 weeks. The Panel considered that, in this study, a higher maximum dose could have been used; however, the highest dose used exceeded the highest estimated average occupational exposure by a factor of about 600. The results of this study did not indicate any relationship between 2,4-D exposure and tumour incidence in either male or female mice. Epidemiological studies conducted on phenoxy herbicide-exposed workers have involved both case-control and cohort type studies. In one series of case control studies conducted in Sweden, an increased relative risk of soft tissue sarcoma and malignant lymphoma from noted; however, this was Zealand. not found exposure to in similar phenoxy herbicides was studies conducted in New In a cohort study in Denmark, however, an excess or soft tissue sarcomas in phenoxy-exposed workers was found. have been negative. Several other cohort studies An excess of Non-Hodgkins Lymphoma, but not soft-tissue sarcoma was observed in a case-control study conducted on herbicide-exposed farmers in Kansas. Based on the available epidemiological studies 2,4-D cannot be exonerated as a reason for the excess cancer risk seen in studies involving the phenoxy herbicides conducted in the U.S., Denmark and Sweden, but neither can these studies identify 2,4-D as being the causative agent. Overall, the epidemiological evidence indicates that a relationship between an increased risk of softtissue sarcoma and non-Hodgkins lymphoma with phenoxy herbicide exposure is tenable; however, in regard specifically to 2,4-D, the evidence for human carcinogenicity must be considered as inadequate. The evaluation of the validity and health significance of existing data pertaining to the carcinogenicity of 2,4-D is difficult. Because the epidemic- logical studies were conducted on persons exposed to several herbicides, it is not possible to identify the role, if any, of 2,4-D on the putative relationship between phenoxy herbicide exposure and increased risk of soft-tissue sarcoma and non-Hodgkins lymphoma. The epidemiological studies, by themselves, �cannot be used to assess the possible carcinogenicity of 2,4-D. Other studies of 2,4-D carcinogenicity have demonstrated an increased incidence tumors in male rats given 2,4-D at 45 ring/kg body weight/day. of brain However, as discussed above, there is insufficient evidence to conclude that the tumors were related to 2,4-D exposure. Overall, the Panel concludes that the existing animal and human data are insufficient to support the finding that 2,4-D is a carcinogen and, consequently, finds insufficient evidence to conclude that existing uses of 2,4-D in Ontario pose a significant human health risk. �2. INTRODUCTION The chlorophenoxy herbicides were developed during the early 1940s and the compounds 2,4-dichlorophenoxyacetic acid (2,4-D,) 2,4,5- trichlorophenoxyacetic acid (2,4,5-T) and (2-chloro-2-methylphenoxyacetic commercially introduced in the mid 1940s. acid (MCPA) were By the mid 1960s, the phenoxy herbicides were the most widely used class of herbicides. chloroThey are generally formulated either as the amine salts or as esters, the latter commonly of isooctyl and butoxyethanol alcohols. As a herbicide, 2,4-D-is used for the selective control of a large number of broad-leaf weeds in cereals, grains and turf crops as well as the control of shrubs, broad-leaf weeds and trees in rangeland, forests and rights-of-way. Rates of application may vary from 0.25 kg/ha in grain crops to 16 kg/ha in spot treatment of trees and bushes in rights-of-way. Average use of 2,4-D in the USA for the years 1978-1983 was 10 million kg (range 14.3-6.2 million kg) while use in Canada was reported to be 3.5 million kg for the years 1974-1976 (IARC, 1987). Total sales of 2,4-D during 1986 in Ontario were reported as 0.5 million kg (DHS, 1987). Concern over the human health implications of exposure to the phenoxy herbicides focussed initially on 2,4,5-T in the late 1960s with the discovery that some formulations containing this chemical were contaminated with dioxins and, in particular, 2,3,7,8-tetrachloro-p_-dibenzodioxin (2,3,7,8-TCDD). Restric- tion were placed on the use of 2,4,5-T in a number of jurisdictions (including Ontario) and it is now no longer manufactured in North America. This concern also resulted in what was probably the most thorough and extensive review of the scientific literature on the subject (Veterans Administration, 1981a and b; 1983: Royal Commission, 1985). The recent discovery of dioxins in certain formulations of 2,4-D (Cochrane et ah, 1981) raised concern for this product as well and prompted the establishment of regulations Canada. limiting dioxin levels in Recent epidemiological evidence, especially 2,4-D products in the so-called "Kansas study" (Hoar et aJL, 1986a and b) and the report that chronic feeding with 2,4-D increased the incidence of astrocytomas in male rats (Hazleton, 1986) have further raised the level of concern for the human health implications of this compound. These were the primary reasons for the commissioning of this report. The terms of reference of the Expert Panel were as- follows: �1. To assess the validity and health significance of existing experimental and epidemiological data on the carcinogenicity of 2,4-D. 2. The determine, on the basis of the existing data on carcinogenicity, whether any of the existing uses of 2,4-D in Ontario pose a significant health risk. In light of these terms of reference, the efforts on the question of carcinogenicity panel has concentrated and possible related effects. its Only brief reference is made to other possible adverse effects. 3. ACUTE AND SUB-CHRONIC TOXICITY The acute and sub-chronic toxicity of 2,4-D is well documented and was recently reviewed by the World Health Organization (WHO, 1984). A summary of the acute and sub-chronic toxicity data on 2,4-D is presented in Table 1. The available evidence indicates that 2,4-D is of moderate acute toxicity to mammals and birds. Clinical signs of acute exposure to high doses of 2,4-D include effects on the gastrointestinal tract, muscular weakness, muscle spasms and depression thought to be of the central due to nervous alterations system in the exposure levels (Elo and Ylitalo, 1977 and acute exposure to physiological 2,4-D are reported and biochemical (CNS). blood-brain 1979). to include processes CNS .depression barrier at is very high The myotoxic effects of changes in muscle in a number of (WHO, 1984). Direct myotoxic effects of 2,4-D may have been mistakenly interpreted as symptoms of peripheral neuropathy in some existing data development are inadequate to of peripheral animals and that the assess the possible role of 2,4-D in the neurotoxicity. More reported any evidence of peripheral neurotoxicity. not find peripheral WHO (1984) stated recent studies have not Mattsson et al. (1986a) did neuropathy in male and female Fischer 344 rats treated dermally with 12% 2,4-D amine for two hours daily, five days a week for three weeks (equivalent to ca. 110 mg 2,4-D acid/animal/day). A similar lack of effect was also noted in male Fischer 344 rats treated with 24% 2,4-D amine for two weeks in the same manner (Mattsson et al., 1986b). There have been some 2,4~D exposure in humans. reports of peripheral neuropathy attributed Symptoms associated with to exposure to phenoxy herbicides were said to include: Reduced peripheral nerve conduction velocity, long-lasting flacid paraparesis (incomplete paralysis) or quadriparesis, abnormal �tendon reflexes, sensory neuropathy. The relationship between 2,4-D exposure and peripheral neuropathy in humans has been questioned. No indications of similar effects were reported in persons exposed to "massive" exposure to 2,4-D or in patients given pure 2,4-D or 2,4,5-T (and their esters) as drugs (WHO, 1984). It is possible that the effects reported were associated with exposure to other agents such as solvents, nutritional or hereditary conditions, infec- tions and alcoholism and it has been suggested that further studies should be carried out using more modern methods (WHO, 1984). Table 1. Acute and chronic toxicity of 2,4-D in animals. Compound/ formulation Species Sex LDijQ or criterion ORAL TOXICITY 2,4-D acid Mouse Rat Guinea-pig Rabbit Dog Chicken M M MF NA NA NA Various ester formulations Mouse Rat Guinea-pig Cat Rabbit Chicken MF 380-570 MF 620-1500 MF 550-848 NA 820 MF 1420 NA 900-2960 Sodium salt Mouse Rat Guinea-pig Rabbit Chicken NA F M NA F 375-368 mg/kg body weight 375-666 469-1000 800 100 541 375 805-2000 551 800 655 SUB-CHRONIC STUDIES Acid or sodium salt Rat NA 31 mg/kg body weight/day NOEL. REPRODUCTIVE EJFFECTS Acid or sodium salt Mammals and NA birds 10 mg/kg body weight/day NOEL for teratogenic, fetotoxic embryotoxic effects. or Source: WHO, 1984 3.1. Contaminants in 2,4-D 3.1.1. Polychlorinated dibenzo-p-dioxins Although Norstrtm et al. (1979) reported that no polychlorinated dibenzo£-dioxins were detected (detection limits were 0.01 to 0.05 mg/L for di- to hexachloro isomers) in samples of 2,4-D and 2,4-D ester produced in 1965 or �earlier, one sample contained 0.06 mg/L of pentachlorodibenzofuran. He also reported that no di-, tri-, penta-, or hexachlorodibenzofurans were detected. The presence of dioxins in 2,4-D was first reported by Cochrane et al^ (1981). Samples of technical and formulated products containing 2,4-D esters and amines were analyzed by gas chromatography/mass spectrometry. formulations of 2,4-D contained 2,7- ranging from 104 to 4,200 ug/L. or 2,8-dichlorodioxin in Isooctyl concentrations Some isooctyl ester samples also contained 1,3,7- or 1,3,8-trichlorodioxin (346 to 2,079 ug/L) and 1,3,6,8-tetrachlorodioxin (226 to 1,752 ug/L). Two of three samples of 2,4-D mixed butyl esters and four of seven samples of 2,4-D dimethylamine salts showed the presence of dioxins. A later study of dioxin contaminants, conducted after regulations of dioxin contamination had been promulgated (limiting the levels of dioxins to less than 10 ug/kg), revealed low dioxin concentrations (Cochrane et al, 1982). Of one hundred and ninety-nine samples that were analyzed, only 0/72, 7/78, and 2/49 samples of 2,4-D acid, amines, and esters, respectively exceeded the regulatory limit of 10 ug/kg. The highly toxic 2,3,7,8-tetrachlorodioxin has not been identified and nor would it be expected in 2,4-D products and formulations. The toxicity of the dioxins identified in 2,4-D products and formulations (2,7- or 2,8-dichlorodioxin, 1,3,7- or 1,3,8-trichlorodioxin, and 1,3,6,8- or 1,3,6,9-tetrachlorodioxin) has been recently reviewed and is considerably less than 2,3,7,8-TCDD (Ontario Ministry of the Environment, 1985). 3.1.2. Nitrosamines Concentrations of N-nitrosodimethylamine have been determined (Cohen et al., 1978). (NDMA) in pesticide products Samples of dimethylamine, which may be used in amine salt formulation, showed NDMA concentrations of 27.5 to 53 mg/L. The NDMA content of formulations of 2,4-D dimethylamine salts ranged from not detectable to 6 mg/L. contamination (up to when nitrite was Studies have revealed N-nitrosamine 0.3 mg/L) in amine formulations of 2,4-D, particularly added as a corrosion inhibitor (WHO, 1984). N-nitrosodi- methylamine has also been detected in dimethylamine salts of 2,4-D in Canada (Reid, 1984). Of one hundred and twelve 2,4-D samples analyzed, ninety-two, sixteen, and four samples contained <_1 mg/L, 1 to 5 mg/L, and 2. 5 mg/L Nnitrosodimethylamine, respectively. �Based Sciences on a risk (NAS, 1981), assessment and the conducted exposures by the estimated National Academy of in this document, the amounts of N-nitrosodimethylamine in 2,4-D pose, at most, a negligible risk. 4. PHARMACOKINETICS AND METABOLISM OF 2,4-D IN HUMANS AND EXPERIMENTAL ANIMALS The absorption, distribution kinetics and metabolism of 2,4-D (in a variety of formulations) has been extensively reviewed (WHO, 1984) with the general conclusion that 2,4-D is not significantly metabolized in animals certain proportion of the absorbed These studies are pivotal to although a dose may be conjugated prior to excretion. the assessment of human exposure and are reviewed in more detail below. 4.1. Animal studies The distribution and elimination of orally administered 2,4-D amine (commercial formulation, triethanolamine salt), 2,4-D K-Na salt ("pure acid"), and 2,4-D ester (commercial formulation, butyl ester) were studied pigs, calves, chicks, and chickens (Erne, 1966a and b). of 2,4-D amine, amounting to 50, in rats, After single oral doses 100, or 200 mg 2,4-D/kg, peak plasma con- centration was reached w i t h i n 2 h after dosing in chickens and 4 to 7 h a f t e r dosing in the mammalian species studied. Plasma half-life of 2,4-D after a single oral dose of 100 mg/kg was determined in several species: Compound Species Half-life, h 2,4-D Rat, male Rat, female Pig Calf Chicken Rat, male Calf Rat, male Pig Calf 2.9 + 3.3 + 12 T 7.5 + 7.7 + 3.5 18.0 + 6 + 10 ~ 10 + " amine 2,4-D K-Na 2,4-D ester 0.4 0.5 2 0.8 0.7 0.5 0.6 1 0.8 1 Repeated oral doses of 50 mg/kg/day 2,4-D amine and ester were given to pigs. In most animals, plasma 2,4-D concentrations declined steadily, and no evidence of accumulation was seen; however, in one pig given 2,4-D amine and in another pig given 2,4-D ester, plasma 2,4-D concentrations rose, and both .animals showed signs of intoxication. Tissue 2,4-D concentrations were also measured after giving a single oral dose of 2,4-D. In general, tissue 2,4-D concentrations were highest in parenchymal organs (liver, kidney, lung). 10 In �male rats given 2,4-D amine (100 mg 2,4-D/kg), plasma concentrations were 150 and 2 ug/g at 6 and 24 h after dosing; liver concentrations 90 and 5 ug/g at 6 and 24 h; kidney concentrations 250 and 27 ug/g at 6 and 24 h. In pigs given 2,4-D amine (100 mg 2,4-D/kg) orally, plasma 2,4-D concentrations at 6, 24, 48 and 72 h after dosing were 210, 55, 10 and 3 ug/g; 24, and 48 h after dosing were 12, 3, and 1.5 ug/g. brain concentrations at 6, In chickens given 2,4-D amine (200 mg 2,4-D/kg) the plasma and brain concentrations 6 h after dosing were 100 and 1.5 ug/g, respectively. feed for 2 months, In pigs fed 500 ppm 2,4-D amine in their plasma, liver, kidney and brain 2,4-D concentrations were 22, 6, 12 and 2 ug/g respectively. It was found that 0 to 18% of the 2,4-D present in urine after giving single or repeated oral doses of 2,4-D amine was present as identified. an acid-hydrolyzable conjugate the structure of which was not The ester of 2,4-D was found to undergo very rapid hydrolysis to 2,4-D (Erne, 1966a and b). Metabolism of orally administered (Khanna and Fang, 1966). metabolite of 2,4-D. 400 g; females: |/4c]2,4-D has been studied in rats Radiolabelled carbon dioxide was not detected as a In rats given 225 to 275g 1 to 10 mg 2,4-D per rat (males: 350 to body weight), 93 to radioactivity was excreted in the urine in 48 h. 99% of the administered When 20 to 100 mg 2 , 4 - D / r a t was given, a smaller fraction of the dose was recovered in the urine over a 12 day period; i.e.: Dose/rat (mg 2,4-D) 20 40 60 80 100 Recovery in urine (%) 91.3 87.1 87.4 77.9 75.5 In rats given I mg 2,4-D/rat, the highest brain concentration of 0.7 u g / g dry tissue was found 6 h after dosing. In rats given 80 mg 2,4-D/rat, the following concentrations were found: Hours after treatment 4 8 24 41 Blood concentration (ug/g) 414 805 268 7 Brain concentration (ug/g) 20 66 16 1 The presence of a urinary metabolite of 2,4-D, which accounted for 0.25% of the administered radioactivity, was detected, for the incorporation of but not identified. 2,4-D or metabolites found. 11 into No evidence tissue constituents was �In male rats dosed orally with 2,4-D (200 mg/kg; 97.9% pure dissolved in peanut oil), a total of 1.4% of the dose was eliminated as a glycine conjugate, and 1.4% as a taurine conjugate (Grunow and Blihme, 1974). In studies designed to evaluate the effects of 2,4-D intoxication on the distribution of 2,4-D, adult male Sprague-Dawley rats (200 to 290 g) were given 0 or 250 mg 2,4-D/kg (sodium salt, 97% pure) by subcutaneous injection (Elo and Ylitalo, 1977; 1979). Three and a half to 4.5 h after treatment, the rats were given 8.8 mg of [1^C]2,4-D (98% pure) intravenously. min. later, the cerebrospinal fluid was collected for 1 h. Starting 30 Plasma and tissue samples were collected immediately after the termination of the cerebrospinal fluid collection period. Although absolute plasma or tissue 2,4-D concentra- tions were not reported, in saline-treated controls the brain and cerebrospinal fluid values amounted to 2.3 and 0.4% respectively, of the plasma values; after intoxication with 250 mg 2,4-D/kg, rose to 15 and 9.4% of the plasma the brain and cerebrospinal values. 2,4-D/kg increased brain and cerebrospinal 6.5- and 23.5-fold, respectively; smaller fluid values The administration fluid tissue/plasma increases, which of 250 mg ratios of ^C amounted 1.6 to 3.3-fold, were seen in liver, testis, lung, heart, and muscle tissue. to The authors concluded that 2,4-D intoxication either increases the influx of 2,4-D into the brain or decreases the efflux of 2,4-D out of the brain. Male Fischer 344 rats were given single oral doses of 10, 50 or 150 mg or intravenous doses of 5 or 90 mg ring labelled [^C]2,4-D (>99% radiochemical purity) and plasma and urine content of 2,4-D measured for 72 h (Smith et a l . , 1980). The rate constant for absorption of orally administered 2,4-D was 1.4 per hour and it was rapidly cleared from the blood in a biphasic manner: The t ] / 2 ( a l p h a ) for the plasma clearance of intravenously and orally administered 2,4-D was 0.92 and 1.01 h respectively; the i\/2 (beta) for the plasma clearance of intravenously and respectively. orally administered 2,4-D was 14.4 and 18.0 h, At doses >50 mg 2,4-D/kg there was a disproportionate increase in plasma ^C concentrations and a decrease in the ^C content of urine. The Km for the saturable clearance of 2,4-D from the plasma was about 79 ug/rnl: at concentrations kinetics. The below the Km, plasma clearance of 2,4-D follows first-order authors conclude that the saturable clearance of 2,4-D is a t t r i b u t a b l e to the saturable urinary excretion of 2.4-D. The pharmacokinetics of dermally administered ring labelled [^^C]2,4-D propylene glycol butyl ether ester (2,4-D PGBE ester; 97.6% chemically pure; 99.4% radiochemically pure) was studied in rats (Smith et al., 1981). 12 The ester �(5 mg/kg) was applied in a single dermal application of an acetone solution to male Fischer rats and elimination of C studied Absorption of 2,4-D PGBE ester through the (tj_/2 = 19.7 recovered h) and in the an average skin followed first-order of 85% of urine after 120 h. for 120 h after treatment. the kinetics applied radioactivity The authors concluded was that the phar- macokinetics of 2,4-D PGBE ester are similar to that of 2,4-D acid. Frantz and Kropscott (1984) studied the pharmacokinetics of the 2-ethylhexyl ester in rats. Male and female Fischer 344 rats were given a single oral dose of 130 mg 2,4-D (2-ethylhexyl ester) in corn oil, sampled for 72 h. The ethylhexyl ester could not be detected in blood or urine for 72 h after treatment, urine. and blood and urine although 2,4-D was present in .both blood and A total of 94.8 +_ 9.2% and 84.3 £ 4.5% of the dose was recovered in the urine of male and female rats, respectively, in 72 h. that 2,4-D 2-ethylhexyl The authors concluded ester is very rapidly hydrolyzed to 2,4-D, which is excreted in the urine. Similar pharmacokinetic studies of 2,4-D have also been conducted in the mouse (Hazleton Laboratories, 90 mg orally as 1984). Male B6C3F1 mice were given 5, 45 or an aqueous solution or 90 mg ring labelled [14C]2,4-D (98% pure) intravenously. Urinary and fecal elimination of ^C was measured for 168 h after dosing. Urinary excretion of 2,4-D amounted to 53 to 71% of the dose; fecal excretion of 2,4-D to 5 - 15% of the dose and a greater fraction of the l^C. was found in the feces of mice in the higher dose groups. for absorption of 2,4-D from the gut was approximately 0.013 h. The t i / 2 Km and V max for the elimination of 2,4-D were dose dependent, i.e.: Dose (mg/kg) 5 45 90 K 4.5 15.4 58.0 7.3 20.7 28.2 m 'max The authors concluded that the elimination of 2,4-D in the mouse was dose dependent and deviated from classical Michaelis-Menten kinetics. In summary, results of animal studies on 2,4-D absorption, distribution, excretion and pharmacokinetics indicate that 2,4-D, its salts and esters are well absorbed from the gastrointestinal tract and peak -plasma concentrations are reached soon after dosing. In addition, 2,4-D is rapidly cleared from the plasma and is excreted largely unchanged in the urine, although small amounts of the glycine and taurine conjugates have been detected. 13 Pharmacokinetic �studies have revealed chemical is that the plasma clearance of 2,4-D is distributed widely among the tissues saturable. of the body; concentrations being found in parenchymal and excretory organs. The the highest Brain 2,4-D concentrations are generally low but may increase if 2,4-D is administered at intoxicating doses. These conclusions agree with those of others (Gehring and Betso, 1978, Leng, 1977; Mullison, 1986; Veterans Administration, 1981a and b; World Health Organization, 1984). 4.2. Human studies The percutaneous absorption of [^^C]2,4-D (purity not stated) and the urinary excretion of [^^C]2,4-D after dermal or intravenous administration was studied in male subjects (age and weight not stated) (Feldman and Maibach, 1974). After intravenous administration of a tracer (1 uCi) dose of [14c]2,4-D, 100 + 2.5% of the dose was excreted in the urine in 5 days; excretion was 13 h. the half-life for After dermal administration of [^^C]2,4-D (1 uCi; 4 ug/sq. cm.), 5.8 + 2.4% of the dose was excreted in the urine. The pharmacokinetics of 2,4-D was studied in five male subjects aged 29 to 40 years and weighing 70 to 90 kg (Sauerhoff et a L , 1977). Each subject ingested 5 mg/kg of analytical grade 2,4-D either as a slurry in milk or as the powder followed by water. Blood samples were collected at 1, 4, 8, 12, 24, 36, 48, 72, 96, 120, and 144 h and urine samples Average t ^ / 2 f° r at 12-h intervals after dosing. absorption of 2,4-D was 3.8 h (range 1.67 to 4.20 h), t j / 2 for clearance from plasma averaged 11.6 h averaged 17.1 h (range 10.2 to 28.4 h). unchanged, but 13% was excreted and t [ / 2 for the urinary elimination Most (82%) of the 2,4-D was excreted as conjugates. The clearance of 2,4-D from the plasma and the urinary elimination of 2,4-D followed first-order kinetics, which could be described by a one-compartment model although one subject showed biphasic clearance of 2,4-D. The authors concluded that 2,4-D was rapidly absorbed from the intestinal tract and rapidly excreted in the urine and would not be expected to accumulate in the body after repeated oral dosing aL usual levels of exposure. Plasma and urine 2,4-D concentrations have been measured in occupationa l l y exposed workers (Kolmodin-Hedman and Erne, 1980). Four male subjects (mean age of 39 years) involved in spraying an emulsion containing 2% 2,4-D (neither purity nor amine or ester studied. content was stated) and kerosene were Blood samples were collected before the start of spraying, immediate- ly after spraying, and at the end of the exposure 14 week; urine samples were �collected at the start and at the end of the days of exposure or, in another study, at 12-h intervals during the exposure period. in air ranged from 0.1 to 0,2 mg/m^. Concentrations Plasma 2,4-D concentrations ranged from 0.02 to 0.2 ug/ml and varied considerably because after exposure, plasma 2,4-D concentrations detection limit (0.02 ug/ml). to 9 mg. The authors of intermittent dropped overnight exposure; to near the Urine 2,4-D concentrations ranged from 3 to 14 ug/ml and the mean peak was 8 ug/ml. ed of 2,4-D concluded Mean 24-h excretion of 2,4-D amountthat 2,4-D may enter the body by inhalation or dermal absorption and that urinary elimination of 2,4-D is rapid. Taskar et al. (1982a and b) measured serum and urine 2,4-D concentrations in 11 male subjects aged 19 to 31 years (weights not stated), who applied 2,4-D (DMA-4, Dow Chemical Co.). Body surface exposure was estimated by measuring the 2,4-D content of gauze pads (620 cm2: 0.67 ft^) attached to the chest and back of each subject and of a paper cap (406 cm^; 0.44 ft^) worn by the subjects. Blood samples were collected before after exposure. collected before and after exposure, during the day of exposure spraying) and twice a day for four to seven days after exposure. Urine was (3 h after At the end of the exposure period, 2,4-D residues of 564, 532, and 319 ug/m^ were found on the head, chest, and back, respectively, of the subjects. Serum 2,4-D concentrations (expressed as "amount of 2,4-D measured as phenolics in serum") at the end of exposure averaged 167 ng/ml (range 15.6 to 484.2 ng/ml). The serum 2,4-D concentrations measured 1, 2, and 3 days after exposure varied considerably. In some subjects a progressive decline in serum 2,4-D concentra- tions was noted, but in other subjects the 2,4-D content of samples taken on the second day after exposure was greater than that in samples taken on the first or third day after exposure. In some subjects, serum 2,4-D concentration was highest on the third day after exposure. Urine 2,4-D levels were ap- parently measured for 84 h after exposure, but no units of concentration were reported in the paper; hence the urine data cannot be evaluated. The authors asserted that serum residues correlated positively with the 2,4-D concentration in the air and with the amount of 2,4-D deposited on the head and back of the subjects. However, no air 2,4-D concentrations were reported in the paper and the results of statistical analyses were not presented. Absorption and urinary excretion of 2,4-D was studied in 36 applicators (sex, age, and weight not stated) occupationally exposed to a 2,4-D/picloram (4-amino-3,5,6-trichloropicolinic acid) mixture (Dow Chemical Tordon 101) or a 2,4-D/dichloroprop (2-(2,4-dichlorophenoxy)propanoic 15 acid) mixture (Pfizer �Chemical) (Libich et al., 1984). concentrations averaged 6.17 group Of workers and procedures procedures that were . measured. In three in 1979, urine 2,4-D + 7.69 (range 0.27 to 32.74) mg/kg (L) in one 3.16 +_ 2.85 (range 0.63 to 12.35) mg/kg (L) of urine in another group of workers. working In one study conducted were In a second introduced study conducted in 1980, and workers were required; moreover, air 2,4-D groups of workers, urine improved instructed on the concentrations were also 2,4-D concentrations averaged 1.42 + 1.76 (range = 0.04 to 8.15), 1.72 ± 1.50 (range = 0.15 to 5.45), and 2.55 + 1.72 (range = 0.44 to 5.07) mg/kg (L); respective air 2,4-D concentrations were 7.1 + 4.9 (1.0 to 19.5), 13.5 + 7 . 6 (0.4 to 35.3), and 55.2 ± 30.7(16.2 to 91.3) ug/m*. Finally, a model was devised that related urine 2,4-D concentrations to daily exposure levels of airborne 2,4-D and allowed the use concentrations The forestry of urine 2,4-D as exposure guides. urinary elimination workers to of 2,4-D after direct 2,4-D has been studied and indirect (Frank et aj_., exposure of 1985). Seven subjects (5 males and 2 females) weighing 51 to 84 kg and aged 20 to 38 years who applied formulations containing 2,4-D isooctyl esters (Estron LV-600 and Pfizer 2,4-D Ester LV600) were used. three workers were directly In an experiment conducted in exposed to 2,4-D for 65 h during an 1981, 11 day period; for the three workers, the highest daily excretion of 2,4-D in the urine was 0.30, 0.94, and 9.59 ug/kg body weight. 1982, three workers were exposed In an experiment conducted in to 2,4-D for 50, 51, and 39 h during an 18 day period; the highest daily excretion of 2,4-D in the urine for each of the workers was 7.73, 8.37 and 22.2 ug/kg body weight/day. was sprayed directly, it was estimated that For one subject who 0.44% of the applied dose was absorbed, and the highest daily excretion of 2,4-D in the urine was 4.75 tig/kg body weight/day. subject; Urinary excretion of 2,4-D was followed for 8 days in this a half-residue decline of 16 h determined. that 2,4-D persisted in urine samples collected Further studies showed during the post-spray period. Analysis of surface swabs of vehicles, helicopters, and living quarters revealed contamination of source of period. the all internal surfaces the 2,4-D detected in urine with 2,4-D which were samples collected in probably the the post-spray The authors calculated that, assuming a h a l f - l i f e of 18 h for 2,4-D, in worker excreting • the most 2,4-D (22.2 ug/kg body weight/day), the maximum dose of 2,4-D absorbed amounted to 60 ug/kg body weight/day. Dermal subjects absorption and urinary excretion of 2,4-D were studied (ages 24 to 57 yr, sex and weight not stated) exposed 16 in four under f i e l d �conditions to 2,4-D amine salts (the commercial formulations used were not described) (Grover et a K , 1986). Urine samples were collected before, during and for 4 to 7 days after the spray operations; dermal exposure was estimated by measuring the 2,4-D content of patches fastened both outside and underneath the clothing and by measuring the amount of 2,4-D removed by washing the hands with a sodium bicarbonate solution after the spray exposure. subjects, the urinary excretion of 2,4-D increased tion. after each spraying opera- The amount of 2,4-D excreted was a function of the number of consecu- tive exposures, the number of days between since the last exposure. a In all function of the exposures, and the time elapsed The cumulative total amounts of 2,4-D excreted were number of consecutive exposures, the number between exposures and the time elapsed since the last exposure. of days The cumula- tive total amounts of 2,4-D excreted ranged from 215 to 6,258 ug. Statistical analysis revealed a positive correlation between the amount of 2,4-D applied and the cumulative amount of 2,4-D excreted. positive and significant correlation between In addition, there was a the amount of 2,4-D deposited on the hands and the amount of 2,4-D excreted in the urine. 4.3. Evaluation of pharmacokinetics and metabolism Studies on the physiological disposition of 2,4-D in human subjects show that 2,4-D is absorbed after oral or dermal administration and is rapidly and almost completely eliminated from the body by urinary excretion. for clearance of 2,4-D from the body is <24 h. The half-life After occupational exposure to 2,4-D, dermal absorption appears to be the major route of entry into the body. These conclusions agree with those of others (IARC, 1987; Veterans administration, 1981a and b; World Health Organization, 1984). The relevant pharmacokinetic studies provide evidence of a reliable and constant relationship between exposure, uptake and urinary elimination of 2,4-D in workers exposed over pharmacokinetics. regularly, several days and who have achieved steady state These studies also indicate that, in workers who use 2,4-D the amount excreted in the urine over a 24-hour period is an reliable measure of the absorbed systemic dose. 5. EXPOSURE ASSESSMENT 5.1. Occupational Exposure to 2,4-D. Frank measurement et aj_. (1985) of urinary reported excretion a study for 2 17 sets on exposure of workers. to Crew 2,4-D, I, by which �included 2 mixer-loaders and a supervisor, wore full protective gear (including respirator) and worked over an 11-day period. sprayed at an application of 2 kg/ha. Approximately 2,200 ha were Crew 2, included 1 mixer-loader, 1 mixer-balloon (flagger) man, and 1 balloon man, also wore protective gear but did not consistently wear respirators. The spray period was proximately 4,000 ha were sprayed with 1.3 kg/ha. 18 days. Ap- Highest daily excretion for crew 1 ranged from 0.30 to 9.59 ug/kg body weight while that for crew 2 was considerably higher, ranging from 7.73 to 22.2 ug/kg body weight. Total excreted doses ranged from 136 ug (supervisor) to 1,600 ug (mixer-loader). In a study by Lavy et al. (1982), urinary excretion data were utilized to estimate total absorbed dose of 2,4-D for 3 crews involved in aerial application of the herbicide to 40 ha tracts of forest in Washington State. was applied at the rate of 2.1 kg/ha. each: The herbicide Crews were involved in two applications one in which conventional clothing was worn (no protective other in which protective gear was worn (without respirator). performed in such a way as to allow estimates of dermal and inhalation routes, results primarily due to dermal contact. gear), the Monitoring was exposure resulting of which indicated from that exposure was This and a later study (Lavy et al., 1987) were not considered further because conditions were not typical of Ontario. Libich (1981) and Libich iet al. (1984) reported studies to assess exposure lo those who spray roadsides, power lines and rights-of-way for Ontario Hydro. Spraying was done by backpack (handheld gun or mist blower) or from v e h i c l e (truck or all-terrain vehicle, using handheld gun), and mixtures of either 2,4-D and 2,4-dichloropropanoic acid (2,4-DP) (1:1) or 2,4-D and picloram (4:1) were used. but Little information was given concerning the amounts of herbicide used, a recent survey 2,4-D/2,4-DP mixture (DHS, at rates 1987) up indicates to 5.5 kg mixture at a rates up to 22.7 kg 2,4-D/ha. that Ontario 2,4-D/ha Hydro and applies 2,4-D/picloram Information on use of protective clothing was also limited to statements that there was general use of gloves, that clean provided. coveralls were issued Average daily intake, daily and that wash-up approximated by average facilities were excretion on Thursday of each spray week, was 3.53 mg, 3.45 mg, and 4.86 mg for rightsof-way sprayers using handheld gun, roadside sprayers using handheld gun, and rights-of-way sprayers using mist blowers, respectively. Occupational exposure to 2,4-D was assessed for commercial lawn care 18 �specialists who apply 2,4-D in combination MCPP [2-(2-methyl-4~chlorophenoxy)propanoic with other herbicides including acid] and dicamba (Yeary, 1986). The diluted mixture contained 2,4-D, MCPP and dicamba in a ratio of Personnel had been involved in application of herbicides for 3 weeks 12:6:1. prior to this analysis and, therefore, were assumed to exhibit steady-state body burdens of 2,4-D. Exposure was estimated by analysis of urinary excretion with the assumption that, at steady-state, the 24-hour urinary excretion of 2,4-D was a reasonable estimate of daily absorbed dose. wore protective clothing including gloves, and rubber boots. protection While mixing herbicide, employees apron or coveralls, face protection, However, during actual spraying, wearing of gloves and eye was optional while rubber boots and clean short-sleeve shirt) were considered standard apparel. uniforms (long pants, Solutions were applied at 2 a rate of 16 L per 93 m - (1.3 kg 2,4-D/ha), and 3,000 to 4,500 L were applied daily (adequate treatment for 2 to 3 ha). Personnel from five locations were monitored; however, in one of these locations spray activities were interrupted by rain. For the other four spray areas, mean urinary excretion values were reported to be 1.4, 3.2, 6.3, and 2.5 ug/kg body weight/day. Average exposure for the four groups combined was 3.3 ug/kg/day. Grover et aj.. (1986) assessed exposure in farmers, exposed multiple times in one season to 2,4-D under field conditions in Saskatchewan. their own tractors and ground rigs and applied 2,4-D at rates applicable to crop and control needs. Dermal exposure was estimated by use of patches and handwashes and total exposure garments Farmers used consisting Number of exposures of two by urinary excretion values. layers of cotton but did not Subjects wore use respirators. per subject ranged from 1 to 7, with those having more exposures excreting greater amounts of 2,4-D in terms of kilogram of herbicide applied. Application rates ranged from 0.35 kg/ha to 0.63 k g / h a , averaging 0.43 kg/ha. Cumulative urinary excretion ranged from 0.2 mg to 6.3 mg- 2,4-D, with an average value of 1.6 mg excreted. One subject who was monitored for only one exposure excreted a total of 0.3 mg as a result of spraying 71 ha at a rate of 0.35 k g / h a . 5.2. Estimation of Exposure Data on urinary excretion of 2,4-D from each of the above reports were used to estimate absorbed dose under various work conditions most typical of the Ontario use pattern of 2,4-D. These estimates are contained in Table 2. 19 �For each of the above studies, an average daily dose was estimated. Information on days per year exposed and number of years exposed (Table 2) were derived from data in a recent survey (DHS, 1987). If such data were not available, values for these parameters were assumed using best professional judgement. Table 2. Occupational exposure of persons involved in the application of 2,4-D by various methods Method of Application Occupation Average daily intake (mg/person) Days/ year Years Exposed Exposed Total Intake (mg) Frank et al., 1985 Helicopter 1.04 0.46 0.34 12 12 12 20 20 20 250 111 80 mixer-loader supervisor 0.15 0.005 12 12 20 20 36 1 3.5 60 10 2107 roadside sprayer 3.4 60 10 2070 rights-of-way sprayer Airplane mixer-loader mixer-flagger flagger 4,,9 60 10 2895 66 13 245 25 166 Pa cksprayers rights -of -way handheld gun sprayer Mist blower Libich, 1981 Yeary, 1986 Hand and tank commercial sprayer 0,29 Grover et al., 1986 Tractor farmer In the reported 0.48 study by Frank et al. 14 (1985), total urinary excretion data were (including post-spray excretion) and average daily dose was ap- proximated by dividing the total urinary excretion by the number of reported spray days. In contrast, the study by Libich (1981) reported urinary excretion on (often non-consecutive) spray days, but not on post-spray days. Libich (1981) indicated that, for successive daily exposure, urinary excretion after the fourth day should approximate the daily exposure. Also, the reported measure- ments were made generally during weeks in which conducted Monday through Friday (personal spraying activities were communication from Libich). Therefore, average daily urinary excretion reported on Thursdays and Fridays was assumed to approximate average daily intake. farmers spraying 2,4-D (Grover et al., Information on exposure to 1986) was expressed as total urinary 20 �excretion of 2,4-D for the total number of spray operations within a short period of time). Average daily intake (all occurring was approximated by dividing total urinary excretion per farmer by the number of spray operations performed by that fanner. The study of Yeary (1986) reported 24-hour urinary excretion of 2,4-D for five groups of commercial herbicide sprayers, in units of mg 2,4-D/kg body weight. The sprayers had been working almost daily for three weeks, so that this 24-hour sample was used as an approximation of average daily intake. recovered by the 2,4-D excreted Each study reported the average percent chromatographic method utilized, and reported were corrected for less than complete of 2,4-D amounts of recovery. It was assumed that the studies utilized reported relatively normal spray practices, i.e. that parameters such as rate of 2,4-D applied and use of protective clothing fell within normal limits. If body weight and total urinary output were not supplied, values of 70 kg and 1.4 L/day were utilized where needed. 5.3. Evaluation of Exposure It is clear that exposure to 2,4-D is dependent on the rate of application of the herbicide. Rights-of-way sprayers use 2,4-D at the highest rate of application and their daily exposure was higher than other groups. workers may be exposed mg/person/spraying day. to the 2,4-D Exposure in this in amounts setting is from Hydro-line 0.005 - 5 highly variable and depends upon the nature of the work performed (mixer-loader, sprayer, flagger, etc.) and the extent to protective gear is worn. daily dose which precautionary procedures Commercial lawn applicators were found to receive a of approximately 0.3 mg/person/spraying day while estimated to receive about these groups 0.5 mg/person/spraying day. farmers were Variation between is due to differences in spray equipment, terrain and to the degree to which the operators tions. are followed and come into contact with concentrated formula- The latter is the most probable reason for the low levels of exposure in commercial lawn applicators who were reported to take appropriate precautions when mixing the formulation. Lifetime exposure to 2,4-D is related to the number of days of spraying and the number of years in the occupation. 21 �6. GENOTOXICITY It is widely accepted that tests of genetic activity, conducted using appropriate in vitro and in vivo systems, may indicate possible carcinogenic activity. Positive results in genetic toxicity tests; however, cannot be said to unequivocally predict carcinogenicity since these tests only measure a limited number of events putatively Similarly, negative results in provide conclusive produce cancer associated with the tests of genotoxicity cannot evidence against carcinogenicity through carcinogenic processes not detected process. be considered to since agents may act to by the currently available short-term tests. Positive results for genotoxic as prokaryotes, fungi activity obtained in in vitro systems such and cultured mammalian cells may suggest that similar effects could occur in animals m vivo. It is therefore important to assess the genetic effects of chemicals in vivo to observe if similar effects are observed in and animals exposed under appropriate doses routes of administration. Positive results in in vivo test systems provide important additional evidence that the chemical is genotoxic and are regarded as being of greater relevance than effects in lower order organisms (IARC, 1987). Attempts to relate genotoxic effects to carcinogenicity must take into consideration possible mechanisms of action and evidence which describes the relationship between the test system and carcinogenicity in whole animals or humans. In this regard it is important to note genotoxicity and carcinogenicity sidered by some investigators regulatory purposes. regulatory use It of the is are far that correlations between from perfect and, indeed, are con- (Mendelsohn, 1985) to be of limited value for therefore results of essential that the interpretation and short-term genotoxicity tests encompass a critical scientific evaluation of the data, keeping in mind its possible relevance to human exposure conditions. The genotoxicity of 2,4-D has been studied extensively in a wide variety of in vitro and in. vivo test systems. As 2,4-D is a highly active and toxic herbicide, it is inappropriate to include those genotoxicity studies conducted on plants and plant tissues. The pivotal studies concerning the potential geno- toxicity of 2,4-D are discussed below. 6.1. In Vitro Studies The salient m vitro genotoxicity studies on 2,4-D are summarized in Table 3. Mutagenicity of 2,4-D has been tested 22 repeatedly in several strains of �Salmonella typhimurium (Klopman et al., 1985; Zetterburg et al., 1977; Anderson et al., 1972; Shiraus et al., 1978; 1983). Mortelmans et al., 1984; Rashid and Mumma, Concentrations of up to 10 rng/plate, a level which produced toxicity in several strains of Salmonella, failed to induce an increase in mutation frequency. In an assay measuring differential toxicity of 2,4-D to Bacillus subtilus, Waters et al. (1982) noted positive results, suggesting that 2,4-D may inhibit DNA repair in this test system. However, no effect on DNA repair, as measured by differential toxicity, was noted in Escherichia coli polA~ strain (Waters et al., 1982) and Shirasu et al. (1976) failed to obtain positive results in the EK subtilus assay. Ahmed et al. (1977a) reported that a formulation of "2,4-D-Fluid" (purity composition and not given) induced unscheduled DNA synthesis (UDS) in cultured human fibroblasts; however, Probst et al. (1981) found no increase in UDS in primary rat hepatocyte cultures and Simmon (1979) found no effect of 2,4-D on UDS in human embryonic lung cells at concentrations up to 100 mg/L. Table 3. In vitro studies on 2,4-D. Test Organism Result Reference and comments Salmonella typhimuri u m h i s t i d i n e reversion assay Klopman et al. (1985). Neither the purity nor the concentration of the 2,4-D was given in the paper. Salmonella typhimuri u m h i s t i d i n e reversion assay Zetterburg et al. (1977). values of 473" or 6.8. Salmonella typhimuri u m h i s t i d i n e reversion assay Anderson et aL (1972). pH not stated but is probably tEat of the medium. Spot test system with concentration of 50 ug/plate. Salmonella typhimurium reversion assay Shirasu et al. (1976). Salmonella typhimurlum reversion assay in TS98, TA100, TA1535 and TA1567 strains. Mortelmans et al. (1984). Used five concentrations over 2 orders of magnitude of 2,4-D acid, n-Butyl, isooctyl esters and amine with and without activation by rat S9 microsomes Salmonella typhimurlum reversion assay in C3S, TA98, TA1000, TA1535, TA1537, TA1538, D3052 and C3076 strains. Probst et al. (1981). Used 10000-fold concentration gradient replicated 4 times of 2,4-D acid with and without activation by Arochlor 1254 induced rat S9 microsomes Salmonella typhimurlum reversion assay in TX97, TA98, TA100, TA1535 and TA1538 strains. Rashid and Mumma (1983). No effects with the alanine, aspartic acid, leucine, methionine and tryptophan conjugates of 2,4-D at concentrations of 10, 100 and 1000 ug/plate Salmonella typhimurlum reversion assay in TA~9~7, TA98, TA100, TA1535 TA1537 and TA 1.538 strains. Mpriya e_t al. (1983). Dose response was determined up to a concentration of 5000 u g / p l a t e . 23 No effects at pH �Escherichia coli DNA repair assay. Waters et al. (1982). Escherichia coli WP 2 tryp. reverse mutation assay. Nagy et aj. (1975). Spot test with undefined concentrations of 2,4-D. Escherichia coli version assay Shirasu et ah (1976). re- Escherichia coli WP 2 tryp. reverse mutation assay. Moriya et al. (1983). Dose response was determined up to a concentration of 5000 ug/plate. Bacillus subtilis DNA repair assay. Waters et al. (1982). Bacillus subtilis recombination assay. Shirasu et al. (1976). Saccharomyces cereyiseae mitotic recombination assay. H— Zetterburg et al. (1977). Effects only observed at pH <_ 4.57 possibly because of lack of uptake of dissociated form of molecule. Saccharomyces cereviseae mitotic recombination assay. Klopman et al. (1985). Comments as for above. Saccharomyces cerevi s e a e h o s t mediated mitotic recombination assay. Zetterburg et al. (1977). Saccharomyces cere18 strain viseaeRf re ve rs e mut ati on assay. Zetterburg (1978). Again, effects only observed at pH <_ 4.5, possibly because of lack of uptake of dissociated form of molecule. Mitotic gene conversion assay in Saccharomyces cereviseae D4 strain. + Seibert and Lemperle (1974). 2,4-D increased convertants 5 to 6-fold at pH 4.5. (See comments on Zetterburg et al., 1977 above) Unscheduled DNA synthesis in human fibroblast cells. + Ahmed e_t al. (1977a). Assay with and without rat S9 microsomal activation was positive at all concentrations tested. The 2,4-D formulation used was not clearly identified except as 2,4-D fluid. The structure was shown to be that of the acid but it was stated that the material was water soluble, suggesting that the amine or the salt may have been used. The possible involvement of mutagenic contaminants cannot be ruled out. Unscheduled DNA synthesis in human embryonic lung cells. Simmon (1979). Cells of the WI-38 strain exposed to concentrations ranging from 0.1 to 100 mg/L in presence and absence of microsomal activation Unscheduled DNA synthesis in rat hepatocyte cells. Probst et al. (1981). Hepatocytes from Fischer 344 rats d~Icl not show increased UDS at concentrations up to 1,000 mg/L. Forward Chinese cells. Ahmed et aL (1977b). A 12-fold increase in forward mutation at a concentration of 4 mg/L at which 60% of cells were killed. The 2,4-D formulation used was not clearly identified except as 2,4-D fluid. The structure was shown to be that of the acid but it was stated that the material was water soluble, suggesting that the amine or the salt may have been used. The possible involvement of mutagenic contaminants cannot be ruled out. mutation in hamster V79 24 �Thymidine kinase gene mutation assay in mouse lymphoma cells (L5178Y). Klopman et al. (1985). Neither the purity nor the concentration of the 2,4-D was given in the paper. SCE in human phocytes. lym- Korte and Jalal (1982). Increases in SCEs at concentrations of 2,4-D _>. 10 mg/L in in vitro system. SCE in human phocytes. lym- Turkula and Jalal. (1985). Statistically significant increase only at 50 mg/L, none at 100 and 250 mg/L. No dose response was observed. Mitotic index in fetal bovine kidney cells. Bongso and Basrur (1973). Increase in mitotic index up to 10 mg/L with a decrease at concentrations up to 1000 mg/L. Some indication of interference with spindle formation. Formulation of 2,4-D not specified. Mitotic index in bovine peripheral blood cells. Bongso and Basrur (1973). Increase in mitotic index up to 10 mg/L with a decrease at concentrations up to 1000 mg/L. No other indications of interference cell division. Formulation of 2,4-D not specified. Chinese hamster ovary cells, SCE. Linnainmaa (1984). Both pure (Acid) and commercial formulations of 2,4-D and MCPA (amine of 2,4-D and isooctyl ester of MCPA) at npntoxic concentrations of 10"^, 10~4 and 10~5 M caused some increases in the presence or absence of activation by rat liver S9 fraction. Although these increases were, in some cases, statistically significant, they did not show a dose response and, in most cases, resulted from somewhat lower rates in the control groups. The author concluded that neither of these compounds appeared to act directly on DNA. In tests employing yeasts, Zetterburg et al. (1977) noted a dose-dependent increase in the frequency of mitotic gene conversion and mitotic recombination in Sac charomyces cereviseae; however, this effect was found only at pH 4.5 and 4.3 and not at higher pH values. affected. At lower pHs survival was markedly Zetterburg (1978) concluded that the pH dependency on mutation frequency was due to the fact that, at lower pHs, 2,4-D is in an molecular form which is readily taken up cells in culture. This conclusion is supported by Zetterburg's observation that 2,4-D did not produce mutagenic affects in S^ cereviseae when tested in a host-mediated assay using mice. Studies by Korte and J a l a l (1982) and Turkula and J a l a l (1985) were said by these authors to demonstrate that 2,4-D produced sister chromatid exchanges (SCEs) in cultured human lymphocytes. Effects noted in these studies were, in most cases, marginal, occurred at near-toxic doses and failed to meet accepted criteria for positive results (Waters et aJL, 1982). In addition, Waters et a_l., (1982) in a d e f i n i t i v e series of tests, did not observe any effect of 2,4-D on SCE frequency in CHO cells while Linnainmaa (1984) observed only s 25 �marginal effect of 2,4-D on SCE frequency in CHO cells which failed to meet accepted criteria for positive results. In conclusion, it may be stated that there is no firm evidence that 2,4-D induces SCE's in cultured mammalian cells. This view is substantiated by the results of in vivo tests in animals and man. 6.2. In Vivo Studies 6.2.1. Animal Studies Studies on the genotoxicity of 2,4-D conducted in animals are summarized in Table 4. As pointed out above the marginally positive reported in in vitro results for SCE systems have not been noted in whole animal studies. Linnainmaa (1984) did not find any increase in SCEs in circulating lymphocytes of rats treated for one week with 2,4-D at a daily dose (close to toxic) of 100 or 200 mg/kg. Similarly, Linnainmaa (1984) failed to demonstrate an increased frequency of SCEs in the bone marrow of hamsters treated with 100 mg/kg/day of 2,4-D for 7 days. Lamb et al. (1981) likewise noted no increase in the frequency of SCEs in the bone marrow of mice given 2,4-D. Pilinskaya (1974); however, reported a slight effect of 2,4-D on chromosomal aberrations in the bone marrow of mice treated at intoxicating doses of 100 or 300 mg/kg but no effects were noted at 10 or 50 mg/kg. A mouse micronucleus test conducted at an i.p. dose of 100 mg/kg produced negative results (Jenssen and Renberg, 1976). A dominant lethal assay in ICR Ha Swiss mice given 125 mg/kg 2,4-D was likewise negative (Epstein e_t al., 1972). Table 4. Mutagenicity of 2,4-D in animal systems. Test Organism Result Reference and comments Male Wistar rats, peripheral lymphocyte SCE. Linnainmaa (1984) Pure (acid) 2,4-D and MCPA did not cause increases in peripheral lymphocyte SCE when fed for one week at doses of 100 and 200 mg/kg body weight/day by gavage. Chinese hamster bone marrow cell SCE. Linnainmaa (1984) No elevations were observed in the case of 2,4-D when both were dosed by gavage at 100 me/kg body weight/day for 7 days. Mouse testicular DNA synthesis. Seiler (1978). A 29% reduction in thymidine uptake after oral dosing of mice with 200 mg/kg. The dose is near to the toxic and results may be general toxic response. No dose-response measured. C57BL/6N mouse bone marrow SCE. Lamb et al. (1981) failed to demonstrate significant elevations in mice fed diets resulting in daily doses of 40 and 20 mg each of 2,4-D, 2,4,5-T (containing TCDD) /kg body weight/day for 8 weeks. ' 26 �Mouse bone marrow cells, chromosomal aberrations. Pilinskaya (1974). Only observed at doses of 100 and 300 mg/kg body weight in combination with intoxication. Not observed at 10 and 50 mg/kg body weight. Mouse test. Jenssen and Renberg (1976). No effects observed at an IP dose of 100 mg/kg body weight. micronucleus Nondisjunction assay in Drosophila melanogaster Magriusson et al. (1977). 2,4-D in diet. No effect Ch ro mos om e lo ss assay in Drosophila melanogaster Magriusson et aL (1977). 2,4-D in diet. No effect at 100 ppm Recessive lethal assay with Karsnas and Muller 5 strains of Drosophila melanogaster Magriusson et ah (1977). Effect with 2,4-D statistically significant at 1000 ppm in diet. Recessive lethal assay with Berlin K strain of Drosophila melanogaster Vogel and Chandler (1974). No effects dietary concentrations of 500 and 1000 ppm. Genetic mutations in stable and unstable strain of Drosophila melanogaster +- at Rasmuson and Svahlin (1978). Positive results in the unstable strain, negative in the stable strain. Epstein et al. (1972). Single injection (IP) of 2,4-D atT25~~mg/kg body weight. Dominant lethal assay in ICR Ha Swiss mice. There is at 100 ppm some evidence from studies in Drosophila melanogaster thai 2,4-D may produce mutations; however, the evidence in this regard is conflicting. Magnusson et al. (1977) noted negative results in a nondisjunction assay and a chromosome loss assay in Drosophila given a diet containing 100 ppm 2,4-D, but noted a statistical increase in a recessive lethal assay in Drosophila given a diet containing 1000 ppm 2,4-D. that the effect Magnusson ej al. (1977) concluded was weak, amounting to only 2-3 times the control levels. Rasmuson and Svahlin (1978) reported an enhanced somatic mutation frequency in unstable but not reported was weak. in stable strains Compared to the classical phonate, which induced a 3.28% increase only a 0.69% increase. of Drosophila; however, the response in mutation frequency, The control mutation studies in Drosophila (Vogel and mutagen ethyl methane sul- Chandler, frequency was 2,4-D induced 0.075%. Other 1974) have failed to demonstrate any significant effect of 2,4-D on the frequency of recessive lethal mutations. The a v a i l a b l e animal 2,4-D is genotoxic. studies do not provide convincing evidence thai Marginally positive results, when reported, have occurred at near-toxic concentrations. The relevance of these positive findings to risk assessment is questionable, particularly in view of the fact that most studies have produced negative results. 27 �6.2.2. Human Studies There is no evidence that, under conditions produces genotoxic effects reported five situations. In a review on 2,4-D, WHO (1984) studies on workers exposed to 2,4-D under manufacturing or use In no case were any chromosomal abnormalities noted. Linnainmaa (1983a SCEs in herbicide effects. in humans. of manufacture or use, 2,4-D and b and 1982) compared the incidence of lymphocyte workers with that in controls and found no exposure related Comparison of 2,4-D levels in the urine of exposed frequency of SCEs failed to show a dose response. exposed group, SCEs were significantly elevated although no differences between degree of elevation. control and workers and In both the control and in those workers who smoked exposed were observed in the Elevation of SCEs in smokers would be expected and, as such, is a positive control for the study. The results failed to demonstrate synergism between 2,4-D exposure and smoking. Mustonen et al. (1986) chromosomal aberrations control workers. reported no difference in lymphocytes from Exposure was confirmed workers between frequency of exposed to by urinary analysis. 2,4-D and As reported above, the frequency of aberrations was higher in smoking than non-smoking workers in both exposed and control groups. Several older studies of chromosome aberrations exposed to 2,4-D were reviewed recently be IARC (1987). and SCEs in humans The results of these studies have been uniformly negative. 6.3. Evaluation of Genotoxicity There is no evidence that 2,4-D is mutagenic in the Ames Salmonella test or in Escherichia coli; however, some conflicting data have been reported in other bacterial systems. Both positive and negative results have been noted in differential toxicity studies in EL subtilus. The significance of these positive results is questionable in view of the fact that this test correlates at all, with carcinogenicity. composition has A formulation of 2,4-D poorly, if "fluid" of unspecified been reported to induce unscheduled DNA synthesis in human fibroblasts; however, other studies with pure formulations of 2,4-D have been unable to confirm these findings in tests involving human embryonic lung cells and cultured rat hepatocytes. It is possible that the positive results reported in human fibroblasts with 2,4-D "fluid" may represent a true finding; however, the possibility that the effects noted were due to impurities or other anomalies in the test cannot be discounted. They also 28 reported that 2,4-D induced �mutations in yeast but positive effects were noted only at a pH below 4.5, leading the authors of these studies to conclude that effects were dependent entirely on pH of the culture media. There are studies indicating that 2,4-D produces SCEs in cultured human lymphocytes but not in hamster embryo cells. The significance of these find- ings is questionable in light of the fact that several in vivo studies involving rats, mice, hamsters and humans have not shown any effects on SCEs in lymphocytes or bone marrow cells when 2,4-D was administered by appropriate routes at up to toxic doses. In addition, SCEs in vitro cannot be viewed as reliable predictors of carcinogenicity (Brusick et al., 1983). There is one report that 2,4-D induced chromosomal aberrations in mouse bone marrow cells (Pilinskaya, 1974); however, the significance of this finding is questionable because the animals were given a dose corresponding to the LD5Q Conflicting data exist on the mutagenic activity of 2,4-D in Drosophila. Unstable strains appear to show weakly positive effects while more stable strains appear to .be resistant even at very high dietary concentrations 1,000 ppm). (e.g. A mouse micronucleus test and a dominant lethal assay in mice conducted at doses of 100-125 mg/kg produced negative results. In vitro studies on the genotoxicity of 2,4-D, in some cases, produced conflicting results; however, there is no convincing evidence that 2,4-D produces mutagenic effects when it is tested in in vivo systems. Overall, the pattern of responses observed in both in vitro and in vivo tests indicates that 2,4-D is not genotoxic. 7. PATHOLOGY AND CARCINOGENICITY The potential carcinogenicity of chemicals is determined primarily by epidemiological studies in humans or by long-term animal experiments. This section deals with studies in experimental animals chronically exposed to 2,4-D. Several animal experiments have been conducted using mice and rats, but most of these were completed over a decade ago and do not meet current standards for determining carcinogenicity (Innes et al., 1969; Hansen et al., 1971; Arkipov & Koxlova, 1974). Rueber (1983) also published an interpretation of the Innes et a_j_. and Hansen et al. studies (1983). tional Agency Two working groups of the Interna- for Research on Cancer have reviewed all of this considered them inadequate for an assessment 1982). of carcinogenicity (IARC, 1977, These studies have not been reviewed in detail for this report 29 data and �Animal experiments the Industry Task Force in rats and mice on 2,4-D Research America, Inc. in Vienna, Virginia. were conducted ments. have recently These Data at been conducted for Hazleton Laboratories studies were completed in 1986 and according to current good laboratory practices (GLP) require- The final study reports and selected rat brain sections, including all brain gliomas, were examined and form the primary basis for the assessment in this section. 7.1. Industry Task Force 2,4-D Rat Study Groups of 60 male and 60 female weanling Fischer 344 rats were treated with 2,4-D (Acid, 97.5% pure) in the diet at levels of 0, 1, 5, 15 or 45 mg/kg body weight/day for up to 104 weeks (Hazleton, 1986). als in each group were sacrificed and subjected At 52 weeks, 10 anim- to pathological examination. The doses were selected based upon results of 13 week subchronic experiments in rats and mice which showed that doses of 60 mg/kg/day or higher produced damage to renal tubular epithelium in rats. Also, at 50 mg/kg/day and higher, there was a break in linear pharmacokinetics whereby excretion did not remain proportional to intake, suggesting a saturation of renal excretory capacity. No treatment-related effects on animal survival, clinical observations or gross pathological findings occurred at either the 52 or 104 week sacrifices. However, in high-dose females, there were significant decreases in bodyweiglH gains at both intervals. There were compound-related increases in histopathological lesions in 2 tissues. At all dose levels except brown tubular cell 1 mg/kg/day, there was an increase pigment in the kidneys of both males and females. in At levels of 15 mg/kg/day and 45 mg/kg/day in males and 45 mg/kg/day in females there was also an increase in renal pelvic microcalculi and there was a slight increase in renal pelvic transitional cell hyperplasia in the 45 m g / k g / d a y females. The hyperplasia was considered secondary to the microcalculi. The nature of the brown pigment was not determined. However, all of these kidney changes occur spontaneously in aging control animals, and it is questionable whether the increases observed represent potential safety concerns at the levels of human exposure. A summary of all tumor incidences is presented in Appendix 1. The only neoplastic finding of concern was an increase in astrocytomas in the brains of high-dose male rats. There was no increase in treated females. 30 Based upon �the standard 3 coronal brain sections examined, (forebrain, midbrain, and hindbrain) the incidence of astrocytomas in male groups was as follows: Table 5. Initial astrocytoma incidence in male rats. Control 1 mg/kg 1/60 0/60 The tumor 5 ing/kg 15 mg/kg 0/60 45 mg/kg 2/58 4/60 in a control male had the earliest onset at apparently was responsible for death of the animal. 21 weeks and No gliomas were found in the spinal cords of male rats. Because of the greater incidence of tumors observed in high-dose animals, the remaining preserved brain tissues from all animals were sectioned, giving a final total of 6-8 brain sections per animal. Two more astrocytomas were found in high-dose male rats in the additional brain tissue. were found in other male groups. 5 mg/kg group female. No further tumors One additional astrocytoma was found in a The final over-all incidence of astrocytomas in males was, as follows: Table 6. Final astrocytoma incidence in male rats. Control 1 mg/kg 5 mg/kg 1/60 0/60 0/60 Statistical analysis of adjusted 15 mg/kg 2/58 45 mg/kg 6/60 data using a 1-tailed Fisher-Irwin Exact test indicated the incidence of astrocytomas in male rats was increased in the high-dose group (p=0.05). Also, a Cochran-Armitage Test indicated a statisti- cally significant positive trend (p<0.01; Hazleton, 1986). Based upon these statistical analyses, the contracting laboratory report states "While the characteristics of these tumors did not conform to published characteristics of chemically induced brain tumors, this finding is, nevertheless, suggestive of a possible carcinogenic effect at a dose of 45 mg/kg/day" (Hazleton, 1986). It is generally accepted that statistical analysis alone should not be the basis for interpreting a biological experiment (Interdisciplinary Panel on Carcinogenicity, 1984: OSTP, 1985). There are many non-quantitative, biological factors to be considered when assessing the evidence for a carcinogenic effect in animals. These include: 31 �1. High variability of spontaneous incidence in control animals of the same strain in concurrent and earlier studies (historical controls). 2. Decreased time-to-tumor development (latency) in treated vs. control animals. 3. A dose-related increase in incidence in more than 1 experimental group or in both sexes. 4. A greater degree of tumor growth (neoplastic progression) in treated vs. control animals. 5. The presence of preneoplastic or toxic lesions in the putative target tissue. 6. The presence of multiple tumors in the putative target tissue. 7. Positive genotoxicity of the test substance. These factors apply to evaluation of suspected carcinogens at any site, including the central nervous system, as discussed by Koestner (1986) and by Ward and Rice (1982). The characteristics generally attributed to a present in this experiment. There was no evidence of decreased tumor latency, the increase was limited to high-dose gliosis were present in treated tumors in treated brain carcinogen were not males, no preneoplastic lesions such as animals, all tumors were solitary, and the animals were not larger or more anaplastic than generally seen in control animals. one in a control male. In fact, the largest and most lethal tumor was the There is a final consideration, i.e. most, if not all known brain carcinogens show clear genotoxicity in mutational assays (Federal Register, 1983 and Kleihues e_t al., 1982), whereas 2,4-D is negative in most such assays. The absence of preneoplastic and toxic lesions in the brains of the highdose male rats warrants particular attention. Generally, when a group of inbred test animals is exposed to a carcinogenic level of a chemical throughout the course of an experiment, the different stages of carcinogenicity are repre32 �sented in many of the animals. It would be unusual for 6 animals to exhibit fully developed tumors while the remaining 54 fail to develop even the earliest stages of neoplasia or other signs of toxicity in the putative target cells. All of these considerations do not, however, totally preclude the sibility that 2,4-D may be a weak neurocarcinogen. pos- Although known animal neurocarcinogens are either relatively potent, genotoxic chemicals or oncogenic viruses, the central nervous system could be a target tissue for relatively weak promotional or indirect carcinogenic effects as reported in other tissues. Pathological evidence of neurotoxicity has not been identified; however, clinical signs of neurotoxicity have been reported in animals exposed to high levels of 2,4-D, indicating that the chemical may functionally affect the central nervous system (See section 3). Since little is known of neurocarcinogenic mechanisms, further consideration of this area would be speculative. The over-all incidence of brain tumors of similar type (gliomas) reported in 2,320 historical control male Fischer 344 rats up to 116 weeks of age in the U.S. National Toxicology Program (NTP) was 0.8% (Solleveld et al., 1984). Among 529 animals allowed to live out their life-span (median age 28 months) the incidence was 2.9%, indicating an increase in incidence with advancing age. If one assumed there was no compound-related effect in the 2,4-D study, the over-all glioma incidence in male rats, combining all groups, was 3.6%. This is considerably higher than the NTP figure for 2 year studies, and slightly higher than the incidence for control rats with a median age of 28 months. It must be pointed out; however, that historical control data is generally based upon 3 brain sections per animal rather than the 6-8 examined in the 2,4-D study. Since most gliomas in rat brains are found only upon microscopic examination, the number of tumors reported is probably a function of the tissue examined histologically. amount of brain Thus, the 4 tumors initially found in 2,4-D treated high-dose male rats may be more appropriate for comparison to historical control rates. This would give an over-all glioma incidence in male rats of 2.8%. The interpretation of animal tumor data where there is high variability in tumor incidences among different control groups must take into consideration the possibility of statistical report that astrocytomas in false positive findings. Fischer rats are one Solleveld et al. (1984) of the tumor types in the NTP testing program that exhibit statistically significant intergroup variability. 33 �7.2. Industry Task Force 2,4-D Mouse Study Groups of 60 male and 60 female weanling B6C3F1 mice were treated with 2,4-D (Acid, 97.5% pure) in the diet at levels of 0, 1, 15 or 45 mg/kg body weight/day for 106 weeks (Hazleton, 1987). No treatment-related effects on animal survival, clinical bodyweights or gross pathological findings occurred. observations, The only histological alteration found to be treatment-related was increased cytoplasmic homogeneity of renal tubular epithelium in male mice receiving 15 mg/kg body weight/day and 45 mg/kg body weight/day. Untreated and low-dose animals had cytoplas- mic vacuoles in the epithelium. The significance of this finding is uncertain. A summary of all tumor incidences Appendix 2. in the mouse study is presented in There were no treatment-related increases at any site. In summary, there was no clear evidence of toxicity as the result of exposure to 2,4-D under the conditions of the experiment, and no carcinogenicity was evident. One may question whether a maximum tolerated dose was employed in the mouse study. However, the doses administered were 600-fold higher than the maximum reported human exposure (Libich et aj.., 1981). 7.3. Evaluation of Pathology and Carcinogenicity Two recent animal experiments with rats and mice conducted for the Industry Task Force on 2,4-D Research Data were adequate to detect potential chronic toxicity or carcinogenicity. The only finding of concern was an increase in the incidence of astrocytomas in the brains of male rats administered 45 mg/kg/day of 2,4-D for 104 weeks. conclude that these tumors were related There is insufficient evidence to to 2,4-D exposure. Although there was a statistically significant increase in treated animals, an assessment of biological factors suggests the tumors were spontaneous rather than compoundrelated. 8. EPIDEMIOLOGY The available epidemiological 2,4-D studies of persons potentially exposed include cohort and case control studies. to In cohort studies, the ex- perience of exposed individuals is followed in comparison with an unexposed group often drawn from the general population. If the exposure is well char- acterized the incidence of a number of different diseases in relation to posure can be assessed. incidence. ex- Often mortality may be used as a substitute for In case control studies, individuals with specific diseases are iden34 �tified and comparable controls and their past exposures ascertained, usually be means of interviews. As these two different classes of studies have different methodologic aspects and potential concern for biases, they will be considered separately. It should also be pointed out that the classification of soft-tissue sarcomas is controversial. As it was not possible to review the data upon which tumors in the epidemiological studies were classified, the reports of the authors have be taken as published. The findings of these studies are sum- marized in Table 7 and their salient points discussed in the following section. Table 7, Summary of epidemiology studies. GROUP FINDINGS REFERENCE Employees manufacturing 2,4-D and 2,4,5-T in Denmark. Two groups sized 3,844 and 615 exposed from 1947/1951 to 1982 Positive: Four cases of soft tissue sarcoma (STS) with only 1.09 expected. Negative for malignant lymphoma s. Lynge, 1985. A group of 348 Swedish railway workers who used several herbicides for at least 40 days/year. No indication of STS or non -Hodgkins lymphoma (NHL). Lacked power to indicate or exonerate 2,4-D. Axelson and Sundell, 1974 and Axelson et al., 1980. A group of 1,971 male herbicide applicators from Finland exposed to herbicides for >2 weeks/year from 1955 to 1971. No excess of cancer, cases of NHL or STS. no Riihimaki et al., 1982. ~~ A group of 1,222 Ontario Hydro sprayers in which exposures to phenoxy herbicides were high, had worked in the forestry trade for >6 months between the years 19501982. No cases have yet but latent group size of NHL or STS been identified period short and was small. Green, 1986. A group of 354,620 Swedish agricultural or male forestry workers born between 1891 and 1940 compared to a reference cohort of ca. 2,000,000 men with other occupations. In men working in land and/or animal husbandry, 253 cases of STS were observed with a relative risk of 0.9. In timber cutting, 49 cases observed with a relative risk of 1.0. A large study with sufficient power but with poor identification of exposure. Wiklund and Holm, 1986. Group exposed to phenoxy herbicides in agriculture and forestry from 1950 to the mid 1970s in Sweden Relative 5.3. of H a r d e 11, 1981: Hardell and Sandstrom, 1979. South Swedish group of workers exposed to phenoxy herbicides. Relative risk for exposure to all phenoxy herbicides of 6.8 for STS. Relative risk for 2,4-D was 4.2. Eriksson ej. a_l., 1981. COHORT STUDIES CASE CONTROL STUDIES 35 risk for STS �Swedish workers exposed to herbicides and chlorophenols. Relative risk of malignant lymphoma with exposure to phenoxy herbicides or chlorophenols was 6 and for exposure to phenoxy herbicides alone, 4.8. No dose response relationship for phenoxy herbicide exposure. Hardell et al., 1981. ~ New Zealand study on workers exposed phenoxy herbicides > 1 d/year. Non significant risk for STS of 1.3 and 1.5 for NHL but information on exposure may not be accurate. Smith et al., 1984. A group of Vietnam veterans who were possibly exposed to various phenoxy herbicides in between 1962 and 1971. Odds ratio (OR) of 0.53 for Vietnam service, OR of 0.7 for exposure to Agent Orange. Short observation period may limit power. Greenwald et al., 1984. ~~ STS in in men and women area in Northern Italy. in an Exposure included 2,4-D, MCPA and 2,4,5-T. No excess risk of cancer associated with phenoxy herbicide exposure in men. Among living women relative risk was 2.7 (90% CI 0.59-12.37). In women alive at time of interview, <75 years old, exposed in 1950-55 period, age adjusted odds ratio was 15.5 (90% CI 1.3-180.3). The study was of low power. Vineis, et al., 1987 ~~ 60 cases of primary mesothelial ovarian tumors and 127 living controls with non-ovarian malignancies. Cases and controls from same hospital based cancer file. Herbicide exposure determined as definite if the subject or next of kin described personal use of herbicides, probable exposure if a farmer resided in areas with known herbicide usage. Bight cases gave a definite history, no controls, combining definite and probable, relative risk for herbicide exposure was 4.38 (1.90-16.07). Series relatively small and recall bias cannot be excluded. Study not informative in terms of 2,4-D exposure. Donna et al., 1984 36 �Conducted on male cases with STS, Hodgkins Disease (HD) and NHL from Kansas (139 STS, 132 HD, 172 NHL). No significant association between farming and/or herbicide use and STS or HD. For NHL and farming the OR was 1.4. Farm herbicide use on any of wheat, corn, sorghum, or pasture gave an OR of 1.6 for NHL. Increasing risk of NHL with increasing duration of herbicide use and/or increasing time since first exposure. Higher risk also noted with greater herbicide use without protective equipment. Use of 2,4-D was not determined directly and exposure to other chemicals may confound analysis. Hoar et al., 1986a and 1986b Case control study in Western Washington State including 128 cases of STS, 575 of NHL and 694 population controls. All data obtained by personal interview. No excess risk for past occupational exposure to phenoxy herbicides for either STS or NHL. Elevated risk of NHL among men who had been farmers (RR of 1.33: 95% CI 1.03-1.7), forestry herbicide applicators, 4.8 (95% CI; 1.2-19-4) and those potentially exposed to phenoxy herbicides for 15 years or more during the period prior to 15 years before cancer diagnosis 1.71 (95%n CI; 1.042.8). Also increased risk of both STS and NHL in individuals reporting prior occurrence of chloracne. Woods, et a_l., 1987 8.1. Cohort Studies In spite of the apparent superiority of the cohort design in many aspects, cohort studies have many deficiencies which makes them less informative than case control studies. One of the important reasons for this is that cancer such as STS and NHL are relatively rare compared to other cancers and also probably occur only after a long latent interval. to be very large and the observation period finding, a feature of the majority A cohort study therefore has very prolonged for a negative of them, to be of much assurance. In addition, there are potential difficulties with regard to exposure, though these are shared with case control studies. One class of cohort study which has been used in the interim evaluation of the potential for phenoxy herbicides to increase cancer risk is identification of individuals in occupations with potential exposure to these substances such as agricultural and forestry workers. Because exposure is not individually identified in such studies, substantial obscuring (dilution) of potential effects 37 �may occur. The value of these studies is very small and, with one exception, studies using occupation to indicate exposure have been ignored. However, many of the other cohort studies suffered from a similar deficiency, in that, even though based on specific groups of workers, details of individual exposure were unknown. An example of this is the recent Ontario Hydro Study (Green, 1986). The other major difficulty is that nearly all cohort studies, at least in part, depended on review of historically available records with follow-up of identified individuals to the present day. Such historical cohort studies pre- sent major difficulties in the identification of individual exposure, particularly in terms of intensity. Thus it is very difficult to evaluate a dose response relationship, a critical consideration of the cohort studies have in human carcinogenesis. incorporated a protocol for Although some follow-up, in nearly every instance this has been of short duration and has not helped to achieve much resolution of the exposure issue. In common with the case control studies, there are few groups who are known to have been exclusively exposed to 2,4-D. In the majority of instan- ces, exposure has been to 2,4,5-T as well, often in excess of 2,4-D and, even in a positive study, it may not be clear which agent was potentially responsible. Potentially the most informative of cohort studies are those on workers involved in the available studies manufacture of of this type workers involved in the sidered further. specific chemicals in specific in the United States manufacture of 2,4,5-T have only plants. The reported on and are therefore not con- There has; however, been one study of this type from Den- mark (Lynge, 1985) in which 3,844 workers in one plant and 615 in another, employed from 1947 and 1951 respectively were followed to December 31, 1982, by linkage with Cancer Register. the Central Population Register for Death and the Danish Exposure appeared to be largely to 2,4-D or other chemicals of a non-phenoxy type, although a small amount of 2,4,5-T was made between 1951 and 1959 in the larger plant. sarcoma was found. In this study an excess of soft tissue Restricting attention to those where the latent period exceeded 10 years, there were 4 observed cases with 1.09 expected (95% confidence intervals [CI] of 1.00-9.39). A corresponding analysis for malignant, lymphomas indicated 4 observed, compared to 3.04 expected, a non-significant difference. This is the only cohort study which has shown an excess of soft tissue sarcomas, but it is also one of the largest which had relevant exposures. 38 �Part of the difficulty in interpretation is the exposure to 2,4,5-T and, for this reason, it cannot be concluded that the excess was due to 2,4-D. All the other cohort studies so far reported were negative. One of the earliest was the study of Axelson (Axelson and Sundell, 1974; Axelson, et al., 1980). This was a small cohort study of Swedish railroad workers, who were selected for having been exposed on at least forty days (per year) to herbicides. Although an initial apparent excess of tumors in those exposed to another unrelated herbicide (amitrole) was reported, this finding was reversed in the second report. However, a non-specific excess of tumors in those exposed to phenoxy herbicides or phenoxy herbicides and amitrole was noted (two stomach cancers, vs. 0.33 expected in the group with a latency of 10 or more years). There were no soft lymphoma (NHL) in this group. tissue sarcomas This study (STS) or non-Hodgkins only involved 348 persons, and lacked the power to clearly indicate the role of herbicides in the causation of stomach cancer as these could have arisen by chance. Riihimaki et al., 1982, reported on 1,971 males who were exposed to 2,4-D and 2,4,5-T as herbicide applicators in Finland for at least two weeks per year from 1955 to 1971. They were only followed for nine years through to 1980 and no excess of cancer with no cases of STS or NHL were noted. In the Ontario Hydro Study (Green, 1986), the numbers of exposed workers was also small. have been high. However, exposures to phenoxy herbicides were known to This study is potentially of importance, not so much in the fact that it has been negative, (no cases of NHL or STS have yet been identified) but because it has the potential for further prolonged follow-up. However, in common with other cohort studies, exposures were to other herbicides in addition to 2,4-D and it would be unable to specifically identify a risk related to 2,4-D. The work of Wiklund and Holm (1986) is of note because it relates to a very large cohort of 354,620 men born between 1891 and 1940 and described as agricultural or forestry workers in the Swedish population and housing census of 1960. These men, together with a reference cohort of nearly two million men with other occupations, have been followed by linking Cancer Environment Registry for 1961 through 1979. categorized according to named occupations. presumed exposure to the Swedish The cohort was to phenoxy herbicides sub- by the Large numbers of STSs occurred but, in the final analysis, there was no significant excess in any of the sub-groups. For example, in those working in land and/or animal husbandry, 253 cases were observed with 39 �a risk of 0.9 relative to the control population (95% CI: 0.8-1.1). Similarly, for timber cutting, 49 cases were observed with a relative risk of 1.0 (95% CI: 0.71.3). Both these groups had presumed exposure to 2,4,5-T and 2,4-D. Al- though this was a large study with sufficient power to identify the increased incidence of STS (excesses) noted in the case control studies conducted in the same country, there was undoubtedly some dilution effect because of the characterization of workers by job titles. There was also a potential shortage of person years of risk for periods where an excess might be expected to occur. Nevertheless, the authors have calculated that, even with dilution, their studies should have been capable of detecting a relative risk of 1.5 which they believe would have been compatible with the relative risks in excess of five noted in the Swedish case control studies (considered below). In many respects this report can be regarded as a reasonably powerful negative study. The study has the potential to further resolve the issue, particularly if further details of exposure are obtained (possibly through a case control approach which is reported to be in the planning stage). In summary therefore, the majority of cohort studies are of limited usefulness in terms of their size and therefore relative lack of power as well as their difficulties in characterizing exposure. The one positive cohort study, that of Lynge (1985) has to be given substantial weight, even though the only excess noted was of soft tissue sarcoma. However, it cannot be used to indicate that the excess was due to 2,4-D alone. 8.2. Case Control Studies The case control studies have been largely responsible for identifying potential risks of cancer following phenoxy herbicide exposure in man and have so far been reported from Sweden, New Zealand, Italy and the United States. Swedish studies pointed to potentially important relative risks in ( > 5 ) for STS and NHL. The studies in New Zealand have been negative or shown small and nonsignificant excess of these two tumors. Of the studies conducted and so far reported in the United States, one was negative but two were positive in relation to NHL. Before proceeding to a detailed review of each issues of methodology is in order. against many of the case control study, a comment on Substantial criticism has been levelled studies, particularly those because of the possibility for bias in the recall of information. from Sweden, It is accepted that recall bias is possible in any case control study (a bias in which cases are 40 �more likely to recall relevant exposures than controls because they have the disease and the incentive to try and find a reason for developing it). Because of the potential for recall bias in any case control study, considerable attention is paid to specific points of detail in order to ensure that it is minimized. Although preferable, this is not always achievable. Interviewers who collect the information should be kept unaware (blinded) as to case and control status, questions should be asked in a pre-assigned format and those relating to specific exposure be only part of a series of questions relating to exposure to a number of different substances. The reports of the Swedish case control studies suggest that sufficient care may not have been taken on these points. Hardell (1981) addressed this issue specifically and, in addition, discussed a suggested bias apparently first proposed by Dr. Philip Cole in testimony in 1980 to the Environmental Protection Agency of the United States. His sug- gestion was that cases might not always directly record employment in agriculture or forestry, but first remember exposure to phenoxy herbicides conditionally on that recall, also remember earlier jobs. invalidate some of the approaches taken by obtain detailed occupational exposures. and then, Such a bias might Hardell and his colleagues to Hardell (1981) claimed that this puta- tive bias was largely discounted by an investigation of colon cancer conducted using the identical approach as in his other studies. In this study a risk related exposure to phenoxy herbicides was not identified; however, this may not discount the possibility of a bias as discussed further below. In any observational epidemiologic inquiry a systematic bias may occur. There may be a systematic bias in the Swedish case control studies which persists throughout all the studies as they were essentially performed using the same technique. However, there may also be a systematic Zealand case control studies which has led negative. bias in the New to those studies tending to be In both sets of studies it was impossible to be certain of the nature of the exposure the cases and controls encountered. However, in view of the high relative risks observed in the Swedish studies, they have to be considered seriously in the present context. Hardell and Sandstrom (1979) reported a case control study of STS which arose from the observation by Hardell in a series of cases under his care that exposure to phenoxy herbicides appeared to be reported more frequently then expected. The case control study largely confirmed this observation with a relative risk of 5.3 in those exposed to phenoxy herbicides in agriculture and 41 �forestry from 1950 to the mid 1970s. A further analysis conducted by Hardell (1981) confirmed this finding. In a second study in South Sweden using a completely different case series, Eriksson et a_l (1981) found a relative risk of STS for exposure to all phenoxy herbicides of 6.8 (95% CI: 2.6.-17.3). It was possible to characterize exposure to non-2,4,5-T phenoxy herbicides including 2,4-D where the relative risk was 4.2. In these studies, as in the other Swedish case control studies, cases were identified from the Tumour Registry and were pathologically firmed. For live cases, live controls Registry and for dead cases, dead case was matched with 2 controls. were identified from controls from the Death con- the Population Registry. Each Exposure data were obtained from a mailed questionnaire with questions relating to phenoxy herbicides as part of a series of questions relating to exposure to specific chemical substances. Where there was doubt over the answers received the answers were supplemented by telephone interviews conducted blind according to case or control status. With this design, the extent to which recall bias will occur, is dependent on the extent to which telephone interviews were indeed used uninterpretable. when answers were If there was a tendency to use more telephone interviews for cases than controls and this occurred in all studies then a systematic bias could in fact have occurred, leading to elevated relative risks. The negative finding in the case control study of colon cancer (Hardell, 1981) is to a certain extent reassuring, providing the use of telephone confirmation was not less for the colon cancer cases than for the STS or NHL cases. ing is the fact that when analyses were restricted Also reassur- to the data obtained from the mailed questionnaire, similar relative risks were obtained. (1981) used the same method to evaluate malignant lymphoma. Hardell et a_l. Once again, the study arose from the observation of a case series where exposure to phenoxy herbicides appeared to be greater than expected. The cases in this study possibly included the case series which prompted the hypothesis and included 60 cases of Hodgkins Disease and 105 of NHL, together with four unclassifiable lymphomas for a total of 169 cases with two controls, each derived in the same method as for the earlier studies. Relative risk for exposure to phenoxy herbicides or chlorophenols was 6 (95% CI: 3.7-9.7); herbicides alone, 4.8 (95% CI: 2.9-8.1). for exposure to phenoxy There was no dose response relation- ship for phenoxy herbicide exposure. The studies observations and in New Zealand were because phenoxy conducted because herbicides are 42 of the extensively used Swedish in that �country. In each instance, the cases and controls were drawn from the Na- tional Cancer Registry. public hospitals as Both cases and controls were restricted to those from there appeared to be some difficulty in contacting and interviewing the relatively small numbers of cases in private hospitals. was derived from telephone interviews of cases and controls. Data The interview schedule, though not given in any of the papers, appeared to be less extensive and potentially less specific in terms of phenoxy herbicide exposure than the schedule used in Sweden. This might contribute to a negative finding though the authors claim that their use of cancer controls tends to overcome the potential problem of recall bias in Swedish studies. The first study related to STS (Smith et ah, 1984) in which there were 82 cases and 92 controls. The relative risk for those potentially exposed to phenoxy herbicides of one day (per year, but not in the cancer registration) was 1.3 (90% CI: 0.6-2.5). In the second study (Pearce et al., 1986), NHL was evaluated by a similar design. 228 population controls. There were 86 cases and A relative risk of contracting NHL of 1.5 (95% CI: 0.8-2.7) was observed for those using any agricultural spray. was five years before 1.3 (95% CI: 0.8-2.1) for cancer The relative risk controls and 1.6 (95% CI: 0.3-3.1) for population controls for those who ever sprayed an agricultural chemical involving exposure to phenoxy herbicides, including both 2,4,5-T and 2,4-D. These studies clearly do not demonstrate the absence of risk. There is a small, though not significant, elevation of risk for both diseases and the confidence intervals would not exclude a relative risk of two or more, depending on the case series. If an effect were really present, it is likely that the risk may have been underestimated because of the difficulty of obtaining exposure information. In the United States, Greenwald e_t al. (1984) attempted to evaluate whether Vietnam service had increased the risk of STS by identifying cases from the New York Tumour Registry. Population controls for living cases were obtained from driver licence files and controls for diseased cases from the Death Certificate Register for men with potential Vietnam aged eighteen to twenty-nine, between 1962 and 1971. been diagnosed between 1962 and 1980. interviews of cases or next of kin. Data service i.e. those The cases had to have were obtained from personal The odds ratio for Vietnam service was only 0.53 and, for reported exposure to Agent Orange, 0.70 (95% CI: 0.17-2.92). Agent Orange is a 1:1 mixture of 2,4,5-T and 2,4-D. This study therefore showed no association though the width of the confidence intervals indicates 43 �that it was not powerful enough to exclude an elevation of risk approximating to three. Further, the analysis appears to have ignored the issue of latency and may not be an appropriate test of the hypothesis. Reports of two case control studies have relate to potential exposure appeared from Italy. Both to phenoxy herbicides in women, in the one case to STS and, in the other, to ovarian tumors. Vineis, et al. (1987) studied soft tissue sarcomas diagnosed in men and women in an area in Northern Italy where rice is grown. Women are tradi- tionally employed as rice weeders and during a period commencing in 1950 they were exposed to increasing amounts of phenoxy herbicides used initially to experimentally control weeds. that were being This exposure included 2,4-D, MCPA and 2,4,5-T; however, use of the latter was banned in 1970. The case series was identified in 1981-1983 and a random sample of controls was drawn from the population. In addition, diseased subjects were chosen as controls for the 37 of the 135 cases who had died at the time of interview. No excess risk of cancer associated with phenoxy herbicide posure was found for men. ex- Among living women the relative risk was 2.7 (90% CI 0.59-12.37) but when attention was restricted to women alive at the time of interview, less than 75 years of age:, exposed in 1950-55 period an age adjusted odds ratio of 15.5 (based on only 15 cases with a 90% CI of 1.3-180.3) was determined. Similarly when exposure to phenoxy herbicides females who had regular jobs in agriculture was considered among living the age adjusted odds ratio for women known to be exposed was 3. Although this study is of low power it suggests an excess risk of STS in women known to have been occupationally exposed to phenoxy herbicides. Donna, et al. (1984) studied a series of 60 cases of primary mesothelial ovarian tumors and 127 living controls with non-ovarian malignancies, drawn from the same hospital based cancer file. Ten of the cases of ovarian tumors were dead and next of kin were interviewed. These cases were studied be- cause of preliminary data suggesting that some of the herbicides widely used in the rural areas from which the cases were drawn were carcinogenic in animals. Herbicide exposure was determined as definite if the subject or next of kin described personal use of herbicides and was familiar with the various commercial brand names, probable exposure if a farmer resided in areas where there is known herbicide usage. Eight cases and no controls gave a definite history of exposure combining definite and probable, the relative risk for herbicide exposure was 4.38 (1.90-16.07). 44 �This was not a population based study. The case series was relatively small, controls were drawn from a cancer file, little detail is given. It is possible that there was an undue emphasis on herbicide exposure so recall bias cannot be excluded, even though the authors claim that it is unlikely with a cancer control series. However, there was no attempt to characterize herbicide exposure according to nature of agent and thus this study is relatively noninformative in terms of 2,4-D exposure. A recent case control study (Hoar et al., 1986a and b) conducted by a group from the environmental epidemiology Cancer Institute, was designed branch from the U.S. National to avoid many of the potential methodologic problems of other case control studies. The study was conducted in Kansas, known to be a wheat producing area and where herbicides •were used more frequently than insecticides. Of the herbicides, 2,4-D was more commonly used; 2,4,5-T was also used "along with myriad other chemicals". It was decided to study male cases with STS, Hodgkins Disease (HD) and (NHL). Cases were identified through the University of Kansas Cancer Data Service which is a population based registry covering the state of Kansas for the years 1976 to 1982. There were 200 males with STS; 173 with HD; 297 with NHL of which 200 were review was selected at random for study. conducted with confirmation of the diagnosis A pathology in 81%, 85% and 90% of the cases respectively (139 STS, 132 HD, 172 NHL). These appear to have been regarded as the eligible cases for the study. Three controls per case were selected by random digit dialing for those less than 65 years of age and from medicare files alive. for those more than 64 if the corresponding case was If the case was dead, controls were selected from Kansas State mor- tality files. Controls were matched to the case by age (plus or minus two years) and vital status and, for the deceased controls, by year of death of the case. STS, A deceased individual was not eligible to be a control if they died of a HD, NHL or a malignancy of an ill-defined site. Deaths resulting from homicide and suicide were also excluded. Half of the cases of STS and NHL and one third of the cases with HD had died before the study commenced. Their next of kin were interviewed, as were the corresponding deceased controls. All interviews were conducted by telephone and were completed in 96% of the eligible STS cases, 92% of the eligible HD cases, 99% of the eligible NHL cases and 94% of the controls. 45 �In the analysis, individuals were considered as "farmers", if they had reported as "having worked or lived on farm-land". An unmatched analysis was used as a "matched analysis yielded results similar to those provided by the unmatched approach". The same set of controls were used for analysis of all sites although, as the major findings were restricted phoma, the detailed analyses were conducted by comparing that set of cases with all controls. to Non-Hodgkins Lym- No significant association was found between farming and/or herbicide use and STS or HD. Significant associations were found with NHL and further discussion will be restricted to these. For NHL there was an association of borderline significance for farming (odds ratio (OR) of 1.4, 95% CI: 0.9-2.1). four specific Farm herbicide use on any of the crops (wheat, corn, sorghum, or pasture) was reported by 40 cases with NHL compared to 192 controls, for an OR of 1.6 (95% CI: 0.9-2.6). There was a significant trend in risk of NHL with increasing duration of herbicide use to an OR of 2.0 for sixteen or more years use, for frequency of herbicide use (with an OR of 6.0 for twenty-one or more days use per year). Risk of NHL also increased with time since first exposure, the greatest risk being found for farmers who started using herbicides before 1946 (OR of 3.3). This trend was diminished by controlling for frequency of herbicide xise but, after this control, farmers who began use before (OR of 2.2). 1946 still had an excess risk This latter trend is reported only in the text, numbers are not provided and it is not indicated whether the elevated risk for use before 1946 is significantly different from the risks for use between 1946 and 1965 which was 1.7. Subjects who usually mixed or applied herbicides themselves had increase risk of NHL with an OR of 1.9 (95% CI: 1.1-3.3). mix herbicides, the OR was 1.1 i.e. not elevated. Among those who did not Higher risk was also noted with greater herbicide use without protective equipment. This appeared to be a well conducted study although, as for any study, some questions can be raised. mous with 2,4-D use. Phenoxy herbicide use was said to be synony- However, the questionnaire frequency of use of each specific did not address dates and herbicide though, given the nature of the data collection including information obtained from proxies of both cases and controls (by design), it seems unlikely that detail of this type could have been anticipated. There has to be concern with the possibility of recall bias, sociated with knowledge of the disease in cases. as- Indeed it is possible that, at the time the study was conducted there already was some information available 46 �to farmers and next of kin of the possible association of herbicide use with cancer from the reports in Sweden. With the use of proxy cases and controls, the opportunity for misclassification of exposure was substantial although, in general, this would normally be expected to reduce risks towards zero and not produce spurious increases in risk. Although the authors clearly indicate that the study is supportive of the possibility that 2,4-D was the responsible agent for the NHL excess, as pointed out by MacMahon (1986, in a review conducted for the U.S. EPA) previous studies had suggested that all three tumors were likely to show increased risk and this study only shows increased risk for one of them. However it is difficult to perceive of recall bias preferentially applying only to NHL. Also, the authors did not analyze data on individuals exposed only to 2,4-D and not other chemicals. Nevertheless, it is questionable as to whether 2,4-D could be regarded as the responsible agent. Apart from the fact herbicide exposure may not reflect use that the estimates of 2,4-D alone, it of phenoxy is possible that exposure in the early part of the historical period covered by this study was to substances dioxins. such as 2,4,5-T, likely to be contaminated with more toxic That contaminated herbicides may be responsible is suggested by the highest risk for those exposed prior to 1946. However, it is not clear yet whether this risk is in fact significantly different from the risk in the ceeding twenty year period. suc- The risk from recent exposure would be expected to be lower than for early exposure, possibly because of greater care in use as well as lack of expiration of the relevant latent period. Woods, e_t al. (1987) conducted a population based case control study in Western Washington State that included 128 cases of STS, 575 of NHL and 694 population controls. All data were obtained by personal interview. There was no excess risk for past occupational exposure to phenoxy herbicides for either STS or NHL. However, there was ing groups: an elevated risk of NHL among the follow- Men who had been farmers with a relative risk of 1.33 (95% CI 1.03-1.7), forestry herbicide applicators, 4.8 (95% CI; 1.2-19-4) and those potentially exposed to phenoxy herbicides in any occupation during the period 1.04-2.8). for 15 years or more prior to 15 years before cancer diagnosis 1.71 (95%n CI; Although these risks came from sub-group analyses, the sub-groups were evaluated because of positive findings in other studies and because of knowledge on latent period effects in relation to carcinogenicity. nificant excesses are compatible with the expectations 47 The sig- from other studies are �therefore important. An additional confirmation was that increased risk of both STS and NHL was observed among those individuals reporting prior occurrence of chloracne. This presumably indicates either those who had severe exposure or might have been unduly susceptible to the toxic effects of phenoxy herbicides. The authors also discussed why lower risks might be found in studies in the United States Sweden tends to compared to Sweden. be concentrated over They point out that a much shorter time herbicide exposure in the United States. exposures in period than for They have calculated a mean maxi- mum daily dose of 45 ug/kg for American workers exposed to 2,4,5-T compared to mean of 90 ug/kg for Swedish workers. They also considered the possibility that Scandinavians might have undue susceptibility herbicides. They found that when their analysis to the effect of phenoxy was restricted to persons from Scandinavia only, the risk estimates for STS in relation to past occupational chemical exposures were substantially greater than those observed among the study population as a whole. This was true both for high level phenoxy herbicide exposure (relative risk of 2.8, CI; 0.5-15.6) and for high level chlorophenol exposure. This analysis was; however, based only on 15 STS cases. This seems to have been a carefully conducted study and, although overall no increased risk was found for phenoxy herbicide exposure and STS or NHL, the sub-groups where increased risk was demonstrated are compatible with a true biological effect. It is important to recognize that when case control studies are performed in a general population group, it is likely that excesses will only be found among sub-groups vant exposures who have had the opportunity for rele- at an appropriate time period. This applies even if the area for study has been selected as one where it is known that herbicide exposure occurs. Another case control Epidemiology Branch of the study being conducted National Cancer Institute in involving 594 Leukemias, 690 Blair, 1986). is cases of NHL and by the Iowa and Minnesota 1,245 controls (Cantor and Preliminary results indicate no overall increased associated with living or working on farming. use of 2,4,5,-T had Environmental risk for NHL However, persons reporting the a two-fold risk of NHL (OR = 2: 95% CI; 0.7, those using 2,4-D had only a slightly elevated risk (OR = 1.2: 5.2) while CI; 0.9, 1.8). Unfortunately, information was not gathered on the number of days per year of pesticide use. Since this was the variable that showed the strongest as- 48 �sociauon risk of NHL in the study of Hoar, e_t al. (1986), the investigators have decided to recontact subjects to try and obtain this information. 8.3. Evaluation of Epidemiology Studies An important feature of studies of potential carcinogenicity is consisten- cy. The difference between the results in New Zealand and Sweden indicates lack of consistency; however consistency has been observed in the finding of an excess of STS in the studies in Sweden and Italy using a case control approach and in Denmark in a cohort approach. Further consistency has been observed in finding an excess of NHL in Sweden and in the United States in case control approaches. Although it is clear that 2,4-D cannot be exonerated as a reason for the excess, especially from the results of the Danish cohort study and the U.S. case control study, neither can these single studies, of themselves, be used to classify the risk as being confirmed. Using IARC terminology, it may be concluded that there is limited evidence of carcinogenicity in man from exposure to phenoxy herbicides. In terms of exposure to 2,4-D specifically, the evidence must still be regarded as inadequate to classify it as a carcinogen. 9. RISK ASSESSMENT OF 2,4-D The panel was of the view that it would be useful to give some indication of the theoretical risk to humans from exposure to 2,4-D if it is assumed that 2,4-D is carcinogenic. calculation because, The human data are not adequate to support amongst specific human exposures to other limitations, the lack of 2,4-D in epidemiological studies. cancer risk was assessed under the theoretical such a information of Accordingly, assumption that the increased incidence of astrocytomas observed in male rats in the Industry Task Force 2,4-D study was caused by exposure to 2,4-D. These estimates are not in- tended necessarily to be accurate estimates of risk nor should the fact that these calculations were made be interpreted as implying that the panel believes that 2,4-D is a carcinogen. The theoretical risk of cancer at doses experienced in humans was were obtained by fitting the multistage mathematical dose response model (Crump, 1984) to the data on astrocytomas in male rats. model (Crump et al., 1977; Crump, 1984) Environmental Protection The multistage dose response has been widely used by the U.S. Agency (EPA, 1983) and the U.S. Occupational Safety and Health Administration, (OSHA, 1983a). 49 The multistage model is used to �calculate statistical 95% upper confidence limits based upon an assumed linear relation between 2,4-D and cancer risk (i.e. proportional to dose). that additional cancer risk is Risk estimates to humans were made assuming that a given dose rate expressed in mg/kg/day gives the same risk in animals and humans. This assumption is supported by a recently completed study that compares animals an human data for 23 carcinogens (Allen et al., 1987). 8 contains the resulting estimates of risk based Table upon the estimated human exposures from Table 2. To help place the theoretical risks estimated for 2,4-D into perspective, cancer risks estimated for exposures to known carcinogens are also tabulated in Table 8. Risks from these carcinogens were computed using methodologies similar to that used for 2,4-D (e.g., a linear relations between exposure and risk was assumed in all cases and risk estimated from animal data were made to apply to humans). Risks from occupational exposure to inorganic arsenic, ethylene oxide and benzene assume exposures at recently promulgated or proposed OSHA standards (OSHA, 1983b). Risk estimates are provided for an exposure duration commen- surate with that estimated for occupational exposure to 2,4-D. The effect of intermittent exposure was accounted for in the same way in estimates for both 2,4-D and non-2,4-D exposures. Risk estimates are also presented for condi- tions which may not generally be regarded as "risky" by the general public: eating peanut products, having a chest X-ray, spending a week in the Rocky Mountains and smoking a single cigarette. The methods used to estimate the theoretical risks contained in Table 8 involve many uncertainties and should be viewed only as crude indicators of risk based upon the stated assumptions. 2,4-D Nevertheless, theoretical risks for and from other sources were obtained using similar assumptions and the panel believes that these estimates may provide useful comparisons. These comparisons suggest that, even if 2,4-D were £ carcinogen, the risk to persons exposed occupationally would be: 1) Considerably less than those for workers exposed to carcinogens at levels recently set by OSHA. 2) Less than those from some activities that the general public may regard as safe. 50 �Table 8. Estimated risks per million persons under various exposure conditions. PART L Hypothetical risk from exposure to 2,4-D based on the theoretical assumption of rat brain carcinogenicity. Application Helicopter Airplane Occupation Days/year Exposed Years Exposed Risks per million mixer-loader mixer-flagger fl agger 12 12 12 20 20 20 0.6 0.3 0.2 mixer-loader supervisor 12 12 20 20 0.09 0.003 Packsprayers handheld right-of-way gun sprayer roadside sprayer mist right-of-way blower sprayer 60 10 5 60 10 5 60 10 8 Hand and commercial tank sprayer 66 13 0.6 14 25 0.4 Tractor farmer PART II. Occupational cancer risks at recently established or proposed OSHA levels. Inorganic arsenic 8 (10 ug/rn 3 ) Ethylene oxide" (1 ppm proposed) 240 60 240 60 45 10 45 10 8000 400 3000 180 Benzene 0 (1 ppm proposed) 240 60 40 10 3000 190 PART IIIj, Other risks Eating peanut products'* (aflatoxin, U.S. average) 11 Having a chest X-raye (Lung cancer) 1.5 Spending a week at 3050 m in the Rocky Mountains 6 (Cancer from terrestrial and cosmic radiation) 0.9 Smoking one cigarette (Lung cancer only)' 0.6 a b c d e f Risks reported in OSHA (1983b) Risks reported in OSHA (1983a) Risks reported in Crump and Allen (1984) Average exposure to aflatoxin in peanut products obtained from FDA (1979). Risk estimates based on animal data in Wogan (1973), Wogan et al. (1974), Nixon et al. (1974) and Alfin-Slater et al. (1969). "~ Based on Hnear-quadTatic model and exposure estimates contained in the National Academy of Sciences BEIR report (NAS, 1980). Estimated from Doll and Peto (1978). 51 �10. GLOSSARY OF TERMS 2,4-D . . . . . . . . . . . . 2,4-dichlorophenoxyacetic acid. 2,4-DP 2,4-dichlorophenoxypropanoic acid. . . . . . . . . . . . 2,4,5-T . . . . . . . . . . . 2,4,5-trichlorophenoxyacetic acid. Adducts Chemical compounds, usually between a small highly reactive molecule and a large molecule such as a protein or nucleic acid. Ames . . . . . . . . . . . . Usually referring to a test for genotoxicity. Anaplastic . . . . . . . . . . A process involving a loss of differentiation of cells usually seen in certain types of tumor. Arochlor^ A commercial phenyl. Astrocyte . . . . . . . . . . A type of cell system. brand of found in polychlorinated the central bi- nervous Astrocytoma A tumor composed of astrocytes, usually in the brain. BEIR Biological Effects of Ionizing Radiation. Biphasic In two parts or two mechanisms. Chlorophenol . A phenol in which one or more of the hydrogen atoms are replaced by chlorine. CHO Chinese Hamster Ovary, cells. usually referring to Chromatid A portion of the chromosome consisting of a strand of DNA attached to the centromere. CI Confidence Interval Ci Curie, a unit of radioactivity. CNS Central Nervous System. Dermal Referring to the skin such as in skin toxicity. Embryotoxic . . . . . . . . . Toxic to the embryo. EPA Environmental Protection Agency of the U.S. F Female. Fetotoxic Toxic to the fetus. Fibroblast A connective tissue cell. Genotoxic . . . . . . . . . . Expression of toxicity which results in changes in the genetic material. Glioma . . . . . . . . . . . A tumor of the glial cells of the nervous system, as well as any tumor of the brain or spinal cord. Gliosis . . . . . . . . . . . An excess of astrocytes in a damaged part of the central nervous system. GLP . Good Laboratory Practice, usually referring to a set of guidelines which must be followed in conducting experiments. Hepatocyte Liver cell. 52 �Hi stops thological . . . . . . Pathology at a microscopic or cellular level. HD . . . . . . . . . . . . . Hodgkins Disease. Hodgkins Disease A malignant condition of the lymph spleen and lymphatic system. . . . . . . nodes, Hyperplasia . . . . . . . . . An abnormal increase cells in a tissue. IARC International Agency for Research on Cancer. . . . . . . . . . . . . in the number of normal ICR . . . . . . . . . . . . . Referring to a rats or mice. IP Intraperitoneal, into t h e body cavity. . . . . . . . . . . . . . specific strain of laboratory The dose, per animal required to kill 50% of the animals so treated. LV . . . . . . . . ..... Low Volume, sprays. usually referring to pesticide M . . . . . . . . . . . . . . Male. Macromolecules Very large molecules, usually of biological origin such as proteins or nucleic acids. . . . . . . . MCPA . . . . . . ..... MCPP . . . . . . . . ..... Mesothelial . . . 2-chloro-2-methylphenoxyacetic acid. 2-(2-methyl-4-chlorophenoxy)propanoic acid. ...... Pertaining to cells of mesodermal origins. MF . . . . . . . . . . . . . Male a n d Female. Microcalculi . . . . . . . . . Small abnormal concretions, usually of mineral origins. Micronucleus . A subcellular organelle in the nucleus which is the site of synthesis of ribosomal RNA. Microsome . . . . . . . . . . A subcellular organelle usually associated with metabolism. Myotoxic Toxic t o muscles. , . ..... . . . . . . . . . . NDMA . . . . . . . . . . . . N-nitrosodimethylamine. Neoplasm . . . . A new growth of tissue in which the multiplication of cells is uncontrolled. Neurocarcinogen . . . . . . . A substance which causes cancer in the tissues of the nervous system. ng . . . . . . . . . . . . . nanogram, 10~9 of a gram. NHL . . . . . . . . . . . . Non-Hodgkins Lymphoma. NOEL . . . . . . No Observable Effect Level: The highest level, usually in food, at which symptoms of toxicity are not observed. Non-Hodgkins Lymphoma . . . A malignant condition of the lymphatic system which does not possess the characteristics of Hodgkins Disease. Nondis junction The failure of bivalent chromosomes to move apart during the process of cell division. . ..... ...... ...... . . NTP . . . . . . . . . . . . . National Toxicology Program. OR . . . . . . . . . . . . . Odds Ratio. 53 �OSHA . . . . . . . . . . . . Occupational Safety a n d Health Administration, of the U.S. OSTP Office of Science the U.S. Parenchymal Referring to organs in the body cavity. Paresis Muscular weakness. Percutaneous . . . . . . . . and Technology Policy, of Through t h e skin. PGBE Propylene Glycol Butyl Ether ester of 2,4-D. pH Acidity of a solution. Pharmacokinetic . . . . . . . Referring to the distribution a chemical in an organism. ppm Parts p e r million. . . . . . . . . . . . . Preneoplastic . . . . . . . . and movement of Referring t o events occurring before development of a tumor. Prokaryotes Organisms without a distinct nucleus. Quadriparesis Muscular weakness in all four limbs. Radiolabelled . . . . . . . . Containing a radioactive isotope. Sister Chromatid . . . . . . . A chromatid from a homologous pair. Sister Chromatid Exchange Exchange of genetic material of sister chromatids as a result of genetic damage and as revealed by changes in banding patterns. . . SCE Sister Chromatid Exchange. STS Soft Tissue Sarcoma, a tumor of the tive tissues. Subchronic Toxicity studies where exposure 0.25 of the lifespan. TCDD tetrachloro-p_-dibenzodioxin. Teratogenic . . . . . . . . . Causing developmental or fetus. defects connec- is less than in the embryo Tryp tryptophan. Turner A new growth of tissue in which the multiplication of cells is uncontrolled. uCi . . . . . . . . . . . . . Unit o f radioactivity. UDS . . . . . . . . . . . . . Unscheduled D N A synthesis. ug microgram. 54 �11. REFERENCES CITED IN TEXT Ahmed, F. E., Hart, R. W. and Lewis, N. J. 1977a damage and its repair in cultured human cells. 161-174. 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Brusick, D. 1986 Genotoxic effects in cultured mammalian cells produced by low pH treatment conditions and increased ion concentrations. Environmental Mutagenesis, 8; 879-886. Burmeister, L. F. Letter to Jerome University of Iowa, Iowa City, Iowa. Blondell from Leon F. September 16, 1986. Burmeister, California State Water Resources Control Board 1984 Water Quality and Pesticides: 2,4-D. State Water Resources Control Board, Sacramento, CA. Special Project Report No. 84-10SP, (1984). Cantor, K. P. and Blair, A. 1986 Agricultural chemicals, drinking water, and public health. An epidemiologic overview. Unpublished report. Cantor, K. P. and Blair, A. Undated. Agricultural chemicals, drinking water, and public health: An epidemiologic overview. National Cancer Institute, Bethesda, Maryland. Carmelli, D., Hofherr, L., Tomsic, J. and Morgan, R. W. 1981 A case-control study of the relationship between exposure to 2,4-D and spontaneous abortions in humans. National Forest Products Association and U.S. Department of Agriculture-Forest Service. August 12, 1981. Casey, P. H. and Collie, W. R. 1984 Severe mental retardation and multiple congenital anomalies of uncertain cause after extreme parental exposure to 2,4-D. Journal of Pediatrics, 104; 313-315. 62 �Chemlawn Employee Exposures 1986 Confidential data supplied by Dr. R.A. Yeary, ChemLawn Services Corporation, Columbus, Ohio. (1987). Cochrane, W. P., Singh, J., Miles, W. and Wakeford, B. 1982a Levels of polychlorinated dibenzo-p-dioxins in 2,4-D technical products. Laboratory Services Division, Food Production and Inspection Branch, Agriculture Canada, Ottawa, Ontario K1A OC5. July, 1982. Cook, R. R. Letter to Shelia Hoar Zahm from Ralph R. Cook, M.D., Director of Epidemiology, The Dow Chemical Company , Midland, Michigan. October 16, 1986. Deloitte Haskins and Sells 1986 A proposal to provide detailed information on the formulation activities and the use of 2,4-D in Ontario and estimate the economic impact of withdrawing 2,4-D from all uses in Ontario. Deloitte Haskins and Sells, Guelph, Ontario. December, 1986. Dietz, D. Undated. Letter from Dave Dietz of the Foundation to Interested Parties. Salem, Oregon. Pesticide Public Policy Donna, A., Betta, P. B., Robutti, P., Crosignani, P., Berrino, F., Bellingeri, D. 1984 Ovarian mesothelial tumors and herbicides: a case control study. Carcinogenesis, 5; 941-942. Draper, W. M. 1982 A multiresidue procedure for the determination and confirmation of acidic herbicide residues in human urine. Journal of Agricultural and Food Chemistry, 30; 227-231. Draper, W. M. and Street, J. C. 1982 Applicator exposure to 2,4-D dicamba, and a dicamba isomer. Journal of Environmental Science and Health, 17; 321-339. Eriksson, M., Hardell, L., Berg, N. 0., Moller, T. and Axelson, 0. 1979 Casecontrol study on malignant mesenchymal tumors of the soft tissue and exposure to chemical substances. Lakartidningen, 76; 3872-75. (Translated for EPA by Literature Research Company, Annandale, Virginia). Fagan, K. and Pollak, J. K. 1984 The effect of the phenoxyacetic acid herbicides 2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid as ascertained by direct experimentation. Residue Reviews, 92; 30-58. Fisher, H. L., Most, B. and Hall, L. L. 1985 Dermal absorption of pesticides calculated by deconvolution. Journal of Applied Toxicology, 5; 163-177. Fleck, H. 1985 103-104. An agent orange: case history. Military Medicine, 150; Frank, R., Sirons, G. J., Campbell, R. A. and Mewett, D. 1983 Residues of 2,4-D, dichlorprop and picloram in wild berries from treated rights-of-way and conifer release sites in Ontario, 1979-1981. Canadian Journal of Plant Science, 63; 195-209. Franklin, C. A., Grover, R., Markham, J. W., Smith, A. E., and Yoshida K. 1982 Effect of various factors on exposure of workers involved in the aerial application of herbicides. American Conference of Government and Industrial Hygienists, Transactions, 43; 97-117. Frantz, S. W. and Kropscott, B. E. 1984 Pharmacokinetic evaluation of the 2-ethylhexyl (isooctyl) ester of 2,4-D administered orally to Fischer 344 rats. Sponsored by: The Industry Task Force on 2,4-D Research Data. Dow Chemical U.S.A., Midland, MI. February 1984. Fraser, A. D., Isner, A. F. and Perry, R. A. 1984 Toxicologic studies in a fatal overdose of 2,4-D, mecoprop, and dicamba. Journal of Forensic Sciences, 29; 1237-1241. Georgian, L. and Tarnavschi, R. 1983 Chromosomal modifications induced in vivo and in vitro by a pest-control agent (2,4-D). Revista Igiena Bacteriologie, Virusologie, Parazitologie, Epidemiologie, Pneumoftiziologia, Igiena, 32; 265-269. (Summary only). 63 �Gray, T. J. B., Lake, B. G., Beamand, J. A., Foster, J. R. and Gangolli, 5. D. 1983 Peroxisome proliferation in primary cultures of rat hepatocytes. Toxicology and Applied Pharmacology, 67; 15-25. Green, G. W. Memorandum on "Herbicides-—Kansas Canadian Forestry Service. January 14, 1987. epidemiological study". Grover, R., Cessna, A. J., Muir, N. I., Riedel, D., Franklin, C. A. and Yoshida, K. 1986 Factors affecting the exposure of ground-rig applicators to 2,4D dimethylamine salt. Archives of Environmental contamination and Toxicology, 15; 677-686. Health and Welfare Canada 1983 A review of the toxicology of the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid). Chronic Diseases in Canada. June, 1983; 4-6. Hobson, L. B. 1984 Human effects of TCDD exposure. Environmental Contamination and Toxicolology, 33; 696-701. Bulletin of Jarzynka, W. and Put, A. 1985 Effect of some herbicides on the parotid glands and oral mucosa in rats. Czasopismo Stomatologiczne, 38; 198-204. (Summary only). Koestner, A. Undated. Histological evaluation of brain sections obtained from F344 rats exposed to various doses of 2,4-D in a 2-year chronic oral toxicity study. Kohli, J. D., Khanna, R. N., Gupta, B. N., Dhar, M. M., Tandon, J. S. and Sircar, K. P. 1979 Absorption and excretion of 2,4-dichlorophenoxyacetic acid in man. Xenobiotica, 4; 97-100. Kolmodin-Hedman, B., Hoglund, S. and Akerblom, M. 1983 Studies on phenoxy acid herbicides. I. Field study. Occupational exposure to phenoxy acid herbicides (MCPA, dichlorprop, mecoprop and 2,4-D) in agriculture. Archives of Toxicology, 54; 257-265. Konstantinova, T. K. and Shevelo, F. S. 1983 Mutagenic activity of the combined exposure to the herbicides 2,4-D and 2,4,5-T. Gigiena Sanitariya, 0; 21-22. Krystynak, R. 1983 An economic assessment of 2,4-D in Canada: The case of grain. Canadian Farm Economics, 18; 7-30. Lavy, T. L. 1979 Measurement of 2,4,5-T exposure of forest workers. August 30 to October 3, 1978. Altheimer Laboratory, University of Arkansas. Lijinsky, W., and Reuber, M. D. 1984 Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses. Cancer Letters, 22; 83-88. Linet, M. S. 1986 Review of "Agricultural herbicide use and risk of Lymphoma and soft tissue sarcoma" (Hoar F.K., Blair, A., Holmes, F. F., et al) and other epidemiologic studies examining the association between the herbicide 2,4-D, herbicides in general, farming and malignant lymphoma. United States Environmental Protection Agency, Washington, D. C. Linnainmaa, K. 1983 Sister chromatid exchanges among workers occupationally exposed to the phenoxy acid herbicides 2,4-D and MCPA. Teratogenesis, Carcinogenesis, Mutagenesis, 3; 269-279. Linnainmaa, K. 1984 The effects of hypolipidemic peroxisome proliferators on the induction of sister chromatid exchanges. Basic Life Science, 29; 965974. Linnainmaa, K. and Vainio, H. 1983 Genetic effects of phenoxyacid herbicides and clofibrate in mammalian cells in vivo and in vitro. Toxicology Letters, 18 (Suppl. 1); 144. Machotka, S. V. 1986 Pathology Summary: Oncogenicity study in mice with 2,4-Dichlorophenoxyacetic acid unscheduled deaths and terminal sacrifice. Project No. 2184-101. Unpublished report. September 16, 1986. (No address) 64 �Maclaren Plansearch Inc. and FDC Consultants Inc. 1985 Drinking Water Quality Criteria Development Document: 2,4-Dichlorophenoxyacetic acid. Report prepared for Ontario Ministry of Environment, Toronto. (1985). Manninen, A., Kangas, J., Klen, T. and Savolainen, H. 1986 Finnish farm workers to phenoxy acid herbicides. Environmental Contamination and Toxicology, 15; 107-111. Exposure of Archives of McLeod, H. L., Bowhey, C. S., Swanson, N. M. and Stephenson, G. R. 1985 Dislodgable-residues of 2,4-D amine and ester formulations on turfgrass. Turfgrass Research Annual Report, Ontario Agricultural College, University of Guelph. Morgan, D. P. Letter to Jerome Blondell from Donald P. Morgan, University of Iowa, Iowa City, Iowa. September 15, 1986. Mullison, W. R. 1981 Public concerns about the herbicide 2,4-D. Proceedings of the 34th Annual Meeting of the Western Society of Weed Science conducted March 17-19, 1981, in San Diego, CA. Mullison, W. R. Undated. Environmental fate of phenoxy herbicides. Mullison, Dow Chemical, 141.2 North Parkway, Midland, Michigan. W. R. Murtagh, T. Letter to John D. Conner from Therese Murtagh, Office of Pesticide Programs, United States Environmental Protection Agency. November 5, 1986. Murthy, M. S. S. 1979 Induction of gene conversion in diploid yeast by chemicals: correlation with mutagenic action and its relevance in genotoxicity screening. Mutation Research, 64; 1-17. National Research Council Canada 1983 2,4-D: Some current issues. National Research Council Canada, Associate Committee on Scientific Criteria for Environmental Quality. Publication No. NRCC 20647, Ottawa, (1983). Petryka, A. J., Pierach, C. A. and Codario, R. A. 1982 High pressure liquid chromatography urinary porphyrins profiles after exposure to 2,4-D and 2,4,5~T. Federation Proceedings, 41; Abstract 5490. Reddy, J. K. and Azarnoff, D. L. 1980 Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature, 283; 397-398. Sankaranarayanan, K. 1982 Determination and evaluation of genetic risks to humans from exposure to chemicals. In: Chemical mutagenesis, human population monitoring and genetic risk assessment. Progress in Mutation Research, 3; 289-322. Seiler, J. P. 1978 The genetic toxicology of phenoxy acids other than 2,4,5-T. Mutation Research, 55; 197-226. Sell, C. R. and Maitlen, J. C. 1983 Procedure for the determination of residues of (2,4-dichlorophenoxy)acetic acid in dermal exposure pads, hand rinses, urine, and perspiration from agricultural workers exposed to the herbicide. Journal of Agricultural and Food Chemistry, 31; 572-575. Sell, C. R., Maitlen, J. C. and Aller, W. A. 1982 Perspiration as an important physiological pathway for the elimination of 2,4-D from the human body. 183rd ACS (American Chemical Society) National Meeting, Las Vegas, Nevada, USA, March 28-April 2, 1982. Abstract of Papers of the American Chemical Society, 183; Pest-74. Shipp, A. M., Hogg, M. L., Crump, K. S. and Kodell, R. L. analysis study on forest plantation herbicide use. Company, Inc., Ruston, Louisiana. (May, 1986.) 1986 Worst case K. S. Crump and Singh, S. V. and Awasthi, Y. C. 1985 Inhibition of human glutathione S-transferases by 2,4-dichlorophenoxyacetate (2,4,-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T). Toxicology and Applied Pharmacology, 81; 328-336. 65 �Steineck, G. and Wiklund, K. (In press, 1986) Multiple myeloma in Swedish agricultural workers. International Journal of Epidemiology. Stellman, S. D. and Stellman, J. M. 1986 Estimation of exposure to agent orange and other defoliants among American troops in Vietnam: A methodological approach. American Journal of Industrial Medicine, 9; 305321. Taskar, P. K., Das, Y. T., Chattopadhyay, S. K. and Brown, H. D. 1982 Human exposure to the herbicide 2,4-dichlorophenoxyacetic acid. Bulletin of New Jersey Academy of Science, 27; 30. (Abstract Only) Taskar, P. K., Das, Y. T., Trout, J. R. Chattopadhyay, S. K. and Brown, *H. D. 1982 Measurement of 2,4-dichlorophenoxyacetic acid (2,4-D) after occupational exposure. Bulletin of Environmental Contamination and Toxicology, 29; 586-591. Thompson, D. G., Stephenson, G. R. and Sears, M. K. 1984 Persistence, Distribution and Dislodgeable Residues of 2,4-D Following its Application to Turfgrass. Pesticide Science, 15; 353-360. Tomkins, D, Kwok, E. and Douglas, G. 1980 Testing of pesticides for induction of sister chromatid exchange in Chinese hamster ovary cells. Canadian Journal of Genetics and Cytology, 22; 681. Toxicology Research Centre 1986 Toxicology of 2,4-Dichlorophenoxyacetic acid (2,4-D): A Review. Toxicology Research Centre, University of Saskatchewan, Saskatoon, Saskatchewan. September, 1986. Vainio, H., Linnainmaa, K., Kahonen, M., Nickels, J., Hietanen, E., Marniemi, J. and Peltonen, P. 1983 Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicides in rats. Biochemical Pharmacology, 32; 2775-2779. Vainio, H., Nickels, J. and Linnainmaa, K. 1982 Phenoxy acid herbicides cause peroxisome proliferation in Chinese hamsters. Scandinavian Journal of Work, Environment and Health, 8; 70-73. Veterans Administration 1985 Review of literature of herbicides, including phenoxy herbicides and associated dioxins. 6 Veterans Administration, Washington, D. C. May 2, 1985. VA Contract # V10(93)P-953. Veterans Administration 1985 Review of literature on herbicides including phenoxy herbicides and associated dioxins. 5 Veterans Administration, Washington, D. C. May 2, 1985. Vineis, P., Terracini, B., Ciccone, G., Cignetti, A., Colombo, E., Donna, A., Maffi, L., Pisa, R., Ricci, P., Zanini, E, and Comba, P. 1987 Phenoxy herbicides and soft-tissue sarcomas in female risce weeders. Scandinavian Journal of Work, Environment and Health, 13. In press. Vural, N. and Burgaz, S. 1984 A gas chroma tograhic method for determination of 2,4-D residues in urine after occupational exposure. Bulletin of Environmental Contamination and Toxicology, 33; 518-524. Walistan, J. D., Flynn, R. R. and Mattice, J. D. 1982 2,4-D exposure received by aerial application crews during forest spray operations. Journal Agricultural and Food Chemistry, 30; 375-381. Waters, M. D., Simmon, V. F., Mitchell, A. D., Jorgensen, T. A. and Valencia, R. 1983 A phased approach to the evaluation of environmental chemicals for mutagenesis and presumptive carcinogenesis, in: In vitro toxicity testing of environmental agents: current and future possibilities. Part B: development of risk assessment guidelines. NATO Conf. Ser. I, 58; 417441. Wiklund, K. 1983 Swedish agricultural workers. risk of cancer. Cancer, 51; 566-568. Wiklund, K. and Eklund, G. (In press, 1986) the Swedish cancer-environment register. 66 A group with a decreased Reliability of record linkage in Acta Radiologica. �Wiklund, K. and Holm, L. E. 1984 agricultural and forestry workers. stitute, 76; 229-234. Soft-tissue sarcoma risk in Swedish Journal of the National Cancer In- Wiklund, K. and Holm, L. E. (Submitted for publication, cancer risks among Swedish agricultural workers. 1986) Trends in Wiklund, K., Einhorn, J., Wennstrom, G., and Rapaport, E. 1981 A Swedish cancer-environment register available for research. Scandinavian Journal of Work, Environment and Health, 7; 64-67. Young, A. L. 1984 Determination and measurement of human exposure to the dibenzo~p-dioxins. Bulletin of Environmental Contamination and Toxicology, 33; 702-709. Young, A. L. and Shepard, B. M. 1983 A review of on-going epidemiplogic research in the United States on the phenoxy herbicides and chlorinated dioxin contaminants. Chemosphere, 12; 749-759. Zahm, S. H. Letter to Ralph R. Cook from Shelia Hoar Zahm, Department of Health and Human Services, National Cancer Institute, Bethesda, Maryland. November 12, 1986. 67 � 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1438 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/. Description An account of the resource Corporate Author: Canadian Centre for Toxicology, Guelph, Ontario Title A name given to the resource Typescript: Expert Panel Report on Carcinogenicity of 2,4-D, March 23, 1987 Subject The topic of the resource dioxin animal testing cancer risk assessment health studies ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/8ce959abd4c29a8ef2aec37f5b90b5bb.pdf b8995078e6335274beb56006cba345d7 PDF Text Text Item ID Number 01430 Author Corporate Author RODOrt/ArtiClO Titlfl Typescript: Agent Orange Project Update Summary, December 4,1986 Journal/Book Title Year 000 ° Month/Day Color Number of ImaDos DOSCrlptOD Notes D 11 Lists ongoing health studies and projects from various agencies. Tuesday, May 15, 2001 Page 1430 of 1514 �AGENT ORANGE PROJECT UPDATE SUMMARY December 4, 1986 Information was taken from two sources: The Domestic Policy Council » Agent Orange Working Group* Status Report, October » 1985 Collection of Research Projects on Dioxins* Number 160, A report of the NATO/CCNS pilot study on International Information Exchange on Dioxins, Spring 1986. (obtained from Dr. Donald Barnes* EPA) Total number of projects identified = 245 Number listed as Complete = Number listed as Ongoing 87 = 158 Source Informations AO Status Report = NATO Report = 47 both reports = 4 Number of projects by Agency: Total Complete Ongoing CDC 11 a 9 DHHS 3 1 2. DoD 22 7 15 EPA 68 25 43 NCI 7 a 5 NIEHS 83 40 43 NIOSH 8 2 6 USDA 8 5 3 35 3 32 VA �Agent Orange Project List (AQ1) 11/27/86 ACC. NO. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 25 37 38 39 40 41 42 43 44 45 46 47 48 49 50 CDC CDC CDC CDC CDC CDC CDC CDC CDC CDC CDC DHHS DHH5 DHHS DoO DoD DoO DoD DoO DoD DoD DoD DoO DoD OoO DoD DoD DoD DoD DoD DoD DoD OoD DoD DoD DoD EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA Conent Title Agency Agent Orange Study Birth defects and iilitary service in Vietnam study Published Aug 1984 Oevelopient of lab lethods for TCDD analysis of huian adipose tissues and bio Epideiiologic study of ground troops exposed lu <ujent orange during the Vietn Measurement of 2,3,7,8-TCDD in adipose tissue in populations in Hissouri National dioxin study Selected cancers study Study for body burden for dioxin in the general population Study of the distribution of 2,3,7,8-TCDD and related compounds in the huian Synthesis of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofur Vietnam Experience Study Detailed current literature reviews with published reports on the state of sc Measurement of TCOD levels in adipose tissue froi potentially exposed persons Reproductive outcomes in persons possibly exposed to 2,3,7,8 RDP 2,3,7,8-TCDD induced iuunosuppression ? Dioxin workers API Sarcota Study Air Force Ranch Hand Study Air Force soil tapping and groundwater survey at herbicide orange sites Anted Forces Institute of Pathology Agent Orange registry of Vietnai veteran CDC selected cancers Degradation of chlorinated xenobiotic compounds by anaerobes Dioxin plan for monitoring Johnston Atoll Environmental cheiistry of herbicide Orange AO 85 - NATO - Daniel HcGee, C NATO - Larry Needhai, CDC, Atl NATO - Larry Needhai, CDC, Atl NATO - Larry Needhai, CDC, Atl NATO - Larry L. Needhai, CDC Why both completed and ongoing _ ES8 ESG NATO - Ken Uade, EGtG Inc, Ida ES8 NATO - Lt Rhodes, Tyndall AFB, NATO - Linda Anderson, CDC, At NATO - Capt Stoddart, Tyndall Environmental cheiistry of herbicide orange and TCOD Epideiiologic investigation of health effects in Air Force personnel followin Fate of TCOD, 2,4-0 and 2,4,5-T at selected locations contaiinated with herbi Herbicide Orange -1U- treatment and environiental lonitoring Herbicide Orange soil tapping and groundwater survey Mechanism of cellular teibrane effects of TCDD Residual levels of 2,3,7,8-TCDD near herbicide Orange storage and loading are Services herbs tapes Site deionstration of full-scale rotary kiln incinerator (transportable) Site demonstrations: environmental restoration technologies VA chloracne VA Soft Tissue Sarcota Analysis of background levels of TCOD in the US environment Analysis of environmental samples for PCDDs and PCDFs Analytical lethods development of monoclonal antibodies Assess of PCS transformer /cap fires Assessment of exposure to TCDD from contaminated media Assessment of methods used for analysis of human adipose tissue Assessment of PCS transformer/capacitor fires Bacterial decomposition of TCDD Baseline in 1983 NATO - HQ AFESC/RDV, Tyndali A NATO - Haj Toi Doane, Brooks A NATO - Lt Rhodes, Tyndall AFB, NATO.- Capt Stoddart, Tyndall ESS NATO - Capt Terry Stoddart, Ty NATO - Capt Stoddart, Tyndall ESG Environiental Support Group NATO - Paul des Rosiers, EPA, Beef fat phase II Behavior of TCDD in blood Bioavailability of TCDD from contaiinated soils Unavailability to aniials Biodeg and carbon adsorption of TCDD Causal structure activity methods applied to the assessient of the toxicity o NATO - Huhae! Gallo, U New Jt NATO - P. Politzer, U New Orle �EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPa EPA EPA EFA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA NCI NCI NCI NCI Clearance of TCDD from dose organists Development of lass spectrometric and fourier transform infrared spectroscopi Dioxin bioavailability - food chain Dioxin photolysis: Soil surfaces Embryotoxicity and pharmacokinetics fo dioxin in Harmosets and monkeys Evaluation municipal waste combustors NATO- Wayne Sovocool, EPA, La NATO - Phillip Cook, EPA, Dulu NATO - Glenn Miller, U Nevada, NATO - Diether Neubert, Berlin 1st table ongoing; 2nd table c Evaluation of combustion sources Evaluation of large scale combustion sources 1st table ongoing; 2nd table c Evaluation of TCOD destruction technologies Evaluation of the EPA mobile incineration system for dioxin-contaminated liqu NATO - Frank Freestone, EPA, E Evaluation of the white rot fungus, Phanerochaete chrososporium, for biodegra NATO - Pat Sferra, EPA, Cincin Exposure assessment methods for 2,3,7,8-TCDD and other dioxins NATO - John Schaum, EPA, Uashi Feasibility of utilizing mines as respositories for dioxin-contaminated soils NATO - Pat Esposito, PEI Assoc Field test of KOH/PE6 reagent to destroy 2,3,7,8-TCDD at a military site NATO - Charles Rogers, EPA, Ci Half-life of chemicals in soil NATO - Charles Nauman, EPA, Ua Health assessment of PCDFs Health assessment of PCOOs Herbicide Orange incinerator studies NATO - Capt Stoddart, Tyndall In-situ stabilization techniques for dioxiin-contaminated soils NATO.- Don Sanning, EPA, Cinci Invest, of in situ stabil. technology Investigation of bioavailability to fresh water fish of TCDDs in fly ash 2nd table indicated study to b LA crayfish/catfish study Methods analys. envir. of TCDD by (lass Spect. Methods for assessing exposure to dioxin related compounds other than 2,3,7,8 NATO - Les Ungers, PEI Assoc., Microb. dissia. of 2,3,7,8-TCDD Mississippi catfish study Movement of TCDD in the environment Annual reports ; Nebraska stud National pesticide monitoring project of human adipose tissue Northwest human milk study Oregon monkey study Performance of RCRA Method 8280 for the analysis of dibenzodioxins and dibenz Pharmacokinetics of 2,3,7,8-TCDD in monkeys Photochemistry Plant uptake and metabolism of polychlorinated dibenzodioxin isomers Plant uptake of dioxin Potential for 2,3,7,8-TCDD transport in soils using both static and dynamic s Preparation of dioxin analytical reference standards for lab analysis of huma Quality assur. support Region I deer and elk study Report of assessment of a field investigation of six-year spontaneous abortio Risk assessment approach for 2,3,7,8-TCDD and other dioxins Round robin survey-methods dioxin analysis in adipose Shallow mines as repositories for dioxin-contaminated soils Short-term bioassays for polychlorinated dibenzo-p-dioxins Sorption/desorption characteristics of 2,3,7,8-TCDD in contaminated soils TCDD vapor-phase photolysis Uptake of 2,3,7,8-tetrachlorodibenzo-p-dioxin by dairy cows Uptake of dioxins by plants and large animals Uptake of dioxins by fish UV photolysis/alkali polyethylene glycolates for the chemical detoxification UV photolysis/KPE6 chemical destruction of chlorinated dioxins and dibenzofur Vapor pressure and partitioning behavior of 2,3,7,8-substituted dioxins and f Wisconsin monkey study yorkshop report on bioavailability Case control study of lymphoaa and soft tissue sarcoma Case-control study of soft tissue sarcomas and lymphomas and their relationsh Control study of lymphoma and soft tissue sarcoma Lung cancer - structural pest control workers NATO - John Ballard, Lockheed NATO - Margaret Chu, EPA, Uash NATO NATO NATO NATO - Johne Coates, Midwest R Craig HcFarlane, EPA, C Richard Walters, U Mary Edward J. Kantor, EPA, Published NATO - Charles Ris, EPA, Uashi NATO NATO NATO NATO NATO - Janet Houthoofd, EPA, C - Richard Phillips, EPA, - Michael Roulier, EPA, C - John Schaum, EPA, Uashi - D.H. Jones, Texas AIM NATO - Charles Rogers, EPA, Ci NATO - R.L. Peterson, 6alson R NATO - Gregory Kew, EPA, Uashi �109 110 111 112 113 114 115 116 117 118 119 120 121 122 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 NCI NCI NCI NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NCI pesticide workers Study of lortality aiong pesticide applicators frot Florida Study of soft tissue sarcotas and non-Hodgkins lytphota in thirteen counties 1,2,4,6,8,9-Hexachlorodibenzofuran disposition 2,3,7,8-TCDD disposistion in rats, lice, and guinea pigs 2,3,7,8-tetrachlorodibenzofuran disposition in rats, tice, guinea pigs 2,4,5-T : Salionella 2,4,5-T cytogenetics 2,4,5-T Drosophilia 2,4,5-T N-butyl ester: salionella 2,4-0 : Salionella 2,4-0 cytogenetics 2,4-0 ditethylatine salt: Salionella 2,4-D Drosophilia 2,4-0 N-butyl esters salionella 2,7-Dichlorodibenzo-p-dioxin: salionella Alter, of cell-surface leibrane for DI Toxkity Arachidonate products in dioxin and PCB toxicity Atonic mission spectroscopy for dioxin trace analysis Bioassay of a lixture of 1,2,3,6,7,8- ? and a tixture of 1,2,3,6,7,8-hexachlo Bioassay of octachlorodibenzo-p-dioxin Bioassay of tetrachloro-dibenzo-p-dioxin Bioavailability of TCDD (rat) denial and oral Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sviss Uebst Carcinogenesis boassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Qsborne-Hend Cotparative species evaluation of cheiical disposition and letabolisi of 2,3, Control of gene expression by dioxin DED-UEEO,LV-69: Salmonella Oi-Epith cell interaction, lechanisi and assay Dibenzofuran: cytogenetics Dibenzofuran: Salionella Dioxin - atoiic emission spectroietry for dioxin trace analysis (detection) Oioxin - toxic halogenated wastes: in vitro bioassay developient . Dioxin chlorinated dibenzo-p-dioxins; lechanisis of toxicity Dioxin environmental pollutants and toxicology of the liver Dioxin environnental health sciences center grant clinical studies Oioxin lechanisi(s) for toxicity of chlorinated dibenxodioxins (toxicology) Dioxin tolecular toxicology of TCDD Dioxin NHR study Dioxin xenobiotic induction of pleiotropic responses in liver Disposition of TCDD fetal distribution in nice Effects of Agent Orange components on lale fertility and reproduction Effects on intestinal cells Effects on intestinal cells UNC-CU grad student Effects on nutrient assiiilation Environiental health science center grant Establishient and laintenance of an international register of persons exposed Hexacholor dibenzo dioxin disposition laiunosuppression by in utero exposure Implications of low level exposure of dioxins Intl res/exposure to phenaxy acid herbicides Lipid assimilation NRSA Lipid assiiilation NRSA Matrix effect and sub parts-per-billion quantitative analysis of TCDD by lass Mechanist of iuunosuppression Mechanists of dioxin toxicity Mechanists of toxicity of the chlorinated-p-dioxins Publication in press Disposition studies cotpleted Disposition studies cotpleted Is the title wrong of what? Uhat is NRSA ? What is NRSA? 1st Table ongoing; 2nd table c �166 167 168 169 170 171 172 173 174 175 176 177 178 173 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 199 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH USDA USDA USDA USDA USDA USDA USDA USDA VA VA VA VA VA VA VA VA VA VA VA VA ! Membrane / LP receptor NRSA ! Membrane / LP receptor NRSA . ! Methods for the measurement of dioxins and furans in human adipose tissue Uhat is NRSA? ! Molecular basis of dioxin toxicity Theoretical biochemical study 1st table ongoing; 2nd table c ! I ! I Molecular modeling of dioxin binding proteins Molecular, biochemical actions of chlorinated-p-dioxins Mutagenicity studies of TCDD, 2,4-0, 2,4,5-T and esters of 2,4-D and 2,4,5-T Neurotoxicity of 2,4-0 in rodents Occupational & environmental health center grant ! Occupational and environmental health center grant (toxicology) Pentachlor & Dioxin contam. in PCP Pest, i Trans, across bil. lip. mem. Pesticides and transport across bilayer lipid membranes (toxicology) Pre-dioxin in PCP biochemistry, effect, and toxicity Quantitative analysis of TCDD by mass spectroscopy Research toward understanding the molecular level mechanisms of toxicity of T Role of TCDD receptor in tumor promotion How can it be marked complete Structure-toxicity relationships Would like to see this report! Studies of the chemical disposition and metabolism of octachlorodibenzodioxin Synthesis of 6 chlorodibenzo-p-dioxins Synthesis of selected chlorinated dibenzo-p-dioxins and related compounds as TCDD effects on steroid hormone synthesis Teratogenicity of TCDD - Cleft palata induction (mice) Theoretical modeling of dioxin receptor Toxic actions of tetrachloroazobenzene dioxins Toxic and anorectic effects of TCDD Toxic his wst in vitro bioassay development Toxicant Ceres Endocrine Heme Biosynthesis Xenobiotic induction of pleiotropic responses in liver Health hazard evaluation and technical assistance involving PCBs, dioxins, et Investigation of leukemia cluster in Madison County, Kentucky allegedly assoc NIOSH dioxin registry and cohort mortality study NIOSH dioxin registry, morbidity and reproductive outcome study . NIOSH industrial morabidity study NJ/Missouri plant worker and worker's spouse reproductive outcom'e study Soft tissue sarcoma investigation Study of persistent health effects in chemical herbicide workers and in commu A case control study of the relationship between exposure to 2,4-D and sponta Biological and economic assessment of 2,4,5-T and Si hex Exposure measurements of mixers, loaders and applicators of 2.4-0 on wheat Exposure of forest workers to ground applications of 2,4-D Photolysis of 2,4,5-T Survey of phenoxy herbicide use by agricultural commodity Survey of phenoxy herbicide literature TCDD residue monitoring in deer A review of the soft tissue sarcoma cases in patient treatment file for Vietn AFIP case control study of soft tissue sarcoma Agent Orange register review Behavioral toxicity of an Agent Orange component 2,4-D Case control study of lymohoma Chronic effects of herbicide exposure on testicular function in Vietnam veter Cohort mortality study of Vietnam veterans Effect of TCDD on lipid metabolism Effects of 2,3,7,3-tetradiiorodibenzodioxins on hepatobiliary function in ani Effects of Agent Orange on sleep Effects of low dose TCDD on nammalian chromosomes and liver cells Fat tissue analysis for 2,3,7,8-TCDD (San Antonio) NATO - Jay Bainbridge, NIOSH, Published NTIS 1984 AQ 85 - 1st table completed it Published Scan J Uork Environ NATO - Marie Haring Sweeney, N 1st table has project ongoing; Annual bibliographies publish* Report in preparation AO 85 -> 1st table end date of Perhaps completed in 1984? Perhaps completed in 1993? End in 86 or 89? End in 86 or 89? End in 86 or 89? �223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA Fat tissue analysis for 2,'3,7,8-TCDD (Dallas) Fetale veteran survey Mechanist of porphyria caused by TCDD and related cheiicals Mechanist of TCDD absorption and toxicity on lipid and lipoprotein tetabolist Mechanists of dioxin induced toxicity using the chloracne aodel - Phase II Mechanists of dioxin induced toxicity using the chloracne todel - Phase I End in 86 or 89? End in 86 or 89? End in 86 or 89 ? Publication in press End in 86 or 89? Hetabolist of the herbicides present in Agent Qrange and Agent White Monographs Neurotuscular toxicity of Agent Orange End in 86 or 89? PTF/Vietnat; service indicator Retrospective study of dioxins and furans in adipose tissue of Vietnat era ve AO 85 -> 1st table pending to Review of literature on herbicides, including phenoxy herbicides and associat Published in 1981; annual upda Review of soft tissue Sarcota study in patient treattent file, Agent Orange registry exatinations Survey of patient treattent file for Vietnat veteran in-patient care Initial 1983 survey TCDD exposed rhesus tonkeys: effects on behavior and stress hortones End in 86 or 89? TCDD in body fat of Vietnat veterans and other ten Published Uptake and tetabolist studies and phamacology and toxicology Urinary 6-hydroxy cortisol: physiological and phartacologk studies (includin Perhaps cotpleted in 1982? VA patient treatment file uview VA/EPA adipose tissue study Vietnat veteran identical twin studies Under review by OTA I AOUS - W Vietnat veteran tortality studies AO 85 -> 1st table end date of �CABINET COUNCIL ON DOMESTIC POLICY AGENT ORANGE WORKING GROUP FEDERALLY SPONSORED HUMAN STUDIES RELATED TO AGENT ORANGE TYPE OF STUDY AGENCY STUDY TITIE Mortality Morbidity Cancer Reproduct Jon Analytical STATUS Completed Estimated Ongoing Completion Date DEPARTMENT OF HEALTH AND HUMAN SERVICES Published NTIS 1984 NIOSli Investigation of Leukemia Cluster in Madison County, Kentucky Allegedly Associated with Pentachlorophenol Treated Aimun it ion Boxes NIOSli Dioxin Registry X NIOSli Soft Tissue Investigation X NIOSH NJ/Missouri plant worker and worker's spouse reproductive outcome study Reproductive outcomes in persons possibly exposed to 2,3,7,8 RDP Measurement of TCDD levels in udipoue tissue from potentially exposed persons in Missouri. Published Scan. J. Work EnvIron Health 1985 X (begins 1985) �TAIil.K I: The K I even M a j o r Kp idemi ol ogi ca 1 S t u d i e s of t l . S . V i e t n a m V e t e r a n s , Agent Orange'am) TCHIJ exposure, dii.l V i e t n a m K x p e i i eiu-'c- C u r r e n t l y Ongoing or Completed i it L i t e U n i t e d S t a l e s ( C o n t i n u e d ) . Responsible * Federal Aqency Ti t ic Tyj>e of Study Total Study E£?CiJi3 Complet ion Vietnam Experience E p i d e m i o l o g i c Study Centers for Disease Control, A t l a n t a Oeorgi a Matched Cohort Morbidity Study o f V i e t n a m and non-Vietnam Veterans 12,000 1987 VA/AFIP Soft Tissue Sarcoma Study Veterans A d m i n i s t r a t i o n Agent Orange Projects Office, W a s h i n g t o n , D.C. Case-Control Study of Soft Tissue Sarcoma 250 cases 750 controls Late Nlo:;il n i o x i n Kcrjiutry N a t i o n a l I n s t i t u t e for Occupational Safety and Health, C i n c i n n a t i . Ohio M o r t a l i t y Study of Workers at 12 Production Sites Where D i o x i n C o n t a i n i n g Products Were M a n u f a c t u r e d 6.0OO 1986 NIOSII I n d i i B t r i a l M o r b i d i ty Study N a t i o n a l I n s t i t u t e for Occupational Safety and Health, C i n c i n n a t i , Ohio M o r b i d i t y Study of Workers at 2 Production Sites Where D i o x i n Containing Products Were Manufactured and a Comparison Group 600 1988 NCI Kansas Soft Tissue Sarcoma Study N a t i o n a l Cancer I n s t i t u t e , IJethesda, M a r y l a n d Case-Control of Soft T i s s u e Sarcoma 1OO cases 3()O controls 1986 1986 �*ALTH MO rtUMN SBVICES/WEHS LAS/LITERATURE STUDIES TYPE OF STUDY STUDY EFFORT Aim smmneaH. ANALYTICAL LITERATURE • STATUS cwtira CUMINS STUDY TQTAc I 1991-97 rji?. 3F TCDO CLFT. PAL. Mfl!£?QSITOF TWO FTL. [J| OIST. IN DICE 10.000 "E-9IOX. IN PCP .. £F.. 4 TOI 1990-1992 I 4. OF 3 CHLflR OlSaZO-MHOl / I 199M89i "44,000 1992 4«C. EH. SPCT, FSR I'OISIIM TR. ANLYS. 172.000 61.000 !99!-!«SS i:0.000 l°90 l-JLs i? TOO *£•:•?• (I 0 I ijgj»i5S3 i'X'.'JOO I 1995-1-97 ««6.000 J 1993-1997 :00) :.'0 I «ORfl 1994-1"! lIO.OOO CTIC £?F--:TS OF TCCD9 / >* « 'SisAHlilS OF 2F riT-ACHLQRO-i)I8ENZOtoao aP-8I3l!.1 j . OF TC2D "iBtflASSjrt". r 4 <C HLS «ST IN TntCReTICAL iflLS OF REEPT3R OF T3HCITY 1983-1*34 ::.yoo 1 H I �- 131 - FORMAT FOR CCMS PILOT PROJECT ON INTERNATIONAL INFORMATION EXCHANGE ON OIOXINS AND RELATED COMPOUNDS WORKING GROUP: A COUNTRY OF ORIGIN: USA TITLE OF PROJECT OR ACTIVITY: VA/AFIP Soft Tissue Sarcoma Study NAME AND ADDRESS OF PRINCIPAL INVESTIGATOR: (INCLUDING TELEPHONE NUMBER) (202)-576-0366 NAME AND ADDRESS OF SUPPORTING AGENCY: (INCLUDING TELEPHONE NUMBER) Han K. Kang, Dr. P. H. Veterans Administration Office of Environmental Epidemiology AFIP Washington, D.C. 20306-6000 ^ Washington, D.C. 20420 (202)-389-3432 or 3886 Veterans Administration Agent Orange Projects Office (10X2) 810 Vermont Avenue, N.W. ? 8 83 STARTING DATE V / IDENTIFYING NUMBER: COMPLETION DATE: 6 30 8f / / GOAL/RATIONALE/SCOPE To determine the relationship of Vietnam service, probable Agent Orange exposure and other factors to the risk of developing soft tissue sarcoma. The study is being conducted in two phases. Phase I will'investigate whether service in Vietnam during 1965-71 increased the risk of developing STS. The histopathology and anatomic site of STS will be compared among Vietnam veterans. Phase II will investigate other host and environmental risk factors for the development of STS.. Information on environmental risk factors will be obtained by interviews and individual analysis. ESTIMATED RESOURCES (IN UNITED STATES DOLLARS TO NEAREST $1,000,) FUNDING * 182,000 1887 1966 1968 YEAR * 73,000 » MAJOR OUTPUTS: (e.g.. technical reports, other publications, patents) A technical report will be prepared and a manuscript will be submitted to a scientific journal for publication. tf other countries are interested, would it be possible to augment your present project? I I YES I X I NO Do you have access to a computer network? Network Name NIH DCRT r Host Name YES NO User Name �AGENT ORANGE PROJECT UPDATE AGENCY: VA DATE: Dec 4, 1986 TITLE: VA/AFIP Soft Tissue Sarcoma Study PRINCIPAL INVESTIGATOR: Han K. Kang, PhD DIVISION/DEPARTMENT: ADDRESS: Office of Environmental Epidemiology AFIP, Veterans Administration TELEPHONE NUMBER: Washington, D.C. 20306-6000 202/576-0366 PROJECT IDENTIFICATION NUMBER: TEST CHEMICAL: OBJECTIVE: To determine the relationship of Vietnam service, probable Agent Orange exposure and other factors to the risk of developing soft tissue sarcoma. EXECUTIVE SUMMARY: APPROACH: The study is being conducted in two phases. Phase I will investigate whether service in Vietnam during 1965-71 increased the risk of developing STS. The histopathology and anatomic site of STS w i l l be compared among Vietnam veterans. Phase II will investigate other host and environmental risk factors for the development of STS. Information on environmental risk factors will be obtained by interviews and individual analysis. FINDINGS/STATUS: SIGNIFICANCE: PUBLICATIONS: START DATE: July 1983 COMPLETION DATE: July 1986 LEVEL OF EFFORT (Total Project) TO DATE: PROJECTED TO COMPLETE PROJECT: FTEs: FUNDING: $ 255,000 $0 SOURCE OF FUNDING: Veterans Administration, Washington � 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1430 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/. Title A name given to the resource Typescript: Agent Orange Project Update Summary, December 4, 1986 Subject The topic of the resource health studies veteran health and hygiene AOWG 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 053 Folder The folder containing the original item. 1398 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/. Description An account of the resource Corporate Author: National Research Council, Committee on Nonoccupational Health Risks of Asbestiform Fibers, Board on Toxicology and Environmental Health Hazard, Commission on Life Sciences Date A point or period of time associated with an event in the lifecycle of the resource 1984 Title A name given to the resource Asbestiform Fibers: Nonoccupational Health Risks Subject The topic of the resource asbestos industrial exposure 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 1341 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/. Description An account of the resource Corporate Author: Council on Scientific Affairs, Division of Scientific Activities, American Medical Association, Chicago 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 October 15 1982 Title A name given to the resource Health Effects of Agent Orange and Dioxin Contaminants Subject The topic of the resource chloracne herbicide toxicology health studies industrial exposure 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 1323 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/. Description An account of the resource Corporate Author: National Veterans Task Force on Agent Orange Date A point or period of time associated with an event in the lifecycle of the resource 1981 Title A name given to the resource Conference Information Packet Subject The topic of the resource VA veteran health and hygiene health studies herbicide regulation ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 047 Folder The folder containing the original item. 1181 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/. Source A related resource from which the described resource is derived Farm Chemicals Date A point or period of time associated with an event in the lifecycle of the resource 1970-08-01 Title A name given to the resource AMA Speaks Up for DDT Subject The topic of the resource environmental inapt health studies pesticide properties 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 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. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> 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. 040 Folder The folder containing the original item. 0904 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/. Description An account of the resource Corporate Author: International Scientific Advisory Committee for Seveso Title A name given to the resource Recommendations for the 4th Meeting of the International Scientific Advisory Committee for Seveso, January 10-14, 1981 Subject The topic of the resource Italy health studies congenital birth defects industrial exposure ao_seriesIII